Infectious Diseases of the Fetus and the Newborn Infant 6th Edition

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Author: Jack S. Remington | Jerome Klein | Carol Baker | Christopher Wilson

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1600 John F. Kennedy Blvd. Suite 1800 Philadelphia, PA 19103-2899

INFECTIOUS DISEASES OF THE FETUS AND NEWBORN INFANT Copyright © 2006, 2001, 1995, 1990, 1983, 1976 by Elsevier Inc.

ISBN 0-7216-0537-0

All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Health Sciences Rights Department in Philadelphia, PA, USA: phone (+1) 215 239 3804, fax: (+1) 215 239 3805, e-mail: [email protected]. You may also complete your request on-line via the Elsevier homepage (http://www.elsevier.com), by selecting ‘Customer Support’ and then ‘Obtaining Permissions.’

Notice Knowledge and best practice in this ﬁeld are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment, and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher

Library of Congress Cataloging-in-Publication Data Infectious diseases of the fetus and newborn infant / [edited by] Jack S. Remington … [et al.]—6th ed. p. ; cm. Includes bibliographical references and index. ISBN 0-7216-0537-0 1. Communicable diseases in newborn infants. 2. Communicable diseases in pregnancy—Complications. 3. Fetus—Diseases. 4. Neonatal infections. I. Remington, Jack S., 1931[DNLM: 1. Communicable Diseases—Infant, Newborn. 2. Fetal Diseases. 3. Infant, Newborn, Diseases. WC 100 I42 2006] RJ275.I54 2006 618.92¢01—dc22 2004051422 Acquisitions Editor: Developmental Editor: Publishing Services Manager: Project Manager: Design Coordinator:

Todd Hummel Jennifer Ehlers Frank Polizzano Lee Ann Draud Ellen Zanolle

Printed in the United States of America Last digit is the print number: 9 8 7 6 5 4 3 2 1

To my sister, Jill J.S.R. To those most dear to us: Linda, Andrea, Bennett, Adam, Zachary, Alex, Evan, and Dana J.O.K. Sherryl, Alyssa and Bryan, Amelia and Floyd, and Helen C.B.W. My parents, Jack and Jane; Marcie, Morven, Susan, Laura, and Tom C.J.B. And to the mentors, colleagues, fellows, and students who have enriched our academic and personal lives, and to the physicians and the women and infants with infectious diseases for whom they care

CONTRIBUTORS

Stuart P. Adler, MD Professor and Division Chair, Department of Pediatrics, Division of Infectious Diseases, Virginia Commonwealth University School of Medicine, Medical College of Virginia Campus, Richmond, Virginia Human Parvovirus Infections Charles A. Alford, Jr., MD Professor Emeritus of Pediatrics, University of Alabama School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama Rubella Ann M. Arvin, MD Lucille Salter Packard Professor of Pediatrics and Professor of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California Herpes Simplex Virus Infections Carol J. Baker, MD Professor of Pediatrics and Professor of Molecular Virology and Microbiology; Head, Section of Infectious Diseases, Baylor College of Medicine; Texas Children’s Hospital Foundation Chair in Pediatric Infectious Diseases, Houston, Texas Current Concepts of Infections of the Fetus and Newborn Infant; Bacterial Sepsis and Meningitis; Group B Streptococcal Infections; Syphilis; Pneumocystis and Other Less Common Fungal Infech‘ons Elizabeth D. Barnett, MD Associate Professor of Pediatrics, Boston University School of Medicine; Maxwell Finland Laboratory for Infectious Diseases, Boston Medical Center, Boston, Massachusetts Bacterial Infections of the Respiratory Tract Catherine M. Bendel, MD Associate Professor of Pediatrics and Director, Neonatal-Perinatal Medicine Fellowship Program, University of Minnesota Medical School, Minneapolis, Minnesota Candidiasis Robert Bortolussi, MD, FRCPC Professor of Pediatrics and Associate Professor of Microbiology and Immunology, Dalhousie University Faculty of Medicine; Chief of Research IWK Health Centre, Halifax, Nova Scotia, Canada Listeriosis John S. Bradlev, MD Associate Professor of Pediatrics, University of California, San Diego, School of Medicine, La Jolla; Director, Division of Infectious Diseases,Children’s Hospital of San Diego, San Diego, California Hepatitis William Britt, M D Professor, Department of Pediatrics and Infectious Disease, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama Cytomegalovirus Infections

James D. Cherty, MD, MSc Professor of Pediatrics, David Geffen School of Medicine at UCLA; Member, Division of Infectious Diseases, Matte1 Children’s Hospital at UCLA, Los Angeles, California Enferovirus and Parechovirus Infections Thomas G. Cleary, MD Professor, University of Texas School of Public Health; Attending Physician, Hermann Hospital, Houston, Texas Microorganisms Responsiblefor Neonatal Diarrhea

Louis Z. Cooper, MD Professor Emeritus of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York Rubella Carl T.D’Angio, MD Associate Professor of Pediatrics, University of Rochester School of Medicine and Dentistry; Attending Neonatologist, Golisano Children’s Hospital at Strong, Rochester, New York Laboratory Aids for Diagnosis of Neonatal Sepsis Toni Darville, MD Professor of Pediatrics and Immunology/Microbiology,University of Arkansas Medical Sciences; Attending Physician, Arkansas Children’s Hospital, Little Rock, Arkansas Chlamydia Infections

Jill K. Davies, MD Assistant Professor, Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center, Denver, Colorado Obstetric Factors Associated with Infections in the Fetus and Newborn Infant Georges Desmonts, M D Chief (retired), Laboratoire de Serologic NConatale et de Recherche sur la Toxoplasmose,Institut de PuCriculture, Paris, France Toxoplasmosis Morven S. Edwards, MD Professor of Pediatrics, Section of Infectious Diseases, Baylor College of Medicine; Attending Physician, Texas Children’s Hospital, Houston, Texas Group B Streptococcal Infections Joanne E. Embree, MD, FRCPC Head and Professor, Department of Medical Microbiology, University of Manitoba Faculty of Medicine; Professor, Department of Pediatrics and Child Health, and Head, Section of Pediatric Infectious Disease, Winnipeg Regional Health Authority, Winnipeg, Manitoba, Canada Gonococcal Infections

viii

Contributors

Roberto R Garofalo, MD Professor of Pediatrics, University of Texas M e d i d Branch at Galveston; Child Health Center, Galveston. Texas Human Milk Michael A. Gerber, MD Professor of Pediatrics, University of Cincinnati College of Medicine; Attending Pediatrician, Cincinnati children’s Hospital Medical Center, Cincinnati, Ohio Lyme Disease Anne A. Gershon,MD Professor of Pediatrics, Columbia University College of Physicians and Surgeons; Director, Division of Pediatric Infectious Diseases, Columbia University Medical Center, New York, New York Chickenpox, Measles, and Mumps Ronald S. Gibbs, MD Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center, Denver, Colorado Obstetric Factors Associated with Infections in the Fetus and Newborn Infant Kathleen M. Gutierrez, MD Assistant Professor, Department of Pediatrics, Stanford University School of Medicine, Stanford, California Herpes Simplex Virus Infections R. Doug Hardv, MD Assistant Professor of Pediatrics and Internal Medicine, University of Texas Southwestern Medical Center; Attending Physician, Children’s Medical Center Dallas and Parkland Hospital, Dallas, Texas Mycoplasmal Infections

Joan A. Heath, BSN,RN Manager, Infection Control Program, Children’s Hospital and Regional Medical Center, Seattle, Washington Infections Acquired in the Nursery: Epidemiology and Control David Zngall, MD Professor Emeritus, Departments of Pediatrics and Obstetrics and Gynecology, Northwestern University Medical School, Chicago; Chairman Emeritus, Department of Pediatrics, Evanston Northwestern Health Care, Evanston, Illinois Syphilis Jerome 0.Klein, MD Professor of Pediatrics, Boston University School of Medicine; Maxwell Finland Laboratory of Infectious Diseases, Boston Medical Center, Boston, Massachusetts Current Concepts of Infections of the Fetus and Newborn Infant; Bacterial Sepsis and Meningitis; Bacterial Infections of the Respiratory Tract; Bacterial Infections of the Urinary Tract William C. Koch, MD Associate Professor, Department of Pediatrics, Virginia Commonwealth University School of Medicine, Medical College of Virginia Campus, Richmond, Virginia Human Parvovirus Infections

David B. Lewis, MD Associate Professor of Pediatrics, Division of Immunology and Transplantation Biology, Stanford University School of Medicine, Stanford; Attending Physician, Lucile Salter Packard Children’s Hospital at Stanford, Palo Alto, California Developmental Immunology and Role of Host Defenses in Fetal and Neonatal Susceptibility to Infection Sarah S. Long, MD Professor of Pediatrics, Drexel University College of Medicine; Chief, Section of Infectious Diseases, St. Christopher’s Hospital for Children, Philadelphia, Pennsylvania Bacterial Infections of the Urinary Tract Timothy L Mailman, MD Assistant Professor of Pediatrics, Division of Infectious Diseases, Dalhousie University Faculty of Medicine; Director of Microbiology, IWK Health Centre, Halifax, Nova Scotia, Canada Listeriosis Yvonne A. Maldonado, MD Associate Professor, Department of Pediatrics and Department of Health Research and Policy, Stanford University School of Medicine, Stanford; Attending Physician, Lucile Salter Packard Children’s Hospital at Stanford, Palo Alto, California Acquired Immunodeficiency Syndrome in the Infant; Less Common Viral Infections; Less Common Protozoan and Helminth Infections; Pneumocystis and Other Less Common Fungal Infections George H. McCracken, Jr., MD Department of Pediatrics, University of Texas Southwestern Medical School, Dallas, Texas Clinical Pharmacology of Antibacterial Agents Rima McLeod, MD Jules and Doris Stein RPB Professor, University of Chicago, Division of Biological Sciences, Pritzker School of Medicine; Attending Physician, University of Chicago Hospitals, Michael Reese Hospital and Medical Center, Chicago, Illinois Toxoplasmosis Julia A. McMillan, MD Professor, Department of Pediatrics, Division of Infectious Diseases, Johns Hopkins University School of Medicine; Attending Physician, Johns Hopkins Hospital, Baltimore, Maryland Smallpox and Vaccinia Michael J. Miller, MD Professor of Pediatrics, Oregon Health Sciences University School of Medicine, Portland, Oregon Pneumocystis and Other Less Common Fungal Infections James €? Nataro, MD, PhD Professor of Pediatrics, Medicine, Microbiology, and Biochemistry, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland Microorganisms Responsible for Neonatal Diarrhea Victor Nizet, MD Associate Professor of Pediatrics, Division of Infectious Diseases, University of California, San Diego, School of Medicine, La Jolla; Attending Physician, Children’s Hospital and Health Center, San Diego, California Group B Streptococcal Infections

Contributors

ix

Pearay L. Ogra, MD Professor, Department of Pediatrics, Division of Infectious Diseases, State University of New York at Buffalo, School of Medicine and Biomedical Sciences; Attending Physician, Women and Children’s Hospital of Buffalo, Buffalo, New York Human Milk

Pablo J. Sanchez, MD Professor of Pediatrics, Divisions of Neonatal-Perinatal Medicine and Pediatric Infectious Diseases, University of Texas Southwestern Medical School; Attending Physician, Parkland Health and Hospital System and Children’s Medical Center Dallas, Dallas, Texas Syphilis

Rachel C. Orscheln, MD Instructor and Fellow, Pediatric Infectious Diseases, Washington University in St. Louis School of Medicine; Attending Physician, St. Louis Children’s Hospital, St. Louis, Missouri Staphylococcal Infections

Eugene D. Shapiro, MD Professor of Pediatrics, Epidemiology, and Investigative Medicine, Yale University School of Medicine; Attending Pediatrician, Children’s Hospital at Yale-New Haven, New Haven, Connecticut Lyme Disease

Miguel L. O’Ryan, MD Professor, Microbiology and Mycology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile Microorganisms Responsiblefor Neonatal Diarrhea

Henry R. Shinefield, MD Clinical Professor of Pediatrics and Dermatology, University of California, San Francisco, School of Medicine; Co-Director, Vaccine Study Center, Kaiser Permanente Medical Group, San Francisco, California Staphylococcal Infections

Gary D. Overturf, MD Professor of Pediatrics and Pathology, University of New Mexico School of Medicine; Director, Pediatric Infectious Diseases, Children’s Hospital of New Mexico, Albuquerque, New Mexico Bacterial Infem‘ons of the Bones and Joints;Focal Bacterial Infections Debra L. Palaui, MD Assistant Professor of Pediatrics, Baylor College of Medicine; Attending Physician, Texas Children’s Hospital, Ben Taub General Hospital, and Woman’s Hospital of Texas, Houston, Texas Bacterial Sepsis and Meningitis Octavio Ramilo, MD Professor of Pediatrics, University of Texas Southwestern Medical Center; Attending Physician, children’s Medical Center Dallas and Parkland Hospital, Dallas, Texas Mycoplasmal Infections David K. Rassin, PhD Professor of Pediatrics, University of Texas Medical Branch at Galveston; Child Health Center, Galveston, Texas Human Milk Jack S. Remington, MD Professor of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford; Marcus A. Krupp Research Chair and Chairman, Department of Immunology and Infectious Diseases, Research Institute, Palo Alto Medical Foundation, Palo Alto, California Current Concepts of Infections of the Fetus and Newborn Infant; Toxoplasmosis Xavier Scfez-Llorens,M D Professor of Pediatrics, University of Panama School of Medicine; Vice-chairman and Head of Infectious Diseases, Hospital del Niiio, Panama City, Panama Clinical Pharmacology of Antibacterial Agents Joseph W. St. Geme ZZZy MD Professor of Pediatrics and Molecular Microbiology, Washington University in St. Louis School of Medicine; Attending Physician, Pediatrics and Pediatric Infectious Diseases, St. Louis Children’s Hospital, St. Louis, Missouri Staphylococcal Infections

Sergio StagnoyMD Professor and Chairman, Department of Pediatrics, University of Alabama at Birmingham School of Medicine; Physician-in-Chief, Children’s Hospital of Alabama, Birmingham, Alabama CytomegalovirusInfections

JeffreyR. Starke, MD Professor and Vice-chairman, Department of Pediatrics, Baylor College of Medicine; Chief of Pediatrics, Ben Taub General Hospital, Houston, Texas Tuberculosis Barbara J. Stoll, MD Chair, Department of Pediatrics, Emory University School of Medicine; President and CEO, Emory Children’s Center; Medical Director, Children’s Healthcare of Atlanta, Atlanta, Georgia Neonatal Infections: A Global Perspective Philippe Thulliez, MD Chief, Laboratoire d’Immunoanalyses et Recherche sur la Toxoplasmose,Institut de Pukriculture, Paris, France Toxoplasmosis Geoffrey A. Weinberg,M D Associate Professor, Department of Pediatrics, Division of Infectious Diseases, University of Rochester School of Medicine and Dentistry; Director, Pediatric HIV Program, Golisano Children’s Hospital at Strong, Rochester, New York LaboratoryAids for Diagnosis of Neonatal Sepsis Richard J. Whitley, MD Professor, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama Herpes Simplex Virus Infections Christopher B. Wilson, MD Professor and Chair, Department of Immunology, and Professor of Pediatrics (Infectious Diseases), University of Washington School of Medicine; Attending Physician, Children’s Hospital and Regional Medical Center, Seattle, Washington Current Concepts oflnfections ofthe Fetus and Newborn Infant; Developmental Immunology and Role of Host Defenses in Fetal and Neonatal Susceptibility to Infection

x

Contributors

Danielle M. Zerr, MD, MPH Assistant Professor, Department of Pediatrics, University of Washington School of Medicine; Chair, Infection Control, Children’sHospital and Regional Medical Center, Seattle, Washington Infections Acquired in the Nursery: Epidemiology and Control

PREFACE

Major advances in biology and medicine made during the past several decades have contributed greatly to our understanding of infections that affect the fetus and newborn. As the medical, social, and economic impact of these infections becomes more fully appreciated, the time is again appropriate for an intensive summation of existing information on this subject. Our goal for the sixth edition of this text is to provide a complete, critical, and contemporary review of this information. We have directed the book to all students of medicine interested in the care and well-being of children and hope to include among our readers medical students, practicing physicians, microbiologists, and health care workers. We believe the text to be of particular importance for obstetricians and physicians who are responsible for the pregnant woman and her developing fetus; pediatricians and family doctors who care for newborn infants; and primary care physicians, neurologists, audiologists, ophthalmologists, psychologists, and other specialists who are responsible for children who suffer the sequelae of infections acquired in utero or during the first month of life. The scope of this book encompasses infections of the fetus and newborn, including those acquired in utero, during the delivery process, and in the early months of life. When appropriate, sequelae of these infections that affect older children and adults are included as well. Infection in the adult is described when pertinent to the developing fetus and newborn infant. Each chapter includes a review of the history, microbiology, epidemiology, pathogenesis and pathology, clinical signs and symptoms, diagnosis, prognosis, treatment, and prevention of the infection. The length of the chapters varies considerably. In some instances, this variation is related to the available fund of knowledge on the subject; in others (e.g., the chapters on toxoplasmosis, neonatal diarrhea, varicella, measles, and mumps), the length of the chapter is related to the fact that no recent comprehensive reviews of these subjects are available. The first, second, third, fourth, and fifth editions of this text were published in 1976, 1983, 1990, 1995, and 2001, respectively. As of this writing, in the spring of 2005, it is most interesting to observe the changes that have occurred in the interval since publication of the last edition. New authors provide fresh perspectives. Major revisions of most chapters suggest the importance of new information about infections of the fetus and newborn infant. Each of the authors of the different chapters is a recognized authority in the field and has made significant contributions to our understanding of infections in the fetus and newborn infant. Most of these authors are individuals whose major investigative efforts on this subject have taken place during the past 25 years. Almost all were supported, in part or totally, during their training period and subsequently, by funds obtained from the National Institutes of Health or from private agencies such as March of Dimes. It is clear that the major advances of this period would not have been

possible without these funding mechanisms and the freedom given to the investigators to pursue programs of their own choosing. Thus, the advances present in this text are also a testimony to the trustees of agencies and the legislators and other federal officials who provided unencumbered research funds from the 1960s to the present day. We were Fellows at the Thorndike Memorial Laboratory (Harvard Medical Unit, Boston City Hospital) in the early 1960s. Although subsequently we worked in separate areas of investigation on the two coasts, one of us as an internist and the other as a pediatrician, we maintained close contact, and, because of a mutual interest in infections of the fetus and newborn infant and their long-term effects, we joined our efforts to develop this text. For this edition, we are proud to have added, as Associate Editors, Carol J. Baker and Christopher B. Wilson. Carol trained in infectious diseases in Boston with J.O.K. and Maxwell Finland, and Chris trained in immunology and infectious diseases in Palo Alto with J.S.R. Carol has become a world-recognized expert in all aspects of group B streptococcal infections and is the Texas Children’s Hospital Foundation Chair in Pediatric Infectious Diseases in Houston. Chris has become a prominent developmental immunologist and is now Chair of the Department of Immunology at the University of Washington School of Medicine. We look to Carol and Chris to help us maintain the quality and value of this text for many editions to come. We are indebted to our teachers and associates and especiallyto the one individual who had a dominant influence in our training, Dr. Maxwell Finland. We deeply appreciate the example he set, his wise counsel, and his interest in and support of our investigativeprograms. We also wish to express our appreciation to Todd Hummel, Jennifer Ehlers, Lee Ann Draud, and the staff of Elsevier, Inc., for guiding this project to a successful conclusion; to Ms. Nancy Ahonen and Robin Schroeder for secretarial assistance; and to Ms. Trisha Mitchell for her editorial assistance. Jack S. Remington Jerome0.Klein

We are pleased to have joined Jack and Jerry in editing this book, which since its inception has been a unique resource for physicians caring for the mother, fetus, and newborn infant. We are also grateful for the investigators working in the field, who have improved life for mother and infant, and for the chapter authors, who bring their comprehensive understanding of their topics to enlighten readers.

Carol J.Baker Christopher B. Wilson

Chapter 1 CURRENT CONCEPTS OF INFECTIONS OF THE FETUS AND NEWBORN INFANT Jerome 0. Klein Carol J. Baker Christopher B. Wilson

Overview 3 Infections of the Fetus 4 Pathogenesis Efficiencyof Transmission of Microorganisms from Mother to Fetus Diagnosis of Infection in the Pregnant Woman Prevention and Management of Infection in the Pregnant Woman

Infections Acquired by the Newborn Infant during Birth 16 Pathogenesis Microbiology Diagnosis Management Prevention Infections of the Newborn Infant in the First Month of Life 20 Pathogenesis and Microbiology Epidemiology Diagnosis and Management

OVERVIEW Current concepts of pathogenesis, microbiology, diagnosis, and management of infections of the fetus and newborn infant are briefly reviewed in this chapter. Also in this first section of the book are chapters providing a global perspective on fetal and neonatal infections and chapters addressing obstetric factors, immunity, host defenses and the role of human breast milk in fetal and neonatal infections. Chapters containing detailed information about specific bacterial, viral, protozoan, helminth, and fungal infections follow. This edition concludes with chapters addressing nosocomial infections and the diagnosis and therapy of infections in the fetus and neonate. A number of changes have occurred in epidemiology, diagnosis, prevention, and management of infectious diseases of the fetus and newborn infant since publication of the last edition of this book. Some of these changes are noted in Table 1-1 and are discussed in this and the relevant chapters. Substantial progress has taken place to reduce the burden of infectious diseases in the fetus and newborn infant. The incidence of early-onset group B streptococcal disease has been reduced by aggressive use of intrapartum chemoprophylaxis and, in particular, by the culture-based chemoprophylaxis strategy now recommended for universal use in the

Jack S. Remington

United States; vertical transmission of human immunodeficiency virus (HIV) has been reduced by identification of the infected mother with subsequent treatment, including the use of brief regimens that are practical for use in countries with high prevalence but limited resources; there has been a commitment of resources by government agencies and philanthropies, such as the Bill and Melinda Gates Foundation, to combat global infectious diseases in mothers and children; use of polymerase chain reaction (PCR) techniques in etiologic diagnosis has expanded, permitting more rapid and specific identification of microbial pathogens; and in the United States, national legislation on postpartum length of hospital stay has been enacted to prevent insurers from restricting insurance coverage for hospitalization to fewer than 48 hours after vaginal deliveries or 96 hours after cesarean deliveries. Setbacks in initiatives to reduce the global burden of infectious disease in the fetus and newborn infant include the continuing increase in the prevalence of HIV infection in many developing countries, particularly among women; the lack of finances to provide effective treatment for these women and their newborn infants; and in the United States, the increase in antimicrobial resistance among nosocomial pathogens, as well as in incidence of invasive fungal infections among infants of extremely low birth weight. Use of the Internet has grown further, allowing access to information hitherto unavailable to physicians or parents. The physician may obtain current information about diseases and management and various guidelines for diagnosis and treatment. The interested parent who has access to the Internet can explore a variety of Internet sites that present a vast array of information and, unfortunately, misinformation. As an example of the latter, a case of neonatal tetanus was associated with the use of cosmetic facial clay (Indian Healing Clay) as a dressing on an umbilical cord stump. The product had been publicized as a healing salve by midwives on an Internet site on “cordcare.”’ Because much of the information on the Internet is from commercial sources and parties with varying interests and expertise, the physician should assist the interested parent and patient in finding Internet sites of value. A selected list of Internet sites pertinent to infectious diseases of the fetus and newborn infant is provided in Table 1-2. Vital statistics relevant to infectious disease risk in neonates in the United States for 2001 are listed in Table 1-3.* Of importance are the disparities in birth weight, prenatal care, and neonatal mortality among different racial and ethnic groups.

4

Section I

General Information

The number of infectious diseases in fetuses and newborn infants must be extrapolated from selected studies (see chapters on diseases). Approximately 1% of newborn infants excrete cytomegalovirus ( C M V ) ,greater than 4% of infants are born to mothers infected with Chlamydia trachomatis, and bacterial sepsis develops in 1 to 4 infants per 1000 live births. Since the institution of intrapartum chemoprophylaxis in the United States, the number of infants with earlyonset group B streptococcal disease has declined, with

Table 1-1

Recent Changes in Epidemiology and Management of infectious Diseases of the Fetus and Newborn infant

Epidemiology Increased viability of very low birth weight infants at risk for invasive infectious diseases Increased number of multiple births (offten of very low birth weight) due t o successful techniques for management of infertility Global perspective of vertically transmitted infectious diseases Early discharge from the nursery mandated by insurance programs reversed by legislation to ensure adequate observation for infants at risk for sepsis Diagnosis Polymerase chain reaction assay for diagnosis of infection in mother, fetus, and neonate Decreased use of fetal blood sampling and chorionic villus sampling for diagnosis of infectious diseases Prevention lntrapartum antibiotic prophylaxis t o prevent early-onset group B streptococcal infection widely implemented Antiretroviral therapy in pregnancy t o prevent transmission of human immunodeficiency virus (HIV) to fetus Treatment Antiretroviral therapy in mother to treat HIV infection in fetus Antitoxoplasmosis therapy in mother to treat infection in fetus Spread within nurseries of multiple antibiotic-resistant bacterial pathogens Increased use of vancomycin for p-lactam-resistant gram-positive infections Increased use of acyclovir for infants with suspected herpes simplex infection

Table 1-2

reduction in incidence from approximately 1.5 cases to 0.4 case per 1000 live births, and is expected to decline further with the universal adoption of the culture-based ~trategy.~ In the United States, the use of maternal highly active antiretroviral treatment (HAART) and peripartum chemoprophylaxis has led to a reduction in the rate of mother-to-child transmission of HIV from approximately 25% of infants born to mothers who received no treatment to 2%; less complex but practical regimens of intrapartum prophylaxis have helped to reduce the rate of transmission in the developing world: Among sexually transmitted diseases, the rate of congenital syphilis declined substantially in the United States to 13.4 per 100,000 live births in 2000, and although rates remain higher in the South, only two states have rates greater than 40 per 100,000 live birth^.^ Immunization has virtually eliminated congenital rubella syndrome in newborn infants of mothers who were themselves born in the United States, but cases continue to occur in infants of foreign-born mothers; 24 of 26 infants with congenital rubella born between 1997 and 1999 were born to foreign-born mothers, and 21 of these were born to Hispanic mothers! Infection acquired in utero can result in resorption of the embryo, abortion, stillbirth, malformation, intrauterine growth retardation, prematurity, and the untoward sequelae of chronic postnatal infection. Infection acquired during the birth process or soon after birth may result in severe systemic disease that leads to death or persistent postnatal infection. Both in utero infection and infection acquired during the birth process may lead to late-onset disease. The infection may not be apparent at birth but may manifest with signs of disease weeks, months, or years later, as exemplified by the chorioretinitis of Toxoplasma gondii infection, the hearing loss of rubella, and the immunologic defects that result from HIV infection. The immediate as well as the long-term effects of these infections constitute a major problem throughout the world.

INFECTIONS OF THE FETUS

Pathogenesis Pregnant women not only are exposed to the infections prevalent in the community but also are likely to reside with young children or to associate with groups of young children,

Selected internet Sites of Value for Physicians interested in infectious Diseases of the Fetus and Newborn infant

Agency for Health Care Policy and Research American Academy of Pediatrics American College of Obstetricians and Gynecologists Centers for Disease Control and Prevention Food and Drug Administration Immunization Action Coalition Information on AIDS Trials Morbidity and Mortality Weekly Report National Center for Health Statistics Pediatric Infectious Diseases and selected bibliographya

h t tp :/lwww. ahc pr.gov http://www.aap.org http://www.acog.org http://www.cdc.gov http:/lwww.fda.gov http://www.immunize.org http://www.actis.org http://www.cdc.govlepolmmwr/mmwr. html http://www.cdc.govlnchs http://www.pedid.uthscsa.edu

'Described in Jenson HB, Baltimore RS. A World Wide Web selected bibliography for pediatric infectious diseases. Clin Infect Dis 28:395-398, 1999.

Chapter 1

Table 1-3

Current Concepts of Infections of the Fetus and Newborn Infant

5

Vital Statistics Relevant to Newborn Health in the United States in 2002 RaciaVEthnic Origin of Mother

Feature Live births” Birth weight ~ ~ - ~ ' ~ The HIV epidemic has raised questions about the safety of breast-feeding in areas in which there is a high prevalence of HIV infection among lactating women.225-233,241,407 HIV may be transmitted through breast-feeding. A major question for any setting is whether the benefits of breast-feeding outweigh the risk of postnatal transmission of HIV through breast milk.407For many areas of the world, where infectious diseases, especially diarrheal diseases, are a primary cause of infant death, breast-feeding, even when the mother is HIV infected, remains the safest mode of infant feeding. Countries with high and low reported rates of exclusive breast-feeding are listed in Table 2-ll3I6

It is universally recognized that poor aseptic techniques during labor and delivery, including performing procedures with unclean hands and unclean instruments and unhygienic cutting of the umbilical cord, are major risk factors for both maternal and neonatal infections.390It is essential to promote safe and hygienic practices at every level of the health care system where women deliver (i.e., home, health center, district Table 2-1 2 Breast-Feeding Rates in or referral hospital). Proper management of labor and Developing Countriesasb delivery can have a significant impact on the prevention of Exclusive Breast-Feeding Exclusive Breast-Feeding neonatal infection. It is important to emphasize the need for Rates of 10% or Less Rates of 50% or More clean hands, clean perineum, clean delivery surface, clean instruments, clean cord care, use of an appropriate clean Country % country % delivery kit, avoidance of harmful traditional practices, prevention of unnecessary vaginal examinations, prevention Niger Rwanda 90 Burundi 89 Nigeria of prolonged labor, and optimal management of pregnancy Ethiopia 74 Angola complications including prolonged rupture of the memTanzania 73 CBte d'lvoire branes, maternal fever, and chorioamnionitis/puerperal Uganda 70 Haiti ~ep s i s .~ Central African 68 Egypt Eritrea 65 Republic If the mother does develop a puerperal infection, the China 4 64 Thailand newborn requires special attention and should be treated for 7 60 Mauritania Cameroon presumed sepsis.3y0Prolonged rupture of the membranes, Bangladesh 7 54 Paraguay maternal fever during labor, and chorioamnionitis are Turkmenistan 8 54 Maldives particular risk factors for early-onset neonatal sepsis and Bolivia 9 53 Senegal 10 Iran 53 pneumonia in both developed and developing c ~ u n t r i e s . ~ ~ ~Dominican . ~ ~ ~ Republic 51 10 India Togo Ideally, high-risk infants who are born at home should be 10 Guatemala 50 Trinidadnobago referred to the nearest health care facility for observation and antibiotic therapy. In practice, this may be either aBreast-feeding in infants younger than 4 months of age. impossible or unacceptable to the family, and ways to deliver bData from DHS MlCS and other nationwide surveys, 1987-1996. care to the mother and the newborn in the home must be From The Progress of Nations 1997. New York, UNICEF, 1997.

Chapter 2

Maternal Education and Socioeconomic Status Maternal education, literacy, and overall socioeconomic status are powerful influences on the health of both mother and n e w b ~ r n . ~ " -Education ~'~ of girls must be promoted and expanded so that women of reproductive age know enough to seek preventive services, understand the implications of danger signs during labor and delivery and in their newborns, and recognize that they must obtain referral care for obstetric or newborn complications, or both. Improvements in education and socioeconomic status are obviously linked. They may affect child health by allowing the mother a greater voice in the family with greater decision-making power, making her better informed about domestic hygiene, disease prevention, or disease recognition, or enhancing her ability to seek medical attention outside the home and to comply with medical advice.

Low Birth Weight and Prematurity Low birth weight (2500 g or less) constitutes a major public health problem. Worldwide, approximately 90% of LBW infants are born in developing countries.412Low birth weight is caused by impaired fetal growth, shortened gestation, or a combination of both. In developing countries, low birth weight is caused more frequently by intrauterine growth retardation than by Data suggest that both preterm and LBW infants are at increased risk for infection and infection-related m ~ r t a l i t y . ~ 'Therefore, ~ - ~ l ~ strategies to reduce the frequency of low birth weight and prematurity could have a measurable impact on neonatal infection. Potential interventions to improve intrauterine growth or to lengthen gestation, or both, include delaying childbearing in adolescents, improved maternal education, caloric supplementation before and during pregnancy, general improvements in nutrition, malaria prophylaxis or treatment, treatment of STDs and other maternal infections, efforts to reduce tobacco use, improved water and sanitation, limitation of maternal work during pregnancy, and general improvement in socioeconomic conditions.332

Community-Based Interventions In parts of the world in which a majority of births occur at home, primary health care at the village level will need to put added emphasis on care of the newborn. The birth attendant is responsible for observation of the newborn at and after birth and deciding that the newborn is healthy and ready to be "discharged" to the care of the mother. It is important to link postpartum care of the mother with surveillance and care of the newborn. The postpartum visit should be used to detect and treat the sick newborn as well as to evaluate the mother. Birth attendants need to be trained to identify problems in the newborn, to treat simple problems (e.g., skin infections), and to refer those that are potentially lifethreatening (e.g., suspected sepsis). Moreover, they should provide all new mothers with breast-feeding support and give advice regarding personal hygiene/cleanliness and other prevention strategies such as immunization. Improvement in domestic hygiene should be encouraged, including sanitary disposal of wastes, use of clean water, and hand washing, so that the newborn enters a clean home and is less likely to encounter pathogenic organisms. In some settings,

Neonatal Infections: A Global Perspective

49

families will refuse to take even a sick newborn to a hospital, and care will need to be brought into the village or home. Community interventions need to be designed and modified to meet the needs of mothers and newborns in different settings in different countries and need further evaluation.

Early Identification and Improved Treatment of Neonates with Infection If untreated, infections in newborns can rapidly become severe and life-threatening. Therefore, early identification and appropriate treatment of newborns with infection are critical to survival. In developing countries, where access to care may be limited, diagnosis and treatment are particularly difficult. It is important to recognize maternal and neonatal factors that increase risk of infection in the newborn. These include maternal infections during pregnancy (STDs, urinary tract infection, others), premature or prolonged rupture of membranes, prolonged labor, fever during labor, unhygienic obstetric practices or cord care, poor hand-washing practices, low birth weight/prematurity, artificial feeding, and generally unhygienic living conditions.2-4 In areas without sophisticated technology and the diagnostic help of laboratory tests and x-ray studies, treatment decisions must be made on the basis of the history and findings on physical examination. In the WHO Young Infant Study, clinical predictors of neonatal sepsis were studied in more than 3000 sick infants younger than 2 months of age in Ethiopia, The Gambia, Papua New Guinea, and the phi lip pine^.^'^ In multivariable analysis, 14 signs were independent predictors of severe disease: reduced feeding ability, absence of spontaneous movement, temperature greater than 38' C, drowsiness or unconsciousness, a history of a feeding problem or change in activity, state of agitation, the presence of lower chest indrawing (retractions), respiratory rate greater than 60, grunting, cyanosis, a history of convulsions, a bulging fontanel, and slow digital capillary refill. The presence of any one of these signs had a sensitivity for severe disease (sepsis, meningitis, hypoxemia, or radiologically proven pneumonia) of 87% and a specificity of 54%. Mothers, birth attendants, and other health care workers and family members must be educated so that they can identify danger signs in the newborn and understand that prompt and appropriate therapy may make the difference between life and death. The positive deviance (PD) approach involves investigating children (in this case newborns) with healthy outcomes despite adverse conditions, identifying model practices among successful families, and designing an intervention to transfer these behaviors to other mothers and families. Save the Children has studied the PD approach in newborns in Pakistan. In-depth interviews were conducted to identify common behaviors among parents of surviving asphyxiated newborns, thriving LBW babies, surviving newborns who demonstrated danger signs, and normal newborns. PD families had better maternal care, better routine and special newborn care, and better care-seeking behavior.417 A study from Sri Lanka, a developing country with relatively low neonatal and infant mortality rates, identified a high level of care-seeking behavior among mothers, particularly for illnesses with acute, high-risk danger signs.418 An integrated approach to the sick child, including the young infant, has been developed by the WHO and

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UNICEE4” This strategy promotes prompt recognition of disease, appropriate therapy using standardized case management, referral of serious cases, and prevention through improved nutrition (breast-feeding of the neonate), and immunization. This approach stresses diagnosis using simple clinical signs that can be taught to health care workers at all levels. The health care worker assesses the child by questioning the mother and examining the child, classifies the illness as serious or not, and determines if the infant needs urgent treatment and referral, specific treatment and advice, or only simple advice and home management. Importance of breastfeeding is stressed, and follow-up instructions are given. All young infants are checked for specific danger signs that equate with need for emergency care and urgent referral. Because the signs of serious bacterial infection in the newborn are not easily recognized, every young infant with danger signs is given treatment for a possible bacterial infection. All newborns with suspected severe infection receive antibiotics as soon as possible and are then referred for hospitalization. In situations where referral is impossible or unacceptable to the family, community-based interventions must be designed, implemented, and evaluated.

CONCLUSION The 1996 World Health Report4” highlights the global importance of infectious diseases, especially among young children, and stresses the impact of new or emerging diseases. Neonatal infections are old diseases. Furthermore, each infection-related death should be considered a potentially preventable death. What is needed is a new recognition that they are important causes of morbidity and mortality and that simple interventions are available that can have a significant impact on reducing the incidence of both infection and death related to infection in developing countries. REFERENCES 1. World Health Report 1998. Geneva, World Health Organization, 1998. 2. Bale JR, Stoll BJ, Lucas A 0 (eds). Improving Birth Outcomes: Meeting the Challenge in the Developing World. Washington, DC, Institute of Medicine, The National Academy Press, 2003. 3. The State of the Worlds Newborns: A Report from Saving Newborn Lives. Washington, DC, Save the Children, 2001. 4. Mother-baby package: Implementing safe motherhood in countries. WHOIFHEIMSMI94. 1 1 . 5. Stoll BJ. The global impact of neonatal infection. Clin Perinatol 24:l-21, 1997. 6. Stoll BJ, Measham AR. Children can’t wait: improving the future for some of the world’s poorest infants. J Pediatr 139:729-733,2001, 7. World Health Organization. Perinatal Mortality: A Listing of Available Information. Geneva, World Health Organization, 1996. 8. Adeyokunnu AA, Taiwo 0, Antia AU. Childhood mortality among 22,255 consecutive admissions in the University College Hospital, Ibadan. Niger J Paediatr 7:7-15, 1980. 9. English M, Ngama M, Musumba C. Causes and outcome of young infant admissions to a Kenyan district hospital. Arch Dis Child 88:438-443,2003. 10. Aganval VK, Gupta SC, Chowdhary SR, et al. Some observations on perinatal mortality. Indian Pediatr 19:233-238, 1982. 1 I . Aiken CGA. The causes of perinatal mortality in Bulawayo, Zimbabwe. Cent Afr J Med 38:263-281,1992. 12. Baja-Panlilio H, Cabigas-Resurreccion J, Matanguihan AT, et al. Perinatal morbidity and mortality in the Philippines. Asia-Oceania J Obstet Gynaecol 12:331-339, 1986.

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General Information

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Chapter 2 373. Shahid NS, Steinhoff MC, Hoque SS, et al. Serum, breast milk, and infant antibody after maternal immunisation with pneumococcal vaccine. Lancet 346:1252-1257, 1995. 374. O'Dempsey TJD, McArdle T, Ceesay SJ, et al. Immunization with a pneumococcal capsular polysaccharide vaccine during pregnancy. Vaccine 14963-970, 1996. 375. Santosham M, Englund JA, McInnes P, et al. Safety and antibody persistence following Haemophilus influenzae type b conjugate or pneumococcal polysaccharide vaccines given before pregnancy in women of childbearing age and their infants. Pediatr Infect Dis J 20~931-940,2001. 376. Mulholland K, Suara RO, Siber G, et al. Maternal immunization with Haemophilus influenzae type b polysaccharide-tetanus protein conjugate vaccine in The Gambia. JAMA 275:1182-1188, 1996. 377. Englund JA, Glezen WP, Thompson C, et al. Haemophilus influenzae type b-specific antibody in infants after maternal immunization. Pediatr Infect Dis J 16:1122-1130, 1997. 378 Bisgard Kh4, Kao A, Leake J, et al. Haemophilus influenzae invasive disease in the United States, 1994-1995: near disappearance of a vaccine-preventable childhood disease. Emerg Infect Dis 4229-237, 1998. 379. Bijlmer HA. Epidemiology of Haemophilus influenzae invasive disease in developing countries and intervention strategies. In EUis RW, Granoff DM (eds). Development and Uses of Haemophilus b ConjugateVaccines. New York, Marcel Dekker, 1994, pp 247-264. 380. Funkhouser A, Steinhoff MD, Ward J. Haemophilus influenzae disease and immunization in developing countries. Rev Infect Dis 13(S~ppl6):S542-S554,1991. 381. Marchant A, Newport M. Prevention of infectious diseases by neonatal and early infantile immunization: prospects for the new millennium. Curr Opin Infect Dis 13:241-246,2000. 382. Smith PG. Case-controlstudies of the efficacy of BCG against tuberculosis. In International Union Against Tuberculosis (ed). Proceedings of the XXVIth IUAT World Conference on Tuberculosis and Respiratory Diseases, Singapore. Japan, Professional Postgraduate Services International, 1987, pp 73-79. 383. Colditz GA, Berkey CS, Mosteller F, et al. The efficacy of bacillus Calmette-Gukrin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literature. Pediatrics 9629-35,1995. 384. Delage G, Remy-Prince S, Montplaisir S. Combined active-passive immunization against the hepatitis B virus: five-year follow-up of children born to hepatitis B surface antigen-positivemothers. Pediatr Infect Dis J 12:126-130,1993. 385. Andre FE, Zuckerman AJ. Review: Protective efficacy of hepatitis B vaccines in neonates. J Med Virol44:144-151, 1994. 386. World Health Organization. Expanded programme on immunization: Global advisory group. Wkly Epidemiol Rec 3:ll-16,1992. 387. Glass RI, Bresee JS, Parashar U, et al. Rotavirus vaccines at the threshold. Nat Med 3:1324-1325,1997. 388. Perez-Schael I, Guntinas MJ, Perez M, et al. Efficacy of the rhesus rotavirus-based quadrivalent vaccine in infants and young children inVenezuela. N Engl J Med 337:1181-1187,1997. 389. Lagos R, Valenzuela MT, Levine OS, et al. Economisation of vaccination against Haemophilus influenzae type b a randomised trial of immunogenicity of fractional-dose and two-dose regimens. Lancet 351:1472-1476,1998. 390. World Health Organization. The Prevention and Management of Puerperal Infections. Geneva, World Health Organization, 1992. 391. World Health Organization. The global elimination of neonatal tetanus: progress to date. Bull World Health Organ 72:155-164,1994. 392. Walker DG, Walker GJ. Forgotten but not gone: the continuing scourge of congenital syphilis. Lancet Infect Dis 2:432-436,2002. 393. Kuate DB. Epidemiology and control of infant and early childhood malaria: a competing risks analysis. Int J Epidemiol 24204-217, 1995. 394. Airede AI. Prolonged rupture of membranes and neonatal outcome in a developing country. Ann Trop Paediatr 12:283-288,1992. 395. Asindi AA, Omene JA. Prolonged rupture of membrane and neonatal morbidity. East Afr Med J 52707-71 1,1980. 396. Raghavan M, Mondal GP, Vishnu BB, et al. Perinatal risk factors in neonatal infections. Indian J Pediatr 59335-340,1992.


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397. Hanson LA, Hahn-Zoric M, Berndes M, et al. Breast feeding: overview and breast milk immunology. Acta Paediatr Jpn 36~557-561,1994. 398. Ashraf RN, Jalil F, &man S, et al. Breast feeding and protection against neonatal sepsis in a high risk population. Arch Dis Child 66:488-490, 1991. 399. Brown KH, Black RE, Lopez de Romana G, et al. Infant-feeding practices and their relationship with diarrheal and other diseases in Huascar (Lima), Peru. Pediatrics 83:3140, 1989. 400. Feachem G, Koblinsky MA. Interventions for the control of diarrhoeal diseases among young children: promotion of breastfeeding. Bull World Health Organ 62:271-291, 1984. 401. Glezen WP. Epidemiological perspective of breastfeeding and acute respiratory illnesses in infants. In Mestedty J (ed). Immunology of Milk and the Neonate. New York, Plenum Press, 1991, pp 235-240. 402. Narayanan I, Murthy NS, Prakash K, et al. Randomised controlled trial of effect of raw and holder pasteurised human milk and of formula supplements on incidence of neonatal infection. Lancet 2~1111-1113,1984. 403. Habicht JP,DaVanm J, Butz XVP.Does breastfeeding really save lives, or are apparent benefits due to biases? Am J Epidemiol 123:279-290, 1986. 404. Srivastava SP, Sharma VK,Jha SP. Mortality patterns in breast versus artificially fed term babies in early infancy: a longitudinal study. Indian Pediatr 31:1393-1396, 1994. 405. Victora CG, Smith PG, Vaughan JP, et al. Infant feeding and deaths due to diarrhea: a case-control study. Am J Epidemioll291032-1041, 1989. 406. Victora CG, Vaughan JP, Lombardi C, et al. Evidence for protection by breast-feeding against infant deaths from infectious diseases in Brazil. Lancet 11:319-322, 1987. 407. Brahmbhatt H, Gray RH.Child mortality associated with reasons for non-breastfeeding and weaning: is breastfeeding best for HIVpositive mothers?AIDS 17:879-885,2003. 408. Bicego GT, Boerma JT, Maternal education and child survival: a comparative study of survey data from 17 countries. SOCSci Med 36:1207-1227,1993. 409. Victora CG, Huttly SRA, Barros FC, et al. Maternal education in relation to early and late child health outcomes: findings from a Brazilian cohort study. Soc Sci Med 34:899-905, 1992. 410. World Development Report 1993: Investing in Health. New York, Oxford University Press, 1993. 411. van Ginneken JK, Lob-Levyt J, Gove S. Potential interventions for preventing pneumonia among young children in developing countries: promoting maternal education. Trop Med Intern Health I :283-294, 1996. 412. Villar J, Belizan JM. The relative contribution of prematurity and fetal growth retardation to low birth weight in developing and developed societies. Am J Obstet Gynecol 143:793-798, 1982. 413. Stoll BJ, Hansen N, Fanaroff AA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics 110285-291,2002. 414. Victora CG, Barros FC, Vaughan JP, et al. Birthweight and infant mortality: a longitudinal study of 5914 Brazilian children. lnt J Epidemiol 16239-245,1987. 415. Victora CG, Smith PG,Vaughan JP, et al. Influence of birth weight on mortality from infectious diseases: a case-control study. Pediatrics 81:807-811, 1988. 416. Weber MW, Carlin JB, Gatchalian S, et al. Predictors of neonatal sepsis in developing countries. Pediatr Infect Dis J 22:711-717,2003. 417. Marsh DR, sternin M, Khadduri R, et al. Identification of model newborn care practices through a positive deviance inquiry to guide behavior-change interventions in Haripur, Pakistan. Food Nutr Bull 233109-118,2002. 418. Amarasiri de Silva MW, Wijekoon A, Hornik R, et al. Care seeking in Sri Lanka: one possible explanation for low childhood mortality. SOC Sci Med 53:1363-1372,2001. 419. World Health Organization. Integrated management of the sick child. Bull World Health Organ 73:435-740,1995. 420. World Health Organization. World Health Report 1996: Fighting Disease, Fostering Development. Geneva, World Health Organization, 1996.

Chapter 3 OBSTETRIC FACTORS ASSOCIATED WITH INFECTIONS IN THE FETUS AND NEWBORN INFANT Jill K. Davies

Ronald 5. Gibbs

Intra-amniotic infection 59 Pathogenesis Microbiology Diagnosis Management and Short-Term Outcome Long-Term Outcome Prevention infection as a Cause of Preterm Birth 66 Histologic Chorioamnionitis and Prematurity Clinical Infection and Prematurity Association of Lower Genital Tract Organisms or Infections with Prematurity Amniotic Fluid Cultures in Preterm Labor Biochemical Links of Prematurity and Infection Antibiotic Trials Premature Rupture of Membranes 71 Definitions Incidence Etiology Diagnosis Natural History Complications Approach to Diagnosis of Infection Treatment of Preterm Premature Rupture of Membranes before Fetal Viability Treatment of Preterm Premature Rupture of Membranes in Early Third Trimester Recurrence Prevention Special Situations Treatment of Term Premature Rupture of Membranes

Early-onset neonatal infection often has its origin in utero. Thus, risk factors for neonatal sepsis include prematurity, premature rupture of the membranes (PROM), and maternal fever during labor (which may be caused by clinical intraamniotic infection). This chapter focuses on these major obstetric conditions. Included in addition to these three “classic”topics is a discussion of new information indicating that intrauterine exposure to bacteria is linked to major neonatal sequelae, including cerebral palsy, bronchopulmonary dysplasia (BPD), and respiratory distress syndrome (RDS).

INTRA-AMNIOTIC INFECTION Clinically evident intrauterine infection during the latter half of pregnancy develops in 1% to 10% of pregnant women

and leads to increased maternal morbidity as well as perinatal mortality and morbidity. In general, the diagnosis is clinically based on the presence of fever and other signs and symptoms, such as maternal or fetal tachycardia, uterine tenderness, foul odor of the amniotic fluid, and maternal leukocytosis. Although not invariably present, rupture of the membranes or labor also occurs in most cases. Some prospective reports have noted higher rates (4.2% to 10.5?40)’-~ than in older retrospective studies (1% to 2%).4A number of terms have been applied to this infection, including chorioamnionitis, intrapartum infection, amniotic fluid infection, and intraamniotic infection (IAI). We use the last designation to distinguish this clinical syndrome from bacterial colonization of amniotic fluid (also referred to as “microbial invasion of the amniotic cavity”) and from histologic inflammation of the placenta (i.e., histologic chorioamnionitis).

Pathogenesis Before labor and membrane rupture, amniotic fluid is nearly always sterile. With the onset of labor or with membrane rupture, bacteria from the lower genital tract usually enter the amniotic cavity. This ascending route is the most common pathway for development of IAI.4 In 1988, Romero and co-workers described four stages of ascending intrauterine infection (Fig. 3-1). Shifts in vaginal or cervical flora and the presence of pathologic bacteria in the cervix represent stage I. Bacterial vaginosis may also be classified as stage I. In stage 11, bacteria ascend from the vagina/cervix into the decidua, the specialized endometrium of pregnancy. The inflammatory response here allows organisms to invade the amnion and chorion leading to chorioamnionitis. In stage 111, bacteria invade chorionic vessels (choriovasculitis) and migrate through to the amnion into the amniotic cavity to cause IAI. Once in the amniotic cavity, bacteria may gain access to the fetus through several potential mechanisms, culminating in stage IV; fetal bacteremia, sepsis, and pneumonia may result.5 Occasional instances of documented IAI in the absence of rupture of membranes or labor support a presumed hematogenous or transplacental route of infection. Fulminant IAI without labor and without rupture of membranes may be caused by Listeria monocytogenes.6-‘oMaternal sepsis due to this organism often manifests as maternal flulike illness and may result in death of the fetus. In an outbreak caused by “Mexican-style’’ cheese contaminated with Listeria, several maternal deaths occurred.” Other virulent organisms, such

60

Section I

General Information with an OR of 2.49; for internal fetal monitoring, the OR was 1.42; and for more than four examinations, the OR was 1.59. One interpretation of these data regarding risk factors among preterm pregnancies is that there was some other risk factor not detected in this survey. Additionally, meconium staining of the amniotic fluid has been associated with an increased risk of chorioamnionitis (4.3% versus 2.1%)." Prior spontaneous and elective abortion (at less than 20 weeks) in the immediately preceding pregnancy has also been associated with development of IAI in the subsequent pregnancy (OR 4.3 and 4.0, respectively).21 In 1996, a multivariable analysis demonstrated quantitatively the importance of chorioamnionitis in neonatal sepsis.22The OR for neonatal sepsis accompanying clinical chorioamnionitis was 25, whereas for preterm delivery, membrane rupture for longer than 12 hours, endometritis, and group B streptococcal colonization, the ORs all were less than 5. Epidural anesthesia has been associated with fever in labor (independent of i n f e ~ t i o n )This . ~ ~ knowledge must be considered in determining the etiology of fever in a patient who has an epidural anesthetic in place. Although Naeye had reported an association between recent coitus and development of chorioamnionitis defined by histologic further analysis of the same population refuted this a s s ~ c i a t i o n .Other ~ ~ studies have not demonstrated any relationship between coitus and PROM, premature birth, or perinatal death.26

Microbiology Figure 3-1 The stages of ascending infection. (From Romero R, Mazor M. Infection and preterm labor: pathways for intrauterine infections. Clin Obstet Gynecol 31 :558, 1988.)

as group A streptococci, also have been the cause of transplacental infection.'* MI may develop less commonly as a consequence of obstetric procedures such as cervical cerclage, diagnostic amniocentesis, cordocentesis (percutaneous umbilical cord blood sampling), or intrauterine transfusion. The absolute risk is small with all of these procedures: IAI develops in 2% to 8% of patients after ~erclage,".'~in less than 1% of patients after amnio~entesis,'~ and in 5% of patients after intrauterine transfusion." Higher risks are encountered, however, when cerclage is performed when the cervix is dilated and effaced. Two large studies of risk factors for IAI identified characteristics of labor as the major risk factors by logistic regression analysis. These features included low parity, increased number of vaginal examinations in labor, as well as increased duration of labor, membrane rupture, and internal fetal monitoring.3s4More recently, risk factors for IAI have been stratified for term versus preterm pregnan~ies.'~ For patients at term with IAI, the study investigators observed, by logistic regression analysis, that the independent risk factors were membrane rupture for longer than 12 hours (odds ratio [OR] 5.81), internal fetal monitoring (OR 2.01), and more than four vaginal examinations in labor (OR 3.07). For preterm pregnancies, these three risk factors were again identified as being independently associated with IAI, but with differing ORs. Specifically, in the preterm pregnancies, membrane rupture for longer than 12 hours was associated

The cause of IAI is often polymicrobial. Gibbs and colleagues reported a microbiologic case-control study of amniotic fluid from 52 patients with clinical IAI.27 The following organisms were found in the amniotic fluid from patients with IAI: Bacteroides species, 25%; group B streptococci, 12%; other aerobic streptococci, 13%; Escherichia coli, 10%; other aerobic gram-negative rods, 10%; Clostridium species, 9%;Peptococcus species, 7%; and Fusobacterium species, 6%. The mean number of bacterial isolates in patients with IAI was 2.2. For the 52 patients with clinical IAI, aerobes and anaerobes were isolated from 48%; aerobes only from 38%; anaerobes alone from 8%; and no aerobes or anaerobes from 6%. Cultures of amniotic fluid from patients with IAI were more likely to have more than lo2colony-forming units (CFUs) of any isolate per milliliter, any number of high-virulence isolates, and more than 10' CFUs/mL of high-virulence isolates. Only 8% of these cultures from control patients had lo2CFUs/mL or more of high-virulence isolates. The isolation rate of low-virulence organisms, such as lactobacilli, diphtheroids, and Staphylococcus epidermidis, was similar in both the IAI and the control groups. In smaller studies, a similar spectrum of organisms was reported.'3728 Neisseria gonorrhoeae was not isolated in any of these studies, but it appears to be an infrequent cause of a m n i o n i t i ~ . ~ ~ ' ~ ~ A role for genital mycoplasmas has been suggested by case reports describing their isolation from amniotic fluid of clinically infected patients and by epidemiologic studies showing an association between the isolation of Mycoplasma hominis or Ureaplasma and placental inflammation.31932 Unfortunately, these latter studies did not demonstrate correlation of isolation of genital mycoplasmas with clinical infection in the mother or neonate. In a controlled study of

Chapter 3

Obstetric Factors Associated with Infections in the Fetus and Newborn Infant

IAI, Blanco and co-workers reported that 35% of cultures of amniotic fluid from patients with IAI yielded M. horninis, whereas only 8% of matched control cultures showed M. horninis (P < .001).33 Ureaplasrna urealyticurn was isolated from amniotic fluid from 50% of the infected and uninfected patients. In a subsequent study, Gibbs and colleagues found M. horninis in the blood of 2% of women with IAI and reported a serologic response in 85% of women with IAI who also had M. hominis in the amniotic This rate of serologic response was significantly higher than that in asymptomatic control women or in infected women without M. horninis in the amniotic fluid (P < .001).34Cultures of blood and serologic results did not clarify the role of U. urealyticurn.Thus, the pathogenic potential of M. horninis is high in IAI,but the pathogenic status of U. urealyticum is unclear in this infection. Data related to the role of Chlamydia trachornatis in infections of amniotic fluid are in conflict. Martin and coworkers prospectively studied perinatal mortality in women whose pregnancies were complicated by antepartum maternal chlamydia1 infection^.^^ Two of the six fetal deaths in the Chlamydia-positive group were associated with chorioamnionitis compared with one of eight in the control group. Wager and colleagues showed that the rate of occurrence of intrapartum fever was higher in patients with antepartum C. trachornatis infection (9%) than in patients without C. trachornatis isolated from the cervix ( l%).36 The data are interesting but must be interpreted with caution because of the limited number of patients and because the control group may not have been sufficiently similar to the infected group. Furthermore, C. trachomatis has not been isolated from amniotic cells or placental membranes of patients with In a preliminary study, no difference was found in the rate of serologic response to C. trachornatis in women with IAI compared with that in asymptomatic women.39 In a large prospective study, Sperling and colleagues reported amniotic fluid culture results from 408 cases of IAI.

Table 3-2

61

The most commonly isolated organisms were U.urealyticum (47%), M. horninis (310/0),Prevotella bivia (29%),Gardnerella vaginalis (24%), group B streptococci (15%), anaerobic streptococci (9%), E. coli (8%), Fusobacteriurn species (6%), enterococci (5%), and other aerobic gram-negative rods (5?40).~’ A summary of representative data for five microbiologic studies is given in Table 3-1. Because of differences among these studies in microbiologic and collection techniques and in reporting format for isolates, Table 3-2 is meant to show broad, overall results. Evidence has shown that maternal bacterial vaginosis is causally linked to IAI!’ The evidence may be categorized as follows: (1) the microorganisms in bacterial vaginosis and in chorioamnionitis are similar; (2) bacterial vaginosis is

Table 3-1

Microbes Isolated in Amniotic Fluid from Cases of Intra-amniotic Infection: A Summary of Studies Representative % Isolated

Microbe Genital Mycoplasmas Ureaplasma urealyticum Mycoplasma hominis Anaerobes Prevotella bivia Peptostreptococcus Fusobacterium species Aerobes Group B streptococci Enterococci Escherichia coli Other aerobic gram-negative rods Gardnerella vaginalis

47-50 3 1-35 11-29 7-33 6-7 12-19 5-11 8-12,55 5-10 24

Data from references 13, 27, 28, 33, and 40. See text.

Comparative Studies of lntrapartum versus Postpartum Maternal Antibiotic Therapy in Treatment of Intra-amnioticInfection

Author, Year

Design/Setting

No. of Patients

Sperling et al,” 1987

Retrospective/pubicteaching hospital in San Antonio, Texas

257

Gilstrap et al,751988

Retrospective/public teaching hospital in Dallas, Texas

273

Gibbs et al,741988

Randomized clinical trial/ same as Sperling (1987)

45

Maternal lntrapartum Antibiotic Regimen

Benefits of lntrapartum Treatment

Penicillin G plus gentamicin IV

NNS reduced from 19.6%

Varied”

Ampicillin plus gentamicin IV

in postpartum treatment group t o 2.8% in intraDartum treatment group (P = .OOI) NNS reduced from 5.7% in postpartum treatment qroup t o 1.5% in inntrapartum treatment group (P= ,061;group B streptococcal bacteremia reduced from 5.7% t o 0% (P = .004) NNS reduced from 21% to 0%; maternal morbidity also decreased ( P = .05) ~~

”Antibiotic regimens noted as 47% received ampicillin or penicillin in combination with gentamicin and clindamycin; 22%. ampicillin or penicillin with gentamicin; 20%. cefoxitin; and 11 %, other antibiotics. IV, intravenously; NNS, neonatal sepsis confirmed by blood culture.

62

Section I

General Information

associated with the isolation of organisms in the chorioamnion; and (3) bacterial vaginosis is associated with development of clinical chorioamnionitis in selected populations.424 It has been demonstrated that treatment of bacterial vaginosis in high risk populations prenatally decreases the risk of chorioamnionitis and other pregnancy 0utcomes.4~However, in the large Maternal Fetal Medicine Units Network trial, screening and treatment did not lead to benefit either in the overall patient population or in the secondary analysis of women with prior preterm Subsequently, an American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin on assessment of risk factors for preterm birth advocated that screening and treating of either high- or low-risk women would not be expected to reduce the overall rate of preterm birth.49However, in select populations of high-risk women such as those with prior preterm birth and bacterial vaginosis early in pregnancy, we still recommend treatment of those women. Amniotic fluid cultures from cases of intra-amniotic infection accompanying a low-birth-weight infant are more likely to contain the anaerobic organism Fusobacterium (21.6% versus only 3.8% in non-low-birth-weight cases, P < .001) and J? bivia (46% versus 28%, P = .035). There were no significant differences, however, in the isolation rates of group B streptococci, E. coli, other aerobes, or genital mycoplasmas between cases from low-birth-weight and non-low-birth-weight infants.40 Bloodstream isolates from newborns in 408 cases of IAI were reported as follows: E. coli, 5 cases; group B streptococci, 4 cases; Staphylococcus aureus, 2 cases; enterococci, 2 cases; other streptococci, 3 cases; and 1 case each for Enterobacter species, Haernophilus influenzae, Haemophilus parainflueme, and microaerophilic streptoco~ci.~~ Thus, of 20 isolates, group B streptococci and E. coli accounted for 45% of isolates, even though these organisms were present in the amniotic fluid of just 20% of cases. The role of viruses in causing IAI is less well delineated. Yankowitz and associates evaluated fluid from 77 midtrimester genetic amniocentesis by polymerase chain reaction (PCR) assay for the presence of adenovirus, enterovirus, respiratory syncytial virus (RSV), Epstein-Barr virus (EBV), parvovirus, cytomegalovirus (CMV), and herpes simplex virus (HSV). Six samples were positive (three adenovirus, one parvovirus, one CMV, and one enterovirus), and two resulted in pregnancy loss, one at 2 1weeks (adenovirus) and one at 26 weeks (CMV).50

Diagnosis Diagnosis of IAI requires a high index of suspicion because the clinical signs and symptoms may be subtle. Moreover, usual laboratory indicators of infection, such as positive stains for organisms or leukocytes and positive culture results, are found more frequently than is clinically evident infection. Microorganisms are easily grown in culture from the amniotic fluid or chorioamniotic membranes using standard techniques. Cassell and colleagues demonstrated positive cultures from the chorioamniotic space twice as frequently as from the intra-amniotic space (20% versus 9%), lending further support to the theory that microorganisms ascend from the vagina through the chorioamniotic space to gain access to the amniotic cavity and then the fetus.5'

The rate of positive amniotic fluid cultures for microorganisms is higher with preterm PROM (32.4%) than with preterm labor with intact membranes ( 12.8%).52 Rates of IAI are probably underestimated with preterm PROM, because severe oligohydramnios may preclude sampling success. Additionally, women in labor on hospital admission generally are not sampled but have been shown to have higher rates of microbial invasion of the amniotic cavity at (39%) than those in women not in labor (25%). When they do enter labor, the risk of microbial invasion of the amniotic cavity is still higher at 75Y0.~~ Clinical diagnosis of IAI usually is based on maternal fever, maternal or fetal tachycardia, uterine tenderness, foul odor of amniotic fluid, and leukocytosis. Other causes of fever in the parturient patient include epidural analgesia, concurrent infection of the urinary tract or other organ systems and perhaps dehydration, illicit drug use and other rare conditions. The differential diagnosis of fetal tachycardia consists of prematurity, medications, arrhythmias, and hypoxia, whereas for maternal tachycardia other possible causes are drugs, hypotension, dehydration, and anxiety as well as intrinsic cardiac conditions, hypothyroidism, as well as pulmonary embolism. In general, the most common clinical and laboratory criteria for diagnosis of IAI are fever, leukocytosis, and ruptured membranes; fetal tachycardia and maternal tachycardia are noted in a variable percentage of Foul-smelling amniotic fluid and uterine tenderness, although more specific signs, occur in a minority of the cases. Bacteremia occurs in less than 10% of cases. Because peripheral blood leukocytosis is common during normal labor, this result does not always indicate infection. As a predictor of IAI, leukocytosis (white blood cell counts greater than 12,000/mm3)had a sensitivity of 67%, specificity of 86%, positive predictive value of 82%, and negative predictive value of 72'%0.~~ Direct examination of the amniotic fluid may provide important diagnostic information. Samples can be collected transvaginally by aspiration of an intrauterine pressure catheter, by needle aspiration of the forewaters, or by amniocentesis. Outside of research protocols, transabdominal amniocentesis is the most common technique. There is a significant association between detecting white blood cells or bacteria in a stain of uncentrifuged amniotic fluid and clinical In a case-control study, white blood cells were seen on smear in 67% of cases of IAI and in only 12% of controls ( P = .001). Bacteria were seen on smear in 81% of cases of IAI and in 29% of controls ( P < .001).27 With suspected IAI, detection of bacteria or white blood cells on a smear of uncentrifuged fluid supports the diagnosis, but there are frequent false-positive and falsenegative results. Several other recent tests of amniotic fluid have been evaluated as predictors of IAI. In a small case-control study, Hoskins and co-workers found that the leukocyte esterase test showed excellent performance (91% sensitivity, 95% specificity, and 95% positive and 91% negative predictive values) when the clinical diagnosis of chorioamnionitis was used as the gold standard.54 Low concentrations of amniotic fluid glucose (variably reported at less than 10 to 20 mg/dL) are strongly associated with positive amniotic fluid culture and less strongly associated with clinical I A I . ~ ~ - ~ ~

Chapter 3


63

comes, including maternal sepsis, neonatal sepsis, pneumonia, Recently, attention has been directed to proinflammatory meningitis, and perinatal death. This section discusses the cytokines as markers of IAI. During the course of intramanagement principles of these short-term outcomes. uterine infection, bacteria reach the decidua, stimulating a In the past, there was debate regarding timing of antimaternal inflammatory response. Once bacteria gain access biotic administration, but it has now become standard to to the amniotic cavity and the fetus, the fetal inflammatory begin treatment during labor, as soon as possible after the response can be activated. maternal diagnosis of IAI is made. Three studies, including a Interleukin-6 (IL-6) is an immunostimdatory cytokine randomized clinical trial, have demonstrated benefits from and a key mediator of fetal host response to infection. Several intrapartum antibiotic therapy compared with immediate lines of investigation indicate that IL-6 may be the future postpartum treatment (see Table 3-2).73-75 In a large, nondiagnostic test of choice. For example, elevated levels of IL-6 randomized allocation of intrapartum versus immediate in the amniotic fluid have been a more sensitive rapid test postpartum treatment, the former treatment was associated for the detection of microbial invasion of the amniotic cavity with a significant decrease in neonatal bacteremia (2.8% than amniotic fluid glucose, amniotic fluid Gram stain, or versus 19.6%; P < .001) and a reduction in neonatal death amniotic fluid white blood cell count. Amniotic fluid IL-6 from sepsis (0.9% versus 4.3%; P = .07).73Another large study levels have also been shown to be increased with positive cultures of either the amniotic fluid or the amnio~horion.~~showed an overall reduction in neonatal sepsis (P = .06), especially bacteremia due to group B streptococci (0% versus Elevation of IL-6 levels in the amniotic fluid also is a very 4.7%; P = .004), with use of intrapartum treatment.75Then, sensitive indicator of acute histologic chorioamnionitis and in a randomized clinical trial, Gibbs and associates demonthe identification of neonates at risk for significant morbidity strated that intrapartum treatment provided both maternal and mortality.60Maternal serum IL-6 levels also have been benefits (decreased hospital stay, lower mean temperature reported to be elevated when preterm labor is associated post partum) and neonatal benefits (decrease in sepsis: with intrauterine infection.6l Finally, fetal production of 0% versus 21%, P = .03, and decreased hospital stay). In this IL-6 (as determined by cordocentesis) is an independent risk study, neonatal treatment was identical and consisted of factor for the occurrence of severe neonatal morbidity, intravenous ampicillin and gentamicin begun within 1 to including sepsis and p n e ~ m o n i a . 6Additional ~~~~ areas of 2 hours of birth and continued for at least 72 hours. If research currently include cervicovaginal production of bacteremia or neonatal pneumonia was diagnosed, anticytokines. biotics were continued for 10 days.74 PCR, a molecular biologic technique that amplifies the Pharmacokinetic studies76done during early pregnancy signal of small amounts of DNA, is likely to change the show that ampicillin concentrations in maternal and fetal future of diagnosis of IN. Several studies have evaluated sera are comparable 60 to 90 minutes after administration amniotic fluid samples using PCR techniques. PCR assay has (Fig. 3-2). Penicillin G levels in fetal serum are one third of a higher sensitivity than that of culture for detection of the maternal levels 120 minutes after admini~tration.~~ In microorganisms in the amniotic fluid, particularly in patients addition, ampicillin has some activity against E. coli. whose amniotic fluid is culture negative but other markers Accordingly, ampicillin is preferable to penicillin G for treatindicate evidence of an inflammatory r e ~ p o n s e . ~ ~ ' " - ~ ~ ment of IAI. When used in combination with an aminoChronic Intra-amniotic Infection glycoside, ampicillin should be administered first, because it has the broader antimicrobial spectrum. In late pregnancy, Increasing evidence is accumulating to suggest that MI also gentamicin also crosses the placenta rapidly, but peak fetal may exist as a chronic condition. Several studies have perlevels may be low, especially if maternal levels are subformed microbiologic studies of midtrimester genetic amniot h e r a p e ~ t i c An . ~ ~initial gentamicin dose of at least 1.5 to centesis fluid. Risk of adverse pregnancy outcome is increased 2.0mg/kg followed by 1.0 to 1.5mg/kg every 8 hours is when patients are asymptomatic but have positive results on indicated because of the potential for unfavorable gentamicin such studies at midtrimester amniocentesis, compared with kinetics. As an alternative, a newer penicillin or cephalosporin patients with culture-negative Similarly, amniotic with excellent activity against aerobic gram-negative bacteria fluid IL-6 concentrations were found to be significantly might be used. However, there is little published experience higher in patients experiencing a loss following midtrimester with these other antibiotics in IAI. Levels of ampicillin and amniocentesis than in those patients delivering at aminoglycosides in amniotic fluid usually are below fetal Emerging evidence also suggests that chronic inflammation serum levels, and peak concentrations in amniotic fluid may may also be present in maternal serum. Goldenberg and ~ . ~ kinetics ' of newer be attained only after 2 to 6 h o ~ r s . ~ The colleagues recently showed elevated granulocyte colonypenicillin and cephamycin antibiotics have not been studied stimulating factor (G-CSF) at 24 and 28 weeks in women extensively in pregnancy. subsequently delivering premat~rely.~' The duration of maternal treatment post partum in cases These data then beg the question of whether infection of chorioamnionitis is debatable. One randomized trial could be present before conception. The documented compared single-dose versus multidose postpartum treatment increased risk of recurrent preterm birth would lend of mothers and reported that single-dose treatment was credence to this hypothesis, but studies have not yet proved accompanied by a shorter time to discharge (33 hours in the this hypothe~is.'~,~~ single-dose group versus 57 hours in the multidose group; P = .001).79However, the single-dose group had a nearly Management and Short-Term Outcome threefold increase in failure of therapy, but this did not achieve statistical significance (1 1% in the single-dose treatTraditionally, the effectiveness of management has been ment group versus 3.7% in the multidose group; P = .27). viewed in terms of short-term maternal and neonatal out-

64

Section I

General Information

Maternal serum Fetal serum Amniotic fluid

A-----~

Figure 3-2 Ampicillin

-

levels achieved with systemic

administration to the mother. (From Bray RE, Boe RW, Johnson WL. Transfer of ampicillin into fetus and amniotic fluid from maternal plasma in late pregnancy. Am J Obstet -

Time after administration ( h r l

Gynecol 96:938, 1966.)

37.7 weeks. There were no maternal deaths, and bacteremia Turnquist and associates also studied postpartum antibiotic was found in only 2.3% of mothers. Among women with therapy given when IAI was present, but only when cesarean IAI, the rate of cesarean delivery was increased approxisection was performed. All patients received one dose of premately threefold to 35%, mainly because of dystocia. In all operative intravenous gentamicin and clindamycin. Patients mothers the outcome was good. There was only one episode were then randomized to receive no further antibiotics or to of septic shock, with no pelvic abscesses or maternal deaths. continue clindamycin plus gentamicin and had received Similar results were reported from Los Angeles County ampicillin intravenously every 6 hours after a diagnosis of H0spital.4~ IAI was made. Our preference is to administer antibiotics for Gibbs and colleagues found that when IAI is present, the 24 hours or more after resolution of fever. perinatal mortality rate (140 per 1000 births) was approxiWith regard to timing of delivery, short-term outcome is excellent without the use of arbitrary time limits.'380781 mately seven times the overall perinatal mortality rate for infants weighing more than 499 g (which was 18.2 per 1000 Cesarean delivery usually is reserved for standard obstetric birth^).^ Yet none of the perinatal deaths was clearly indications, not for IAI itself. In nearly all cases, delivery attributable to infection; of live-born infants weighing more occurred within 8 hours after diagnosis of IAI (mean than 1000 g, none died of infection. In the study by Koh and interval was 3 to 5 hours). No critical interval from diagnosis co-workers, the perinatal mortality rate was lower (28.1 per of amnionitis to delivery could be identified. Yet nearly in all 1000 births), which probably reflected the higher mean of these cases the pregnancy was at or near term. Rates of gestational age (39.3 weeks)!5 There were no intrapartum cesarean section are two to three times higher among fetal deaths and only four neonatal deaths. Again, no deaths patients with IAI than in the general population, owing to were due to infection. Neither perinatal nor maternal patient selection (most cases occur in women with dystocia already diagnosed) and a poor response to o ~ y t o c i n . ~ ' , ~ ~complications correlated with more prolonged diagnosis-todelivery intervals. Because patients who underwent cesarean There is no demonstrated advantage of the extraperitoneal section had more complicated courses, it was concluded that caesarean technique over the transperitoneal technique in cesarean section should be reserved for patients with decreasing maternal complications of IAI.84-87 standard obstetric indications for this procedure in addition In the past, we used a combination of an intravenous to IAI. penicillin and intravenous gentamicin as soon as the diagYoder and colleagues later provided a prospective, casenosis was made and cultures had been obtained.'T46Several control study of 67 neonates with microbiologically confirmed studies have reported good results with similar regimens." IAIat term.46There was only one perinatal death, which was When a cesarean section is necessary, clindamycin should be unrelated to infection. Cerebrospinal fluid culture results added post partum to these antibiotics because of the were negative for all 49 infants tested, and there was no importance of anaerobes in post-cesarean section infection clinical evidence of meningitis. Findings on chest radioand the high failure rate (20%) with therapy with penicillingraphs were interpreted as possible pneumonia in 20% of gentamicin after cesarean section for IAI.4 Other initial patients and as unequivocal pneumonia in only 4%. regimens with cefoxitin alone or ampicillin plus a newer Neonatal bacteremia was documented in 8%. There was no cephalosporin may be equally effective, but no comparative significant difference in the frequency of low Apgar scores trials have been performed. between the IAI and control groups. Since 1979, retrospective studies have shown a vastly Two other retrospective studies have been confirmatory. improved perinatal outcome compared with that reported in In 1984, Looff and Hager reported the outcomes of 104 earlier studies. Gibbs and colleagues reported a retrospective pregnancies with clinical chorioamnionitis.80 The mean study of 171 patients with IAI in whom therapy (with gestational age was 36 weeks. The perinatal mortality rate penicillin G and kanamycin) usually was begun at the time was 123 per 1000 births. Nearly all of the excess mortality of diagnosis? The mean gestational age of the neonate was

Chapter 3 Table 3-3


65

Perinatal Outcome in Preterm Amnionitis (Intra-amniotic Infection) Amnionitis'

Measure (%) Perinatal death

Respiratory distress syndrome Total infections lntraventricular hemorrhage

Referencees (N = 47)

Controla

Referencem (N = 92)

Referencees (N = 204)

13 34 17

25 62 28

NR

56

3b 16b 7b NR~

Referenceas (N = 606) 6b 3 5b 1l b 22b

aAt centers reporting these results, there were active referral services. In these series of consecutive patients with preterm premature rupture of membranes, those with amnionitis are compared with those without.

bRates are significantly lower than for amnionitis group in corresponding study.

NR, not

reported

was attributed to prematurity rather than to sepsis. These authors also reported an increase in the cesarean delivery rate (26%). In 1985, Hauth and co-workers reviewed data for 103 pregnancies with clinical chorioamnionitis at term." The mean interval from diagnosis of amnionitis to delivery was 3.1 hours, which confirmed the absence of a critical interval for delivery. In this study, the overall perinatal mortality rate was 9.7 per 1000 births and the cesarean delivery rate was 42%. Neonates born prematurely have a higher frequency of complications if their mothers have MI. Garite and Freeman noted that the perinatal death rate was significantlyhigher in 47 preterm neonates with IAI than in 204 neonates with similar birth weights but without IN.'' The group with IAI also had a significantly higher percentage (13% versus 3%; P < .05) with RDS and total infection. A larger but similar comparative study of 92 patients with chorioamnionitis and 606 controls of similar gestational age also demonstrated significant increases in mortality, RDS, intraventricular hemorrhage (IVH), and clinically diagnosed sepsis in the group with chorioamnionitis (Table 3-3).89When Sperling and associates stratified outcomes in cases of IAI by birth weight, cases leading to low birth weight were associated with more frequent maternal bacteremia (13.5% versus 4.9%; P = .06), early-onset neonatal sepsis (16.2% versus 4.1%; P = .005), and neonatal death from sepsis (10.8% versus 0; P < .001).40 In a retrospective, case-control study, Ferguson and coworkers reported neonatal outcome after chorioamnionitis.gO Seventy percent of newborns weighed less than 2500 g. In 116 matched pairs, the authors found more deaths (20% versus 1 l%), more sepsis (6% versus 2%), and more asphyxia (27% versus 16%) in the group with chorioamnionitis. None of these differences, however, achieved statistical significance. Choriamnionitis has been previously a maternal infection. Increasing evidence indicates that the fetus is primarily involved in the inflammatory response leading to premature delivery. The fetal inflammatory response syndrome (FIRS), well described by Yoon and co-authors, characterizes preterm PROM and spontaneous preterm labor, with a systemic proinflammatory cytokine response resulting in earlier delivery and with an increased risk of complications?' Additionally, these investigators show an association between the fetal inflammatory cascade and fetal white matter damage.92It remains unclear, however, whether cytokines mediate this damage or directly cause the damage, or if infection itself is

responsible for the damage. Cytokines also can be stimulated by a number of noninfectious insults such as hypoxia, reperfusion injury, and toxins.93

Long-Term Outcome Hardt and colleagues studied long-term outcomes in preterm infants (weighing less than 2000 g) born after a pregnancy with chorioamnionitis and found a significantlylower mental development index (Bayley's score) for these infants than noted for preterm control infants (104 f 18 versus 112 14; P = .017).94Morales reported 1-year follow-up of preterm infants born after pregancy with chorioamnionitis and of control infants. He did not observe differences in mental and physical development, but adjustments were made for IVH and RDS, both of which were more frequent in the amnionitis group.89 Intriguing new information strongly suggests that intrauterine exposure to bacteria is associated with long-term serious neonatal complications, including cerebral palsy or its histologic precursor, periventricular leukomalacia ( P n ) , as well as major pulmonary problems of bronchopulmonary dysplasia (BPD) and RDS. The unifying hypothesis states that intrauterine exposure of the fetus to infection leads to abnormal fetal production of proinflammatory cytokines. This leads in turn to fetal cellular damage in the brain, lung, and potentially other organs. This FIRS has been likened to the systemic inflammatory response syndrome (SIRS) in adults. The evidence linking infection to cerebral palsy may be summarized as follows:

+

1. Intrauterine exposure to maternal or placental infection is associated with an increased risk of cerebral palsy both in preterm and term infants.95s96 2. Clinical chorioamnionitis in very low birth weight infants is significantly associated with an increase in PVL (P = .oo1).97 3. The levels of inflammatory cytokines are increased in the amniotic fluid of infants with white matter lesions (PVL), and there is overexpression of these cytokines in neonatal brain with PVL.98 4. Experimental intrauterine infection in rabbits leads to brain white matter lesions.99 5. Marked inflammation of the fetal side of the placenta is associated with adverse neurologic outcomes. Coexisting evidence of infection and thrombosis, particularly on the

66

Section I

General Information

fetal side of the placenta, is associated with a heightened risk of cerebral palsy or neurologic impairment in term and preterm infants. Additionally, histologic funisitis is associated with an increased risk of subsequent cerebral palsy (OR 5.5, 95% confidence interval [CI] 1.2 to 24.5).97,’w*’0’ This risk underscores the importance of sending placentas for gross and microscopic examination in the setting of IAI. The association between IAI and cerebral palsy differs for the term infant and the preterm infant. A recent review article nicely outlines the controversies in this area, including the associations among microbiologic, clinical, and histologic chorioamnionitis. lo’ Additionally, emerging evidence points to genetic predispositions to inflammation and thrombosis; cytokine polymorphisms also may be linked to cerebral ~alsy.9~ In addition to cellular and tissue damage in the fetal brain, an overexuberant cytokine response induced by bacteria may damage other fetal tissues, such as the lung, contributing to RDS and BPD.lo3In support of this hypothesis, a case-control study of infants with and without RDS was conducted. Those with RDS were signhcantly more likely to have elevated levels of amniotic fluid tumor necrosis factor (TNF)-a, a positive culture of the amniotic fluid, and severe histologic chorioamnionitis ( P < .05 for each association). Elevated amniotic fluid IL-6 levels were also twice as common in the group with RDS, but this association did not achieve statistical significance. Furthermore, preterm fetuses with elevated cord blood IL-6 concentrations (greater than 11 pglmL) were more likely to develop RDS (64% versus 24%; P < .005) than were those without elevated cord IL-6 levels. Rates of occurrence of BPD also were increased (11% versus 5%), but the observed difference was not statistically significant.62Curley and associates found elevated matrix metalloproteinase-9 (MMP-9) concentration in bronchoalveolar lavage fluid in preterm neonates with pregnancies complicated by chorioamnionitis compared with agematched uninfected controls. These investigators hypothesize that increased MMP levels in the lung cause destruction of the extracellular matrix, breaking down type IV collagen in the basement membrane and leading to the failure of alveolarization and to fibrosis components of chronic lung disease.’” More recently, genetic predisposition toward exuberant host response to tissue injury has been described. Proinflammatory cytokine polymorphisms such as TNF-a 308 relate to bacterial endotoxin and an increased risk of preterm delivery.’05-’07 In summary, IAI has a significant adverse effect on mother and neonate, but vigorous antibiotic therapy and reasonably prompt delivery result in an excellent short-term prognosis, especially for the mother and the term neonate. With the combination of prematurity and amnionitis, serious sequelae are more likely for the neonate. Newly developing information suggests that intrauterine infection is linked to major neonatal long-term complications. A complex interplay of cytokine genotype may contribute to long-term complications as well. Conclusion The unanswered question remains: Why does IAI develop in some patients and not in others? Investigations of maternal and fetal genotypes for pro-inflammatory markers, among

Table 3-4

Proposed Prevention Strategies for Clinical Intra-amniotic Infection

Prompt management of dystocia Induction of labor with premature rupture of membranes a t term Antibiotic prophylaxis with preterm premature rupture of membranes Antibiotic prophylaxis with preterm labor, but with intact membranes Antibiotic prophylaxis for group B streptococcal infection Prenatal treatment of bacterial vaginosis Chlorhexidine vaginal irrigations in labor Infection control measures

others, as well as study of mucosal immunity and host response, may help to answer this important question, as well as clarifymg when neonatal damage will occur. It is not until we understand the answers to these questions that satisfactory therapeutic approaches can be developed.

Prevention As categorized in Table 3-4, numerous approaches have been proposed for the prevention of IAI. Among these, prompt management of dystocia has been shown to decrease chorioamnionitis, as well as to shorten labor and reduce the cesarean section rate.”* Similarly, induction in women with PROM at term most likely results in fewer maternal infections than may occur with expectant management.”’ Antibiotic prophylaxis for patients with preterm PROM decreases chorioamnionitis as well as other complications.”0*’I ’ Treatment for bacterial vaginosis in high-risk women decreases incidence of preterm birth. Antibiotic prophylaxis for patients in preterm labor (but with intact membranes) does not appear to decrease frequency of chorioamnionitis.”’ Intrapartum prophylaxis for the prevention of neonatal group B streptococcal sepsis is now a national standard in known group B streptococci-colonized parturients or those in at-risk categories. It is presumed that this approach also decreases chorioamnionitis, but there are no definitive data to support this. Prenatal treatment of bacterial vaginosis in low-risk women, chlorhexidine vaginal washes in labor, and specific infection control measures have not been demonstrated to be e f f e c t i ~ e . ’ ~ ~ ” ~ - ” ~

INFECTION AS A CAUSE OF PRETERM BIRTH Preterm birth is the leading perinatal problem in the United States. Infants born before week 37 of gestation account for approximately 11% of births but for 60% to 80% of all perinatal In most cases, the underlying cause of premature labor is not evident. Evidence from many sources points to a relationship between preterm birth and genitourinary tract infections (Table 3-5).1’9,120 Infection leading to preterm birth may arise in the lower genital tract, the urinary tract, or a more remote site such as the lung or periodontal tissues.

Chapter 3

Table 3-5


67

Evidence for Relationship between Preterm Births and Subclinical GenitourinaryTract Infection

The incidence of histologic chorioamnionitis is increased after preterm birth. The incidence of clinical infection is increased after preterm birth in both mother and neonate. Some lower genital tract microbes or infections are

associated with an increased risk of preterm birth. There are biochemical mechanisms linking prematurity and infection. Infection and inflammation cause cytokine release and prostaglandin production. Bacteria and bacterial products induce preterm delivery in

animal models.

Amniotic fluid tests for bacteria are positive in some patients in premature labor. Some antibiotic trials have shown a decrease in numbers of preterm births.

Histologic Chorioamnionitis and Prematurity Over the past 3 decades, one of the most consistent observations is that placentas in premature births are more likely to demonstrate evidence of inflammation (i.e., histologic chorioamnionitis) (Fig. 3-3). In a series of 3500 consecutive placentas, Driscoll found infiltrates of polymorphonuclear cells in 1 Clinicallyevident infection developed in only a few of the women in this study, but the likelihood of neonatal sepsis and death was i n~re a se d.'~~ An association has been established between histologic chorioamnionitis and chorioamnion infection (defined as a positive ~ulture)."~ Odds ratios (ORs) have been reported from 2.8 to 14, this relationship being stronger among preterm deliveries than among term deliveries. Overall, the organisms found in the chorioamnion are similar to those found in the amniotic fluid in cases of clinical IAI. This array of organisms supports an ascending route for chorioamnion infection in most cases. Although it is not certain how histologic chorioamnionitis and membrane infection cause preterm delivery or preterm PROM, studies suggest that they lead to weakening of the membranes (as evidenced by lower bursting tension, less work to rupture, and less elasticity124in vitro) and to production of prostaglandins by the a m n i ~ n . ' ~ ~ , ' ~ ~

Clinical Infection and Prematurity Both premature infants and women who previously gave birth to premature infants are more likely to develop clinically evident i nfe ~t i0n.I~~ In a large study of more than 9500 deliveries, confirmatory evidence has shown that chorioamnionitis, endometritis, and neonatal infection all were significantly increased in preterm pregnancies, even after correcting for the presence of PROM.Iz8These observations suggest that subclinical infection led to the labor and that infection became clinically evident after delivery. Some investigators argue that there is no causal relationship but that infection develops more frequently in premature infants because, for example, they are compromised hosts or because they have more invasive monitoring in the nursery.

Figure 3-3 Infiltrates of polymorphonuclear cells are seen in the fetal membranes. Inflammation of the placenta and membranes has been consistently observed more often after preterm births than after term births.

Association of Lower Genital Tract Organisms or Infections with Prematurity Premature birth has been associated with isolation of several organisms from the maternal lower genital tract and with subclinical infections, as listed in Table 3-6. Lower genital tract colonization with U.urealyticum is not associated with preterm birth. Similarly,cervical infection with C. trachomatis is not associated with preterm birth. However, other lower genital tract or urinary infections, including those due to N. gonorrhoeae and Trichomonas vaginalis and bacteriuria, are associated with preterm birth. Bacterial vaginosis, characterizedby high concentrations of anaerobes, Gardnerella vaginalis, and genital mycoplasmas, with a corresponding decrease in the normal vaginal lactobacilli, has been consistently associated with premature birth. Maternal genital tract colonization with group B streptococci may lead to neonatal sepsis, especially when birth occurs prematurely or when the membranes have been ruptured for prolonged intervals. In addition, an association between colonization of the cervix with these organisms and premature birth has been found by Regan and c o - ~ o r k e r s . ' ~ ~ These investigators noted delivery at less than 32 weeks in 1.8% of the total population but in 5.4% of women colonized with group B streptococci ( P < .005).PROM also occurred significantly more often in the colonized group

68

Section I

Table 3-6

General Information

Association of Lower Genitourinary Tract Infections with Preterm Birth Odds Ratio for Preterm Birth confidence interval)

Infection

(95%

Ureaplasma urealyticum Chlamydia trachomatis Neisseria gonorrhoeae Trichomonas vaginalis Bacterial vaginosis Bacteriuria

1.O (0.8-1.2)" 0.7 (0.36-1 .37)b'' 5.31 (1.57-17.9)d 1.3 (1.1-1.4)e 2.19 (1.54-3.12)' 1.64 (1.35-1.78)'

aDatafrom Carey JC, Blackwelder WC, Nugent RP, et al. Antepartum cultures for Ureaplasma urealflicum are not useful in predicting pregnancy outcome. Am J Obstet Gynecol 1991; 1641728. bData from Sweet RL, Landers DV, Walker C, et al. Chlamydia trachomatis infection and pregnancy outcome. Am J Obstet Gynecol 156:824, 1987. 'Data from Harrison HR, Alexander ER, Weinstein L, et al. Cervical Chlamydia trachomatis and mycoplasmal infections in pregnancy. JAMA 250: 172 1, 1983. dData from Elliott B, Brunham RC, Laga M, et at. Maternal gonococcal infection as a preventable risk factor for low birth weight. J Infect Dis 161:531, 1990. eData from Cotch MF, Pastorek JG, Nugent RP, et al. Trichomonas VJghJh5 associated with low birth weight and preterm delivery. Sex Transm Dis 24:353, 1997. 'Data from Leitich H, Bodner-Adler B, Brunbauer M, et al. Bacterial vaginosis as a risk factor for preterm delivery: a meta-analysis. Am J Obstet Gynecol 189:139, 2003. gRomero R, Oyarzun E, Mazor M, et al. Meta-analysis of the relationship between asymptomatic bacteriuria and preterm delivery/low birth weight. Obstet Gynecol 73:567, 1989.

(15.3% versus 8.1%; P < .005). Of six studies evaluating the association between group B streptococci genital colonization and preterm labor or delivery, five found no association.12' In contrast with the conflicting data regarding group B streptococcal genital colonization, group B streptococcal bacteriuria has been consistently associated with preterm delivery, and treatment of this bacteriuria resulted in a marked reduction in prematurity (37.5% in the placebo '~~ group versus 5.4% in the treatment g r o ~ p ) . ' ~ ' -Current recommendations for prevention of perinatal group B streptococcal infection from the Centers for Disease Control and Prevention (CDC) are for intrapartum treatment only, with the exception of group B streptococcal bacteriuria, which should be treated antepartum. The CDC recommend adoption of universal screening. The universal screening approach involves screening women at 35 to 37 weeks of gestation with proper coUection and culture techniques, followed by intrapartum treatment for all women with positive Untreated acute pyelonephritis has been found to be consistently associated with a 30% risk of preterm labor and delivery. A m e t a-a na l y~i sl~~ showed that women with asymptomatic bacteriuria had a 60% higher rate of low birth weight (95% CI 1.4 to 1.9) and a 90% higher rate of preterm delivery (95% CI 1.3 to 1.9).

Amniotic Fluid Cultures in Preterm Labor Among patients with signs and symptoms of preterm labor, the probability of finding a positive result on tests for bacteria

depends on several factors. These factors are the specimen tested, the population under investigation, and the technique used for microbial detection. Thus, when standard culture techniques have been used for the amniotic fluid of patients clinically defined as being in preterm labor, the likelihood of positive cultures ranges from 0% to 25%. Yet with culture of the amniotic fluid of patients in preterm labor who deliver a preterm infant within 72 hours of the amniocentesis, the likelihood of a positive result has been 22%. With use of more sensitive assays such as PCR assay, the probability of finding bacteria in the amniotic fluid of patients in preterm labor has been as high as 30% to 55%.'35-'39 Because bacteria are likely to be present in the amniotic membranes before appearing in the amniotic fluid, the rate of positive cultures of the membranes for patients in preterm labor has been 32% to 6 1%. Histologic evidence of chorioamnion infection is extremely common, being found in approximately 80% of placentas after the birth of an infant weighing 1000 g or less.

Biochemical Links of Prematurity and Infection The widely accepted working hypothesis is that bacteria ascending into the uterine cavity are able to directly stimulate cytokine activity. IL- 1, IL-6, and TNF-a, the proinflammatory cytokines, have been shown to be produced by the fetal membranes, decidua, and myometrium. Patients with elevated levels of these cytokines in the amniotic fluid have shorter amniocentesis-to-delivery intervals than those for patients without elevated cytokine levels. Levels also are elevated when preterm labor is associated with IAI.I4' In addition, elevated amniotic fluid IL-6 levels have been found to prospectively identify those fetuses destined for significant neonatal morbidity and m~rtality.'~' Similarly, Gomez and associates demonstrated that elevated fetal plasma levels of IL-6 in patients with preterm PROM, but not in labor, had a higher rate of delivery within 48 hours compared with those who delivered more than 48 hours after cordocentesis. These important findings suggest a fetal inflammatory cytokine response triggers spontaneous preterm de1i~ery.I~~ Immunomodulatory cytokines such as IL- 1 receptor antagonist (IL- Ira), IL- 10, and transforming growth factor (TGF)-P play a regulatory role in the cytokine response, allowing for a downregulation of this response. IL-Ira has been shown in humans to increase in response to IAI.'43 Similarly, IL- 10 inhibits IL- 1 pinduced preterm labor in a rhesus m0de1.I~~ Animal models have been used to evaluate cytokinemediated initiation of preterm birth. Romero and colleagues demonstrated that systemic administration of IL- 1 induced preterm birth in a murine m0de1.l~~ Similarly, Kaga and co-workers gave low-dose lipopolysaccharide (LPS) intraperitoneally to preterm mice, causing preterm delivery.14' Again in the murine model, others demonstrated preterm birth after intrauterine inoculation of E. coli. Other investigators have used inoculation of live bacteria to study the infection-cytokine-preterm birth pathway. For example, in rabbits, we found that intrauterine inoculation of E. coli, Fusobacterium species, or group B streptococci led to rapid induction of labor at 70% gestation with an accompanying increase in histologic infiltrate and elaboration of TNF-a into the amniotic fluid. More recently, using our rabbit model, we demonstrated that intrauterine inoculation

Chapter 3

Table 3-7


69

Randomized Trial of Erythromycin for Treatment of Vaginal Ureaplasma urea/yticurn Infection in Pregnancy Treatment Group Erythromycin (N = 605) Placebo (N = 576)

Outcome

*

Birth weight (9, mean SD) Birth weight 11.30 ng/mL) Gram stain plus glucose (514 mg/dL) plus WBC count (250 cells/mm3) Gram stain plus WBC count (250 cells/mm3) plus IL-6 (21 1.30 ng/mL) Gram stain plus qlucose (514 mqldL) .plus

IL-6 (21 1.30 ng/mL) Gram stain plus WBC count (250 cellslmm3) plus IL-6 (21 1.30 ng/ml) plus glucose (514 mg/dL)

Negative Predictive

IL-6, interleukin-6;WBC, white blood cell. Data from Romero R, Yoon BH, Mazor M, Gomez R, et al. The diagnostic and prognostic value of amniotic fluid white blood cell count, glucose, interleukin-6, and Gram stain in patients with preterm labor and intact membranes. Am J Obstet Gynecol 1691805,1993.

stain and culture of amniotic fluid to have a modest positive predictive value for clinical chori~amnionitis.~’~ Thus, clear evidence for the widespread use of amniocentesis in PROM is not available. In view of the more recent information regarding the association of cerebral palsy and infection, these issues should be reinvestigated in a controlled fashion. Noninvasive procedures such as measuring the level of maternal serum C-reactive protein and amniotic fluid volume have also been suggested as predictors of infection. Several groups have evaluated C-reactive protein as such a An elevated level of C-reactive protein in serum from patients with PROM has a modest positive predictive value for histologic amnionitis (40% to 96%), but its predictive value for clinically evident infection is poor (10% to 45%). The value of a normal level of C-reactive protein for predicting absence of clinical chorioamnionitis is better (80% to 97%). In view of the low predictive value of a positive test, a decision to attempt delivery based solely on an elevated C-reactive protein level does not appear wise. Women who have PROM with oligohydramnios appear to be at increased risk for clinically evident infection, but the positive predictive value is modest (33% to 47%). In 1985, Gonik and co-workers noted that “amnionitis” developed in 8 (47%) of 17 patients with no pocket of amniotic fluid larger than 1 by 1 cm on ultrasound examination, whereas amnionitis developed in 3 (14%) of 22 patients with adequate pockets (i.e., larger than 1 by 1 cm) (P < .05).227To improve the predictability of these tests, Vintzileos and colleagues used a biophysical profile that included amniotic fluid volume, fetal movement and tone, fetal respirations, and a nonstress test.228However, positive predictive value of the biophysical profile has been variable (31% to 60% for clinical chorioamnionitis and 31% to 47% for neonatal

Treatment of Preterm Premature Rupture of Membranes before Fetal Viability Because fetal viability is nil throughout nearly all of the second trimester, the traditionally recommended approach to PROM in this period of gestation has been to induce labor. However, retrospective reports have provided pertinent data on expectant management for PROM before fetal ,,iabGty.229-233 As expected, the latent period is relatively long (mean, 12 to 19 days; median, 6 to 7 days). Although in these reports, maternal clinically evident infections were common (amnionitis in 35% to 59% and endometritis in 13% to 17%), none of these infections were serious, but maternal death from sepsis has been reported.234Of note, there was an appreciable neonatal survival rate of 13% to 50%, depending on gestational age at membrane rupture and duration of the latent period. In cases with PROM at less than 23 weeks, the perinatal survival rate was 13% to 47%; whereas with PROM at 24 to 26 weeks, it was 50%.232,233 The incidence of stillbirths is higher ( 1 5%) with midtrimester preterm PROM than with later preterm PROM (1%). The incidence of lethal pulmonary hypoplasia is 50% when membrane rupture occurs before 19 weeks.235Accordingly, with appropriate counseling, expectant management may be offered even in the second trimester for selected cases of PROM (Table 3-14). As neonatal survival in the periviable periods continues to improve, the numbers of infants afflicted by moderate to severe disabilities remains substantial.236These concerns should be clearly communicated to the mother before delivery. As discussed subsequently, a plan for group B streptococcal surveillance and treatment also would be indicated.

InvestigationalTreatment Measures Highly experimental protocols are investigating the possibility of extrinsic materials to promote resealing of the amniotic membranes.237This idea stems from the use of a blood patch

Chapter 3

Table 3-14


75

Summary of Management Plans for Premature Rupture of Membranes

Management In Second Trimester (32 wk, randomized trials show no neonatal benefit to expectant management

At or Near Term (>35 wk)

A. Early induction, within 12-24 hr B. Late induction, after approximately 24 hr C. Expectant management until labor or infection develop D. Prostaglandin E, and E, preparations t o ripen cervix/ induce labor

Recent evidence supports both option A and option C Randomized trials and historical data support safety and efficacy

CDC, Centers for Disease Control and Prevention.

for treatment of spinal heada~he.’~’An aggressive interventional protocol for early midtrimester PROM using gelatin sponge for cervical plugging in patients with spontaneous or iatrogenic preterm PROM at less than 22 weeks with significant oligohydramnios (maximal vertical pocket less than 1.5 cm) evaluated transabdominal or transcervical placement of the gelatin sponge. This measure was in addition to broad-spectrum antibiotic therapy and cervical cerclage. Eight of 15 women undergoing the procedure reached a late enough stage in gestation to allow fetal viability, and 30% of infants survived to hospital discharge. Three of the surviving infants had talipes equinovarus, and two had bilateral hip dysplasia and torticollis. Quintero and colleagues239introduced an “amniopatch consisting of autologous or heterologous platelets and cryoprecipitate through a 22-gauge needle intra-amniotically into seven patients with preterm PROM 16 to 24 weeks following fetoscopy or genetic amniocentesis and reported a fetal survival rate of 42.8% (three of seven). Of the remaining patients, two had unexplained fetal death, one miscarried, and a fourth had an underlying bladder outlet obstruction that prevented resealing of membranes. With spontaneous rupture of membranes, 0 of 12 patients have had resealing of their rnernbrane~.’~’The investigators speculate that with spontaneous rupture of membranes, rupture sites are larger, are located over the internal cervical os, are less amenable to patching, and are more susceptible to ascending infection and weakening of the lower portion of the membranes by proinflammatory agents. To address the larger defect with spontaneous preterm PROM, Quintero and colleagues have investigated the use of an “amnio graft,” achieved by laser-welding the amniotic membranes using Gore-Tex materials and a collagen-based graft material (Biosis), as well as combined use with a fibrin glue, with variable success in both animal models and selected patient^.^^'-'^' Use of a fibrin sealant was associated with a 53.8% survival rate when the sealant was placed

transcervically. In their study, mean gestational age at rupture of membranes was 19 weeks 4 days; at treatment, 20 weeks 5 days; and at delivery, 27 weeks 4 days, with a mean latency of 48 days from initial rupture to delivery. Additional research in this area is necessary to establish the safety and efficacy of this modality.

Treatment of Preterm Premature Rupture of Membranes in Early Third Trimester It is at the gestational age interval of 24 to 34 weeks that management is most controversial.Yet new information has become available, and sophisticated meta-analyses have been performed. Controversial components of therapy, including corticosteroids, tocolytics, and antibiotics, are reviewed here. Specific situations such as HSV and HIV infection and cerclage coexisting with PROM are reviewed later in the chapter (see Table 3-14). Corticosteroids Many investigators have used corticosteroids in at least some patients with PROM.241-243 In some studies, the investigators found evidence for an increased rate of maternal postpartum infection after administration of corticosteroids. The infections occurred mainly after vaginal delivery and were mild. Of still greater concern is the observation of some investigators that the rate of neonatal sepsis was increased when corticosteroids were used. However, most studies have not found this association. Some studies reported significant (or nearly significant) decreases in the occurrence of RDS, but others found no significant decrease when corticosteroidswere used in patients with PROM.244-253 There are major difficulties in interpreting these studies. In some of the more rigorously designed studies of corticosteroid use, the numbers of patients with PROM were small. Thus, real differences may have been

76

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General Information

missed (a beta error). In most studies, there were at least small decreases in the incidence of RDS in the corticosteroid group. A relatively wide range of gestational ages was studied. The minimum number of weeks of gestation for entry into a study ranged from 25 to 32, and the maximum ranged from 32 to 37. Because an equal effect of corticosteroids on the rate of RDS is unlikely at all gestational age intervals, real differences may have been missed in some intervals, because data for these intervals were combined with data for other gestational ages. Finally, experiments measuring the surfactant-inducing potency of corticosteroids suggest differences in the efficacy of various corticosteroid preparations and various dosages. Several studies, including three meta-analyses, have attempted to resolve the onf fusion?^^-^^^ Unfortunately, the authors reached differing conclusions. Ohlsson concluded that in preterm PROM, corticosteroid treatment "cannot presently be recommended to prevent RDS ... outside a randomized controlled trial.254The reasons underlying this conclusion are that the evidence that it decreases RDS is weak and its use increases the incidence of endometritis and may increase neonatal infections." On the other hand, Crowley and associates concluded that corticosteroids were effective in preventing RDS after preterm PROM (OR 0.44, 95% CI 0.32 to 0.60) and that they were not associated with a significant increase in perinatal infection (OR 0.84,95% CI 0.57 to 1.23) or neonatal infection (OR 1.61, 95% CI 0.9 to Lovett and colleagues, in a prospective, double-blind trial of treatment for preterm PROM, did use corticosteroids in all patients. They also found significant decreases in mortality, sepsis, and RDS rates, as well as increased birth weight, when corticosteroids and antibiotics were given compared with use of corticosteroids alone. In addition, Lewis and co-workers investigated use of ampicillinsulbactam in preterm PROM and then randomized patients to receive weekly corticosteroids versus placebo between 24 and 34 weeks. They found a decrease in RDS (44% versus 18%; P = -03 or .29,95% CI 0.10% to 0.82%) in the corticosteroid treatment group with no increase in maternal or neonatal infection complications.256 Lee's group also evaluated use of weekly steroids in a randomized doubleblind trial in women at 24 to 32 weeks with preterm PROM, compared with only a single course of steroids. Although the investigators found no differences in the overall composite neonatal morbidity between the groups (34.2% versus 41.8%), they did find an increased rate of chorioamnionitis in the weekly-course group (49.4% versus 31.7%; P = .04). Of note, in the group with gestational age at delivery of 24 to 27 weeks, there was a significant reduction in RDS from 100% in the single-course group to 26.5% ( P = .001) in the weekly-course Leitich and associates concluded that corticosteroids appear to diminish the beneficial effects of antibiotics in the treatment of preterm PROM. This was based on the results of their meta-analysis of five randomized trials of antibiotics and preterm PROM in which corticosteroids were used, which they compared with those of their previous metaanalysis of preterm PROM without corticosteroids. They found nonsignificant differences in mortality, sepsis, RDS, IVH, and necrotizing enterocolitis when both antibiotics and corticosteroids were used. By contrast, when antibiotics but not corticosteroids were used, they found a significant

decrease in chorioamnionitis (OR 0.37, P = .0001), postpartum endometritis (OR0.47, P= .03),neonatal sepsis (OR 0.27, P = .002), and IVH (OR 0.48, P = .02)?58 The National Institutes of Health (NIH) Consensus Development Panel in 1995 recommended that corticosteroids be given in the absence of IAI to women with preterm PROM at less than 30 to 32 weeks of gestation because the benefits of corticosteroids may outweigh the risk at this gestational age, particularly with IVH. Because the number of patients receiving corticosteroids with PROM at more than 32 weeks of gestation was small, the consensus panel chose to restrict its recommendation to less than 32 weeks of gestation. Recommended dosing includes betamethasone 12mg intramuscularly every 24 hours for two doses or dexamethasone 6mg every 12 hours for four doses. The consensus panel reconvened in 2000 and reconfirmed their original recommendations. Repeat dosing of steroids was not recommended outside of randomized trials. Guinn and colleagues found no decrease in neonatal morbidity with serial weekly courses of betamethasone compared with single course the rap^.'^'

Antibiotics Patients with preterm PROM are candidates for prophylaxis against group B streptococci.260-262 In addition, one innovative report noted use of combination antibiotics in an asymptomatic patient with preterm PROM because of bacterial colonization of the amniotic fluid, which was detected by amniocentesis. A second amniocentesis 48 hours after therapy revealed a sterile culture.263 Some studies of preterm pregnancies have found an increased rate of amnionitis to be associated with an increasing length of the latent period,205,208*264 whereas otherszo7have not. In patients with preterm PROM, digital vaginal examination should be avoided until labor develops, although transvaginal or transperineal ultrasound can be safely used to assess cervical length without increasing the risk of infection.265Some studies noted that prolonged ROM decreased the incidence of RDS,z'",zl' others noted no significant effeCt.207-20Y,242,245,266,267 These discrepancies may be explained by differences in experimental design (such as grouping of various gestational ages and using different sample sizes) or in definitions of clinical complications. Antibiotics of several classes have been found to prolong pregnancy in the setting of preterm PROM. Two large multicenter clinical trials with different approaches had adequate power to evaluate the utility of antibiotics in the setting of preterm PROM. Mercer and Arheart268evaluated the use of antibiotics in PROM with a meta-analysis. They evaluated such outcomes as length of latency, chorioamnionitis, postpartum infection, neonatal survival, neonatal sepsis, RDS, IVH, and necrotizing enterocolitis. Several classes of antibiotics were used, including penicillins and cephalosporins, although few studies used either tocolytics or corticosteroids. Benefits of antibiotics in this analysis included a significant reduction in chorioamnionitis, IVH, and confirmed neonatal sepsis. There was a significant decrease in the number of women delivering within 1 week of membrane rupture (OR 0.56, CI 0.41 to 0.76), but no significant differences were seen in necrotizing enterocolitis, RDS, or mortality. The evidence currently supports use of antibiotics in preterm PROM to prolong latency and to

Chapter 3


decrease maternal and neonatal infectious complications, but further studies to select the preferred agent have yet to be performed. The Maternal Fetal Medicine Units Network of the National Institutes of Child Health and Development (NICHD) conducted a large, multicenter trial of antibiotics after PROM but also did not use tocolytics or corticosteroids. Patients with preterm PROM at between 24 and 32 weeks were included. Patients were randomized to receive aggressive intravenous antibiotic therapy consisting of ampicillin (2 g intravenously [IV] every 6 hours) and erythromycin (250 mg IV every 6 hours) for the first 48 hours, followed by 5 days of oral therapy of amoxicillin (250mg every 8 hours) and enteric coated erythromycin (333mg orally every 8 hours) or placebo. Antibiotic treatment resulted in prolongation of pregnancy. Twice (50%) as many patients in the antibiotic treatment group remained pregnant after 7 days and 21 days composite neonatal morbidity was reduced in the antibiotic treatment group from 53% to 44% ( P < .05). In addition, individual neonatal comorbid conditions occurred less often in the antibiotic treatment group: RDS (40.5% versus 48.7%), stage 3/4 necrotizing enterocolitis (2.3% versus 5.8%), patent ductus arteriosus (PDA) ( 1 1.7% versus 20.2%), BPD (13.0% versus 20.5%) ( P < .05 for each). Occurrence rates for specific infections including neonatal group B streptococci-associated sepsis (0% versus 1.5%), overall neonatal sepsis (8.4% versus 15.6%), and pneumonia (2.9% versus 7.0%) all were significantly less ( P < .05) in the antibiotic treatment group. The second large trial was the multicenter, multiarm ORACLE trial of oral antibiotics in women with preterm PROM at less than 37 weeks. Over 4000 patients were randomized to receive oral erythromycin, amoxicillinclavulanic acid, both, or placebo for up to 10 days. AU of the antibiotic regimens prolonged pregnancy compared with placebo. Amoxicillin-clavulanic acid, however, increased the risk for neonatal necrotizing enterocolitis ( 1.9% versus 0.5%; P = .001), and this regimen is now advised against. The investigators demonstrated a significant decrease in perinatal morbidity, RDS, and necrotizing enterocolitis with use of ampicillin and erythr~mycin.~~’ Egarter and associates found in a meta-analysis of seven published studies a 68% reduction of neonatal sepsis and a 50% decreased risk of IVH in infants born to mothers receiving antibiotics after preterm PROM. They did not, however, find any significant differences in either RDS or neonatal m~rtality.~” The Cochrane Library has reviewed antibiotic use in preterm PROM in more than 6000 women in 19 trials. This meta-analysis also found that antibiotic use in preterm PROM was associated with an increased latent period at 48 hours and 7 days and reduction in major neonatal comorbid conditions or indicators such as neonatal infection, surfactant use, oxygen therapy, and abnormalities on head ultrasound examination prior to hospital discharge. Of interest, there was an increased risk of necrotizing enterocolitis in the two trials involving 2492 babies in which coamoxiclav was administered to the mother (relative risk 4.6, 95% CI 1.98 to 10.72). Another included trial in the metaanalysis compared erythromycin to co-amoxiclav; the investigators found fewer deliveries at 48 hours in the co-amoxiclav group but no difference at 7 days. However,

77

they also found a decrease in necrotizing enterocolitis when erythromycin rather than co-amoxiclav was used (relative risk 0.46,95% CI 0.23 to 0.94).271Thus, they recommended that co-amoxiclav should be avoided in the setting of preterm PROM. Owing to concerns of emergence of resistant organisms, another question involves duration of antibiotic therapy in preterm PROM. Two recent small trials have evaluated this question. Segel and assocites compared 3 days and 7 days of ampicillin in patients at 24 to 33 weeks with preterm PROM. In their 48 patients, there was no difference in 7-day latency as well as no difference in rates of chorioamnionitis, postpartum endometritis, and neonatal morbidity and Lewis and colleaguesstudied 3 days versus 7 days of ampicfinsulbactam ( 3 g IV every 8 hours) and similarly found no difference in outcomes between Both of these studies are small, so the final answer to this important question remains unanswered. We use 7 days of antibiotics, usually ampicillin and erythromycin, following the dosing from the NICHD trial.

Tocolytics and Development of Respiratory Distress Syndrome Older studies suggested a decrease in the rate of RDS with use of beta-adrenergic drugs, but in the National Collaborative Study, use of tocolytics in patients with ruptured membranes increased the likelihood of RDS by about 350%.274In addition, two small randomized controlled trials have assessed use of tocolytics in the presence of Neither found any significant increase in time to delivery or in birth weight or any decrease in RDS or neonatal hospital stay. These studies, however, did not use antibiotics or corticosteroids. Tocolytics have been shown to prolong pregnancy by about 48 hours in patients with intact membranes, but their efficacy with preterm PROM remains debatable. In the patient with preterm PROM and no contractions, tocolytics need not be given. In the patient with preterm PROM and contractions, IAI should be ruled out before consideration of tocolytics. Tocolytics could be considered in the early third trimester to maximize impact of antenatal corticosteroids (48-hour delay) on neonatal morbidity and mortality. Interested readers are referred to a recent review of this

Determination of Fetal Lung Maturity Some clinicians determine the status of fetal pulmonary maturity and proceed with delivery if the lungs are mature. Amniotic fluid may be collected by amniocentesis or from the posterior vagina. Either presence of phosphatidylglycerol or a lecithin-to-sphingomyelin ratio higher than 2 in amniotic fluid has been reported to be a good predictor of pulmonary maturity. In a series of patients with PROM before 36 weeks, Brame and MacKenna determined whether phosphatidylglycerol was present in the vaginal pool and delivered patients when there was presence of phosphatidylglycerol, spontaneous labor, or evidence of sepsis.278Of 2 14 patients, 47 had phosphatidylglycerol present initially and were delivered. Of the remaining 167,36 (21%) were subsequently found to have phosphatidylglycerol and were induced or delivered by cesarean section. Evidence of maternal infection developed in 8 (5%) and spontaneous labor developed in 123 (74%) of the 167 patients. Phosphatidylglycerol in

78

Section I

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amniotic fluid from the vagina reliably predicted fetal lung maturity; however, its absence did not necessarily mean that RDS would develop. Of 131 patients who did not show phosphatidylglycerol in the vaginal pool in any sample, 82 (62%) were delivered of infants who had no RDS. Lewis and colleagues also showed the presence of a mature AmniostatFLM (Hana Biologies, Irvine, Calif) in a vaginal pool sample from 18% of 201 patients, and none developed RDS.

Intentional Preterm Induction in the Mid-Third Trimester Even with PROM, delivery of a premature infant simply because the lungs show biochemical maturity may be questioned in view of other potential hazards of prematurity and the potential difficulties of the induction. Two papers have examined this controversial issue. With respect to the new information regarding the association among preterm PROM, chorioamnionitis, and subsequent development of cerebral palsy, the use of intentional midthird-trimester induction is receiving increased attention. Mercer and colleagues compared expectant management and immediate induction in 93 pregnancies complicated by PROM between 32 and 36 weeks 6 days, when mature fetal lung profiles were documented. They found significant prolongation of latent period and of maternal hospitalization, as well as increased neonatal length of stay, and increased antimicrobial use in the expectant management group despite no increase in documented neonatal sepsis. Thus, they concluded that in women with preterm PROM at 32 through 36 weeks with a mature fetal lung profile, immediate induction of labor reduces the duration of hospitalization in both mother and neonate^."^ Cox and Leveno similarly studied pregnancies complicated by preterm PROM at 30 to 34 weeks of gestation. Consenting patients were randomly assigned to one of two groups: expectant management versus immediate induction. Corticosteroids, tocolytics, and antibiotics were not used in either group. Fetal lung profiles were not determined. The investigators found a significant increase in the incidence of chorioamnionitis and antepartum hospitalization in the expectant management group. In addition, they found no clinically significant differences in birth weight or frequency of IVH, necrotizing enterocolitis, neonatal sepsis, RDS, or perinatal death. They concluded that there were no clinically significant neonatal advantages to expectant management of ruptured membranes and decreased antepartum hospitalization in those women managed with immediate induction.280

Fetal Surveillance Owing to concerns regarding cord compression and cord prolapse as well as the development of intrauterine and fetal infection, daily fetal monitoring in the setting of preterm PROM has been studied. Vintzileos and colleagues demonstrated that infection developed when the nonstress test became nonreactive 78% of the time, compared with only 14% when the nonstress test remained reactive.281Similarly, the biophysical profile score of 6 or less also predicted perinatal infection.282As a result, we recommend daily monitoring with nonstress tests. If the nonstress test is nonreactive, further workup with biophysical profile should be performed. Because there are currently no large studies

evaluating outpatient management of preterm PROM, we recommend hospitalization until delivery.

Conclusion Despite availability of recent data and sophisticated metaanalyses, we believe the evidence supports the use of expectant management in the absence of IAI and in the absence of documented fetal lung maturity in the third trimester until 34 completed weeks. If expectant management is chosen, corticosteroids to enhance fetal organ maturation should be given until 32 weeks. In addition, broad-spectrum antibiotics consisting of ampicillin and erythromycin should be administered for 7 days. Bacterial vaginosis should also be treated if present. In general, tocolytics should be avoided. Daily fetal surveillance is also recommended. Appropriate group B streptococcal prophylaxis in this high-risk group is strongly encouraged during labor. From a cost-effectiveness standpoint, Grable and co-workers looked at PPROM between 32 and 36 weeks. Using their decision analysis based on 1996 cost data, they weighed the costs of maternal hospitalization, latency, infection, and minor/major neonatal morbidity versus that of immediate induction. They found that it is most effective to delay delivery by 1 week between 32 and 34 weeks and to induce at presentation at or after 35 weeks.2R392s4

Recurrence Recurrence of PPROM in a subsequent pregnancy following an index pregnancy complicated by PPROM has been estimated to be 13.5% to 44%. In Lee and colleagues' population-based case-control study, there was an odds ratio of 20.6 for recurrent PPROM and 3.6 for recurrent preterm birth. However, the estimated gestational age of index preterm PROM is poorly predictive of subsequent timing of recurrent events. The other two studies had higher recurrence of risks but probably included transferred patients, so that the study populations constituted a more select g r o ~ p . ~ ' ~ - ~ ' '

Prevention Because preterm PROM often is accompanied by both maternal and neonatal adverse events, prevention of preterm PROM is desirable. Prediction of preterm PROM was evaluated in a large prospective trial, the Preterm Prediction Study:" sponsored by the NICHD Maternal Fetal Medicine Units Network. Prior preterm birth and preterm birth secondary to preterm PROM were associated with subsequent preterm birth. In nulliparas, preterm PROM is associated with medical complications, work in pregnancy, symptomatic contractions, bacterial vaginosis, and low body mass index. In multiparas, associated risk factors included prior preterm PROM, prior preterm birth due to preterm labor, and low body mass index. In both nulliparas and multiparas, a cervix found to be shorter than 25mm by endovaginal ultrasound examination was associated with preterm PROM. A positive fetal fibronectin also was predictive of preterm PROM in both nulliparas (16.7%) and multiparas (25%). Multiparas with a prior history of preterm birth, a short cervix, and a positive fetal fibronectin had a 31-fold higher risk of PROM and delivery before

Chapter 3


35 weeks compared with women without these risk factors (25% versus 0.8%; P = .001).28y

Special Situations Cerclage and Preterm Premature Rupture of Membranes Classic obstetric dogma has suggested immediate removal of the cervical cerclage stitch when preterm PROM occurs. Risks associated with the retained stitch include maternal infection from bacterial proliferation emanating from the foreign body and cervical lacerations consequent to progression of labor despite the retained stitch. Small retrospective studies have shown conflicting results. Currently, there are not enough data in the literature to recommend removal or retention of the suture. If there is no evidence of IAI or preterm labor in very premature gestations, one could consider leaving the stitch in during corticosteroid administration while there is uterine quiescence. After corticosteroids are maximized after 48 hours, then the stitch might be r e m o ~ e d . ~ ~ - ~ ' ~

Preterm Premature Rupture of Membranes and Herpes Simplex Virus In a retrospective review from 1986 to 1996 of 29 patients with preterm PROM and a history of recurrent genital herpes, there were no cases of neonatal herpes. However, the 95% CI suggests that the risk of vertical transmission could be as high as 10%. The mean estimated gestational age at membrane rupture was 27.7 weeks. Mean estimated gestational age at maternal herpetic lesion development was 28.7 weeks. With continued expected management, mean estimated gestational age at delivery was 30.6 weeks in the study group. Of the 29 patients, 13 (45%) were delivered by cesarean section. Additionally, although delivery was performed for obstetric indication only, 8 of 13 patients undergoing cesarean section had active lesions as the only or a secondary indication for cesarean section. In this study, risk of neonatal death from complications of prematurity was 10%. Risk of major neonatal morbidity was 41%. The risks of major morbidity and mortality would have been considerably higher had there been iatrogenic delivery at the time of development of their herpetic lesion. Thus, it appears prudent when there is a history of recurrent HSV infection to continue expectant management in the significantly preterm gestation. In the setting of primary herpes (or nonprimary first episode), with the higher viral loads that entails, early delivery theoretically may prevent vertical transmission, but this has not been specificallystudied. Only 8 of the patients in this study received acyclovir treatment. Thus, use of acyclovir for symptomatic outbreaks would theoretically reduce the risk of transmission, as well as decreasing the number of cesarean sections performed for presence of active lesions at the time of delivery.295 Additionally, Scott and associates have demonstrated a decreased cesarean section rate in term patients with a history of recurrent HSV infection.2y6

Human Immunodeficiency Virus and Preterm Premature Rupture of Membranes There are no specific data regarding the subset of patients with preterm PROM who are seropositive for HIV. With

79

highly active antiretroviral therapy (HAART) and a low viral load, expectant management of preterm PROM after clinical exclusion of IAI might be considered, because the complications of prematurity with gestational age of less than 32 weeks, and certainly less than 28 weeks, are significant. With continued HAART, the risk of vertical transmission should remain low. The physician should discuss and document potential risks and benefits with the mother regarding the possibility of vertical transmission or neonatal morbidity and mortality. Intravenous infusion of zidovudine should be initiated at admission, if the antiretroviral regimen permits, because latency can be unpredictively short in many patients with preterm PROM.2y7If, after a period of observation and no evidence of spontaneous preterm labor, intravenous zidovudine may be discontinued and oral HAART continued.

Treatment of Term Premature Rupture of Membranes Approximately 8% of pregnant women at term experience PROM, although contractions commence spontaneously within 24 hours of membrane rupture in 80% to 90% of patients.'" After greater than 24 hours elapses following membrane rupture at term, the incidence of neonatal infection is approximately 1%, but this risk increases to 3% to 5% when clinical chorioamnionitis is diagn~sed.'~'For many years, the practice in most institutions had been to induce labor in term patients within approximately 12 hours of PROM, primarily because of concerns about development of chorioamnionitis and neonatal infectious complications. More recently, three studies have demonstrated that in most patients, expectant management can be safely applied (see Table 3-14). The designs of these three reports were different. Kappy and associates reported a retrospective review in a private population.2yy Duff and colleagues performed a randomized study in indigent patients with unfavorable cervix characteristics (less than 2 cm dilated, less than 80% effaced) and with no complications of pregnancy (e.g., toxemia, diabetes, previous cesarean section, malpresentation, meconium-stained fluid) .300 In the patients assigned to the induction group, initiation of induction generally was at 12 hours after rupture of membranes. The excess cesarean deliveries in the induction group were for failed induction. In the induction group, there was a higher probability of IAI. In the study by Conway and colleagues, all patients were observed until the morning after admis~ion.~" Induction of labor was then undertaken if the patient was not in labor. Wagner and co-workers provided yet another variant by comparing early induction (at 6 hours after PROM) to late induction (at 24 hours after PROM).302In their population at a Kaiser Permanente hospital, the results favored early induction by shortening maternal hospital stay and decreasing neonatal sepsis evaluations. Recent work also has evaluated use of oral and vaginal prostaglandin preparations (prostaglandins E, and E,) to ripen the cervix or induce labor after PROM at term. These preparations appear to be effective in shortening labor without increasing maternal or neonatal i n f e ~ t i o n . ~ ' ~ - ~ ' ~ Hannah and colleagues evaluated four management schemes in women with PROM at term: (1) immediate induction with oxytocin, (2) immediate induction with

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vaginal prostaglandin E,, (3) expectant management for up to 4 days followed by oxytocin induction, and (4) expectant management followed by prostaglandin E2 induction. Although no differences in cesarean section rates or frequency of neonatal sepsis were found, an increase in chorioamnionitis was noted in the expectant management groups, and all deaths not caused by congenital anomalies occurred in the expectant management group. Of note, patient satisfaction was higher in the immediate induction group. A secondary analysis demonstrated five variables as independent predictors of neonatal sepsis: clinical chorioamnionitis (OR 5.89), presence of group B streptococci (OR 3.08), seven to eight vaginal examinations (OR 2.37), duration of ruptured membranes 24 to 48 hours (OR 1.97), greater than 48 hours from membrane rupture to active labor (OR 2.25), and maternal antibiotics before delivery (OR 1.63).306 We endorse immediate induction with oxytocin in women with PROM at term if the condition of the cervix is favorable and the patient is willing. If the condition of the cervix is unfavorable, induction with appropriate doses of prostaglandins may be used before use of oxytocin. Intrapartum antibiotic prophylaxis against group B streptococci should be used according to the 2002 guidelines,260which emphasize universal screening of all gravidas at 35 to 37 weeks. All seropositive women should receive intravenous antibiotics in labor. Changes in the 2002 recommendations over the previous guidelines also include antibiotic guidelines for those with high- and low-risk penicillin allergy, as well as checking antibiotic sensitivities due to emerging antibiotic resistance, particularly resistance of erythromycin and clindamycin to group B streptococci. REFERENCES 1.

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16. Harger JH. Comparison of success and morbidity in cervical cerclage procedures. Obstet Gynecol56:543, 1980. 17. Burnett RG, Anderson WR. The hazards of amniocentesis. J Iowa Med SOC58:133, 1968. 18. Queenan JT. Modern Management of the Rh Problem, 2nd ed. Hagerstown, Md, Harper & Row, 1977, p 180. 19. Soper DJ, Mayhall CG, Froggatt JW. Characterization and control of intra-amniotic infection in an urban teaching hospital. Am J Obstet Gynecol 175:304, 1996. 20. Tran SH, Caughey AB,Musci TJ. Meconium-stained amniotic fluid is associated with puerperal infections. Am J Obstet Gynecol 189:746, 2003. 21. Krohn MJ, Germain M, Muhlemann K, Hickok D. Prior pregnancy outcome and the risk of intra amniotic infection in the following pregnancy. Am J Obstet Gynecol 178:381, 1998. 22. Yancey MK, Duff P, Kubilis P, et al. Risk factors for neonatal sepsis. Obstet Gynecol 87:188, 1996. 23. Herbst A, Wolner-Hanssen P, Ingemarsson I. Risk factors for fever in labor. Obstet Gynecol 86:790, 1995. 24. Naeye RL. Coitus and associated amniotic-fluid infections. N Engl J Med 301:1198,1979. 25. Klebanoff MA, Nugent RP, Rhoads GG. Coitus during pregnancy: is it safe? Lancet 2:914, 1984. 26. Mills JL, Harlap S, Harley EE. Should coitus late in pregnancy be discouraged? Lancet 2: 136,1981. 27. Gibbs RS, Blanco JD, St. Clair PJ, et al. Quantitative bacteriology of amniotic fluid from patients with clinical intra-amniotic infection at term. J Infect Dis 145:1, 1982. 28. Gravett MG, Eschenbach DA, Speigel-Brown CA, et al. Rapid diagnosis of amniotic fluid infection by gas-liquid chromatography. N Engl J Med 306725,1982. 29. Nickerson CW. Gonorrhea amnionitis. Obstet Gynecol42:815,1973. 30. Handsfield HH, Hodson WA, Holmes KK. Neonatal gonococcal infection: I. Orogastric contamination with Neisseria gonorrhoeae. JAMA 225:697, 1973. 31. Brunnel PA, Dische RM, Walker MB. Mycoplasma, amnionitis, and respiratory distress syndrome. JAMA 2072097, 1969. 32. Shurin PA, Alpert S, Rosner B, et al. Chorioamnionitis and colonization of the newborn infant with genital mycoplasmas. N Engl J Med 293:5, 1975. 33. Blanco JD, Gibbs RS, Malherbe H, et al. A controlled study of genital mycoplasmas in amniotic fluid from patients with intra-amniotic infection. J Infect Dis 147:650, 1983. 34. Gibbs RS, Cassell GH, Davis JK, et al. Further studies o n genital mycoplasmas in intra-amniotic infection: blood cultures and serologic response. Am J Obstet Gynecol 154:717, 1986. 35. Martin DH, Koustsky L, Eschenbach DA, et al. Prematurity and perinatal mortality in pregnancies complicated by maternal Chlamydia trachornatis infections. JAMA 2471585, 1982. 36. Wager GP, Martin DH, Koustsky L, et al. Puerperal infectious morbidity: relationship to route of delivery and to antepartum Chlamydia trachoniatis infection. Am J Obstet Gynecol 138:1028, 1980. 37. Pankuch GA, Applebaum PC, Lorenz RP, et al. Placental microbiology and histology and the pathogenesis of chorioamnionitis. Obstet Gynecol64:803, 1984. 38. Dong Y, Ramzy I, Kagan-Hallet SK, et al. A microbiologic clinical study of placental inflammation at term. Obstet Gynecol 70:175, 1987. 39. Gibbs RS, Schachter JS. Chlamydia1 serology in patients with intraamniotic infection and controls. Sex Transm Dis 14213, 1987. 40. Sperling RS, Newton E, Gibbs RS. Intra-amniotic infection in low birth weight infants. J Infect Dis 157:113, 1988. 41. Gibbs RS. Chorioamnionitis and bacterial baginosis. Am J Obstet Gynecol 169:460, 1993. 42. Silver HM, Sperling RS, St. Clair PJ, et al. Evidence relating bacterial vaginosis to intra-amniotic infection. Am J Obstet Gynecol 161:808, 1989. 43. Gravett MG, Nelson HP, DeRouen T, et al. Independent associations of bacterial vaginosis and Chlamydia trachornatis infection with adverse pregnancy outcome. JAMA 2561899,1986. 44. Newton ER, Piper J, Peairs W. Bacterial vaginosis and intra-amniotic infection. Am J Obstet Gynecol 176:672, 1997. 45. Koh KS, Chan FH, Monfared AH, et al. The changing perinatal and maternal outcome in chorioamnionitis. Obstet Gynecol 53:730, 1979.

Chapter 3


46. Yoder RP, Gibbs RS, Blanco JD, et al. A prospective, controlled study of maternal and perinatal outcome after intra-amniotic infection at term. Am J Obstet Gynecol 145:695, 1983. 47. McDonald H, Brocklehurst P, Parsons J, Vigneswaran R. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev CD00262(13), 2003. 48. Carey JC, Klebanoff MA, Hauth JC, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. N Engl J Med 342:534,2000. 49. ACOG Practice Bulletin No. 31. Assessment of Risk Factors for Preterm Birth. Washington, DC, American College of Obstetricians and Gynecologists, 2001. 50. Yankowitz J, Weiner CP, Henderson J, Grant S, Towbin JA. Outcome of low risk pregnancies with evidence of intraamniotic viral infection detected by PCR on amniotic fluid obtained at second trimester genetic amniocentesis. J SOCGynecol Invest 3:132A, 1996. 51. Cassell G, Andrews W, Hauth J, et al. Isolation of microorganisms from the chorioamnion is twice that from amniotic fluid at cesarean delivery in women with intact membranes. Am J Obstet Gynecol 168:424, 1993. 52. Goncalves LF, Chairworapongsa T, Romero R Intrauterine infection and prematurity. Mental retardation and developmental diabilities. Intrauter Infect Prematurity 83,2002. 53. Romero R, Quintero R, Oyarzun E. et al. Intraamniotic infection and the onset of labor in preterm premature rupture of the membranes. Am J Obstet Gynecol 159661,1988. 54. Hoskins IA, Johnson TRB, Winkel CA. Leukocyte esterase activity in human amniotic fluid for the rapid detection of chorioamnionitis. Am J Obstet Gynecol 157:730, 1987. 55. Miller JM, Pupkin MJ, Hill GB. Bacterial colonization of amniotic fluid from intact fetal membranes. Am J Obstet Gynecol 136:796, 1980. 56. Romero R, Jimenez C, Lohda A, et al. Amniotic fluid glucose concentration: a rapid and simple method for the detection of intraamniotic infection in preterm labor. Am J Obstet Gynecol 163:968, 1990. 57. Kirshon B, Rosenfeld B, Mari G, et al. Amniotic fluid glucose and intra-amniotic infection. Am J Obstet Gynecol 164:818, 1991. 58. Kiltz R, Burke M, Porreco R. Amniotic fluid glucose concentration as a marker for intra-amniotic infection. Obstet Gynecol78:619, 1991. 59. Andrews WW, Hauth JC, Goldenberg RL, et al. Amniotic fluid interleukin-6: correlation with upper genital tract microbial colonization and gestational age in women delivered after spontaneous labor versus indicated delivery. Am J Obstet Gynecol 173:606, 1995. 60. Yoon BH, Romero R, Kim CH, et al. Amniotic fluid interleukin-6 a sensitive test for antenatal diagnosis of acute inflammatory lesions of preterm placenta and prediction of perinatal morbidity. Am J Obstet Gynecol 172:960, 1995. 61. Greig PC, Murtha AP, Jimmerson CJ, et al. Maternal serum interleukin-6 during pregnancy and during term and preterm labor. Obstet Gynecol90465,1997. 62. Gomez R, Romero R, Ghezzi F, et al. The fetal inflammatory response syndrome. Am J Obstet Gynecol 179:194, 1998. 63. Gomez R, Ghezzi F, Romero R, et al. Premature labor and intraamniotic infection. Clin Perinatol 22:281,1995. 64. Hitti J, Riley DE, Krohn MA, et al. Broad spectrum bacterial rDNA polymerase chain reaction assay for detecting amniotic fluid infection in women in preterm labor. Clin Infect Dis 241228, 1997. 65. Oyarzun E, Yamamoto M, Kato S, et al. Specific detection of 16 micro-organisms in amniotic fluid by polymerase chain reaction and its correlation with preterm delivery occurrence. Am J Obstet G-pecol 179:1115, 1998. 66. Markenson GR, Martin RK, Tillotson-Criss M, et al. The use of the polymerase chain reaction to detect bacteria in amniotic fluid in pregnancies complicated by preterm labor. Am J Obstet Gynecol 177:1471, 1997. 67. Goncalves LF, Chainvorapongsa T, Romero R. Intrauterine infection and prematurity. Mental retardation and developmental disabilities. Intrauter Infect Prematurity 8:3,2002. 68. Romero R, Munoz H, Gomez R, et al. Two-thirds of spontaneous abortiodfetal deaths after genetic amniocentesis are the results of pre-existing subclinical inflammatory process of the amniotic cavity. Am J Obstet Gynecol 172:261,1995. 69. Wenstrom KD, Andrews WW, Tamura T, et al. Elevated amniotic fluid interleukin-6 levels at genetic amniocentesis predict subsequent pregnancy loss. Am J Obstet Gynecol 175:830, 1996.

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70. Goldenberg RL, Andrews WW, Mercer BM, et al. The Preterm Prediction study: granulocyte colony-stimulating factor and spontaneous preterm birth. Am J Obstet Gynecol 182:625,2000. 71. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med 342:1500,2000. 72. Andrews WW, Goldenberg R, Hauth J, et al. lnterconceptional antibiotics to prevent spontaneous preterm birth (SPTB): a randomized trial. Am J Obstet Gynecol2003;189S57 (abstract). 73. S p e r h g RS, Ramamurthy RS, Gibbs RS. A comparison of intrapartum versus immediate postpartum treatment of intra-amniotic infection. Obstet Gynecol70:861, 1987. 74. Gibbs RS, Dinsmoor MJ, Newton ER, et al. A randomized trial of intrapartum vs immediate postpartum treatment of women with L4I. Obstet Gynecol 72823, 1988. 75. Gilstrap LC, Laveno KJ, Cox SM, et al. Intrapartum treatment of acute chorioamnionitis: impact on neonatal sepsis. Am J Obstet Gynecol 159:579, 1988. 76. Bray RE, Boe RW, Johnson WL. Transfer of ampicdlin into fetus and amniotic fluid from maternal plasma in late pregnancy. Am J Obstet Gynecol96938,1966. 77. Charles D. Dynamics of antibiotic transfer from mother to fetus. Semin Perinatol 1:89,1977. 78. WeinsteinA], Gibbs RS,Gallagher M. Placental transfer of clindamycin and gentamicin. Am J Obstet Gynecol 124688, 1976. 79. Chapman SJ, Owen J. Randomized trial of single-dose versus multiple-dose cefotetan for the postpartum treatment of intrapartum chorioamnionitis. Am J Obstet Gynecol 177831, 1997. 80. Looff JD, Hager WD. Management of chorioamnionitis. Surg Gynecol Obstet 158161, 1984. 81. Hauth JC, C i t r a p K, Hankins GDV, et al. Term maternal and neonatal complications of acute chorioamnionitis. Obstet Gynecol66:59,1985. 82. Duff P, Sanders R, Gibbs RS. The course of labor in term patients with chorioamnionitis. Am J Obstet Gynecol 147:391, 1983. 83. Silver RK, Gibbs RS, Castillo M. Effect of amniotic fluid bacteria on the course of labor in nulliparous women at term. Obstet Gynecol 68:587, 1986. 84. Perkins RP. The merits of extraperitoneal cesarean section: a continuing experience. J Reprod Med 19:154, 1977. 85. Hanson H. Revival of the extraperitoneal cesarean section. Am J Obstet Gynecol 130102, 1978. 86. Imig JR, Perkins RP. Extraperitoneal cesarean section: a new need for old skills: a preliminary report. Am J Obstet Gynecol 125:51, 1976. 87. Yonekura ML, Wallace R,E g h t o n WR. Amnionitis-optimal operative management: extraperitoneal cesarean section vs low cervical transperitoneal cesarean section. Third Annual Meeting of the Society of Perinatal Obstetricians, San Antonio, January 1983 (abstract 24A). 88. Garite TJ, Freeman RK. Chorioamnionitis in the preterm gestation. Obstet Gynecol 59:539, 1982. 89. Morales WJ. The effect of chorioamnionitis o n the developmental outcome of preterm infants at one year. Obstet Gynecol70:183,1987. 90. Ferguson MG, Rhodes PG, Morrison JC, et al. Clinical amniotic fluid infection and its effect on the neonate. Am J Obstet Gynecol 151:1058, 1985. 91. Yoon BH, Romero R, Park JS, et al. The relationship among inflammatory lesions of the umbilical cord (funisitis), umbilical cord plasma interleukin 6 concentration, amniotic fluid infection, and neonatal sepsis. Am J Obstet Gynecol 183:1124,2000. 92. Yoon BH, Jun JK, Romero R, et al. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-lbeta. and tumor necrosis factor-alpha),neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol 17719, 1997. 93. Gibson CS, MacLennan AH, Goldwater PN, Dekker GA. Antenatal causes of cerebralpalsy: associationsbetween inherited thrombophilias, viral and bacterial infection, and inherited susceptibility to infection. Obstet Gynecol Surv 58:209,2003. 94. Hardt NS, Kostenbauder M, Ogburn M, et al. Influence of chorioamnionitis on long-term prognosis in low birth weight infants. Obstet Gynecol655, 1985. 95. Murphy DJ, Seller S, MacKenzie 12, et al. Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet 3461449, 1995. 96. Grether JK, Nelson KB. Maternal infection and cerebral palsy in infants of normal birth weight. JAMA 278:207, 1997. 97. Alexander JM, Gilstrap LC, Cox SM, et al. Clinical chorioamnionitis and the prognosis for very low birth weight infants. Obstet Gynecol 91:725, 1998.

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228. Vintzileos AM, Campbell WA, Nochimson DJ, et al. The fetal biophysical profile in patients with premature rupture of the membranes-an early predictor of fetal infection. Am J Obstet Gynecol 152:510, 1985. 229. Beydoun SN, Yasin SY. Premature rupture of the membranes before 28 weeks. conservative management. Am J Obstet Gynecol 155:471, 1986. 230. Taylor J, Garite TJ. Premature rupture of membranes before fetal viability. Obstet Gynecol 64615, 1984. 231. Major CA, Kitzmiller JL. Perinatal survival with expectant management of midtrimester rupture of membranes. Am J Obstet Gynecol 163:838, 1990. 232. Moretti M, Sibai BM. Maternal and perinatal outcome of expectant management of premature rupture of membranes in the midtrimester.Am J Obstet Gynecol 159390, 1988. 233. Dinsmoor MJ, Bachman R, Haney E, et al. Outcomes after expectant management of extremely preterm premature rupture of the membranes. Am J Obstet Gynecol 190:183,2004. 234. Moretti M, Sibai B. Maternal and perinatal outcome of expectant management of premature rupture of the membranes in the midtrimester. Am J Obstet Gynecol 159390, 1988. 235. Rotschdd A, Ling EW, Puterman ML. Neonatal outcome after prolonged preterm rupture of membranes. Am J Obstet Gynecol 162:46, 1990. 236. American Academy of Pediatrics. Perinatal care at the threshold of viability. Pediatrics 96974, 1995. 237. OBrien JM, Barton J, Milligan DA. An aggressive interventional protocol for early midtrimester premature rupture of the membranes using gelatin sponge for cervicalplugging. Am J Obstet Gynecol1871143,2002. 238. Quintero R4.Treatment of previable premature ruptured membranes. C h Perinatol 30:573,2003. 239. Quintero RA, Morales WJ, M e n M, et al. Treatment of iatrogenic previable premature rupture of membranes with intra-amniotic injection of platelets and cryoprecipitate (amniopatch); preliminary experience. Am J Obstet Gynecol 181:744, 1999. 240. Scissione AC, Manley JS, Pollock M, et al. Intracervical fibrin sealants: a potential treatment for early preterum premature rupture of membranes. Am J Obstet Gynecol 184368,20013. 241. Liggins GC. Prenatal glucocorticoid treatment: prevention of respiratory distress syndrome: lung maturation and prevention of hyaline membrane disease. Report of the 70th Ross Conference on Pediatric Research. Columbus, Ohio, Ross Laboratories, 1976, p 97. 242. Block MF, Klin OR, Crosby WM. Antenatal glucocorticoid therapy for the prevention of respiratory distress syndrome in the premature infant. Obstet Gynecol 50:186, 1977. 243. Morrison JC, Whybrew WD, Bucovaz ET, et al. Injection of corticosteroids into mothers to prevent neonatal respiratory distress syndrome.Am J Obstet Gynecol 131:358, 1978. 244. Taeusch HW,Frigoletto F, KitzmiUer J, et al. Risk of respiratory distress sfldrome after prenatal dexamethasone treatment. Pediatrics 63:64, 1979. 245. Papageorgiou AN, Desgranges MF, Masson M, et al. The antenatal use of betamethasone in the prevention of respiratory distress syndrome: a controlled double-blind study. Pediatrics 63:73, 1979. 246. Collaborative Group on Antenatal Steroid Therapy. Effect of antenatal dexamethasone administration on the prevention of respiratory distress syndrome. Am J Obstet Gynecol 141:276, 1981. 247. Garite TJ, Freeman RK, Linzey EM, et al. Prospective randomized study of corticosteroids in the management of premature rupture of the membranes and the premature gestation. Am J Obstet Gynecol 141:508, 1981. 248. Barrett JM, Boehm FH. Comparison of aggressive and conservative management of premature rupture of fetal membranes. Am J Obstet Gynecol 144:12, 1982. 249. Schmidt PL, Sims ME, Strassner HT, et al. Effect of antepartum glucocorticoid administration upon neonatal respiratory distress syndrome and perinatal infection. Am J Obstet Gynecoll48178,1984. 250. Iams JDE, Talbert ML, Barrows H, et al. Management of preterm prematurely ruptured membranes: a prospective randomized comparison of observation versus use of steroids and timed delivery. Am J Obstet Gynecol 151:32, 1985. 251. Simpson GF, Harbert GM Jr. Uses of P-methasone in management of preterm gestation with premature rupture of membranes. Obstet Gynecol66168, 1985. 252. Nelson LH, Meis PJ, Hatjis CG, et al. Premature rupture of membranes: a prospective, randomized evaluation of steroids, latent phase, and expectant management. Obstet Gynecol66:55, 1985.

Chapter 3


253. Morales WJ, Diebel ND, Lazar AJ, et al. The effect of antenatal dexamethasone administration on the prevention of respiratory distress syndrome in preterm gestations with premature rupture of membranes. Am J Obstet Gynecol 154:591, 1986. 254. Ohlsson A. Treatments of preterm premature rupture of the membranes: a meta-analysis. Am J Obstet Gynecol 160890, 1989. 255. Crowley PA. Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1 9 9 4 . h J Obstet Gynecol 173:322,1995. 256. Lewis DF, Brody K, Edwards MS, et al. Preterm premature ruptured membranes: a randomized trial of steroids after treatment with antibiotics. Obstet Gynecol88:801, 1996. 257. Lee MJ, Davies J, Guinn D, et al. Single versus weekly courses of antenatal steroids in preterm premature rupture of membranes. Obstet Gynecol 103:274,2004. 258. Leitich H, Egarter C, Reisenberger K, et al. Concomitant use of glucocorticoids: a comparison of two meta-analysis on antibiotic treatment in PROM. Am J Obstet Gynecol 178:899,1998. 259. Guinn D, Davies J, and the Betamethasone Study Group. Multicenter randomized trial of single versus weekly courses of antenatal corticosteroids (ACS). Presented by D. Guinn at the Society for MaternalFetal Medicine 2001 Annual Meeting. Am J Obstet Gynecol 184S6, 2001. 260. U.S. Department of Health and Human Services. Prevention of perinatal group B streptococcal disease: revised guidelines from CDC. MMWR Morbid Mortal Wkly Rep 51(RR1l):l, 2002. 261. Minkoff H, Mead P. An obstetric approach to the prevention of earlyonset group B beta-hemolytic streptococcal sepsis. Am J Obstet Gynecol 154973,1986. 262. Boyer KM, Gotoff SP. Prevention of early-onset neonatal group B streptococcal disease with selective intrapartum chemoprophylaxis. N Engl J Med 3141665,1986. 263. Romero R, Scioscia AL, Edberg SC, et al. Use of parented antibiotic therapy to eradicate bacterial colonization of amniotic fluid in premature rupture of membranes. Obstet Gynecol67:15S, 1986. 264. Thibeault DW, Emmanouilides GC. Prolonged rupture of fetal membranes and decreased frequency of respiratory distress syndrome and patent ductus arteriosus in preterm infants. Am J Obstet Gynecol 129:43, 1977. 265. Schutte MF, Treffess PE, Kloostrerman GJ, et al. Management of premature rupture of membranes: the risk of vaginal examination to the infant. Am J Obstet Gynecol 146:395, 1983. 266. Christensen KK, Christensen P, Ingemarsson L, et al. A study of complications in preterm deliveries after prolonged premature rupture of the membranes. Obstet Gynecol48:670,1976. 267. Jones MD Jr, Burd LI, Bowes WA Jr, et al. Failure of association of premature rupture of membranes with respiratory-distress syndrome. N Engl J Med 292:1253,1975. 268. Mercer BM, Arheart KL. Antimicrobial therapy in expectant management of preterm premature rupture of the membranes. Lancet 346:1271, 1995. 269. Mercer BM, Miodovnik M, Thurnau GR, et al. Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes. JAMA 278:989, 1997. 270. Egarter C, Leitich H, Karas H, et al. Antibiotic treatment in PPROM and neonatal morbidity: a meta-analysis. Am J Obstet Gynecol 174589,1996. 271. Kenyon S , Boulvain M, Neilson J. Antibiotics for preterm rupture of membranes. Cochrane Database Syst Rev CD001058(2), 2003. 272. Segel SY,Miles AM, Clothier B, et al. Duration of antibiotic therapy after preterm premature rupture of fetal membranes. Am J Obstet Gynecol 189799,2003. 273. Lewis DF, Adair CD, Robichan AG, et al. Antibiotic therapy in preterm premature rupture of membranes: are seven days necessary? A preliminary, randomized clinical trial. Am J Obstet Gynecol 188:1413,2003. 274. Curet LB, Rao AV, Zachman RD, et al. Association between ruptured membranes, tocolytic therapy, and respiratory distress syndrome. Am J Obstet Gynecol 148263,1984. 275. Garite TJ, Keegan KA, Freeman RK, et al. A randomized trial of ritodrine tocolysis versus expectant management in patients with premature rupture of membranes at 25 to 30 weeks of gestation. Am J Obstet Gynecol 157:388, 1987. 276. Weiner CP, Renk K, Klugman M. The therapeutic efficacy and cost effectiveness of aggressive tocolysis for premature labor associated with premature rupture of the membranes. Am J Obstet Gynecol 159:216, 1988.

85

277. Fontenot MT, Lewis DF. Tocolytic therapy and preterm premature rupture of membranes. Clin Perinatol28:787,2001. 278. Brame RG, MacKenna J. Vaginal pool phospholipids in management of premature rupture of membranes. Am J Obstet Gynecol 145:992, 1983. 279. Mercer BM, Crocker LG, Boe NM, et al. Induction versus expectant management in premature rupture of the membranes with mature amniotic fluid at 32 to 36 weeks: a randomized trial. Am J Obstet Gynecol 169:775, 1993. 280. Cox SM, Leveno KJ. Intentional delivery versus expectant management with preterm ruptured membranes at 30 to 34 weeks’ gestation. Obstet Gynecol86875, 1995. 281. Vintzileos AM, Campbell WA, Nochimson DJ, et al. The use of the nonstress test in patients with premature rupture of membranes. Am J Obstet Gynecol 155:149, 1986. 282. Hanley ML, Vintzileos AM. Biophysical testing in premature rupture of the membranes. Semin Perinatol20418, 1996. 283. Grable IA. Cost effectiveness of induction after preterm premature rupture of membranes. Am J Obstet Gynecol 187:1153,2002. 284. Naef RW, AUbert JR, Ross EL, et al. Premature rupture of membranes at 34 to 37 weeks’ gestation: aggressive versus conservative management. Am J Obstet Gynecol 178:126, 1998. 285. Lee T, Carpenter MW, Heber WW, Silver HM. Preterm premature rupture of membranes: risks of recurrent complications in the next pregnancy among a population-based sample of gravid women. Am J Obstet Gynecol 188:209,2003. 286. Naeye RL. Factors that predispose to premature rupture of the fetal membranes. Obstet Gynecol60:93, 1982. 287. Asrat T, Lewis DF, Garite TJ, et al. Rate of recurrence of preterm premature rupture of membranes in consecutive pregnancies. Am J Obstet Gynecol 165:1111,1991. 288. Mercer BM, Goldenberg RL, Moawad AH, et al. The Preterm Prediction Study: effect of gestational age and cause of preterm birth on subsequent obstetric outcome. Am J Obstet Gynecol181:1216,1999. 289. Mercer BM, Goldenberg RL, Meis PJ, et al. The Preterm Prediction Study: prediction of preterm premature rupture of membranes through clinical findings and ancillary testing. The National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol 183:738,2000. 290. Blickstein J, Katz 2, Lancet M, Molgimer BM. The outcome of pregnancies complicated by preterm rupture of membranes with and without cerclage. Int J Obstet Gynecol28:237, 1989. 291. Yeast JD, Garite TR. The role of cervical cerclage in the management of preterm premature rupture of the membranes. Am 1 Obstet Gynecol 158106,1988. 292. Ludmir, Bader J, Chen L, et al. Poor perinatal outcome associated with retained cerclage in patients with premature rupture of membranes. Obstet Gynecol84:823, 1994. 293. Jenkins TM, Berghella V, Shlossman PA, et al. Timing of cerclage removal after preterm premature rupture of membranes: maternal and neonatal outcomes. Am J Obstet Gynecol 183:847,2000. 294. McElrath TF, Nonvitz ER, Leiberman ES, H e h e r LI. Preinatal outcome after preterm premature rupture of membranes with in situ cervical cerclage. Am J Obstet Gynecol 187:1147,2002. 295. Carol A, Major CA, Towers CV, et al. Expectant management of preterm premature rupture of membranes complicated by active recurrent genital herpes. Am J Obstet Gynecol 188:155,2003. 296. Scott LL, Sanchez PJ, Jackson GL, et al. Acyclovir suppression to prevent cesarean delivery after first-episode genital herpes. Obstet Gynecol87:69, 1996. 297. Watts DH. Management of human immunodeficiency virus infection in pregnancy. N Engl J Med 3461879,2002. 298. Gerdes JS. Clinicopathologic approach to the diagnosis of neonatal sepsis. Clin Perinatol 18:361, 1991. 299. Kappy KA, Cetrulo CL, Knuppel RA, et al. Premature rupture of the membranes at term: a comparison of induced and spontaneous labors. J Reprod Med 27:29, 1982. 300. Duff WP, Huff RW, Gibbs RS. Management of the term patient who has premature rupture of the membranes and a cervix unfavorable for induction. Obstet Gynecol63:697, 1984. 301. Conway DI, Prendiville WJ, Morris A, et al. Management of spontaneous rupture of the membranes in the absence of labor in primigravid women at term. Am J Obstet Gynecol 150947, 1984. 302. Wagner MV, Chin VP, Peters CJ, et al. A comparison of early and delayed induction of labor with spontaneous rupture of membranes at term. Obstet Gynecol 7493, 1989.

86

Section I

General Information

303. Meikle SF, Bissell ME, Freedman WL, et al. A retrospective review of the efficacy and safety of PGE, with premature rupture of the membranes at term. Obstet Gynecol 80:76, 1992. 304. Mahmood TA, Dick MJ, Smith NC, et al. Role of prostaglandin in the management of prelabour rupture of the membranes at term. Br J Obstet Gynaecol99112,1992.

Ray DA, Garite TJ. Prostaglandin E, for induction in patients with premature rupture of membranes at term. Am J Obstet Gynecol 166836, 1992. 306. Seaward PGR, Hannah ME, Myhr TL, et al. International multicenter Term PROM Study: evaluation of predictors of neonatal infection in infants born to patients with premature rupture of membranes at term. Am J Obstet Gynecol 179:635, 1998.

305.

Chapter 4 DEVELOPMENTAL IMMUNOLOGY AND ROLE OF HOST DEFENSES IN FETAL AND NEONATAL SUSCEPTIBILITY TO INFECTION David B. Lewis

Christopher B. Wilson

T Lymphocytes and Antigen Presentation 88 Overview Basic Aspects of Antigen Presentation Antigen Presentation in the Fetus and Neonate Circulating Neonatal Dendritic Cells Basic Aspects of T Cell Development and Function T Cell Development and Function in the Fetus and Neonate Gamma-Delta T Cells Antigen-Specific T Cell Function in the Fetus and Neonate Fetal T Cell Sensitization to Maternally Administered Vaccines and Maternally Derived Antigens Summary

8 Cells and Immunoglobulin 127 Basic Aspects of B Cells and Immunoglobulin Production Ontogeny of B Cells and Immunoglobulins Immunoglobulin Synthesis by the Fetus and Neonate Summary Natural Killer Cells

143

Basic Aspects of Natural Killer Cells and Their Function Natural W e r Cell Development and Function in the Fetus and Neonate Summary

Phagocytes 149 Origin and Differentiation of Phagocytes Neutrophilic Polymorphonuclear Leukocytes Neutrophils in the Fetus and Neonate Eosinophilic Granulocytes Mononuclear Phagocytes Mononuclear Phagocytes in the Fetus and Neonate Summary Humoral Mediators of Inflammation and Opsonization 160 Complement C-Reactive Protein Mannan-Binding Lectin Surfactant Apoproteins Lipopolysaccharide-BindingProtein Fibronectin Opsonic Activity Chemotactic Factor Generation Summary Host Defense against Specific Classes of Neonatal Pathogens 164 Pyogenic Bacteria: Group B Streptococci Viruses Nonviral Intracellular Pathogens

lmmunoprophylaxisin the Neonate 180 Passive Immunization Active Immunization Recognition of Primary Immunodeficiency in the Neonate

The human fetus and neonate, particularly the premature neonate, are unduly susceptible to a wide variety of microbes. This susceptibility results from limitations of both innate and adaptive (antigen-specific)immunity, and from limitations in processes through which the innate immune system facilitates and directs the development of protective antigenspecific immunity. This chapter focuses on the ontogeny of the cellular and humoral components of the immune system and their function in the human fetus, neonate, and young infant. Antigen-specific immunity is discussed first, followed by innate mechanisms of host defense. The relationship between deficiencies in immune function in the neonate and fetus and their increased susceptibility to bacterial, viral, and protozoal infections are examined, followed by a brief review of current and potential applications of immunotherapy as therapeutic adjuncts or for the prevention of these infections. The immune system is composed of hematopoietic cells, including lymphocytes, mononuclear phagocytes, myeloid and lymphoid dendritic cells (DCs), and granulocytes; certain nonhematopoietic cells, such as follicular DCs and thymic epithelial cells; and humoral factors, such as cytokines (Tables 4-1 and 4-2) and complement components. The mature hematopoietic cells of mammals are derived from pluripotent hematopoietic stem cells (HSCs). HSCs are generated during ontogeny from embryonic para-aortic tissue (the splanchnopleure), fetal liver, and bone marrow.' The yolk sac, which is extraembryonic, is a major site of nonlymphoid hematopoiesis starting at about the third week of embryonic development and is supplanted by the fetal liver at 8 weeks of gestation and, finally, by the bone marrow after 5 months of gestation. HSCs are found in the para-aortic tissue region by day 27 of human gestation, and cells with blood-forming potential in vitro have been identified in this region as early as day 19 of development.2 Hematopoiesis by the fetal liver and bone marrow is established by seeding of these sites with circulating HSCs derived from para-aortic t i ~ s u e .All ~ major lineages of hematopoietic cells that are part of the immune system are present in the human by the beginning of the second trimester. Their ontogeny from HSCs is discussed in separate sections of this chapter.

Section I

88

Table 4-1

General Information

Major Human Cytokines and TNF Family Ligands: Structure, Cognate Receptors, and Receptor-MediatedSignal Transduction Pathways

Cytokine Family

Members

Structure

IL-1

IL-la, IL-1P. IL-18 (IL-ly), and IL-1

P-Trefoil, monomers; processed and

receptor antagonist

Hematopoietin

TNF ligand

IL-2-IL-7, IL-9-IL3, IL-15, IL-17, IL-19, IL-29, CSFS, oncostatin-M,and IFNs (a, 0, y, and others); class II subfamily consists of IL-10. IL-19, IL-20. IL-22, IL-24, IL-26, and IFNs TNF-a, lymphotoxin-a, -p, CD27L. CD3OL. CD40L, OX40L. TRAIL, and others

secreted Four a-helical; monomers except for IL-5 and IFNs (homodimers)and IL-12, IL-23, and

Cognate Receptor Family

Proximal Signal Transduction Pathway(s)

IL-1 receptor

IRAK; INK

Hematopoietin receptors

JAK tyrosine kinased STAT, Src and Syk

TNF receptor family

TRAFs and proteins

TGF-P receptors type 1 and type 2

Smad proteins

tyrosine kinases

IL-27

(heterodimers); secreted P-Jellyroll;

homotrimers; type II membrane

mediating apoptosis

proteins and

TGF-P

TGF-P1, -P2, -p3, bone

morphogenetic proteins

secreted Cysteine knot; processed and secreted

heterodimers

(intrinsic serine threonine

kinases) Three-stranded

Chemokines

P-sheet; all but

fractalkine are secreted CXC ligand subfamily CC ligand subfamily

C ligand subfamily CX3C ligand subfamily

CXCL1-14, CXCL16 CCLl-5, CCL7, CCL8, C C L l l , CCL13-CCL28 XCL1 (lymphotactin), XCL2 (SCM-1 P) CX3CL (fractalkine)

Seven membranespanning domains

G protein-mediated

CXCRl-CXCR6 CCRl-CCRlO XCR1

CX3CR1

interferon; IL, interleukin; IRAK, IL-1 receptor-associated serinehhreonine kinase; JNK, c-Jun N-terminal kinase; STAT, signal transducer and activator of transcription;TGF, transforming growth factor; TNF, tumor necrosis factor; TRAFs, TNF-a receptor-associated factors; TRAIL, TNF-related apoptosis-inducing ligand.

CSF, colony-stimulating factors; IFN,

T LYMPHOCYTES AND ANTIGEN PRESENTATION

Overview T lymphocytes, which are commonly referred to as T cells, are so named because the vast majority originate in the thymus. Along with B lymphocytes (B cells), which develop in the bone marrow, T cells comprise the adaptive or antigenspecific immune system. T lymphocytes play a central role in antigen-specific immunity because they directly mediate cellular immune responses and play a critical role in facilitating antigen-specific humoral immune responses by B cells. Most T cells recognize antigen in the form of peptides bound to major histocompatibility complex (MHC) molecules on antigen-presenting cells (APCs). Antigen-specific T cell receptors (TCRs) are heterodimeric molecules composed of either a and P chains (UP-TCRs) (Fig. 4-1) or y and 6 chains (~G-TCRS).~ The amino-terminal portion of each of these chains is variable and is involved in antigen recognition. As

discussed later, the highly variable nature of this portion of the TCR is generated, in large part, as a result of TCR gene rearrangement of variable (V), diversity (D), and joining (J) segments. By contrast, the carboxy-terminal region of each of the four TCR chains is monomorphic or constant. The TCR on the cell surface is invariably associated with the nonpolymorphic complex of CD3 proteins, which include CD3-y, -6,-E, and -6 (see Fig. 4-1).5*6 The cytoplasmicdomains of proteins of the CD3 complex include 10 immunoreceptor tyrosine-based activation motifs (ITAMs), which serve as docking sites for intracellular tyrosine kinases that transduce activation signals to the interior of the cell after the TCR has been engaged by antigen.6 Nearly all T cells that bear an aP-TCR, hereafter referred to as aP T cells, also express on their surface the CD4 or CD8 co-receptors in a mutually exclusive manner. The CD4 co-receptor is expressed as a monomeric or homo-oligomeric complex.’ The CD8 co-receptor may consist either of CD8-dCD8-P heterodimers or CD8-aICD8-a homodimers.8 The aP T cells mainly express CD8-aICD8-P heterodimers; a subset of T cells with y8-TCRs, hereafter referred to as yS

Chapter 4

Table 4-2

Developmental Immunology and Role o f Host Defenses in Susceptibility to Infection

lmmunoregulatory Effects of Select Cytokines, Chemokines, and TNF Ligand Family Proteins and Their Production by Human Neonatal Cells

Cytokine

Principal Cell Source

Major Biologic Effects

IL-la, IL-1-p

Many cell types; Mg are a major source

IL-2

T cells

IL-3

T cells

Fever, inflammatory response, cofactor in T and B cell growth T > B cell growth, increased cytotoxicity by T and NK cells, increased cytokine production and sensitivity t o apoptosis by T cells, growth and survival of regulatory T cells Growth of early hematopoietic precursors (also known as multi-CSF)

IL-4

T cells, mast cells, basophils, eosinophils

IL-5

T cells, NK cells, mast celIs, basophiIs, eosinophils Mg, fibroblasts, T cells

IL-6

Required for IgE synthesis; enhances B cell growth and MHC class II expression; promotes T cell growth and TH2 differentiation, mast cell growth factor; enhances endothelial VCAM-1 expression Eosinophil growth, differentiation, and survival Hepatic acute-phase protein synthesis, fever, T and B cell growth and differentiation

Stromal cells of bone marrow and thymus Mg, endothelial cells, fibroblasts, epithelial cells, T cells

Essential thymocyte growth factor Chemotaxis and activation of neutrophils

IL-9

T cells, mast cells

IL-10

Mg, T, cells, B cells, NK cells, B cells, NK cells, keratinocyes, eosinophils

T cell and mast cell growth factor Inhibits cytokine production by T cells and mononuclear cell inflammatory function; promotes B cell growth and isotype switching, NK cell cytotoxicity

IL-11

Marrow stromal cells, fibroblasts

IL-7 IL-8 (CXCL8)

89

Hematopoietic precursor growth, acute-phase reactants by hepatocytes

Production by Neonatal versus Adult Cells MNCs: normal after LPS treatment; ?reduced in premature T cells: normal with most polyclonal stimuli; neonatal < adult after CD3 mAb treatment

T cells: neonatal and

adult naive < adult memory MNCs: neonatal < adult T cells: Neonatal and adult naive c adult memory

Reference(s) 1080, 1405 326, 342, 343

342, 1406, 1407

342, 343

T cells: neonatal and adult naive < adult memory T cells: neonatal c adult naive < adult memory MNC: term normal t o slightly reduced; premature -25% of adult Mg: neonatal < adult after RSV infection Whole blood: neonatal = adult Not known

342

MNCs: neonatal < adult or normal in different studies using LPS stimulation; preterm c term Mg: decreased after GBS incubation Whole blood: neonatal = adult Not known

1082, 1083, 1408, 1413

T cells: neonatal and adult naive < adult memory MNC: neonatal < adult (lectin or LPS) Mg: neonatal c adult Whole blood: neonatal = adult Fibroblasts: neonatal > adult

346, 731, 1088, 1408

1408-1412

1414

contimed

90

Section I

Table 4-2

General Information

lmmunoregulatory Effects of Select Cytokines, Chemokines, and TNF Ligand Family Proteins and Their Production by Human Neonatal Cells-cont'd

Cytokine



IL-12

Dendritic cells, MI$

Enhances T1, differentiation, T cell growth, T cell and NK cell cytotoxicity; induces IFN-y secretion by T cells and NK cells; enhances B cell response t o TI antigens

IL-13

T cells, mast cells, basophils, eosinophils

IL-15

Epithelial cells, bone marrow stromal cells, activated monocytes

IL-17

T cells

IL-18

Macrophages, hepatic Kupffer cells, intestinal and skin epithelia

IL-21

T cells

IL-23

Dendritic cells, M@

IL-25

TH2 cells, mast cells

IL-27

Dendritic cells, M@

IFN-u

Dendritic cells, M@

Very similar t o those of IL4, with possible exception of lacking direct T cell effects and greater effect on goblet cells of lung Enhances NK cell development, growth, survival, cytotoxicity, and cytokine production; T cell chemoattractant and growth factor Enhances T cell proliferation; proinflammatory cytokine release by macrophages Promotes TH1 differentiation; production of IL-2 and GM-CSF by T cells, and IFN-y by T cells, NK cells, and B cells; T cell- and NK cell-mediated cytotoxicity, DC recruitment Enhances proliferation of B cells, naive T cells; NK cell differentiation and cytotoxicity Similar effects t o those of IL-12 Promotes T,2 cytokine secretion by T cells and APCs (?Me) Promotes responsiveness of T cells t o IL-12; inhibits T2 , differentiation Inhibits viral replication; increases MHC class I expression and NK cell cytotoxicity

IFN-P

Fibroblasts, epithelial cells, dendritic cells T cells, NK cells, eosinophils (?), IL-18-st imu Iat ed B cells

IFN-.I

Same as for IFN-a Same as for IFN-a and -P; also activates M@, increases MHC class II and antigen presentation molecules, inhibits IgE production, enhances B cell response t o TI antigens, promotes TH1 differentiation

Production by Neonatal versus Adult Cells MNCs: neonatal and young children < adult or normal after LPS in different studies; normal in response t o 5. aureus DC: neonatal < adult in response t o LPS or pertussis toxin T cells: neonatal and adult nai've CD4' < adult memory CD4' Neonatal CD8+> adult CD8' MNC: neonatal < adult after LPS stimulation

Reference(s) 69, 73, 85-88, 91 1, 1415, 1416

358, 1417

89 1

Not known MNCs: neonatal 65% of adult in response t o group B streptococci

1093

Not known

Not known Not known Not known MNCs: normal to some sti rnuIi but reduced t o most stimuli, including HSV, pa rainf luenza virus, unmethylated CpG DNA and poly (l:C), particularly in premature MNC: normal

69, 82, 83, 84, 1091, 1418

T cells: neonatal and adult nai've < adult memory; neonatal < adult nai've with allostirnulation NK cells: normal after HSV and IL-2 st imulat ion MNCs: neonatal < adult after IL-12 and IL-15 treatment

86, 326, 343, 356, 891, 924, 1415, 1419

82

continued

Chapter 4

Table 4-2

Developmental Immunology and Role of Host Defenses in Susceptibility to Infection

91

lmmunoregulatory Effects of Select Cytokines, Chemokines, and TNF Ligand Family Proteins and Their Production by Human Neonatal Cellcont'd ~~

Cytokine



TNF-a

Mg, T cells, and NK cells

Fever and inflammatory response effects similar t o IL-1, shock, hemorrhagic necrosis of tumors, and increased VCAM-1 expression on endothelium; induces catabolic state

T cells, lower amounts

B cell growth factor; promotes isotype switching, promotes IL-12 production by dendritic cells, activates Mg

CD40 ligand (CD154)

by B cells and DCs

Fas ligand

Flt-3 ligand

Activated T cells, NK cells retina, testicular epithelium Bone marrow stromal cells

G-CSF

Mg, fibroblasts, epithelial cells

GM-CSF

M@,endothelial cells, T cells

CCL3 (MIP-la)

Mg, T cells

CCL5 (RANTES)

Mg, T cells, fibroblasts, epithelial cells

TGF-D

Mg, T cells, fibroblasts, epithelial cells, others

Induces apoptosis of cells expressing Fas, including effector B and T cells Potent DC growth factor; promotes growth of myeloid and lymphoid progenitor cells in conjunction with other cytokines Growth of granulocyte precursors

Growth of granulocyte-Mg precursors and dendritic cells, enhances granulocyte-M@function and B cell antibody production Mg chemoattractant; T cell activator M@and memory T cell chemoattractant; enhances T cell activation; blocks HIV co-receptor Inhibits M@activation; inhibits T,1 T cell responses

Production by Neonatal versus Adult Cells T cells: neonatal c adult

MNCs: neonatal < adult after IL-15 or LPS treatment Me: neonatal c adult after RSV infection; preterm c adult after LPS treatment Whole blood: neonatal = adult T cells: neonatal < adult naive after calcium ionophore and phorbol ester; neonatal I adult or adult nalve after CD3 mAb and allostimulation T cells: neonatal < adult after CD3 and CD28 mAbs Unknown

Reference(s) 348, 891, 1080, 1408, 1412, 1420

356, 362, 364, 376-379

362

MNCs: neonate normal or slightly 24 hours), and cesarean section or instrument delivery. The reservoirs for transmission of Klebsiella infections include the hands of health care workers and the gastrointestinal tracts of hospitalized infants. Multidrug resistance, in the form of extended spectrum p-lactamase production, of Klebsiella strains causing neonatal infections and nursery outbreaks has become a substantial problem in some nurseries and is associated with increased morbidity and mortality.'24-'26Enhanced infection control measures and changes in use of routine broad-spectrum antibiotics can reduce the frequency of these serious infections. Among the Enterobacter aerogenes (i.e., Aerobacter aerogenes) species, Enterobacter cloacae, Enterobacter sakazakii, and Enterobacter hormaechei have caused sepsis and a severe form of necrotizing meningitis in neonate^.'*^-'^* Enterobacter septicemia was the most common nosocomial infection in neonates at the Ondokuz Mayis University Hospital in Samsun, Turkey, from 1988 to 1992.'33Willis and Robinson'28 reviewed 17 cases of neonatal meningitis caused by E. sakazakii; cerebral abscess or cyst formation developed in 77% of the infants, and 50% of the infants died. Bonadio and colleague~'*~ reviewed 30 cases of E. cloacae bacteremia in children, including 10 infants younger than 2 months old. Of importance was the high frequency of multidrug resistance among isolates from patients in the neonatal intensive care units that was attributed to routine extended spectrum cephalosporin usage.'34 In addition to the gastrointestinal tracts of hospitalized infants and hands of health care personnel, sources and modes of transmission of Enterobacter infections in the neonate include contaminated infant f ~ r m u l a , ' ~contaminated ~,'~~ total parented nutrition f l ~ i d , ' ~ ~bladder , ' ~ ' catheterization device~,'~'and contaminated ~ a1ine. I~ Effective ~ infection control measures require reinforcement of procedures, including proper hand hygiene, aseptic technique, isolation protocols, and disinfection of environmental surfaces.

Citrobacter Species Organisms of the genus Citrobacter are gram-negative bacilli that are occasional inhabitants of the gastrointestinal tract and are responsible for disease in neonates and debilitated or immunocompromised patients. The genus has undergone

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255

hygiene washes,151and lipid parented feeds.'53The gastrofrequent changes in nomenclature, making it difficult to relate the types identified in reports of newborn disease over intestinal tracts of hospitalized infants provide a reservoir the years. For example, in 1990, Citrobacter koseri replaced for transmission and infe~ti0n.l~' In a review of neonatal bacteremia and meningitis caused Citrobacter diver~us.'~'For the purposes of this chapter, by S. marcescens by Campbell and colleague^,'^^ 11 (29%) of C. koseri replaces C. diversus, even though the original article 38 infants had meningitis as a complication of their may refer to the latter name. bacteremia. Mean gestational age and birth weight were Citrobacter species are responsible for sporadic and 28 weeks and 1099g, respectively. All patients required epidemic clusters of neonatal sepsis and meningitis, and C. koseri is uniquely associated with brain a b s c e s s e ~ . ~ ~ mechanical ~ - ~ ~ ~ ventilation, 90% had central venous catheters in situ, 90% had received prior antibiotics, 50% had a prior Neonatal disease can occur as early-onset or late-onset preintraventricular hemorrhage, 40% had a hemodynamically sentations. Outbreaks of C. koseri in neonatal intensive care units resulting in sepsis and meningitis, septic arthritis, and significant patent ductus arteriosis treated medically or skin and soft tissue infections were reviewed by Doran.14' surgically, and 20% had necrotizing enterocolitis with perfoOther focal infections in neonates due to Citrobacter species ration. All patients were treated for a minimum of 21 days include bone, pulmonary, and urinary tract infection^.'^' with combination antimicrobial therapy that included a During the period of 1960 to 1980,74 cases of meningitis third-generation cephalosporin or a ureidopenicillin and an aminoglycoside, typically gentamicin. Three of 10 patients caused by Citrobacter species were reported to the Centers for Disease Control and Prevention (CDC) of the U.S. Public died. Four of the seven survivors developed severe hydroHealth Servi~e.'~' In 1999, Doran reviewed an additional 56 cephalus requiring ventriculoperitoneal shunt placement and cases of neonatal meningitis due to Citrobacter species.'40 had poor neurologic outcome. Poor neurologic outcome also was documented in a report of S. marcescens brain abscess Combining results from the two studies, brain abscess resulting in multicystic encephalomalacia and severe developdeveloped in 73 (76%) of 96 patients for whom information mental retardati~n.'~~ was available. The pathogenesis of brain abscess caused by C. koseri is uncertain; cerebral vasculitis with infarction and l? aeruginosa usually is a cause of late-onset disease in bacterial invasion of necrotic tissues is the likely explanation.146 infants who are presumably infected from their endogenous Persistence of C. koseri in the central nervous system is flora or from equipment, from aqueous solutions, or suggested by a case report of recovery of the organism from occasionally from the hands of health care workers. Stevens the CSF during a surgical procedure 4 years after treatment and colleague^'^ reported nine infants with Pseudomonas sepsis, four of whom presented in the first 72 hours of life. In of neonatal meningiti~.'~~ The mortality rate for meningitis three of these infants, the initial signs were those of due to Citrobacter specieswas about 30%; most of the infants respiratory distress, and chest radiographs were consistent who survived had some degree of mental retardation. A with hyaline membrane disease. Noma (i.e., gangrenous review of 110 survivors of Citrobacter meningitis revealed lesions of the nose, lips, and mouth) in a neonate has been only 20 infants who were believed to have structurally intact associated with bacteremia caused by l? aerugir~osa.'~~ brains and development that was age appr~priate.'~' Citrobacter species usually are resistant to ampicillin and A retrospective review of sepsis in infants admitted over variably susceptible to aminoglycosides. Historically, most the 10-year period from 1988 through 1997 to the neonatal intensive care unit at Children's Hospital of the King's infants were treated with a combination of penicillin or Daughters in Norfolk, Virginia, identified 825 cases of latecephalosporin plus an aminoglycoside. Surgical drainage has onset sepsis.17Infants with Pseudomonas sepsis had the highest been used in some cases with variable success. Choosing antimicrobial agents with the most advantageous susceptibility frequency of clinically fulminant onset (56%), and 20 (56%) pattern and selected surgical drainage appears to be the most of the 36 (56%) infants with Pseudomonas sepsis died within promising approach to therapy, but no one regimen has 48 hours of blood culture collection. been found to be more successful than another. Plasmid l? aeruginosa conjunctivitis in the neonate is a danger because it is rapidly destructive to the tissues of the eye profiles, biotypes, serotypes, and chromosomal restriction endonuclease digests are useful as epidemiologic markers for and because it may lead to sepsis and meningitis. Shah the study of isolates of C. koseri. Morris and colleague^'^^ and Gallagher'58 reviewed the course of 18 infants at Yale-New Haven Hospital newborn intensive care unit used these markers to investigate an outbreak of six cases of who had l? aeruginosa isolated from cultures of the conneonatal meningitis caused by C. koseri in three Baltimore junctiva during the 10 years beginning in 1986. Five infants hospitals between 1983 and 1985. Identification of a specific outer membrane protein associated with strains isolated developed bacteremia, including three with meningitis, and from CSF but uncommon elsewhere can provide a marker two infants died. for virulent strains of C. koseri according to some investigator~.'~~

Salmonella Species

Serratia marcescens and Pseudomonas Species Like other members of Enterobacteriaceae,Serratia marcescens increasingly is associated with hospital-acquired infections among infants in the neonatal intensive care nit.'^^-'^^ Lateonset sepsis has occurred in infants infected from health care e q ~ i p m e n t , ' ~ ' -the ' ~ ~h ands of heath care workers,154milk bottle^,'^' aqueous solutions such as the~phylline,'~'hand

Nontyphi Salmonella infection is an uncommon cause of sepsis and meningitis in neonates, but a significant proportion of cases of Salmonella meningitis occur in young infants. The CDC observed that approximately one third of 290 Salmonella isolates from CSF reported during 1968 to 1979 were from patients younger than 3 months of age, and more than one half were from infants younger than 1 year of age.'59A 21-year review of gram-negative enteric meningitis

256

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Bacterial Infections

in Dallas beginning in 1969 identified Salmonella as the cause in 4 of 72 cases.@Investigators from Turkey reported seven cases of neonatal meningitis caused by Salmonella during the years 1995 to 2001.'60Two of the five survivors developed communicating hydrocephalus, and one had a subdural empyema. Reed and Kl~gman'~' reviewed 10 cases of neonatal typhoid that occurred in a rural African hospital. Six of the infants had early-onset sepsis with acquisition of the organism from the maternal genital tract, and four had late-onset infection with acquisition from a carrier or an environmental source. Two neonates developed meningitis, and three died.

mortality rate was 90% for 20 infants with a gestation lasting less than 30 weeks. Clinical and epidemiologic characteristics were similar to those of neonatal disease caused by group B streptococci, including early-onset (within 24 hours of birth) and late-onset presentations, signs simulating respiratory distress syndrome, and a high mortality rate. Autopsy of infants with bacteremia related to nontypeable H. influenzae and signs of respiratory distress syndrome revealed hyaline membranes with gram-negative coccobacilli within the membranes, similar to findings of hyaline membranes due to group B streptoc~cci.'~'Examination of placentas from mothers of infants with sepsis caused by nontypeable H. influenzae revealed acute chorioamnionitis and acute villitis in some.183H. influenzae also has been responsible for Neisseria meningitidis maternal disease, including bacteremia, chorioamnionitis,'88 acute or chronic salpingitis, and tubo-ovarian abscess.'84 Although N. meningitidis is a leading cause of bacterial sepsis and meningitis among children and adolescents, it Neonatal sepsis caused by Haem~philwparainfluenzae'~~-'~' rarely is associated with invasive infection in and Haemophilus a p h r o p h i l ~ s 'has ~ ~ been reported. N. rneningitidis may colonize the female genital t r a ~ t ' ~ ' . ' ~ ~ and has been associated with pelvic inflammatory disease.IM Streptococcus pneumoniae The infant can be infected at delivery by organisms present Although pneumococci rarely are isolated from cultures in the maternal genital tract, or intrauterine infection can result during maternal meningoc~ccemia.'~~ Meningococcal from the cervix or vagina of gynecologic patients or pregnant sepsis is rare in the neonate, but more than 50 cases women, cases of early-onset pneumococcal sepsis in neonates have been r e p ~ r t e d . ' ~ ~Bortolussi -'~' and colleague^"^ (including 13 from the preantibiotic era) have been d e ~ c r i b e d . ' ~Early-onset ~-'~~ and late-onset f ~ r r n s ' ~ ~of * ' ~ , reported '~~ five infants with pneumococcal sepsis who had respiratory distress and clinical signs of infection on the first meningococcal sepsis in neonates have been reported. Purpura day of life. Three infants died, two within 12 hours of onset. similar to that of meningococcemia in older children has been observed in a 15-day-0ld'~'and a 25-day-old infant.'72 S. pneumoniae was isolated from the vaginas of three of the Shepard and colleagues'70from the CDC reported 22 mothers. Radiographic features were consistent with hyaline neonates with invasive meningococcal disease from a membrane disease or pneumonia, or both. The clinical 10-year active, population-based surveillance of 10 states features were strikingly similar to those of early-onset group with diverse populations and more than 31 million persons. B streptococcal infection, including the association of The average annual incidence was 9 cases per 100,000 people prolonged interval after rupture of membranes, early-onset (versus 973.8 per 100,000 for group B Streptococcus). Sixteen respiratory distress, abnormal chest roentgenograms, hypotension, leukopenia, and rapid deterioration. Fatal pneumopatients had meningitis, and 6 of these also had meningococcemia. Six patients had early-onset disease. The overall coccal bacteremia in a mother 4 weeks postpartum, and the same disease and outcome in her healthy term infant who mortality rate was 14%. Ten isolates were serogroup B, four died at 6 weeks of age, suggested an absence of protective were serogroup C, three were serogroup Y, one was nonantibody in mother and groupable, and four were unavailable. Hoffman and colleagues from the United States Multicenter Pneumococcal Surveillance G r o ~ p "reported ~ 20 cases Haemophilus influenzae of neonatal S. pneumoniae sepsis or meningitis in a review of 4428 episodes of pneumococcal infection at eight children's Because of the introduction of H. influenzae type b conjuhospitals from 1993 to 2001. Ninety percent of the infants gate vaccines in 1988, there has been a substantial decrease were born at term, with a mean age at the onset of infection in the incidence in H. influenzae type b disease in infants and children in the United States and many other c ~ u n t r i e s . ' ~ ~ - 'of ~ ~18.1 days. Only two of the mothers had clinically apparent Given the estimated proportion of individuals that are infections at the time of delivery. Eight neonates had completely immunized, the decrease in H. influenzae type b meningitis and 12 had bacteremia; four of the bacteremic neonates also had pneumonia. The most common infecting invasive disease has exceeded expectations. The reduction in H. influenzae carriage associated with vaccination and the pneumococcal serotypes were 19 (32%), 9 (18%), and 18 consequent decreased transmission from immunized (11Yo). Penicillin and ceftriaxone nonsusceptibility were observed in 21.4% and 3.6% of isolates, respectively. Three children to unimmunized infants and children likely deaths (15%) occurred, all within 36 hours of presentation. explains this Despite increased reporting of invasive infections caused by nontypeable H. influenzae in adults and older ~ h i l d r e n , ' ~ ~ - ' ~ ' Anaerobic Bacteria such infections in neonates remain uncommon.182-'85Four clinical syndromes have been associated with neonatal Improvements in techniques for isolation and identification of the various genera and species of anaerobic bacteria have disease caused by H. influenzae: sepsis or respiratory distress provided a better understanding of the anaerobic flora of syndrome; meningitis; soft tissue or joint infection; and humans and their role in disease.'99With the exception of otitis media or mastoiditis. The overall mortality rate was Clostridium tetani and Clostridium botulinum, all of the 5.5% for 45 cases reviewed by Friesen and Cho'"; the

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257

anaerobic bacteria belong to the normal flora of humans. In contrast to the United States, most cases of tetanus worldwide occur in neonates. In developing countries, the Anaerobes are present on the skin, in the mouth, in the incidence and mortality of neonatal tetanus remain high.222-224 intestines, and in the genital tract. They account for the Mustafa and colleagues225conducted a retrospective neonatal greatest proportion of the bacteria of the stool. AU are tetanus survey among rural and displaced communities in present in the intestines, and have been isolated from the the East Nile Province in the Sudan and observed that neoexternal genitalia or vagina of pregnant and nonpregnant natal tetanus was a major cause of neonatal mortality. The women.200-202 Newborns are colonized with these organisms incidence in the displaced community was 7.1 cases per 1000 during or just before delivery. A review of the literature on livebirths, more than double that reported from the stable neonatal bacteremia due to anaerobic bacteria by Brook203in rural community (3.2 per 1000). In both communities, 1990 included 179 cases, with a mortality rate of 26%. coverage with two doses of tetanus toxoid was about 58%. Bacteroides and Clostridiurn species were the most common isolates. Predisposing factors for infection included premature The mortality rate for neonatal tetanus in Djakarta in 1982 was 6.9 deaths per 1000 livebirths; in the island provinces rupture of membranes, preterm delivery, and necrotizing of Indonesia, it was 10.7 deaths per 1000 livebirths.226The enterocolitis. mortality rate for neonates with tetanus in Lima, Peru, was Anaerobic bacteria have been isolated from the blood of 45% and was not improved with use of intrathecal tetanus newborns with sepsis,2M-2M from various or ans at autopsy:o4 from an infant with an adrenal abscess? from an infant antitoxin.227However, a meta-analysis of intrathecal therapy in tetanus suggested benefit in adults but not in neonates.22s with an infected cephalhematoma?" and from infants with Application of contaminated materials to the umbilical necrotizing fasciitis of the scalp associated with placement of cord is associated with deep-rooted customs and rituals in a scalp ele~trode.2'~ Fede?' reviewed meningitis caused by developing countries. A case-control study to identify risk Bacteroides fragilis; seven of nine reported cases occurred in factors for neonatal tetanus in rural Pakistan identified neonates. application of ghee (i.e., clarified butter from the milk of The incidence of neonatal sepsis caused by anaerobic water buffaloes or cows) to the umbilical wound as the single bacteria remains uncertain, but recent data are available from some surveys that suggest the incidence is low (lo00 per mm3),with a majority of polymorphosuccess. Among products that have been evaluated and nuclear cells, suggest rupture of the abscess into the CSF. found to be inadequate to distinguish bacterial meningitis from other neurologic disease (including cerebroventricular hemorrhage and asphyxia) are y-aminobutyric acid?% lactate Laboratory Aids dehydr~genase?~~ and creatine kinase brain i~oenzyme.~*~ Laboratory aids in the diagnosis of systemic and focal Cycli~-3',5'-adenosine monophosphate was elevated in the infection in the neonate include peripheral white blood cell CSF of neonates with bacterial meningitis compared with and differential counts, platelet counts, acute-phase reactants, the CSF of infants who had nonbacterial meningitis or a blood chemistries, histopathology of the placenta and control group.589Elevated CSF concentrations of C-reactive umbilical cord, smears of gastric or tracheal aspirates, and protein have been reported for infants older than 4 weeks diagnostic imaging studies. New assays for diagnosis of earlywith bacterial meningitis5903591; however, the test was found onset sepsis, including serum concentrations of neutrophil to be of no value in neonate^.^^',^^^ Current investigations of CD 1lb,M15 granulocytecolony-stimulatingfactor,% interleukin the pro-inflammatory cytokines interleukin-6 and interleukinreceptor interle~kin-6,60~-~'~ and pro~alcitonin,6'~-~~~ 8 indicate that there is a cytokine response in the CSF after show promise for increased sensitivity and specificity birth asphyxia and that these assays are not useful in compared with other laboratory assessments, such as white detecting the infant with meningitis.593B594 blood cell count, absolute neutrophil count, and acute-phase THE TRAUMATIC LUMBAR PUNCTURE reactants. However, pro-inflammatory cytokines, including interleukin- 1 and interleukin-6 and tumor necrosis factor-a, A traumatic lumbar puncture can result in blood in the CSF have been identified in serum and CSF in infants after and can complicate the interpretation of the results for CSF perinatal asphyxia, raisin doubts about the specificity of white blood cell count and chemistries. Schwersenski and some of these r n a r k e r ~ ? ~ ~ Mehr ~ ~ ~ and " ' ~Doyle6I6 ~ ~ ' ~ review colleagues563found that 13.8% of 712 CSF specimens the recent literature on cytokines as aids in the diagnosis of obtained during the first week of life were bloody and that neonatal bacterial sepsis. These assays and procedures are an additional 14.5% were considered inadequate for testing. discussed in detail in Chapter 36. If the total number of white blood cells compared with the number of red blood cells exceeds the value for whole blood, the presence of CSF pleocytosis is suggested. Some MANAGEMENT investigators have found that the observed white blood cell counts in bloody CSF were lower than would be predicted based on the ratio of white-to-red blood cells in peripheral If the maternal history or infant clinical signs suggest the blood; the white blood cells lyse more rapidly than red blood possibility of neonatal sepsis, blood and CSF (all infants) and cultures of urine and other clinically evident focal sites cells, or the number of white blood cells is decreased for should be collected (all infants with suspected late-onset other reason^.^^^-^^' Several formulas have been used in an infection). If respiratory abnormalities are apparent or attempt to interpret cytologic findings in CSF contaminated

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respiratory status has changed, a radiograph of the chest should be performed. Because the clinical manifestations of sepsis can be subtle, the progression of the disease can be rapid, and the mortality rate remains high when compared with that for older infants with serious bacterial infection, empirical treatment should be initiated promptly. Many infants who have a clinical course typical of bacterial sepsis are treated empirically because of the imperfect sensitivity of a single blood culture in the diagnosis of sepsis.

Choice of Antimicrobial Agents Initial Therapy for Presumed Sepsis The choice of antimicrobial agents for the treatment of suspected sepsis is based on knowledge of the prevalent organisms responsible for neonatal sepsis by age of onset and hospital setting as well as on their patterns of antimicrobial susceptibility. Initial therapy for the infant who develops clinical signs of sepsis during the first few days of life (early-onset disease) must include agents active against gram-positive cocci, particularly group B Streptococcus, other streptococci, and L. rnonocytogenes, and gram-negative enteric bacilli. Treatment of the infant who becomes septic while in the nursery after age 6 days (late-onset disease) must include therapy for hospital-acquired organisms, such as S. aureus, gram-negative enteric bacilli, CoNS (in the VLBW infant), and occasionally I? aeruginosa, as well as for maternally acquired etiologic agents. Group B streptococci continue to demonstrate uniform in vitro susceptibility to penicillins and cephalosporins. In a study of 231 isolates of group B streptococci from patients with invasive infection, all strains were killed by concentrations of penicillin G of less than 0.25 ~LglmL.6~~ Ampicillin, the penicillinase-resistant penicillins, and third-generation cephalosporins also are active in vitro but aminoglycosides are relatively inactive. In vitro studies6'8-620 and experimental animal models of bacteremia,6z'.6z2however, indicate that the bactericidal activity of ampicillin and penicillin against group B streptococci and L. monocytogenes is enhanced by the addition of gentamicin (synergy). Some physicians prefer to continue the combination of ampicillin and gentamicin for 48 to 72 hours, but once group B Streptococcus is identified as the etiologic agent, the drug of choice for therapy is penicillin administered intravenously for the remainder of the treatment regimen. There are no clinical data to indicate that continuing an aminoglycoside in combination with a penicillin results in more rapid recovery or improved outcome for infected neonates (see Chapter 13). Most strains of S. aureus that cause disease in neonates produce P-lactamase and are resistant to penicillin G and ampicillin. Many of these organisms are susceptible to the penicillinase-resistant penicillins, such as nafcillin, and to first-generation cephalosporins. Methicillin-resistant staphylococci that are resistant to other penicillinase-resistant penicillins and cephalosporins have been encountered in many nurseries in the United States. Antimicrobial susceptibility patterns must be monitored by surveillance of staphylococcal strains causing infection and disease in each neonatal intensive care unit. Bacterial resistance must be considered whenever staphylococcal disease is suspected or confirmed in a patient, and empirical vancomycin therapy

should be initiated until the susceptibility pattern of the organism is known. Virtually all staphylococcal strains isolated from neonates have been susceptible to vancomycin. Synergistic activity is provided by the combination of an aminoglycoside (see Chapter 17). Vancomycin- or glycopeptideresistant S. aureus has been reported from Japan and the United States, but none of these strains has been isolated from neonates. CoNS can cause systemic infection in VLBW infants and in neonates with or without devices such as an intravascular catheter or a ventriculoperitoneal shunt. Vancomycin is the drug of choice for treatment of serious CoNS infections. If daily cultures from an indwelling device continue to grow CoNS, removal of the foreign material probably will be necessary to cure the infection. Group D streptococci vary in their susceptibility to penicillins. Nonenterococcal strains, including S. bovis, are highly susceptible to penicillin, but Enterococcus species are only moderately susceptible to penicillin and highly resistant to cephalosporins. Optimal antimicrobial therapy for neonatal infections caused by Enterococcus includes ampicillin or vancomycin in addition to an aminoglycoside, typically gentamicin or tobramycin. L. monocytogenes is susceptible to penicillin and ampicillin and resistant to cephalosporins. Ampicillin is the preferred agent for treating L. monocytogenes, although an aminoglycoside can be continued in combination with ampicillin if the patient has meningitis. Specific management of L. monocytogenes infection is discussed in Chapter 14. The choice of antibiotic therapy for infections caused by gram-negative bacilli depends on the pattern of susceptibility for these isolates in the nursery that cares for the neonate. These patterns vary by hospital or community and by time within the same institution or community. Although isolates from neonates should be monitored to determine the emergence of new strains with unique antimicrobial susceptibility patterns, the general pattern of antibiotic susceptibility in the hospital is a good guide to initial therapy for neonates. The aminoglycosides, including gentamicin, tobramycin, netilmicin, and amikacin, are highly active in vitro against virtually all isolates of E. coli, €? aeruginosa, and Enterobacter, Klebsiella, and Proteus species.

Role of Third-Generation Cephalosporins The third-generation cephalosporins, cefotaxime, ceftriaxone, and ceftazidime, possess attractive features for therapy for bacterial sepsis and meningitis in newborns. These features include excellent in vitro activity against group B streptococci and E. coli and other gram-negative enteric bacilli. Ceftazidime is highly active in vitro against I? aeruginosa. None of the cephalosporins is active against L. rnonocytogenes or Enterococcus, and activity against S. aureus is variable. These cephalosporins provide concentrations of drug at most sites of infection that greatly exceed the minimum inhibitory concentrations of susceptible pathogens, and there is no dose-related toxicity. Clinical and microbiologic results of studies of sepsis and meningitis in neonates suggest that the third-generation cephalosporins are comparable to the traditional regimens of penicillin and an aminoglycoside (see Chapter 37).623-626Because ceftriaxone can displace bilirubin from serum albumin, it is not recommended for

Chapter 6 use in neonates unless it is the only agent effective against the bacterial pathogen. The rapid development of resistance of gram-negative enteric bacilli when cefotaxime is used extensively for presumptive therapy for neonatal sepsis suggests that extensive use of third or fourth-generation cephalosporins can lead to rapid emergence of drug-resistant bacteria in nurseries.627 Empirical use of cefotaxime in neonates should be restricted to those with evidence of meningitis or with gram-negative sepsis. Continued cefotaxime therapy should be limited to those infants with gram-negative meningitis caused by susceptible organisms or those with ampicillin-resistant enteric infections.628

Current Practice The combination of ampicillin and an aminoglycoside,usually gentamicin or tobramycin, is suitable for initial treatment of presumed early-onset neonatal sepsis.629If there is a concern for endemic or epidemic staphylococcal infection, typically occurring beyond 6 days of age, the initial treatment of lateonset neonatal sepsis should include vancomycin. The increasing use of antibiotics, particularly in neonatal intensive care units, can result in alterations in antimicrobial susceptibilitypatterns of bacteria and can necessitate changes in initial empirical therapy. This alteration of the microbial flora in nurseries where the use of broad-spectrum antimicrobial agents is routine supports recommendations from the CDC for the judicious use of antibiotics. The hospital laboratory must regularly monitor isolates of pathogenic bacteria to assist the physician in choosing the most appropriate therapy. The clinical pharmacology and dosage schedules of the various antimicrobial agents considered for neonatal sepsis are provided in Chapter 37.

Continuation of Therapy When Results of Cultures Are Available The choice of antimicrobial therapy should be reevaluated when results of cultures and susceptibility tests become available. The duration of therapy depends on the initial response to the appropriate antibiotics but should be 10 days, with sepsis documented by positive culture of blood and minimal or absent focal infection. The usual duration of therapy for infants with meningitis caused by gram-negative enteric bacilli is 21 days. However, in complicated cases of meningitis caused by gram-negative enteric bacilli, group B streptococci, or other pathogens, the duration of therapy is variable and is best determined in consultation with an infectious diseases specialist. The third-generation cephalosporins cefotaxime, ceftriaxone, and ceftazidime have important theoretical advantages for treatment of sepsis or meningitis compared with therapeutic regimens that include an aminoglycoside. Unlike the aminoglycosides, third-generation cephalosporins are not associated with ototoxicity and nephrotoxicity. However, little toxicity from aminoglycosides occurs when use is brief or, when continued for the duration of therapy, if serum trough levels are maintained at less than 2 pg/mL. Because cephalosporins have no dose-related toxicity, measurements of serum concentrations, obligatory with the use of aminoglycosides beyond 72 hours or in infants with renal


277

insufficiency, are unnecessary. However, routine use of the cephalosporins for presumptive sepsis therapy in neonates often leads to problems with drug-resistant enteric organisms. Extensive use of the third-generation cephalosporins in the nursery could result in the emergence of resistance caused by de-repression of chromosomally mediated p-lactamase~.~~~ Cefotaxime is preferred to other third-generation cephalosporins for use in neonates because it has been used more e x t e n ~ i v e l y ~ ~and ~ - ~because ~ ~ ' ~ ~ it' does not affect the binding of b i l i r ~ b i n . 6Ceftazidime ~ ~ ~ ~ ~ ~ in combination with an aminoglycosideshould be used in therapy for ??aeruginosa meningitis because of its excellent in vitro activity and its good penetration into the CSF. Use of ceftriaxone in the neonate should be determined on a case-by-case basis because of its ability to displace bilirubin from serum albumin and result in biliary sludging.

Management of the Infant Whose Mother Received lntrapartum Antimicrobial Agents Antimicrobial agents commonly are administered to women in labor who have risk factors associated with sepsis in the fetus, including premature delivery, prolonged rupture of membranes, fever, or other signs of chorioamnionitis or group B streptococcal colonization. Antimicrobial agents cross the placenta and achieve concentrations in fetal tissues that are parallel to concentrations achieved in other wellvascularized organs. Placental transport of antibiotics is discussed in more detail in Chapter 37. Protocols for prevention of group B streptococcal infection in the newborn by administration of a penicillin to the mother were published in 1992 by ACOG633and the American Academy of Pediatrics These guidelines were revised in 1996 by the CDC,635in 1997 by the and in 2002 by the CDC,637AAP,and ACOG.504Recent data suggest that nearly 50% of women receive intrapartum chemoprophylaxis because of the presence of one or more risk factors for neonatal sepsis or because of a positive antenatal screening culture for group B Streptoco~cus.6~~ When ampicillin or penicillin is administered to the mother, drug concentrations are achieved in the fetus that are more than 30% of the concentrations in the blood of the mother.639 Concentrations of penicillin, ampicillin, and cefazolin that are bactericidal for group B streptococci are achieved in the amniotic fluid approximately 3 hours after completion of a maternal intravenous dose. Parenteral antibiotic therapy administered to a mother with signs of chorioamnionitis in labor essentially is treating the fetus early in the course of the intrapartum i n f e ~ t i o n . ~How~~'~~' ever, for some infected fetuses, the treatment administered in utero is insufficient to prevent signs of early-onset group B streptococcal disease. Although maternal intrapartum prophylaxis has been associated with a 75% decrease in the incidence of early-onset group B streptococcal disease since 1993,641,642 the regimen has had no impact on the incidence of late-onset disease.643 The various algorithms prepared to guide empirical management of the neonate born to a mother with risk factors for group B streptococcal disease who received intrapartum antimicrobial prophylaxis for prevention of earlyonset group B streptococcal disease focus on three clinical scenari0s504,637,644,645.

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1. Infants who have signs of sepsis should receive a full diagnostic evaluation and should be treated, typically with ampicillin and gentamicin, until laboratory studies are available. 2. Infants born at 35 or more weeks' gestation who appear healthy and whose mothers received intrapartum prophylaxis with penicillin, ampicillin, or cefazolin for 4 or more hours before delivery do not have to be evaluated or treated but should be observed in the hospital for 48 hours. 3. Infants who are less than 35 weeks' gestation who appear healthy and whose mothers received penicillin, ampicillin, or cefazolin for less than 4 hours before delivery should receive a limited evaluation, including a blood culture and a complete blood cell count with a differential count, and be observed for 48 hours in the hospital. The same management probably is necessary for infants of any gestation whose mothers received vancomycin for prophylaxis because nothing is known about the amniotic fluid penetration of this drug or its efficacy in preventing early-onset group B streptococcal disease.

scores were significant risk factors for late-onset ~ e p s i s . 5 ~ ~ Benjamin and colleagues526reported a retrospective study at Duke University from 1995 to 1999 of all neonates who had central venous access. The goal of the Duke study was to evaluate the relationship between central venous catheter removal and outcome in bacteremic neonates. Infants bacteremic with S. aureus or a gram-negative rod who had their catheter retained beyond 24 hours had a 10-fold higher rate of infection-related complications than those in whom the central catheter was removed promptly. Compared with neonates who had three or fewer positive intravascular catheter blood cultures for coagulase-negative staphylococci, neonates who had four consecutive positive blood cultures were at significantlyincreased risk for end-organ damage and death. In neonates with central venous catheter-associated infection, prompt removal of the device is advised unless there is rapid clinical improvement and sterilization of blood cultures after initiation of therapy.

The first two clinical scenarios are readily identified, but the third category often leads to controversy regarding optimal management. Recent recommendations for prevention and treatment of early-onset group B streptococcal infection are discussed in detail in Chapter 13. Management of the infant born to a mother who received an antimicrobial agent within hours of delivery must include consideration of the effect of the drug on cultures obtained from the infant after birth. Intrapartum therapy provides some treatment of the infant in utero, and variable concentrations of drug will be present in the infant's body fluids. If the infant is infected and the bacterial pathogen is susceptible to the drug administered to the mother, cultures of the infant can be sterile despite a clinical course suggesting sepsis.

Treatment of Neonatal Meningitis

Treatment of the Infant Whose Bacterial Culture Results Are Negative Whether or not the mother received antibiotics before delivery, the physician must decide on the subsequent course of therapy for the infant who was treated for presumed sepsis and whose bacterial culture results are negative. If the neonate appears to be well and there is reason to believe that infection was unlikely, treatment can be discontinued at 48 hours. If the clinical condition of the infant remains uncertain and suspicion of an infectious process remains, therapy should be continued as outlined for documented bacterial sepsis unless another diagnosis becomes apparent. Significant bacterial infection can occur without bacteremia. Squire and colleaguesM found that results of premortem blood cultures were negative in 7 (18%) of 39 infants with unequivocal infection at autopsy. Some infants with significant systemic bacterial infection may not be identified by the usual single blood culture technique. The physician must consider this limitation when determining length of empirical therapy. However, if treatment for infection is deemed necessary, parenteral administration for 10 days is recommended.

Management of the Infant with Catheter-Associated Infection Investigators in Connecticut found that multiple catheters, low birth weight, low gestational age at birth, and low Apgar

Because the pathogens responsible for neonatal meningitis are largely the same as those that cause neonatal sepsis, initial therapy and subsequent therapy are similar. Meningitis caused by gram-negative enteric bacilli can pose special management problems. Eradication of the pathogen often is delayed, and serious complications can occur.443"9~3883631 The persistence of gram-negative bacilli in CSF despite bactericidal levels of the antimicrobial agent led to the evaluation of lumbar intrathe~al"~and intraventricularW8 gentamicin. Mortality and morbidity were not significantly different in infants who received parenteral drug alone or parenteral plus intrathecal the rap^.^' The study of the intraventricular gentamicin was stopped early because of the high mortality in the parenteral plus intraventricular therapy group."8 Feigin and colleagues629provide a review of the management of meningitis in children, including neonates. Ampicillii or penicillin G, initially with an aminoglycoside, are appropriate antimicrobial agents for treating infection caused by group B streptococci. Cefotaxime has superior in vitro and in vivo bactericidal activity against many microorganism^.^^^ Treatment of enteric gram-negative bacillary meningitis should include cefotaxime and an aminoglycosideuntil results of susceptibility testing are known. If meningitis develops in a low-birth-weight infant who has been in the nursery for a prolonged period or in a neonate who has received previous courses of antimicrobial therapy for presumed sepsis, alternative empirical antibiotic regimens should be considered. Enterococci and antibioticresistant, gram-negative enteric bacilli are potential pathogens in these settings. A combination of vancomycin, an aminoglycoside, and cefotaxime may be appropriate. Ceftazidime in addition to an aminoglycoside should be considered for I? aeruginosa meningitis. Other antibiotics may be necessary for the treatment of highly resistant organisms. Mer~penem,"~ ~iprofloxacin,6~'-~~~ or trimethoprim-sulfarnetho~azole~~'~~~~ can be the only antimicrobial agents active in vitro against bacteria that are highly resistant to broad-spectrum p-lactam antibiotics or aminoglycosides. Some of these drugs require careful monitoring because of toxicity to the newborn (see Chapter 37), and ciprofloxacin has not been approved for use in the United

Chapter 6

Table 6-18

Infectious and Noninfectious Causes of Aseptic Meningitisain the Neonate

Cause Infectious agent Bacteria

Viruses

Spirochetes Parasites Mycoplasma Fungi Noninfectious causes Trauma Malignancy

Disease Partially treated meningitis Parameningeal focus (brain or epidural abscess) Tuberculosis Herpes simplex meningoencephalitis Cytomegalovirus Enteroviruses Rubella Acquired immunodeficiency syndrome Lymphocytic choriomeningitis Varicella SyphiIis Lyme disease Toxoplasmosis Chagas' disease Mycoplasrna horninis infection Ureaplasrna urealyticurn infection Candidiasis Coccidioidomycosis Cryptococcosis Subarachnoid hemorrhage Traumatic lumbar puncture Teratoma Medulloblastoma Choroid plexus papilloma and carcinoma

aAsepticmeningitis is defined as meningitis in the absence of evidence of bacterial pathogen detectable in cerebrospinal fluid by usual laboratory techniques.

States in infants younger than 3 months. Definitive treatment of meningitis caused by gram-negative enteric bacilli should be determined by in vitro susceptibility tests, and assistance from an infectious diseases specialist can be helpful. If cultures of blood and CSF for bacterial pathogens by usual laboratory techniques are negative in the neonate with meningitis, the differential diagnosis of aseptic meningitis must be reviewed, particularly in view of diagnosing treatable infections (Table 6-18).

Management of the Infant with a Brain Abscess If purulent foci or abscesses are present, they should be drained. However, some brain abscesses resolve with medical therapy alone.388*654 Brain abscesses can be polymicrobial or result from organisms that uncommonly cause meningitis such as C i t r o b a ~ t e r , ' ~ Enterobacter,'28 '~'~~ P r o t e ~ s , ~and ~' Salmonella ~pecies.6~~ Aspiration of the abscess provides identification of the pathogens to guide rational antimicrobial therapy.


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Treatment of the Infant with Meningitis Whose Bacterial Culture Results Are Negative In the absence of a detectablebacterial pathogen, an aggressive diagnostic approach is necessary for the infant with meningitis, defined by CSF pleocytosis and variable changes in the concentration of CSF protein and glucose. The most frequent cause of aseptic or nontuberculous bacterial meningitis in the neonate is prior antimicrobial therapy resulting in negative blood and CSF cultures. Congenital infections need to be excluded. Treatable diseases, such as partially treated bacterial disease, meningoencephalitis due to herpes simplex virus, syphilis, cytomegalovirus, toxoplasmosis, Lyme disease in regions where Borrelia is prevalent, tuberculosis, and malignancy, need to be considered in the differential diagnosis. The history of illness and contacts in the mother and family and epidemiologic features, such as animal exposures and recent travel, should be explored. Reexamination of the infant for focal signs of disease, including special techniques such as ophthalmologic examination, and consideration of appropriate diagnostic imaging studies of the long bones, skull, and brain can provide further information in determining the source of infection. Treatment of possible bacterial or nonbacterial causes of aseptic meningitis may be necessary before the results of culture, polymerase chain reaction, or serology tests are available to indicate the diagnosis.

Treatment of Anaerobic Infections The importance of anaerobic bacteria as a cause of serious neonatal infection is uncertain. Clostridium, Peptococcus, and Peptostreptococcus are highly sensitive to penicillin G, but B. fiagilis sp. usually are resistant. If anaerobic organisms are known or suspected to be responsible for infection (as in peritonitis), initiating therapy with a clinically appropriate agent, such as clindamycin, metronidazole, ticarcillin, or piperacillin, is warranted.

Adjunctive Therapies for Treatment of Neonatal Sepsis Despite appropriate antimicrobial and optimal supportive therapy, mortality rates resulting from neonatal sepsis remain high, especially for the VLBW infant. With the hope of improving survival and decreasing the severity of sequelae in survivors, investigators have considered adjunctive modes of treatment, including granulocyte transfusion, exchange transfusion, and the use of standard intravenous immune globulin or pathogen-specific polyclonal or monoclonal antibody reagents for deficits in neonatal host defenses. These therapies are discussed in further detail in Chapters 4 and 13. Pentoxifylline has been documented to reduce plasma tumor necrosis factor-a concentrations in premature infants with sepsis and to improve survival, but the number of infants treated (five of five survived) and number of controls (one of four survived) was too small to provide more than a suggestion of efficacy.655In neutropenic infants with sepsis, the administration of granulocyte colony-stimulating factor and human granulocyte-macrophage colony-stimulating factor have had variable effects on O U ~ C O ~Although ~ . ~ ~ the results of selected studies indicate that some of these

~ - ~ ~ ~

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ortality from sepsis is higher for preterm than for term infants in virtually all published studies7,16,2~.21,24,31.468,469 but is approximately the same for all major bacterial (see Tables 6-4 and 6-5). In recent surveys, the mortality rate for neonatal meningitis has declined from 25%2n,423666v668 to 10% to 15vn.31A45,669,670 This decrease represents a significant improvement from prior years, when studies reported a case-fatality rate of more than 300/~.39,455,647.648.671 Mortality is greater among preterm than term infantS.31,44,45,497,672 Significant sequelae develop in 17% to 60% of infants who survive neonatal meningitis caused by gram-negative enteric bacilli or group B ~ t r e p t o c o c c i . ~ , ~ Th*ese ~~>~~~-~ sequelae include mental and motor disabilities, convulsive disorders, hydrocephalus, hearing loss, and abnormal speech patterns. The most extensive experience with the long-term observation of infants who had group B streptococcal meningitis as neonates was reported by Edwards and colleague~.~ Sixty-one ’~ patients were treated between 1974 and 1979, and 21% died. Of the 38 survivors who were available for evaluation at 3 years of age or older, 29% had severe neurologic sequelae, 2 1% had minor deficits, and 50% were functioning normally. Presenting factors that were associated PROGNOSIS with death or severe disability included comatose or semicomatose state, decreased perfusion, total peripheral white blood cell count less than 5000/mm3, absolute neutrophil Before the advent of antibiotics, almost all infants with count less than 1000/mm3,and CSF protein level greater than neonatal sepsis died.’ Dunham2 reported that physicians 300 mg/dL. A comparable study evaluating 35 newborns over used various treatments, including “erysipelas serum” and a period of 3 to 18 years demonstrated more favorable outtransfusions, without altering the course of the disease. The comes with 60% of survivors considered normal at the time introduction of sulfonamides and penicillin and later introof follow-up compared with sibling controls, 15% with mild duction of broad-spectrum antibiotics such as chloramto moderate neurologic residua, and 25% with major phenicol and streptomycin decreased the mortality rate to ~equelae.6~’ Franco and c o - w o r k e r ~reported ~ ~ ~ the results of about 60%.335 During this period, some infants undoubtedly frequent and extensive neurologic, developmental,and psychodied because of treatment with high dosages of chlorammetric assessments on a cohort of 10 group B streptococcal phenicol, which can cause cardiovascular collapse (i.e., gray meningitis survivors followed for one to 14 years and found baby syndrome). that one child had severe central nervous system damage, five The introduction of the aminoglycosides, first with children, including one with hydrocephalus, had mild academic kanamycin in the early 1960s and gentamicin late in that or behavioral problems, and four children were normal. decade, vastly improved therapy for bacteremia due to The neurodevelopmental outcomes described for infants gram-negative organisms, the leading cause of sepsis at that with gram-negative bacillary meningitis are similar to those These therapies, together with an improved underreported for group B streptococcal meningitis. Unhanand standing of neonatal physiology and advances in life-support and colleaguesMreported findings from their 21-year experisystems, combined to result in a steady decrease in neonatal ence with gram-negative meningitis at two hospitals in Dallas, mortality in the United Statesm and in Texas. Among 72 patients less than 28 days old at the onset during the period from 1960 to 1985. Mortality rates for of symptoms, there were 60 survivors, 43 of whom were sepsis, including infants of all weights and gestational ages, decreased from 40% to 50% in the 1 9 6 0 ~ ~ to~ 10% ~ ~ to” ’ ~followed ~ ~ ~ and evaluated for a period of at least 6 months. Neurologic sequelae, occurring alone or in combination, 20% in the 1970s and 1980s.2n~21,24,468~469,664,666 Populationwere described in 56% and included hydrocephalus (=30%), based surveillance of selected counties in the United States seizure disorder (=30%), developmental delay (=30%), conducted by the CDC from 1993 to 1998 reported 2196 cerebral palsy (25%), and hearing loss (15%). Forty-four cases of neonatal sepsis due to group B Streptococcus, of percent of the survivors were developmentally normal at which 92 (4%) were follow-up. Among infants with gram-negative bacillary The postnatal age at which infection occurs, once thought meningitis, thrombocytopenia, CSF white blood cell count to be of prognostic significance, has become less important greater than 2000/mm3,CSF protein greater than 200 mg/dL, within the past 2 decades. Fulminant sepsis, with signs of CSF glucose-to-blood glucose ratio of less than 0.5, proillness present at birth or during the first day of life, has a longed (>48 hours) positive CSF cultures, and elevated high mortality rate, varying from 14% to 20%21*31333n.”’ to as endotoxin and interleukin- 1 concentrations in CSF were high as 70%.“7 However, when infections occurring during the first 24 hours of life, most of which are caused by group indicators of a poor O U ~ C O Investigators ~ ~ . ~ in~ ~ ~ ~ England and Wales67nfound that independent predictors of B Streptococcus, are excluded from the analysis, the adverse outcome 12 hours after admission were the presence percentage of deaths due to early-onset sepsis does not of seizures, coma, ventilatory support, and leukopenia. differ significantly from that associated with late-onset

techniques improved survival, the potential adverse effects (e.g., graft-versus-host reaction, pulmonary leukocyte sequestration) are sufficiently concerning to warrant further study in experimental protocols. Human immunoglobulin preparations for intravenous administration (IGIV) have been assessed for adjunctive therapy for neonatal sepsis based on the hypothesis that infected infants lack circulating antibodies against bacterial pathogens and that IGIV can provide some antibody for protection. Hill6” reviewed four clinical trials and reported a mortality rate of 15% (9 of 60) in untreated infants and 3% (2 of 59) in IGIV-treated infants. A meta-analysis of studies of IGIV for the treatment of neonates with sepsis showed a sixfold decrease in the mortality rate in infants who received IGIV in addition to standard therapies.“’ In contrast, Noya“’ concluded that IGIV has not been demonstrated conclusively to be effective in the treatment of neonatal sepsis. A multicenter randomized placebo-controlled trial of IGIV therapy for neonatal sepsis in infants with a birth weight greater than 1000 g showed no difference in mortality between the IGIVtreated and untreated

infection.zn~2i,24,96,469,664.66s

Chapter 6 Computed tomography reveals a high incidence of central nervous system residua among newborns with meningitis. McCracken and colleagues677report that, among 44 infants with gram-negative bacillary meningitis, only 30% of computed tomographic scans were considered normal. Hydrocephalus was found in 20% of cases; areas of infarct, cerebritis, diffuse encephalomalacia, or cortical atrophy in 30%; brain abscess in about 20%; and subdural effusions in 7%. Two or more abnormalities were detected in about one third of infants. The prognosis of brain abscess in the neonate is guarded because about one half of these children die, and sequelae such as hydrocephalus are common among survivors. Of 17 children who had brain abscess during the neonatal period and were followed for at least 2 years, only 4 had normal intellect and were free of seizures.388In neonates with brain abscess, the poor outcome probably is caused by destruction of brain parenchyma as a result of hemorrhagic infarcts and necrosis.

PREVENTION Obstetric Factors Improvement in the health of pregnant women with increased use of prenatal care facilities has led to lower rates of prematurity. Increased use of antenatal steroids in pregnant women with preterm labor and of surfactant in their infants has resulted in significantly fewer cases of respiratory distress syndrome. More appropriate management of prolonged interval after rupture of maternal membranes, maternal peripartum infections, and fetal distress has improved infant outcome. Because these factors are associated with sepsis in the newborn, improved care of the mother should decrease the incidence of neonatal infection. The development of neonatal intensive care expertise and units with appropriate equipment has resulted in the survival of VLBW infants. Increasingly, obstetric problems are anticipated, and mothers are transferred to medical centers with neonatal intensive care units before delivery.

Chemoprophylaxis The use of antibiotics to prevent infection can be valuable when they are directed against specific microorganisms for a limited time. In the neonate, the use of silver nitrate eye drops or intramuscular cefiriaxone to prevent gonococcal ophthalmia, vaccination with bacillus Calmette-Guirin (BCG) or prophylactic use of isoniazid to reduce morbidity from tuberculosis in infants who must return to endemic areas, and use of hexachlorophene baths to prevent staphylococcal disease have been recognized as effective modes of chemoprophylaxis. The value of using antimicrobial agents against unknown pathogens in infants believed to be at high risk of infection or undergoing invasive procedures is uncertain. Studies of penicillin administered to the mother during labor for prevention of neonatal disease caused by group B streptococci are reviewed earlier and in Chapter 13. Baier and colleagues678investigated daily administration of vancomycin for the prevention of CoNS bacteremia in low-birth-weight infants. Vancomycin was effective in reducing


281

colonization and bacteremia when added to parenteral nutrition fluids for infants weighing 500 to 1500 g. Infants were randomized to receive vancomycin or no antibiotic for the duration of parenteral nutrition in a study blinded to the investigators. Nine infants in the control group developed bacteremia or fungemia, and one infant in the vancomycintreated group developed candidemia. All invasive episodes occurred in infants weighing less than 1000 g, and there were no isolates of vancomycin-resistant strains of CoNS. Although the data suggest a beneficial effect for the vancomycin-treated infants, the number of patients studied was too small to verify this conclusion with adequate statistical power and this prophylactic regimen is not recommended.

Maternal Factors The antiviral and antibacterial activity of human milk has been recognized for many years679-682 and is discussed extensively in Chapter 5. Evidence that breast-feeding defends against neonatal sepsis and gram-negative meningitis was reported more than 30 years ago from S ~ e d e n . 6Later ~~ studies carried out in Pakistan have shown that even partial breast-feeding appears to be protective among neonates in a resource-limited nation with a high neonatal mortality rate from clinical s e p ~ i sBreast-fed .~ infants have a lower incidence of gastroenteritis, respiratory illness, and otitis media than those who are formula fed. A protective effect of breastfeeding against infections of the urinary tract also has been ~uggested.6~’ Observations that breast-feeding enhances lymphocyte responses to a purified protein derivative (PPD) of M. tuberculosis in infants given BCG vaccination at birth indicates that the effects of breast milk are not limited to those of an antibody-mediated mucosal protection.686 The clinical significance of this increased specific cellular immune response during the first few weeks of life remains to be determined.

lmmunoprophylaxis The immaturity of the neonatal immune system is characterized by decreased levels of antibody against common pathogens; decreased complement activity, especially alternative pathway components; diminished polymorphonuclear leukocyte production, mobilization,and function; diminished T lymphocyte cytokine production to many antigens; and reduced concentrationsof plasma and cell surfacefibronecthm Recognition of these factors has resulted in attempts at therapeutic intervention aimed specifically at each component of the deficient immune response. Infants are protected from infection by passively transferred maternal IgG. To enhance the infant’s ability to ward off severe infections, immunization of pregnant women and women in the childbearing years has been selectively ad~pted.~~~@’~ Programs to immunize pregnant women in resource limited countries with tetanus toxoid have markedly decreased the incidence of neonatal tetanus. Investigational programs for immunization of pregnant women with polysaccharide pneumococcal, H. influenme type b and group B streptococcalvaccines aim to provide infants with protection in the first months of life. Studies of safety and immunogenicity of polysaccharide conjugate vaccines for group B

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hemostasis; vascular integrity; tissue repair; T lymphocyte streptococci show promise of a reduction in incidence of activation; leukocyte migration, adhesion, and phagocytosis; late-onset and early-onset disease in n e ~ b o r n s . 6Use ~ ~ of and reticuloendothelial clearance. Plasma fibronedin concenvaccines in pregnant women is discussed in Chapter 1. trations in newborns are about one third to one half those of Several clinical trials have explored the use of IGIV to adults, and premature infants have levels significantly lower correct the antibody deficiency of neonates, particularly very than those of term infants. These concentrations are further preterm newborns, and thereby reduce the incidence of decreased in neonates with perinatal asphyxia, respiratory sepsis. The results of these investigations were reviewed in distress syndrome, and sepsis.699Studies in animal models 1993 by Two of six studies indicated that IGIV and adults with sepsis suggest that fibronectin administration reduced the incidence of late-onset infections, particularly can be of value in improving host defenses and in reducing those due to coagulase-negative staphylococci, but did not the risk of nosocomial infection in neonates. affect mortality. The remaining four studies failed to demonstrate any effect of IGIV on the incidence of late-onset sepsis, mortality, morbidity, or length of hospital stay. A metaDecontamination of Fomites analysis performed in 1998 by Jenson and Pollack661found Because contamination of equipment poses a significant that prophylactic IGIV was of minimal but demonstrable infectious challenge for the newborn, disinfection of all benefit in preventing sepsis in premature, low-birth-weight materials that are involved in the care of the newborn is an infants. A recent prospective, randomized, placebo-controlled, important responsibility of nursery personnel. The basic multicenter trial found no effect of prophylactic IGIV on mechanisms of large pieces of equipment must be cleaned preventing sepsis when administered to neonates who were appropriately or replaced because they have been implicated less than 33 weeks’ gestation?% The use of hyperimmune in nursery epidemics. The use of disposable equipment and IGIV preparations and human monoclonal antibodies to materials packaged in individual units, such as containers of prevent specific infections (e.g., CONS, S. aureus) in highsterile water for a nebulization apparatus, are important risk neonates is being explored. advances in the prevention of infection. The frequency of Sidiropoulos and co-worker~~~l studied the benefit of catheter-associated CONSsepsis has led to attempts to prevent low-dose (12g in 12 hours) or high-dose (24g daily for bacterial colonization of intravascular catheters through use 5 days) IGIV given to pregnant women at risk for preterm of attachment-resistant polymeric materials, antibiotic delivery because of chorioamnionitis. Cord blood IgG levels impregnation, and immunotherapy directed against adherence were doubled in infants older than 32 weeks’ gestational age factors.’@’ These procedures are reviewed in Chapter 35. whose mothers received the higher dosage schedule but were unaffected in infants born earlier, suggesting little or no placental transfer of IGIV before the 32nd week of gestation. Epidemiologic Surveillance Among the infants delivered after 32 weeks, 6 (37%) of 16 Endemic Infection born to untreated mothers developed clinical, laboratory, or radiologic evidence of infection and required antimicrobial Nursery-acquired infections can become apparent days to therapy, whereas none of 7 infants born to treated mothers several months after discharge of the infant. A surveillance became infected. Although this study suggeststhat intrauterine system that provides information about infections within fetal prophylaxis can be beneficial in selected cases, widethe nursery and involves follow-up of infants after discharge spread use of IGIV for all women having premature onset of should be established. Various techniques can be used for labor is not feasible because of timing before delivery, widesurveillance and are reviewed in Chapter 35. spread shortages of IGIV, and cost. Epidemic Infection The decreased number of circulating polymorphonuclear leukocytes and reduced myeloid reserves in the bone marrow The medical and nursing staff must be aware of the possibility of newborns have been ascribed to impaired production of of outbreaks or epidemics in the nursery. Prevention of cytokines, interleukin-3, granulocyte colony-stimulating disease is based on the level of awareness of personnel. factor, granulocyte-macrophage colony-stimulating factor, Infection in previously well infants who lack high-risk tumor necrosis factor-a, and interfer0n-y.6~~~~~~ Considerable factors associated with sepsis must be viewed with suspicion. experience with in vitro myeloid cell cultures and animal Several cases of infection occurring within a brief period, models694*695 and with human trials696suggests that cytokine caused by the same or an unusual pathogen, and occurring therapy can be an effective aid in preventing sepsis among in close physical proximity should raise concern about the newborns with hereditary or acquired congenital neutropenia. possibility of a nursery outbreak. Techniques for management Treatment of a small number of infants with early signs of of infection outbreaks in nurseries are discussed in Chapter 35. sepsis with pentoxifylline to reduce the concentrations of tumor necrosis factor-a showed pr0mise,6~~ but there are no studies that have used pentoxifylline for prevention of SEPSIS IN THE NEWBORN RECENTLY sepsis. Similarly, preliminary studies of granulocyte colonyDISCHARGED FROM THE HOSPITAL stimulating factor in neonates are inconsistent in demonstrating that absolute neutrophil counts are increased or that When fever or other signs of systemic infection occur in the the incidence of sepsis is first weeks after the newborn is discharged from the nursery, Fibronectins are high-molecular-weight glycoproteins, appropriate management requires consideration of the produced primarily by the liver and endothelial cells, that facilitate cell-to-cell and cell-to-substrate a d h e ~ i o n . ~ ~possible ~ . ~ ~ ~sources of infection. Infection acquired at birth or from a household contact is the most likely cause. Congenital They are involved in numerous functions, including

Chapter 6 infection can be present with signs of disease that are detected after discharge. Late-onset infection from microorganisms acquired in the nursery can occur weeks or occasionally months after birth. Infection can occur after discharge because of underlying anatomic, physiologic, or metabolic abnormalities. The newborn is susceptible to infectious agents that colonize or cause disease in other household members. If an infant whose gestation and delivery were uneventful is discharged from the nursery and develops signs of an infectious disease in the first weeks of life, the infection was probably acquired from someone in the infant’s environment. Respiratory and gastrointestinal infections are common and can be accompanied by focal disease such as otitis media. A careful history of illnesses in household members can suggest the source of the infant’s infection.

Congenital Infection Signs of congenital infection can appear or be identified after discharge from the nursery. Hearing impairment caused by congenital rubella or cytomegalovirus infection can be noticed by a parent at home. Hydrocephalus with gradually increasing head circumference caused by congenital toxoplasmosis can be apparent only after serial physical examinations. Chorioretinitis, jaundice, or pneumonia can occur as late manifestations of congenital infection. A lumbar puncture may be performed in the course of a sepsis evaluation. CSF pleocytosis and increased protein concentration can be caused by congenital infection and warrant appropriate diagnostic studies.

Late-Onset Disease Late-onset disease can present after the first week to months after birth as sepsis and meningitis or other focal infections. Group B Streptococcus (see Chapter 13) is the most frequent cause of late-onset sepsis in the neonate. Organisms acquired in the nursery also can cause late-onset disease. Skin and soft tissue lesions or other focal infections, including osteomyelitis and pneumonia from S. aureus, can occur weeks after birth. The pathogenesis of late-onset sepsis is obscure in many cases. The reason why an organism becomes invasive and causes sepsis or meningitis after colonizing the mucous membranes, skin, or upper respiratory, genitourinary, or gastrointestinal tracts remains obscure. Nosocomially acquired or health care-associated organisms are discussed in further detail in Chapter 35.


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during the 10-month period after introduction into the home of an infant with a staphylococcal lesion. The incidence of suppurative infections in household contacts of infants without lesions was less than 2%. Damato and c o - w ~ r k e r s ~ ~ ~ demonstrated colonization of neonates with enteric organisms possessing R factor-mediated resistance to kanamycin and persistence of these strains for more than 12 months after birth. During the period of observation, one third of the household contacts of the infants became colonized with the same strain. Infections in infants have been associated with bites or licks from household pets. Pasteurella multocida is part of the oral flora of dogs, cats, and rodents. Meningitis caused by l? multocida was reported in seven infants younger than 2 month^."^ A 5-week-old infant with l? multocida meningitis frequently was licked by the family dog, and the organism was identified in cultures of the dog’s mouth but not of the parents’ throats. l? multocida meningitis in a 3-week-old infant may have resulted from transmission of the organism from the family cat to the mother and then to the infant.’04 The epidemiologic link between cats and dogs and infection in young infants suggests that parents should limit contact between pets and infants.

Fever in the First Month of Life Reviews of fever in the first weeks of life indicate that elevation of temperature (>38.8’ C [ 101.8” F])705-712 is relatively uncommon. However, when fever occurs in the young infant, the incidence of severe disease, including sepsis, meningitis, and pneumonia, is sufficiently high to warrant careful evaluation and conservative management. A careful history of the pregnancy, delivery, nursery experience, interval since discharge from the nursery, and infections in the household should be obtained. Physical examination should establish the presence or absence of signs associated with congenital infection and late-onset diseases. Culture of blood and urine should be performed if no other focus is apparent, and culture of the CSF and a chest radiograph should be considered if the infant is believed to have systemic infection. Practice guidelines prepared by Baraff and colleagues705 for the management of infants and children with fever without source state that all febrile infants younger than 28 days should be hospitalized for parented antibiotic therapy. The group designated that a rectal temperature of 38.0” C (100.4’ F) or higher should be used as the definition of fever. The sepsis evaluation includes a culture of blood, urine, and CSF; a complete blood cell and differentialcount; examination of CSF for cells, glucose, and protein; and a urinalysis.

Infections in the Household Infection can be associated with an underlying anatomic defect, physiologic abnormality, or metabolic disease. The infant who fails to thrive or presents with fever can have a urinary tract infection as the first indication of an anatomic abnormality. Infants with lacrimal duct stenosis or choanal atresia can develop focal infection. Sepsis caused by gramnegative enteric bacilli occurs frequently in infants with galactosemia (see “Pathogenesis”). The infected infant can be an important source of infection to family members. In one study in New York,”’ 12.6% of household contacts developed suppurative lesions

Acknowledgment Dr. S. Michael Marcy was a co-author of this chapter in the first four editions. The authors are indebted to Dr. Marcy for his continued interest in the preparation of this chapter.

REFERENCES 1. Gapes RP, Edwards JR, Jarvis WR, et al. Nosocomial infections among neonates in high-risk nurseries in the United States. Pediatrics 93~357,1996. 2. Dunham EC. Septicemia in the newborn. Am J Dis Child 45229, 1933.

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Chapter 6 669. Harvey DC, Holt DE, Bedford H. Bacterial meningitis in the newborn: a prospective study of mortality and morbidity. Semin Perinatol 23:218, 1999. 670. Klinger G, Chin C-N, Beyene J, Perlman M. Predicting the outcome of neonatal bacterial meningitis. Pediatr 106477,2000. 671. Wald E, Bergman I, Chiponis D, et al. Long-term outcome of group B streptococcal meningitis. Pediatrics 77217, 1986. 672. Franco SM, Cornelius VE, Andrews BF. Long-term outcome of neonatal meningitis. Am J Dis Child 146567,1992. 673. Horn KA, Zimmerman RA, Knostman JD, et al. Neurological sequelae of group B streptococcal neonatal infection. Pediatrics 53:501, 1974. 674. Edwards MS, Rench MA, Haffar AAM,et al. Long-term sequelae of group B streptococcal meningitis in infants. J Pediatr 106717,1985. 675. Yang YJ, Liu CC, Wang SM. Group B streptococcal infections in children: the changing spectrum of infections in infants. J Microbiol Immunol Infect 3:107, 1998. 676. McCracken GH Jr, Mustafa M, Ramilo 0, et al. Cerebrospinal fluid interleukin-1B and tumor necrosis factor concentrations and outcome from neonatal gram-negative enteric bacillary meningitis. Pediatr Infect Dis J 8:155, 1989. 677. McCracken GH Jr, Threlkeld N, Mize S, et al. Moxalactam therapy for neonatal meningitis due to gram-negative enteric bacilli: a prospective controlled evaluation. JAMA 252:1427, 1984. 678. Baier J, Bocchini JA Jr, Brown EG. Selective use of vancomycin to prevent coagulase-negative staphylococcal nosocomial bacteremia in high risk verylow birth weight infants. Pediatr Infect Dis J 17179,1998. 679. Van de Perre P. Transfer of antibody via mother’s milk. Vaccine 21:3374,2003. 680. Hanson LA, Karlsson B, Jalil F, et al. Antiviral and antibacterial factors in human milk. In Hanson LA (ed). Biology of Human Milk. New York, Raven Press, 1988, pp 141-157. 681. Mathus NB, Dwarkadas AM, Sharma VK, et al. Anti-infective factors in preterm human colostrum. Acta Paediatr Scand 79:1039, 1990. 682. Isaacs CF, Kashyap S, Heird WC, et al. Antiviral and antibacterial lipids in human milk and infant formula feeds. Arch Dis Child 65:861,1990. 683. Winberg J, Wessner G. Does breast milk protect against septicaemia in the newborn? Lancet 1:1091,1971. 684. Ashraf RN,Jalil F, Zaman S, et al. Breast feeding and protection against neonatal sepsis in a high risk population. Arch Dis Child 66:488,1991. 685. Coppa GV, Gabrielli OR, Giorgi P, et al. Preliminary study of breastfeeding and bacterial adhesion to uroepithelial cells. Lancet 1:569,1990. 686. Pabst HF, Godel J, Grace M, et al. Effect of breast-feeding on immune response to BCG vaccination. Lancet 1:295, 1989. 687. Englund JA,Glezen WP. Maternal immunization for the prevention of infection in early infancy. Semin Pediatr Infect Dis 2225, 1991. 688. Vicari M, Dodet B, Englund J. Protection of newborns through maternal immunization. Vaccine 21:3351,2003. 689. Baker CJ, Rench MA, McInnes P. Immunization of pregnant women with group B streptococcal type I11 capsular polysaccharide-tetanus toxoid conjugate vaccine. Vaccine 21:3468,2003. 690. Sandberg K, Fasth A, Berger A, et al. Preterm infants with low immunoglobulin G levels have increased risk of neonatal sepsis but do not benefit from prophylactic immunoglobulin G. J Pediatr 137623, 2000. 691. Sidiropoulos D, Herrman U Jr, Morell A, et al. Transplacental passage of intravenous immunoglobulin in the last trimester of pregnancy. J Pediatr 109505,1986.


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692. Cairo MS, Dana R, Park L, et al. Reduced cytokine production (IL-3, G-CSF, GM-CSF) from stimulated cord mononuclear cells compared to adult but normal cytokine receptor expression on newborn effector cells: possible mechanism in the dysregulation of neonatal granulopoiesis. Pediatr Res 29273A, 1991. 693. Cairo MS. Cytokines: a new immunotherapy. Clin Perinatol 18:343, 1991. 694. Roilides E, Pizm PA. Modulation of host defenses by cytokines: evolving adjuncts in prevention and treatment of serious infections in immunocompromised patients. Clin Infect Dis 15:508, 1992. 695. Roberts RL,Szelc CM, Scates SM, et al. Neutropenia in an extremely premature infant treated with recombinant human granulocyte colony-stimulating factor. Am J Dis Child 145:808,1991. 696. Cairo MS, Agosti J, Ellis R, et al. A randomized, double-blind, placebocontrolled trial of prophylactic recombinant human granulocytemacrophage colony-stimulating factor to reduce nosocomial infections in very low birth weight neonates. J Pediatr 13464, 1999. 697. Yang KD, Bohnsack FJ, Hill HR. Fibronectin in host defense: implications in the diagnosis, prophylaxis and therapy of infectious diseases. Pediatr Infect Dis J 12:234, 1993. 698. Yoder MC. Therapeutic administration of fibronectin: current uses and potential applications. Clin Perinatol 18:325, 1991. 699. Dyke MP, Forsyth KD. Decreased plasma fibronectin concentrations in preterm infants with septicemia. Arch Dis Child 68:557, 1993. 700. Goldmann DA, Pier GB. Pathogenesis of infections related to intravascular catheterization. Clin Microbiol Rev 6:176, 1993. 701. Klein JO. Family spread of staphylococcal disease following a nursery outbreak. N Y State J Med 60861,1960. 702. Damato JJ, Eitzman DV, Baer H. Persistence and dissemination in the community of R-factors of nosocomial origin. J Infect Dis 129205, 1974. 703. Thompson CM, Pappu L, Leukoff AH, et al. Neonatal septicemia and meningitis due to Pmteurella rnultocida. Pediatr Infect Dis 1 3:559, 1984. 704. Bhave SA, Guy LM. PasteureZla rnultocida meningitis in an infant with recovery. BMJ 2741,1977. 705. Baraff LJ, Bass JW, Fleisher GR, et al. Practice guideline for the management of infants and children 0 to 36 months of age with fever without source. Agency for Health Care Policy and Research. Ann Emerg Med 22:1198,1993. 706. Baker MD. Evaluation and management of infants with fever. Pediatr Clin North Am 46:1061,1999. 707. Ferrera PC, Bartfield JM, Snyder HS. Neonatal fever: utility of the Rochester criteria in determining low risk for serious bacterial infections. Am J Emerg Med 15:299,1997. 708. Dagan R, Sofer S, Phillip M, et al. Ambulatory care of febrile infants younger than 2 months of age classified as being at low risk for having serious bacterial infections. J Pediatr 112:355,1988. 709. King JC Jr, Berman ED, Wright PF. Evaluation of fever in infants less than 8 weeks old. South Med J 80948,1987. 710. Klein JO, Schlessinger PC, Karasic RB. Management of the febrile infant under three months of age. Pediatr Infect Dis J 3:75, 1984. 711. Crain EF, Shelov SP. Febrile infants: predictors of bacteremia. J Pediatr 101:686, 1982. 712. Pantell RH, Naber M, Lamar R, et al. Fever in the first six months of life. Clin Pediatr (Phila) 1977, 1980.

Chapter 7 BACTERIAL INFECTIONS OF THE RESPl RATORY TRACT Elizabeth D. Barnett

Jerome 0. Klein

Infections of the Oral Cavity and Nasopharynx 297 Pharyngitis, Retropharyngeal Cellulitis, and Retropharyngeal Abscess Noma Epiglottitis Laryngitis Infection of the Paranasal Sinuses Diphtheria Pertussis

Otitis Media 301 Pathogenesis and Pathology Epidemiology Microbiology Diagnosis Treatment Prognosis

Mastoiditis 305 Pneumonia 305 Pathogenesis and Pathology Microbiology Epidemiology Clinical Manifestations Diagnosis Differential Diagnosis Management Prognosis

INFECTIONS OF THE ORAL CAVITY AND NASOPHARYNX

Pharyngitis, Retropharyngeal Cellulitis, and Retropharyngeal Abscess Neonates with bacterial infection of the oropharynx may present with pharyngeal inflammation with or without exudate or with retropharyngeal cellulitis or abscess. Extension of infection to the surrounding structures may occur, leading to deep neck abscess formation. Microorganisms identified as the etiologic agents of these infections and their manifestations of disease include the following: Stuphylococcus uureus. Although many children are colonized in the throat and nasopharynx with S. uureus, this organism is rarely a primary agent in the etiology of pharyngitis in infants (or adults). There have, however, been reports of localized abscesses in the oral cavity related to S. uureus. Clark and Barysh, in 1936, reported a case of retropharyngeal abscess in a

6-week-old infant.' The child was critically ill but recovered after incision and drainage of the abscess. Steinhauer reported a case of cellulitis of the floor of the mouth (Ludwig's angina) in a 12-day-old infant.2 The child was febrile and toxic; examination of the mouth revealed swelling under the tongue. Purulent material was subsequently drained from this lesion, and S. uureus was isolated from the pus. A laceration was noted in the floor of the mouth, and the author considered this wound to be the portal of entry of the infection. Streptococcus pyogenes. Fever and pharyngeal inflammation may result from infection with this organism in the n e ~ n a t e . ~ Streptococcus ugaluctiue. Retropharyngeal cellulitis has been associated with bacteremia caused by group B ~treptococci.~*~ The affected neonates presented with poor feeding, noisy breathing, and widening of the retropharyngeal space on radiographs of the lateral neck. Stridor also may be associated with retropharyngeal abscess, as reported in a 13-day-old infant in Hong Kong.6 A retropharyngeal abscess caused by group B streptococci occurred in one of three neonates reported in a series of 31 cases of retropharyngeal abscess seen in children in Camperdown, Australia, between 1954 and 1990.778This infant was found to have a third branchial arch pouch that was subject to recurrent infection until age 5 years. Listeriu monocytogenes. Small focal granulomas on the mucous membrane of the posterior pharynx have been observed in neonates with L. monocytogenes infection. Necrosis of some of the granulomas results in ulcers on the pharynx and tonsils. Treponema pallidum. Mucous patches occur on the lips, tongue, and palate of congenitally infected infants. Rhinitis may appear after the first week of life. Neisseria gonorrhoeae. A yellow mucoid exudate of the pharynx may be present simultaneously with ophthalmia (A Yu, personal communication, 1981). A case report of in utero gonococcal infection with involvement of multiple tissues included pharyngeal abscess.' Enterococcus faeculis. A case of retropharyngeal abscess in which culture of aspirated pus grew E. faecalis as well as two strains of coagulase-negative staphylococci occurred in a 2-week-old full-term infant from Australia.' The infant was severely ill and had atlantoaxial dislocation resulting in paraplegia. At autopsy the findings included bacterial endocarditis, diffuse bilateral pneumonia, and renal infarcts.

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Escherichia coli. This organism can be a rare cause of infection of the pharyngeal cavity. Pus from a retropharyngeal abscess in a l-week-old infant grew two strains of E. coli? The infant was afebrile on presentation and had a large midline pharyngeal swelling.

Infants may have coryza and other signs of upper respiratory tract disease due to infection with respiratory viruses. Infections with respiratory viruses may damage the respiratory mucosa, thereby increasing susceptibility to bacterial infection of the respiratory tract. Eichenwald” described an apparent synergy of respiratory viruses and staphylococci that produced an upper respiratory tract infection called the “stuffy nose syndrome.” The syndrome occurred only when both organisms were present. He and his group also documented increased dissemination of bacteria by newborns carrying staphylococci and echovirus 20 or adenovirus type 2 in the nasopharynx and coined the term cloud babies for these infants.’’ These studies have not been repeated by other investigators, and the significance of synergy of two or more microorganisms in neonatal respiratory infections remains uncertain.

Noma Noma (cancrum oris) is a destructive gangrenous process that may affect the nose, lips, and mouth. It occurs almost exclusively in malnourished children in developing countries; nutrient deficiencies have been postulated to play a role in its pathogenesis.12 Although it is usually a chronic, destructive process in older children, in neonates it may be rapidly fatal. Affected neonates are usually premature and of low birth weight. In older children and adults, noma is caused by hsospirochetes such as Fusobacterium necrophor~m.’~ The disease in neonates is usually due to Pseudomonas aeruginosa. Ghosal and co-workers, from Calcutta, reported bacteriologic and histologic findings in 35 cases of noma in neonate^.'^ l? aeruginosa was isolated from blood or the gangrenous area in more than 90% of the cases. An Israeli full-term infant with bilateral choanal atresia who required an airway developed gangrenous lesions of the cheek on day 11 and palatal lesions that progressed to ulceration and development of an oronasal fistula. Cultures of material from the lesions grew I? a e r ~ g i n o s a . ’ Freeman ~ and associates reported the development of noma neonatorum in the third week of life in a 26-week-gestation premature infant; they suggest that this entity represents a neonatal form of ecthyma gangrenosum.I6

Epiglottitis Epiglottitis caused by S. aureus in an 8-day-old infant was reported by Baxter in a survey of experience with the disease at Montreal Children’s Hospital between 1951 and 1965.” A second case of epiglottitis due to S. aureus in a 5-day-old infant was reported by Rosenfeld and associates.’*The infant presented with bradycardia, hoarseness, and inspiratory stridor and had diffuse inflammation of the arytenoids and epiglottis. S. aureus was cultured from pus on the epiglottic surface; blood culture was negative. Epiglottitis due to group B streptococci was reported in an 11-week-old infant in 1996.19

Laryngitis Laryngitis in the newborn is rare. The child with congenital syphilis may have laryngitis and an aphonic cry. Hazard and co-workers described a case of laryngitis caused by Streptococcus pneumoniae.” A term infant was noted at 12 hours to have a hoarse cry, which progressed to aphonia during the next 3 days. Direct examination of the larynx revealed swelling and redness of the vocal cords. The child was febrile (38.5OC), but the physical examination was unremarkable. S. pneumoniae was isolated from the amniotic fluid, the maternal cervix, and the larynx of the infant. The child responded rapidly to treatment with parenteral penicillin G .

Infection of the Paranasal Sinuses The paranasal sinuses of the fetus begin to differentiate at about the fourth month of gestation. The sinuses develop by local evagination of nasal mucosa and concurrent resorption of overlying bone. The maxillary and ethmoid sinuses are developed at birth and may be sites for suppurative infection. The sphenoid and frontal sinuses are rudimentary at birth and are not well defined until about 6 years of age.z’~zz Inflammatory reaction may occur simultaneously in the paranasal sinuses, the middle ears, and the lungs. Autopsy may reveal that purulent exudate and leukocytic infiltration of the mucosa are present at one or more of these sites. Infection of the ethmoid and maxillary sinuses may be severe and life-threatening in the newborn. Clinical manifestations include general signs of infection such as fever, lethargy, irritability, and poor feeding as well as focal signs indicative of sinus involvement (i.e., nasal congestion, purulent drainage from the nostrils, and periorbital redness and swelling). Proptosis may occur in severely affected children. Although any of the organisms responsible for neonatal sepsis may cause sinusitis, S. aureus and group A and group B streptococci are responsible for most infection^.*^-^^ Suppurative infection of the maxillary sinus may progress to osteomyelitis of the superior maxilla (see Chapter 8).24 Blood specimens, nasopharyngeal secretions, and purulent drainage material (if present) should be obtained for culture before treatment. Antibacterial therapy must include a penicillinase-resistant penicillin or cephalosporin for activity against Staphylococcus and group A and group B streptococci. If no material is available for examination of Gram-stained pus or if results of the preparation are ambiguous, initial therapy should include an aminoglycoside or a third-generation cephalosporin to ensure activity against gram-negative enteric bacilli (see discussion of management in Chapter 6). Surgical drainage of the infected site should be considered. Drainage of the suppurative maxillary sinus should be performed through the nose to avoid scars on the face and damage to the developing teeth.24

Diphtheria Neonatal diphtheria, although now extremely rare in the United States, was common before the development and extensive use of immunization with diphtheria toxoid.

Chapter 7 Outbreaks occurred in hospital nurseries. One of the most striking reports describes three separate epidemics in a “foundling hospital” in Tipperary, Ireland, between 1937 and 1941; 36 infants younger than 1 month of age were afflicted, and 26 died.26Goebel and Stroder described 109 infants younger than 1 year of age with diphtheria in Germany during the period extending from the fall of 1945 to the summer of 1947: 59 infants were younger than 1 month of age, and 26 died.27 In a report from the Communicable Disease Unit of the Los Angeles County Hospital covering the 10-year period ending June 1950, 1433 patients were admitted to the hospital with diphtheria; 19 patients were younger than 1 year of age, but just 2 patients were younger than 1 month of age.28Elsewhere, the disease also appears to be on the wane; only three cases of neonatal diphtheria were identified in India between 1974 and 1984 by Mathur and

Bacterial Infections of the Respiratory Tract

299

laboratory about the possibility of diphtheria is important. Specimens of both nasal and pharyngeal secretions may improve yield of positive cultures.42Infants with suspected diphtheria should be isolated and receive penicillin or erythromycin to eradicate the organism from the respiratory tract or other foci of infection to terminate toxin production and decrease likelihood of transmission. The mainstay of therapy, however, is diphtheria antitoxin, which should be administered as soon as the diagnosis of diphtheria is considered. This product is available in the United States from the CDC?3

Pertussis

Infants and young children in the United States are at the highest risk for pertussis and its complication^.^^ Although associate^.^^ the incidence of pertussis has declined markedly since 1934, Respiratory diphtheria has been well controlled in the when more than 250,000 cases were recorded, resurgence United States since the introduction of diphtheria toxoid in of disease since the early 1980s underscores the need for the 1920s, although it remained endemic in some states continued awareness of this disease.45There were 29,134 through the 1970~.~’ The results of a survey of cases of cases of pertussis in the US in the years 1997 to 2000; 29% diphtheria reported to the Centers for Disease Control [and occurred in infants younger than 1 year of age, representing Prevention] (CDC) of the U.S. Public Health Service,Atlanta, an 11% increase from surveillance data for 1994 to 1996.& The number of deaths in infants younger than 4 months of Georgia, for the period 1971 to October 1975 showed that no cases involved children younger than 1 month of age and age increased from 49 (64% of deaths from pertussis) in that only six cases occurred in children younger than 1 year 1980 to 1989 to 84 (82% of deaths) in 1990 to 1999.47There of age (the youngest was 5 months old) (G Filice, personal were 17 deaths due to pertussis in the United States in 2000; communication, 1981). During the period 1980 through in all cases, onset of symptoms was before 4 months of age!8 1995,41 cases of respiratory diphtheria were reported to the Pertussis occurs in exposed and unprotected newborns.49 CDC; 4 (10%) were fatal, all of which occurred in unvacciBetween 1959 and 1977, pertussis was diagnosed in 400 nated ~hildren.~’ Importation of diphtheria from countries children in Dallas hospitals; 69 patients (17%) were younger where diphtheria remains endemic, including areas of the than 12 weeks of age. An adult in the household with world experiencing a resurgence of disease such as in the undiagnosed mild disease was the usual source of infection former Soviet Union, account for a majority of the cases in for these neonates and young infants.” A report of a nursery outbreak in Cincinnati highlights the persistent threat of industrialized nations.32Reemergence of diphtheria in these newly independent states of the former Soviet Union underpertussis in the young infant and in hospital per~onnel.~’ scores the need to maintain control measures in the United Between February and May 1974, pertussis developed in six newborns, eight physicians, and five nurses (documented by States, including universal childhood immunization, adult boosters, and maintenance of surveillance a ~ t i v i t i e s . ~ ~isolation of Bordetella pertussis from the nasopharynx). Four Maternal immunization may provide some protection to additional infants had clinical illness, but the organism was infants in the neonatal period before diphtheria vaccine is not isolated from the upper respiratory tract. Two mothers given.34 of uninfected infants became ill. The initial case was that of The newborn receives antibodies to Corynebacterium a 1-month-old infant managed in a ward whose infection spread to the nursery when house officers became infected diphtheriae from the mother if she is immune, and the titers of mother and child at birth are approximately e q ~ i v a l e n t . ~ ~and transmitted the organism to other newborns. Protection of some degree results in the neonate from this In the United States in the early 1990s, cases of pertussis passively transferred antibody. Serologic surveys performed were reported from every state, and large outbreaks occurred in the United States in the 1970s and 1980s suggested that in Cincinnati and Chi~ago.~’ In the Chicago outbreak, the highest attack rate was in infants younger than 6 months of 20% to 60% of adults older than 20 years of age may be susceptible to di~htheria.~~.~’ Additional data from Europe age; factors associated with transmission of pertussis in this confirmed that many adults remain susceptible to age group included young maternal age and cough lasting d i ~ h t h e r i a . As ~ ~ is , ~ the ~ case in general with passively 7 days or longer in their mothers.53Another risk factor for transferred immunity, protection depends on the level of pertussis may be low birth weight. A study of cases of maternal antibody at the time of the infant’s birth, and pertussis in Wisconsin infants and young children concluded protection decreases during the months after birth unless that children of low birth weight were more likely than their the infant is imm~nized.~’,~’ normal-birth-weight counterparts to contract pertussis and to be hospitalized with the disease.54 Fatal pertussis Neonatal diphtheria usually is localized to the nares. was identified through a pediatric hospital-based active Diphtheria of the fauces is less common. The skin and surveillance system in 16 infants in Canada from 1991 to mucous membranes may be affected; the two infants in Los 2001; 15 of 16 infants were 2 months of age or younger. Angeles included an 8-day-old neonate with diphtheritic When fatal cases were matched with 32 nonfatal cases by age, conjunctivitis.” Because isolation of C. diphtheriae requires date, and geography, pneumonia and leukocytosis were inoculation of special culture media, notification of the

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Section I1


identified as independent predictors of a fatal outcome in hospitalized infants.55 Antibody to B. pertussis crosses the placenta, and titers in immune mothers and their newborns are approximately equal.35356 If high titers of the passively transferred antibody are present, the antibody is protective for the newborn. This was demonstrated by Cohen and Scadron, who observed protection of 6 months’ duration in the offspring of recently immunized women.56 Three cases of clinical pertussis occurred among six infants who were exposed to infection and whose mothers had not been immunized, whereas no cases occurred among eight similarly exposed infants of immunized mothers. In the group of infants aged 7 to 12 months, there were two cases of clinical pertussis in offspring of immunized and unimmunized mothers, which suggests that passively transferred immunity was no longer present in the infants whose mothers had been immunized during pregnancy. Many women who were vaccinated during infancy have low levels of antibody when they reach childbearing age, and this concentration of antibody may be insufficient to protect offspring if the infants are exposed to pertussis during the first few months of life (before they are immunized). Older children and adults are important sources of infection for infant^.^' These findings suggest that maternal immunization would provide sufficient antibody to protect infants before durable immunity could be provided by infant immunization. In addition, adolescent and adult immunization could reduce the number of individuals able to contract pertussis and infect infants.58 Clinical presentation of pertussis in newborns is similar to that in older children but may lack some features typical of disease in older children. The incubation period may vary, ranging from 5 to 10 days. The initial sign usually is mild coughing, which may progress over a period of several days to severe paroxysms with regurgitation and vomiting of food. The characteristic “whoop” may be absent in infants. The clinical picture of the most severely affected infants may be dominated by marked respiratory distress, cyanosis, and apnea, rather than significant cough. Fever is usually absent. Lymphocyte counts are frequently in excess of 30,000/mm3. Cockayne described a case of clinical pertussis in a neonate whose mother and brother were infectious at the time of birth.59The infant began to cough on the fifth day of life and had a high white blood cell count (36,000/mm3), with a majority of lymphocytes. Phillips reported two cases of pertussis in newborns who were infected by an obstetric nurse.@’ The infants began to cough on the eighth and tenth days of life, respectively.Clinical signs of respiratory infection caused by Chlamydia trachomatis are similar to those of pertussis (see Chapter 11). Complications of pertussis in young infants include convulsions, bronchopneumonia, and hemorrhage. Bacterial and viral superinfection may occur. In a study of 182 infants and children younger than age 2 hospitalized with pertussis from 1967 to 1986 in Dallas, apnea and convulsions occurred significantly more frequently in infants younger than 3 months of age; the three deaths all were in 1-month-old infants with secondary bacterial infection.6’ Mortality among infants younger than 3 months is high; in the earlier Dallas series, 5 of 69 infants (7%) with onset of signs at between 2 and 6 weeks died.50B. pertussis pneumonia may progress rapidly; pulmonary hypertension resulting from difficulty perfusing

the congested lung may result in right-sided heart failure or fatal cardiac arrhythmiasF2 Long-term sequelae of whooping cough in infancy and early childhood were studied by Johnston and co-workers; there was a significant reduction in forced vital capacity in adulthood in persons who had pertussis before age 7 compared with those who did not have pertussis.63 A case of hemolytic uremic syndrome in a neonate has been reported following pert~ssis.6~ Diagnostic methods for pertussis depend on the age of the patient and the duration of cough. In children younger than 11 years of age and older patients with cough lasting less than 14 days, nasopharyngeal specimens should be obtained for bacterial culture using Dacron or calcium alginate swabs. Best results will be obtained if specimens are inoculated at the bedside or taken immediately to the laboratory in appropriate transport media. It is helpful to inform the laboratory of suspicion of pertussis because specialized agar (Regan-Loweor Bordet-Gengou) is required. The organism is isolated most easily during the catarrhal or early paroxysmal stage of illness and rarely is found after the fourth week of illness. Direct fluorescent antibody testing of nasopharyngeal secretions has low sensitivity and variable specificity and cannot be relied on to diagnose pertussis. Polymerase chain reaction (PCR) assay shows promise as a diagnostic to01,65965a but it is not yet widely available or standardized between laboratories. Serologic testing is the diagnostic method of choice for patients 11years of age or older and has excellent sensitivity and specificity when done in an experienced laboratory on paired specimens, the first having been collected as early as possible during the course of illness. No single serologic marker has been identified as diagnostic for pertussis; efforts to standardize serologic studies are under way. Antimicrobial therapy may lessen severity of the disease if it is given in the catarrhal stage, but it has no clinical effect once paroxysms occur. Antibiotic therapy does eliminate carriage of the organisms from the upper respiratory tract and is of value in limiting communicability of infection, even if given late in the clinical course. The antibiotic of choice for treatment of pertussis is erythromycin estolate, 40 to 50mgIkg per day orally in four divided doses, with a maximum daily dose of 2g. Resistance of B. pertussis to erythromycin has been reported66but does not appear to be widespread. The newer macrolide antibiotics-azithromycin (10 to 12mgIkg per day orally, in one dose for 5 days; maximum daily dose of 600 mg) and clarithromycin (15 to 20mglkg per day orally, in two divided doses, for 7 days; maximum daily dose of 1 @--may be as effective as erythromycin and have the advantage of fewer side effects and better adherence but are not approved for use in neonates.66a Penicillins and first- and second-generation cephalosporins are ineffective against B. pertussis. One study demonstrated clinical efficacy in treating pertussis with highdose specific pertussis globulin from donors immunized with acellular pertussis although efficacy of this regimen on a larger scale has not been proved. One investigator has proposed a role for inhaled corticosteroids in the treatment of pertussis.68 There are no data available to evaluate the role of albuterol or other beta-adrenergic agents in the treatment of pertussis. Erythromycin also is of value in prevention of pertussis in exposed infants. Granstrom and colleagues described its use

Chapter 7 in 28 newborns of mothers with p e r t u ~ s i sThe . ~ ~ women had serologic or culture-confirmed pertussis at the time of labor. Mothers and their newborns received a 10-day course of erythromycin. The infected and treated mothers were allowed to nurse their infants. None of the infants developed signs or serologic evidence of pertussis. Erythromycin has also been shown to be effective in preventing secondary spread within households in which infants resided.70 Erythromycin (40 to 50mg/kg per day, orally in four doses, maximum 2 g per day) for 14 days is recommended for household70and other close contacts, such as those in the hospital, including medical and surgical per~onnel.~~ Although their efficacies have not been established, clarithromycin, azithromycin, and trimethoprim-sulfamethoxazolemay be alternatives for patients who cannot tolerate erythr~mycin.~'" Azithromycin (10-12 mg/kg per day orally in one dose for 5 days) or clarithromycin (15-20 mg/kg per day orally in two divided doses for 7 days) may have fewer adverse effects and better compliance than erythromycin for treatment of the infected infant.71 Reports of clusters of cases of pyloric stenosis among infants given erythromycin for prophylaxis after exposure to pertussis have raised concern about using erythromycin in A study of 469 infants given erythromycin this during the first 3 months of life confirmed an association between systemic (but not ophthalmic) erythromycin and pyloric stenosis and identified that risk was highest in the first 2 weeks of life.74Because erythromycin remains the only medication proven effective for this purpose, and pertussis can be life-threatening in the neonate, the drug remains the recommended agent until alternative regimens can be shown to be safe and effective. Health care professionals who prescribe erythromycin to newborns should inform parents of the risk of pyloric stenosis and counsel them about signs and symptoms of pyloric stenosis.

OTITIS MEDIA Otitis media in the newborn may be an isolated infection, or it may be associated with sepsis, pneumonia, or meningitis. Acute otitis media is defined as the presence of fluid in the middle ear (middle ear effusion) accompanied by an acute sign of illness. Middle ear effusion may be present without other signs of acute illness. Diagnostic criteria for otitis media in the newborn are the same as in the older child, but the vulnerability of the newborn infant and potential differences in the microbiology of otitis media in the neonate, especially in the first 2 weeks of life, make it necessary to exercise special considerations in choosing antimicrobial therapy.

Pathogenesis and Pathology During fetal life, amniotic fluid bathes the entire respiratory tree, including the lungs, paranasal sinuses, and middle ear cleft. Amniotic fluid and cellular debris usually are cleared from the middle ear in most infants within a few days after birth.75In term infants, the middle ear usually is well aerated, with normal middle ear pressure and normal tympanic membrane compliance, within the first 24 hours.76A study of 68 full-term infants examined by otoscopy, tympanometry, and acoustic reflectometry within the first 3 hours of life


301

revealed the presence of middle ear effusion in all neonates; fluid was absent at 72 hours of life in almost all infants.77 Studies of the middle ear at autopsy provide important information about the development of otitis media in the neonate. Inflammation in the lungs or paranasal sinuses usually was accompanied by inflammation in the middle ear.75-80DeSa examined 130 infants, including 36 stillborn infants, 74 neonates who died within 7 days of life, and 20 infants who died between 8 and 28 days. In 56 cases, the middle ear was aerated or contained a small amount of clear fluid. In 55 cases, amniotic debris was present; in 2 additional cases, cellular material was mixed with mucus. A purulent exudate was present in the middle ear of 17 infants; these exudates were cultured, and a bacterial pathogen was isolated from 13.Amniotic material was present in specimens obtained from most of the stillborn infants. Purulent exudate was not seen in the stillborns; the frequency of its presence increased with postnatal age at time of death. Of the 20 infants who lived for 7 or more days, 11 had purulent exudate in the middle ear. Each of the 17 infants with otitis media had one or more significant infections elsewhere; 12 had pneumonia, and 6 had meningiti~.~~ The author subsequently identified mucosal metaplasia and chronic inflammation in the middle ears of newborns receiving ventilatory support." Factors that may affect the development of otitis media in the neonate include the nature of the amniotic fluid, the presence of other infectious processes, the need for resuscitative efforts (especially positive-pressure ventilation), the presence of anatomic defects such as cleft palate, the immunologic status of the infant, and the general state of health of the infant. Aspiration of infected amniotic fluid through the eustachian tube may be one factor in the development of otitis media in the neonate; dysfunction of the eustachian tube, which is shorter, wider, and more horizontal than in the older child:* and failure to clear aspirated material from the middle ear probably have etiologic roles as well. Piza and associatesa3speculate that infants born through thick meconium fluid may be at greater risk for otitis media because of the inflammatory nature of this fluid. DeSa noted that many infants in whom otitis media developed had required assistance in respiration and speculated that the pressure of ventilation efforts was responsible for propelling infected material into the middle ear.75In infants, as in older children, middle ear effusionappears to be frequent in patients with nasotracheal tubes, and the effusion occurs first on the side of i n t ~ b a t i o nBerman .~~ and colleaguesa5described an association between nasotracheal intubation for more than 7 days and the presence of middle ear effusion. Infants with cleft palate are at high risk for recurrent otitis media and conductive hearing loss due to the persistence of middle ear effusion. Attempts to reduce the incidence of permanent hearing impairment have included intensive monitoring of children with cleft palate for middle ear effusion and repair of these defects earlier in infancy. One study, however, found that early cleft palate repair did not reduce significantly the subsequent need for ventilating tubes in these children.86 Breast-fed infants are at lower risk than bottle-fed infants for acute otitis media. Results of studies of Canadian Eskimo infantsa7and of infants in India,88Finland,89Denmark?' and the United States" indicate a significant decrease in the incidence of infection of the middle ear in breast-fed compared

302

Section I1


with bottle-fed infants. A study from Cooperstown, New York, identified a significantly lower incidence of acute lower respiratory tract infection in infants who were breast-fed compared with infants who were bottle-fed; the incidence of otitis media was lower in the breast-fed infants, but this difference was not statistically significant.’* Boston infants who were breast-fed had a lower risk for either having had one or more episodes of acute otitis media or having had recurrent acute otitis media (three or more episodes) during the first year of life. Of interest was the fact that the protective association of breast-feeding did not increase with increased duration of breast-feeding; infants who were breast-fed for 3 months had an incidence of otitis media in the first year of life that was as low as infants who were breast-fed for 12 m0nths.9~ The beneficial effects of breast-feeding may be due to immunologic factors in breast milk or to development of musculature in the breast-fed infant that may affect eustachian tube function and assist in promoting drainage of middle ear fluid. Alternatively,the findings could indicate harmful effects of bottle-feeding, including the reclining or horizontal position of the bottle-fed infant that allows fluid to move readily into the middle allergy to one or more components in cow’s milk or formula, or aspiration of fluids into the middle ear during feeding. The hypothesis that breast milk is protective is substantiated by the results of studies of a special feeding bottle for infants with cleft palate. Among infants who were fed by this bottle containing breast milk, the number of days with middle ear effusion was less than in infants fed by this device containing formula, which suggests that protection was more likely to be a quality of the milk rather than of the mode of feeding.96Adherence of S. pneumoniae and Haemophilus influenzae to buccal epithelial cells was inhibited by human breast milk?7 Early onset of pneumococcal otitis media has been associated with low levels of cord blood pneumococcal irnmunoglobulin G (IgG) antibodies. Among a group of infants who had siblings with middle ear disease, low concentrations of cord blood antibody to pneumococcal serotype 14 or 19F were associated with earlier onset of otitis media.98Low cord blood antibody concentrations to serotype 19F predicted more episodes of otitis media over the first year of life in a cohort of 415 infants whose mothers enrolled in the study during pregnancy?’ In these infants, early otitis media was associated significantly with type 14 IgGl in the lowest quartile, but not with type 19F IgGl antibody or with either IgG2 antibody.ImThese findings prompted study of maternal immunization to prevent pneumococcal disease in neonates. Immunization of pregnant chinchillas with heptavalent pneumococcal vaccine resulted in reduced incidence and severity of experimental otitis in their infants.’O’ Immunization of pregnant women in Bangladesh, the Gambia, and the United States with pneumococcal polysaccharide vaccine resulted in pneumococcal antibody concentrations that were higher at birth in infants of immunized mothers than in control^.'^^^'^^ In addition, pneumococcal IgG antibody acquired by infants of immunized mothers had greater opsonophagocyticactivity than that in control infants.’” A trial is under way to assess the role of maternal pneumococcal immunization in prevention of early infant otitis media.’05 Antibody to pneumococci in breast milk has been proposed to have a role in prevention of early otitis media.

Early colonization with pneumococci or other bacteria is associated with early otitis media.lo6The role of antibodies to pneumococci in human milk in prevention of nasopharyngeal colonization of infants with pneumococci remains controversial. A study in Sweden involving 448 motherinfant pairs failed to demonstrate reduction in carriage of pneumococci in neonates fed milk with anticapsular and antiphosphorylcholine activity and showed an increase in colonization when infants were fed milk with anti-cell wall polysaccharide antibody activity.’” Maternal immunization with pneumococcal polysaccharide vaccine resulted in higher breast milk IgA antibodies to serotype 19F,but not type 6B.I”

Epidemiology The incidence of acute otitis media or middle ear effusion in the newborn is uncertain because of the paucity of definitive studies. Warren and Stool examined 127 consecutive infants whose birth weights were less than 2300 g and found 3 with middle ear effusions (at 2,7, and 26 days of life).’” Jaffe and co-workers examined 101 Navajo infants within 48 hours of birth and identified 18 with impaired mobility of the tympanic membrane.’0’ Berman and co-workers identified effusion in the middle ear of 30% of 125 consecutively examined infants who were admitted to a neonatal intensive care unit (NICU).” The clinical diagnosis was corroborated by aspiration of middle ear fluid. The basis for the differences in incidence in the various studies is uncertain, but there may be an association with procedures used in the nurseries. Acute otitis media is common in early infancy. In the prospective study of Boston children, 9% of children had an episode of middle ear infection by 3 months of age?3 Age at the time of first episode of acute otitis media appears to be an important predictor for recurrent otitis media.93*’09’L10 Children who experience a first episode during the first months of life are more likely to experience repeated infection than children whose first episode occurs after the first birthday. Additional risk factors include parental smoking and low socioeconomic status.”””2 Some host factors that also are present in infants with neonatal sepsis have been identified in infants with middle ear infection. The incidence of infection is higher in premature infants than in those delivered at term in some ~ t u d i e s , ” ~but ~ ” ~not in the prospective study of Boston ~hildren.9~ Male infants are more frequently infected than female infants.’13 Otitis media also is associated with a prolonged interval after rupture of maternal membranes and with other obstetric d i f f i ~ u l t i e s . ~Middle ~ , ’ ~ ~ear infection is more severe in Native Americans and Canadian Eskimos than in the general population, and it is likely that this is true in neonates and older infants as Children with cleft palate have a high incidence of otitis media, which may begin soon after birth.’I6 Prenatal, innate, and early environmental exposures were assessed in relation to early otitis media in a cohort of 596 infants followed prospectively from birth. In multivariable analysis, prenatal factors were not associated with early onset of otitis media, but environmental (day care, upper respiratory infection, birth in the fall) and innate factors (parental and sibling history of otitis media) were associated with early and/or recurrent otitis media.Il7

Chapter 7

Microbiology The bacteriology of otitis media in infants has been studied by investigators in H~nolulu,"~ Dallas,I14Huntsville,"' Boston,"8 Milwaukee,' Tampere Hospital in Finland,''0 and Beer-Sheva, Israel (see Table 7-1).12' S. pneurnoniae and H. influenzae are isolated frequently from fluid aspirated from the middle ear in the very young, as is the case in older infants and children. Although it has been suggested that otitis media in the youngest neonates (younger than 2 weeks of age) is caused more frequently by organisms associated with neonatal sepsis, such as group B streptococci, S. aureus, and gram-negative enteric bacilli, this pattern does not emerge consistently when multiple studies are examined. Pneumococci were isolated from middle ear fluid in the first 2 weeks of life, and otitis associated with gram-negative enteric organisms and group B streptococci occurred in older infants. Microbiology of middle ear disease in infants who are in neonatal intensive care nurseries may be an exception to the pattern associated with otitis media in previously healthy infants and may reflect pathogens present in the NICU setting. In a small series of 13 such infants, only gram-negative enteric organisms and staphylococcal species were identified in the 10 samples of middle ear fluid from which bacteria were identified.85 Table 7-1 shows the microbiology of middle ear isolates from 8 studies of otitis media in infants; when possible, data from the youngest neonates have been separated from data from older infants. Susceptibility patterns of organisms causing otitis media in newborns reflect local patterns. In general, trends toward increasing resistance of pneumococci to antibacterial agents, and colonization and disease due to pneumococcal serotypes not present in the pneumococcal conjugate vaccine used routinely in the United States and other countries, have been observed. Gram-negative enteric bacilli have been the predominant organisms isolated at autopsy from purulent effusions of the middle ear. Of 17 infants studied by deSa, 7 were found to have E. coli and 6 had l? aer~ginosa.'~Beta-hemolytic streptococci (not further identified) were isolated from one infant, and no organism was recovered from the remaining three. Because pneumonia and meningitis accompanied the otitis in all of these cases, the predominance of gramnegative pathogens in this series is not unexpected. Congenital tuberculosis of the ear"' and of the ear and parotid gland'23 has been reported in preterm infants from Hong Kong and Turkey. Both cases were notable for significant regional lymphadenopathy, lack of response to antibacterial therapy, and presence of active pulmonary tuberculosis in the mother. Authors of both reports suggest that there is continued need for a high index of suspicion for this disease in appropriate circumstances. Otitis media and bacteremia due to I? aeruginosa occurring at 19 days of life was thought to occur following inoculation of the organism during a water birth.Iz4B. pertussis was isolated from middle ear fluid in a 1-month-old infant hospitalized with pertussis; intubation of the child's airway may have facilitated spread of the organism from the nasopharynx to the middle ear.125

Diagnosis During the first few weeks of life, examination of the ear requires patience and careful appraisal of all of the


303

structures of the external canal and the middle ear.:126 The diagnostic criteria for acute otitis media in the neonate are the same as those in the older child presence of fluid in the middle ear accompanied by signs of acute illness. Middle ear effusion and its effect on tympanic membrane mobility are best measured with a pneumatic otoscope. The normal tympanic membrane moves inward with positive pressure and outward with negative pressure. The presence of fluid in the middle ear dampens tympanic membrane mobility. In the first few days of life, the ear canal is filled with vernix caseosa; this material is readily removed with a small curette or suction tube. The canal walls of the young infant are pliable and tend to expand and collapse with insufflation during pneumatic otoscopy. Continuing pneumatic insufflation as the speculum is advanced is helpful because the positive pressure expands the pliable canal walls. The tympanic membrane often appears thickened and opaque, and mobility may be limited during the first few days of life.Iz7 In many infants, the membrane is in an extreme oblique position, with the superior aspect proximal to the observer (Fig. 7-1). The tympanic membrane and the superior canal wall may appear to lie almost in the same plane, so it is often difficult to distinguish the point where the canal ends and the pars flaccida of the membrane begins. The inferior canal wall may bulge loosely over the inferior position of the tympanic membrane and move with positive pressure, simulating movement of the tympanic membrane. The examiner must distinguish between the movement of the canal walls and the movement of the membrane. The following considerations are helpful in recognition of these structures: Vessels are seen within the tympanic membrane but are less apparent in the skin of the ear canal; and the tympanic membrane moves during crying or respiration when the middle ear is aerated. The ear canals of most neonates permit entry of only a 2-mm-diameter speculum. Because the entire eardrum cannot be examined at one time, owing to the small diameter of the speculum, quadrants must be examined sequentially. By 1 month of age, the infant's tympanic membrane has assumed an oblique position that is less marked than in the first few weeks of life and is similar to the position in the older child. Tympanometry is of limited value in diagnosis of middle ear effusion in the neonate. The flat tympanogram indicative of effusion in children 6 months of age or older often is not present in the younger infant, even when fluid is documented by aspiration.'" Acoustic reflectometry may be advantageous compared with tympanometry in the neonate because it does not require insertion into the ear canal or the achievement of a seal within the canal, but there are insufficient data to identify sensitivity and ~pecificity.'~~ Culture of the throat or nasopharynx is an imperfect method of identifylng the bacterial pathogens responsible for otitis media. Many studies have demonstrated the diagnostic value of needle aspiration of middle ear effusions (tympanocentesis) in acute otitis media. The specific microbiologic diagnosis defines the appropriate antimicrobial therapy and is sufficiently important in the sick neonate to warrant consideration of aspiration of the middle ear fluid. Aspiration of middle ear fluid is more difficult in the neonate than in the older child, and usually the assistance of an otolaryngologist (using an otoscope with a surgical head or an otomicroscope) is required.

Honolulu (1970-1971)

Dallas (1974-1976) Denver (1 975- 1976) Denver (1975-1976) Huntsville, Boston (1976)

Finland (19801985)

Milwaukee (1994-1995)

Israel (1995-1999)

Bland"'

Tetzlaff et a1114 Balkany et alas' Berman et aIn5 Shurin et allla

Karma et all2'

Nozicka et

Turner et all2'

0-1 mo 1-2 mo 0-2 wk 2-8 wk 0-2 wk 2-8 wk

10-14 days 15-42 days 0-5 wk 0-4 mo 0-4 mo 0-6 wk

Age Range

14 93 Unknown" Unknown" 5 109"

2 19" 42" 21 13' 17

No. in Series S. pneumoniae 3 (12) 11 (26)

H. influenzae

0

5 (35) 55 (60) 0 9 (35)

Staphylococcal Species

Enteric GramNegative Species

Causative Organism: No. of Cases ( O h )

some infants, more than one organism was identified, or cultures of middle ear fluid yielded no growth. bNonpathogenin this study. Clncludesgroup A and group B streptococci, Staphylococcus species, Neisseria species, diphtheroids, and hemolytic streptococci. H. influenzae, Haemophilus influenzae; NA, not applicable; NICU, neonatal intensive care unit; S. pneumoniae, Streptococcus pneumoniae.

Site (yeads])

Patients

Microbiology of Otitis Media in Newborn Infants

Authods)

Table 7-1

Other

"Nontoxic" outpatients Outpatients

Outpatients Outpatients NICU patients 3 nursery patients ages 4,4, and 26 days

Outpatients

Comment

2

0

a.iP

s

Chapter 7 Neonate

Older infant and child

Lateral section


305

otitis media.93J09J 10 The earlier in life the child has an episode of otitis media, the more likely the child is to have recurrent infections. It is uncertain whether this means that an early episode of otitis media damages the mucosa of the middle ear and makes the child more prone to subsequent infection, or whether early infection merely identifies children with dysfunction of the eustachian tube or subtle or undefined immune system abnormalities who have a propensity to infection of the middle ear because of these abnormalities.

MAST0IDIT1S Short process- _ _ _ _ _ _ _ _

Otoscopic view

Figure 7-1 Lateral section of the middle ear and otoscopic view of the tympanic membrane in the neonate and older infant and child. (Courtesy of Charles D. Bluestone, MD.)

The mastoid air cells are not developed at birth and usuaUy consist of only a single space each. Therefore, mastoiditis rarely occurs in the neonate. One report, however, cited a case of meningitis and mastoiditis caused by H. influenme in a n e ~ b 0 r n . Roentgenograms l~~ of the mastoid area demonstrated a cloudy right antrum. At operation, the middle ear was normal but the antrum was filled with infected mesenchymal tissue.

PNEUMONIA When spontaneous perforation has occurred, the fluid exuding into the external canal from the middle ear is contaminated by the microflora from the canal. Appropriate cultures may be obtained by carefully cleaning the canal with 70% alcohol and obtaining cultures from the area of perforation as the fluid emerges or by needle aspiration through the intact membrane.

Treatment Initial therapy for febrile or ill-appearing infants with otitis media during the first 2 weeks of life is similar to that for children with neonatal sepsis. Both a penicillin and an aminoglycoside or third-generation cephalosporin should be used. Specific therapy can be provided if needle aspiration is performed and the pathogen is identified. Infants who remain in the nursery because of prematurity, low birth weight, or illness require similar management during the first 4 to 6 weeks of life. If the infant was born at term, had a normal delivery and course in the nursery, has been in good health since discharge from the nursery, is not ill-appearing, and is 2 weeks of age or older, the middle ear infection probably is due to S. pneumoniae or H. influenzae and may be treated with an appropriate oral antimicrobial agent such as amoxicillin or amoxicillin-~lavulanate.~~~ The infant may be managed outside the hospital if he or she does not appear to have a toxic condition. For infants born at term who have acute otitis media and are in a toxic condition, the physician must consider hospitalization, cultures of blood and cerebrospinal fluid, and use of parenterally administered antimicrobial agents because of possible systemic infection, a focus of infection elsewhere, or presence of a resistant organism.

Prognosis Infants who have infections of the middle ear in the neonatal period appear to be susceptible to recurrent episodes of

Pneumonia, inflammation of the lungs, in the fetus and newborn can be classified into four categories according to the time and mode of acquisition of inflammation:

Congenital pneumonia acquired by the transplacental route: The pneumonia is one component of generalized congenital disease. Intrauterine pneumonia: This is an inflammatory disease of the lungs found at autopsy in stillborn or live-born infants who die within the first few days of life, usually associated with fetal asphyxia or intrauterine infection and thus includes infectious and noninfectious causes. Pneumonia acquired during birth: The signs of pneumonia occur within the first few days of life, and infection is due to microorganisms that colonize the maternal birth canal. Pneumonia acquired after birth: The illness manifests itself during the first month of life, either in the nursery or at home; sources of infection include human contacts and contaminated equipment. Although helpful as a general framework for understanding neonatal pneumonia, these four categories have clinical features and pathologic characteristics that overlap. Thus, management of pneumonia is essentially the same for all four categories, requiring aggressive supportive measures for the respiratory and circulatory systems along with treatment for the specific underlying infectious disorder. Pneumonia in the neonate may be caused by viruses, bacteria, or parasitic organisms. Detailed information about causative organisms mentioned in this chapter other than bacteria is found in the appropriate chapters in this book; bacterial disease is covered in detail here. Pneumonia acquired by the transplacental route may be caused by rubella, cytomegalovirus, herpes simplex virus, a d e n o v i r u s e ~ mumps , ~ ~ ~ virus,133Toxoplasma gondii, L. monocytogenes, or T. pallidum. Some of these organisms

306

Section I1


and the enteroviruses, genital mycoplasmas, C. trachomatis, of the lung of some infants without pneumonia do yield and Mycobacterium tuberculosis are also responsible for ba~teria.'~' Fetal asphyxia or hypoxia appears to be a factor intrauterine pneumonia resulting from aspiration of infected in most cases of congenital pneumonia. The asphyxia may amniotic fluid. Fatal pneumonitis due to echovirus has also cause death directly or by eliciting a pulmonary response been reported in newborns (see Chapter 24).'34Isolation of consisting of hemorrhage, edema, and inflammatory cells. Trichomonus vaginalis from the tracheal aspirates of infants From his studies of congenital pneumonia, Barter concluded with pneumonia suggests a possible association of this that hypoxia or infection may produce similar inflammation organism with respiratory tract disease in the n e ~ n a t e . ' ~ ~ ' " ~in the 1~ngs.I~' In addition, Bernstein and Wang found that Group B streptococci constitute the most frequent cause evidence of fetal asphyxia was frequently present at autopsy of bacterial pneumonia acquired at delivery. Pneumonia due in infants with congenital pneumonia who also had to group B streptococci and to other bacteria such as E. coli generalized petechial hemorrhage, subarachnoid and intraor L. monocytogenes may resemble hyaline membrane disease. cerebral hemorrhage, liver cell necrosis, or ulceration of the Pneumonias acquired after birth, either in the nursery or gastrointestinal m~cosa.'~' at home, include those caused by respiratory viruses such as Although it is likely that asphyxia and infection can respiratory syncytial virus, influenzavirus, or adenoviruses; produce similar inflammatory patterns in lungs of the fetus, gram-positive bacteria such as pneumococci and S. aureus; available information is insufficient to determine which is gram-negative enteric bacilli; C. trachomaris; Mycoplusrna; more important or more frequent. In a review of fetal and and Pneumocystis c ~ r i n i i . 'Pneumonia ~~ caused by nonperinatal pneumonia, Finland concluded that "pulmonary bacterial microorganisms is discussed in the appropriate lesions certainly play a major role in the deaths of the stillchapters. Bacterial pneumonia and neonatal sepsis acquired born and of infants in the early neonatal period. Infection, during or soon after birth share many features of pathoon the other hand, appears to play only a minor role in what genesis, epidemiology, and management, and these aspects has been called 'congenital pneumonia,' that is, the inflamare discussed in Chapter 6. This section consists of a matory lesion seen in the stillborn or in those dying within discussion of pneumonia in the fetus and newborn not the first few hours, or possibly the first day or two; it assumes greater importance in pneumonias that cause death later in presented elsewhere in the text. the neonatal period."'52 Davies noted that the histologic presentation of congenital pneumonia appears to represent aspiration of materials in amniotic fluid, including maternal Pathogenesis and Pathology leukocytes and amniotic debris, rather than infection Congenital or Intrauterine Pneumonia originating in the pulmonary airspaces. Evidence of infiltration of alveoli or destruction of bronchopulmonary tissue Histologic features of congenital or intrauterine pneumonia have been described from autopsy findings in infants who is rarely present.'53 are stillborn or who die shortly after birth (usually within Pneumonia Acquired during the Birth Process and 24 hours). An inflammatory reaction is found in histologic in the First Month of Life sections of lung. Polymorphonuclear leukocytes are present The pathology of pneumonia acquired during or after birth in the alveoli and often are mixed with vernix and squamous is similar to that in older children or adults. The lung contains cells. Infiltrates of round cells may be present in interstitial areas of densely cellular exudate with vascular congestion, tissue of small bronchioles and interalveolar hemorrhage, and pulmonary n e c r ~ s i s . ' ~ ' ~Bacteria ' ~ ' ~ ' ~ ~often Alveolar macrophages may be present and have been associare seen in sections of the lung. S. aureus (see Chapter 17) ated with both duration of postnatal life and inflammatory and Klebsiella p n e ~ m o n i a e ' ~may ~ ~produce '~~ extensive tissue pulmonary lesions.'44 The inflammation is diffuse and damage, microabscesses, and empyema. Pneumatoceles are a usually is uniform throughout the lung. Bacteria are seen common manifestation of staphylococcal pneumonia but infrequently, and cultures for bacteria are often negative. also may occur in infections with K. p n e ~ m o n i a e ' ~and ~.'~~ Davies and Aherne14' noted that the usual characteristics of E. ~ 0 l i . lHyaline ~ ~ membranes similar to those seen in bacterial pneumonia are missing in congenital pneumonia; respiratory distress syndrome have been observed in the among these characteristics are pleural reaction, infiltration lungs of infants who died with pneumonia caused by group or destruction of bronchopulmonary tissue, and fibrinous B streptococci. Cocci were present within the membranes, exudate in the alveoli. and in some cases, exuberant growth that included masses The pathogenesis of congenital pneumonia is not well u n d e r ~ t o o d . 'Asphyxia ~~ and intrauterine infection, acting of organisms was apparent. Although most thoroughly alone or together, appear to be the most important fa~t0rs.l~' documented in cases of pneumonia caused by group B streptococci, similar membranes have been seen in It is thought that microorganisms of the birth canal histologic sections of the lungs of infants who died with contaminate the amniotic fluid by ascending infection after early rupture of maternal membranes or through minimal pneumonia caused by H. influenme and gram-negative enteric bacilli.15' and often unrecognized defects in the membranes. Evidence of aspiration of amniotic fluid is freq~ent.'~'Naeye and The pathogenesis of pneumonia acquired at or immediately colleagues proposed that microbial invasion of the fetal after birth is similar to that of neonatal sepsis and is dismembranes and aspiration of infected amniotic fluid cussed in Chapter 6. Presumably, aspiration of infected constitute a frequent cause of chorioamnionitis and amniotic fluid or secretions of the birth canal are responsible congenital pne~rnonia.'~~-'~' Bacteriologic studies, however, for most cases of pneumonia acquired during delivery. After have given equivocal results. Many infants with congenital birth, the infant may become infected through human pneumonia do not have bacteria in their lungs, yet cultures contact or contaminated equipment. Infants who receive

Chapter 7


307

autopsy from the lungs of many infants with and without assisted ventilation are at risk because of the disruption of pneumonia. the normal barriers to infection due to the presence of the Information about bacterial etiology of pneumonia also endotracheal tube and possible irritation of tissues near the can be obtained by culturing blood, tracheal aspirates and tube. Bacteria or other organisms may invade the damaged tissue, which may result in tracheitis or tracheobr~nchitis.'~~ pleural fluid and by needle aspiration of the lungs of living children with pneumonia. Ventilator-associated pneumonia may be prevented by The bacterial species responsible for fetal and neonatal reducing bacterial colonization of the aerodigestive tract and pneumonia are those present in the maternal birth canal; decreasing the incidence of aspiration. A recent review highincluded in this flora are gram-positive cocci such as group lighted strategies for prevention of pneumonia in patients A, group B, and group FIffl streptococci and gram-negative receiving mechanical ventilation, including nonpharmacologic enteric bacilli, predominantly E. coli and, to a lesser extent, strategies such as attention to hand washing and standard Proteus, Klebsiella, and Enterobacter species. Microorganisms precautions, positioning of patients, avoiding abdominal acquired postnatally may, for those infants who remain distention, avoiding nasal intubation, and maintaining hospitalized, reflect the microbial environment of the inventilator circuits and suction catheters and tubing, as well patient setting. For those infants who develop pneumonia in as pharmacologic strategies such as appropriate use of antithe community, typical organisms causing communitymicrobial agents.'60 Newborns with congenital anomalies acquired pneumonia predominate. In the 1950s and 1960s, such as tracheoesophageal fistula, choanal atresia, and S. aureus was a common cause of neonatal pneumonia; this diaphragmatic hernia have an increased risk of developing is uncommon now. Few data exist about relative frequency pneumonia. of specific etiologic agents of neonatal pneumonia or inLung abscess and empyema are uncommon in neonates cidence of pneumonia due to specific organisms. One review and usually occur as complications of severe pneumonia. of invasive pneumococcal disease monitored prospectively Abscesses also may occur as a result of infection of by the U.S. Pediatric Multicenter Pneumococcal Surveillance congenital cysts of the lung. Group identified 29 cases of pneumococcal infection in infants younger than 30 days of age among 4428 cases in Microbiology children; 4 of these were bacteremic ~ n e u m 0 n i a . In l ~addition ~ to S. pneumoniae,'66-'68 H. i n j 7 ~ e n z a e ' ~and ~ ~ Moraxella '~~ Most information about the bacteriology of fetal and ~atarrhalis'~'also are infrequent causes of pneumonia in neonatal pneumonia has been derived from studies done at the newborn. Pneumonia caused by these organisms is autopsy of stillborn infants and of infants who die during frequently associated with bacteremia, and sometimes with the first month of life. A study reviewing causes of death of meningitis.141,166,168.'69 Many other organisms have been very low birth weight infants concluded, on the basis of histologic studies done at autopsy, that pneumonia was an reported in association with pneumonia in neonates, underrecognized cause of death in these infants.l6' including a fatal case of congenital pneumonia caused by Bacteriologic studies at autopsy of infants with and without Pasteurella multocida in a full-term neonate associated with pneumonia were reported by Barter and Hudson.'49 The maternal infection and colonization of the family cat with incidence of bacteria in the lungs increased with age in the same 0rgani~m.I~' A case of pneumonia and sepsis due to ampicillin-resistant Morganella morganii was reported from infants dying with and without pneumonia; among those Texas'72; the authors speculate about the role of increased infants with pneumonia, bacteria were cultured from the use of intrapartum antibiotics in predisposing to colonizlungs of 55% of stillborn infants and infants who died ation and infection with ampicillin-resistant organisms. during the first day of life, 70% of infants who died between Certain bacteria are associated with a predilection for 24 hours and 7 days of age, and 100% of infants who died developing lung abscess or empyema. During the 1950s and between 7 and 28 days of age. Among those infants without 1960% outbreaks of staphylococcal pneumonia occurred; pneumonia, bacteria were cultured from the lungs of 36% of stillborn infants and infants who died within the first many times these infections were accompanied by empyemas 24 hours, 53% of infants who died between 24 hours and and pneumatoceles. This is now seen infrequently. Although rare in newborns, H. inj7uenzae was associated with 7 days of age, and 75% of infants who died between 7 and pneumonia and e m ~ y e m a until ' ~ ~ its virtual disappearance 28 days of age. The bacterial species were similar in the after hitiation of universal immunization in the early 1990s. infants with and without pneumonia, with the exception of Single or multiple abscesses may also be caused by group B group B streptococci, which was found only in infants with streptococci, E. coli, and K. p n e ~ m o n i a e . ' ~Cavitary ~ ? ' ~ ~ lesions pneumonia. These results were corroborated by Penner and McInnis: may develop in pneumonia due to Legionella p n e ~ m o p h i l a . ' ~ ~ Lung abscess and meningitis caused by Citrobacter koseri was Bacteria were cultured from 92% of the lungs of fetuses and reported recently in a previously health I-month-old infant.'77 neonates with pneumonia and from 40% of the lungs of Nosocomial infection due to L. pneumophila has been fetuses and neonates without pneumonia.'43 Davies did lung reported, including cases of fatal necrotizing pneumonia and punctures in stillborn and live-born infants immediately cavitary p n e ~ m o n i a . ' Reports ~~ have identified Citrobacter after death, and bacteria were cultured from the lungs of diversus as a cause of lung abscess'79and Bacillus cereus as a 74% of 93 infants, although pneumonia was diagnosed in cause of a necrotizing pneumonia in premature infants.'" only 9 cases.16' Barson identified bacteria in lung cultures at Empyema can also be associated with extensivepneumonia. autopsy of 252 infants dying with bronchopneumonia; Empyema due to E. coli and Klebsiella has been reported in positive cultures were obtained in 60% of infants dying 6- and 8-day-old infants,l8' and Serratia marcescens was on the first day of life and in 78% of infants dying between isolated from blood, tracheal aspirate, and empyema fluid in 8 and 28 days of age.'63 Thus, bacteria were cultured at

308

Section I1

Table 7-2


Incidence of Congenital and Neonatal Pneumonia Based on Findings at Autopsy No. with Pneumonia/TotalNo. of Infants (%)

Place (Reference No.), Yeads) of Study

Stillbirths Premature

Term

Live-BornInfants Total

Premature

Term

Age or Weight of Infants at Death

Total ~

Helsinki (138). 1951 Helsinki (154). 1946-1952

2101315 (67)

Newcastle (139). 1955-1956 Adelaide (140). 1950-1951

318 (38)

Detroit (151). 1956-1959 Winnipeg (186). 1954-1960

428l676 (63) 10B1 (32) 12/40 (30) 551231 (24)

c29 days

271110 (25) 22/80 (26) 1001512 (20) 5912 19 (27)

c7 days

15/46 (33)

Winnipeg (187). 1954-1957 Edinburgh (188). 1922 NIH Collaborative Study (189), 1959-1964 Manchester (142), 1950-1954

331125 (26)

Los Angeles (185). 1990-1993

a premature neonate.la2The past decade was characterized by emergence of increased incidence of invasive disease due to group A streptococci. Cases of pleural empyema due to group A streptococci have been reported from the United Kingdom and it remains to be seen whether these reports represent isolated cases or are part of a generalized increase in this disease.

Epidemiology INCIDENCE

The incidence of pneumonia at autopsy of stillborn and liveborn infants is given in Table 7-2. Pneumonia remains a significant cause of death in the neonatal period,Ia5 and infection of amniotic fluid leading to pneumonia may be the most common cause of death in extremely premature infants.la6 The definition of pneumonia in the autopsy studies usually was based on the presence of polymorphonuclear leukocytes in the pulmonary alveoli or interstitium or both. The presence or absence of bacteria was not important in the definition of pneumonia. The incidence rates for congenital and neonatal pneumonia at autopsy are similar despite the different times of study (1922 to 1999) and different locations’38~’40~’42~151~184~’89 (with the single exception of a report from Helsinki154):15% to 38% of stillborn infants and 20% to 32% of live-born infants had evidence of pneumonia. The incidence rates for pneumonia were similar in premature and in term infants. Rates of pneumonia derived from epidemiologic studies are scarce. Sinha and colleagues report an attack rate of 0.4 per 100 infants diagnosed during a nursery stay, and 0.03 and 0.01 per 100 infants diagnosed at pediatric office visits and in hospital or emergency department visits, respectively. They

15,000 cells/mm3). Other reports have identified group B streptococci624and I? m i r a b i l i ~ ~as ' ~ causes of breast abscesses. Brook632found that 5 of 14 breast abscesses contained anaerobic bacteria (i.e., Bacteroides sp. and Peptostreptococcus), but S. aureus, group B streptococci, or enteric bacteria predominated; anaerobic bacteria occurred alone in only 2 of 14 cases. Paronychia may occur in neonates after injury to the cuticle. The lesion is usually caused by S. aureus or P-hemolytic streptococci.650The authors of a report on an outbreak of paronychia in a Kuala Lumpur nursery suggest but do not prove that the lesions were caused by an anaerobic Veillonella ~ p . ~ ~ ' Omphalitis is defined by the presence of erythema or serous or purulent discharge from the umbilical stump or periumbilical tissues. A review by C ~ s h i n g ~provided ~' a useful discussion of the pathophysiology, microbiology, diagnosis, and management of omphalitis. The incidence of infection is more frequent in low-birth-weight infants and in those with complications of delivery. A survey of infants born at the Royal Woman's Hospital in B r i ~ b a n identified e~~~ an incidence of approximately 2% among term infants. The mean age of presentation of omphalitis was 3.2 days. Perhaps because hexachlorophene bathing was used, gram-negative bacilli were more frequently associated with infection than were gram-positive cocci. However, microbiologic results are difficult to interpret because swabs of the site of infection do

8'

not exclude surface contaminants unless cultures are taken with extreme care and precision. A series from the United States6" found that periumbilical fasciitis was more frequent in males but did not find that umbilical catheterization,low birth weight, or septic delivery was associated with a high risk; overall, the incidence of omphalitis was equal in males and females. In this series, omphatitis presented as discharge, cellulitis,or fasciitis;grampositive organisms were found in 94% of cultures, and gram-negative bacteria were found in 64%. S. aureus was the most frequent isolate, with E. coli and Klebsiella sp. the next most common. Group A streptococci have been responsible for nursery outbreaks that may include an indolent form of omphalitis characterized by erythema and oozing of the umbilical stump for days to weeks, accompanied by pustular lesions of the abdominal wall in some cases.655Neonatal tetanus usually occurs as a result of contamination of the umbilical wound by Clostridium tetani at delivery. Acute necrotizing fasciitis is a bacterial infection of subcutaneous tissue and fascial sheath.630*656*657 Infection can arise in an operative wound or in a focal infection such as a breast abscess, or there may be no apparent predisposing cause. Necrotizing fasciitis has been reported after circumand as a complication of insertion of a fetal monitor?95 The trunk and extremities are the areas most commonly involved; inflammation spreads rapidly along fascial planes, producing thrombosis and extensive necrosis, with infarcts developing in overlying skin. Vesicles and bullae appear, and the skin may become blue-gray or black. Myositis and bacteremia may accompany fasciitis. Staphylococci,group B strepto~occi,6~' E. coli, P. aeruginosa, anaerobic bacteria,596 and mixtures of gram-positive and gram-negative bacteria have been associated with this disease. The bacteria are present in skin lesions, deep fascia, and in some cases, blood. The mortality is high despite the use of fasciotomy, wide debridement, and antibiotics. Perirectal abscesses may occur in newborns. Unlike older children, most newborns with perirectal abscess do not have underlying immunodeficiency, although infants with acquired or congenital immunodeficiencyoften present with this condition. The most common cause of perirectal abscess is S. aureus, E. coli, or other enteric b a ~ i t l i ~ ~however, ~,~~'; anaerobic bacteria can also be involved. S. aureus and enteric bacilli may be more common in infants and newborns.660 Recent rectal surgery for conditions such as Hirschsprung's disease or imperforate anus (myotomy or rectal dilatation) may be predisposing causes in infants; as in older children, neutropenia may be associated with an increased risk for perirectal abscess. Otitis externa is uncommon in the newborn. Victori#' described an outbreak of neonatal infections in which l? aeruginosa was cultured from seven infants with suppuration of the auditory canal. The author suggested that this outbreak was caused by contaminated bath water used in the nursery.

Diagnosis The appearance of a skin lesion alone may be sufficiently typical to suspect certain etiologic agents (e.g., ecthyma gangrenosum), but more often, the appearance is nonspecific. A microbiologic diagnosis should be sought to

Chapter 10 provide specific therapy. The lesion and the surrounding tissue should be cleaned with 70% ethanol to prevent contamination from organisms that colonize the surface. If crusts are present, they should be lifted with a sterile swab to provide drainage, and cultures should be obtained from the base of the lesion. Vesicles and pustules can be aspirated with a needle (20 to 25 gauge) attached to a syringe, or they can be opened and exudate collected on a sterile swab. In general, swabs are not preferred for specimen collection because swab materials bind or inactivate bacterial organisms. Aspiration of abscesses is important; more than one aspiration may be required because the suppurative focus may not be easily distinguished from the surrounding inflammatory tissue. Aspiration of the leading edge or point of maximal inflammation of an area of cellulitis may be of value and should be performed if no other suppurative or purulent sites are available for culture. A small needle (25 or 26 gauge) should be attached to a tuberculin or other smallvolume syringe fitled with 0.25 to 0.50mL of sterile nonbacteriostatic saline; the needle should be inserted into the area of soft tissue to be sampled, with continuous, gentle aspiration applied to the syringe. If no fluid is returned to the syringe, a small amount of fluid should be injected and immediately aspirated back into the syringe. Collected material may be sent to the laboratory in the syringe for Gram stain and culture, or, alternatively,the contents may be washed into a tube of bacteriologic broth medium for transport and subsequent culture. If swabs are used, care must be taken that the material does not dry before it is plated on bacteriologic media. Swabs preferentially should be directly inoculated or rinsed in bacteriologic media and immediately transported to the microbiology laboratory.Alternatively, they may be refrigerated or placed in appropriate transport media if more than a few hours will elapse before inoculation of media in the laboratory. Whenever sufficient material is available (on swabs or in liquid), several slides should be prepared for Gram staining. It is often difficult to distinguish petechiae from vascular dilatation. Pressure with a glass slide on the border of the lesion is a simple and reliable method for detecting extravasation of red blood cells. If the lesion disappears on pressure, it is probably caused by dilatation of small vessels, whereas persistence of the lesion after application of pressure indicates extravasation of red blood cells. Bacteria may be present in petechial lesions that occur in infants with bacterial sepsis. Blood obtained by aspiration or gentle scraping with a scalpel at the center of the petechiae may reveal the causative organism on Gram stain or culture.

Differential Diagnosis

Focal Bacterial Infections

371

Sclerema neonatorum is a diffuse, spreading, waxy hardness of the skin and subcutaneous tissue that occurs during the first weeks of life.%,& The subcutaneous tissue seems to be bound to underlying muscle and bone. This condition is usually seen on the thighs, buttocks, and trunk. Although associated with sepsis in some infants, sclerema also afflicts infants with dehydration, acidosis,and shock. Most evidence supports the hypothesis that sclerema is a manifestation of shock and insufficiency of the peripheral circulation. When it occurs in infants with generalized infection, sclerema is associated with a poor prognosis. In a review of cases of sepsis at The New York Hospital, sclerema was detected in 6 of 71 infants, 5 of whom died.667 Milia are yellow or pearly white papules that are 1mm in diameter and usually found scattered over the cheeks, forehead, and The lesion is a small cyst formed from retention of sebum in sebaceous glands. Because the cyst is capped by a shiny surface of epidermis, it may be confused with a small pustule. Milia are common; Gordon668 estimated that 40% of healthy newborns have milia. The lesions are common in the first few weeks of life. These cysts may be distinguished from staphylococcal pustules by aspiration and Gram stain of the material. Erythema toxicum consists of several types of lesions, including 1- to 3-mm, yellow-white papules or pustules on an erythematous base, erythematous macules, or diffuse erythema. These lesions are usually present on the trunk but may involve the head and neck and extremities as well. Most lesions appear within the first hours of life and are uncommon after 2 days of age. Erythema toxicum is uncommon in low-birth-weight or premature ir1fants.6~~ The affected infants have no signs of systemic illness or local irritation. A smear of the contents of pustules reveals the presence of eosinophils and an absence of bacteria. Other noninfectious pustular lesions of newborns include neonatal pustular melanosis, which is marked by a mixed infiltrate that has a predominance of ne~trophils,6~' and infantile acropustulosis, which is characterized by an eosinophilic infiltration of the &,.671,672 Bullae may occur on the skin of the wrist or forearm and usually are caused by t r a ~ m a . Sucking 6 ~ ~ of the extremity by the infant is believed to cause the bullae, which contain sterile serous fluid. Purpura may be caused by noninfectious causes,including trauma, erythroblastosis fetalis, or less frequently,coagulation disorders, maternal drug ingestion, congenital leukemia, and congenital Letterer-Siwe disease. Diaper rash is primarily a contact dermatitis associated with soilage of the skin by urine and st001.674-676 The rash may occur as a mild erythema or scaling, a sharply demarcated and confluent erythema, or discrete shallow ulcerations. A beefy red, confluent rash with raised margins, satellite (e.g., folliculitis) oval lesions, or discrete vesicular-pustular lesions indicates secondary invasion by C. albicans or S. aureus. Systemic infectious illnesses that manifest as disseminated rashes (e.g., herpes, varicella, syphilis) may be characterized by early typical lesions in the diaper area.

Sclerema neonatorum, milia, and erythema toxicum are noninfectious lesions that are often confused with infections of the skin.662Bullous and purpuric lesions may be caused by noninfectious disorders, including mast cell diseases (e.g., urticaria pigmentosa),histiocytosisX, acrodermatitisenteropathica, dermatitis herpetiformis, epidermolysis bullosa, congenital porphyria,'*' and pemphigus v u l g a r i ~ .A~ ~ ~ Treatment syndrome of generalized erythroderma, failure to thrive, The treatment of localized skin lesions consists of the and diarrhea has been associated with various forms of use of local antiseptic materials, systemic antimicrobial immunodeficiency.664

372

Section I1


agents, and appropriate incision and drainage or debridement. Hexachlorophene (3% detergent emulsion) and chlorhexidine (4% solution) are of value in cleaning small, abraded areas and discrete pustular lesions. Because of the concern over its neurotoxicity and cutaneous absorption, hexachlorophene should not be used on large open areas of skin (see Chapter 17). Systemic antibiotics should be considered for therapy whenever there is significant soft tissue infection with abscess or cellulitis. The specific antibiotic choice should be made on the basis of the microbiology of the lesion; streptococci may be treated effectively with penicillin G, ampicillin, or extended-spectrum cephalosporins (i.e., cefotaxime or ceftriaxone),whereas staphylococci generally must be treated with penicillinase-resistant penicillins or vancomycin. Infections due to gram-negativeenteric bacilli may be treated with aminoglycosides or extended-spectrum cephalosporins based on the results of susceptibility testing. Infections due to Pseudomonas organisms can be effectively treated with aminoglycosides or ceftazidime. Local heat and moist dressings over areas of abscess formation may facilitatelocalization or spontaneousdrainage. Indications for incision and drainage of abscesses in infants are the same as for those in older children and adults.

Prevention Prevention of local skin infections is best provided by appropriate routine hygiene, maintenance of the integrity of skin (i.e., avoidance of drying, trauma, or chemical contact), frequent diaper changes, and hygienic care of the umbilicus or other wounds or noninfectious skin inflammation. The following measures of skin care are recommended by the Committee of the Fetus and Newborn of the American Academy of Pediatrics676to prevent infection: 1. The first bath should be postponed until the infant is thermally stable. 2. Nonmedicated soap and water should be used; sterile sponges (not gauze) soaked in warm water may be used. 3. The buttocks and perianal should be cleaned with fresh water and cotton or with mild soap and water at diaper changes. 4. Ideally, agents used on the newborn skin should be dispensed in single-use containers. 5. No single method of cord care has proved to be superior, and none is end0rsed.6~~

Cord care may include application of alcohol, triple dye (i.e., brilliant green, proflavine hemisulfate, and crystal violet) or antimicrobial agents such as bacitracin. Alcohol hastens drying of the cord but is probably not effective in preventing cord colonization and omphalitis. A randomized study of triple dye, povidone-iodine, silver sulfadiazine, and bacitracin ointment showed comparability in antimicrobial During nursery outbreaks, the Centers for Disease Control and Prevention recommend the judicious use of hexachlorophene bathing.678Daily hexachlorophenebathing of the diaper area679and umbilical cord care with 4% chlorhexidine solutionm0 have demonstrated efficacy for prevention of staphylococcaldisease (see Chapter 17).

CONJUNCTIVITIS AND OTHER EYE INFECTIONS Conjunctivitis in the newborn usually results from one of four causes: infection with N. gonorrhoeae, infection with S. aureus, inclusion conjunctivitis caused by Chlamydia trachomatis, or chemical conjunctivitis induced by silver nitrate solution.681*682 Less commonly, other microorganisms have been implicated as a cause of conjunctivitis, including group A and B streptococci, S. pneumoniae, H. influenzae (nontypeablem and group b683),I? aeruginosa, Moraxella (Neisseria) ~atarrhalis,~'~Neisseria meningitidi~,~'~ Corynebacterium diphtheriae,686 Pasteurella m ~ l t o c i d a , ~ ' ~ ~' simplex virus, echoviruses, Clostridium ~ p . , ~herpes M. hominis, and Candida sp. In addition to meningococcal infections, other neisserial species can be confused with gonococcal infections; Neisseria cinerea has been reported to cause conjunctivitis that was indistinguishable from gonococcal in fe ~ tio n .~An '~ epidemic of erythromycinresistant s.aureus conjunctivitis affected 25 of 215 newborns during a 10-month period; control of the epidemic was achieved by identification of staff carriers and substitution of silver nitrate prophylaxis for erythr0mycin.6~~ The major causes of conjunctivitis in the neonate are discussed in Chapter 12 and Chapter 17. Cultures of the conjunctivae of neonates with purulent conjunctivitis and from the comparable eyes of a similar number of infants chosen as controls revealed significant differences,suggesting causality for S. viridans, S. aureus, E. coli, and Haemophilus sp.691,692 Compared with chemical (e.g., silver nitrate) conjunctivitis, other noninfectious causes for conjunctivitis occur only rarely. Eosinophilic pustular folliculitis has been described since 1970693;although this disease usually occurs after 3 months of age, some infants younger than 4 to 6 weeks have been described. These infants present with recurrent crops of pruritic papules primarily affecting the scalp and brow. Biopsy specimens reveal folliculitis with a predominant eosinophilic infiltrate; most infants also have a leukocytosis and eosinophilia. Other acute or chronic cutaneous conditions may also manifest as conjunctival or periorbital inflammation, such as seborrhea, atopic dermatitis, acropustulosis of infancy, and erythema toxicum (see "Infections of the Skin and Subcutaneous Tissue"). In a review by Hammer~chlag:~~ the incidence of the two major pathogens ranged from 17% to 32% for C. trachomatis and 0% to 14.2% for N. gonorrhoeae in four United States studies. In other developed countries such as investigators found 8 cases of gonococcal infection and 44 cases of chlamydial infection amon 86 newborns with ophthalmia neonatorum; in Denmark!96 investigatorsfound that 72% of infants with conjunctivitis at 4 to 6 days after birth had positive cultures, but 70% were caused by staphylococci (both S. aureus and S. epidermidis), and that chlamydiae were isolated from only 2 of 300 newborns. The incidence and microbiology of neonatal conjunctivitis is dependent on the incidence of transmissible infections in the maternal genital tract or the nursery and the use and efficacy of chemoprophylaxis. In Nairobi, Kenya, in a hospital where ocular prophylaxis had been discontinued, the incidence of gonococcal and chlamydial ophthalmitis was 3.6 and 8.1 cases per 100 livebirths, re~pectivelf~~; whereas in Harare, Zimbabwe, in a hospital where prophylaxis

Chapter 10 also was not used, the most common cause of conjunctivitis was S. a u r e ~ sThe . ~ ~introduction ~ of tetracycline ointment for prophylaxis at Bellevue Hospital (New York City) led to an overall increase in conjunctivitis associated with an increase in the incidence of gonococcal infection699 because of the emergence of tetracycline resistance among gonococci. Infections related to I! aeruginosa deserve special attention. Although uncommon, pseudomonal conjunctivitis may be a devastating disease if not recognized and treated appro~riately.6~~ The infection is usually acquired in the nursery, and the first signs of conjunctivitis appear between the 5th and 18th days of life. At first, the clinical manifestations are localized to the eye and include edema and erythema of the lid and purulent discharge. In some children, the conjunctivitis progresses rapidly, with denuding of the corneal epithelium and infiltration with neutrophils. With extension of the corneal infiltration, perforation of the cornea may occur. The anterior chamber may fill with fibrinous exudate, and the iris can adhere to the cornea. Subsequent invasion of the cornea by small blood vessels (pannus) is characteristic of pseudomonal conjunctivitis. The late ophthalmic complications may be followed by bacteremia and septic foci in other organs.700 Pseudomonal eye infections in neonates can occur in epidemic form, with subsequent high rates of mortality and ophthalmic morbidity. Burns and R h o d e ~ ’reported ~ a series of eye infections caused by I! aeruginosa in premature infants with purulent conjunctivitis rapidly progressing to septicemia, shock, and death in four infants. Five other children with conjunctivitis alone survived, but one child required enucleation. Drewett and c o - w ~ r k e r sdescribed ~~~ a nursery outbreak of pseudomonal conjunctivitis believed to be caused by contaminated resuscitation equipment; of 14 infected infants, 1 became blind, and another had severe corneal opacities. Rapidity of the course of this infection is indicated in a case report of a 10-day-old infant who developed a corneal ulcer with perforation within 2 days after first observation of a purulent di~charge.”~ An outbreak of four cases of Pseudomonas conjunctivitis in premature infants occurred within a period of 2 weeks at the American University of Beirut Medical Center703;no cause for the outbreak was found. A review by Lohrer and B e l o h r a d ~ k yof ~ ~bacterial endophthalmitis in neonates underlines the importance of I! aeruginosa in invasive bacterial eye infections ranging from keratitis to panophthalmitis. The literature review included 16 cases of invasive eye infections in neonates; 13 were caused by P. aeruginosa, and the others were cases of endophthalmitis caused by group B streptococci and S. pneumoniae. Other opportunistic gram-negativepathogens associated with outbreaks of infections in nurseries may also include conjunctivitis as a part of the infection syndrome. In a report by Christensen and co-w~rkers?~~ a multiply antibiotic-resistant S. marcescens was responsible for 15 cases of pneumonia, sepsis, and meningitis and for 20 cases of conjunctivitis, cystitis, and wound infection over a 9-month period in a neonatal intensive care unit. Dacryocystitis may complicate a congenital lacrimal sac distention (i.e., dacryocystocele). Harris and DiClementi706 described an infant who presented on day 4 of life with edema and erythema of the lower lid. Purulent material


373

emerged from the puncta after moderate pressure over the lacrimal sac; S. marcescens was grown from the material. The physician responsible for management of the child with purulent conjunctivitis must consider the major causes of the disease and must be alert to the rare pathogen. In hospitals that practice Credk’s method (i.e., silver nitrate application), purulent conjunctivitis during the first 48 hours of life is almost always caused by chemical After the first 2 days, the pus of an exudative conjunctivitis must be carefully examined by Gram stain for the presence of gram-negative intracellular diplococci, gram-positivecocci in clusters, and gram-negative bacilli. Appropriate cultures should be used for isolation of the organisms concerned. If the smears are inconclusiveand no pathogens are isolated on appropriate media and if the conjunctivitis persists, a diagnosis of inclusion or chlamydial infection is likely.706,798,709 The treatment of gonococcal and staphylococcal conjunctivitis is discussed in Chapters 12 and 17. Chlamydial conjunctivitis is reviewed in Chapter 11. If infection with Pseudomonas species is suspected, treatment should be started at once with an effective parented antibiotic such as an aminoglycoside (e.g., tobramycin, amikacin,or gentamicin)with or without an antipseudomonal penicillin or ceftazidime (see Chapter 35) and with a locally applied ophthalmic ointment. The use of subconjunctival gentamicin or other antipseudomonal aminoglycoside is of uncertain value; however, if the cornea appears to be extensively involved, there is a risk of rapid development of endophthalmitis, and the subconjunctival injection of antibiotics should be considered in consultation with an ophthalmologist. If the diagnosis is confirmed, this regimen is continued until the local signs of Pseudomonas infection resolve. Recommendations for ocular chemoprophylaxis are discussed in chapter 12 on gonococcal and Chapter 11 on chlamydial infections. Additional information is available in the 2000 edition of the Report of the Committee on Infectious Diseases published by the American Academy of pediatric^.^" REFERENCES Infections of the Liver 1. Murphy FM, Baker CJ. Solitary hepatic abscess: a delayed complication of neonatal bacteremia. Pediatr Infect Dis J 7:414,1988. 2. Guillois B, Guillemin MG, Thoma M, et al. Staphylococcie pleuropulmonaire nkonatale avec abces hkpatiques multiples. Ann Pediatr 36681,1989. 3. Dehner LP, Kissane JM. Pyogenic hepatic abscesses in infancy and childhood. J Pediatr 74763,1969. 4. Wright HT Jr. Personal communication, 1987. 5. Moss TJ, Pysher TJ. Hepatic abscess in neonates. Am J Dis Child 135726, 1981. 6. Chusid MJ. Pyogenic hepatic abscess in infancy and childhood. Pediatrics 62554, 1978. 7. Dineen P. Personal communication, Cornell University Medical College, New York, NY. 8. Bitfinger TV,Hayden CK, OIdham KT, et al. Pyogenic liver abscesses in nonimmunocompromisedchildren. South Med 7 7937,1986. 9. Beutow KC, Klein SW, Lane RB. Septicemia in premature infants: the characteristics,treatment, and prevention of septicemia in premature infants. Am J Dis Child 11029,1965. 10. Dunham EC. Septicemia in the newborn. Am J Dis Child 45229, 1933. 11. Nyhan W, Fousek MD. Septicemia of the newborn. Pediatrics 22:268, 1958. 12. Gotoff SP, Behrman RE.Neonatal septicemia. J Pediatr 76142, 1970.

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13. Hamilton JR, Sass-Kortsak A. Jaundice associated with severe bacterial infection in young infants. J Pediatr 63:121,1963. 14. Hanninen P, Terhe P, Toivanen A. Septicemia in a pediatric unit: a 20-year study. Scand J Infect Dis 3:201,1971. 15. Potter E. Pathology of the Fetus and Infant, 3rd ed. Chicago, Year Book Medical Publishers, 1975. 16. SilverrnanWA, Homan WE. Sepsis of obscure origin in the newborn. Pediatrics 3:157.1949. 17. Smith RT, Platau ES,Good RA. Septicemia of the newborn: current status of the problem. Pediatrics 17:549,1956. 18. Gersony WM,McCracken GH Jr. Purulent pericarditis in infancy. Pediatrics 40:224,1967. 19. Axton JHM. Amoebic proctocolitis and liver abscess in a neonate. S Afr Med J 46258,1972. 20. Botman T, Ruys PJ. Amoebic appendicitis in newborn infant. Trop Geogr Med 15221,1963. 21. Brans YW, Ceballos R, Cassady G. Umbilical catheters and hepatic abscesses. Pediatrics 53:264, 1974. 22. Cohen HJ, Dresner S. Liver abscess following exchange transfusion for erythroblastosis fetalis. Q Rev Pediatr 16148, 1961. 23. deBeaujeu J, Bethenod M, MoUard P, et al. Abces hepatique h forme tumorale c h a un nourrisson. Pediatrie 23:363, 1968. 24. Heck W, Rehbein F, Reismann B. Pyogene Leberabszesse im Saughgsalter. Z Kinderchir Suppl 1:49,1966. 25. Kandall SR, Johnson AB, Gartner LM. Solitary neonatal hepatic abscess. J Pediatr 85567, 1974. 26. Kutsunai T. Abscess of the liver of umbilical origin in infants: report of two cases. Am J Dis Child 51:1385,1936. 27. Madsen CM, Secouris N. Solitary liver abscess in a newborn. Surgery 47:1005,1960. 28. Martin C, Saint-Supery G, Babh JP, et al. Abces gazeux du foie avec coagulopathie chez le nouveau-ne gukrison (2 propos de 2 observations). Bordeaux Med 5:1181, 1972. 29. Pouyanne, Martin D. Abces du foie h staphylococques c h a un

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48. Cantwell MF, Shehab ZM, Costello AM, et al. Brief report: congenital tuberculosis. N Engl J Med 3301051,1994. 49. Abughal N, van der Kuyp F, Amable W, et al. Congenital tuberculosis. Pediatr Infect Dis J 13:738, 1994. 50. Simma B, Dietze 0, Vogel W, et al. Bacille Calmette-Guerinassociated hepatitis. Eur J Pediatr 150423, 1991. 51. Lide TN. Congenital tularemia. Arch Pathol43:165,1947. 52. Regan JC, Litvak A, Regan C. Intrauterine transmission of anthrax. JAMA 801769,1923. 53. Hicks HT, French H. Typhoid fever and pregnancy with special reference to foetal infection. Lancet 1:1491, 1905. 54. Sarram M, Feiz J, Foruzandeh M, et al. Intrauterine fetal infection

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with Brucella melitensis as a possible cause of second-trimester abortion. Am J Obstet Gynecol 119657,1974. Brim A. A bacteriologic study of 100 stillborn and dead newborn infants. J Pediatr 15680, 1939. Madan E, Meyer MP, Amortegui AJ. Isolation of genital mycoplasmas and Chlamydia trachomatis in stillborn and neonatal autopsy material. Arch Pathol Lab Med 112:749,1988. Oppenheimer EH, Hardy JB. Congenital syphilis in the newborn infant: clinical and pathological observations in recent cases. Johns Hopkins Med J 12963,1971. Stokes JH, Beerman H, Ingraham NR Jr. Modern Clinical Syphilology: Diagnosis, Treatment, Case Study, 3rd ed. Philadelphia, WB Saunders, 1944. Venter A, Pettifor JM, Duursma J, et al. Liver function in early congenital syphilis: does penicillin cause a deterioration? J Pediatr Gastroenterol Nutr 12:310, 1991. Lindsay S, Luke JW. Fetal leptospirosis (Weil’s disease) in a newborn infant: case of intrauterine fetal infection with report of an autopsy. J Pediatr 34:90,1949. Topciu V, Manu E, Strubert L, et al. Voie transplacentaire dans un cas de leptospirose humaine. Gynecol Obstet 65617, 1966. GseU H O Jr, Olafsson A, Sonnabend W, et al. [Intrauterine leptospirosis pomona: 1st reported case of an intrauterine transmitted and cured leptospirosis.] Dtsch Med Wochenschr 961263,1971. German. Cramer HHW. Abortus bein Leptospirosis canicola. Arch Gynecol 177:167, 1950. Chung H, Ts’ao W, Mo P, et al. Transplacental or congenital infection of leptospirosis: clinical and experimental observations. Chin Med J 82:777, 1963. Fuchs PC, Oyama AA. Neonatal relapsing fever due to transplacental transmission of Borrelia. JAMA 208690,1969. Yagupsky P, Moses S. Neonatal Borrelia species infection (relapsing fever). Am J Dis Child 139:74, 1985. Fuchs PC. Personal communication, 1973. Weber K, Bratzke H-J, Neubert U, et al. Borrelia burgdorferi in a newborn despite oral penicillin for Lyme borreliosis during pregnancy. Pediatr Infect Dis J 7286, 1988. Steere AC. Lyme disease. N Engl J Med 321:586, 1989. Lipinski JK. Vega JM, Cywes S, et al. Falciform ligament abscess in the infant. J Pediatr Surg 20556,1985. Betke K, Richarz H. Nabelsepsis mit Pyelphlebitis, multiplen kberabscessen, Lungenabscessen, und Osteomyelitis. Ausgang in Heilung. Monatsschr Kinderheilkd 105:70, 1957. Elliott RIK. The ductus venoms in neonatal infection. Proc R SOC Med 62:321, 1969. McKenzie CG. Pyogenic infection of liver secondary to infection in the portal drainage area. BMJ 4:1558, 1964. Menzel K, Buttenberg H. Pyelophlebitis mit multiplen Leberabszessen als Komplikation mehrfacher Sondierung der Nabelvene. Kinderaerztl Prax 40:14,1972, Sarrut S, Alain J, Alison F. Les complications prkcoces de la perfusion par la veine ombilicale chez le premature. Arch Fr Pediatr 26651, 1969. Santerne B, M o d e P, Touche D, et al. Diagnostic et traitement d’une abcedation hepatique neo-natale multifocale par l’kchographie. Presse Med 1612, 1987. Scott J. Iatrogenic lesions in babies following umbilical vein catheterization. Arch Dis Child 40426,1965. Shaw A, Pierog S. “Ectopic” liver in the umbilicus: an unusual focus of infection in a newborn infant. Pediatrics 44448, 1969. Morison JE. Umbilical sepsis and acute interstitial hepatitis. J Pathol Bacteriol56531, 1944. Bernstein J, Brown AK. Sepsis and jaundice in early infancy. Pediatrics 29:873, 1962.

Chapter 10 81. Parker RGF. Jaundice and infantile diarrhea. Arch Dis Child 33:330, 1958. 82. Gwinn JL, Lee FA. Radiologic case of the month: pyogenic liver abscess. Am J Dis Child 123:50, 1972. 83. Martin DJ. Neonatal disorders diagnosed with ultrasound. Clin Perinatol 12:219, 1985. 84. Pineiro-Carrero VM, Andres JM. Morbidity and mortality in children with pyogenic liver abscess. Am J Dis Child 143:1424,1989. 85. Caron KH. Magnetic resonance imaging of the pediatric abdomen. Semin Ultrasound CT MR 12:448,1991. 86. Halvorsen RA Jr, Foster WL Jr, Wilkinson RH Jr, et al. Hepatic abscess: sensitivity of imaging tests and clinical findings. Gastrointest Radiol 13:135,1988. 87. Weinreb JC, Cohen JM, Armstrong E, et al. Imaging the pediatric liver: MRI and CT. AJR Am J Roentgenol 147785,1986. 88. Cohen MD. Clinical utility of magnetic resonance imaging in pediatrics. Am J Dis Child 140947, 1986. 89. Diament MJ, Stanley P, Kangarloo H, et al. Percutaneous aspiration and catheter drainage of abscesses. J Pediatr 108204,1986. 90. Rubinstein 2, Heyman 2,Morag B, et al. Ultrasound and computed tomography in the diagnosis and drainage of abscesses and other fluid collections. Isr J Med Sci 191050,1983. 91. Reynolds TB. Medical treatment of pyogenic liver abscess. Ann Intern Med 96:373, 1982. 92. Loh R, Wallace G, Thong YH. Successful non-surgical management of pyogenic liver abscess. Scand J Infect Dis 19:137,1987. 93. Keidl CM, Chusid MJ. Splenic abscesses in childhood. Pediatr Infect Dis J 8368,1989.

Infections of the Biliary Tract 94.. Bowen A. Acute gallbladder dilatation in a neonate: emphasis on ultrasonography. J Pediatr Gastroenterol Nutr 3:304, 1984. 95. Goldthom J6Thomas DW, Ramos AD. Hydrops of the gallbladder in stressed premature infants. Clin Res 28:122A, 1980. 96. Brill PW, Winchester P, Rosen MS. Neonatal cholelithiasis. Pediatr Radiol 12985, 1982. 97. Callahan J, Haller 70, Cacciarelli AA, et al. Cholelithiasis in infants: association with total parenteral nutrition and furosemide. Radiology 143:437, 1982. 98. Keller MS, Markle BM, Laffey PA, et al. Spontaneous resolution of cholelithiasis in infants. Radiology 157345, 1985. 99. Schirmer WJ, Grisoni ER, Gauderer MWL. The spectrum of cholelithiasis in the first year of life. J Pediatr Surg 241064, 1989. 100. Debray D, Pariente D, Gauthrer F, et al. Cholelithiasis in infancy: a study of 40 cases. J Pediatr 12238,1993. 101. Neu J, Arvin A, Ariagno RL. Hydrops of the gallbladder. Am J Dis Child 134891,1980. 102. Leichty EA, Cohen MD, Lemons JA, et al. Normal gallbladder appearing as abdominal mass in neonates. Am J Dis Child 136468, 1982. 103. Peevy KJ, Wiseman HJ. Gallbladder distension in septic neonates. Arch Dis Child 5275,1982. 104. Dutta T, George V, Sharma GD, et al. Gallbladder disease in infancy and childhood. Prog Pediatr Surg 8:109,1975. 105. Saldanha RL, Stein CA, Kopelman AE. Gallbladder distention in ill preterm infants. Am J Dis Child 1371179, 1983. 106. El-Shafie M, Mah CL. Transient gallbladder distention in sick premature infants: the value of ultrasonography and radionuclide scintigraphy. Pediatr Radiol 16468, 1986. 107. Modi N, Keay AJ. Neonatal gallbladder distention. Arch Dis Child 57562, 1982. 108. Amodio JB, Fontanetta E, Cohen M, et al. Neonatal hydrops of the gallbladder: evaluation by cholescintigraphy and ultrasonography. N Y State J Med 85565,1985. 109. McGahan JP, Phillips HE, Cox KL. Sonography of the normal pediatric gallbladder and biliary tract. Radiology 144:873, 1982. 110. Haller JO. Sonography of the biliary tract in infants and children. AJRAm J Roentgenol 157:1051,1991. 111. Guthrie KJ, Montgomery GL. Infections with Bacterium entm'tidis in infancy with the triad of enteritis, cholecystitis, and meningitis. J Pathol Bacteriol49:393, 1939. 112. Faller W, Berkelhamor JE, Esterly JR. Neonatal biliary tract infection coincident with maternal methadone therapy. Pediatrics 48:997, 1971. 113. Jamieson PN, Shaw DG. Empyema of gallbladder in an infant. Arch Dis Child 50482,1975.


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114. Arnspiger LA, Martin JG, Krempin HO. Acute noncalculous cholecystitis in children: report of a case in a 17-day-old infant. Am J Surg 100103,1960. 115. Ternberg JL, Keating JP. Acute acalculous cholecystitis: complication of other illnesses in childhood. Arch Surg 110:543,1975. 116. Crystal RF, Fink RL. Acute acalculous cholecystitis in childhood a report of two cases. Clin Pediatr 10423, 1971. 117. Robinson AE, Erwin JH, Wiseman HJ, et al. Cholecystitis and hydrops of the gallbladder in the newborn. Radiology 122:749,1977. 118. Snyder WH Jr, Chaffin L, Oettinger L. Cholelithiasis and perforation of the gallbladder in an infant, with recovery. JAMA 1491645,1952. 119. Washburn ME, Barcia PJ. Uncommon cause of a right upper quadrant abdominal mass in a newborn: acute cholecystitis. Am J Surg 140:704,1980. 120. Thurston WA, Kelly EN, Silver MM. Acute acalculous cholecystitis in a premature infant treated with parenteral nutrition. Can Med Assoc J 135:332, 1986. 121. Pieretti R, Auldist AW, Stephens CA. Acute cholecystitis in children. Surg Obstet Gynecol 14016,1975. 122. Hanson BA, Mahour GH, Woolley MM. Diseases of the gallbladder in infancy and childhood. J Pediatr Surg 6277,1971. 123. Dewan PA, Stokes KB, Solomon JR Paediatric acalculous cholecystitis. Pediatr Surg Int 2:120, 1987. 124. Denes J, Gergely K, Mohacsi A, et al. Die FriihgeborenenAppendicitis. 2 Kinderchir 5400, 1968. 125. Traynelis VC, Hrabovsky EE. Acalculous cholecystitis in the neonate. Am J Dis Child 139893,1985. 126. Aach RD. Cholecystitis in childhood. In Feigin RD, Cherry JD (eds). Textbook of Pediatric Infectious Diseases, 2nd ed. Philadelphia, WB Saunders, 1987, pp 742-743. 127. Wyllie R, Fitzgerald JF.Bacterial cholangitis in a 10-week-old infant with fever of undetermined origin. Pediatrics 65:164, 1980. 128. Becroft DMO. Biliary atresia associated with prenatal infection by Listeria monocytogenes.Arch Dis Child 47656, 1972.

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147. Gross M, Kottmeier PK, Waterhouse K. Diagnosis and treatment of neonatal adrenal hemorrhage. J Pediatr Surg 2:308, 1967. 148. Vigi V, Tamisari L, Osti L, et al. Suprarenal abscess in a newborn. Helv Paediatr Acta 36263, 1981. 149. Suri S, A g a d a ML, Mitra S, et al. Adrenal abscess in a neonate presenting as a renal neoplasm. Br J Urol54:565, 1982. 150. Mittelstaedt CA, Volberg FM, Merten DF, et al. The sonographic diagnosis of neonatal adrenal hemorrhage. Radiology 131:453,1979. 151. Rey A, Arena J, Nogues A, et al. Hemorragia suprarenal encapsulada en el recien nacido: estudio de ocho casos. An Esp Pediatr 21:238, 1984. 152. Black J, Williams DI. Natural history of adrenal hemorrhage in the newborn, Arch Dis Child 48:173,1973. 153. Iklof 0, Mortensson W, Sandstedt B. Suprarenal haematoma versus

neuroblastoma complicated by haemorrhage: a diagnostic dilemma in the newborn. Acta Radiol Diagn 27:3,1986. 154. white SJ, Stuck KJ, Blane CE, et al. Sonography of neuroblastoma. Am J Radiol 141:465, 1983. 155. Shkolnik A. Applications of ultrasound in the neonatal abdomen. Radiol Clin North Am 23:141, 1985.

APPe!ndicitis* 156. Etherington-Wilson WE. Appendicitis in newborn: report of a case 16 days old. Proc R SOCMed 38:186,1945. 157. Puri P, O’Donnell B. Appendicitis in infancy. J Pediatr Surg 13:173, 1978. 158. Landaas B. Diagnosis of appendicitis in young children. Tidsskr Nor Laegeforen 68:335, 1948. 159. Reuter G, Krause I. Beitrag zur Problematik der Appendizitis des Neugeborenen. Kinderaerztl Prax 47:289, 1975. 160. Norris WJ. Appendicitis in children. West J Surg Obstet Gynecol 54183,1946. 161. Parsons JM, Miscall BG, McSherry CK. Appendicitis in the newborn infant. Surgery 67:841,1970. 162. Schaupp W, Clausen EG, Ferrier PK. Appendicitis during the first month of life. Surgery 48:805,1960. 163. Stanley-Brown EG. Acute appendicitis during the first five years of life. Am J Dis Child 108:134, 1964. 164. Snyder WH Jr, Chaffm L. Appendicitis during the first 2 years of life: report of 21 cases and review of 447 cases from the literature. Arch Surg M.549, 1952. 165. Fields IA,Naiditch MJ, Rothman PE. Acute appendicitis in infants. Am J Dis Child 93:287, 1957. 166. Dick W, Hirt H-J, Vogel W. Die Appendizitis im Saglings- und Kleinkindesalter. Fortschr Med 94125,1976. 167. Gross RE. The Surgery of Infancy and Childhood: Its Principles and Techniques. Philadelphia, WB Saunders, 1953. 168. Grosfeld JL.,Weinberger M, Clatworthy HW Jr. Acute appendicitis in the first two years of life. J Pediatr Surg 8:285, 1973. 169. Janik JS, Firor HV. Pediatric appendicitis: a 20-year study of 1.640 children at Cook County (Illinois) Hospital. Arch Surg 114717,1979. 170. Benson CD, Coury JJ Jr, Hagge DR. Acute appendicitis in infants: fifteen-year study. Arch Surg 61:561, 1952. 171. Massad M, Srouji M, Awdeh A, et al. Neonatal appendicitis: case report and a review of the Enghsh literature. 2 Kinderchir 41:241, 1986. 172. Schorlemmer GR, Herbst CA Jr. Perforated neonatal appendicitis. South Med J 76536,1983. 173. Diess F. Die Appendizitis im Basler Kinderspital. Bade Dissertations, 1908. Case No. 36, p 63. Cited in reference 138 and in Abt. I A Appendicitis in infants. Arch Pediatr 34641, 1917. 174. Bartlett RH, Eraklis AJ, Wilkinson RH. Appendicitis in infancy. Surg Gynecol Obstet 130:99, 1970. 175. Broadbent NRG, Jardine JL.Acute appendicitis in a premature infant: a case report. Aust N Z J Surg 40362,1971. 176. Bryant LR, Trinkle JK, Noonan JA, et al. Appendicitis and appendiceal perforation in neonates. Am Surg 36:523, 1970. 177. Creery RDG. Acute appendicitis in the newborn. BMJ 1:871, 1953. 178. Hardman RP, Bowerman D. Appendicitis in the newborn. Am J Dis Child 105:99, 1963. 179. Klimt F, Hartmann G. Appendicitis perforata mit tiefsitzenden Diindarmverschluss beim Neugeborenen. Paediatr Prax 1:271,1962.

180. Kolb G, Schaeffer EL. Ober Appendizitis mit Perforation in den ersten Lebenwochen. Kinderaerztl Prax 1:1, 1955. 181. Liechti RE, Snyder WH Jr. Acute appendicitis under age 2. Am Surg 29:92, 1963. 182. Meigher SC, Lucas AW. Appendicitis in the newborn: case report. Ann Surg 1361044,1952. 183. Meyer JF. Acute gangrenous appendicitis in a premature infant. J Pediatr 41:343, 1952. 184. Neve R, Quenville NF. Appendicitis with perforation in a 12-day-old infant. Can Med Assoc J 94447, 1966. 185. Nilforoushan MA. Fever and ascites in a newborn. Clin Pediatr 14878, 1975. 186. Nuri M, Hecker WC, Duckert W. Beitrag zur Appendicitis im Neugeborenenalter. Z Kinderheilkd 91:1,1964. 187. Parkhurst GF, Wagoner SC. Neonatal acute appendicitis. N Y State J Med 69:1929, 1969. 188. Phillips SJ, Cohen B. Acute perforated appendicitis in newborn children. N Y State J Med 71:985, 1971. 189. Smith AL, MacMahon RA. Perforated appendix complicating rhesus immunization in a newborn infant. Med J Aust 2:602,1969. 190. Tabrisky J, Westerfeld R, Cavanaugh J. Append Am J Dis Child 1 1 1:557,1966. 191. Vinz H, Erben U, Winkelvoss H. Neugeborenen peritonitis. Bruns Beitr Klin Chir 215:321, 1967. 192. Walker RH. Appendicitis in the newborn infant. J Pediatr 51:429, 1958. 193. Morehead CD, Houck PW. Epidemiology of Pseudomonas infections in a pediatric intensive care unit. Am J Dis Child 124564, 1972. 194. Trojanowski JQ,Gang DL, Goldblatt A, et al. Fatal postoperative acute

195. 196. 197. 198.

199.

200. 201. 202. 203. 204. 205. 206. 207. 208.

209.

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‘The list of references for intra-abdominal neonatal appendicitis is not exhaustive; additional cases can be found in the articles listed here.

215.

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Chapter 10 216. Charif P. Perforated appendicitis in premature infants: a case report and review of the literature. Johns Hopkins Med J 125:92, 1969. 217. Stone HH, Sanders SL, Martin JD Jr. Perforated appendicitis in children. Surgery 69:673, 1971. 218. Dennis JE, Rhodes KH, Cooney DR, et al. Nosocomial Rhizopus infection (zygomycosis)in children. J Pediatr 96824, 1980. 219. Buschard K, Kjaeldgaard A. Investigation and analysis of the position, fixation, length, embryology of the vermiform appendix. Acta Chir Scand 139:293, 1973. 220. Jones WR, Kaye MD, Ing RMY. The lymphoid development of the fetal and neonatal appendix. Biol Neonatal 20334, 1972. 221. Smith GM. Inflammatory changes in the appendix during early infancy. Am J Dis Child 1:299,1911. 222. Hill WB, Mason CC. Prenatal appendicitis with rupture and death. Am J Dis Child 29:86, 1925. 223. Corcoran WJ. Prenatal rupture of the appendix. Am J Dis Child 39:277, 1930. 224. Jackson WF. A case of prenatal appendicitis.Am J Med Sci 127710, 1904. 225. Kiimmell EW. Cited in Etherington-Wilson WE. Appendicitis in newborn: report of a case 16 days old. Proc R SOCMed 38186,1945. 226. Martin LW, Glen PM. Prenatal appendiceal perforation: a case report. J Pediatr Surg 21:73, 1986. 227. Wilkinson RH, Bartlett RH, Eraklis AJ. Diagnosis of appendicitis in infancy: the value of abdominal radiographs. Am J Dis Child 118:687, 1969. 228. Holder TM, Leape LL. The acute surgical abdomen in the neonate. N Engl J Med 278:605,1968. 229. Chang JHT. The use of antibiotics in pediatric abdominal surgery. Pediatr Infect Dis 3:195,1984.

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377

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282. Touloukian RJ, Kadar A, Spencer RP. The gastrointestinal compli-

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287. 288. 289. 290. 291. 292. 293. 294. 295. 296. 297.

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313. Eidelman AI, Inwood RJ. Marginal comments: necrotiziig entero-

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339. 340.

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Endocarditis

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647. Cohen SM, Miller BW, Orris HW. Meningitis complicating cephalhematoma.J Pediatr 30327,1947. 648. Rudoy RC, Nelson JD. Breast abscess during the neonatal period a review. Am J Dis Child 1291031,1975. 649. Walsh M, McIntosh K. Neonatal mastitis. Clin Pediatr 25:395,1986. 650. Langewisch WH. An epidemic of group A, type 1 streptococcal infections in newborn infants. Pediatrics lk438.1956. 651. S i a h D, Sandiford BR, Dugdale AE. Subungual infection in the newborn: an institutional outbreak of unknown etiology, possibly due to Veillonella.Clin Pediatr 11:690,1972. 652. Cushing AH. Omphalitis: a review. Pediatr Infect Dis 4282,1985. 653. McKenna H, Johnson D. Bacteria in neonatal omphalitis. Pathology 7:11, 1977. 654. Mason WH, Andrews R, Ross LA, et al. Omphalitis in the newborn infant. Pediatr Infect Dis J 8521,1989. 655. Geil CC, Castle WK, Mortimer EA Jr. Group A streptococcal infections in newborn nurseries. Pediatrics 46:849, 1970. 656. Kosloske AM, Cushing AH, Borden TA, et al. Cellulitis and necrotizing fasciitis of the abdominal wall in pediatric patients. J Pediatr Surg 16246,1981. 657. Goldberg GN, Hansen RC, Lynch PJ. Necrotizing fasciitis in infancy: report of three cases and review of the literature. Pediatr Dermatol 255, 1984. 658. Ramamurthy RS, Srinivasan G, Jacobs NM. Necrotizing faxiitis and necrotizing cellulitis due to group B Streptococcus. Am J Dis Child 131:1169, 1977. 659. Krieger RW, Chusid MJ. Perirectal abscess in childhood. Am J Dis Child 133411,1979. 660. Arditi M,Yogev R. Perirectal abscess in infants and children: report of 52 cases and review of the literature. Pediatr Infect Dis J 9411, 1990. 661. Victorin L. An epidemic of otitis in newborns due to infection with Pseudomonas aeruginosa. Ada Paediatr Scand 56:344, 1967. 662. Laubo EJ, Paller AS. Common skin problems during the first year of life. Pediatr Clin North Am 41:1105,1994. 663. Merlob P, Metzker A, Hazaz B, et al. Neonatal pemphigus vulgaris. Pediatrics 78:1102, 1986. 664. Glover MT, Atherton DJ, Levinsky RJ. Syndrome of erythroderma, failure to thrive, and diarrhea in infancy: a manifestation of immunodeficiency.Pediatrics 81:66,1988. 665. Prod’hom LS,Choffat J-M, Frenck N, et al. Care of the seriously ill neonate with hydme membrane disease and with sepsis (sderema neonatorum). Pediatrics 53:170, 1974. 666. Hughes WE, Hammond ML. Sclerema neonatorum. J Pediatr 32:676, 1948. 667. McCracken GH Jr, Shinefield HR. Changes in the pattern of neonatal septicemia and meningitis. Am J Dis Child 112:33,1966. 668. Gordon I. Miliary sebaceous cysts and blisters in the healthy newborn. Arch Dis Child 24286,1949. 669. Carr JA, Hodgman JE,Freedman RI,et al. Relationshipbetween toxic erythema and infant maturity. Am J Dis Child 112:219,1966. 670. Merlob P, Metzker A, Reisner SH. Transient neonatal pustular melanosis. Am J Dis Child 136521,1982. 671. Kahn G, Rywlm AM. Acropustulosis of infancy. Arch Dermatol 115831,1979. 672. Lucky AW, McGuire JS. Infantile acropustulosis with eosinophilic pustules. J Pediatr 100:428,1982. 673. Murphy WF, Langley AL. Common bullous lesions--presumably self-irQicted-ccurring in utero in the newborn infant. Pediatrics 32:1099, 1963. 674. Weston WL, Lane AT, Weston JA. Diaper dermatitis: current concepts. Pediatrics 66532,1980. 675. Nappy rashes. Editorial. BMJ 282:420, 1981. 676. Hauth JC, Merenstein GB (eds). Guidelinesfor Perinatal Care, 4th ed. Elks Grove, Ill, American Academy of Pediatrics and American College of Obstetricians and Gynecologists, 1997. 677. Gladstone IM, Clapper L, Thorp JW,et al. Randomized study of six umbilical cord care regimens. Clin Pediatr 27127,1988. 678. Centers for Disease Control. National nosocomial infections study report: nosocomial infections in nurseries and their relationship to hospital infant bathing practicesa preliminary report. Atlanta, Centers for Disease Control, 1974, pp 9-23. 679. Gezon HM, Schaberg MJ, Klein 70.Concurrent epidemics of Staphylococcus aureus and group A Streptocowus disease in a newborn nursery-control with penicillin G and hexachlorophene bathing. Pediatrics 51:383, 1973.

680. Seeberg S, Brinkhoff B, John E, et al. Prevention and control of neonatal pyoderma with chlorhexidine.Acta Paediatr S a n d 73:498, 1984.

Conjunctivitis and Other Eye Infections 681. de Toledo AR, Chandler JW. Conjunctivitis of the newborn. Infect Dis Clin North Am 6:807,1992. 682. Whitcher JP. Neonatal ophthalmia: have we advanced in the last 20 years? lnt Ophthalmol Clin 3039,1990. 683. Millard DD, Yogev R. Haernophilus influenme type b: a rare case of congenital conjunctivitis.Pediatr Infect Dis 2363,1988. 684. McLeod DT, Ahmad F, Calder MA. Branhamella catarrhalis (beta lactamase positive) ophthalmia neonatorum. Lancet 2:647,1984. 685. Ellis M, Weindling DC, Ho N, et al. Neonatal conjunctivitis associated with meningococcal meningitis. Arch Dis Child 621219, 1992. 686. Naiditch MJ, Bower AG. Diphtheria: a study of 1433 cases observed during a ten year period at Los Angeles County Hospital. Am J Med 17229,1954. 687. Khan MS, Stead SE. Neonatal Pasteurella multocida conjunctivitis following zoonotic infection of mother. J Infect Dis 1:289, 1979. 688. Brook I, Martin WJ, Finegold SM. Effect of silver nitrate application on the conjunctival flora of the newborn, and the occurrence of clostridial conjunctivitis. J Pediatr Ophthalmol Strabismus 15:179, 1978. 689. Bourbeau P, Holla V, Piemontese S. Ophthalmia neonatorum caused by Neissm’a cinerea. J Clin Microbiol28:1640,1990. 690. Hedberg K, Ristinen TL, Soler JT, et al. Outbreak of erythromycinresistant staphylococcal conjunctivitis in a newborn nursery. Pediatr Infect Dis J 9268, 1990. 691. Paentice MJ, Hutchinson GR, Taylor-Robinson D. A microbiological study of neonatal conjunctivitis. Br J Ophthalmol61:9,1977. 692. Sandstrom KI, Bell TA, Chandler JW, et al. Microbial causes of neonatal conjunctivitis. J Pediatr 105:706, 1984. 693. Duarte AM, Kramer J,Yusk W, et al. Eosinophilicpustular folliculitis in infancy and childhood. Am J Dis Child 147:197,1993. 694. HammerschlagMR. Conjunctivitis in infancy and childhood. Pediatr Rev 5285, 1984. 695. Wincelaus J, Goh BT, Dunlop EM, et al. Diagnosis of ophthalmia neonatorum. BMJ 295:1377,1987. 696. Molgaard I-L, Nielsen PB, Kaern J. A study of the incidence of neonatal conjunctivitis and of its bacterial causes including Chlamydia trachomatis. Acta Ophthalmol62:461,1984. 697. Laga M, Nzanze H, Brunham RC, et al. Epidemiology of ophthalmia neonatorum in Kenya. Lancet 2:1145, 1986. 698. Nathoo KJ, Latif AS, Trijssenaar JES. Aetiology of neonatal conjunctivitis in Harare. Cent Afr J Med 30123, 1984. 699. Stenson S, Newman R, Fedukowicz H. Conjunctivitis in the newborn: observations on incidence, cause, and prophylaxis. Ann Ophthalmol 13:329, 1981. 700. Burns RP, Rhodes DH Jr. Pseudomonas eye infection as a cause of death in premature infants. Arch Ophthalmol65:517,1961. 701. Drewett SE, Payne DJH, Tuke W, et al. Eradication of Pseudornonas aeruginosa infection from a special-care nursery. Lancet 1:946,1972. 702. Cole GA, Davies DP, Austin DJ. Pseudomonas ophthalmia neonatorum: a cause of blindness. BMJ 281:440,1980. 703. Traboulsi El, Shammas IV,Ratl HE, et al. Pseudomonas aeruginosa ophthalmia neonatorum. Am J Ophthalmol98:801,1984. 704. Lohrer R, Belohradsky BH. Bacterial endophthalmitis in neonates. Eur J Pediatr 146:354,1987. 705. Christensen GD, Korones SB, Reed L, et al. Epidemic Serratia marcexens in a neonatal intensive care unit: importance of the gastrointestinal tract as a reservoir. Infect Control 3:127, 1982. 706. Harris GJ, DiClementi D. Congenital dacryocystocele. Arch Ophthalmol 1001763,1982. 707. Nishida H, Risemberg HM. Silver nitrate ophthalmic solution and chemical conjunctivitis. Pediatrics 56:3368, 1975. 708. Kripke SS, Golden B. Neonatal inclusion conjunctivitis: a report of three cases and a discussion of differential diagnosis and treatment. Clin Pediatr 11:261, 1972. 709. Naib ZM. Cytology of TRIC agent infection of the eye of newborn infants and their mothers’ genital tracts. Acta Cytol 14390, 1970. 710. Peter G (ed). Prevention of neonatal ophthahia. In Report of the Committee on Infectious Diseases, 24th ed. Elk Grove Village, Ill, American Academy of Pediatrics, 1997, pp 601-603.

Chapter I 1 CHLAM YDlA INF E CTI0 N5 Toni Darville

Epidemiology and Transmission Microbiology

385

386

The Pathogen Chlamydia1 Developmental Cycle

Pathogenesis 387 Conjunctivitis Pneumonia

transmitted from an infected mother to her newborn during delivery, producing conjunctivitis or pneumonia. C. trachomatis is the most common cause of conjunctivitis in infants younger than 1 month of age worldwide and often is a cause of afebrile pneumonia in infants younger than 3 months of age.

EPIDEMIOLOGY AND TRANSMISSION

Pathology 387 Clinical Manifestations 387 Conjunctivitis Pneumonia Perinatal Infections at Other Sites

Diagnosis 388 Conjunctivitis Pneumonia

Differential Diagnosis 389 Conjunctivitis Pneumonia

Prognosis 389 Conjunctivitis Pneumonia

Therapy

390

Prevention

390

In 191 1, Lindner and colleagues identified typical intracytoplasmic inclusions in infants with a nongonococcal form of ophthalmia neonatorum called inclusion con'unctivitis of the newborn (ICN) or inclusion blennorrhea.1 Mothers of affected infants were found to have inclusions in their cervical epithelial cells, and fathers of such infants had inclusions in their urethral cells. For 50 years, cytologic demonstration of chlamydial inclusions in epithelial cells was the only diagnostic procedure available. When methods to isolate Chlamydia trachomatis were developed, first in the yolk sac of the embryonated hen's egg and then in tissue culture, studies again demonstrated this organism as the etiologic agent for conjunctivitis in the newborn infant and then confirmed the maternal genital tract reservoir for transmission of this agent.2Although ICN was studied for 60 years, it was not until the late 1970s, with the impetus of the report by Beem and Saxon3, that the importance of chlamydial infection of the respiratory tract in infants was recognized. C. trachomatis now is appreciated as the most common sexually transmitted pathogen in Western industrialized society? Although most C. trachornatis infections in men and women are asymptomatic, infection can lead to severe reproductive complications in women. The infection can be

C. trachomatis is the most common bacterial cause of sexually transmitted infections in the United state^.^'^ Reported prevalence rates in the United States have ranged from 2% to 7% among female college students, from 4% to 12% among women attending a family planning clinic, and from 6% to 20% among men and women attending a clinic for sexually transmitted diseases or persons entering correctional facilitie~.~,' In the United Kingdom, recent data suggest that the rate of infection among young women exceeds lo%.' Prevalence rates have declined in areas where screening and treatment programs have been implemented." Many men and most women infected with C. trachomatis are either asymptomatic or minimally symptomatic, and presentation for diagnosis is a result of a routine screening program, or of presence of symptoms in a contact. In gonococcal infections, by contrast, symptoms develop in most infected persons, who then present acutely for care. Regional estimates are hampered by underdiagnosis and underreporting of cases. Because symptoms are absent or minimal in most women and many men, a large reservoir of asymptomatic infection is present that can sustain the pathogen within a community. Age younger than 20 years is the demographic factor in women most strongly associated with chlamydial infection (relative risk is 2 to 3.5 among women younger than 25 years compared with older women): Although the prevalence of chlamydial infection is increased among black or economically disadvantagedpersons, broad socioeconomicand geographic distribution of infection e ~ i s t s . ~ * "Other ~ ' ~ ~ risk ' ~ factors for cervical chlamydial infection in women are anatomic or hormonal (e.g., use of depot forms of medroxyprogesterone acetate'' or ectopy following use of oral contraceptive^),'^"^ behavioral (e.g., number of sexual and microbiologic (e.g., concurrent g~norrhea).~.'~ For purposes relevant to this chapter, the major method of transmission of C. trachomatis is sexual. The child-tochild and intrafamilial infecting patterns that predominate in trachoma-endemic areas have not been proved to cause disease in newborns?' Chlamydiae cause between one third and one half of nongonococcal urethritis cases in men, and concomitant infections with gonococci are common in men and An infant born to a mother with a chlamydial infection of the cervix has a 60% to 70% risk of acquiring the infection

386

Section I1


during passage through the birth canal?’-’* Conjunctivitis develops in 20% to 50% of exposed infants, and pneumonia in 10% to 20%. The rectum and vagina of infants exposed during delivery also may be infected, but a clear-cut relationship with disease in these sites has not yet been elucidated.25s26 In utero transmission is not known to occur. Infection after cesarean section occurs rarely, usually in association with atterm or premature rupture of the membranes. No evidence exists to support postnatal transmission from the mother or other family members. Studies in the 1980s identified C. trachomatis in 14% to 46% of infants younger than 1 month of age with conjun~tivitis.’’-~~ The prevalence of neonatal Chlamydia inclusion conjunctivitis has decreased in recent years in areas where screening and treatment of chlamydial infection in pregnant women constitute routine practice.” No evidence exists to suggest that infants with chlamydial infections should be isolated. Transmission of the organism to other infants in nurseries or intensive care units has not been reported. Standard precautions consisting of hand hygiene between patient contacts is recommended. Use of protective gloves, masks or face shields, and nonsterile gowns are recommended for performing procedures likely to generate splashes of body fluids, secretions, or excretions.

MICROBIOLOGY

The Pathogen Chlamydiae are obligate intracellular parasites that cause a variety of diseases in animal species at virtually all phylogenic levels. Traditionally, the order Chlamydiales has contained one genus with four recognized species: Chlamydia trachomatis, Chlamydia psittaci, Chlamydia pneumoniae, and Chlamydia pecorum. Recent taxonomic analysis involving the 16s and 23s rRNA genes have found that the order Chlamydiales contains at least four distinct groups at the family level and suggested splitting the genus Chlamydia into two genera, Chlamydia and Chlamyd~phila.~’ The genus Chlamydophila would contain C. pneumoniae, C. pecorum, and C. psittaci. This new classification continues to be controversial, and for the purposes of this chapter these organisms all are referred to as Chlamydia. C. psittaci is responsible for psittacosis, a chlamydial infection contracted by human beings from infected birds that is characterized by interstitial pneumonitis. It should be suspected in any patient with atypical pneumonia who has had contact with birds. C. pneumoniae causes pneumonia, pharyngitis, and bronchitis in humans and may accelerate atherosclerosis. Epidemiologic studies have revealed that C. pneumoniae is a fairly common cause of infection in schoolaged children and young adults; along with Mycoplama, it probably is the most common cause of community-acquired pneumonia in these age groups. It is not known to cause disease in newborns and therefore is not discussed further. The species C. trachomatis is associated with a spectrum of diseases and contains serologically distinct variants (up to 18) known as serovars. Serovars A, B, Ba, and C cause ocular trachoma, a major cause of blindness in many developing countries. Ocular trachoma is considered the most common cause of preventable blindness in the world. Three serovars,

L,, Lz, and L,, are associated with lymphogranuloma venereum, a sexually transmitted disease that is rare in the United States but remains quite prevalent in many developing countries, and are particularly prevalent in tropical and subtropical areas. Perinatal transmission is rare with lymphogranuloma venereum. Serovars D to K produce infection of the genital tract-urethritis and epididymitis in the male, cervicitis and salpingitis in the female-the most prevalent chlamydial diseases. Major complications of female genital tract disease include acute pelvic inflammatory disease, ectopic pregnancy, infertility, and infant pneumonia and conjunctivitis. Like gram-negative bacteria, chlamydiae have an outer membrane that contains lipopolysaccharide and membrane proteins, but their outer membrane contains no detectable peptidoglycan, despite the presence of genes encoding proteins for its syr~thesis.~’ This recent genomic finding is the basis for the so-called chlamydial peptidoglycan paradox, for it has been known for years that chlamydial development is inhibited by p-lactam antibiotics. Although chlamydiae contain DNA, RNA, and ribosomes, during growth and replication they obtain high-energy phosphate compounds from the host cell. Consequently, they are considered energy parasites. The chlamydial genome size is only 660 kDa, which is smaller than that of any other prokaryote except mycoplasmas. All chlamydiae encode an abundant protein, the major outer membrane protein (MOMP) that is surface exposed in C. trachomatis and C. psittaci, but not in C. p n e ~ r n o n i a e MOMP .~~ is the major determinant of the serologic classification of C. trachomatisand C.psittaci isolates.

Chlamydia1 Developmental Cycle The biphasic developmental cycle of chlamydiae is unique among microorganisms and involves two highly specialized morphologic forms shown in Figure 11-1. The extracellular form, or elementary body (EB), contains extensive disulfide cross-links both within and between outer membrane proteins, giving it an almost sporelike structure that is stable outside of the cell. The small (350nm in diameter) infectious EB is inactive metabolically. The developmental cycle is initiated when an EB attaches to a susceptible epithelial cell. A number of candidate adhesions have been proposed, but their identity and that of associated epithelial cell receptors remain uncertain. One documented mechanism of entry into the epithelial cell is by receptor-mediated endocytosisthrough clathrin-coated pits,34but evidence suggests that chlamydiae may exploit multiple mechanisms of entry.35The process of EB internalization is very efficient, suggesting that EBs trigger their own internalization by cells that are not considered professional phagocytes. Once the EB is inside the cell, surface antigens of the EB appear to prevent fusion of the endosome with lysosomes, protecting itself from enzymatic destruction. Evading host attack by antibody- or cell-mediated defenses, it reorganizes into the replicative form, the reticulate body (RB). RBs successfully parasitize the host cell and divide and multiply. As the RB divides by binary fission, it U s the endosomenow a cytoplasmic inclusion-with its progeny. After 48 to 72 hours, multiplication ceases, and nucleoid condensation occurs as the reticulate bodies transform to new infectious EBs. The EBs then are released from the cell by cytolysis?6 or

Chapter 11

0 Hr

2 Hr

18 Hr

36 Hr

by a process of exocytosis or by extrusion of the whole inclu~ion?~ leaving the host cell intact. The last mechanism may explain the frequency of asymptomatic or subclinical chlamydial infections. The release of the infectious EBs allows infection of new host cells to occur.

PATHOGENESIS Conjunctivitis Chlamydiae replicate extensively in epithelial cells of the conjunctiva and cause considerable inflammation. The cells of the inflammatory reaction are mostly polymorphonuclear leukocytes. Conjunctivitis in a majority of untreated patients resolves spontaneously during the first few months of life. Occasionally, infants maintain persistent conjunctivitis, and the pannus formation (neovascularization of the cornea) and scarring typical of trachoma have been rep0rted.2'~'Loss of vision is rare. Micropannus and some scarring may occur in infants if they do not receive treatment within the first 2 weeks of the disease course.39 If the infection is treated early, no ocular sequelae develop.

Pneumonia The nasopharynx is the most frequent site of perinatally acquired chlamydial infection, with approximately 70% of infected infants demonstrating a positive result on cultures at that Most of these infections are asymptomatic and may persist for up to 29 months." Chlamydial pneumonia develops in only about 30% of infants with nasopharyngeal infection. Conjunctivitis is not a prerequisite for development of pneumonia.

Chlamydia Infections

387

Figure 11-1 The Chlamydia frachomatis developmental cycle. Infection is initiated by elementary bodies (EBs). 0 Hr, Immediately after endocytosis, EBs are found within tightly associated membrane vesicles. 2 Hr, Within a few hours, EBs differentiate into the larger, metabolically active reticulate bodies (RBs). 18 Hr, As the RBs multiply, the inclusion increases in size to accommodate the bacterial progeny. RBs are typically obsetved juxtaposed to the inclusion membrane. 36 Hr, As the infection progresses, increasing numbers of chlamydiae are observed unattached in the interior of the inclusion. These unattached organisms are, for the most part, EBs and intermediate developmental forms. EBs accumulate within the inclusion even as RBs, still associated with the inclusion membrane, continue to multiply, until the cell undergoes lysis at 40 to 48 hours following infection. (In Stephens RS led]. Chlamydia, lntracellular Biology, Pathogenesis, and Immunity. Washington, D.C., ASM Press, p 102.)

PATHOLOGY In inclusion conjunctivitis, the affected conjunctiva is highly vascularized and edematous. Inclusions are found in the conjunctival epithelial cells. A massive polymorphonuclear leukocyte infiltration occurs,and pseudomembrane formation may be seen. Lymphoid follicles such as are seen in adults or older children with chlamydial infection of the conjunctiva usually are not observed until the disease has been active for 1 to 2 months. Because in most infants the conjunctivitis spontaneously resolves by that time, lymphoid follicles are not commonly observed. Because the pneumonia is rarely fatal and in most infants the course is relatively benign, there has been little occasion to obtain lung specimens. When such specimens have been obtained, no characteristic features have been described. Examination of biopsy material has shown pleural congestion and alveolar and bronchiolar mononuclear cell inliltrates with eosinophils, along with focal aggregations of n e u t r o p h i l ~ . ~ ~ ~ ~

CLINICAL MANIFESTATIONS The principal clinical manifestations in infants are conjunctivitis, occurring in the first 3 weeks of life (usually 7 to 10 days), and pneumonia, which occurs within the first 3 months (typically about 6 to 8 weeks).

Conjunctivitis Inclusion conjunctivitis (ICN) usually has an incubation period of 5 to 14 days after delivery, or onset may be earlier if amniotic membranes ruptured prematurely. Conjunctivitis develops in approximately one third of infants exposed to

388

Section I1

Bacterial Infections degree of comfort indicated by the infant’s breathing; expiratory wheezes are distinctly uncommon. Hyperinflation of the lungs usually accompanies the infiltrates found on chest radiographs, but in most infants this is quite mild. Infiltrates most commonly are bilateral and interstitial; reticulonodular patterns and atelectasis also have been de~cribed.~’ Possible laboratory findings include a distinctive peripheral eosinophilia (fewer than 400 cells per mm3), mild arterial hypoxemia in some patients, and elevated serum immunoglobulins. Untreated disease can linger or recur. In very young infants, infection may be more severe and associated with apnea, but the requirement for mechanical ventilation for this illness is rare.

Perinatal Infections at Other Sites Infants born to Chlamydia-positive mothers also can become infected in the rectum and urogenital tract.” Despite the presence of clinical abnormalities, these infections may go undiagnosed and persist for up to 3 ~ e a r s . 2Consequently, ~ differentiating infection acquired perinatally from infection due to sexual abuse can be particularly difficult in young children.

DIAGNOSIS

Conjunctivitis Several nonculture methods are approved by the Food and Drug Administration (FDA) for the diagnosis of chlamydial conjunctivitis. These methods include enzyme immunoassays (E1As)-specifically, Chlamydiazyme (Abbott Diagnostics, Chicago) and MicroTrak EM (Genetic Systems,Seattle)-and direct fluorescent antibody assays (DFAs) using fluoresceinchlamydiae during vaginal d e l i ~ e r y . ’ * ~ ~Disease ~ , ~ ~ - ~mani’ conjugated monoclonal antibodies to stain chlamydial EBs festations can vary widely and range from mild Conjunctival in a smear, including Syva MicroTrak (Genetic Systems) and injection with scant mucoid discharge to severe Pathfinder (Sanofi-Pasteur, Chaska, Minn.). These tests mucopurulent conjunctivitis with chemosis and perform well on conjunctival specimens, with sensitivities of pseudomembrane formation. The eyelids swell, and the greater than 90% and specificities of 95% or greater.28’51’52 conjunctivae become injected and swollen (Fig. 11-2). In resource-poor settings, a useful diagnostic method is The”pseudomembrane” consists of inflammatory exudate examination of Giemsa-stained conjunctival scraping for the that adheres to the inflamed surface of the conjunctiva. presence of blue-stained intracytoplasmic inclusions within Except for micropannus formation, the cornea usually is epithelial cells. The sensitivityof this diagnostic method varies, spared. The duration of the illness typically is 1 to 2 weeks ranging from 22% to 95%, depending on the technique of but ICN can last a few days to several weeks. specimen collection and the examiner’s expertise. This method also allows visualization of bacteria, such as gonococci, and Pneumonia of cytologic features suggestive of viral infection. Isolation of the chlamydiae from conjunctival scraping inoculated into Neonatal chlamydial pneumonia was first reported in 1975, and the characteristicclinical picture was described in 1977.3348 tissue cell culture is a more reliable, although more costly, method of diagnosis. Serologic diagnosis of chlamydial conMost infants with chlamydial pneumonia are symptomatic junctivitis (in contrast to pneumonia) is not reliable because before the eighth week of life. The illness is characterized by of the presence of maternally transmitted IgG antibody and the insidious development of nasal obstruction or discharge, tachypnea, and a repetitive staccato cough. In some infants, the unreliable appearance of IgM antibody in this infection. these clinical features appear as early as the second week of Even if a firm diagnosis of chlamydial conjunctivitis is established, the possibility of a dual infection, particularly life, initially involving the upper respiratory tract. Characwith Neisseria gonorrhoeae, should be kept in mind. For this teristically, infants have been symptomatic for 3 or more reason, appropriate studies by stain and culture of the weeks before presentation. Most are only mildly or moderately conjunctival exudate always should be performed. ill and are afebrile. A history of conjunctivitis can be elicited, Highly sensitive nucleic acid amplification tests (NAATs) or the presence of conjunctivitis noted, in half of the cases.49 Apnea may develop in some infants. Bilateral crepitant are commercially available for the diagnosis of genital chlamydial infection in adolescents and a d ~ l t s . NAATs ~~,~~ inspiratory rales are prominent and out of proportion to the

Figure 11-2 An infant with chlamydial conjunctivitis. (In Long 5, Pickering LK, Prober CG [eds]. Principles and Practice of Pediatric Infectious Diseases. New York, Churchill Livingstone, 2003, p 904.)

Chapter 11 have FDA approval for cervical swabs from women, urethral swabs from men, and urine from men and women. These tests have a high sensitivity, detecting perhaps 10% to 20% more cases of genital chlamydial infection than is possible with culture, while retaining high ~pecificity.~~ Information on the use of NAATs in children is limited, but preliminary data suggest that polymerase chain reation (PCR) assay is equivalent to culture for the detection of C. trachomatis in the conjunctiva and nasopharynx of infants with c~njunctivitis.~~

Pneumonia EIAs and DFAs for chlamydia do not perform well with nasopharyngeal specimens and are not approved for this purpose. The definitive diagnosis of pneumonia can be made by culture of the organism from the respiratory tract. Chlamydia culture has been defined by the Centers for Disease Control and Prevention (CDC) as isolation of the organism in tissue culture and confirmation by microscopic identification of the characteristic inclusions by fluorescent antibody staining5 The likelihood of obtaining a positive culture result is enhanced by obtaining a specimen by deep suction of the trachea or by collecting a nasopharyngeal aspirate rather than obtaining a specimen with a ~ w a b . ~An ,~’ acute microimmunofluorescenceserum titer of C. trachoma& specific immunoglobulin (Ig) M greater than 1:32 also is diagnostic. Detection of C. trachomatis-specific IgG is not diagnostic because passively transferred maternal antibodies may persist at high titers for months. The serologic test of choice is the microimmunofluorescence procedure of Wang and G r a y s t ~ n in , ~ ~which elementary bodies are used as antigen. Only a few clinical laboratories perform this test. Indirect evidence of chlamydial pneumonia includes hyperinflation and bilateral diffuse infiltrates on chest radiographs, eosinophilia with peripheral blood counts of 0.3 to 0.4 x 109/L (300 to 400/pL) or more, and increased total serum IgG (less than 5g/L [500mg/dL]) and IgM (greater than 1.1g/L [ 110 mg/dL]) concentrations. The absence of these findings, however, does not exclude the diagnosis of C. trachomatis infection.

DIFFERENTIAL DlAGNOSIS

Conjunctivitis Inclusion conjunctivitis must be distinguished from that produced by pyogenic bacteria, particularly N. gonorrhoeae. Gonococcal ophthalmia usually occurs at an earlier age, typically 2 to 5 days after birth, although overlap in age at onset can occur. Gonococcal disease usually is more rapidly progressive than that due to C. trachomatis. Gonococcal infection can be diagnosed presumptively by examination of the Gram-stained smear of the exudate and confirmed by culture of the exudate. Staphylococcal conjunctivitis usually is acquired in the nursery or home environment. It is characterized more by purulent discharge than by redness. This and other forms of pyogenic conjunctivitis-which may be due to Streptococcus pneumoniae, Haemophilus species, or gram-negative bacteria such as Pseudomonas aeruginosacan easily be diagnosed by Gram stain and culture of the exudate.


389

Of the viral infections, neonatal herpes simplex (see Chapter 26) is the most important. This infection is characterized by vesicle formation and lesions of the skin as well as the conjunctiva. Corneal involvement may occur. Adenovirus infection of the newborn is very rare but has been described. Chemical conjunctivitis related to instillation of silver nitrate at birth also can produce marked redness and a purulent discharge. These signs begin on the first day of life and disappear after a few days, however, thereby distinguishing this entity from a chlamydial infection.

Pneumonia The afebrile, tachypneic infant presenting with a staccato cough in the first 3 months of life is very likely to have chlamydial disease. Cytomegalovirus (CMV) can produce an interstitial pneumonia in preterm newborns who receive transfusions from CMV-positive donors; however, it often produces clinical signs in other organ systems. Congenital infection by the rubella virus and Toxoplasma gondii also produces multiorgan involvement, as does perinatal infection with the herpes simplex virus. Adenovirus or parainfluenza virus infection can cause an interstitial pneumonia, but without the characteristic staccato cough or eosinophilia. Respiratory syncytial virus (RSV), a common cause of pneumonia in early infancy, often produces fever in the early stages, and wheezing due to airway obstruction is typical. RSV infection is not associated with eosinophilia. RSV infection can be rapidly diagnosed by performing an EIA of a nasopharyngeal wash specimen. Many pyogenic bacteria may produce lower respiratory tract infections in infancy. Group B P-hemolytic streptococci, S. pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and the coliform group of bacteria are the most common. Affected infants generally are much sicker, are more toxic and febrile, and have pulmonary consolidation rather than interstitial infiltrates. Bordetella pertussis classically causes a paroxysmal cough with or without accompanying fever, but lymphocytosis is a nonspecific diagnostic clue, and apnea occurs in infants younger than 6 months of age. In infants with Pneumocystis jiroveci pneumonia, a characteristic syndrome develops that includes subacute diffuse pneumonitis with dyspnea at rest, tachypnea, oxygen desaturation, nonproductive cough, and fever. Most have an underlying immune disorder.

PROGNOSIS

Conjunctivitis

If untreated, inclusion conjunctivitis can persist for many weeks, but it usually resolves spontaneously without complications. The scarring that occurs in trachoma that leads to lid deformities is not seen. Superficial corneal vascularization and conjunctival scar formation can occur, h ~ w e v e r . ~ ~ ’ ~ ~ ~ ~ ~

Pneumonia Without treatment, affected infants usually are ill for several weeks, with frequent cough, poor feeding, and poor weight gain. A small number require oxygen, and fewer require

390

Section I1 Bacterial Infections

ventilatory support. Beem and colleagues6' found in a series of 11 infants that the duration of the clinical course was between 24 and 61 days, with a mean of 43 days, and that death was exceptionally rare. Follow-up evaluation of a small cohort of children who had C. rruchornuris pneumonia in infancy demonstrated an increased prevalence of chronic cough and abnormal lung function when compared with that in age-matched controls.61

THERAPY Topical treatment of inclusion conjunctivitis is not recommended, primarily because of failure to eliminate concurrent nasopharyngeal infection. Recommended therapy for conjunctivitis or pneumonia is oral erythromycin, 40 mg/kg/day in 4 divided doses for 14 days. The failure rate is around 20%, and a second course of therapy may be Problems with compliance and tolerance are frequent. Oral sulfonamides can be used after the immediate neonatal period for infants who do not tolerate erythromycin. Convincing evidence suggests that this treatment shortens the clinical course of pneumonia and eliminates the organism from the respiratory tract. Beyond specific antimicrobial therapy, the infants require standard supportive care measures, with attention to nutrition and to fluid status. Oxygen and ventilatory therapy may be required in a minority of cases. A specific diagnosis of C. rruchornaris infection in an infant should prompt treatment of the mother and her sexual partner(s). An association between orally administered erythromycin and infantile hypertrophic pyloric stenosis (IHPS) has been reported in infants younger than 6 weeks of age who were given the drug for prophylaxis after nursery exposure to pertu~sis.~"'The risk of IHPS after treatment with other macrolides (e.g., azithromycin dihydrate, clarithromycin) is unknown. Because confirmation of erythromycin as a contributor to cases of IHPS requires additional investigation and because alternative therapies are not as well studied, the American Academy of Pediatrics continues to recommend use of erythromycin for treatment of C. truchornaris infection in infants. Parents of infants given erythromycin should be informed about the signs and potential risks of developing IHPS. Cases of pyloric stenosis developing after use of oral erythromycin should be reported to the Food and Drug Administration as an adverse drug reaction. One small study suggests that a short course of orally administered azithromycin, 20 mglkg in a single daily dose for 3 days, may be effe~tive.~' Prophylactic therapy of infants born to mothers known to have untreated chlamydial infection is not indicated, because the efficacy of such prophylaxis is unknown. Such infants should be monitored for signs of infection and to ensure appropriate treatment if infection develops. If adequate follow-up cannot be ensured, prophylaxis may be considered.

PREVENTION Because C. trachornatis infections are transmitted vertically from mother to infant during delivery, an effective prevention

measure is screening and treatment of pregnant women for C. rrachornuris infection before delivery. The CDC currently recommends screening all pregnant women during their first prenatal visit, and during the third trimester if they are at high risk (age younger than 25 years or other risk factors such as new or multiple sexual partner^).^ Either erythromycin base (2 g/day in four divided doses) or amoxicillin (1.5 g/day in three divided doses) for 7 days is the recommended treatment regimen for pregnant women. Half-doses of erythromycin daily for 14 days may be given in pregnant women intolerant of the full-dose regimen. Because these regimens are not highly efficacious, a second course of therapy may be needed. Azithromycin (1 g orally in a single dose) is an alternative; preliminary data suggest that it is safe and effective.66 Doxycycline and ofloxacin are contraindicated during pregnancy. Ocular prophylaxis with topical erythromycin or tetracycline has reduced the incidence of gonococcal ophthalmia but does not appear to be effective against C. rr~chornatis.6~ Thus, the only means of preventing chlamydial infection of the newborn is treatment of maternal infection before delivery. Ongoing efforts to develop a C. truchomatis vaccine to protect persons from genital tract infection have concentrated primarily on the use of peptides derived from the MOMP or recombinant synthetic MOMP polypeptides as immunogens. Future work may incorporate molecular technology and our increasing understanding of the host response to chlamydiae to develop one or more new vaccines. Stimulation of long-term mucosal immunity in the genital tract is a challenge; it is unclear whether all genital infections could be prevented or whether only more invasive disease, such as salpingitis, might be preventable using vaccine technology. REFERENCES 1. Lindner L. Zur Aetiologie der gonokokkenfreienUrethritis. Wiem Klin Wochenschr 22:1555,1910. 2. Jonesboro Al-Hussaini MK, Dunlop EMC. Genital infection in association with TRlC virus infection of the eye: I. Isolation of virus from urethra, cervix, and eye: preliminary report. Br J Vener Dis 40~19-24,1964. 3. Beem MO, Saxon EM. Respiratory tract colonization and a distinctive pneumonia syndrome in infants infected with Chlamydia trachomatis. N Engl J Med 296306-310,1977. 4. Schachter J. Chlamydial infections (third of three parts). N Engl J Med 298~540-549,1978. 5. Sexually transmitted diseases treatment guidelines 2002. Centers for Disease Control and Prevention.MMWR Recomm. Rep 51:30-36,2002. 6. Sexually transmitted disease surveillance. 9- 1-2002. Atlanta, Centers for Disease Control and Prevention, 2002. 7. Starnm WE. Chlamydia trachomatis infections of the adult. In Holmes KK, Mardh PA, Sparling PF (eds). Sexually Transmitted Diseases. New York, McGraw-Hill, 1999, pp 407-422. 8. Hardick J, Hsieh YH, Tulloch S, et al. Surveillance of Chlamydia trachomatis and Neisseria gonorrhoeae infectionsin women in detention in Baltimore, Maryland. Sex Transm Dis 30:64-70,2003. 9. Tobin JM. Chlamydia screening in primary care: is it useful, affordable and universal?Curr Opin Infect Dis 1531-36,2002. 10. Herrmann B, Egger M. Genital Chlamydia trachomatis infections in Uppsala County, Sweden, 1985-1993: declining rates for how much longer? Sex Transrn Dis 22:253-260, 1995. 11. Blythe MJ, Katz BP, Orr DP, et al. Historical and clinical factors associated with Chlamydia trachomatis genitourinary infection in female adolescents. J Pediatr 112:lOOO-1004, 1988. 12. Chacko MR, Lovchik JC. Chlamydia trachomatis infection in sexually active adolescents: prevalence and risk factors. Pediatrics 732336440, 1984.

Chapter 11 13. Shafer MA, Beck A, Blain B, et al. Chlamydia trochomatis: important relationships to race, contraception, lower genital tract infection, and Papanicolaou smear. J Pediatr 104141-146,1984, 14. Burstein GR, Gaydos CA, Diener-West M, et al. Incident Chlamydia trachomatis infections among inner-city adolescent females. JAMA 280521-526, 1998. (See comments.) 15. Gaydos CA, Howell MR, Pare B, et al. Chlamydia fruchomatisinfections in female military recruits. N Engl J Med 339:739-744, 1998. (See comments.) 16. Eagar RM, Beach RK, Davidson AJ, Judson FN. Epidemiologic and clinical factors of Chlamydia trachomatis in black, Hispanic and white female adolescents. West J Med 143:37-41, 1985. 17. Fraser JJ Jr, Rettig PJ, Kaplan DW. Prevalence of cervical Chlamydia trachomatis and Neisseria gonorrhoeae in female adolescents. Pediatrics 71~333-336,1983. 18. Jacobson DL, Peralta L, Farmer M, et al. Relationship of hormonal contraception and cervical ectopy as measured by computerized planimetry to chlamydial infection in adolescents. Sex Transm Dis 22313-319,2000. 19. Louv WC, Austin H, Perlman J, Alexander WJ. Oral contraceptive use and the risk of chlamydial and gonococcal infections. Am J Obstet Gynecol 160396-402,1989. 20. Jones BR. The prevention of blindness from trachoma. Trans Ophthalmol SOCUK 95:16-33,1975. 21. Holmes KK, Handsfield HH, Wang SP, et al. Etiology of nongonococcal urethritis. N Engl J Med 292:1199-1204, 1975. Alexander ER, Pheiffer TA, et al. Ophthalmia neonatorum 22. Chandler JW, associated with maternal chlamydial infections. Trans Am Acad Ophthalmol Otolaryngol83:302-308, 1977. 23. Hammerschlag MR, Anderka M, Semine DZ, et al. Prospective study of maternal and infantile infection with Chlamydia trachomatis. Pediatrics 64:142-148,1979. 24. Schachter 1, Grossman M, Sweet RL, et al. Prospective study of perinatal transmission of Chlamydia trachomatis. JAMA 255:3374-3377, 1986. 25. Schachter J, Grossman M, Holt J, et al. Prospective study of chlamydial infection in neonates. Lancet 2:377-380, 1979. 26. Schachter J, Grossman M, Holt J, et al. Infection with Chlamydia trachomatis: involvement of multiple anatomic sites in neonates. J Infect Dis 139232-234,1979. 27. Hammerschlag MR, Roblin PM, Gelling M, Worku M. Comparison of two enzyme immunoassays to culture for the diagnosis of chlamydial conjunctivitis and respiratory infections in infants. J Clin Microbiol 28: 1725-1727,1990. 28. Rapoza PA, Quinn TC, Kiessling LA, et al. Assessment of neonatal conjunctivitis with a direct immunofluorescent monoclonal antibody stain for Chlamydia. JAMA 2553369-3373,1986. 29. Roblin PM, Hammerschlag MR, Cummings C, et al. Comparison of two rapid microscopic methods and culture for detection of Chlamydia trachomatis in ocular and nasopharyngeal specimens from infants. J Clin Microbiol22968-970,1989. 30. Hammerschlag MR, Gelling M, Roblin PM, et al. Treatment of neonatal chlamydial conjunctivitis with azithromycin. Pediatr Infect Dis J 17~1049-1050,1998. 31. Everett KD, Bush RM, Andersen A. Emended description of the order Chlamydiales, proposal of Parachlamydiaceae fam.nov. and Simkaniaceae fam. nov., each containing one monotypic genus, revised taxonomy of the family Chlamydiaceae, including a new genus and five new species, and standards for the identification of organisms. Int J Syst Bacteriol 492:415-440,1999. 32. Kalman S, Mitchell W, Marathe R, et al. Comparative genomes of Chlamydia pneumoniae and C. trachomaris. Nat Genet 21:385-389, 1999. 33. Rockey DD, Lenart J, Stephens RS. Genome sequencing and our understanding of chlamydiae. Infect Immun 68:5473-5479,2000. 34. Wyrick PB, Choong J, Davis CH, et al. Entry of genital Chlamydia trachomatis into polarized human epithelial cells. Infect Immun 57:2378-2389, 1989. 35. Wyrick PB. Cell biology of chlamydial infection. In Stephens RS, Byrne GI, Christiansen G (eds). Proceedings of the 9th International Symposium of Human Chlamydial Infection. San Francisco, International Chlamydia Symposium, 1998, p 69. 36. de la Maza LM, Peterson EM. Scanning electron microscopy of McCoy cells infected with Chlamydia trachomatis. Exp Mol Pathol36:217-226, 1982. 37. Todd WJ, Caldwell HD. The interaction of Chlamydia trachomatis with host cells: ultrastructural studies of the mechanism of release of a

38.

39. 40. 41.

42. 43. 44. 45. 46. 47. 48. 49. 50. 51.

52.

53. 54.

55. 56.

57. 58.

59. 60. 61. 62. 63. 64.


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biovar I1 strain from HeLa 229 cells. J Infect Dis 151:1037-1044, 1985. Mordhorst CH, Wang SP, Grayston JT. Childhood trachoma in a nonendemic area in Danish trachoma patients and their close contacts, 1963 to 1973. JAMA 239:1765-1771, 1978. Mordhorst CH, Dawson C. Sequelae of neonatal inclusion conjunctivitis and associated disease in parents. Am J Ophthalmol 71:861-867, 1971. Hammerschlag MR. Chlamydial infections. J Pediatr 114:727-734,1989. Hammerschlag MR, Chandler JW, Alexander ER, et al. Longitudinal studies on chlamydial infections in the first year of life. Pediatr Infect Dis 1:395-401, 1982. Bell TA, Stamm WE, Wang S, et al. Chronic Chlamydia trachomatis infections in infants. JAMA 262400-402, 1992. Frommell GT, Bruhn FW,Schwartzman JD. Isolation of Chlamydia trachomatis from infant lung tissue. N Engl J Med 2961 150-1152,1977. Arth C, Von Schmidt B, Grossman M, Schachter J. Chlamydia] pneumonitis. J Pediatr 93:447-449, 1978. Schachter J: Chlamydial infections (third of three parts). N Engl J Med 298:540-549,1978. (Review.) Frommell GT, Rothenberg R, Wang S, McIntosh K. Chlamydial infection of mothers and their infants. J Pediatr 95:28-32, 1979. Hammerschlag MR, Anderka M, Semine DZ, et al. Prospective study of maternal and infantile infection with Chlamydia trachomatis. Pediatrics 64142-148,1979. Schachter J, Lum L, Gooding CA, Ostler B. Pneumonitis following inclusion blennorrhea. J Pediatr 87779-780, 1975. Tipple MA, Beem MO, Saxon EM. Clinical characteristics of the afebrile pneumonia associated with Chlamydia trachomatis infection in infants less than 6 months of age. Pediatrics 63:192-197, 1979. Radkowski MA, Kranzler JK, Beem MO, Tipple MA. Chlamydia pneumonia in infants: radiography in 125 cases. Am J Resp Dis 137:703-706,1981. Hammerschlag MR, Roblin PM, Gelling M, Worku M. Comparison of two enzyme immunoassays to culture for the diagnosis of chlamydial conjunctivitis and respiratory infections in infants. J Clin Microbiol 28~1725-1727,1990. Roblin PM, Hammerschlag MR, Cummings C, et al. Comparison of two rapid microscopic methods and culture for detection of Chlamydia trachomatis in ocular and nasopharyngeal specimens from infants. J Clin Microbiol27:968-970, 1989. Schachter J, Stamm WE, Quinn TC, et al. Ligase chain reaction to detect Chlamydia trachomatis infection of the cervix. J Clin Microbiol 32~2540-2543,1994. Jaschek G, Gaydos CA, Welsh LE, Quinn TC. Direct detection of Chlamydia trachomatis in urine specimens from symptomatic and asymptomatic men by using a rapid polymerase chain reaction assay. J Clin Microbiol31:1209-1212, 1993. Black CM. Current methods of laboratory diagnosis of Chlamydia trachomatis infections. Clii Microbiol Rev 10160-184,1997. Hammerschlag MR, Roblin PM, Gelling M, et al. Use of polymerase chain reaction for the detection of Chlamydia trachomatis in ocular and nasopharyngeal specimens from infants with conjunctivitis. Pediatr Infect Dis J 16993-297,1997. Harrison HR, English MG, Lee CK, Alexander ER. Chlamydia trachomatis infant pneumonitis: comparison with matched controls and other infant pneumonitis. N Engl J Med 298:702-708,1978. Wang SP, Grayston JT, Alexander ER, Holmes KK. Simplied microimmunofluorescence test with trachoma lymphogranuloma venereurn (Chlamydia trachomatis) antigens for use as a screening test for antibody. Clin Microbiol 1:250-255, 1975. Schachter J, Dawson CR. Human Chlamydial Infections. Littleton, Mass, PSG Publishing Company, 1978. Beem MO, Saxon E, Tipple MA. Treatment of chlamydial pneumonia of infancy. Pediatrics 63:198-203, 1979. Harrison HR, Taussig LM, Fulginiti VA. Chlamydia trachomatis and chronic respiratory disease in childhood. Pediatr Infect Dis J 1:29-33, 1982. Hammerschlag MR, Chandler JW, Alexander ER, et al. Longitudinal studies on chlamydial infections in the first year of life. Pediatr Infect Dis J 1:395-401, 1982. Patamasucon P, Rettig PJ, Faust KL, et al. Oral v topical erythromycin therapies for chlamydial conjunctivitis. Am J Dis Child 136817-821, 1982. Hypertrophic pyloric stenosis in infants following pertussis prophylaxis with erythromycin-Knoxville, Tennessee, 1999. MMWR Morb Mortal Wkly Rep 48:1117-1120, 1999.

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65. Centers for Disease Control and Prevention. Hypertrophic pyloric stenosis in infants following pertussis prophylaxis with erythromycinKnoxville, Tennessee, 1999. JAh4A 283:471-472,2000. 66. Miller JM, Martin DH. Treatment of Chlamydia trachomafis infections in pregnant women. Drugs 60597-605,2000.

67. Hammerschlag MR, Cummings C, Roblin PM, et al. Effiaqof neonatal ocular prophylaxis for the prevention of chlamydial and gonococcal conjunctivitis.N Engl J Med 320:769-772, 1989.

Chapter 12 GONOCOCCAL INFECTIONS Joanne E. Embree

Epidemiology and Transmission 393 Microbiology

395

Pathogenesis

395

Pathology 396 Clinical Manifestations 396 Diagnosis 396 Differential Diagnosis

397

Treatment (Therapy/Management)

care, as well as aggressive pilot programs for prevention and treatment of sexually transmitted diseases (STDs) in conjunction with HIV infection/acquired immunodeficiency syndrome (AIDS)prevention strategies, have continued to decrease the incidence of gonococcal infection and its complications, such as ophthalmia neonatorum, in areas where these interventions have been introduced. lo Despite the overall decreasing prevalence of N. gonorrhoeae infection worldwide, however, gonococcal ophthalmia neonatorum remains a significant illness.

397

Prognosis 398 Prevention 398

Infections of the fetus and newborn infant due to Neisseria gonorrhoeae are restricted primarily to mucosal surfaces of the newborn infant. The most common condition related to infection by this organism during the neonatal period is ophthalmia neonatorum, or neonatal conjunctivitis. N. gonorrhoeae produces purulent conjunctivitis in the newborn that, if untreated may lead to blindness. This is the primary disease entity discussed in this chapter. Ophthalmia neonatorum had been a well-recognizedentity, affecting between 1% and 15% of newborns, in Europe and North America when Hirschberg and Krause first described neonatal infection due to N. gonorrhoeae in an infant with purulent conjunctivitis in 1881.' Shortly thereafter, the topical instillation of silver nitrate into the newborn's eyes immediately after birth dramatically reduced the incidence of this disease due to N. gonorrhoeae, albeit with the complication in most infants of milder conjunctivitis, limited to the first 24 hours of life, due to the silver Use of erythromycin or tetracycline ointments for this purpose has proved to be efficaciousfor preventing gonococcal ophthalmia, with markedly reduced problems related to the chemical conjunctivitis seen with silver nitrate.4-6Systemic neonatal infection is unusual, but infants may present with a variety of clinical syndromes (in particular, arthritis), which implies that dissemination of the bacteria does Maternal systemic infection during pregnancy also is rare, and transplacental congenital infection of the fetus has not been described. Maternal genital mucosal infection, however, may result in an ascending infection, with chorioamnionitis leading to premature rupture of the placental membranes and preterm delivery.' In developed countries, screening and treatment of pregnant women for gonococcal infections with tracing of named contacts, along with the use of neonatal ophthalmic prophylaxis, have substantially reduced the incidence of gonococcal ophthalmia neonatorum. In medically developing areas, improvementsin access to medical

EPIDEMIOLOGY AND TRANSMISSION The incidence of neonatal gonococcal illness is related to the prevalence of N. gonorrhoeue colonization among women of childbearing age, and to the rates of acute infection during pregnancy. This is quite variable worldwide and now is heavily influenced by the human immunodeficiency virus type 1 infection (HIV-1) epidemic. In general, once antibiotic treatment for gonorrhea became available in the mid20th century, rates of infection among women decreased worldwide, as these agents became more readily accessible and heath care programs improved. With the emergence of penicillin chromosomal resistance, the development of penicillinase production by some strains, and the expansion of the AIDS epidemic in the 1990s, however, rates began to rise again during that decade. In response, efforts to control this infection-which some authorities had hoped could ultimately be eliminated by the middle of this century-have been increased. Estimates by the World Health Organization (WHO) of the burden of gonorrheal disease in various regions at the end of the twentieth century are presented in Table 12-1." Although these estimates are useful in indicating areas of high burden of disease, considerable variation within regions exists. This variation is reflected in the differences seen in the number of reported cases of gonorrhea among women in North America. In the United States, during 2001, 361,705 cases of gonorrhea were tallied, resulting in a reported prevalence of 128 cases per 100,000 population, which was similar to that reported in 2000 (129 per 100,000), 1999 (132 per 100,000),and 1998 (131 per 100,000).'2 Overall, no changes have been noted in the prevalence rate among women in the United States during these years. The prevalence among women has equaled that among men since 1998. Infection rates have fallen since 1986, when the prevalence among women was approximately 310 cases per 100,000 population. Further significant differences are noted among populations in the United States, however, when rates are compared for groups of different races or ethnicity and for location. The prevalence among blacks in the United States is still considerably higher than in other ethnic groups but dropped

394

Section I1

Table 12-1


WHO Estimated Numbers of Cases of Gonorrhea in Adults 1999

Geographical Location

Estimated No. of Cases

~~

North America Latin America Western Europe Eastern Europe and Central Asia East Asia South and Southeast Asia North Africa and the Middle East Sub-Saharan Africa New Zealand and Australia

1 .5 million 7.5 million 1 million 3.5 million 3 million 27 million 1.5 million 17 million

120,000

WHO, World Health Organization. Data from World Health Organization. Global prevalence and incidence of selected curable sexually transmitted infections. Overview and estimates. WHO/CDS/CSREDC/2001. 1O:l-50. 2001.

from approximately 2100 cases per 100,000 population in 1986 to around 800 per 100,000 in 2001. The background prevalence also differs significantly among the various states, with 6 states reporting rates greater than 200 per 100,000 in 2001, 17 states reporting between 100 and 200 cases per 100,000 and the rest reporting less than 100 per 100,000. The United States has set a goal of reducing the national prevalence of gonorrhea to less than 19 cases per 100,000 among adults. In 2001,8 states reported a prevalence of disease below this target goal. In Canada, however, rates of gonorrhea are considerably lower than in the United States. Canada has placed an emphasis on STD control as well but has an exclusively publicly funded health care system. Gonorrhea prevalence rates have decreased steadily from 1980, when the prevalence among women was 166 per 100,000 population. The highest rates at that time were among women 15 to 19 and 20 to 24 years of age, which were extremely high at 5 10 and 598, respectively, per 100,000. In 2000, the prevalence among women was approximately 15 per 100,000, which actually represented an increase from 1997, when rates had dropped to a low of 11 per 100,000. The increase occurred primarily among women aged 15 to 19 and 20 to 24 years; in these age groups, rates increased from 69 and 60, respectively, per 100,000 in 1997 to 96 and 73 per 100,000. In 1997, Canada had set as its goal the elimination of endemic transmission of N. gonorrhoeae by the year 2010. This increase in prevalence has led to a call for an assessment of STD control and reporting procedures in Canada to determine why the previously observed declines in prevalence had stopped. l3 Factors that increase a pregnant woman’s risk of acquiring N. gonorrhoeae infection are similar to those that increase the risk of acquisition of any other sexually transmitted infe~tion.’~ The prevalence of N. gonorrhoeae in the population or network in which she socializes and chooses her sexual partners will determine the likelihood of exposure to this pathogen. Women who have multiple sexual partners or whose partners have multiple sexual contacts increase their risk of exposure to N. gonorrhoeae. Women who do not use condoms or other barrier protection will increase their risk of acquisition of N. gonorrhoeae infection on exposure to the organism. It is unknown whether women who are HIV positive have an increased risk of infection by N. gonorrhoeae

on exposure to it. Factors associated with an increased likelihood of at-risk behavior that results in an increased risk of gonococcal infection among pregnant women include younger age, unmarried status, homelessness, problems with drug or alcohol abuse, prostitution, low-income professions, and, in the United States, being black. Gonococcal infections are diagnosed more frequently in the summer months in the United States, probably reflecting transient changes in social behavior during vacation^.'^ Varying gonococcal rates reported in various studies worldwide reflect the differences in risk among the populations studied. In a recent study in Brazil, involving a cross-sectional study of 200 women aged 14 to 29 years who attended an HIV testing site in central Rio de Janeiro, the prevalence of gonorrhea was high at 9.5%. Of the 200 women, 8% were HIV infected, confirming that the population studied had a high risk of STD exposure.I6The prevalence of gonorrhea among 547 pregnant women attending a first-visit antenatal hospital clinic during 1999 and 2000 in Vila, Vanuatu, was 5.9%, but no women were found to be HIV infected at that time.” The occurrence rates of gonorrhea were quite high among this population, reflecting the prevalence in the general population. A study in Thailand in 1996 that investigated the prevalence of STDs among pregnant women, where case reporting suggested a marked decrease in STDs following a campaign promoting condom use during commercial sex, showed that the prevalence of gonorrhea was extremely low at 0.2Y0.’~By contrast, in a population in Nairobi, where condom use was advocated for commercial sex workers but not promoted to the same extent as in Thailand and not routinely practiced by the at-risk general population, in a cross-sectional study of 520 women seeking treatment at an STD clinic, 4% were infected with gonorrhea and 29% were HIV positive.” In Nigeria, where the prevalence of HIV infection is low, the rate of gonorrhea also is lower among pregnant women. In a cross-sectional study, 230 pregnant women attending the antenatal clinic of a teaching hospital in Nigeria from January 2000 to December 2000 were screened randomly to determine the prevalence of common STDs; 1.3% were found to have gonorrhea.20 N. gonorrhoeae usually is transmitted from the infected maternal cervix during vaginal delivery. Ascending infection does occur, however, in the instance of prolonged ruptured membranes and has been observed after cesarean section delivery following ruptured It has been estimated that colonization and infection of the neonate occur in only one third of instances in which the mother is infected.25 The infant’s mucous membranes become colonized when swallowing contaminated fluid during labor and delivery. In instances of congenital infection, it is speculated that the chorioamnion is infected through an ascending infection.26 Premature rupture of membranes then occurs, with early onset of labor and premature delivery or septic a b o r t i ~ n . ~ > ~ ~ - ~ ~ This association was dramatically shown in one study in which premature rupture of membranes occurred in 6 (43%) of 14 women with untreated gonococcal infection during pregnancy, compared with 4 (3%) of 144 women whose infection had been treated.” Thus, screening and treatment programs for gonococcal infections during pregnancy are appropriate to reduce the risk of adverse pregnancy outcomes related to maternal infection.

Chapter 12

MICROBIOLOGY N. gonorrhoeae is a gram-negative diplococcus. It utilizes glucose for growth but not maltose, sucrose, or lactose. This is one of the characteristics used to distinguishN. gonorrhoeae isolates from N. meningitidis and other colonizing Neisseria species such as N. cinerea, N. flava, N. subflava, N. lactamica, N rnucosa, and N. sicca. N. gonorrhoeae produces acid only when grown in glucose. In addition, the organism is oxidase positive, hydroxyprolylaminopitidasepositive, nitrate negative, DNase negative, catalase positive, strongly superoxol positive, and colistin re~istant.~'It is an obligate aerobe but lacks superoxide dismutase, which moderates the effects of oxygen radicals in most other aerobic bacteria. When grown in anaerobic conditions, virulent strains express a lipoprotein called Pan 1. Its function is unknown,but it elicits an immunoglobulin M (IgM) antibody response in acute infection. When cultured in the laboratory, 'N. gonorrhoeae forms four different colony types. Pinpoint colonies, classified as type 1 and type 2, usually are only seen on primary isolation. What distinguishes these colony types from the large granular colonies classified as types 3 and 4 is the presence of pili, which are thin bacterial appendages on the cell surface that are involved in attachment to mammalian cells. N. gonorrhoeae has the genetic capacity to turn on and turn off the expression of ~ i l i . ~With ' repeated subculturing at 37OC, the genes are no longer expressed and the pili disappear, resulting in colonial-type changes, with type 1 colonies shifting to type 4 and type 2 colonies to type 3. Associated with this change is a reduction in ~irulence.~' N. gonorrhoeae also may form colonies that are either opaque or clear. This characteristic is related to the presence of a specific surface protein called outer membrane protein 11. Transparent colonies lack outer membrane protein I1 and are more resistant to phagocytosis. Individual strains can also shift from forming opaque to forming clear colonies.33 Colonial morphology is of no use in differentiating gonococcal types or strains. Strains can be differentiated by auxotyping. Different strains have differing stable auxotrophic requirements for amino acids, purines, pyrimidines, or vitamins. Typing based on these requirements has been useful in some epidemiologic surveys. Additionally, enzymelinked immunosorbent typing, based on differences in protein I, can be done. Nine distinct strains are detectable with this typing system. It is clinically relevant in that type 1 and type 2 strains are more likely to disseminate in adult patients. Use of serologic typing schemes can detect three serogroups: WI, WII, and WIII. Strains 1 to 3 are usually found in serogroup WI, strains 4 to 8 in serogroup WII, and strain 9 in serogroup Finally, strains also are typed by coagulation testing following exposure to monoclonal antibodies made against the outer membrane protein I. Two major serogroups exist: lA, which has 26 subgroups, and IB, with 32 subgroup^.^' The combination of awiotyping and serologic typing is now used in most epidemiologic studies to determine the linkages among infected persons.36

PATHOGENESIS To produce infection, N. gonorrhoeae first attaches to epithelial cells, penetrates into them, and then destroys the

Gonococcal Infections

395

infected cells. Attachment to epithelial cells is related to the presence of pili, as well as the outer membrane protein II.37 Penetration of the gonococcus into cells is through either phagocytosis or endocyt~sis.~~-~' Several bacteria usually are present in each infected cell, but whether this represents invasion of the cell by multiple organisms or growth and multiplication of organisms within the infected cell is unknown. Gonococci possess a cytotoxic lipopolysaccharide and produce proteases, phospholipases, and elastases that ultimately destroy the infected cells. Some strains of gonococci appear to be relatively less susceptible to phagocytosis and are thus thought to be more capable of causing disseminated infection. Gonococci are found in the subepithelial connective tissue very quickly after infection. This dissemination may be due to the disruption of the integrity of the epidermal surface with cell death, or the gonococci may migrate into this area by moving between cells. Epithelial cell death triggers a vigorous inflammatory response, initially with neutrophils and then macrophages and lymphocytes in untreated patients. Human serum contains IgM antibody directed against lipopolysaccharide antigens on the gonococcus, which inhibits invasion. An IgG antibody against a surface protein antigen, however, also is normally present on some gonococci that are classified as serum-resistant gonococci; this antibody blocks the bactericidal action of the antilipopolysaccharide IgM antib~dy.~'.~' These serum-resistant strains are the most common ones involved in systemic infections in adults and probably in neonates as well.43Of note, infants' sera, in which maternal IgM antibody is absent, do not demonstrate serum bactericidal activity against N . gonorrhoeaeU; thus, in theory, infants should be highly susceptible to invasive infection. Because such infection does not occur frequently, additional protective factors must function to prevent it. N. gonorrhoeae produces IgAl protease, which inactivates secretory IgA by cleaving it at the hinge region. This inactivation facilitates mucosal colonization and probably plays a role in the poor mucosal protection seen against subsequent gonococcal reinfection. It also is a proinflammatory protein and can trigger the release of proinflammatory cytokines from human monocytic subpopulationsand a dose-dependent T,l-type T-cell response?' Although symptomaticgonococcal infection triggers a brisk inflammatory response, it does not produce a significant immunologic There is very little immunologic memory; as a result, recurrent infections occur easily on re-exposure. Epidemiologic evidence suggests that at least partial protection is obtained against subsequent infection with the same ser0type.4~In general, however, antibody responses are modest after initial infection, and no evidence of a boosting effect has been found when antibody levels are studied in response to subsequent infections. Also, adults with mucosal gonococcal infections have a discernible decreased CD4' count, which recovers with treatment or clearance of the infection. Thus, it has been speculated that the gonococci actually have a suppressive effect on the host immune response. In support of this theory, N. gonorrhoeae Opa proteins recently were shown to be able to bind CEACAMl expressed by primary CD4' T lymphocytes and to suppress their activation and proliferati~n.~~ This immune suppressive effect may have significant consequences in populations with co-existing epidemics of gonorrhea and

396

Section I1


HIV infection/AIDS. In a study of prostitutes in Nairobi, the presence of gonococcal cervicitis has been shown to reduce the interferon-g production by HIV- 1 epitope-specific CD8’ T-lymphocyte populations, demonstrating a deleterious effect of gonococcal cervicitis on HIV-1 immune control and s~sceptibility.4~ Because only approximately one third of neonates exposed to N . gonorrhoeue during vaginal delivery become colonized and infected, additional protective innate factors obviously are in effect. Recently, significant antibacterial polypeptide activity has been demonstrated both in human amniotic fluid and within the vernix c a s e ~ s a ? ~ The , ~ ~presence of a number of antibacterial polypeptides in the vernix may be important for surface defense against gonococcal infection, but specific studies have yet to be done. Antibiotic resistance to penicillin, tetracycline, the quinolones, and spectinomycin has become problematic in many regions?2 Penicillin resistance can be a result of either alterations in the penicillin-binding protein or the production of p e n i ~ i l l i n a s e . ~ By~ -1991, ~ ~ 11% of all strains of N . gonorrhoeue in the United States were penicillinase producing, and 32% of all strains were resistant to at least one antimicrobial agent. As a result, penicillin is no longer recommended for primary therapy for gonococcal disease in the United States and in other regions where these strains are commonly found.

PATHOLOGY In most affected infants, gonococcal disease manifests itself as infection of mucosal membranes. The eye is most frequently involved, but funisitis and infant vaginitis, rhinitis, and urethritis also have been ~ b s e r v e d . Primary ~~.~~ mucosal infection by N . gonorrhoeue involves the columnar and transitional epithelia. When pharyngeal colonization is looked for, it is found in 35% of ophthalmia neonatorum cases6’ Systemic infection is rarely observed among neonates, but cases of meningitis and arthritis have been de~cribed.6’-~’ Gonococcal scalp abscesses attributed to intrauterine fetal monitoring, omphalitis, and gingival abscess also have been rep~rted.~’.” One case of gonococcal ventriculitis has been reported in an infant who received a ventriculoamniotic shunt in ~ t e r o . ~ ~

CLINICAL MANIFESTATIONS Ophthalmia neonatorum due to N. gonorrhoeae is classically an acute purulent conjunctivitis that appears from 2 to 5 days after birth. Occasionally, however, the initial presentation is more subacute, or the onset may be delayed beyond 5 days of life.79380 Asymptomatic colonization has been documented.”’ Infants who become infected in utero may have symptoms at or shortly following Typically, early in the illness, tense edema of both lids develops, followed by profuse purulent conjunctival exudates (Fig. 12-1). If treatment is delayed, the infection progresses beyond the superficial epithelial layers of the eye to involve the subconjunctival connective tissue of the palpebral conjunctivae and the cornea. Infection of the cornea can lead to ulcerations, perforation, or rarely panophthalmitis. In some

Figure 12-1 Bilateral acute gonococcal ophthalrnia neonatorurn. Appearance after inappropriate topical therapy for 2 weeks with neornycin-polyrnyxin B-bacitracin (Neosporin), sulfonarnide, and chloramphenicol ophthalmic ointments.

instances it may result in loss of the eye!* Neonatal sepsis, arthritis, and skin abscesses due to N. gonorrhoeae are not clinically distinguishable from conditions caused by other bacterial pathogens more commonly associated with these syndromes in this age group.

DIAGNOSIS Clinicians should suspect gonococcal ophthalmia neonatorum in an infant in whom purulent conjunctivitis develops during the first week of life, or if what was thought to be chemical conjunctivitis is prolonged beyond 24 to 48 hours. Gram stain of the exudate usually reveals the gramnegative intracellular bean-shaped diplococci typical of N . gonorrhoeae, which will provide a presumptive diagnosis. Other Neisseria species-in particular, N. rneningitidiscannot be distinguished from the gonococcus by Gram stain appearance. N. gonorrhoeae must be isolated and tested for antibiotic susceptibility before a definitive diagnosis is made. A definitive diagnosis is important because of the public health and social consequences of the diagnosis of gonorrhea in an infant. If gonococcal ophthalmia neonatorum is suspected on the basis of the Gram stain appearance, cultures should be obtained from additional mucosal sites in the infant. The mother and her sexual partner(s) also should be tested for gonorrhea. Additional testing of the infant, the mother, and her sexual partner(s) for other sexually transmitted infections, including HIV infection, is strongly rec~mmended.~~.~~ Isolation of N. gonorrhoeae from the exudate by culture is the diagnostic “gold standard.” Samples of the exudate should be collected by swabbing and should be inoculated directly onto blood agar, MacConkey’s agar, and chocolate agar or chocolate-inhibitory media. The inhibitory medium should be placed in a commercial carbon dioxide incubator or candle jar to provide an adequate concentration of carbon dioxide and should then be incubated at 36’ C. Cultures are examined daily for the presence of typical colonies. Colonies resembling

Chapter 12 N. gonorrhoeae are further identified by Gram stain, by a positive oxidase test, and by utilization of glucose but not maltose, sucrose, or lactose. Antibiotic sensitivity and penicillinase production should be tested. Further testing to confirm the identification of the isolate may be carried out in a reference laboratory if desired. Newer DNA- and polymerase chain reaction (PCR)-based technologies have replaced gonococcal cultures in many lab~ratories.'~-'~ These assays have a high degree of sensitivity and actually detect more true cases of gonorrheal infection in adults than can be achieved by current culture methods. When correctly used, they also are very specific. Their suitability for diagnosis of gonorrheal infections in children without the additional use of culture methods, with the associated legal implications in older children, has not been extensively studied, however. Additionally, extensive use of these methods for primary diagnosis impairs the tracking of antimicrobial resistance patterns. If gonococcal ophthalmia neonatorum is presumptively or definitively.diagnosed, then testing also should be conducted for other sexually transmitted pathogens, in particular, Chlamydia trachomatis, because the two organisms frequently are found to co-infect pregnant women." Also, the diagnosis of gonococccal infection in the neonate should trigger an investigation of the infant's mother and her sexual partner or partners for STDs.

DIFFERENTIAL DIAGNOSIS At present, N. gonorrhoeae causes less than 1% of cases of ophthalmia neonatorum in North America, western Europe, Australia, and New Zealand and in areas and communities elsewhere where there is access to prenatal care and STD prevention programs. In other areas, the risk of gonococcal ophthalmia is higher depending on the prevalence of gonococcal infection among the pregnant women in the population. Even in areas with high prevalence rates, however, ophthalmia due to N. gonorrhoeae accounts for less than 5% of the cases of neonatal conjunctivitis. The other organisms that can produce conjunctivitis in the newborn period and the relative overall frequency of resultant

Table 12-2

Gonococcal Infections

infections, the usual time of presentation since birth, and relative severity are shown in Table 12-2. In general, conjunctivitis seen within 24 hours of birth usually is assumed to be a reaction to silver nitrate, if this has been used for prophylaxis. As described previously, however, in the instance of prolonged rupture of membranes and premature delivery, symptomatic gonococcal ophthalmia may be observed during this period as well. Also, some infants have a less acute course, with appearance of symptoms after 5 days of age. Therefore, reliance on the timing between 2 and 5 days after delivery of the onset of symptoms may be an unreliable clinically distinguishing feature. The possibility of gonococcal infection should be considered in every neonate with conjunctivitis present after 24 hours of birth, and the appropriate diagnostic testing to detect the organism should be done. In some instances, neonates with gonococcal ophthalmia neonatorum may be infected by additional pathogens, in particular, C. trachomatis. The differential diagnosis of cutaneous or systemic gonococcal infection of the neonate includes the bacterial or fungal pathogens that are frequently involved in these types of infections during this time period and are discussed in more detail in Chapters 6 and 10.

TREATMENT (THERAPYMANAGEMENT) The principles of management of STDs in any age group apply when a neonate is determined to have a suspected or confirmed gonococcal infection. As stated previously, investigation and treatment of the mother and her sexual contacts for N. gonorrhoeae are essential, as is the investigation of the infant, the mother, and her sexual contacts for other sexually transmitted infections. STDs are like wolvesthey travel in packs. As discussed previously, because a significant proportion of gonococci worldwide is resistant to penicillin, either by decreased penicillin binding or by penicillinase production, this antibiotic is no longer recommended for therapy unless the infecting isolate has been tested and found to be sensitive. Most recommendations and guidelines for the treatment of gonococcal ophthalmia neonatorum identify

Differential Diagnosis of Ophthalmia Neonatorum

Etiologic ConditiodAgent Chemical conjunctivitis Neisseria gonorrhoeae Neisseria meningitidis Neisseria cinerea Herpes simplex virus Chlamydia trachomatis Other bacteria Group A and B streptococci Staphylococcus aureus Haemophilus species Klebsiella pneumoniae Escherichia coli Pseudomonas aeruginosa Enterococcus Pneumococcus

Percentage of Cases Dependent on use 1 mo) doses Daily dose x 10-14 days

IM IM

Single dose Single dose

IM

Single dose

01

None or inadequated

Absent

Procaine Aqueous

IM IM or IV

Of

Procaine Of

Adequate (during pregnancy)

Absent

Adequate (before pregnancy)

Absent

Benzathine Benzathine (CDC) or Follow-up only (AAP) Follow-up only Of

Benzathine (only if follow-up cannot be ensured) ~

~~

~

aCloseand frequent follow-up, including serologic test for syphilis, is essential. bTest mother for HIV antibody. 'Inadequate maternal treatment: not documented, within 4 weeks of delivery, or with erythromycin or nonpenicillindrug; or serologic antibody titers do not fall appropriately (see text). dSome experts would not treat if follow-up is ensured. HIV, human immunodeficiencyvirus; IM, intramuscular; IW, intravenous.

such an infant without clinical abnormalities should undergo a second RPR test within 3 to 4 weeks. If the risk of exposure to the infant is considerable (e.g., if the child was born to a known syphilitic with no documented treatment history), a reasonable case can be made for immediate penicillin therapy. If the newborn has clinical manifestations that are thought to be consistent with the diagnosis of congenital syphilis, a negative RPR test result makes this clinical diagnosis highly questionable; reevaluation is indicated. Finally, the appearance of secondary or tertiary syphilis in the mother within the year after delivery should prompt a thorough reevaluation of the infant for the possibility of congenital syphilis.

Penicillin Penicillin remains the drug of choice for treatment of congenital syphilis (Table 18-13).88,98,'36,'",359,37',372,375 Infants who are 4 weeks of age or younger and who have proven or highly probable disease are likely to have CNS invasion by T pallidum.88 These include (1) infants with physical findings compatible with congenital syphilis; (2) infants who lack such physical findings but have abnormalities on CSF examination, on bone radiographs, or on laboratory evaluation; (3) infants who have a serum quantitative nontreponemal serologic titer that is four times greater than the mother's titer; and (4) infants who have a positive result on darkfield or fluorescent antibody test of body fluids. The e ~ a l u a t i o n ' ~ of " ~ ~these infants should begin with CSF analysis to detect evidence of possible neurosyphilis and to establish a baseline for follow-up evaluation. A complete blood cell count and platelet count also should be

performed, because anemia and thrombocytopenia may not be readily detected by physical examination only. Other tests such as chest radiography, cranial ultrasound study, ophthatmologic examination, and auditory-evoked brainstem response evaluation should be performed as clinically indicated. Infants with proven or highly probable disease should receive treatment for 10 days with either (1) aqueous crystalline penicillin G, 50,000 units/kg intravenously every 12 hours for the first week of life and every 8 hours beyond 1 week of age or (2) aqueous procaine penicillin G , 50,000 units/kg administered intramuscularly once daily for 10 days.'56s372 If more than 1 day of therapy is missed, the entire course of penicillin be r e ~ t a r t e d . Although '~~ the CSF levels of penicillin are higher in infants who receive intravenous aqueous penicillin G than in those given intramuscular procaine penicillin, the significance of this finding remains unclear, because both therapies have resulted in clinical and laboratory cure.376Similarly, infants and children who are identified as having congenital syphilis after the neonatal period (beyond 4 weeks of age) should receive aqueous penicillin G, 50,000 units/kg intravenously every 6 hours for 10 days.'56 For older children, the amount of penicillin should not exceed that recommended for adults (see Table 18-11). The efficacy of a 10-day course of penicillin for eradication of spirochetes from neonatal CSF has been For infants who have normal findings on physical examination and a serum quantitative nontreponemal serologic titer that is the same as or less than four times the maternal titer, the evaluation is dependent on the maternal treatment history, maternal stage of infection, and planned

Chapter 18 infant treatment (see Table 18-13).156If maternal treatment for syphilis was not given, was undocumented, was a nonpenicillin regimen, or was administered 4 weeks or less before delivery, or if the adequacy of maternal treatment for early syphilis cannot be evaluated because the nontreponemal serologic titer has not decreased fourfold, or relapse or reinfection is suspected because of a fourfold increase in the maternal nontreponemal serologictiter, then the infant should receive the following treatment: (1) aqueous penicillin G or procaine penicillin G for 10 days or (2) benzathine penicillin G, 50,000 units/kg (single dose intramuscularly) with close serologic follow-up s t ~ d i e s . ' ~If~the , ~ ~infant ~ receives a 10-day course of parented penicillin, then a complete evaluation consisting of a lumbar puncture, complete blood cell count and platelet count, and bone radiographs may not be necessary, because the infant will receive adequate therapy for proven or highly probable disease (see earlier), including possible neurosyphilis.'I6 Nevertheless, abnormalities found on these tests may further support a diagnosis of congenital syphilis, and performance of a lumbar puncture may document CSF abnormalities that would prompt close follow-up. On the other hand, if the infant is to receive a single intramuscular injection of benzathine penicillin G, then a complete evaluation (lumbar puncture, complete blood cell count with platelet count, and bone radiographs) is m a n d a t ~ r y . ' ~Using ~ . ~ ~RIT ~ as the diagnostic standard, Michelow and colleagues326have shown that most infants with 7: pallidum infection of the CNS can be identified by this combination of tests. If any test has an abnormal result, or if any part of the evaluation is not done, then a 10-day course of penicillin is recommended. The decision by both the CDC116 and the American Academy of Pediatrics372to allow the expanded use of a single intramuscular dose of benzathine penicillin G is based on the finding that, in contrast with the infant with clinical manifestations of congenital syphilis, the prevalence of CNS invasion by 1:pallidum as documented by RIT is very low in infants who lack physical, radiographic, or laboratory evidence of congenital infection.88 Single-dose benzathine penicillin therapy has been widely used in the past, and its use allows for earlier hospital discharge of the infant with subsequent improved maternal-infant interaction and decrease in hospitalization This regimen has been supported by two small clinical s t ~ d i e s . ~ ~ ' , ~ ~ ~ Nonetheless, failure of a single injection of benzathine penicillin G administered to three infants has been r e p ~ r t e d . ~ ' ~These . ~ ~ ' infants were born to mothers with early syphilis and were not fully evaluated for evidence of congenital syphilis at delivery. These treatment failures have been attributed to the inability of benzathine penicillin G to adequately penetrate and achieve treponemicidal concentration in certain sites, such as the aqueous humor and CNS.382p383 Michelow and colleagues325have documented the presence of spirochetes in the CSF of three infants without clinical manifestations who received a single injection of benzathine penicillin; at follow-up evaluation, findings on CSF examination were normal and the results of RIT for spirochetes were negative. These investigators recommend that if the evaluation for congenital syphilis is not complete or not performed, the infant should receive empirical therapy that will eradicate ?: pallidum from the CNS.

Syphilis

571

For infants who appear healthy on physical examination and have a serum quantitative nontreponemal serologic titer that is the same as or less than four times the maternal titer, evaluation is unnecessary if during pregnancy the maternal treatment was appropriate for the stage of infection, and (1) it was given more than 4 weeks before delivery, (2) it was for early syphilis and the nontreponemal serologic titers decreased fourfold after appropriate therapy, or (3) it was for late latent syphilis, the nontreponemal titers remained stable and low, and evidence of maternal reinfection or relapse is 1a~king.l~~ The CDC recommends that in these situations, a single intramuscular dose of benzathine penicillin G 50,oOO units/kg be administered to the infant.'56 Some experts, however, would not treat these infants but would provide close serologic follow-up For infants who have normal findings on physical examination and a serum quantitative nontreponemal serologic titer that is the same as or less than four times the maternal titer, evaluation and treatment are unnecessary if the maternal treatment was before pregnancy and the nontreponemal serologic titers remained low and stable before and during the pregnancy and at de1i~ery.I~~ If compliance with follow-up is uncertain, a single intramuscular dose of benzathine penicillin G, 50,000 units/kg, may be given. Infants born to mothers co-infected with syphilis and HIV do not require different evaluation or therapy for syphilis from that recommended for all infants.156These infants born to co-infected women may be at higher risk of infection with ?:pallidurng8~'"; however, it is not known whether co-infected infants respond to treatment for congenital syphilis differently from infants uninfected with HIV. Close serologic follow-up evaluation of these infants is mandatory. Alternative Drugs

Very few alternative regimens are available for infants with congenital syphilis. Clinical studies of the treatment of congenital syphilis with ampicillin or ceftriaxone, or other new cephalosporins that readily penetrate the blood-brain barrier, have not been reported, although theoretically these drugs should be effective.384 Infants with congenital syphilis should receive procaine penicillin or benzathine penicillin G for treatment (see Table 18-13). The lack of adequate CNS penetration by erythromycin or oral tetracycline makes these drugs inappropriate for the treatment of congenital syphilis. In addition, tetracycline and doxycycline are not advised for children younger than 8 years of age because they may stain the teeth and possibly cause bone toxicity.

Jarisch-Herxheimer Reaction The Jarisch-Herxheimer reaction, a common occurrence in the treatment of acquired early syphilis in consists of chills, fever, generalized malaise, hypotension, tachycardia, tachypnea, accentuation of the cutaneous lesions, leukocytosis, and, exceedingly rarely, death. It begins within 2 hours of treatment, peaks at approximately 8 hours, and disappears in 24 to 36 hours. The cause of the reaction is not known,386 although release of T. pallidurn membrane lipoproteins that stimulate pro-inflammatory cytokines likely explains this clinical phen~rnenon.~'~

572

Section I1

Table 18-14


Follow-up after Treatment or Prophylaxis for Congenital Syphilis

Patient Category

Follow-up Procedures 1. RPR testing every 2-3 m o until negative or decreased fourfold. If RPR titer is stable or increasing after 6-12 mo after treatment, reevaluate and re-treat. 2 . Perform treponemal antibody test after age of 15 mo. 3. If initial CSF was abnormal or infant showed signs of CNS disease, repeat CSF evaluation every 6 mo until normal. With abnormal CSF not due to intercurrent illness on re-testing, re-treat.

Infants diagnosed as having congenital syphilis

4. Careful developmental evaluation, vision testing, and hearing testing

are indicated.

Infants who received treatment in utero or at birth

because of maternal syphilis Women who received treatment for syphilis during

1. RPR testing at birth and then every 3 mo until result is negative. 2. Treponemal antibody test after age of 15 mo. 1. RPR testing as often as monthly until delivery, then every 6 m o until

pregnancy 2.

negative result obtained or titer decreased fourfold. Re-treatment any time there is a fourfold rise in RPR titer.

~~

CNS, central nervous system; CSF, cerebrospinal fluid; RPR, rapid plasma reagin.

Modified from Rathbun KC. Congenital syphilis: a proposal for improved surveillance, diagnosis and treatment. Sex Transm Dis 10:102, 1983, with permission; and MMWR Morb Mortal Wkly Rep 51(RR-6):1, 2002.

Approximately 40% of pregnant women who receive treatment for syphilis demonstrate a Jarisch-Herxheimer In addition, these women may experience the onset of uterine contractions and preterm labor, with decreased fetal activity and fetal heart rate changes, including late decelerations, which last up to 24 to 48 hours and may lead to fetal death. These manifestations of the JarischHerxheimer reaction in pregnancy possibly are mediated by the prostaglandin pathway. No prophylactic measure or treatment currently is available. Abnormal ultrasonographic findings in the fetus, as well as fetal monitoring for 24 hours, may identify pregnancies at highest risk. In congenital syphilis, the incidence of the JarischHerxheimer reaction is low, although it may be more common when treatment occurs later in i n f a n e ; when it does occur, it varies in severity, ranging from fever to cardiovascular collapse and seizures.88 In Platou’s series,234 almost half of the infants sustained a febrile reaction during the first 36 hours after initiation of penicillin therapy. No relationship was observed between the severity or the outcome of the infection and this temperature elevation.

Post-treatment Follow-up Recommendations for follow-up evaluation are summarized in Table 18-14. It is advisable to monitor the outcome of therapy by repeated W R testing. Patients responding to therapy should have falling titers (fourfold or better decrease), and as many as 70% to 93% should become seronegative withii 1 Re-treatment should be considered if signs persist or recur, if any increase in the titer of a nontreponemal test is noted, if an initially high-titer nontreponemal test fails to decrease fourfold in the first year, or if the repeated lumbar puncture plus CSF analysis at 6 months shows persistent abnormalities, including a positive VDRL test result.’56 The recommendation of a second treponemal test beyond 15 months as a way of retrospectively diagnosing congenital syphilis308is not merely for epidemiologic use-an established diagnosis can help in medical and developmental follow-up evaluation of the child.

Although treatment can cure the infection, the prognosis in treated congenital syphilis depends on the degree of damage before the initiation of therapy. In general, the earlier treatment is initiated, the more likely it is that a satisfactory response can be obtained.’” If marked damage to the fetus has occurred, treatment in utero may not prevent abortion, stillbirth, or neonatal death, and even if treatment keeps the newborn infant alive, stigmata can remain. If the treatment is provided prenatally or within the first 3 months of life, and such stigmata have not yet become apparent, they generally can be prevented.253Interstitial keratitis is an exception; this complication does not seem to be responsive to specific antibiotic therapy. On occasion, dramatic relief has been afforded by the use of corticosteroids and mydriatics, although relapses have occurred with cessation of corticosteroid therapy. The osseous lesions seem to heal independently of specific therapy. Treatment of congenital syphilis in the late stage does not reverse the stigmata.’94 A number of reports describe the persistence of treponemes after therapy for syphilis in both humans and animal^.^^'.^^^ T. pallidurn has been shown to survive in the lymph nodes, eye, and CSF after doses of penicillin that are presumed adequate. S i l v e r s t e i r ~ ’ ~observed ~ ’ ~ ~ ~ that monkeys inoculated in utero with T. pallidurn had a significant number of viable treponemes in the aqueous humor of their clinically normal eyes 6 months after birth. Hardy and associates396described a newborn with congenital syphilis treated with penicillin in whom the aqueous humor contained virulent treponemes, and a number of cases of recrudescence of neurosyphilis in adults have been described after treatment with recommended doses of p e n i ~ i l l i n . ~ ~ Survival ’ - ~ ~ ~ of the organism in the eye or CSF is ascribed to inadequate penetration of penicillin, but this explanation does not account for persistence of treponemes in lymph nodes after treatment.

Chapter 18

PREVENTION

.

Congenital syphilis is a preventable disease. To minimize the likelihood of its occurrence, every woman who becomes pregnant should undergo at least one serologic test for For communities syphilis during the first trimester.”2*’44~307~400 and populations in which the prevalence of syphilis is high or for women in high-risk groups (see Table 18-3), repeated testing at the beginning of the third trimester (at 28 weeks of g e ~ t a t i o n ) ’ ~ ~ ” at ~ ~delivery a n d is re~ommended.’”.~”Sanchez and associate^'^^ have documented the importance of maternal serologic screening for syphilis at delivery in a high-risk inner-city population. During the years 1987 to 1990, approximately 3% of 58,387 pregnant women had reactive serologic tests for syphilis; in 5% of these women, an antepartum RPR test was nonreactive, but an RPR test at delivery was reactive. Screening tests at delivery should be performed in mothers and not in infant^."^"^^'^^^ An infant’s serologic titer often is one to two dilutions less than that of the mother’s; thus, an infant may have a nonreactive umbilical cord VDRL test but have a mother with a reactive serologic test for syphilis at delivery. From 1987 to 1990, Sanchez and c o - ~ o r k e r s compared ’~~ results of maternal serologic studies at delivery with those obtained from VDRL testing of umbilical cord blood. These investigators documented 534 cases with reactive maternal serologic tests at delivery but negative umbilical cord blood VDRL test results. Eightyseven, or 16%, of these infants were born to mothers with untreated syphilis at delivery and were therefore at risk for infection if treatment was not given. It is clear that these infants would not have been identified if only the umbilical cord blood had been screened. No infant should be discharged from the nursery before results of maternal serologic screening have been documented. With the practice of early discharge at 48 hours or less, it becomes the responsibility of the health care provider to arrange for adequate follow-up in infants who are discharged before the result of the maternal serologic test is known. In most clinical facilities, prenatal testing is required by law or as a matter of institutional procedure. Some states also mandate serologic screening at delivery for all women. The alternative of targeted testing is impractical to implement and would save little money, even as rates of syphilis decline in women and infant^.^" Printed requirements do not eliminate human error, and prenatal testing requirements are not applicable to a woman who does not enter the medical care system until the moment before delivery. In an infant born to a woman who is incubating syphilis at delivery and whose serologic tests are nonreactive, congenital syphilis is, by current methods, impossible to p r e ~ e n t . ’ ~ ~In’ ~areas ~ ’ with a high incidence of congenital syphilis, a postpartum serologic test for syphilis at 6 weeks can be helpful in detecting infants in this high-risk group. Reporting of cases to the local health department will allow rapid-contact investigation of named sexual partners and appropriate follow-up for infected persons. Patients who have had sexual contact with an untreated person should have clinical evaluation, serologic testing, and treatment. The time periods before treatment used for identifylng atrisk sexual partners are (1) 3 months plus duration of symptoms for primary syphilis; (2) 6 months plus duration

Syphilis

573

of symptoms for secondary syphilis; and (3) 1 year for early latent ~yphilis.”~ Persons who were exposed within 90 days preceding the diagnosis of primary, secondary, or early latent syphilis in a sexual partner might be infected even if seronegative and should receive presumptive treatment. As partner notification has become more challenging because of anonymous sex and the inability to locate sexual partners, attention has focused on identifylng core environments and populations in which syphilis transmission is occurring.m2 Such knowledge has resulted in provision of prophylactic syphilis treatment to groups of people in highrisk populations. Recently, the CDC has designed a strategy to assist public health providers at both state and local levels to design interventions for targeted at-risk populations that are locally identified.403 Called the rapid ethnographic community assessment process (RECAP), the assessment is a package of activities and tools designed to use ethnographic methods for improving community involvement, as well as developing interventions that fit a population’s social and behavioral context. It has been used in North Carolina with suc~ess.4~~ Ultimately, prevention of congenital syphilis will be accomplished only if elimination of syphilis becomes a reality. REFERENCES 1. Ballantyne JW. Manual of Antenatal Pathology and Hygiene. Edinburgh, William Green & Son Publishers, 1902. 2. Goodman H. Notable Contributions to the Knowledge of Syphilis. New York, Froben Press, 1943. 3. Dennis CC. A History of Syphilis. Springfield, Ill, Charles C Thomas, 1962. 4. Truffi M. Hieronymous Fracastor’s Syphilis: A Translation in Prose, 2nd ed. St Louis, Urologic and Cutaneous Press, 1931.

5. Pusey WA. The History and Epidemiology of Syphilis. Springfield, Ill, Charles C Thomas, 1933. 6. Brown WJ, Donohue JF,Axnick NW, et al. Syphilis and Other Venereal Diseases. Cambridge, Mass, Harvard University Press, 1970. 7. Hutchinson J. On the different forms of the inflammation of the eye consequent on inherited syphilis.Ophthalmol Hosp Rev 1:191,1858. 8. Rosebury T. Microbes and Morals: The Strange Story of Venereal Disease. New York, Viking Press, 1971. 9. Hovind-Hougen K. Determination by means of electron microscopy of morphological criteria of value for classification of some spirochetes in particular treponemes. Acta Pathol Microbiol Scand B Suppl225,1976. 10. Canale-Parola E. Physiology and evolution of spirochetes. Bacteriol Rev 41:181, 1977. Treponemal Infection. New York, Marcel Dekker, 1982, p 3. 11. Fohn MJ, Wisnall S, Baker-Zander SA, et al. Specificity of antibodies from patients with pinta for antigens of Treponerna pallidurn subspeciespallidurn. J Infect Dis 157:32, 1988. 2. Krieg NR, Holt JG (eds). Bergey’s Manual of Systematic Bacteriology, vol 1. Baltimore/London, Williams & Willcins, 1984, p 50. 3. Centurion-bra A, Castro C, CastdIo R, et al. The flanking region sequences of the 15-kD lipoprotein gene differentiate pathogenic treponemes. J Infect Dis 1721036,1997. 4. Fraser CM, Norris SJ,Weinstock GM, et al. Complete genome sequence of Treponemapallidurn, the syphilis spirochete. Science 281:375,1998. 5. Roman GC, Roman LN. Occurrence of congenital, cardiovascular, visceral, neurologic, and neuro-ophthalmologic complications in late yaws: a theme for future research. Rev Infect Dis 8:760, 1986. 16. Turner TB, Hollander DH. Biology of the treponematoses. WHO Monogr Ser 351,1957. 17. Wilcox RR, Guthe T. Treponerna pallidurn: a bibliographical review of the morphology, culture and survival of T. pallidurn and associated organisms. Bull World Health Organ 35:1, 1966. 18. Turner TB. Syphilis and the treponematoses. In Mudd S (ed). Infectious Agents and Host Reactions. Philadelphia, WB Saunders, 1970, p 346.

574

Section I1


19. Jenkin HM, Banook PC. In vitro cultivation of treponemal infections.

20.

21. 22.

23.

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Neurol51:957,1998. 24. Fitzgerald TJ. Experimental congenital syphilis in rabbits. Can J Microbiol31:757, 1985. 25. Wicher K, Baughn RE, Wicher V, et al. Experimental congenital syphilis: guinea pig model. Infect Immun 60:271, 1992. 26. Kajdacsy-Balla A, Howeedy A, Bagasra 0. Experimental model of congenital syphilis. Infect h m u n 61:3559,1993. 27. Wicher K, Baughn RE, Abbruscato F, Wicher V. Vertical transmission

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Chapter 18 195. Park EA, Jackson DA. The irregular extensions of the end of the shaft

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351. Shann S, Wilson J. Treatment of neurosyphilis with ceftriaxone. Sex Transm Infect 79:415,2003. 352. Hook EW 111, Roddy RE, Handsfield HH. Ceftriaxone therapy for incubating and early syphilis. J Infect Dis 158881, 1988. 353. Moorthy TT,Lee CT,Lim KB, et al. Ceftriaxone for treatment of primary syphilis in men: a preliminary study. Sex Transm Dis 14116, 1987. 354. Schofer H, Vogt HJ, Milbradt R. Ceftriaxone for the treatment of primary and secondary syphilis. Chemotherapy 35:140, 1989. 355. Vignale R, Burno J, Gibert P. Ceftriaxone in the treatment of primary and secondary syphilis: a comparative study with benzathine penicillin. In Hall TC (ed). Prediction of Response to Cancer Therapy. Proceedings of the 15th International Chemotherapy Congress, Istanbul, Turkey, July 19-24,1987. New York, Alan R Liss, 1988, p 75. 356. Hook EW 111, Baker-Zander SA, Moskovitz BL, et al. Ceftriaxone therapy for asymptomatic neurosyphilis: case report and Western blot analysis of serum and cerebrospinal fluid IgG response to therapy. Sex Transm Dis 13:185, 1986. 357. Dowell ME, Ross PG, Musher DM, et al. Response of latent syphilis or neurosyphilis to ceftriaxone therapy in persons infected with human immunodeficiency virus. Am J Med 93:481, 1992. 358. Marra C, Slatter V, Tartaglione T, et al. Comparison of ceftriaxone and aqueous crystalline penicillin G for central nervous system syphilis in an experimental model. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, Georgia, October 21-24, 1990, p 101 (abstract 87). 359. Philipson A, Sabath LD, Charles D. Transplacental passage of erythromycin and clindamycin. N Engl J Med 288:1219,1973. 360. South MA, Short DH, Knox JM. Failures of erythromycin estolate therapy in in utero syphilis. JAMA 199:70, 1964. 361. Montgomery CH, Knox JM. Antibiotics other than penicillin in the treatment of syphilis. N Engl J Med 261:277, 1959. 362. Schultz JC, Adamson JS Jr, Workman WW, et al. Fatal liver disease after intravenous administration of tetracycline in high doses. N Engl J Med 269:999,1963. 363. Tetracycline in pregnancy. Editorial. BMJ 1:743, 1965. 364. Demers P, Fraser RB, Goldbloom J, et al. Effects of tetracycline on skeletal growth dentition: a report to the Nutrition Committee of the Canadian Pediatric Society. Can Med Assoc J 99849,1968. 365. Verdon MS, Handsfield HH, Johnson RB. Pilot study of azithromycin for the treatment of primary and secondary syphilis. Clin Infect Dis 19:486, 1994. 366. Mashkilleyson AL, Gomberg MA, Mashkilleyson N. Treatment of syphilis with azithromycin. Int J STD AIDS 213, 1996. 367. Centers for Disease Control and Prevention. Azithromycin treatment failures in syphilis infections-San Francisco, California, 2002-2003. MMWR Morb Mortal Wkly Rep 53: 197,2004. 368. Lukehart SA, Godornes C, Molini BJ, et al. Macrolide resistance in Treponema pallidurn in the United States and Ireland. N Engl J Med 351:122,2004. 369. Notice to readers: shortage of intravenous penicillin G U n i t e d States. MMWR Morb Mortal Wkly Rep 48:974, 1999. 370. Alternatives to intravenous penicillin G for specific infections. Available at http://www.cdc.gov/nchstp/dstd/penicilllinG.htm 371. Sanchez PJ. Syphilis. In Burg FD, Ingelfinger JR, Wald ER (eds). Gellis and Kagan’s Current Pediatric Therapy 14. Philadelphia, WB Saunders, 1993, p 590. 372. American Academy of Pediatrics. Syphilis. In Report of the Committee o n Infectious Diseases (Red Book), 26th ed. Elk Grove Village, Ill, American Academy of Pediatrics, 2003, p 595. 373. Beeram MR, Chopde N, Dawood Y, et al. Lumbar puncture in the evaluation of possible asymptomatic congenital syphilis in neonates. J Pediatr 128:125, 1996. 374. Moyer VA, Schneider V, Yetman R, et al. Contribution of long-bone radiographs to the management of congenital syphilis in the newborn infant. Arch Pediatr Adolesc Med 152:353, 1998. 375. Centers for Disease Control and Prevention. 1993 Sexually transmitted diseases treatment guidelines. MMWR Morb Mortal Wkly Rep 42(NO. RR-14):40, 1993. 376. Azimi PH, Janner D, Berne P, et al. Concentrations of procaine and aqueous penicillin in the cerebrospinal fluid of infants treated for congenital syphilis. J Pediatr 124649, 1994. 377. Bateman DA, Phibbs CS, Joyce T, Heagarty MC. The hospital cost of congenital syphilis. J Pediatr 130:752, 1997. 378. Paryani SG,Vaughn A], Crosby M, Lawrence S. Treatment of asymptomatic congenital syphilis: benzathine versus procaine penicillin G therapy. J Pediatr 125:471, 1994.

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379. Radcliffe M, Meyer M, Roditi D, et al. Single-dose benzathine penicillin in infants at risk of congenital syphilis: results of a randomized study. S Afr Med J 87:62,1997. 380. Beck-Sague C, Alexander ER. Failure of benzathine penicillin G treatment in early congenital syphilis. Pediatr Infect Dis J 61061, 1987. 381. Woolf A, Wilfert C, Kelsey D, et al. Childhood syphilis in North Carolina. N C Med J 41:443,1980. 382. McCracken GH, Kaplan JM. Penicillin treatment for congenital syphilis: a critical reappraisal. JAMA 228:855, 1974. 383. Speer ME, Taber LH, Clark DB, et al. Cerebrospinal fluid levels of benzathine penicillin G in the neonate. J Pediatr 91:966, 1977. 384. Norris SJ, Edmondson DG. In vitro culture system to determine MICs and MBCs of antimicrobial agents against Treponema pallidurn subsp. pallidurn (Nichols strain). Antimicrob Agents Chemotherapy 32:68, 1988. 385. Gelfano JA, Elin RJ, Berry F W Jr, et al. Endotoxemia associated with the Jarisch-Herxheimer reaction. N Engl J Med 295:211, 1976. 386. Young EJ, Weingarten NM, Baughn RE, et al. Studies on the pathogenesis of the Jarisch-Herxheimer reaction: development of animal model and evidence against a role for classical endotoxin. J Infect Dis 146606,1982. 387. Radolf JD, Norgard MV, Brandt ME, et al. Lipoproteins of Borrelia burgdorferi and Treponema pallidurn activate cachectinltumor necrosis factor synthesis: analysis using a CAT reporter construct. J Immunol147:1968,1991. 388. Klein VR, Cox SM, Mitchell MD, Wendel GD Jr. The JarischHerxheimer reaction complicating syphilotherapy in pregnancy. Obstet Gynecol75:375-380, 1990. 389. Myles TD, Elan G, Parik-Hwang E, Nguyen T. The Jarisch-Herxheimer reaction and fetal monitoring changes in pregnant women treated for syphilis. Obstet Gynecol92:859, 1998. 390. Tan KL. The re-emergence of early congenital syphilis. Acta Paediatr Scand 62661,1973. 391. Goldman JN, Girard KF. Intraocular treponemes in treated congenital syphilis. Arch Ophthalmol78:47, 1967.

392. Dunlop EMC, King AJ, Wickinson AE. Study of late ocular syphilis: demonstration of treponemes in aqueous humour and cerebrospinal fluid. 3. General and serological findings. Trans Ophthalmol SOCUK 88275,1969. 393. Dunlop EMC. Persistence of treponemes after treatment. BMJ 2:577, 1972. 394. Ryan SJ,Hardy PH, Hardy JM, et al. Persistence of virulent Treponema pallidurn despite penicillin therapy in congenital syphilis. Am J Ophthalmol73:259, 1972. 395. Report of the World Health Organization Expert Committee on Venereal Infections and Treponematoses. World Health Organ Tech Rep Ser 674:27,1982. 396. Hardy JB, Hardy PH, Oppenheimer EH. Failure of penicillin in a newborn with congenital syphilis. JAMA 212:1345,1970. 397. Bayne LL, Schmidley JW, Goodwin DS. Acute syphilitic meningitis: its occurrence after clinical and serologic cure of secondary syphilis with penicillin G. Arch Neurol43:137, 1986. 398. Jorgensen J, Tikjob G, Weisman K. Neurosyphilis after treatment of latent syphilis with benzathine penicillin. Genitourin Med 62:129, 1986. 399. Markovitz DM, Beutner KR, Maggio RR, et al. Failure of recommended treatment for secondary syphilis. JAMA 256:1767, 1986. 400. Hurtig AK, Nicoll A, Carne C, et al. Syphilis in pregnant women and their children in the United Kingdom: results from national clinician reporting surveys, 1994-97. BMJ 317:1617,1998. 401. Wendel GD Jr, Sheffield IS, Hollier LM et al. Treatment of syphilis in pregnancy and prevention of congenital syphilis. Clin Infect Dis 35(suppl2):s200,2002. 402. Williams LA, Klausner JD, Whittington AB, et al. Elimination and reintroduction of primary and secondary syphilis.Am J Public Health 8 9 1093, 1999. 403. Centers for Disease Control and Prevention. Outbreak of primary and secondary syphilis-Guilford County, North Carolina, 1996-1997. MMWR Morb Mortal Wkly Rep 47:1070,1998.

Chapter I9 TUBERCULOSIS Jeffrey R. Starke

Terminology

581

Mycobacteriology 582 Epidemiology

582

Tuberculosis in Pregnancy 583 Pathogenesis Effect of Pregnancy on Tuberculosis Effect of Tuberculosis on Pregnancy Screening for Tuberculosis in Pregnancy Congenital Tuberculosis 586 Tuberculosis in the Mother In Utero Routes of Transmission Criteria for Diagnosis of Congenital Tuberculosis Clinical Features and Diagnosis of Congenital "bberculosis Treatment of Tubercuiosis 589 General Principles Pregnant Women Neonates and lnfants Following the Infant on Therapy Prognosis Vaccination against Tuberculosi-ach Calmette-GuMn 593 History and Development of B a d e CaLnette-GukrinVaccines Vaccine Preparation and Administration Adverse Reactions to Bacille Calmette-GukrinVaccination Effect of Bacille Calmette-GukrinVaccination on Tuberculin Skin Test Results Effectiveness of the B a d e Calmette-GukrinVaccines Management of a Neonate Born to a Mother with a Positive Tuberculin Skin Test Result 595 Management of Neonates after Postnatal Exposure 595 Conclusion 5%

Tuberculosis is a classic familial disease.' The household is the main setting throughout the world for the person-toperson spread of Mycobacterium tuberculosis.With the recent resurgence of tuberculosis in many industrialized nations, issues concerning pregnant women and their children have been reexamined by practitioners of tuberculosis control. Before 1985, tuberculosis in the pregnant woman and newborn had become an infrequent event in the United States.Although specific statistics concerning tuberculosis in pregnancy are not reported, the increase in total tuberculosis cases in the late 1980s and 1990s and the shift in numbers to young adults and children suggested that tuberculosis in pregnancy may become a more prevalent pr~blem.~" This problem disproportionately affects minority urban populations because they have very high tuberculosis case rates, a greater relative shift in cases to adults of childbearing age, and, in general, less access to prenatal care and screening for disease and infection caused by M . tuberculosis.

The influence of pregnancy on the occurrence and prognosis of tuberculosis has been discussed and debated for centuries. At various times, pregnancy has been thought to improve, worsen, or have no effect on the prognosis of tuberculosis. This controversy has lost much of its importance since the advent of effective antituberculosis chemotherapy. The greatest areas of debate at present concern ( 1 ) the use of chemotherapy to prevent the progression of M. tuberculosis infection to tuberculosis during pregnancy and the postpartum period and (2) the treatment of exposed infants to prevent the development of serious tuberculo~is.~

TERMINOLOGY A practical approach to tuberculosis terminology is to follow the natural history of the disease, which can be divided into three stages: exposure, infection, and di~ease.~ Exposure implies that the patient has had recent (less than 3 months) and significant contact with an adult with suspected or confirmed contagious pulmonary tuberculosis. For example, an infant born into a family in which an adult has active tuberculosis would be in the exposure stage. In this stage, the child's tuberculin skin test is negative, the chest radiograph result is normal, and the child is free of signs and symptoms of tuberculosis. Unfortunately, it is impossible to know whether a young child in the exposure stage is truly infected with M . tuberculosis, because the development of delayedtype hypersensitivity to a tuberculin skin test for tuberculin may take up to 3 months after the organisms have been inhaled. M. tuberculosis infection is present if an individual has a positive tuberculin skin test result but lacks signs or symptoms of tuberculosis. In this stage, findings on the chest radiograph either are normal or reveal only granuloma or calcification in the lung parenchyma or regional lymph nodes. The purpose of treating M. tuberculosis infection is to prevent future disease. In newborns, the progression from infection to disease can occur very rapidly, within several weeks to months. Tuberculosis disease occurs if signs or symptoms or radiographic manifestations caused by M . tuberculosis become apparent. Because 25% to 35% of children with tuberculosis have extrapulmonary involvement, a thorough physical examination, in addition to a high-quality chest radiograph, is essential to rule out di~ease.~ Genitourinary tuberculosis in women often causes only subtle symptoms until it is far advanced. Ten to 20% of immunocompetent adults and children with the disease initially have a negative tuberculin skin test result, usually because of immunosuppression by tuberculosis itself. The rate of negative skin test results with disease due to M . tuberculosis, however, is much higher in newborns and small infants, especially if they have life-

582

Section 11 Bacterial Infections

threatening forms of tuberculosis such as disseminated disease or meningitis.

MYCOBACTERIOLOGY Mycobacteria are nonmotile, non-spore-forming, pleomorphic, weakly gram-positive rods that are 1 to 5 pm long, usually slender, and slightly curved. M. tuberculosis may appear beaded or clumped. The cell wall constituents of mycobacteria determine their most striking biologic properties. The cell wall is composed of 20 to 60% lipids bound to proteins and carbohydrates. These and other properties make mycobacteria more resistant than most other bacteria to light, alkali, acid, and the bactericidal activity of antibodies. Growth of M. tuberculosis is slow, with a generation time of 12 to 24 hours on solid media. Acid-fastness, the capacity to form stable mycolate complexes with certain aryl methane dyes that are not removed even by rinsing with 95% ethanol plus hydrochloric acid, is the hallmark of mycobacteria. The cells appear red when stained with carbol fuchsin (Ziehl-Neelsen or Kinyoun stains) or purple with crystal violet, or they exhibit yellowgreen fluorescence under ultraviolet light when stained with auramine and rhodamine (Truant stain). Truant stain is considered the most sensitive stain, especially when small numbers of organisms are present. Approximately 10,000 cells per mm3 must be present in a sample for them to be seen in an acid-fast stained smear. Identification of mycobacteria depends on their staining properties and their biochemical and metabolic characteristics. Mycobacteria are obligate aerobes with simple growth requirements.M. tuberculosis can grow in classic media, whose essential ingredients are egg yolk and glycerin (LowensteinJensen or Dorset media), or in simple synthetic media (Middlebrook, Tween-albumin). Isolation on solid media takes 2 to 6 weeks, followed by another 2 to 4 weeks for drugsusceptibility testing. More rapid isolation (7 to 2 1 days) can be achieved using a synthetic liquid medium in an automated radiometric system, the most common one being BACTEC (Becton, Dickinson, and Co. [BD], Sparks, Md). A specimen is inoculated into a bottle of medium containing carbon14-labeled palmitic acid as a substrate. As mycobacteria metabolize the palmitic acid, carbon dioxide- 14 accumulates in the head space of the bottle, where radioactivity can be measured. Unfortunately, because bottles are often analyzed in series by repetitive needle aspiration in an automated, single-needle system, cross-contamination leading to a falsepositive culture can occur. Drug susceptibility testing can be performed on the same system using bottles with antimicrobial agents added to the medium. In this radiometric system, identification and drug-susceptibility testing often can be completed in 2 to 3 weeks, depending on the concentration of organisms in the patient sample. Unfortunately, it is often difficult to isolate M. tuberculosis from infants and toddlers with t u b e r c u l ~ s i s Infants . ~ ~ ~ and children with pulmonary tuberculosis rarely produce sputum, the usual culture material for adults. The preferred source of culture for children is the gastric aspirate, performed early in the morning before the stomach has been emptied of the respiratory secretions swallowed overnight. For older children, the culture yield from gastric aspirates obtained on three

consecutive mornings is 20% to 40Y0.8The yield from infants is usudy higher, up to 75%? For many infants with congenital pulmonary tuberculosis, M. tuberculosis can be cultured from a tracheal aspirate owing to the large number of organisms in the lungs. Several types of nucleic acid amplification have been developed to detect M. tuberculosis in patient samples. The main form of nucleic acid amplification studied in children with tuberculosis is the polymerase chain reaction (PCR), which uses specific DNA sequences as markers for microorganisms. Various PCR techniques, most using the mycobacterial insertion element IS6110 as the DNA marker for M. tuberculosis complex organisms, have a sensitivity and specificity of more than 90% compared with sputum culture for detecting pulmonary tuberculosis in adults. However, test performance varies even among reference laboratories. The test is relatively expensive and requires fairly sophisticated equipment and scrupulous technique to avoid crosscontamination of specimens. Use of PCR in childhood tuberculosis has been limited. Compared with a clinical diagnosis of pulmonary tuberculosis in children, the sensitivity of PCR has varied from 25 to 83% and specificity has varied from 80% to 100Y0.’~The PCR of gastric aspirates may be positive in a recently infected child even when the chest radiograph result is normal, demonstrating the occasional arbitrariness of the distinction between M. tuberculosis infection and disease in children. The PCR may have a useful but limited role in evaluating children for tuberculosis. A negative PCR result never eliminates tuberculosis as a diagnostic possibility, and a positive result does not confirm it. The major use of PCR will be in evaluating children with significant pulmonary disease when the diagnosis is not established readily on clinical or epidemiologic grounds. PCR particularly may be helpful in evaluating immunocompromised children with pulmonary disease, especially children with human immunodeficiency virus (HIV) infection, although published reports of its performance in such children are lacking. PCR also may aid in confirming the diagnosis of extrapulmonary tuberculosis, although only a few case reports have been published. No information has been published concerning the accuracy of PCR or other techniques of nucleic acid amplification in samples from pregnant women or neonates with congenital or postnatally acquired tuberculosis. Relatedness of strains of M. tuberculosis was determined in the past by analysis of bacteriophages, a cumbersome and difficult task. A newer technique, restriction fragment length polymorphism analysis of mycobacterial DNA, has become an accurate and powerful tool for determining strain relatedness.” It is used frequently in some communities and may help determine whether an infant with tuberculosis has true congenital infection or was infected by another source.

EPIDEMIOLOGY Tuberculosis remains the leading infectious disease in the world.’* The World Health Organization (WHO) estimates that during the 1990s 90 million individuals developed tuberculosis and 30 million people died of the disease worldwide. The WHO also estimates that, in the developing world, there are 1.3 million cases of tuberculosis and 400,000 tuberculosis-

Chapter 19 related deaths annually among children younger than 15 years of age. In most developing countries, the highest rates of tuberculosis occur among young adult men and women. Although much attention has been given recently to the growing number of children orphaned in developing countries by their parents' deaths from HIV-related illnesses, many orphans also are being created by tuberculosis. In the United States from 1953 through 1984, the incidence of tuberculosis disease declined an average of 5% per year. From 1985 through 1992, there was a 20% increase in total cases of tuberculosis in the United States and a 40% increase in tuberculosis cases among ~hildren.'~ Most experts cite four major factors contributing to this increase: (1) the co-epidemic of HIV infe~tion,'~ which is the strongest risk factor known for development of tuberculosis disease in an adult infected with M. t~berculosis'~; (2) the increase in immigration of people to the United States from countries with a high prevalence of tuberculosis, enlarging the pool of infected (3) the increased transmission of M. tuberindi~iduals'~~''; culosis in congregate settings, such as jails, prisons, hospitals, nursing homes, and homeless shelters; and (4) the general decline in tuberculosis-relatedpublic health servicesand access to medical care for the indigent in many comrnunities.l8 Fortunately, in 2003, the approximately 15,500 cases of tuberculosis in the United States was a 40% decline from the peak number of cases in 1992. In the early 20th century in the United States, when tuberculosis was more prevalent, the risk of becoming infected with M. tuberculosis was high across the entire population. Currently, tuberculosis has retreated into fairly well-defined pockets of high-risk individuals, such as foreign-born persons from or persons who travel to high-prevalence countries, inmates of correctional institutions, illicit drug users, unprotected health care workers who care for high-risk patients, migrant families, homeless persons, and anyone likely to encounter people with contagious tuberculosis. One must distinguish the risk factors for becoming infected with M. tuberculosis from those that increase the likelihood that an infected individual will develop disease. A compromised immune system and recent infection with M. tuberculosis are the major risk factors for progression of infection to disease. Although tuberculosis occurs throughout the United States, cases are disproportionately reported from large urban areas. Cities with populations exceeding 250,000 account for only 18% of the nation's population but almost 50% of its tuberculosis cases. The number of tuberculosis cases in the United States is increasing among foreign-born persons from countries with a high prevalence of tuberculosis. The percentage of total cases of tuberculosis in the United States that occurs in foreign-born individuals had increased from 22% in 1986 to more than 50% in 2003.17 In previous estimates, two thirds of foreign-born individuals with tuberculosis were younger than 35 years of age when entering the United States, and in many cases their disease could have been prevented if they had been identified as infected after immigration and given appropriate treatment for M. tuberculosis infection. Unfortunately, new immigrants to the United States older than 15 years of age are required to have a chest radiograph but no tuberculin skin test to detect asymptomatic infection; children younger than 15 years old receive no tuberculosis testing as part of immigration. l 9 Studies have estimated that

Tuberculosis

583

30% to 50% of the almost 1 million annual new immigrants to the United States are infected with M. t~berculosis.'~ Clearly, foreign-born women and adolescents of childbearing age should be one group targeted for appropriate tuberculosis screening and prevention.20 Another factor that has had a great impact on tuberculosis case rates in the United States has been the epidemic of HIV infe~tion.'~ The proportion of women with HIV infection is increasing,and because risk factors for HIV infection intersect with those for tuberculosis the number of co-infected women will In most locales experiencing recent increases in tuberculosis cases, the demographic groups with the greatest tuberculosis morbidity rates are the same as those with high morbidity rates from HIV infection. HIV-infected persons with a reactive tuberculin skin test develop tuberculosis at a rate of 5% to 10% per year compared with a historical average of 5% to 10% for the lifetime of an immunocompetent adult. There is controversy concerning the infectiousness of adults with HIV-associated pulmonary tuberculosis. Although some studies have indicated dually infected adults are as likely as non-HIV-infected adults with tuberculosis to infect others, some studies have shown less transmission from HN-infected adults.** The current epidemiology of tuberculosis in pregnancy is unknown. From 1966 to 1972, the incidence of tuberculosis during pregnancy at New York Lying-In Hospital ranged from 0.6% to l.O%?* During this time, 3.2% of the patients with culture-proven pulmonary tuberculosis were first diagnosed during pregnancy, a rate equal to that of nonpregnant women of comparable age. There have been only two series of pregnant women with tuberculosis reported from the United States in the past 2 Increased risk of tuberculosis is most striking for foreign-born women, who have high rates of tuberculosis infection, and poor minority women. In the United States, almost 40% of tuberculosis cases in minority women occur before 35 years of age. Approximately 80% of tuberculosis cases among children in the United States occur in minority population^.'^ Most of these cases occur after exposure to an ill family member. In all populations, whether the disease incidence is high or low, tuberculosis infection and disease tend to occur in clusters, often centered on the close or extended family, meaning that minority newborns are at greatly increased risk of congenital and postnatally acquired tuberculosis infection and disease.

TUBERCULOSIS IN PREGNANCY Pathogenesis The pathogenesis of tuberculosis infection and disease during pregnancy is similar to that for nonpregnant individual^.^^.^^ The usual portal of entry for M. tuberculosis is the lung through inhalation of infected droplet nuclei discharged by an infectious individual. The inoculum of organisms necessary to establish infection is unknown but is probably fewer than 10." Once tubercle bacilli are deposited in the lung, they multiply in the nonimmune host for several weeks. Usually, this uninhibited replication produces no symptoms, but a patient may experience low-grade fever, cough, or mild pleuritic pain. Shortly after infection, some organisms are carried from the initial pulmonary focus within macrophages

584

Section I1

Bacterial Infections carefully during the pregnancy; delay could result in disease in the mother, the infant, or both. The second mechanism by which a fetus can become infected with M . tuberculosis is directly from established genitourinary tuberculosis in the mother. Genital tuberculosis is most likely to start around the time of menarche and can have a very long and relatively asymptomatic course. The fallopian tubes most often are involved (in 90%-100% of women), followed by the uterus (50%-60%), ovaries (20%-30%), and cervix (5%-15’%0).*~~~* Sterility often is the presenting complaint of tuberculosis endometritis, which diminishes the likelihood of congenital tuberculosis If infection of the placenta occurs, it results more frequently from disseminated tuberculosis in the mother than from a local endometritis. Tuberculous endometritis, however, can lead to congenital infection of the Tuberculosis in the mother as a complication of in vitro fertilization has been described.”

Effect of Pregnancy on Tuberculosis

Figure 19-1 Chest radiograph of the mother of the child shown in Figure 19-2. This radiograph reveals early miliary tuberculosis.

to the regional lymph nodes3’ From there, organisms enter lymphatic and blood vessels and disseminate throughout the body; the genitalia, endometrium, and, if the woman is pregnant, the placenta may be seeded.32By 1 to 3 months after infection, the host usually develops cell-mediated immunity and hypersensitivity to the tubercle bacillus, reflected by the development of a reactive tuberculin skin test.33As immunity develops, the primary infection in the lung and foci in other organs begin to heal through a combination of resolution, fibrosis, and/or cal~ification.~~ Although walling-off of these foci occurs, viable tubercle bacilli persist. If the host’s immune system later becomes suppressed, these dormant bacilli may become active, leading to “reactivation” tubercul~sis.~~ There are two major ways that tuberculosis infection in the mother can lead to infection of the fetus in utero. If dissemination of organisms through the blood and lymphatic channels occurs during pregnancy, the placenta may be infected directly. This can occur either during the asymptomatic dissemination that is part of the mother’s initial infection or during pulmonary, miliary, or disseminated tuberculosis disease in the m~ther.’~.~’ Miliary tuberculosis in women can arise from a long-standing dormant infection but more often complicates a recent infection (Fig. 19-1). Therefore, infection with M . tuberculosis that occurs during pregnancy, as opposed to dormant infection that occurred before the pregnancy, probably poses a greater risk to the fetus. This is a major reason why pregnant women with new onset of M. tuberculosis infection usually should be treated

Over the past 2 millennia, medical opinions regarding the interaction of pregnancy and tuberculosis have varied considerably. Hippocrates believed that pregnancy had a beneficial effect on tuberculosis, a view that persisted virtually unchallenged well into the 19th century.’’ In 1850, Grisolle reported 24 cases of tuberculosis that developed during pregnancy.59In all patients the progression of tuberculosis during pregnancy was more severe than that usually seen in nonpregnant women of the same age. Shortly thereafter, several other papers were published that implied that pregnancy had a deleterious effect on tuberculosis. This view gained so much support that by the early 20th century, the practice of induced abortion to deal with the consequences of tuberculosis during pregnancy became widely accepted. The opinion that pregnancy had a deleterious effect on tuberculosis predominated until the late 1940s. In 1943, Cohen6’ detected no increased rate of progression of tuberculosis among 100 pregnant women with abnormal chest radiograph results. In 1953, H e d ~ a l presented l~~ a comprehensive review of published studies concerning tuberculosis in pregnancy. He cited studies totaling more than 1000 cases that reported deleterious effects of pregnancy on tuberculosis. He discovered a nearly equal number of reported cases, however, in which a neutral or favorable relationship between pregnancy and tuberculosis was observed. In his own study of 250 pregnant women with abnormal chest radiograph results thought to be due to tuberculosis, he noted that 9% improved, 7% worsened, and 84% remained unchanged during pregnancy. During the first postpartum year, 9% improved, 15% worsened, and 76% were stable. Cromie6* noted that 31 of 101 pregnant women with quiescent tuberculosis experienced relapse after delivery. Twenty of the 31 relapses occurred in the first postpartum year. Several other investigators observed the higher risk of relapse during the puerperium. Several theories were proposed to explain this phenomenon, including postpartum descent of the diaphragm, nutritional stress of pregnancy and lactation, insufficient sleep for the new mother, rapid hormonal changes, and depression in immunity in late pregnancy and the postpartum period. A similar number of other studies, however, failed to support an increased risk of progression of tuber-

Chapter 19 A study by Cohen and culosis in the postpartum colleagues failed to demonstrate an increase in activity of tuberculosis during pregnancy or any postpartum interval.62 Rosenbach and GangemiM and Cohen and colleagues6' showed that only 9% to 13% of women with long-standing tuberculosis had progression of disease during the pregnancy or first postpartum year, a rate thought to be comparable to that in nonpregnant women. Few of these studies had adequate control populations. From all the studies reported, it became clear that the anatomic extent of disease, the radiographic pattern, and the susceptibility of the individual patient to tuberculosis were more important than the pregnancy itself in determining the course and prognosis of the pregnant woman with tuberculosis. The controversy concerning the effect of pregnancy or the postpartum period on tuberculosis has lost most of its importance with the advent of effective chemotherapy.6'~~~ With adequate treatment, pregnant women with tuberculosis have the same excellent prognosis as nonpregnant women. Several studies document no adverse effects of pregnancy, birth, the postpartum period, or lactation on the course of tuberculosis in women receiving chem~therapy.~~,~' Most studies have dealt with the risk of reactivation of tuberculosis among women with abnormal chest radiograph results but no evidence of active tuberculous lesions. It is not clear whether women with asymptomatic M. tuberculosis infection but no radiographic findings are at increased risk of developing tuberculosis during pregnancy or the postpartum period. In 1959, Pridie and Stra~Uing~~ found that the incidence of pulmonary tuberculosis among pregnant women was the same as that in the nonpregnant female population of the area. From 1966 to 1972, Schaefer and associates25found that the annual pulmonary tuberculosis case rate among pregnant women in New York Lying-In Hospital was 18 to 29 per 100,000population, comparable to the incidence of tuberculosis during the same period in women of childbearing age in of all New York City. Although no definitive study has been reported, it appears unlikely that progression from asymptomatic M. tuberculosis infection to tuberculosis disease is accelerated during pregnancy or the postpartum period.

Effect of Tuberculosis on Pregnancy In the prechemotherapyera, active tuberculosis at an advanced stage carried a poor prognosis for both mother and child. Schaefer and associates25reported that the infant and maternal mortality rates from untreated tuberculosis were between 30% and 40%. In the chemotherapy era, the outcome of pregnancy rarely is altered by the presence of tuberculosis in the mother, except in the rare cases of congenital tuberculosis. One study from Norway revealed a higher incidence of toxemia, postpartum hemorrhage, and difficult labor in mothers with tuberculosis compared with that in control subjects.72The incidence of miscarriage was almost 10 times higher in the tuberculous mothers, but there was no significant difference in the rate of congenital malformations in children born to mothers with and without tuberculosis. Another study reported an incidence of prematurity for infantsborn to untreated mothers in a tuberculosis sanitarium ranging from 23% to 64%, depending on the severity of tuberculosis in the mother.73 Most experts now believe,

Tuberculosis

585

however, that with proper treatment of the pregnant woman with tuberculosis, the prognosis of the pregnancy should not be affected adversely by the presence of tuberculosis. Because of the excellent prognosis for the mother and child, the recommendation for therapeutic abortion has been abandoned.

Screening for Tuberculosis in Pregnancy For all pregnant women, the history obtained in an early prenatal visit should include questions about a previously positive tuberculin skin test result, previous treatment for M. tuberculosis infection or disease, current symptoms compatible with tuberculosis, and known exposure to other adults with the d i ~ e a s e .Membership ~~'~~ in a high-risk group is a sufficient reason for a tuberculin skin test. For many high-risk women, prenatal or peripartum care represents their only contact with the health care system, and the opportunity to test them for tuberculosis infection or disease should not be lost. Some experts believe that all pregnant women should receive a tuberculin skin test.77Most experts believe, however, that only women with specific risk factors for M. tuberculosis infection or disease should be tested. It must be emphasized that women co-infected with HIV and M. tuberculosis may show no reaction to a tuberculin skin test. Pregnant women with high risk for or with known HIV infection should have a thorough investigation for tuberculosis. Changes in the interpretation of the Mantoux tuberculin skin test have been promoted by the Centers for Disease Control and Prevention, the American Thoracic Society, and the American Academy of pediatric^.^^,^^ The rationale for using different sizes of induration as representing a positive result in different populations has been discussed thoroughly in many publications. The current recommendation is that for individuals at the highest risk of having M. tuberculosis infection progress to tuberculosis-contacts of adults with infectious tuberculosis, patients with an abnormal chest radiograph result or clinical evidence of tuberculosis, or persons with HJY infection or other immunocompromisea Mantoux tuberculin skin test reaction of at least 5 mm is classified as positive, indicating infection with M. tuberculosis. For other high-risk groups, a reaction of at least 10 mm is positive. For all other persons deemed at low risk for tuberculosis, a reaction of at least 15 mm is positive. Obviously, this classification scheme depends on the ability and willingness of the family and health care provider to develop a thorough epidemiologic history of tuberculosis exposures and risk. It also depends on accurate interpretation of the skin test result. One recent study implied that pediatricians tend to under-read induration in tuberculin skin tests.79 There have been no studies to verify whether the classification scheme for the Mantoux tuberculin skin test is valid in pregnant women, but there is no reason to suspect otherwise.60v81 The effect of pregnancy on tuberculin hypersensitivity as measured by the tuberculin skin test is controversial.82 Some studies have shown a decrease in in vitro lymphocyte reactivity to purified protein derivative during pregnancy.83 In vivo studies using patients as their own controls, however, have demonstrated no effect of pregnancy on cutaneous delayed hypersensitivity to t u b e r c ~ l i n .Most ~ ~ ~ ~experts ~ believe the tuberculin skin test by the Mantoux technique is valid throughout pregnancy. There is no evidence that the

586

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tuberculin skin test has adverse effects on the pregnant mother or fetus or that skin testing reactivates quiescent foci of tuberculosis One of the most difficult problems in the interaction of tuberculosis and pregnancy is deciding whether a pregnant woman with M. tuberculosis infection should receive immediate treatment or whether the treatment should be postponed until after the child is deli~ered.'~ Not all infected individuals have the same chance of developing tuberculosis during a short period of time. Individuals who were infected remotely (more than 2 years previously) have a low chance of developing tuberculosis during a given %month period. Individuals who have been infected more recently, however, particularly if their infection is discovered during a contact investigation of an adult with active tuberculosis, are at much higher risk; about half of the lifetime risk of progression of infection to disease occurs during the first 1 to 2 years after infection. Other vulnerable adults, particularly those co-infected with HIV, also are at greatly increased risk of having progression of infection to disease. In general, treatment for tuberculosis infection should be initiated during pregnancy if the woman likely has been infected recently (especially in the setting of a contact investigation of a recently diagnosed case) or if she is at increased risk of rapid development of tuberculosis. Although isoniazid (INH) is not thought to be teratogenic, some experts recommend waiting until the second trimester of pregnancy to begin treatment. Unfortunately, patient adherence to INH treatment for tuberculosis infection appears to be very low if the initiation of treatment is delayed until after the child is delivered. The reason for this low adherence is not clear, but several problems include the perception of nonimportance because a treatment delay of many months is allowed, transfer of care from one segment of the health care system to another, and, perhaps, the lack of reinforcement by health care professionals concerning the importance of the treatment. Although screening and treatment of high-risk pregnant women may seem to be an effective strategy to prevent future cases of tuberculosis, it has not yet been demonstrated that this strategy is successful in the U.S. health care system." Routine chest radiography is not advisable as a screening tool for pregnant women because the prevalence of tuberculosis remains fairly With appropriate shielding, however, pregnant women with positive tuberculin skin test results should have chest radiographs to rule out tuberculo~is.~' In addition, a thorough review of systems and physical examination should be carried out to exclude extrapulmonary tuberculosis.

CONGENITAL TUBERCULOSIS

Tuberculosis in the Mother In general, the clinical manifestations of tuberculosis in the pregnant woman are the same as those in nonpregnant individuals.The most important determinants of the clinical presentation are the extent and anatomic location of disease. In one series of 27 pregnant and postpartum women with pulmonary tuberculosis, the most common clinical findings were cough (74%), weight loss (41%), fever (30%), malaise and fatigue (30%),and hemoptysis (19Y0).~~ Almost 20% of

patients had no significant symptoms; other studies also have found less significant symptoms in pregnant women with tuberculosis.26 The tuberculin skin test result was positive in 26 of 27 patients. The diagnosis was established in all cases by culture of sputum for M. tuberculosis. Sixteen of the patients in this series had drug-resistant tuberculosis; their clinical course was marked by more extensive pulmonary involvement, a higher incidence of pulmonary complications, longer sputum conversion times, and a higher incidence of death. In other series, 5% to 10% of pregnant women with tuberculosis have had extrapulmonary disease, a rate comparable with nonpregnant women of the same age.26 Although the female genital tract may be the portal of entry for a primary tuberculosis infection, more often infection at this site originates by continuity from an adjacent focus of disease or by blood-borne seeding of the fallopian tubes.51Progression of disease usually is by descent in the genital tract. Mucosal ulceration within the fallopian tube develops, and pelvic adhesions occur frequently. Many patients are asymptomatic. The most common complaints are sterility and menstrual irregularity with menorrhagia or amenorrhea. These findings greatly diminish the likelihood of congenital tuberculosis. Other less frequent signs and symptoms include lower abdominal pain and tenderness, weight loss, fever, and night sweats. Diagnosis in the nonpregnant woman is usually established by culture and histologic examination of tissue recovered after uterine curettage. The highest recovery rates of M. tuberculosis are obtained from scraping obtained just before or during menstruation. Tuberculosis mastitis is very rare in the United States but occurs almost exclusively in childbearing-aged ~ o m e n . ~ * - ~ ~ The most common finding is a single breast mass, with or without a draining sinus. Nipple retraction and peau d'orange skin changes suggestive of carcinoma also may be present. The ipsilateral axillary lymph nodes usually are enlarged. Diagnosis is confirmed by biopsy of the mass or axillary node and culture of the tissue for M. tuberculosis. Transmission of M. tuberculosis to the infant through breast milk is exceedingly rare, if it occurs at all.

In Utero Routes of Transmission Tuberculosis in the neonate can be either truly congenital (i.e., acquired in utero) or truly neonatal (i.e., acquired early in life from the mother, contagious members of the family, family friends, or caretakers). Each of these two kinds of perinatal tuberculosis may be subdivided. Congenital tuberculosis can be acquired in any one of three ways: (1) from the infected placenta via the umbilical vein, (2) by inhalation of infected amniotic fluid, and (3) by ingestion of infected amniotic fluid. Neonatal tuberculosis can be acquired in four different ways: (1) by inhalation of infected droplets, (2) by ingestion of infected droplets, (3) by ingestion of infected milk (theoretical), and (4) by contamination of traumatized skin or mucous membranes. It is not always possible to be sure of the route of infection in a particular neonate, and, with effective chemotherapy at hand, it is not essential for the care of the infant. However, it is important to try to identify the source of infection so that the person infecting the infant can be treated and further transmission can be p r e ~ e n t e d . ~ ~

Chapter 19

Table 19-1

Modes of Inoculation of the Fetus or Newborn with Mycobcterium tuberculosis

~~~

Maternal Focus

Mode of Spread

Placentitis Amniotic fluid Cervicitis Pneumonitis

Hematogenous (umbilical vessel) Aspiration Direct contact Airbone (postnatal)

The potential modes of inoculation of the fetus or newborn infant with M. tuberculosis from the mother are shown in Table 19-1.96Infection of the fetus through the umbilical cord has been rare, with fewer than 350 cases reported in the Enghsh-languageliterature.97These infants' mothers frequently suffer from tuberculous pleural effusion, meningitis, or disseminated disease during pregnancy or soon In some series of congenital tuberculosis, however, fewer than 50% of the mothers were known to be suffering from tuberculosis at the time of delivery and beginning of symptoms in the In most of these cases, diagnosis of the child led to the discovery of the mother's tuberculosis. The intensity of lymphohematogenous spread during pregnancy is one of the factors that determines whether congenital tuberculosis will occur. Hematogenous dissemination in the mother leads to infection of the placenta with subsequent transmission of organisms to the fetus. M. tuberculosis has been demonstrated in the decidua, amnion, and chorionic villi of the placenta. The organisms also have been shown to reach the placenta through direct extension from a tuberculous salpingeal tube. Even massive involvement of the placenta with tuberculosis, however, does not always give rise to congenital tuberculosis."' It is not clear whether the fetus can be infected directly from the mother's bloodstream without a caseous lesion forming first in the placenta, although this phenomenon has been demonstrated in experimental animal models.Io2 In hematogenous congenital tuberculosis, the organisms reach the fetus through the umbilical vein. If bacilli infect the liver, a primary focus develops with involvement of the periportal lymph nodes. The bacilli can pass through the liver, however, into the main circulation through the patent foramen ovale. Alternately, they can pass through the right ventricle into the pulmonary circulation, leading to a primary focus in the lung. The organisms in the lung often remain dormant until after birth when oxygenation and circulation increase significantly, leading to the growth of organisms and pulmonary tuberculosis in the young infant. In many children with congenital tuberculosis, multiple lesions occur throughout the body; it is not possible to determine whether they represent multiple primary foci or some occur secondary to primary lesions in the lung or liver. The only lesion of the neonate that is unquestionably associated with congenital infection is a primary complex in the liver. Congenital infection of the infant also can occur through aspiration or ingestion of infected amniotic fluid.Io3If the caseous lesion in the placenta ruptures directly into the amniotic cavity, the fetus can inhale or ingest the bacilli. Inhalation or ingestion of infected amniotic fluid is the most

Tuberculosis

587

likely cause of congenital tuberculosis if the infant has multiple primary foci in the lung, gut, or middle ear.Io4In congenital tuberculosis caused by aspiration, the primary complex can be in the liver, the lung, or both organs. The pathology of congenital tuberculosis in the fetus and newborn usually demonstrates the predisposition to dissemination ensured by the modes of transmission, particularly through the umbilical vein. The liver and lungs are the primary affected organs, with bone marrow, bone, gastrointestinal tract, adrenal glands, spleen, kidneys, abdominal lymph nodes, and skin also frequently affected.'053'06 The histologic patterns of involvement are similar to those in adults;tubercles and granulomasare common. Central nervous system involvement occurs in fewer than 50% of In most recent series, the mortality rate of congenital tuberculosis has been close to 50%, primarily because of the failure to suspect the correct diagnosis. Most fatal cases are diagnosed at a u t o p ~ y . ~ ~ , ' ~ Postnatal acquisition of M. tuberculosis through airborne inoculation is the most common route of infection of the neonate.Io7-lo9 It may be impossible to differentiate postnatal infection from prenatal acquisition on clinical grounds alone."' Any adult in the neonate's environment can be a source of airborne tuberculosis, including health care Up to 40% of infants with untreated M. tuberculosis infection develop tuberculosis disease within 1 to 2 years. There are few data concerning the time of onset of tuberculosis when the infection is acquired at or shortly after birth. In one series of 48 infants exposed postnatally to mothers with pulmonary tuberculosis in the pretreatment era, 2 1 became infected; of those who became ill, signs such as fever, tachypnea, weight loss, and hepatosplenomegaly developed in 4 to 8 weeks.'13 Because newborns infected with the organism are at extremely high risk for developing severe forms of disease, investigation of an adult with tuberculosis whose household contacts include a pregnant woman or newborn should be considered a public health emergency. In addition, all adults in contact with an infant suspected of having M. tuberculosis infection or disease should undergo a thorough investigation for disease. The skin and mucous membranes are rare portals of entry for M. tuberculosis in neonates. Infection through the skin has been mentioned several times in association with lesions of the head and face, very likely related to minor traumatic lesions being infected by kissing. Primary lesions of the mucous membranes of the mouth also have been recognized, although usually in infants beyond the newborn period. In both of these situations, the primary lesion was insignificant, but the enlarged regional lymph nodes called attention to the problem. A previously well-known form of skin and mucous membrane infection was tuberculosis of the male genitalia after circumcision, in the years when it was customary for the individual performing the circumcision to suck the blood around the incision.This procedure was obviously dangerous if that individual happened to have bacilli in the sputum. The primary focus of inoculation on the penis was often inconspicuous, but within 1 to 4 weeks, ulceration, suppuration, and bilateral inguinal lymphadenopathy would develop. At first firm and nontender, the nodes might later break down with sinus formation to the exterior. H ~ l t , ' in '~ his review of circumcision tuberculosis, described a case with

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extensive ulceration of the penis and scrotum, greatly swollen lymph nodes, a generalized rash resembling varicella, hepatosplenomegaly, fever, cough, rales, and a positive tuberculin test result, with recovery of tubercle bacilli from sputum and penile discharge. Of the 41 patients described by Holt, 16 died and 6 recovered, with the outcome of the others unkno~n.~l~

Criteria for Diagnosis of Congenital Tuberculosis In 1935, Beitzke"' suggested criteria for diagnosis of congenital tuberculosis in a thoughtful, detailed, and often-quoted review of the reported cases up to that time: 1. Tuberculosis in the child must be firmly established; 2. A primary complex in the liver is proof of congenital tuberculosis because this complex could arise only through perfusion of the liver with tubercle bacilli contained in umbilical cord blood; 3. If a primary complex is lacking in the liver, then tuberculosis can be considered to be congenital only if tuberculous lesions are present in a fetus or in a newborn only a few days old; or in an older infant, extrauterine infection can be excluded with certainty, that is, if the child was removed from the tuberculous mother at birth to a tuberculosis-free environment.

A study by Cantwell and co-w~rkers:~based on a review of cases of congenital tuberculosis published before and after 1980, proposed the following modification of Beitzke's criteria: the infant must have proven tuberculous lesions and at least one of the following: (1) lesions in the first week of life; (2) a primary hepatic complex or caseating hepatic granulomas; (3) tuberculosis infection of the placenta or maternal genital tract, or both; or (4)exclusion of postnatal transmission by a thorough contact investigation. Although Beitzke's criteria are in fact fully met by many of the 350 or so reported cases of congenital tuberculosis, in other cases it is impossible to be certain whether infection was transmitted in utero or was acquired during the early days or weeks of life. In many cases of true congenital tuberculosis, the mother was not known to be suffering from active tuberculosis. Two articles contain tables with detailed information on 26 cases and 15 cases?9v'"In only 10 of the 26 cases was tuberculosis diagnosed in the mother ante partum, although it became apparent in another 15 after diagnosis in the infant.99Five of the 26 mothers died of tuberculosis, an indirect confirmation of the fact that the diagnosis was made very late. In the series of 15 cases, 7 mothers were thought to be well at the time of delivery, but all 15 were subsequently found either to have had pleural effusion antepartum (four cases) or to have developed endometrial, miliary, or meningeal tuberculosis post parturn."'

Clinical Features and Diagnosis of Congenital Tuberculosis The clinical manifestations of tuberculosis in the fetus and newborn vary in relation to the site and size of the caseous lesions. Symptoms may be present at birth but more commonly begin by the second or third week of life. The most frequent signs or symptoms of true congenital tuberculosis

Table 19-2

Most Frequent Signs and Symptoms of Congenital Tuberculosis

Symptom or Sign Hepatosplenomegaly Respiratory distress Fever Lymphadenopathy Abdominal distention Lethargy or irritability Ear discharge Papular skin lesions Vomiting, apnea, cyanosis, jaundice, seizures, petechiae

Frequency (%) 76 72 48 38 24 21 17 14 4 0 each

Adapted from Cantwell MF, Shebb ZM, Costello AM, et al. Brief report: congenital tuberculosis. N Engl J Med 330:1051-1054, 1994; with permission, copyright 1994, Massachusetts Medical Society. All rights reserved.

Figure 1%2 Chest radiograph of a 1-month-old infant with congenital tuberculosis.

are listed in Table 19-2.97)99."6-'47 Most infants have an abnormal chest radiograph result, with about half having a miliary pattern.I4' Some infants with a normal chest radiograph result early in the course develop profound radiographic abnormalities as the disease progresses (Fig. 19-2). The most common abnormalities are adenopathy and parenchymal infiltrates.Occasionally,the pulmonary involvement progresses very rapidly, leading to c a ~ i t a t i o n . ' ~Tuberculosis ~''~~ of the middle ear in children with congenital tuberculosis has been described fairly often.993108,149,151-154 The eustachian tube in newborns permits ready access to infected pharyngeal fluids or vomitus. Multiple perforation or total destruction of the tympanic membrane, otorrhea, enlarged cervical lymph nodes, and facial paralysis are all possible sequelae.

Chapter 19 Table 19-3

Tuberculosis

589

Antituberculosis Drugs in Children

Drugs

Dosage Forms

Daily Dose (mglkg)

Twice-Weekly Dose (mglkglper dose)

lsoniazid

Scored tablets:

10-15

20-40

Daily: 300 mg Twice weekly: 900 mg

10-20

10-20

600 mg

20-40

50-70

29

20-40 (IM)

20-40 (IM)

l g

15-25

50

2.5 g

100 mg 300 mg Syrup: 10 mg/ml

Rifampin

Capsules:

Maximum Dose

150 mg 300 mg

Syrup: formulated in syrup from capsules

Pyrazinamide

Scored tablets: 500 mg

Streptomycin Ethambutol

Vials: 1%49

Scored tablets: 100 mg 400 mg

The clinical presentation of tuberculosis in the newborn is similar to that caused by bacterial s e ~ s i s ' ~and ~ - congenital '~~ infections with syphilis and cytomegalovirus? Abnormalities of liver function are ~ o m m o n . ~ ~The * * ' diagnosis ~~ of congenital tuberculosis should be suspected in any infant with signs and symptoms of sepsis or viral infection who does not respond to vigorous antibiotic therapy and whose evaluation for other congenital infections is unrevealing. Of course, suspicion also should be high if the mother has or has had tuberculosis or if she is in a high-risk group for tuberculosis.The importance of obtaining an adequate history for the presence of risk factors for tuberculosis in the mother cannot be overemphasized. Suspicion should increase if the mother has suffered from unexplained pneumonia, bronchitis, pleural effusion, meningeal disease, or endometritis during, shortly before, or even after pregnancy. Evaluation of both parents and other family members can yield important clues about the presence of tuberculosis within the family. The timely diagnosis of congenital or neonatal tuberculosis Whenever possible, the placenta is often should be examined and cultured for M. tuberculosis. The tuberculin skin test result is always negative initially, although it may become positive after 1 to 3 months of treatment. The diagnosis must be established by finding acid-fast bacilli in body fluids or tissue or by culturing M. tuberculosis. A positive acid-fast bacilli smear of an early morning gastric aspirate obtained from a newborn should be considered indicative of tuberculosis, although falsepositive results can occur.' Direct acid-fast bacilli smears from middle-ear fluid, bone marrow, tracheal aspirate, or biopsy tissue can be useful and should be obtained more ~ f i e n . ' ~ , ' ~geman ~ H a and colleagueswfound positive cultures for M. tuberculosis in 10 of 12 gastric aspirates, three of three liver biopsies, three of three lymph node biopsies, and two of four bone marrow aspirations from children with congenital tuberculosis. Open-lung biopsy also has been used to establish the diagn~sis.'~'The cerebrospinal fluid should be examined and cultured, although the yield for isolating M. tuberculosis is less than 20% and meningitis occurs in only one third of cases of congenital tuberculosis.

TREATMENT OF TUBERCULOSIS The drugs used most commonly to treat M. tuberculosis infection and disease, their dosage forms, and doses are listed in Table 19-3.159 Detailed discussion of the pharmacokinetics of each drug is beyond the scope of this chapter. No published study has examined in detail the pharmacokinetics of drugs used as antituberculosis agents in premature or term neonates.I6' INH is the mainstay of treatment for tuberculosis infection and disease in infants, children, and adults. It is inexpensive, highly effective in preventing the multiplication of tubercle bacilli, of low molecular weight and therefore readily diffusible to all tissues in the body, and relatively nontoxic to children. It can be administered orally or intramuscularly. When it is taken orally, high plasma, sputum, and cerebrospinal fluid levels are reached within a few hours and persist for at least 6 to 8 hours. Because of the slow multiplication of M. tuberculosis, the total daily dose can be given at one time. The principal toxic effects of INH are peripheral neuritis and hepatitis. Peripheral neuritis, resulting from competitive inhibition of pyridoxine, is almost unknown in North American children because both cow's milk (or formula) and meat are the main dietary sources of pyridoxine. In some well-nourished children, serum pyridoxine concentrations are mildly depressed by INH, but clinical signs are not apparent. For most children, therefore, it is not necessary to use supplementary pyridoxine. However, in pregnancy, in teenagers whose diets may be inadequate, in children from ethnic groups with a low milk and meat intake, and in breast-fed babies, pyridoxine supplementation ( 2 5 to 50 mg/day) is important. Hepatotoxicity from INH, rare in children, increases in frequency with age. Monitoring serum aspartate aminotransferase and serum alanine aminotransferase sometimes reveals transient increases during treatment with INH, but the levels usually return to normal spontaneously without interruption of treatment. Liver enzyme abnormalities in adolescents receiving INH likewise are rather common and usually disappear spontaneously, but severe hepatitis can

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occur. Although neonates usually tolerate INH well, some experts recommend routine biochemical monitoring in the first several months of therapy. The usual dosage of INH in children is 10 to 20 mg/kg per day, to a maximum of 300 mg per day. INH is available in tablets of 100 and 300mg. A syrup of INH in sorbitol (lOmg/mL) appears to be satisfactory; however, it is unstable at room temperature and should be kept cool. Many children develop significant gastrointestinal intolerance (nausea, vomiting) while taking the INH suspension, but neonates and infants tolerate the lower required volume of suspension well. If tablets are used, they are easily crushed in a dessert spoon and given with some soft food such as applesauce, mashed banana, thawed undiluted frozen orange juice, or another palatable medium. The crushed tablets should not be added to the nursing bottle or offered in milk or water because they will be ingested only partially. Rifampin (RIF) is a semisynthetic drug derived from Streptomyces mediterranei. The drug is absorbed readily from the gastrointestinal tract in the fasting state. Excretion mainly is through the biliary tract; however, effective levels are achieved in the kidneys and urine. In many patients receiving RIF treatment, the tears, saliva, urine, and stool turn orange as a result of a harmless metabolite, and the patient and parents always must be warned of this in advance. RIF can be made into a suspension easily for use in children. RIF is very well tolerated by neonates and infants. The incidences of hepatitis, leukopenia, and thrombocytopenia are extremely low. RIF should be used alone only when treating M. tuberculosis infection due to an INH-resistant organism. If one uses INH, 20 mg/kg, and FUF, 15 to 20 mg/kg, there is an appreciable incidence of hepatotoxicity. Therefore, when using the two together, one would be wise to approximate INH, 10 mg/kg, and RIF, 15 to 20 mg/kg. Pyrazinamide (PZA) contributes to the killing of M. tuberculosis, particularly at a low pH such as that within macrophages. The exact mechanism of action of PZA is a subject of controversy. PZA has no effect on extracellular tubercle bacilli in vitro but clearly contributes to the killing of intracellular bacilli. Primary resistance is very rare, except that Mycobacterium bovis is resistant. The drug diffuses readily into all areas, including the cerebrospinal fluid. The usual adult daily dose is 20 to 40 mg/kg. The optimal dose for infants and children has not been established firmly because no formal pharmacokinetic studies have been reported. The adult dose is tolerated well by infants and children, results in high cerebrospinal fluid concentrations, and clearly is effective in therapy trials for active tuberculosis in children. PZA appears to exert its maximum effect during the first 2 months of therapy. Hepatotoxicity can occur at high doses but is rare at the usual dose. PZA routinely causes an increase in the serum uric acid concentration by inhibiting its excretion through the kidneys. Toxic reactions in adults include flushing, cutaneous hypersensitivity, arthralgia, and overt gout; however, the considerable experience with this drug in children in Latin American countries, Hong Kong, and the United States has revealed few problems. Ethambutol (EMB) has been used for many years as a companion drug for INH in adults. The usual oral dose is 15mg/kg per day. At this dose, the drug primarily is bacteriostatic, its major role being to prevent emergence of resistance to other drugs. However, at doses of 25 mg/kg per

day or 50 mgkg given twice a week, EMB has some bactericidal action. Unfortunately, at these higher doses, optic neuritis or red-green color blindness has occurred in some adults. Although the incidence of ophthalmologic toxicity in children is extremely low, if it occurs at all, EMB is not recommended for routine use in young children in whom visual field and color discrimination tests are difficult and inaccurate. However, it is used frequently and safely in children with life-threatening forms of tuberculosis or with drug-resistant tuberculosis. Streptomycin (STM) is a valuable drug to be used in conjunction with INH and RIF in life-threatening forms of tuberculosis. It is bactericidal and tolerated well by children in the usual dose of 20 to 40 mg/kg per day intramuscularly up to 1 g. Usually, STM can be discontinued within 1 to 3 months if clinical improvement is definite.

General Principles The tubercle bacillus can be killed only during replication, which occurs among organisms that are active metabolically. In one model, bacilli in a host exist in different population^.^ They are active metabolically and replicate freely when oxygen tension is high and the pH is neutral or alkaline. Environmental conditions for growth are best within cavities, leading to a large bacterial population. Older children with pulmonary tuberculosis and patients of all ages with only extrapulmonary tuberculosis are infected with a much smaller number of tubercle bacilli because the cavitary population is not present. However, neonates with congenital tuberculosis tend to have a large burden of organisms at diagnosis. Naturally occurring drug-resistant mutant organisms occur within large populations of tubercle bacilli even before chemotherapy is started. All known genetic loci for drug resistance in M. tuberculosis are located on the chromosome; no plasmid-mediated resistance is known. The rate of resistance within populations of organisms is related to the rate of mutations at these loci. Although a large population of bacilli as a whole may be considered drug susceptible, a subpopulation of drug-resistant organisms occurs at a fairly predictable rate. The mean frequency of these drug-resistant mutations is about lo4 but varies among drugs: STM, INH, 10”; and RIF, lo-’. A cavity containing lo9 tubercle bacilli has thousands of single drug-resistant mutant organisms, whereas a closed caseous lesion contains few, if any, resistant mutants. The population size of tubercle bacilli within a patient determines the appropriate therapy. For patients with a large bacterial population (adults with cavities or extensive infiltrates), many single drug-resistant mutants are present and at least two antituberculosis drugs must be used. Conversely, for patients with M. tuberculosis infection but no disease, the bacterial population is very small (about lo3 to lo4 organisms), drug-resistant mutants are rare, and a single drug can be used. Older children with pulmonary tuberculosis and patients of all ages with extrapulmonary tuberculosis have medium-sized populations in which drugresistant mutants may or may not be present. In general, these patients should be treated with at least two drugs. Neonates and infants with tuberculosis disease have large mycobacterial populations, and several drugs are required to effect a cure.

Chapter 19 Tuberculosis

Pregnant Women The only drug with well-documented efficacy against M. tuberculosis infection in pregnant women is INH. Infants and children tolerate INH very well, and adverse reactions are rare. However, adverse reactions are more common in adults. Between 5% and 10% of young adults taking INH have an asymptomatic increase in serum liver transaminase levels; 1% to 2% suffer from symptomatic hepatitis, which is reversible if the medication is stopped immediately. For most young adults, monitoring for hepatitis is done clinically. Routine or periodic evaluation of serum liver enzyme tests is reserved for adults with underlying liver disease or those taking other potentially hepatotoxic drugs. However, some experts think that all pregnant women taking INH should have routine biochemical monitoring for hepatitis. Serum liver enzyme elevations of three to four times normal are common and do not necessitate discontinuation of the drug. There is no evidence that giving INH to a pregnant woman adversely affects the liver of the fetus. The other important adverse reaction of INH is peripheral neuritis caused by inhibition of pyridoxine metabolism. Pyridoxine should be given to pregnant adolescents or women and breast-feeding infants because breast milk has low concentrations of pyridoxine, even if the mother is receiving vitamin supplements.161 The current recommendation of the Centers for Disease Control and Prevention is to treat adults and children infected with M. tuberculosiswith INH for 9 monthsY6Usudy, the medication is taken daily under self-supervision. If poor patient adherence is likely and resources are available, INH can be given twice weekly using directly observed therapy.'62 Directly observed therapy requires that a health care worker, often from the local health department, observe the patient take antituberculosis medications. In general, directly observed therapy should be used for all patients with tuberculosis disease because of the difficulty in predicting patient adherence and the consequences of poor adherence (relapse and development of drug resistance). Directly observed therapy is often used for high-risk newborns with tuberculosis exposure or infants with M. tuberculosis infection. For patients who cannot take INH for treatment of M. tuberculosis infection either because of side effects of the medication or because they are infected with an INH-resistant but RIF-susceptible strain of M. tuberculosis, the treatment of choice for M. tuberculosis infection is RIF, which also can be given daily or twice a week under directly observed therapy.'63 If the mother is known to be infected with a strain of tuberculosis that is resistant to both INH and RIF (multidrug-resistant tuberculosis), an expert should be consulted for the management of the mother and the child after delivery.'@ Although treatment of a woman with active tuberculosis during pregnancy is unquestioned, treatment of a pregnant woman who has an asymptomatic M. tuberculosis infection is more controversial.Some clinicians prefer to delay therapy until after delivery, because pregnancy does not seem to increase the risk of developing active tuberculosis. Others believe that because recent infection can be accompanied by hematogenous spread to the placenta, it is preferable to treat without delay or to wait until the second trimester to start chemotherapy.A report by Franks and colleague^'^^ suggests

591

that the risk of INH-associated hepatitis and death is higher in women than in men and that women in the postpartum period are slightly more vulnerable to INH hepatotoxicity. These investigators suggest that it might be prudent to avoid INH during the postpartum period or at least to monitor postpartum women taking INH with frequent examinations and laboratory studies. The possible increased risk of INH hepatotoxicity must be weighed against the risk of developing active tuberculosis as well as the consequences to both mother and infant should active tuberculosis develop. The indications for treatment and the basic principles of management for the pregnant woman with tuberculosis disease are no different from those for the nonpregnant patient. The recommendations for which drugs to use and how long to give them are slightly different, however, mostly because of possible effects of several of the drugs on the developing fetus. The currently recommended treatment for drug-susceptible pulmonary tuberculosis in the United States in nonpregnant individuals is 6 months of INH and RIF, supplemented during the first 2 months with PZA and either EMB or STM.'59,166 With any of the regimens, the drugs usually are given every day for the first 2 weeks to 2 months; then they can be given daily or twice a week (under directly observed therapy) for the remainder of therapy with equal effectiveness and rates of adverse rea~ti0ns.I~~ There is no doubt that untreated tuberculosis represents a far greater risk to a woman and her fetus than does appropriate treatment of the disea~e.@.'~~-'~* Extensive experience with the use of INH in pregnancy has been reported. Even though it crosses the placenta, it is not teratogenic even when given during the first 4 months of ge~tati0n.l~~ EMB also appears to be safe during pregnancy. In 650 cases in which pregnant women were treated with EMB, no evidence of fetal malformations, including eye abnormalities, was f o ~ n d . ~ ~ The * ' ~action ~ - ' ~of~ RIF to inhibit DNA-dependent RNA polymerase combined with its ability to cross the placental barrier has created some concern about its use in pregnancy.'77Only 3% of 446 fetuses exposed in utero to RIF had abnormalities, however, compared with 2% for EMB and 1% for INH.a6The noted abnormalities included limb reductions, central nervous system abnormalities, and hypoprothrornbinemia. Hemorrhagic disease of the newborn also has been described after the use of RIF in the mother. The incidence of abnormalities in fetuses not exposed to antituberculosis medications ranges from 1% to 6%. In general, the powerful antituberculosis effect of RIF outweighs concern about its effect on the fetus. Nonpregnant women receiving RIF should receive contraception counseling because receiving RIF can impair the efficacy of oral contraceptives, leading to unintended pregnancy in a tuberculous woman.'78 Several antituberculosis drugs generally are not used in pregnant women because of possibly toxicity to the fetus.179-'82 STM has variable passage across the placental barrier. Its use in pregnancy is now limited by the availability of better drugs and its effect on the f e t u ~ . ' ~ ' In - ' ~a~review of 206 infants exposed in utero to STM, 34 (17%) had significant eighth nerve damage, the abnormalities ranging from mild vestibular damage to profound bilateral deafnesa6 The deleterious effects of STM are independent of the critical periods earlier in embryogenesis,and it is potentially hazardous throughout gestation. It is assumed that capreomycin,

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kanamycin, and amikacin, other aminoglycosides with antituberculosis activity, could have the same toxic potential as STM. Little is known about the specific effects of PZA on the fetus. Although there are no data, an increasing number of experts are using PZA during pregnancy with no reported adverse reactions. Nonspecific teratogenic effects have been attributed to ethionamide.Is5 The central nervous system effects of cycloserine and the gastrointestinal effects of paraaminosalicylic acid in adults make their use in pregnancy undesirable. The currently recommended initial treatment of drugsusceptible tuberculosis disease in pregnancy is INH and RIF daily, with the addition of EMB initially, under directly observed therapy.'86.'87 Pyridoxine (50 mg daily) always should be given with INH during pregnancy because of the increased requirements for this vitamin in pregnant women. After drug susceptibility testing of the isolate of M. tuberculosis reveals it to be susceptible to both INH and RIF, the EMB can be discontinued. If PZA is not used in the initial regimen, INH and RIF must be given for 9 months instead of 6 months. After the first 2 weeks to 2 months of daily treatment, the drugs can be given twice a week under directly observed therapy, which is the preferred method of treatment by most experts. The treatment of any form of drug-resistant tuberculosis during pregnancy is extraordinarily difficult and should be handled by an expert with great experience with the d i s e a ~ e . " ~ * ' ~ ~ Because treatment of tuberculosis in pregnant women often continues after delivery, there is concern as to whether it is safe for the mother to breast-feed her infant. Snider and Powell'goconcluded that a breast-feeding infant would have serum levels of no more than 20% of the usual therapeutic levels of INH for infants and less than 11% of other antituberculosis drugs. Potential toxic effects of drugs delivered in breast milk have not been reported. Because pyridoxine deficiency in the neonate can cause seizures, however, and because breast milk has relatively low levels of pyridoxine, infants who are taking INH or whose breast-feeding mothers are taking INH should receive supplemental pyridoxine.'"

Several studies have shown that RIF can be given safely to premature infants for indications other than tuberculosis. In addition, anecdotal information supports the notion that PZA, STM, and kanamycin are safe in neonates. Young infants taking these drugs should have biochemical monitoring of serum liver enzymes and uric acid (for PZA) performed on a regular basis. Although the pharmacokinetics of antituberculosis drugs in the neonate are essentially unknown, extensive clinical experience suggests that the doses listed in Table 19-3 are effective and safe. All neonates and infants with tuberculosis should be treated by directly observed therapy.

Following the Infant on Therapy Follow-up of children treated with antituberculosis drugs has become somewhat more streamlined in recent years. While receiving chemotherapy, the patients should be seen monthly, both to encourage regular taking of the prescribed drugs and to check, by a few simple questions (concerning appetite, well-being) and a few observations (weight gain; appearance of skin and sclerae; palpation of liver, spleen, and lymph nodes), that the disease is not spreading and that toxic effects of the drugs are not appearing. Repeat chest radiographs probably should be obtained 1 to 2 months after the onset of chemotherapy to ascertain the maximal extent of disease before chemotherapy takes effect; thereafter, radiographs rarely are necessary. Chemotherapy has been so successful that follow-up beyond its termination is not usually necessary, except for children with serious disease, such as congential tuberculosis or meningitis, or those with extensive residual chest radiographic findings at the end of chemotherapy. Every case of definite or suspected tuberculosis must, by law, be reported immediately by telephone to the health department to ensure ( 1) prompt contact i n ~ e s t i g a t i o n ' ~ ~ - ' ~ ~ and (2) free antituberculosis drugs, which are available for diagnosed cases and for intimate contacts in almost every state of the United States.

Prognosis Neonates and Infants The optimal treatment of congenital tuberculosis has not been established, because the rarity of this condition precludes formal treatment trials. It would appear that the basic principles for treatment of other diseases in children and adults also apply to the treatment of congenital tuberc u l ~ s i s . ' ~ All ~ ~ children ' ~ ~ ~ ' ~with ~ suspected congenital tuberculosis should be started on four antituberculosis medications (INH, RIF, PZA,plus either EMB or STM) until the diagnostic evaluation and susceptibility testing of isolated organisms is concluded. Although the optimal duration of therapy has not been established, many experts treat infants with congenital or postnatally acquired tuberculosis for a total duration of 9 to 12 months because of the decreased immunologic capability of the young infant. INH given alone is known to be safe in neonates, including premature infants. There are no comparable data for INH given in combination with other drugs or for other drugs alone.

The prognosis for congenital tuberculosis was dismal in the prechemotherapy era.*'' In Hughesdon's report,Io43 infants died on the first day of life, 8 between 18 and 30 days, 15 between 31 and 60 days, and 3 between 65 and 112 days. Hageman and associate^^^ reviewed 26 patients born since the introduction of INH in 1952: 12 died, and 9 of these were untreated, the diagnosis being established only at autopsy. The results in survivors were good, but the follow-up was usually short.'52920' The child reported by Nemir and O'Hare,"' who was treated intensively with INH, STM, and aminosalicylic acid in the 1950s,recovered, was followed for 27 years, and is herself the mother of two tuberculin-negative children. There is little question that today's multidrug, shortcourse chemotherapeutic regimens should be extremely effective in bringing the disease under rapid and permanent control, if it is due to drug-susceptible organisms. Experience with treatment of disease due to drug-resistant organisms is so limited as to preclude prognosis.

Chapter 19

VACCINATION AGAINST TUBERCULOSISBACILLE CALMElTE-GUERIN B a d e Calmette-Gukrin (BCG) vaccines are the oldest of the vaccines used throughout the world. They have been given to 4 billion people and have been used routinely since the 1960s in every country of the world except the United States and the Netherlands. However, despite their widespread use, tuberculosis remains among the most destructive infectious diseases in the world, indicating that the BCG vaccines alone will not be sufficient to eliminate or even control the disease.

Tuberculosis

593

in neonates, including lymphadenitis and o ~ t e i t i s . ~ There ’~-~’~ is no consensus about which strain of BCG is optimal for general use. It has been postulated that investigators and public health authorities have selected BCG strains by their desire to maximize tuberculin reactivity and minimize adenitis, which may create strains that are the inverse of the ideal vaccine. It also appears that some BCG strains have lost efficacy over time.216

Vaccine Preparation and Administration

Seed lots are lyophilized bacilli that are part of the original harvest of the various BCG strains. The bacilli usually are History and Development of Bacille Calmettegrown in Sauton medium and are harvested early (day 6 to Guerin Vaccines 9) to ensure good survival of organisms after lyophilization. The mass of mycobacterial cells is filtered, pressed, homogThe BCG vaccines are attenuated strains of M. bovis. Starting enized, diluted, then freeze dried. Reconstituted vaccines in 1908,the original strain was subcultured every 3 weeks for contain both live bacilli and dead bacteria. Regulating the 13 years.202The genotype changes that resulted at various ratio of live to dead organisms is an important aspect of stages cannot be determined because the original cultures quality control, and can affect both efficacy and rates of and subcultures were not preserved. This long process was adverse reactions. marked by a loss of virulence first for calves, then for guinea Most BCG vaccine programs favor the intradermal route pigs. In 1948, despite the complete lack of reported controlled of administration using a syringe and needle. Japan and trials or case-control studies, the First International BCG most of South Africa use percutaneous administration with Congress stated that the BCG vaccines were effective and a multipuncture device. It is generally accepted that the safe. After World War 11, the WHO and UNICEF organized intradermal method is more accurate and consistent because campaigns to promote vaccination with BCG in several the dose is measured precisely and the administration is countries. The seed lot system for BCG was established in controlled. The deltoid region of the arm is the most common 1956:’’ and the WHO developed requirements for freezeinjection site, although many other body sites are used in dried BCG in 1966.203By the end of 1974, more than 1.5 individual patients. More than 90% of patients receiving their billion individuals had received a BCG vaccination. Since first BCG vaccination develop a local reaction (erythema, 1977, BCG vaccination has been included in the WHO induration, tenderness) followed by healing and scar formation Expanded Programme on Immunization. Approximately within 3 months. 100 million children receive a BCG vaccination each year, Other methods of administration were developed to try expanding the total number of individuals who have to address problems of local reactions created by intradermal received it to more than 4 billion. administration. Subcutaneousinjection appears to be effective The original strain of M. bovis used to make BCG was but often produces retracted scars. Other techniques, such as maintained by serial passage at the Pasteur Institute until it scarification, jet injection, and use of bifurcated needles, was lost or discarded. It previously was distributed to dozens have yielded highly variable and, in some cases, inadequate of laboratories, each of which produced and maintained its There have been no conclusive reported trials that own BCG stain. It soon became apparent that the conditions compared the various techniques of BCG administration for for culture used in the various laboratories resulted in the protection against tuberculosis, but local complication rates production of many “daughter” BCG strains that differed generally are lowest with the multipuncture devices. widely in growth characteristics, biochemical activity, ability to induce delayed hypersensitivity,and animal ~ i r u l e n c e . ~ ~ ~ - ~ ’ ~ The patterns of large restriction fragments created by the Adverse Reactions to Bacille Calmette-Guerin digestion of BCG DNA vary among strainsFo8In the 1960s, Vaccination the WHO recommended stabilization of the biologic characteristics of the derivative strains by lyophilization and Local ulceration and regional lymphadenitis are the most storage at low temperature^.^'^ common complications, occurring in less than 1% of immunocompetent recipients after intradermal administration Interlaboratory studies and genomic evaluation have of BCG>18,219 These lesions usually occur within a few weeks shown that the BCG strains in use today vary widely in many to months after vaccination but can be delayed for months characteristics.2’0’2’1 However, the possible consequences on in immunocompetent persons and for years in immunovaccine efficacy and adverse effects are not known. When comparing the various published clinical trials and casecompromised hosts.”’ M a r y , cervical, or supraclavicular nodes may be involved on the ipsilateral side of vaccination. control series, it is difficult to demonstrate that one strain of Outbreaks of lymphadenitis after BCG vaccination have BCG is superior to another in the protection of humans followed the introduction of a new BCG strain into the against tuberculosis.Some laboratory and clinical observations vaccination program.221v222 There is no evidence that have suggested that BCG strains can be separated into children who experience local complications are more likely “strong” (Pasteur 1173 P2, Danish 1331) and “weak” (Glaxo to have immune deficits or to have enhanced or diminished 1077, Tokyo 172) groups. Although the relative efficacy of protection against tuberculosis.22’,222 Because the risk of these two groups has been inconsistent, the strong strains lymphadenitis is significantly higher when newborns are have been associated with a higher rate of adverse reactions

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given a full dose of BCG, the WHO recommends using a reduced dose in children younger than 30 days of age. The treatment of local adenitis as a complication of BCG vaccination is controversial, ranging from observation to surgicaldrainage to administration of antituberculosischemotherapy to a combination of surgery and chemotherapy.223 Nonsuppurative lymph nodes usually resolve spontaneously, although resolution may take several The WHO recommends drainage and direct instillation of an antituberculosis drug into the lesion for adherent or fistulated lymph nodes.226However, one study of 120 patients with BCG-induced lymphadenitis treated for 6 months with an oral antituberculosis drug showed that medical therapy was no better than observation and that the rate of spontaneous drainage of lymph nodes was higher among children who received isoniazid than among those who were only 0bserved.2~’Most experts now agree that nonsuppurative adenitis associated with BCG vaccination should be managed by observation only. Other complications of BCG vaccination are far less frequent. The mean risk of osteitis after BCG vaccination has varied from 0.01 per million in Japan to 300 per million in Fdand.228-230 As with lymphadenitis, osteitis rates occasionally have increased dramatically after introduction of a new vaccine strain into a vaccination program. Other very rare complications of BCG vaccination include lupus vulgaris, erythema nodosum, iritis, and osteomyelitis. In general, these complications should be treated with antituberculosis medications (except pyrazinamide, to which M. bovis is resistant). Generalized BCG infection is extremely rare in immunocompetent However, overall rates of fatal disseminated BCG disease in recently vaccinated persons have been reported at 0.19 to 1.56 cases per million vaccinated, most cases occurring in children with severe defects in cellular immunity, such as severe combined immunodeficiency, malnutrition, cancer, Di George syndrome, interferon-y receptor deficiency, or symptomatic HIV infection.2’8*234-240 It is likely that the real incidence of disseminated BCG infection is higher, as some cases undoubtedly are misdiagnosed as disseminated tuberculosis. The exact safety of BCG vaccination in children and adults with HIV infection is unknown. Disseminated BCG infection has been described in an HIVinfected adult 30 years after he received BCG.24’One French study showed that 9 of 68 HIV-infected children given BCG vaccine developed complications: 7 had large satellite adenitis and 2 developed disseminated lesions.242The WHO recommends giving BCG vaccination to asymptomatic HIV-infected infants who live in high-risk areas for tuberculosis. BCG vaccine is not recommended for symptomatic HIV-infected children, even if local tuberculosis case rates are high. Despite the presence of live BCG organisms in ulcerated vaccination sites, person-to-person transmission of BCG has never been documented.

Effect of Bacille Calmette-Guerin Vaccination on Tuberculin Skin Test Results Although BCG vaccines have an effect on the result of the tuberculin skin test, the effect is variable, and no reliable method can distinguish tuberculin reactions caused by BCG vaccination from those caused by infection with M. tuber-

culosis. In various studies with different populations, the proportion of individuals who were vaccinated with BCG previously who have had significant skin test reactions has varied from 0% to 90%.243-247 The size of the skin test reaction after BCG vaccination varies with the strain and dose of the vaccine, 245*248 the route of a d m i n i ~ t r a t i o n , 2 ~ ~ > ~ ~ ~ the age at the child’s nutritional status, the time interval since v a c c i n a t i ~ n , and ~ ~ ~the * ~frequency ~~ of skin testing.25’ Several studies have demonstrated that when newborns are given a BCG vaccination, up to 50% have a negative tuberculin skin test reaction at 6 months of age and the vast majority have a negative reaction by 2 to 5 years of age?447252 However, interpretation of the skin test result in BCGvaccinated children may be complicated by the booster phenomenon. The booster effect is the increase in reaction size caused by repetitive testing in a person sensitized to mycobacterial antigens.253Skin test reactions can be boosted in children who previously received a BCG vaccination, giving the false impression of “conversion” of a skin test from negative to positive, which usually indicates a new tuberculosis infection.254 Strong or severe reactions to a tuberculin skin test are rare in individuals who have been vaccinated with BCG previously who are not also infected with M. tuberculosis. Prior receipt of a BCG vaccine is never a contraindication for tuberculin skin testing. Most skin reactions due to BCG vaccination are less than 10 mm in size. In general, the tuberculin skin test should be interpreted in the same manner for an adult or child who has received a BCG vaccination as it is for a person with similar epidemiologic characteristics who has not received BCG.

Effectiveness of the Bacille Calmette-Guerin Vaccines A detailed discussion of the effectiveness of the BCG vaccines and the variables that may have an impact on effectivenessis beyond the scope of this chapter. There have been eight major controlled trials conducted in a variety of populations and many published case-control and cohort studies of various BCG preparation^.^^^,^^^ Investigators at the Harvard School of Health found 15 prospective trials and 12 casecontrol studies that met their criteria for adequacy in study design and controls against potential bias. In the prospective trials, the protective effect of BCG vaccines against tuberculosis disease was 51%.256Analysis of eight studies involving only vaccination of newborns revealed a protective effort of 55%.255For trials that measured these outcomes, BCG vaccines showed 71% protection against death from tuberculosis, 64% protection against tuberculosis meningitis, and 72% protection against disseminated tuberculosis. Different BCG preparations and strains used in the same population gave similar levels of protection, whereas genetically identical BCG strains gave different levels of protection in different p o p ~ l a t i o n s The . ~ ~duration ~ ~ ~ ~ ~of any protective effect is poorly studied and unknown but probably short-lived (less than 10 years at best). It appears that BCG vaccines have worked well in some circumstances but poorly in others. Because only a small percentage of infectious cases of tuberculosis in adults are prevented by childhood BCG vaccination, BCG vaccination

Chapter 19 Tuberculosis as currently practiced is not an effective instrument of disease control. The best use of BCG is the prevention of lifethreatening forms of tuberculosis-meningitis and disseminated, severe pulmonary diseasein infants and young children.

MANAGEMENT OF A NEONATE BORN TO A MOTHER WITH A POSITIVE TUBERCULIN SKIN TEST RESULT

595

become nonadherent to her treatment, or if she is thought to be infected with a drug-resistant strain of M. tuberculosis. INH therapy should be continued in the infant at least until the mother has been shown to be culture negative for 3 months. At that time, a Mantoux tuberculin skin test is done on the child. If the result is positive, the infant should be investigated for the presence of tuberculosis with a physical examination and chest radiograph and further appropriate workup if disease is suggested. If disease is absent, the infant should continue INH for a total of 9 months. If the followup skin test result is negative and the mother or contact with tuberculosis has good adherence and response to treatment, INH many be discontinued in the infant. The infant needs close follow-up, and it is prudent to repeat a tuberculin s h n test after 6 to 12 months. If the mother or other family member with contagious tuberculosis has disease caused by a multidrug-resistant strain of M. tuberculosis or has poor adherence to treatment and better supervision of therapy for the adult and infant is not possible, the Centers for Disease Control and Prevention recommends that the infant be separated from the contagious adult and BCG vaccination be considered.261,262 Vaccination with BCG appears to decrease the risk of tuberculosis in exposed infants, but the effect is ~ a r i a b l e . ~ ~ ~ - * ~ Kendig265 reported 117 infants born to mothers with active tuberculosis around the time of delivery; none of the 30 BCG-vaccinated infants developed tuberculosis, and 38 cases of tuberculosis and three deaths occurred among the 75 infants who received neither BCG vaccine nor INH therapy. However, 24 of the 30 infants who received BCG vaccine also were separated from their mother for at least 6 weeks; it is impossible to determine what degree of protection was conferred by this separation. Similar studies in England and Canada also describe the apparent efficacy of BCG given to neonates.266Usually, the child must be kept out of the household, away from the contagious case, until the skin test result becomes reactive (marking protection from infection). However, some infants who receive a BCG vaccination do not develop a reactive tuberculin skin test. It is unknown whether developing a reactive skin test correlates with protection. It is also unknown whether a second BCG vaccination given to a child who maintains a negative tuberculin skin test reaction after the first BCG vaccination will cause an enhanced level of protection. Although BCG vaccines have some protective effect for the exposed newborn, most experts in the United States feel that ensuring appropriate separation and taking whatever steps are necessary to provide adequate chemotherapy for the child and the contagious adult are a better approach than BCG vaccination. The use of directly observed therapy has made the need for BCG vaccination of infants in the United States almost nonexistent.

If the mother is well and her chest radiograph result is normal, no separation of the mother and infant is required. Although the mother is a candidate for treatment of M. tuberculosis infection, the infant does not need special evaluation or therapy. Other family members should have a tuberculin skin test and further evaluation, if indicated. The local health department, however, often does not have the resources to do this testing, which should be performed by the treating physicians. It is not necessary to delay discharge of the infant from the newborn nursery pending the results of this family investigation. The need for further skin testing of the infant depends on whether disease is found in the family or cannot be excluded within the family's environment. If the radiograph result is abnormal, the mother and child should be separated until the mother has been evaluated thoroughly. If active tuberculosis is present in the mother, she should be started on effective antituberculosis medications right away. Examination of the mother's sputum for acidfast organisms always is necessary even if obtaining a sample requires vigorous measures. All other household members and frequent visitors should be investigated for M. tuberculosis infection and disease. If the mother's chest radiograph result is abnormal but the history, physical examination, sputum smear, and evaluation of the radiograph reveal no evidence of active tuberculosis, it is reasonable to assume that the infant is at low risk for infection and that the radiographic abnormality is due to another cause or a quiescent focus of previous infection with M. tuberculosis.If the mother remains untreated, however, she may develop reactivation tuberculosis and subsequently expose her infant. The mother, if not previously treated, should receive appropriate therapy, and she and her infant should receive frequent follow-up care. In this situation, the infant does not need chemotherapy. All household members should be evaluated for tuberculosis by a clinician. If the mother has clinical and radiographic evidence of active, possibly contagious, tuberculosis, the local health department should be informed immediately about the mother so that a contact investigation can be performed. The infant should be evaluated for congenital tuberculosis with a physical examination and high-quality posteroanterior and lateral chest radiographs. If possible, serologic testing MANAGEMENT OF NEONATES AFTER for HIV should be performed on the mother and her infant. POSTNATAL EXPOSURE The mother and infant should be separated until the infant is receiving chemotherapy or the mother is judged to be From time to time, workers in nurseries have been found to n o n c o n t a g i o ~ s .Prophylactic ~~~ INH (10 mg/kg per day) for have infectious t u b e r c u l ~ s i s . " ~ These ~ ~ ~ ~experiments of newborns born to mothers with tuberculosis has been so efficacious that separation of the mother and infant is no nature provide useful data on the risk to the infants. In longer considered mandatory once therapy is ~ t a r t e d . ~ ~ ' -general, ~ ~ ~ risk of infection of neonates in a modern hospital nursery appears to be low. Most nurseries have large air Separation should occur only if the mother is ill enough volumes, flows, and adequate air exchanges to decrease the to require hospitalization, if she has been or is expected to

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risk of infection. Also, the minute volume of neonates is low, diminishing the risk of infection after a brief time of exposure. Light and co-w~rkers’~~ followed 437 infants exposed to a nurse with a cough and a sputum smear that was positive for tuberculosis. Of these infants, 160 were considered to be at greatest risk and received daily INH for 3 months; all infants remained tuberculin-negative. However, Steiner and colleagues”’ observed development of miliary tuberculosis in 2 of 1647 infants exposed in a nursery. Thus, infection is rare under nursery conditions, but it can and does occur. Strict control measures should prevent such episodes. Nursery personnel should undergo Mantoux testing before starting work and, if the result is negative, yearly thereafter. If the skin test is positive, a prospective employee should have a chest radiograph. If the radiograph result is normal, appropriate therapy for M. tuberculosis infection should be given, accompanied by careful medical follow-up. Prospective employees with positive skin tests and abnormal chest radiographs must be carefully and thoroughly evaluated. Many require antituberculosis therapy. Theoretically, these same guidelines apply to workers in licensed and unlicensed daycare facilities, but in many cases they have not yet been implemented. Children with primary tuberculosis are rarely contagious because of the nature of their pulmonary disease, absence of forceful cough, and small number of organisms in the diseased t i s s ~ e . ~ ~Infants * , ~ ~ ’with congenital tuberculosis often have extensive pulmonary involvement with positive acid-fast stains of tracheal aspirates and large numbers of tubercle bacilli in the lungs and In several cases, there has been evidence of transmission of M. tuberculosis from congenitally infected infants to health care workers; transmission to other infants has not been rep~rted.’~’-’~~ Neonates with suspected congenital tuberculosis should be placed in appropriate isolation until it can be determined that they are not infectious, by acid-fast stain and culture of respiratory secretions. If a member of the household other than the mother is found to have or to have had tuberculosis recently, the roles of chemotherapy and BCG vaccine for the infant remain controversial. If the tuberculous family member has completed treatment in the past, that individual should undergo a checkup before the infant enters the home. If the family member is still being treated, he or she should have been sputum culture negative for at least 3 months before contact with the infant. If the infant must return to a home in which one of the family members has only recently started treatment, he or she should receive daily INH for at least 3 to 4 months, which Dormer and associates258showed to be very effective in preventing the development of tuberculosis in infants born to mothers in a sanatorium. If the family cannot be relied on to administer daily medication, if directly observed therapy is impossible, or if there are a number of household members who may have tuberculosis, BCG vaccination of the neonate should be considered.

CONCLUSION Perinatal tuberculosis, although rare, will continue to occur, particularly among high-risk groups such as blacks, Hispanics, Asian or Pacific Islanders, Native Americans Alaskan natives, and particularly among recent immigrants to the United

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culosis infection and disease after household exposure to adult index cases in Alaska. J Pediatr 132:509-513, 1998. 195. MacIntyre CR, Plant AJ. Preventability of incident cases of tuberculosis in recently exposed contacts. Int J Tuberc Lung Dis 2:56-61, 1998. 196. Mehta JB, Bentley S. Prevention of tuberculosis in children: missed opportunities. Am J Prev Med 8:283-286,1992. 197. Nolan R Jr. Childhood tuberculosis in North Carolina: a study of the opportunities for intervention in the transmission of tuberculosis in children. Am J Public Health 7626-30,1986. 198. Rodrigo T, Cayla JA, de Olalla PG, et al. Characteristics of tuberculosis patients who generate secondary cases. Int J Tuberc Lung Dis 1~352-357,1997. 199. Spark RP, Pock NA, Pedron SL, et al. Perinatal tuberculosis and its public health impact: a case report. Texas Med 92:50-53, 1996. 200. Kendig EL Jr. Prognosis of infants born of tuberculous mothers. Pediatrics 2697- 100, 1960. 201. Laurance BM. Congenital tuberculosis successfully treated. Letter to the editor. BMJ 2:55, 1973. 202. International Union against Tuberculosis. Phenotypes of BCG vaccine seed lot strains: results of an international cooperative study. Tubercle 5 9 139- 142,1978. 203. Milstein JB, Gibson JJ. Quality control of BCG vaccines by WHO: a review of factors that may influence vaccine effectiveness and safety. Bull World Health Org 68:93-108,1990. 204. Osborn TW.Changes in BCG strains. Tubercule 641-13,1983. 205. Jacox RF, Meade GM. Variation in the duration of tuberculin skin test sensitivity produced by two strains of BCG. Am Rev Tuberc 60541-546, 1949. 206. Dubos RJ, Pierce CH. Differential characteristics in vitro and in vivo of several substrains of BCG. I. Multiplication and survival in vitro. Am Rev Tuber Pulm Dis 74655-666,1956. 207. Dubos RJ, Pierce CH. Differential characteristics in vitro and in vivo of several substrains of BCG. IV. Immunizing effectiveness. Am Rev Tuberc Pulm Dis 74699-717,1956, 208. Zhang Y, Wallace RJ Jr, Mazurek GH. Genetic differences between BCG substrains. Tuberc Lung Dis 76:43-50, 1995. 209. Gheorghiu M. The present and future role of BCG vaccine in tuberculosis control. Biologicals 18135-141, 1990. 2 10. Gheorgluu M, Lagrange PH. Viability, heat stability and immunogenicity of four BCG vaccines prepared from four different BCG strains. Ann Irnmunol (Paris) 134C125-147,1983. 21 1. Behr MA. Correlation between BCG genomics and protective efficacy. Scan J Infect Dis 33:249-252,2001. 212. Lehman HG, Englehardt H, Freudenstein H, et al. BCG vaccination of neonates, infants, school children and adolescents. 11. Safety of vaccine with strain 1331 Copenhagen. Dev Biol Stand 43:133-135, 1979. 213. Expanded Programme o n ImmunizationlBiologicals Unit. Lymphadenitis associated with BCG immunization. Wkly Epidemiol Rec 63:381-388, 1988. 214. Expanded Programme on ImmunizationlBiologicals Unit. BCG associated lymphadenitis in infants. Wkly Epidemiol Rec 30231-323, 1989. 215. Kroger L, Brander E, Korppi M, et al. Osteitis after newborn vaccination with three different bacillus Calmette-GuCrin vaccines: twenty-nine years of experience. Pediatr Infect Dis J 12:113-116, 1994. 216. Behr MA, Small PM. Declining efficacy of BCG strains over time? A new hypothesis for an old controversy [abstract]. Am J Respir Crit Care Med 155~4222,1997. 217. Ten Dam HG. Research on BCG vaccination. Adv Tuberc Res 21: 79-106,1984. 218. Lotte A, Wasz-Hockert 0, Poisson N, et al. Second IUATLD study on complications induced by intradermal BCG-vaccination. Bull Int Union Tuberc 63:47-59, 1988. 219. Turnbull FM, McIntyre PB, Achat HM, et al. National study of adverse reactions after vaccination with bacille Calmette-GuCrin. Clii Infect Dis 34447-453,2002. 220. Reynes J, Perez C, Lamaury I, et al. Bacille Calmette-Gukrin adenitis 30 years after immunization in a patient with AIDS. Letter to the editor. J Infect Dis 160727, 1989.

600

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221. Helmick CG, D’Souza AJ, Goddard N. An outbreak of severe BCG axillary lymphadenitis in Saint Lucia, 1982-83. West Indies Med J 35:12-17,1986. 222. Praveen KN, Smikle MF, Prabhakar P, et al. Outbreak of bacillus Calmette-GuCrin-associated lymphadenitis and abscesses in Jamaican children. Pediatr Infect Dis J 9:890-893, 1990. 223. Goraya JS, Virdi VS. Treatment of Calmette-Guerin bacillus adenitis: a meta-analysis. Pediatr Infect Dis J 20:632-634.2001. 224. Singla A, Singh S, Goraya JS, et al. The natural course of nonsuppurative Calmette-GuCrin bacillus lymphadenitis. Pediatr Infect Dis J 2146-448,2002. 225. Oguz F, Mujgan S, Alper G, et al. Treatment of bacillus CalmetteGuCrin associated lymphadenitis. Pediatr infect Dis J 11:887-888,1992. 226. World Health Organization. BCG Vaccination of the Newborn: Rationale and Guidelines for Country Programs. Geneva, World Health Organization, 1986. 227. Micheli I, de Kantor IN, Colaicicovo D, et al. Evaluation of the effectiveness of BCG vaccination using the case control method in Buenos Aires, Argentina. Int J Epidemiol 17629-634, 1988. 228. Lotte A, Wasz-Hockart 0,Poisson N, et al. BCG complication: estimates of the risks among vaccinated subjects and statistical analysis of their main characteristics. Adv Tuberc Res 21:107-193, 1984. 229. Kroger L, Korppi M, Brander E, et al. Osteitis caused by bacillus Calmette-GuCrin vaccination: a retrospective analysis of 222 cases. J Infect Dis 172:574-576, 1995. 230. Bottiger M. Osteitis and other complications caused by generalized BCGitis. Acta Paediatr Scand 71:471-478, 1982. 231. Pederson FK,Engbaek HC, Hertz H,Vergmann B. Fatal BCG infection in an immunocompetent girl. Acta Paediatr Scand 67:519-523, 1978. 232. Trevenen CL, Pagtakhan RD. Disseminated tuberculoid lesions in infants following BCG. Can Med J 15:502-504, 1982. 233. Tardieu M, Truffot-Pernot C, Carriere JP,et al. Tuberculosis meningitis due to BCG in two previously healthy children. Lancet 1:440-441, 1988. 234. Hesseling AC, Schaaf HS, Hanekom WA, et al. Danish bacilli CalmetteGuerin vaccine-induced disease in human immunodeficiency virusinfected children. Clin Infect Dis 37:1226-1233,2003. 235. Casanova JL, Blanche S , Emile JF, et al. Idiopathic disseminated bacilli Calmette-Guerin infection: a French national retrospective study. Pediatrics 98:774-778, 1996. 236. Gonzalez B, Moreno S , Burdach R, et al. Clinical presentation of bacillus Calmette-Guerin infections in patients with immunodeficiency syndromes. Pediatr Infect Dis J 8:201-206, 1989. 237. Houde C, Dery P. Mycobacterium bovis sepsis in an infant with human immunodeficiency virus infection. Pediatr Infect Dis J 11:810-811,1988. 238. Talbot EA, Perkins MD, Silva SFM, et al. Disseminated bacille Calmette-Guerin disease after vaccination: case report and review. Clin Infect Dis 241139-1 146, 1997. 239. Jovanguy E, Altare F, Lamhamedi S, et al. Interferon-yreceptor deficiency in an infant with fatal b a d e Calmette-Guerin infection. N Engl J Med 3351956-1961, 1996. 240. Elloumi-Zghal H, Barbouch MR, Chemli J, et al. Clinical and genetic heterogeneity of inherited autosomal recessive susceptibility to disseminated Mycobacterium bovis bacille Calmette-Guerin infection. J Infect Dis 1851468-1475,2002. 241. Armbruster C, Junker W, Vetter N, et al. Disseminated bacille Calmette-Guerin infection in AIDS patient 30 years after BCG vaccination. Letter to the editor. J Infect Dis 162:1216, 1990. 242. Besnard M, Sauvion S, Offredo C, et al. Bacillus Calmette-Guerin infection after vaccination of human immunodeficiency virus-infected children. Pediatr Infect Dis J 12:993-997, 1993. 243. Menzies R, Vissandjee B. Effect of bacille Calmette-Guerin vaccination on tuberculin reactivity. Am Rev Respir Dis 145:621-625, 1992. 244. Lifschitz M. The value of the tuberculin skin test as a screening test for tuberculosis among BCG vaccinated children. Pediatrics 36:624-627, 1965. 245. Honvitz 0, Bunch-Christensen K. Correlation between tuberculin sensitivity after 2 months and 5 years among BCG-vaccinated subjects. Bull World Health Organ 47:49-58, 1972. 246. Comstock GW, Edwards LB, Nabangxang H. Tuberculin sensitivity eight to fifteen years after BCG vaccination. Am Rev Respir Dis 103:572-575, 1971. 247. Landi S , Ashley MJ, Grzybowski S. Tuberculin skin sensitivity following the intradermal and multiple puncture methods of BCG vaccination. Can Med Assoc J 97:222-225,1967.

248. Ashley MJ, Seibenmann CO. Tuberculin skin sensitivity following BCG vaccination with vaccines of high and low viable counts. Can Med Assoc J 97:1335-1338, 1967. 249. Kemp EB, Belshe RB, Hoft DF. Immune responses stimulated by percutaneous and intradermal b a d e Calmette-Guerin. J Infect Dis 174~113-119,1996. 250. Joncas JH, Robitaille R, Gauthier T. Interpretation of the PPD skin test in BCG-vaccinated children. Can Med Assoc J 113:127-128,1975. 251. Mangus K, Edwards LB. The effect of repeated tuberculin testing on post-vaccination allergy. Lancet 1:643-644, 1955. 252. Karalliede S , Katugha LP, Uragoda CG. The tuberculin response of Sri Lankan children after BCG vaccination at birth. Tubercle 68:33-38, 1987. 253. Thompson NJ, Glassroth JL, Snider DE, et al. The booster phenomenon in serial tuberculin testing. Am Rev Respir Dis 119587-597, 1979. 254. Sepulveda RL, Burr C, Ferrer X, et al. Booster effect of tuberculin testing in healthy 6-year-old school children vaccinated with bacillus Calmette-Guerin at birth in Santiago, Chile. Pediatr Infect Dis J 7~578-581,1988. 255. Colditz G, Berkey CS, Mosteller F, et al. The efficacy of bacillus CalmetteGuerin vaccination of newborns and infants in the prevention of tuberculosis: meta-analysis of the published literature. Pediatrics 96~29-35,1995. 256. Colditz GA, Brewer TF, Berkey CS, et al. Efficacy of BCG vaccine in the prevention of tuberculosis: meta-analysis of the published literature. JAMA 271:698-702, 1994. 257. Avery ME, Wolfsdorf J. Diagnosis and treatment: approaches to newborn infants of tuberculous mothers. Pediatrics 42:519-521,1968. 258. Dormer BA, Harrison I, Swart JA,et al. Prophylactic isoniazid protection of infants in a tuberculosis hospital. Lancet 2:902-903,1959. 259. Light IJ, Saidleman M, Sutherland JM. Management of newborns after nursery exposure to tuberculosis. Am Rev Respir Dis 109:415-419, 1974. 260. Raucher HS, Grimbetz I. Care of the pregnant woman with tuberculosis and her newborn infant: a pediatrician’s perspective. Mt Sinai J Med 53:70-75, 1986. 261. Centers for Disease Control and Prevention. The role of BCG vaccine in the prevention and control of tuberculosis in the United States: a joint statement by the Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 45(RR-4):1-18,1996. 262. Sedaghatian MR, Hashem F, Hossain MM. Bacille Calmette Guerin vaccination in pre-term infants. Int J Tuberc Lung Dis 2679-682, 1998. 263. Lorber J, Menneer PC. Long-term effectiveness of BCG vaccination of infants in close contact with infectious tuberculosis. BMJ 1:14301433, 1959. 264. Pabst HF, Godel J. Grace M, et al. Effect of breastfeeding on immune response to BCG vaccination. Lancet 1:295-297, 1989. 265. Kendig EL Jr.The place of BCG vaccine in the management of infants born to tuberculous mothers. N Engl J Med 281:520-523,1969. 266. Curtis HM, Bamford FN, Leck I. Incidence of childhood tuberculosis after neonatal BCG vaccination. Lancet 1:145-148, 1984. 267. Nivin B, Nicholas P, Gayer M, et al. A continuing outbreak of multidrugresistant tuberculosis with transmission in a hospital nursery. Clin Infect Dis 26:303-307, 1998. 268. Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities. MMWR Morb Mortal Wkly Rep 43(RR-13):1-133,1994. 269. Starke JR. Transmission of Mycobacterium tuberculosis to and from children and adolescents. Sem Pediatr Infect Dis 12:llS-123, 2001. 270. Lee HL, LeVea CM, Graman PS. Congenital tuberculosis in a neonatal intensive care unit: case report, epidemiological investigation, and management of exposures. Clin Infect Dis 27:474-477, 1998. 271. Manji KP, Msemo G, Tamian B, et al. Tuberculosis (presumed congenital) in a neonatal unit in Dar-es-Salaam, Tanzania. J Trop Pediatr 47:153-155,2001, 272. Pillay T, Adhikari M. Congenital tuberculosis in a neonatal intensive care unit. Clin Infect Dis 29:467-268, 1999. 273. Machin GA, Honore LH, Fanning EA, et al. Perinatally acquired neonatal tuberculosis: report of two cases. Pediatr Pathol 12707-716, 1992. 274. Rabalais G, Adams G, Stover B. PPD skin test conversion in healthcare workers after exposure to Mycobacteriurn tuberculosis infection in infants. Lancet 338:826, 1991.

Chapter 19 275. Saitoh M, Ichiba H, Fujioka H, et al. Connatal tuberculosis in an extremely low birth weight infant: case report and management of exposure to tuberculosis in a neonatal intensive care nursery. Eur J Pediatr 160:88-90,2001.

Tuberculosis

601

276. Laartz BW, Narvarte HJ, Hold D, et al. Congenital tuberculosis and management of exposures in a neonatal intensive care unit. Infect Control Hosp Epidemiol23:573-579,2002.

Chapter 20 MICROORGANISMS RESPONSIBLE FOR NEONATAL DIARRHEA Miguel L. O'Ryan

James P. Nataro

Thomas G. Cleary

Enteric Host Defense Mechanisms 604

Aeromonas hydrophila 633

Protective Factors in Human Milk 604

Nature of the Organism, Epidemiology, and Pathogenesis Clinical Manifestations Diagnosis and Therapy

Escherichia coli 605 Enterotoxigenic Escherichia coli Enteroinvasive Ercherichia coli Enteropathogenic Escherichia cork Classic Serotypes Enterohemorrhagic Escherichia coli Enteroaggregative Escherichia coli Other Escherichia coli Pathotypes

Salmonella 619 Nature of the Organism Epidemiology and Transmission Clinical Manifestations Diagnosis Therapy Prevention

Plesiomonasshigelloides 634 Other Bacterial Agents and Fungi 634 Parasites 635 Entamoeba histolytica Giardia lamblia Ctyptosporidium

Viruses 636 Enteric Viruses Rotavirus Differential Diagnosis 640

Shigella 624 Nature of the Organism Epidemiology Clinical Manifestations Diagnosis Therapy Prevention

Campylobacter 627

. .

Nature of the Organism Pathogenesis Pathology Epidemiology Clinical Manifestations Diagnosis Therapy Prevention

Closttidium difficile 631 Nature of the Organism and Pathophysiology Epidemiology Clinical Manifestations Diagnosis Therapy Prevention

Vibrio cholerae 632 Nature of the Organism Pathogenesis Epidemiology Clinical Manifestations Diagnosis Therapy and Prevention

Yersinia enterocolitica 633 Nature of the Organism, Epidemiology, and Pathogenesis Clinical Manifestations Diagnosis Therapy

At the beginning of the 1st century, diari..eal disease continues to be a significant cause of morbidity and mortality worldwide. During the period of 1986 to 2000, an estimated 1.4 billion children younger than 5 years suffered an episode of acute diarrhea every year in developing countries; among these, 123.6 million required outpatient medical care, and 9 million required hospitalization. Approximately 2 million diarrhea-associated deaths occurred in this age group annually, primarily in the most impoverished areas of the world.' These estimates are somewhat lower than the more than 3 million annual deaths from diarrhea reported in the prior 10 years? indicating progress in prevention and treatment of acute diarrhea. In the United States, approximately 400 childhood deaths per year were reported during the late 1 9 8 0 ~ ,although ~*~ the actual number may be higher: Accurate incidence rates for acute diarrhea in neonates from different populations are not readily available. The relative sparing of the newborn probably results from low exposure to enteropathogens and protection associated with brea~t-feeding.~-' After the first few months of life, increasing interaction with other individuals and the environment, including introduction of artificial feeding, increases the risk of exposure to enteropathogens. For most pathogens, the incidence of acute diarrhea peaks in children between 6 months and 4 years old? Neonatal diarrhea is more common in underdeveloped areas, where low educational levels, crowding,and poor standardsof medical care,environmentalsanitation, and personal hygiene favor early contact with enteropathogens. As the incidence of neonatal gastroenteritis rises, there is a proportional increase in neonatal deaths because medical care for the poor often is inadequate.'0*"For very low birth

604

Section I1


weight infants (~~~ cations of salmonellosis include p e r i ~ a r d i t i s ,p~y~e l i t i ~ , ~ ~Salmonella if two or three different enteric media (i.e., peritonitis:77 otitis media:77 mas ti ti^,^^^ chole~ystitis,~~' MacConkey's, eosin-methylene blue, Salmonella-Shigella, Tergitol 7, xylose-lysine-deoxycholate,brilliant green, or en d o p h t h al m i t i~,~~~ cutaneous abscesses,492and infected bismuth sulfite agar) are used. Stool, rather than rectal swab cephal~hematoma?~'Other focal infections seen in older material, is preferable for culture, particularly if the aim of children and adults, such as endocarditis and infected aortic culture is to detect carriers.560On the infrequent occasions aneurysms, rarely or never have been reported in neowhen proctoscopy is performed, mucosal edema, hyperemia, Although the mortality rate in two reviews of nates.537,549 friability, and hemorrhages may be seen.*' Infants who are nursery outbreaks was 3.7% to 7.0%,"959496 in some series, it bacteremic often do not appear sufficiently toxic to raise reached 18%.485 the suspicion of b a ~ t e r e m i a .Blood ~ ~ ~ cultures should be Enteric fever, most often related to S. typhi but also obtained as a routine part of evaluation of neonates with occurring with S. paratyphi A, S. paratyphi B, S. paratyphi C, suspected or documented Salmonella infection. Ill neonates and other Salmonella species, is reported much less with Salmonella infection should have a cerebrospinal fluid commonly in infants than in older patients. Infected infants examination performed. Bone marrow cultures also may be develop typical findings of neonatal sepsis and meningitis. indicated when enteric fever is suspected. There are no Current data suggest that mortality is about 30Y0.~~' In utero abnormalities in the white blood cell count. infection with S. typhi has been described. Typhoid f e ~ e r ~ " * ~ consistent ~' Serologic studies are not helpful in establishing the diagand nontyphoidal Salmonella infections552during pregnancy nosis, although antibodies to and flagellar put women at risk of aborting the fetus. Premature labor antigens487develop in many infected newborns. usually occurs during the second to the fourth week of If an outbreak of salmonellosis is suspected, further maternal typhoid if the woman is untreated.522In a survey of characterization of the organism is imperative?64 Determityphoid fever in pregnancy during the preantibiotic era, 24 nation of somatic and flagellar antigens to characterize the of 60 women with well-documented cases delivered specific serotype may be critical to investigation of an prematurely, with resultant fetal death; the rest delivered at outbreak. When the serotype found during investigation of term, although only 17 infants survived.553The outlook for an outbreak is a common one (e.g., S. typhimurium), anticarrying the pregnancy to term and delivering a healthy infant appears to have improved dramatically during the microbial resistance testing475,565 and use of molecular techantibiotic era. However, one of seven women with typhoid niques such as plasmid char a~ ter ization~ can~be ~ helpful in determining whether a single-strain, common-source outin a series still delivered a dead fetus with extensive liver necrosis.554In the preantibiotic era, about 14% of pregnant break is in progress. women with typhoid fever died.555With appropriate antimicrobial therapy, pregnancy does not appear to put the Therapy woman at increased risk of death. Despite these welldescribed cases, typhoid fever is rare early in life. As in all enteric infections, attention to fluid and electrolyte Of 1500 cases of typhoid fever that Osler and M ~ C r a e ~ abnormalities is the first issue that must be addressed by the ~~ physician. Specific measures to eradicate Salmonella reported, only 2 were in the first year of life. In areas where intestinal infection have met with little success. Multiple typhoid fever is still endemic, systematic search for infants with enteric fever has failed to find many cases. The few studies show that antibiotic treatment of Salmonella gastroinfections with S. typhi documented in children in the first enteritis prolongs the excretion of S a l m ~ n e Z l a . ~Almost ~~-~'~ year of life often present as a brief nondescript "viral one half of the infected children in the first 5 years of life ~ * ~ ~ diarrhea, ' cough, continue to excrete Salmonella 12 weeks after the onset of syndrome" or as p n e ~ r n o n i t i s ? ~ Fever, vomiting, rash, and splenomegaly may occur; the fever may infection; more than 5% have positive cultures at 1 year.574 be high, and the duration of illness may be many weeks.522 No benefit of therapy has been shown in comparisons of ampicillin or neomycin versus placebo,570chloramphenicol versus no antibiotic treatment:69 neomycin versus placebo:71 Diagnosis ampicillin or trimethoprim-sulfamethoxazoleversus no antibiotic:@' and ampicillin or amoxicillin versus placebo.572 The current practice of early discharge of newborn infants, although potentially decreasing the risk of exposure, can In contrast to these studies, data suggest that there may be a role for quinolone antibiotics in adults and ~ h i l d r e n , ~ ~ ~ , ~ ~ ~ make recognition of a nursery outbreak difficult. Diagnosis of neonatal salmonellosis should trigger an investigation for but these drugs are not approved for use in neonates, and other cases. Other than diarrhea, signs of neonatal Salmonella resistance has been en~ountered.~'~ Because these studies have few data as to the risk-benefit ratio of therapy in the infection are similar to the nonspecific findings seen in most neonate, it is uncertain whether they should influence treatneonatal infections. Lethargy, poor feeding, pallor, jaundice, ment decisions in neonates. Studies that have included a apnea, respiratory distress, weight loss, and fever are small number of neonates suggest little benefit from anticommon. Enlarged liver and spleen are common in those microbial therapy.477*487*56835773578 neonates with positive blood cultures. Laboratory studies are However, because bacteremia is common in neonates, antimicrobial therapy for infants required to establish the diagnosis because the clinical picture is not distinct. The fecal leukocyte examination reveals younger than 3 months who have Salmonella gastroenteritis polymorphonuclear leukocytes in 36% to 82%359.559 often is recommended,532v533v561 especially if the infant of appears toxic. Premature infants and those who have other persons with Salmonella infection, but it has not been

Chapter 20 significant debilitating conditions also should probably be treated. The duration of therapy is debatable but should probably be no more than 3 to 5 days if the infant is not seriously ill and if blood cultures are sterile. If toxicity, clinical deterioration, or documented bacteremia complicates gastroenteritis, prolonged treatment is indicated. Even with antimicrobial therapy, some infants develop complications. The relatively low risk of extraintestinal dissemination must be balanced against the well-documented risk of prolonging the carrier state. For infants who develop chronic diarrhea and malnutrition, hyperalimentation may be required; the role of antimicrobial agents in this setting is unclear. The infant with typhoid fever should be treated with an antimicrobial agent; relapses sometimes occur after therapy. Colonized healthy infants discovered by stool cultures during evaluation of an outbreak ought to be isolated but probably should not receive antimicrobial therapy. Such infants should be discharged from the nursery as early as possible and followed carefully as outpatients. Antimicrobial treatment of neonates who have documented extraintestinal dissemination must be prolonged. Bacteremia without localization is generally treated with at least a 10-day course of therapy. Therapy for Salmonella meningitis must be given for at least 4 weeks to lessen the risk of relapse. About three fourths of patients who have relapses have been treated for three weeks or less?37Similar to meningitis, treatment for osteomyelitis must be prolonged to be adequate. Although cures have been reported with 3 weeks of therapy, 4 to 6 weeks of therapy is recommended. In vitro susceptibility data for Salmonella isolates must be interpreted with caution. The aminoglycosides show good in vitro activity but poor clinical efficacy, perhaps because of the low pH of the phagolysosome. Aminoglycosides have poor activity in an acid environment. The stability of some drugs in this acid environment also may explain in vitro and in vivo disparities. The intracellular localization and survival of Salmonella within phagocytic cells also presumably explains the relapses encountered with virtually every regimen. Resistance to antibiotics has long been a problem with Salmonella i n f e c t i ~ n . ~ ~There , ~ ~ has ~ , ~been ~ ' a steady increase in resistance to Salmonella in the United States over the last 20 years.581With the emergence of typhimurium type DT 104, resistance to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline has increased from 0.6% in 1979and 1980 to 34% in 1996.582Resistance plasmids have been selected and transmitted, partly because therapy has been given for mild illness that should not have been treated566and partly because of use of antibiotics in animal feeds. Resistance to chloramphenicol and ampicillin has made trimethoprim-sulfamethoxazoleincreasingly important for the treatment of Salmonella infection in those patients who require therapy. However, with increasing resistance to all three of these agents in Asia?83the Middle E ~ r o p e , ~Ar ~ gentina,580 ~ , ~ ' ~ and North America,5793588,589 the third-generation cephalosporins and quinolones represent drugs of choice for invasive salmonellosis. The quinolones currently are not approved for persons younger than 18 years. Cefotaxime, ceftriaxone, and cefoperazone represent acceptable alternative drugs for typhoidal and nontyphoidal salmonellosis when resistance is e n c o ~ n t e r e d . ~Because ~"~~~ the second-generation cephalosporins, such as cefuroxime, are less active in vitro than the third-generation cephalosporins

Microorganisms Responsible for Neonatal Diarrhea

623

and are not consistently clinically effective, they should not be Data suggest that cefoperazone may sterilize blood and cause patients with typhoid fever to become afebrile more rapidly than with chl~ ramphenicol,~~~ perhaps because cefoperazone is excreted into bile in high concent r a t i o n ~ The . ~ ~ third-generation ~ cephalosporins may have higher cure and lower relapse rates than ampicillin or chloramphenicol in children with Salmonella meningitis.595 The doses of ampicillin, chloramphenicol, or cefotaxime used in infants with gastroenteritis pending results of blood cultures are the same as those used in treatment of sepsis. Because of the risk of gray baby syndrome, chloramphenicol should not be used in neonates unless other effective agents are not available. Trimethoprim-sulfamethoxazole, although useful in older children and adults, is not used in neonates because of the risk of kernicterus. Nosocomial infection with strains of Salmonella resistant to multiple antibiotics, including third-generation cephalosporins, has emerged as a problem in South America.580 Nonantibiotic interventions are important in the control of Salmonella infections. Limited data suggest that intravenous immune globulin (IGIV) (500 mg/kg on days 1,2,3, and 8 of therapy) along with antibiotic therapy may decrease the risk of bacteremia and death in preterm infants with Salmonella ga~troenteritis.~~~

Prevention Early recognition and intervention in nursery outbreaks of Salmonella are crucial to control. When a neonate develops salmonellosis, a search for other infants who have been in the same nursery should be undertaken. When two or more cases are recognized, environmental cultures, cultures of all infants, cohorting and contact isolation of infected infants, rigorous enforcement of hand hygiene, early discharge of infected infants, and thorough cleaning of all possible fomites in the nursery and delivery rooms are important elements of control. If cases continue to occur, the nursery should be closed to further admissions. Cultures of nursery personnel are likely to be helpful in the unusual situation of an S. typhi outbreak in which a chronic carrier may be among the caretakers. Culture of health care personnel during outbreaks of salmonellosis caused by other Salmonella species is debatable, although often recommended. Data suggest that nurses infected with Salmonella rarely infect patients in the hospital setting.597 The fact that nursing personnel are sometimes found to be colonized during nursery outbreaks468,474.487.489,490 may be a result rather than a cause of those epidemics. The potential role of vaccines in control of neonatal disease is minimal. For the vast number of non-S. ryphi serotypes, there is no prospect for an immunization strategy. Multiple doses of the commercially available oral live attenuated vaccine (Ty2la; Vivotif, Berna), has been shown in Chilean schoolchildren to reduce typhoid fever cases by more than 70%.598,599 However, the vaccine is not recommended for persons younger than 6 years, in part because immunogenicity of Ty2la is age dependent; children younger than 24 months fail to respond with development of immunity!" Vi capsular polysaccharide vaccine is available for children older than 2 years and is effective in a single dose. Whether some degree of protection of infants could

624

Section I1


Table 20-4 Shige//aSerogroups Serogroups

Species

No. of Serotypes

A B C D

5. dysenteriae 5. flexneri 5. boydii 5. sonnei

13

15 (including subtypes) 18 1

occur if stool carriage were reduced or could be transferred to infants by the milk of vaccinated mothers’ remains to be studied. Data suggest that breast-feeding may decrease the risk of other Salmonella infections.601

SHIGELLA

Nature of the Organism On the basis of DNA relatedness.- shieellae and E. coli v organisms belong to the same species.602However, for historical reasons and because of their medical significance, shigellae have been maintained as separate species. Shigellae are gram-negative bacilli that are unlike typical E. coli in that they do not metabolize lactose or do so slowly, are nonmotile, and generally produce no gas during carbohydrate use. They are classically divided into four species (serogroups) on the basis of metabolic and antigenic characteristics (Table 20-4). The mannitol nonfermenters usually are classified as S. dysenteriae. Although the lipopolysaccharide antigens of the 13 recognized members of this group are not related to each other antigenically,these serotypes are grouped together as serogroup A. Serogroup D (Shigella sonnei) are ornithine decarboxylase positive and slow lactose fermenters. All S. sonnei share the same lipopolysaccharide (0antigen). Those shigellae that ferment mannitol (unlike S. dysenteriae) but do not decarboxylate ornithine or ferment lactose (S. sonnei) belong to serogroups B and C . Of these, the strains that have lipopolysaccharideantigens immunologically related to each other are grouped together as serogroup B (Shigellaflexneri), whereas those whose 0 antigens are not related to each other or to other shigellae are included in serogroup C (Shigella boydii). There are six major serotypes of S. flexneri and 13 subserotypes (la, Ib, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6, X and Y variant). There are 19 antigenically distinct serotypes of S. boydii. For S. dysenteriae and S. boydii serogroup confirmation, pools of polyvalent antisera are used. The virulence of shigellae has been studied extensively since their recognition as major pathogens at the beginning of the 20th century. The major determinants of virulence are encoded by a 120- to 140-MDa p l a ~ m i d .This ~~~ plasmid, .~~~ which is found in all virulent shigellae, encodes the synthesis of proteins that are required for invasion of mammalian cells and for the vigorous inflammatory response that is characteristic of the d i s e a ~ e . Shigellae ~ ~ * ~ ~ that have lost this plasmid, have deletions of genetic material from the region involved in synthesis of these proteins, or have the plasmid inserted into the chromosome lose the ability to invade eukaryotic cells and become aviru1ent6O7;maintenance of the plasmid can be detected in the clinical microbiology lab by

ability to bind Congo red. The ability to invade cells is the basic pathogenic property shared by all ~ h i g e l l a e and ~ ~ ’by ~~~~ the Shigella-like invasive E. coli, which also possesses the Shigella virulence plasmid.205~605~606~610~611 In the laboratory, Shigella invasiveness is studied in tissue culture (HeLa cell invasion), in animal intestine, or in rabbit or guinea pig eye, where instillation of the organism causes keratoconjunctivitis (Serenytest).”’ Animal model studies have shown that bacteria penetrate and kill colonic mucosal cells and then elicit a brisk inflammatory response. In addition to the virulence plasmid, several chromosomal loci enhance virulence.612v613 This has been best studied in S. flexneri in which multiple virulence-enhancing regions of the chromosome have been defined.604s612-614 The specific gene products of some of the chromosomal loci are not known; one chromosomal virulence segment encodes for synthesis of the 0 repeat units of lipopolysaccharide. Intact lipopolysaccharide is necessary but not sufficient to cause virulence.6129615 At least two cell-damaging cytotoxins that also are chromosomally encoded are produced by shigellae. One of these toxins (Shiga toxin) is made in large quantities by S. dysenteriae serotype 1 (the Shiga bacillus) and is made infrequently by other shigellae.616Shiga toxin is a major virulence factor in S. dysenteriae, enhancing virulence at the colonic mucosa and also giving rise to sequelae similar to those caused by STEC (discussed earlier). This toxin kills cells by interfering with peptide elongation during protein ~ y n t h e s i s . ~ ’Additional ~-~’~ toxins may also be secreted by shigellae, although their roles in virulence are not established.620

Epidemiology Although much of the epidemiology of shigellosis is predictable based on its infectious dose, certain elements are unexplained. Shigellae, like other organisms transmitted by the fecal-oral route, are commonly spread by food and water, but the low infecting inoculum allows person-to-person spread. Because of this low inoculum, Shigella is one of the few enteric pathogens that can infect swimmers.621The dose required to cause illness in adult volunteers is as low as 10 organisms for S. dysenteriae serotype 1,6” about 200 organisms for S. f l e ~ n e r iand , ~ ~500 ~ organisms for S. ~ o n n e i . Person~’~ to-person transmission of infection probably explains the continuing occurrence of Shigella in the developed world. Enteropathogens that require large inocula and hence are best spread by food or drinking water are less common in industrialized societies because of sewage disposal facilities, water treatment, and food-handling practices. In the United States, daycare centers currently serve as a major focus for acquisition of shigell~sis.~’~ Numerous outbreaks of shigellosis related to crowding, poor sanitation, and the low dose required for diseases have occurred in this setting. Given the ease of transmission, it is not surprising that the peak incidence of disease is in the first 4 years of life. It is, however, paradoxical that symptomatic infection is uncommon in the first year of life.626-629 The best data on the age-related incidence of shigellosis come from M a t a ’ ~ ~ ’ ~ prospective studies of Guatemalan infants. In these studies, stool cultures were performed weekly on a group of children followed from birth to 3 years old. The rate of infection was more than 60-fold lower in the first 6 months of life than

Chapter 20

Microorganisms Responsible for Neonatal Diarrhea

625

decreases.636Data from Bangladesh suggest that S. dysenteriae is less common in neonates, but S. sonnei and S. boydii are more c0mmon.6~~

Clinical Manifestations lo/

0

u I-

a 4 I

L 0.10 W U z

V."

I.

I

0-25

26-51

52-77

78-103 104-129 130-155

AGE IN WEEKS

Figure 2&1 Age-related incidence of Shigella infection. (Data from Mata LG: The Children of Santa Maria Cauque: A Prospective Field Study of Health and Growth. Cambridge, Mass, MIT Press, 1978.)

between 2 and 3 years (Fig. 20-1).626The same age-related incidence has been described in the United States629and in a rural Egyptian village.628This anomaly has been explained by the salutary effects of brea~t-feeding.~~'-~~' However, it is likely that breast-feeding alone does not explain the resistance of infants to shigellosis. A review of three large case series633-635 suggests that about 1.6%(35 of 2225) of shigellosis cases occur in infants in the neonatal period. The largest series of neonatal ~ h i g e l l o s i ssuggests ~~~ that the course, complications, and etiologic serogroups are different in neonates than in older children. Although newborns are routinely contaminated by maternal feces, neonatal shigellosis is rare. Other aspects of the epidemiology of shigellosis elude simple explanation. The seasonality (summer-fall peak in the United States, rainy season peak in the tropics) is not well explained. The geographic variation in species causing infection likewise is not well understood. In the United States, most Shigella infections are caused by S. sonnei or, less commonly, S. flexneri. In most of the developing world, the relative importance of these two species is reversed, and other Shigella serotypes, especially S. dysenteriae serotype 1, are identified more frequently. As hygiene improves, the proportion of S. sonnei increases and that of S. flexneri

There appear to be some important differences in the relative frequencies of various complications of Shigella infection related to age. Some of these differences and estimates are based on data that are undoubtedly compromised by reporting biases. S. dysenteriae serotype 1 characteristically causes a more severe illness than other shigellae with more complications, including pseudomembranous colitis, hemolysis, and HUS. However, illnesses caused by various Shigella serotypes usually are indistinguishable from each other and conventionally are discussed together. The incubation period of shigellosis is related to the number of organisms ingested, but in general, it is between 12 and 48 hours. Volunteer studies have shown that after ingestion, illness may be delayed for a week or more. Neonatal shigellosis seems to have a similar incubation period. More than one half of the neonatal cases occur within 3 days of birth, consistent with fecal-oral transmission during parturition. Mothers of infected neonates are sometimes carriers, although more typically they are symptomatic during the perinatal period. Intrauterine infection is rare. In the older child, the initial signs are usually high fever, abdominal pain, vomiting, toxicity, and large-volume watery stools; diarrhea may be bloody or may become bloody. Painful defecation and severe, crampy abdominal pain associated with frequent passage of small-volume stools with gross blood and mucus are characteristic findings in older children or adults who develop severe colitis. Many children, however, never develop bloody diarrhea. Adult volunteer studies have demonstrated that variations in presentation and course are not related to the dose ingested because some patients develop colitis with dysentery but others develop only watery diarrhea after ingestion of the same i n o c u l ~ m . ~ ~ ~ The neonate with shigellosis may have a mild diarrheal syndrome or a severe ~ o l i t i s . Fever ~ ~ ~in~neonates ~ ~ ~ -is~ ~ usually low grade (1500 cells/pL (>25%) 750-1499 cells/pL (15-24%)

>lo00 cells/pL (>25%) 500-999 cells/pL (1 5-24%) SO0 cells/pL (>25%) 200-499 cells/pL (15-24%) 1 mo of age Histoplasmosis, disseminated (other than or in addition t o lungs or cervical lymph nodes) Kaposi's sarcoma Lymphoma, primary, in brain Lymphoma, small, noncleaved cell (Burkitt's), or immunoblastic or large cell lymphoma of B cell or unknown immunologic phenotype Mycobacterium tuberculosis, disseminated or extrapulmonary Mycobacterium, other species or unidentified species, disseminated (other than or in addition t o lungs, skin, or cervical or hilar lymph nodes) Mycobacterium avium-intracellulare complex or Mycobacterium kansasii, disseminated (other than or in addition t o lungs, skin, or cervical or hilar lymph nodes) Pneumocystiscarinii pneumonia Progressive multifocal leukoencephalopathy Salmonella (nontyphgoid) septicemia, recurrent Toxoplasmosis of the brain with onset >1 mo of age Wasting syndrome in the absence of a concurrent illness other than HIV infection that could explain the following findings: (a) persistent weight loss >lo% of baseline or (b) downward crossing of at least two of the following percentile on weight-for-height chart on two consecutive measurements >30 d apart plus (a) chronic diarrhea (i.e., at least two loose stools per day for >30 d) or (b) documented fever (for >30 d, intermitent or constant) ~~~

~~

aChildrenwhose HIV infection status is not confirmed are classified by using the grid with a letter E (for vertically exposed) placed before the appropriate classification code (e.g., EN2). bBothcategoty C and lymphoid interstitial pneumonitis in category B are reportable to state and local health departments as acquired immune deficiency syndrome. From Centers for Disease Control and Prevention. Recommendations of the US. Public Health Service Task Force on the use of zidovudine to reduce perinatal transmission of human immunodeficiency virus. MMWR Morb Mortal Wkly Rep 43: 1-20, 1994.

674

Section I11 Viral Infections

Table 21-4

Acquired Immunodeficiency Syndrome Indicator Diseases Diagnosed in 8086 Children Younger than Age 13 Years Reported to the Centers for Disease Control and Prevention Through 1997

Disease

No. of Children Diagnosed

Percent of Total’

2700 1942 1619 1419 1322 1266 658 639 370 307 291 162

33 24 20 18 16 16 8 8 5 4 4 2

fneumocystis carinii pneumonia Lymphocytic interstitial pneumoi’litis Recurrent bacterial infections Wasting syndrome Encephalopathy Candida esophagitis Cytomegalovirus disease Mycobacterium avium infection Severe herpes simplex infection Pulmonary candidiasis Cryptosporidiosis Cancer

The sum of percentages is greater than 100 because some patients have more than one disease. From Centers for Disease Control and Prevention (CDC). US. HIV and AIDS cases reported through December 1997.HIV/AIDS Surveillance report: year-end edition. MMWR Morb Mortal Wkly Rep 9:l-44,1997.

of energy, hepatosplenomegaly, respiratory tract infections, and recurrent and chronic otitis and sinusitis. Other commonly encountered characteristics are failure to thrive, sometimes associated with chronic diarrhea; failure to grow; the presence and persistence of mucocutaneous candidiasis; and many nonspecific cutaneous manifestations.

Infectious Complications Infections in the HIV-infected newborn or infant can be serious or life threatening. The difficulty in treating these infectious episodes, their chronicity, and their tendency to recur distinguish them from the normal infections of early infancy. It is therefore helpful to document each episode and to evaluate the course and frequency of their recurrences. Bacterial Infections Recurrent serious bacterial infections such as meningitis, sepsis, and pneumonia are so typical of HIV infection in children that they were included in the revised CDC definition of 1987.’42,143 In a study of 42 vertically infected children, a mean of 1.8 febrile visits per child-year of observation was reported.IMEleven of the 27 positive blood cultures grew Streptococcus pneumoniae, and 16 grew organisms that were considered central venous line related (coagulase-negative Staphylococcus, gram-negative enterics, Staphylococcus aureus, Pseudomonas aeruginosa, Candida species). This increased incidence of pneumococcal infections has been confirmed by other s t ~ d i e s . ’ ~ ~ , ’ ~ Infections in the HIV-infected newborn have the same pattern as that seen commonly in the neonatal period. A syndrome of very-late-onset group B streptococcal disease (at the age of 3.5 to 5 months of life) has been described in HIV-infected ~hildren.’~’Other rare infections such as congenital syphilis or neonatal gonococcal disease may become more frequent in the future as the incidence rises among pregnant w ~ m e n . ’ ~Congenital ~ - ’ ~ ~ syphilis may be missed if serologic tests are not performed on the mother and her child at the time of delivery and repeated later if indicated.

Mycobacterial infections have assumed an increasingly important role in the pathology of the HIV-infected infant and child. Although the number of HIV-infected children with Mycobacterium tuberculosis infection is still small, organisms resistant to multiple antituberculosis drugs cultured from adults and children pose a threat not only to other immunocompromised patients but also to health care provider^.'^'^'^^ An important issue for the neonatologist is whether the mother is infected with M . tuberculosis and may transmit the disease to her child. The diagnosis of M. tuberculosis infection is complicated in the HIV-infected patient because of the frequent anergy leading to a negative Mantoux test result even in the presence of infection. To diagnose anergy, a control (e.g., for mumps, Candida, or tetanus) should always be placed simultaneously with the Mantoux te~t.”~,’’~ Treatment of M. tuberculosis infection in children is complicated by the lack of pediatric formulations but usually includes isoniazid, rifampin, and during the first 2 months, pyra~inamide.’~~ Infection with Mycobacterium avium-intracellukzrecomplex occurs in almost 20% of HIV-infected children with advanced disease and presents as nonspecific symptoms such as night sweats, weight loss, and low-grade f e v e r ~ . ’ ’ ~Treatment ~’~~ usually consists of three or more drugs (e.g., clarithromycin; ethambutol; rifampin or amikacin, or both; ciprofloxacin; clofazimine) but commonly provides only temporary symptomatic relief and not eradication of the infection. Prophylaxis with clarithromycin or azithromycin should be initiated in infants younger than 1 year with a CD4 count less than 750 cells/mm3, in children 1 to 2 years old with a CD4 count less than 500 cells/mm3, and in children 2 to 6 years old with a CD4 count less than 75 cells/mm3. In children older than 6 years, the adult threshold of 50 cells/mm3 can be used.’60 Viral Infections Viral infections are important causes for morbidity and mortality in HIV-infected children. Primary varicella can be unusually severe and can recur as zoster, often presenting with very few, atypical lesions. The virus may become resistant

Chapter 2 1 to standard treatment with a c y ~ l o v i r . ' ~Cytomegalovirus ~-'~~ infection can result in esophagitis, hepatitis, enterocolitis, or r e t i n i t i ~ . ' ~ Cytomegalovirus .'~~ can become resistant to the treatment with ganciclovir, necessitating the use of foscarnet or even combination regimen^.'^'.'^' Other commonly encountered viruses in the HIV-infected infant and child are hepatitis A, B, and C, often associated with a more fulminant or chronic a gressive course than in the non-HIV-infected patient.'70-17' Hepatitis C infection has been shown to be more common in children born to HIV-infected mothers in some studies,'72 but others have found no association between maternal HIV status and perinatal hepatitis C transmi~sion.'~~"'~ Infection with the measles virus is associated with a high mortality in HIV-infected children and often presents without the typical rash and can result in a fatal giant cell p n e ~ m o n i a . ' ~Infection ~ " ~ ~ with respiratory syncytial virus or adenovirus, alone or in combination, can also result in rapid and sometimes fatal respiratory compromise and in chronic or persistent viral shedding or infe~tion.'~'-'~' An interesting observation is the occurrence of a polyclonal lymphoproliferative syndrome, often associated with evidence of primary or reactivated Epstein-Barr virus infection. These patients develop impressive lymphadenopathy and sometimes have concurrent lymphocytic interstitial pneumonitis or parotitis.182The distinction between a selflimited, benign hyperproliferation and the development of a monoclonal lymphoid malignancy is crucial for determining treatment and prognosis.

Acquired Immunodeficiency Syndrome in the Infant

675

Most children with PCP present with an acute illness, hypoxemia, and without a typical radiographic p i ~ t u r e . ' ' ~ , ' ~ ~ The diagnosis is usually made by obtaining an induced sputum (which can be done by experienced therapists even in very young children) or by performing a bronchoalveolar lavage, and only rarely is an open lung biopsy necessary.1983199 Treatment options are high-dose intravenous trimethoprimsulfamethoxazole (TMP-SMX) or pentamidine as first-line drugs.2"" Early adjunctive treatment with corticosteroids has been beneficial in adults and children with moderate to severe PCP and is commonly recommended for patients with an initial arterial oxygen pressure of less than 70mmHg or an arterial-alveolar gradient of more than 35 mm Hg.20'-204 Unfortunately, PCP has been associated with a mortality of 39% to 65% in infants despite improved diagnosis and In 1991, the CDC issued guidelines for PCP prophylaxis in children, taking into account the agedependent levels of normal CD4 cell However, these recommendations were applicable only if a child was known to be HIV infected. A survey published in 1995 revealed basically no change between 1988 and 1992 in the incidence of PCP among infants born to HIV-infected mothers.208Two thirds of these infants had never received PCP prophylaxis, and 59% of those children were recognized as having been exposed to HIV infection within 30 days or less of PCP diagnosis. Among the infants known to be HIV infected who had a CD4 count performed within 1 month of PCP diagnosis, 18% had a CD4 count higher than 1500 cells/mm3, the recommended threshold for initiation of PCP prophylaxis.2o8At the same time, it was shown that Fungal and Protozoal Infections primary prophylaxis during the first year of life was highly effective in the prevention of PCP.209These pivotal studies Oral candidiasis is common even in healthy, non-HIV-infected newborns and infants. However, infection beyond infancy, led to revised guidelines in 1995.193The major new recommendation was that all infants born to HIV-infected women involvement of pharynx and esophagus, and persistence should be started on PCP prophylaxis at 4 to 6 weeks of age, despite treatment with antifungal agents are more typical for regardless of their CD4 counts. More details are presented in the immunocompromised child. Disseminated candidiasis Table 21-5. is, however, uncommon in the absence of predisposing factors such as central venous catheters or total parented n ~ t r i t i o n . ' ~ ~ The recommended prophylactic regimen is TMP-SMX with 150 mg/m2/dayof TMP and 750 mg/m2/dayof SMX given Infection with Cryptococcus neoformans, although orally in divided doses twice each day during 3 consecutive common in adults with HIV infection, is less common in days per week. If TMP-SMX is not tolerated, alternative ~hildren.'~~.''~ Colonization with Aspergillus species and regimens are dapsone taken orally (2 mg/kg/day, not to exceed invasive disease has been described in adult patients with 100mg) once daily or aerosolized pentamidine. However, HIV infection, and we have observed at least one infant with breakthrough infections can occur with every regimen and perinatally acquired HIV infection and associated myelodysappear to be most frequent with intravenous pentamidine plastic syndrome who developed fatal pulmonary aspergillosis. 186-188 The incidence of other fungal infections varies and least common with TMP-SMX.210,2'1 Encephalitis caused by Tomplasma gondii is common in with the prevalence of the organism in the specific geographic adults with HIV infection but only rarely seen in children."' area. Disseminated histoplasmosis as the AIDS-defining However, several case reports of T gondii encephalitis in illness has been described in a few i n f a n t ~ . ' ~ ~ - ' ~ l infants between 5 weeks and 18 months old have been Early in the HIV epidemic, Pneumocystis jiroveci (formerly published. Some of these infants probably acquired toxoknown as Pneumocystis curinii) pneumonia (PCP) was the plasmosis infection in ~ t e r o . ~Toxoplasmosis ' ~ , ~ ~ ~ remains an AIDS indicator disease in almost 40% of the pediatric cases important differential diagnosis in the patient with an intrareported to the CDC.'92 However, this has changed cerebral mass. dramatically since the introduction of guidelines for PCP Protozoal infections of the gastrointestinal tract often prophylaxis in HIV-exposed infants and HIV-infected represent difficult diagnostic and therapeutic problems children and in 1997 accounted for only 25% of the AIDS and can be associated with an intractable diarrhea. Infection The peak incidence of PCP in infancy occurs with cryptosporidia has a prevalence of 3.0% to 3.6% during the first 3 to 6 months of life, often as the first among children with diarrhea?I5 HIV-infected children are symptom of HIV infection. Presumably, this represents at risk for prolonged diarrheal disease with often severe primary infection in these infants. At least one case of maternalwasting. fetal transmission of PCP has also been doc~mented."~

676

Section 111 Viral Infections

Table 21-5

Recommendations for Pneumocystis jiroveci Pneumonia (PCP) Prophylaxis and CD4 Monitoring in HIV-Exposed Infants and HIV-Infected Children

Age/HIV-Infection Status

PCP Prophylaxis

CD4+ Monitoring

Birth t o 4-6 wk, HIV exposed or infected

No prophylaxis (because PCP is rare and due to concerns regarding kernicterus with TMP/SMX) Prophylaxis Prophylaxis No prophylaxis

1 mo 3 rno 6, 9, 12 rno None

4-6 wk to 4 rno, HIV exposed 4-12 rno HIV infected or indeterminate HIV infection reasonably excludeda 1-5 yr, HIV infected

Older than 6 yr, HIV infected

~~~

Every 3-4 rno (more frequently if indicated)

Prophylaxis if CD4’ count is c 5 0 0 cells/rnm3 or CD4’ percentage is c 15% Prophylaxis if CD4’ count c 200 cells/mrn3 or CD4’ percentage is < 15% ~

~

~~~

Every 3-4 yr

~

aTwo or more negative HIV diagnostic tests (i.e., HIV culture or polymerase chain reaction), both performed at 2 1 rno of age and one of which was performed at 2 4 mo of age, or 2 2 negative HIV IgG antibody tests performed at 2 6 mo of age among children without clinical evidence of HIV disease. HIV, human immunodeficiencyvirus; TMPISMX, trimethorprim-sulfamethoxazole. From Centers from Disease control and Prevention. 1995 Revised guidelines for prophylaxis against Pneurnocystis carinii pneumonia for children infected with or perinatally exposed to human immunodeficiency virus. MMWR Morb Mortal Wkly Rep 44:l-12,1995.

receptive language appears to be slightly less affe~ted.’~~.’~~ Physical examination can reveal hypotonia or spasticity, and microencephaly may be present. Radiologic examination can Several case reports of malignancies associated with HIV suggest cerebral atrophy, calcifications in the basal ganglia infection in infants and children have been published; however, cancer is the AIDS-defining illness in only 2% of and periventricular frontal white matter, and decreased children, compared with 14% of the adult^.^^"^ The most attenuation in the white matter (Fig. 21-1).235-239 common cancer in HIV-infected children is non-Hodgkin’s HN-1 can be found in brain monocytes, macrophages, lymphoma as a systemic disease or as a primary central and microglia, and Limited expression of the regulatory gene nervous system t ~ m o r . ~ ’ ~Kaposi’s ” ’ ~ sarcoma has been nef, but not of structural gene products, has been demondescribed in a few children, including a 6-day-old infant, strated in a s t r ~ c y t e s . ~ Analysis ~ ~ - ’ ~ ~ of cerebrospinal fluid but remains relatively uncommon.220-222 Leiomyomas and revealed HIV RNA in 90% of samples, and more than 10,000 leiomyosarcomas, soft tissue tumors associated with copies/mL were associated with severe neurodevelopmental Epstein-Barr virus infection in immunocompromised delay.244s245 It is likely that immune-mediated mechanisms or patients, are increasingly common.220~223~224 the secretion of toxic cytokines by infected cells contributes to the pathogenesis of central nervous system disease in AIDS patients.246The level of quinolinic acid, a neurotoxin Encephalopathy that has been implicated in the development of HIV-related Encephalopathy, often with early onset, was a frequent and encephalopathy, is elevated in children with symptomatic typical manifestation of HIV infection in children before central nervous system disease and decreased during treatment with z i d o v ~ d i n e . ~ ~ ~ , ’ ~ ~ the introduction of antiretroviral therapy. Symptoms of encephalopathy in the newborn or young infant initially Postmortem examination shows variable degrees of white include delayed head control or delayed acquisition of a matter abnormalities, calcific deposits in the wall of blood social smile and variable degrees of truncal h y p ~ t o n i a . ’ ~ ~ ~vessels ’ ~ ~ of the basal ganglia and the frontal white matter, and Subsequently, impairment of cognitive, behavioral, and subacute encephalitis. At least one report described an HIVmotor functions becomes apparent. Typical findings included related meningoencephalitis in a newborn, supporting the a loss of or failure to attain normal developmental milestones, assumption of an intrauterine infe~tion.2~~ Spinal cord disease, weakness, intellectual deficits, or neurologic symptoms such manifested by vacuolar myelopathy, has been described in as ataxia and pyramidal tract signs, including spasticity or children but is less common than in a d ~ l t s . 2 ~ ~ rigidity.228Seizures are rare but have been described, and Dramatic improvements in the degree of encephalopathy cerebrovascular disease resulting in strokes or the formation have been achieved by treating the children with zidovudine, of giant aneurysms at the base of the brain has been especially when given as a continuous intravenous infusion rep~rted.’~~’’~’ The course can be static, wherein the child (see later).251Therapy with corticosteroids has also been attains milestones, albeit at a slower rate than normal for shown to be beneficial in some patient^.'^' age, or the development can reach a plateau and then the child ceases to acquire new milestones. The most severe form Ophthalmologic Pathology is manifested by a subacute-progressive course in which the child loses previously acquired capabilitie~.’~’*~~~ The older The ophthalmologic complications associated with HIV child has impaired expressive language function, whereas infection can be particularly devastating. HIV- 1 can infect

Malignancies

Chapter 2 1 Acquired Immunodeficiency Syndrome in the Infant A

677

6

Computed tomographic scans of the brains of two infants with HIV-associated encephalopathy. A, Cerebral atrophy with enlarged ventricles and widened sulci. B, Calcifications in basal ganglia and frontal white matter. Figure 21-1

the retina and manifest as cotton-wool s ots on examination, but it rarely leads to impaired vision.25,254 However, several other pathogens, some of them acquired in utero, can affect the eye and affect visual acuity. Fortunately, the incidence of blindness remains low in pediatric AIDS, but the infections caused by herpesviruses and especially by cytomegaloviral retinitis can be difficult to control and require intensive intravenous treatment.’64”66”67 A few children have been described with congenital toxoplasmosis and associated chorioretinitis,and one of the extrapulmonary manifestations of P. juroveci infection is involvement of the retina.255‘257 Early recognition and aggressive intervention are crucial to prevent progression of visual impairment, and routine ophthalmologic examinations should be part of the care of all HIV-infected children.

B

Interstitial Lung Disease Lymphocyticinterstitial pneumonitis, or pulmonary lymphoid hyperplasia, is seen almost exclusively in the pediatric patient with HIV infection and is still included into the CDC definition of AIDS-defining diseases for children younger than 13 years old (see Table 21-3). The incidence of lymphocytic interstitial pneumonitis is difficult to assess but may affect as many as 50% of the HIV-infected childrenz5’ Clinically, there is a wide spectrum in the severity of this disease; a child may be asymptomatic with only radiologic changes, or he or she can become severely compromised with exercise intolerance or even with oxygen dependency and the need for high-dose corticosteroid therapy. Children with lymphocytic interstitial pneumonitis are at higher risk to develop frequent bacterial and viral infections.259 A diffuse, interstitial, often reticulonodular infiltrative process is typically observed on radiologic examination and is sometimes associated with hilar or mediastinal lymphadenopathy (Fig. 21-2).258On biopsy, peribronchiolar lymphoid aggregates or a diffuse lymphoid infiltration of the alveolar septa and peribronchiolar areas is seen.”* Treatment of lymphocytic interstitial pneumonitis is only indicated in

Chest radiograph of an 8-year-old girl with severe lymphocytic interstitial pneumonitis who is oxygen and steroid dependent. Figure 21-2

the symptomatic child with hypoxia and consists of oral therapy with corticosteroids, to suppress the lymphocytic pr0liferation.2~~Lymphocytic interstitial pneumonitis has been associated in some studies with a better prognosis than other HIV-related manifestations such as encephalopathy or PCP, with a median survival of 72 months after diagnosis compared with 1 and 11 months, respectivelyz6’

678


Cardiovascular Complications

Nephropathy

Cardiovascular abnormalities are seen in more than 50% of HIV-infected adults and have been described in children.261,262 A progressive left ventricular dilatation and an increase in ventricular afterload were demonstrated in a group of 51 children with symptomatic HIV disease but with a normal initial echocardiogram.262Clinical manifestations include hepatosplenomegaly, tachypnea, and tachycardia, often with an S, gallop or another arrhythmia. Postmortem examination is remarkable for biventricular dilatation with grossly unremarkable valves and coronary arteries and, less frequently, a pericardial effusion. Cardiomyopathy is more commonly found in children with HIV-related encephalopathy (30%) than in those without this manifestation (2%).227 Microscopically, a hypertrophy of the myocardium with only rare foci of inflammatory lymphocytic infiltrates is usually HIV RNA can be demonstrated in only a small number of cells, probably representing macrophages, monocytes, or endothelial cells, but the distribution does not correlate with the structural damage.265v266 Another poorly understood phenomenon is the formation of aneurysms of the cerebral and coronary arteries in association with HIV i n f e c t i ~ n . A’ child ~ ~ ~who ~ ~developed ~~~~ large cerebral aneurysms, leading to hypothalamic dysfunction and neurologic impairment, has been described.269

Renal disease in children with HIV infection presents most often as focal glomerulosclerosis or mesangial hyperplasia. In one study, 12 of 155 children between the ages of 7 months and 8 years were found to have proteinuria, and 5 of them developed severe renal failure within a year of d i a g n o s i ~ ? ~ ~ , ~ ~ ~ This nephrotic syndrome is often resistant to treatment with corticosteroids, but cyclosporins may induce a remission.z84 IgA nephritis has been observed in a few HIV-infected children and adults, clinically manifesting as recurrent gross h e r n a t ~ r i a ? However, ~ ~ ’ ~ ~ ~an infection with cytomegalovirus or treatment with the protease inhibitor indinavir can also cause hematuria. 167s287,288

Pathology of the GastrointestinalTract Dysfunction of the digestive tract is a frequent problem in children with AIDS. In an Italian study of 200 HIV-infected children, Galli and colleagues270observed a higher incidence of hepatitis and diarrhea with onset during the first year of life (occurring in 20% to 50% of cases) than at any later time. Commonly encountered pathogens that may cause severe diarrhea are Cryptosporidium, M. avium-intracellulare complex, Microsporidium, SaZmoneZla, and Shigella.271HIV nucleic acids have been found in the feces of children with persistent diarrheal disease.272However, many HIV-infected children have a gastrointestinaldysfunction due to disaccharide intolerance, and their clinical status can be improved with careful attention to dietary intake.272 Progressive weight loss, anorexia, and sometimes pathogennegative diarrhea characterize the wasting syndrome often seen in association with HIV disease.273-276 The cause is not clear but probably represents a combination of a metabolic imbalance with hypermetabolism, disturbed nitrogen balance, and increased cytokine levels. No specific treatment is available,but individual patients may benefit from appetite stimulants, dietary supplements, or parenteral nutrition.277 Liver dysfunction resulting from an infection, including that from cytomegalovirus, Epstein-Barr virus, the hepatitis viruses, M. avium-intracellulare complex, or HIV- 1, is a common feature and can evolve into a chronic hepatitis or c h o l a n g i t i ~ .Candida ~ ~ ~ . ~ albicans ~~ and the herpesviruses are often the cause of infections of the oral cavity and of esophagitis. Esophagitis in the HIV-infected child does not necessarily manifest as the typical symptoms or dysphagia but may be the cause of poor appetite and weight loss. Pancreatitis is a rare complication of HIV infection in children and may occur as the result of opportunistic infections such as cytomegalovirus or as a side effect or therapeutic agents.280,281

Pathology of Endocrine Organs Failure to thrive or grow is commonly seen in children with HIV infection. In a study of 35 HIV-positive hemophiliacs, a decrease of more than 15 percentile points in height or weight for age was a predictive marker for children who become symptomatic for AIDS.28g-291 Whereas a few patients may have some dysregulation of thyroid function or a lack of growth hormone, often there is no definable endocrine cause recognizable.2929293 The exception is the child with adrenal insufficiency, which may be caused by cytomegalovirus infection of the adrenal gland.294One child with severe salt craving is described who required therapy with fluorocortisol. In a study of 167 HIV-infected children, Hirschfeld and associates295found low levels of free thyroxine in 18% and increased thyrotropin or thyroid binding globulin levels in 30% of children.

Involvement of Lymphoid Organs and Thymus Thymic abnormalities have been found in 3 of 37 fetuses aborted between 20 and 27 weeks’ gestation.296This may represent the initial injury to the lymphoid system. In children with AIDS, the thymus can show precocious involution, with marked depletion of lymphocytes and loss of corticomedullary differentiation, or a thymitis, characterized by the presence of lymphoid follicles with germinal centers or a diffuse lymphomononuclear infiltration.297An interesting phenomenon is the occurrence of multilocular thymic cysts, often detected as an incidental finding.297Lymphadenopathy is common among infected children and adults, and lymphoid organs function as reservoirs for HIV- 1.298-301

Hematologic Problems Anemia is the most common hematologic disorder observed in HIV-infected children, with the incidence depending on the severity of HIV disease, the age group, and the use of antiretroviral therapy.302-304 In a retrospective study of 75 HIV-infected children, 19.7% had anemia at age 6 months, 32.9% at 9 months, and 37.3% at 12 m0nths.3’~Bone marrow aspirate or biopsy specimens may show lymphoid aggregates, some degree of dysplasia, or an ineffective erythropoiesis?06 Pure red cell aplasia from acute or persistent B19 parvovirus infection has been described in some HIV-infected children and adults and should be considered when the red blood cell production rate is less than expected for the degree of anemia.307-309

Chapter 2 1 Acquired Immunodeficiency Syndrome in the Infant A white blood cell count of less than 3000 cells/mm3has been observed in 26% to 38% of untreated pediatric patients, and neutropenia, defined as an absolute neutrophil count of less than 1500 cells/mm3, has been found in 43%.302"04This can result from HIV infection, infection with opportunistic pathogens such as M. avium-intracellulare complex or cytomegalovirus, or therapy with a myelotoxic drug, including zidovudine. In the patient population at the National Cancer Institute, a platelet count of less than 50,000 cells/mm3was found in 19% of the children; thrombocytopenia has also been described in HIV-infected Treatment options are similar to those of noninfected children and include intravenous g-globulins, corticosteroids, and WinRho. However, improvement is often best achieved by optimizing the antiretroviral therapy and decreasing the circulating viral load. Deficiency of the vitamin K-dependent factors 11, VII, IX, and X is common in HIV-infected children and can result in a coagulopathy that is relatively easy to correct. Also commonly seen are autoimmune phenomena, such as lupus anticoagulants and antiphospholipid or anti-cardiolipid a n t i b ~ d i e s . ~ lDisseminated ~-~'~ intravascular coagulopathy has been described as a complication of filminant infectious conditions, but there are no data to indicate that this complication occurs more frequently in HIV-infected individuals.

Skin Mucocutaneous disease is very common in pediatric HIV infection but often manifests in an unusual or atypical form.316,317 The most common lesions with an infectious cause are oral thrush and diaper rash (C. albicans), chickenpox (acute or chronic), and recurrent shingles (varicella zoster virus), and molluscum c o n t a g i o ~ u m .Bacterial ~~~ infections and a highly contagious form of scabies have also been reported with some frequency. Severe seborrheic dermatitis or an unspecific intensely pruritic eczematous dermatitis can pose difficult and frustrating clinical problems, necessitating prolonged therapy. Because of the atypical presentations and wide variety of possible causes, it is often prudent to culture lesions for bacteria or for varicella zoster virus or even to perform a scraping or biopsy. Drug eruptions appear to be more common in HIV-infected patients and can develop into a toxic epidermal n e c r ~ l y s i s However, .~~~ most drugrelated rashes resolve after stopping the causative agent.

MORBIDITY, MORTALITY, AND PROGNOSIS Thanks to more effective treatment of HIV infection and associated complications and to improved guidelines for the prophylaxis of opportunistic infections, major decreases in the morbidity and mortality rates of HIV-infected children and adults have occurred. However, infants who are not known to be HIV infected or do not have access to early intervention are still at high risk for early and severe morbidity and continue to have a high mortality rate.319-321 Although the course of HIV infection in children is in general more accelerated than in adults, distinct subgroups are noticeable. Perinatally acquired HIV infection follows a bimodal course, with about one third of the children becoming symptomatic within the first 2 years of life and the

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remainder in the next several years. Only a minority of patients remains relatively asymptomatic until the age of 8 years or older. In a study of HIV-seropositive and HIVseronegative women and their newborns in Nairobi, Kenya, no statistically significant difference was found between the groups regarding occurrence of congenital malformations, stillbirths,Apgar score, or gestational age. However, the mean birth weight of singleton neonates of HIV-positive mothers was significantly lower than that of controls.322Although not as pronounced, there was also a difference between the height and weight of birth of HIV-infected infants born in the United States compared with uninfected infants.323These studies of natural history of perinatal HIV infection were performed before the routine use of antiretroviral therapy in pregnant women and their infants. In a European study of 392 HIV-infected children, Blanche and colleagues319found that 20% of children died or developed an AIDS-defining symptom (CDC category C; see Table 21-3) within the first year of life and 4.7% per year thereafter, reaching a cumulative incidence of 36% by 6 years of age. Two thirds of the children alive at 6 years of age had only minor symptoms, and one third had well preserved CD4 counts ( ~ 2 5 %despite ) prior clinical manifestations. Children with HIV infection acquired through a transfusion during the neonatal period tend to have a prolonged asymptomatic period.324 Both clinical and laboratory factors have been evaluated in regard to their prognostic value. Children born to mothers with low CD4 counts and high viral load tend to progress more rapidly to category C disease or death, emphasizing the importance of diagnosis and adequate treatment of HIVinfected pregnant women:231138325Early manifestation of clinical symptoms in the infant, especially opportunistic infections, encephalopathy, or hepatosplenomegaly, has repeatedly been associated with a poor A high virus copy number in the blood has been shown to be a strong predictor for progression of HIV cllsease.107*328-330 Infants with very high HIV RNA copy numbers shortly after birth are presumed to have been infected in utero and tend to have early onset of symptoms?29Dickover and associates?29 when calculating HIV-infected infants followed for up to 8 years, found that a 1 -log higher HIV- 1 RNA copy number at birth increased the relative hazard of developing CDC class A or B symptoms by 40% ( P = .004), to develop AIDS by 60% (P = .Ol), and the risk of death by 80% ( P = .023). The peak HIV- 1 RNA copy number during the period of primary viremia was also predictive of progression to AIDS (relative hazard 9.9; 95% CI, 1.8%-541%; P = .008) and death (relative hazard, 6.9; 95% CI, 1.1%-43.8%; P = .04).329

PREVENTION An important goal in the care of HIV-infected people is the prevention of further infections and especially the transmission from mother to infant. Many countries have initiated large educational programs to halt the spread of the epidemic in the heterosexual community. However, the prevalence of HIV infection is so high in certain populations, especially in developing countries, that a change in behavior results in only a very slow decrease in the number of new infections. Identifying pregnant women who are HIV infected is

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essential for the potential initiation of therapy and for the coordination of optimal prenatal care.330,331 The birth order and delivery route appear to play a role in the infection rate. In the absence of zidovudine treatment, HIV infection occurred in 35% of first-born twins and 15% of second-born twins who were delivered vaginally, compared with 16%of first-born and 8% of second-born twins delivered by cesarean section.50The European Collaborative Study of 1254 HIV-infected mothers and their children estimated that cesarean section resulted in a 50% reduction of the transmission rate.333However, there is a potential bias in the indication for cesarean section. Obstetricians may be less likely to perform a surgical procedure in a mother with advanced HIV infection; emergency cesarean section is more common in the case of larger infants (who are less likely to be infected), and monitoring during vaginal deliveries may itself increase the risk for transmission, especially if fetal scalp electrodes are being used.51A European randomized clinical trial of 414 women demonstrated decreased perinatal HIV transmission among infants born by caesarean section It has also versus vaginal delivery (1.7% versus 10.6%).3343335 been demonstrated that prolonged rupture of membranes (>4 hours before delivery) increases the risk for perinatal transmission and should therefore be avoided.58759 The success of the AIDS Clinical Trials Group 076 (PACTG 076) protocol has had a major impact on the prevention of perinatal transmission of HIV- 1 and has resulted in guidelines issued by the CDC.”-’I In that landmark study, pregnant HIV-infected women received oral zidovudine starting at 14 to 34 weeks’ gestation and intravenous zidovudine during labor and delivery, whereas the infants were treated with 6 weeks of oral zidovudine post partum (Table 21-6). This resulted in a 67% reduction in the perinatal transmission rate, from 25% to 8.3% ( P = .00006).’9It has also been demonstrated that a high maternal plasma

Table 21-6

Pediatric AIDS Clinical Trials Group 076 Regimen

Time of Zidovudine Administration Anterpartum

lntrapartum

Postpartum

Regimen 100 mg zidovudine five times daily, initiated at 14-34 wk of gestation and continued throughout pregnancy During labor, intravenous administration of zidovudine in a 1-hr initial dose of 2 mglkg, followed by continuous infusion of 1 mglkg per hr until delivery Oral zidovudine to the newborn (zidovudine syrup at 2 mg/kg per dose every 6 hr) for t h e first 6 wk of life, beginning at 8-12 hr after birth. If an infant cannot tolerate oral zidovudine, it can be given intravenously at a dosage of 1.5 mglkg every 6 hr

From Centers for Disease Control and Prevention. Public Health Service task force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. MMWR Morb Mortal Wkly Rep 47:l-31, 1998.

concentration of HIV-1 is a risk factor for transmission to the infant.I3 The identification of HIV-infected pregnant women and their prompt treatment has already led to a marked decrease in the number of newly HIV-infected children in industrialized c o ~ n t r i e s . ~ ~ ~ , ~ ~ ’ This treatment regimen is not feasible for developing countries, where 1600 new perinatal infections occur per day. Discussions regarding the ethics of clinical trials in developing countries, especially trials involving a placebo group, occurred early in the course of developing strategies appropriate for developing countries.338Ultimately, a number of randomized clinical trials conducted in some of these countries led to a good understanding of the benefits and obstacles in developing effective and sustainable perinatal prevention programs. An attempt to decrease the transmission rate by cleansing the birth canal with dilute chlorhexidine solutions has unfortunately not been successfil, although higher concentrations of chlorhexidine have been found to be safe and tolerable and may be studied as potential interv e n t i o n ~ . ~Results ” ~ ~ from a study performed in Thailand as a collaboration between the Thailand Ministry of Health and the CDC demonstrated a 50% reduction in perinatal HIV transmission in a non-breast-feeding population.22This trial enrolled non-breast-feeding women who were treated with zidovudine (300 mg twice daily) beginning at week 36 of gestation. During labor and delivery, the oral dose of zidovudine was increased to 300 mg every 3 hours; the newborns were not treated. The estimated efficacy of this therapy was 51% (decrease from 18.6%transmission rate in placebo group to 9.2% in treated group). Although this transmission rate is somewhat higher than the one reported with the PACTG 076 regimen, it indicates that a two-part regimen without the intravenous and postnatal component (a more feasible alternative for developing countries) merits further investigation. Other studies, particularly in a variety of African countries, have demonstrated substantial reductions in perinatal transmission, especially with a simple and inexpensive two-dose nevirapine regimen studied in Uganda. This trial (HIVNET 012) demonstrated a 47% reduction in transmission at 14 to 16 weeks of age and a 41% reduction by 18 months of age when the mother was given a single 200-mg nevirapine tablet at the onset of labor and when a single 2-mg/kg oral dose of nevirapine suspension was given to the neonate at 72 hours after birth or at discharge from the A major challenge in the prevention of perinatal HIV transmission is the management of breast-feeding transmission in settings where replacement feeding is not feasible. The risks of acquiring HIV infection through breast-feeding may be lower than the risk of death from diarrheal diseases and malnutrition in areas where replacement feeding is not available or unsafe. Decision models to determine the optimal choice of interventions to reduce breast-feeding transmission have been proposed.341For developing areas of the world, the WHO recommends exclusive breast-feeding through the first 6 months of life with early weaning in countries where replacement feeding is “acceptable, feasible, affordable, sustainable, and safe.”342 Immunoglobulins of the IgG class are readily transported through the placenta, and passive immunization of the mother may protect the fetus, a model that has been extensively used in the prevention of neonatal hepatitis B infection. Passive

Chapter 21 immunization of the fetus in combination with antiretroviral therapy has been studied in a U.S. study called ACTG 185. Pilot studies evaluating the safety and toxicity of highly purified human immune globulin prepared from asymptomatic HIV-seropositive persons were conducted and demonstrated that HIV immune globulin ( H M G ) appeared However, the results of to be safe and well ACTG 185 demonstrated no decrease in the perinatal transmission rate because of the widespread concurrent use of antiretroviral therapy among pregnant HIV-infected women in the United States.343

TREATMENT

Supportive Care and General Management Optimizing prenatal care, including nutrition, avoidance of drugs and other harmful substances, and recognition and treatment of concurrent infections, is crucial to prevent the premature delivery of children with low birth weight. The general care of the newborn and infant is not different for children born to seropositive mothers, but special attention should be given to the documentation of developmental milestones, frequency and course of infections, and nutritional status. The AAP recommends routine immunizations with some modifications for all seropositive children, whether they are infected or not.79Similar to other newborns, children born to HIV-infected mothers should receive hepatitis B vaccinations, but if the mother is HBsAg positive, the child should also receive HBIG within 12 hours after birth. The current recommendation is that live virus vaccine (oral poliovirus) or live bacterial vaccines (bacillus Calmette-Gukrin) should not be given to patients with HIV infection. The exception is MMR, because the risk for measles in immunocompromised children is much higher than the risk associated with the vaccination, although only children with mild to moderate immunosuppression should have the MMR vaccine.’76However, varicella-zoster immunization is contraindicated in HIV-infected children and adults. A recommended prophylaxis regimen in HIV-infected infants is the administration of intravenous immunoglobulin (IGIV) or specific hyperimmune globulin within 72 to 96 hours after the exposure to varicella-zoster virus or m e a s l e ~ . ’ Immunization ~~*~~ with the conjugated pneumoccocal vaccine series may be started at 2 months of age. Alternatively, children older than 2 years with HIV infection should be administered the 23-valent polysaccharide pneumococcal vaccine, and revaccination should be offered after 3 to 5 years in children younger than 10 years and after 5 years in older children.l6’ However, prior immunization does not give complete protection from further infection, as has been described for pertussis occurring in previously immunized ~ h i l d r e n . 3 ~ ~ The monthly administration of IGIV has been studied in asymptomatic and symptomatic children with HIV infection. IGIV has been shown to prevent serious bacterial infections in patients with congenital immunodeficiencies.However, in a group of children who did not receive any antiretroviral treatment, only children with a CD4 count of 200 cells/mm3 or more appeared to benefit from monthly IGIV administ r a t i ~ nA. study ~ ~ ~ evaluating children receiving antiretroviral


681

therapy did not find a statistically significant difference between children who received IGIV and children treated with placebo (albumin), as long as they were also receiving PCP prophylaxis with TMP-SMX. The current recommendation is to use prophylactic IGIV (400 mglkg per dose every 28 days) in HIV-infected children with hypogammaglobulinemia, poor functional antibody performance (i.e., lack of antibody response after immunizations), or significant recurrent infections despite therapy with appropriate antibiotics.’60 Prophylactic measurements for the prevention of PCP have been discussed previously. Prophylaxis for M. tuberculosis exposure follows the guidelines used for immunocompetent children, but all children born to HIV-infected mothers should have a purified protein derivative test placed at or before 9 to 12 months of age and should be retested every 2 to 3 years.’@Prophylaxis with clarithromycin or azithromycin for M. avium-intracellulare complex infection should be offered to children younger than 12 months if their CD4 count is less than 750 cells/pL, children 1 to 2 years old with CD4 counts less than 500 cells/pL, children 2 to 6 years old with CD4 counts less than 75 pL, and children older than 6 years if the CD4 count is less than 50 cells/pL.160 The evaluation and therapy for an infectious complication in the HIV-infected child mandates a high level of suspicion for unusual presentations, an aggressive approach for the establishment of the diagnosis, and the use of intravenous antibiotics, at least during the initial days. Chronic and recurrent infections can compromise the nutritional status of the child and influence the neurodevelopmental state. However, these symptoms are also typical for progressive HIV infection and should be monitored carefully.

Antiretroviral Therapy-General

Guidelines

As our knowledge about the dynamics of viral replication and its implications for disease progression and prognosis has evolved, it has become clear that early and aggressive therapy offers the potential benefit of a prolonged asymptomatic time period. Panels of experts have developed guidelines for the use of antiretroviral agents in children, adolescents, and adults, including pregnant women, with HIV i n f e c t i ~ n . * ’ * The ~ ~ ~indications ”~~ for the initiation of antiretroviral therapy include clinical, immunologic, and virologic parameters (Table 2 1-7). Pediatric HIV experts agree that infected infants with clinical symptoms of HIV disease or with evidence of immune compromise should be treated, but there remains controversy regarding treatment of asymptomatic infants with normal immunologic status. Guidelines from The Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children recommend initiation of therapy for infants younger than 12 months who have clinical or immunologic symptoms of HIV disease, regardless of HIV RNA level, and consideration of therapy for HIV-infected infants younger than 12 months who are asymptomatic and have normal immune parameters (see Table 21-7). Because of the high risk for rapid progression of HIV disease, many experts would treat all HIV-infected infants younger than 12 months, regardless of clinical, immunologic, or virologic parameters. Other experts would treat all infected infants younger than 6 months old and use clinical and immunologic parameters and assessment of adherence issues for decisions regarding initiation of therapy

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Section I11

Table 21-7

Viral Infections

Indications for the Initiation of Antiretroviral Therapy

Initiation of Therapy These recommendations are continuously updated by the Panel on Clinical Practices for Treatment of HIV infection and reflect the opinions of the Panel. For information on a diversity of recommendations from other HIV experts and for the most up-to-date recommendations, the Panel summary statements can be viewed at http://aidsinfo.nih.gov/guidelines/. Infants < 12 Months Old All HIV-infected infants < 12 months old, with clinical or immunologic symptoms of HIV disease, regardless of HIV RNA level, should be treated. Consideration of therapy should be made for those who are asymptomatic and have normal immune parameters Children > 12 Months Old Therapy should be started for all children > 12 months old with AIDS (clinical category C [see Table 21-31) or severe immune suppression (immune category 3) Therapy should be considered for children who have Mild t o moderate clinical symptoms (clinical categories A or B [see Table 21-31) Moderate immunologic suppression (immune category 2) And/or confirmed plasma HIV RNA levels 2 100,000 copies/mL From Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the Use of Antiretroviral Agents in HIV-1 infected Adolescents and Adults. http://aidsinfo.nih.gov/guidelined/, accessed January 2004.

in infants 6 to 12 months old. The Working Group recommends that treatment should be started for all children older than 12 months with AIDS (clinical category C) or severe immune suppression (immune category 3) and be considered for children who have mild to moderate clinical symptoms (clinical categories A or B), moderate immunologic suppression (immune category 2), or confirmed plasma HIV RNA levels higher than 100,000 copies/mL (see Table 2 1-7). Many experts would defer treatment in asymptomatic children older than 1 year with normal immune status in situations in which the risk for clinical disease progression is low (e.g., HIV RNA < 100,000 copies/mL) and when other factors (i.e., concern for adherence, safety, and persistence of antiretroviral response) favor postponing treatment. In such cases, the health care provider should closely monitor virologic, immunologic, and clinical status. Monotherapy is no longer considered appropriate treatment for the HIV-infected child or adult. The only exception is the use of zidovudine monotherapy in infants of indeterminate HIV status during the first 6 weeks of life as part of the regimen to prevent perinatal transmission. As soon as a child is proved to be infected, therapy should be changed to a combination of agents.348Based on results from trials in adults, a recommended three-drug combination provides the best opportunity to preserve immune function and to prevent disease progression. This therapy should include a highly active protease inhibitor plus two dideoxynucleoside reverse transcriptase inhibitors (NRTIs) as the initial therapeutic regimen or two NRTIs and a non-nucleoside reverse transcriptase inhibitor (NNRTI).348 As of January 2004, 20 antiretroviral drugs were approved for use in the United

States in HIV-infected adolescents and adults; of those, 12 have approved pediatric indications. Therapeutic drugs fall into four major classes based on mechanism of action: nucleoside analogues or nucleotide reverse transcriptase inhibitors (NRTIs, NtRTIs), NNRTIs, protease inhibitors, and fusion inhibitors. More detailed information about these agents can be obtained at the U.S. federal AIDS information website (http://aidsinfo.nih.gov/guidelines).The most pediatric experience with NRTIs is with zidovudine (ZDV), lamivudine (3TC), didanosine (ddI), and stavudine (d4T). All are available in a liquid formulation. Dual NRTI combinations are the backbone of highly active antiretroviral therapy (HAART) in adults and children. The combinations of NRTIs with the most data available include zidovudine and didanosine (ZDV/ddI), zidovudine and lamivudine (ZDV/3TC), and stavudine and lamivudine (d4T/3TC). Added to this dual NRTI backbone is an NNRTI or a protease inhibitor The acceptable NNRTIs for pediatric use are nevirapine or efavirenz (approved for children > 3 years old); efavirenz is not available in a liquid formulation. Delavirdine is the other available NNRTI but is not approved for pediatric use. The one available NtNRTI, tenofovir, is approved only for adult use, and pediatric trials are underway. The protease inhibitors recommended for pediatric use are nelfinavir, ritonavir, and lopinavir plus ritonavir. These are available in powder or liquid formulations. Other protease inhibitors available for pediatric use are available in capsule formulation only and include indinavir, saquinavir, and amprenavir. However, no data are available for the long-term tolerance and efficacy of any of these combinations in children. Certain combinations are not recommended because of overlapping toxicities, including zalcitabine plus didanosine, zalcitabine plus stavudine, and zalcitabine plus lamivudine. The combination of stavudine and zidovudine is not recommended because of their antagonism. The most commonly used antiretroviral agents in newborns and infants, the NRTIs zidovudine, didanosine, lamivudine, the NNRTI nevirapine, and the protease inhibitors nelfinavir and ritonavir, are briefly reviewed. More extensive reviews are available in specific textbooks or the current recommendations from the CDC and the federal guidelines website (http://aidsinfo.nih.g~v)?~~~~~~ Because the standards of care are still evolving, collaboration between the child’s primary health care provider and an HIV treatment center is strongly suggested. Whenever possible, children should be enrolled in clinical trials; access and information can be obtained by calling 1-800-TRIALS-A (AIDS Clinical Trials Group [ACTG]), or 301-402-0696 (HIV & AIDS Malignancy Branch, National Cancer Institute).

Zidovudine Only limited data are available regarding the appropriate dosing of antiretroviral drugs in the neonate. Zidovudine does cross the placenta and can be measured in amniotic fluid, cord blood, and fetal The total body clearance and terminal half-life of zidovudine is similar in nonpregnant women and in women during the third trimester of pregnancy, and the half-life in the neonate is about lo-fold longer than in the Elimination of the drug and its main metabolite is markedly prolonged during the first 24 to 36 hours of life, with a mean serum

Chapter 21

+


683

half-life after maternal ingestion of 14.4 7.5 h o ~ r ~ . ~ ~The ~ recommended , ~ ~ ~ - dosage ~ ~ ~ of didanosine (in combination The total-body clearance of zidovudine increases rapidly with other antiretroviral agents as discussed earlier348)is as within the first few weeks of life from 10.9mL/min/kg in follows: infants 14 days old or younger to 19.0 mL/min/kg in older Premature babies: no data available infants (P < .0001)?579358 Oral bioavailability decreases from Neonatal dosage (infants younger than 90 days old): 89% in the younger group to 61% in infants older than 50 mg/m’ per dose every 12 hours given orally 14 days. Pediatric dosage: 120mg/m2 per dose every 12 hours Some studies have demonstrated that zidovudine is orally (range, from 90 to 150 mg/m’ per dose every 8 to incorporated into the DNA of newborn mice and monkeys 12 hours) and into the nuclear DNA of cord blood samples drawn from children whose mothers were being treated with Lamivudine z i d ~ v u d i n eStudies . ~ ~ ~ of ~ ~the ~ ~offspring of mice who had Lamivudine has been approved for the use in combination been treated with zidovudine during the last trimester of with zidovudine. Lamivudine at doses between 0.5 to pregnancy revealed an increased risk for developing tumors 20 mg/kg/day given to children in two daily doses was well of the liver, lung, and reproductive organs. However, a similar t ~ l e r a t e d . ~ ~ ’Side . ~ ~ ’effects include hyperactivity (2%), study performed by Burroughs Wellcome, the manufacturer increase in liver function to more than 10 times normal of zidovudine, was not able to support these findings. A (3%), neutropenia (3%), and reversible pancreatitis (8%). panel convened by the National Institutes of Health, although Other less common toxicities include peripheral neuropathy acknowledging the validity of the findings, recognized that and lactic acidosis with severe hepatomegaly and steatosis. the benefit of preventing transmission of HIV disease in most Lamivudine was rapidly absorbed after oral administration children outweighs the potential concerns about carcinoand 66% f 25% of the oral dose was absorbed. genicity. The recommended dosage of lamivudine (in combination Common side effects of zidovudine include bone marrow with other antiretroviral agents as discussed earlier348)is as suppression, myopathy, and liver S evere, follows: unusual toxicity includes lactic acidosis and severe hepatomegaly with steatosis. Premature babies: no data available The recommended dosage of zidovudine (in combination Neonatal dosage (infants < 30 days old): 2 mg/kg per dose with other antiretroviral agents as discussed earlier348)is as given twice daily orally follows: Pediatric dosage: 4 mg/kg per dose administered twice daily Premature babies (under study): 1.5 mg/kg per dose given Nevirapine intravenously or 2 mg/kg given orally every 12 hours from birth to 2 weeks of age; then increase to 2 mg/kg Nevirapine is also a reverse transcriptase inhibitor but, unlike per dose every 8 hours at 2 weeks (neonates 230 weeks zidovudine, didanosine, and lamivudine, does not belong to gestational age) or at 4 weeks (neonates ll If a mother develops measles immediately ante partum or post partum and her infant is born with congenital measles, the mother and infant should be isolated together until 72 hours after the appearance of the exanthem. Close observation of the neonate for signs of bronchopneumonia and other complications is warranted. Other susceptible mothers, neonates, and hospital personnel should receive immediate prophylaxis with immunoglobulin as outlined previously, followed by vaccination at a later date. If a mother develops perinatal measles but her infant is born without signs of infection, each should be isolated separately. The infant may be incubating transplacentally acquired measles or may be at risk for postnatally acquired droplet infection. In either case, the infant should receive immunoglobulin. The mother may be discharged with her infant after the third day of exanthem. The neonate should be followed closely and observed for signs of modified measles, which may require up to 18 days' observation because

of the abnormally long incubation period of modified measles?1' The availability of virus diagnostic facilities varies, and the approach to potential nosocomial spread of measles therefore may differ from place to place. If serologic testing is expensive or unavailable, it may be simpler to administer immunoglobulin to all exposed persons who do not have an unequivocal history of previous measles or previous vaccination with live-attenuated measles virus vaccine. Serologic testing of those exposed who are thought to possibly be susceptible to measles, with administration of immunoglobulin to those exposed who are truly susceptible, would seem to be the ideal management for prevention of nosocomial measles. Neonates or mothers isolated because of measles require a separate room with the door closed. Only immune visitors and staff should enter the room. Gown and hand-washing precautions must be observed, and containment of bedding and tissues soiled with respiratory excreta by double bagging and autoclaving is indicated. Because measles virus is excreted in the urine during the early exanthematous phase, it is also advisable to treat the urine as potentially infectious

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Section I11

Viral Infections

and to disinfect bedpans. Terminal disinfection of the room is recommended.

Mumps is an acute, generalized, communicable disease whose most distinctive feature is swelling of one or both parotid glands. Involvement of other salivary glands, the meninges, the pancreas, and the testes of postpubertal males is also common. The origin of the name is obscure but probably is related to the Old English verb to mump, meaning ‘86Oophoritis is far less common. It is associated with lower abdominal pain, and the ovaries rarely may be palpable. Oophoritis does not lead to sterility. Aseptic meningitis may occur in children and adults of either sex but is more common in males. Although pleocytosis of the cerebrospinal fluid may occur in up to 50% of cases of clinical mumps, signs of meningeal irritation occur in a smaller proportion of cases, variably estimated at 5% to 25%. The cerebrospinal fluid contains up to 1000 cells/mm3. Within the first 24 hours, polymorphonuclear leukocytes may predominate, but by the second day, most cells are lymphocytes. In the absence of parotitis, the syndrome of aseptic meningitis in mumps is indistinguishable clinically from that caused by enteroviruses and other viruses. The course is almost invariably self-limited. Rarely, cranial nerve palsies have led to permanent sequelae, of which deafness is the most common. Mumps pancreatitis may cause abdominal pain. The incidence of this manifestation is unclear because reliable diagnostic criteria are difficult to obtain. An elevated serum amylase level may be present in parotitis or pancreatitis. The character of the abdominal pain is rarely sufficiently distinctive to permit unequivocal diagnosis. Other complications of mumps include mastitis, thyroiditis, myocarditis, nephritis, and arthritis. The peripheral blood cell count in mumps is not characteristic. The white blood cell count may be elevated, normal, or depressed, and the differential count may reveal a mild lymphocytosis or a polymorphonuclear leukocytosis.

Maternal Effects of Mumps Unlike varicella and measles, when mumps occurs in pregnant women, the illness is generally benign and is not appreciably more severe than it is in other adult women!86-495 In a 1957 “virgin soil” epidemic of mumps among the Inuit, 20 infections occurred in pregnant women. Of these, only 8 (40%) were clinically apparent, compared with an incidence of 57 clinically apparent cases (62%) among 92 nonpregnant women. Overt disease therefore does not appear to be more common during ~regnancy.4~~ Some complications such as mastitis and perhaps thyroiditis are more frequent in postpubertal women than in men but probably do not occur more commonly in pregnant women than in other adult women.492Mumps virus has been isolated on the third postpartum day from the milk of a woman who developed parotitis 2 days ante artu urn.^% Her baby, who was not breastfed, did not develop clinically apparent mumps. Aseptic meningitis, apparently without unduly high incidence or

Chickenpox, Measles, and Mumps

727

severity, has also been reported in pregnant women.497In pregnant women, as well as in the population as a whole, deaths from mumps are exceedingly rare. One death has been reported in a woman who developed mumps complicated by glomerulonephritis at 8 months’ gestation.497

Effects of Gestational Mumps on the Fetus ABORTION

An excessive number of abortions is associated with gestational mumps when the disease occurs during the first trimester. In prospective studies of fetal mortality in virus diseases, Siege1 and associate^'^^ observed 9 fetal deaths (27%) among 33 first-trimester pregnancies complicated by mumps, compared with 131 (13%) of 1010 matched uninfected controls (see Table 22-6). This difference is significant = 5.6; P < .02). Mumps-associated fetal deaths occurred in only 1 of 51 second-trimester pregnancies and none of 43 third-trimester pregnancies. Unlike fetal deaths associated with measles, those associated with mumps were closely related temporally to maternal infection: 6 of the 10 deaths occurred within 2 weeks after the onset of maternal mumps.178 Many other reports describe isolated cases of abortion associated with gestational mumps. Most cases occurred in the first 4 months of pregnancy.4879492y4939495,498-500 In one instance, mumps virus was isolated from a 10-week fetus spontaneously aborted 4 days after the mother developed clinical mumps.500

(x2

PREMATURITY

In the only prospective study of low birth weight in relation to maternal mumps infection, no significant association was found.’78Nine (7.7%) of 117 pregnant women with mumps gave birth to infants with birth weights of less than 2500 g, compared with 4 (3.3%) of 122 uninfected pregnant women in a control group (see Table 22-5). CONGENITAL MALFORMATIONS

In experimentally infected animals, mumps virus may induce congenital malformation^.^^'-^^^ Definitive evidence of a teratogenic potential for mumps virus in humans, however, has not been shown. Many reports describe the occurrence of congenital malformations after gestational mumps, but no data are available in most of these studies regarding the incidence of anomalies in uninfected matched control pregnancies. Swan498reviewed the literature in 1951 and found 18 anomalies in the offspring of 93 pregnancies complicated by mumps. These included four malformations originating in the first trimester (i.e., cutaneous nevus, imperforate anus, spina bifida, and Down syndrome) and nine originating in the second trimester (i.e., four had Down syndrome and miscellaneous other malformations). Other reports have described malformation of the external ear,488intestinal a t r e ~ i a ; chorioretinitis ~~ and optic atrophy in the absence of evidence of congenital tox~plasmosis,~~~ corneal catara~ts,’’~~ and urogenital abn~rmalities.~’~ One case of hydrocephalus caused by obstruction of the foramen of Monro in an infant whose mother had serologically proven mumps during the fifth month of pregnancy has been described.506A similar phenomenon has been seen after extrauterine mumps with encephalitis507and in an animal In the only controlled, prospective study, the rate of congenital malfor-

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mations in children whose mothers had mumps during pregnancy (2 of 117) was essentially identical to the rate of those in infants born to uninfected mothers (2 of 123)." Neither of the two affected infants, both of whom were mentally retarded, was born tq any of the 24 pregnant women who had mumps in the first trimester. Similarly, no association between gestational mumps and fetal malformations was reported by British investigators, who evaluated the outcomes of 501 pregnancies complicated by maternal mumps and found no significant differences compared with a control series.50" ENDOCARDIAL FIBROELASTOSIS

A postulated association between gestational mumps infection and endocardial fibroelastosis in the offspring was at one time the subject of much debate.HW An extensive review of evidence for and against an etiologic role for mumps virus in this condition was made by Finland in the 1970s that was inconclusive, and there was little more information in the literature for the next 30 years.510The issue remains unresolved. The rarity of mumps during pregnancy and the rarity of endocardial fibroelastosis as a possible sequel in the fetus make it unlikely that conclusive data will ever be obtained. Molecular approaches, however, seem to have shed new light on the issue. Using PCR, mumps virus genome was detected in two of two fatal cases of fibroelast~sis.~"In another study of 29 fatal cases of this disease, fragments of the mumps genome were identified in 20 cases.512 Adenovirus was identified in the remainder. It was hypothesized that endocardial fibroelastosis is the end result of myocarditis. As mumps has become rare because of vaccination, endocardial fibroelastosis has also become rare.512The possible role of intrauterine mumps was not addressed in these two modern studies and may be impossible to evaluate further given the rarity of mumps in developed countries today.

delivery, One infant had parotitis, and the other had pneumonia; presumably, transplacental transmission had occurred.515Mumps virus was also isolated from a fetus spontaneously aborted on the fourth day after the onset of maternal mumps.485 However, transplacental passage of virus should not be assumed to occur invariably because in several instances passage could not be d o c ~ m e n t e d . " ~ ~ * ~ ~ ~ . ~ ~ A differentiation between lack of susceptibility and subclinical infection as explanations for failure of the neonate to develop parotitis or other manifestations of mumps can be made only by adequate serologic investigations and viral isolation attempts. Unfortunately, these data are not available. Several investigatorshave observed that clinicallyapparent mumps with p a r ~ t i t i s ~or ~ ~o ,r '~~h~i t i during s ~ ~ ~ the first year of life tends to be a very mild disease and that age-specific attack rates for manifest disease related to mumps increase progressively until the age of 5 years.522Antibodies to mumps virus are known to cross the placenta and to persist for several months.'23

Diagnosis and Differential Diagnosis

The diagnosis of mumps is easy when there is acute, bilateral, painful parotitis with a history of recent exposure. More difficulty is encountered when the disease is unilateral or when the manifestations are confined to organs other than the parotid gland. In these cases, laboratory confirmation by virus isolation or demonstration of a rising antibody titer may be performed. Among neonates, few conditions need be considered in the differential diagnosis. Clinical parotitis in this age group is rare. Suppurative parotitis of the newborn, usually caused by S. aureus, is most often unilateral.524Pus can be expressed from the parotid duct, and there is a polymorphonuclear leukocytosis of the peripheral blood. Other diagnostic considerations in the neonate include infection with parainfluenza viruses and coxsackieviruses,drug-induced parotitis, Perinatal Mumps and facial cellulitis. In addition to these conditions in the neonate, the In contrast to congenital chickenpox and measles, congenital differential diagnosis in pregnant women includes anterior mumps or even postnatally acquired perinatal mumps has cervical lymphadenitis, idiopathic recurrent parotitis, salivary rarely been documented virologically or serologically. gland calculus with obstruction, sarcoidosis with uveoparotid Although several cases of parotitis have been reported in women near delivery and their neonates and infants,492'513-516fever, and salivary gland tumors. Other entities should be considered when the manifesthe significance of these reports is often uncertain, especially tations appear in organs other than the parotid. Testicular when clinically apparent mumps only is present in the torsion in infancy may produce a painful scrota1 mass mother. Other viral, bacterial, and noninfectious causes are resembling mumps o r ~ h i t i s . Aseptic ~ " ~ meningitis related to difficult to exclude without laboratory evidence of mumps mumps typically occurs in the winter and early spring, and infection. enterovirus aseptic meningitis is most common in the Among the possible explanations for the rarity of transsummer and early autumn. Other viruses may also cause placental and postnatally acquired mumps in neonates are aseptic meningitis that is clinically indistinguishable from the rarity of mumps today, protection of the neonate by mumps. passive maternal antibodies, exclusion of mumps virus from the fetus by a hypothetical placental barrier, relative insusceptibility of fetal and neonatal tissues to infection Therapy by mumps virus, and occurrence of infections that are predominantly subclinical. Treatment of parotitis is symptomatic. Analgesics and application of heat or cold to the parotid area may be helpful. Passage of mumps virus across the human placenta has occasionally been reported. Live-attenuated mumps virus Mumps immune globulin has no proven value in the prehas been recovered from the placenta of pregnant women vention or treatment of mumps. Mastitis may be managed (but not from fetal tissues) who were vaccinated 10 days by the application of ice packs and breast binders. Testicular pain may be minimized by the local application of cold and before undergoing saline-induced a b~rt ion.~" Mumps virus gentle support for the scrotum. In some instances, severe was isolated from two infants whose mothers had mumps at

Chapter 22 cases of orchitis have appeared to respond to the systemic administration of corticosteroids.

Prevention Active Immunization Live-attenuated mumps virus vaccine induces antibodies that protect against infection in more than 95% of recipients. The subcutaneously administered vaccine may be given to children older than 1 year, but its use in infants younger than this is not recommended because of possible interference by passive maternal antibodies. Usually, it is administered simultaneously with measles and rubella vaccines when children are 15 months old. The vaccine is recommended for older children and adolescents, particularly adolescent males who have not had mumps; it is not recommended for pregnant women, for patients receiving corticosteroids, or for other immunocompromised hosts.

Passive Immunization Passive immunization for mumps is ineffective and unavailable.

Prevention of Nosocomial Mumps in the Newborn Nursery In contrast to chickenpox and measles, mumps does not appear to be a potentially serious hazard in the newborn nursery. No outbreaks of nosocomial mumps have been described in this setting, and transmission of mumps in a Most mothers are hospital setting is highly immune, and even neonates born to nonimmune mothers rarely develop clinically apparent mumps. Prudence dictates that mothers who develop parotitis or other manifestations of mumps in the period immediately ante partum or post partum should be isolated from other mothers and neonates. The case is less strong for isolating the puerperal mother with mumps from her own newborn. In the hospital setting, isolation of patients with mumps from the time of onset of parotitis has proved to be ineffective in preventing the spread of disease.526Infected subjects shed mumps virus in respiratory secretions for several days before the onset of parotitis or other manifestations recognizable as mumps. At one time, exposed hospital personnel, particularly postpubertal males, and mothers with a negative history of mumps could be given mumps immunoglobulin, although the prophylactic effectiveness of this product was never established. This preparation is no longer available. Liveattenuated mumps virus vaccine has not been evaluated for protection after exposure but may theoretically modify or prevent disease by inducing neutralizing antibodies before the onset of illness because of the long incubation period of mumps. It should be considered for exposed susceptible hospital personnel and puerperal mothers. Some hospitals have the facilities to test for susceptibility to mumps by measurement of antibody titers, whereas others do not. Testing for susceptibility could eliminate some use of vaccine for the previously described situation. Isolation procedures for mumps include the use of a single room for the patient with the door closed at all times except to enter. Immune personnel caring for the patient should exercise gown and hand-washing precautions. Isolation is continued until parotid swelling has subsided. Terminal disinfection of the room is desirable.


729

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Chapter 22 87. Kjersem H, Jepsen S. Varicella among immigrants from the tropics, a health problem. Scand J SOCMed 18171,1990. 88. Longfield JN, Winn RE, Gibson RL, et al. Varicella outbreaks in army recruits from Puerto Rico. Arch Intern Med 150970,1990. 89. Maretic Z, Cooray MPM. Comparisons between chickenpox in a tropical and a European country. J Trop Med Hyg 66311,1963. 90. Sinha DP. Chickenpox-a disease predominantly affecting adults in rural west Bengal, India. Int J Epidemiol5:367,1976. 91. Brunell P. Placental transfer of varicella-zoster antibody. Pediatrics 38:1034, 1966. 92. Mendez D, Sinclair MB, Garcia S, et al. Transplacental immunity to varicella-zoster virus in extremely low birthweight infants. Am J Perinatol9236, 1992. 93. Raker R, Steinberg S, Drusin L, Gershon A. Antibody to varicellazoster virus in low birth weight infants. J Pediatr 93:505, 1978. 94. Wang E, Prober C, Arvin AM. Varicella-zoster virus antibody titers before and after administration of zoster immune globulin to neonates in an intensive care nursery. J Pediatr 103:113,1983. 95. Baba K, Yabuuchi H, Takahashi M, Ogra P. Immunologic and epidemiologic aspects of varicella infection acquired during infancy and early childhood. J Pediatr 100:881,1982. 96. Gustafson TL, Shehab Z, Brunell P. Outbreak of varicella in a newborn intensive care nursery. Am Dis Child 138548,1984. 97. Hyatt HW. Neonatal varicella. J Natl Med Assoc 5932,1967. 98. Newman CGH. Perinatal varicella. Lancet 2:1159,1965. 99. Readett MD, McGibbon C. Neonatal varicella. Lancet 1644, 1961. 100. Freud P. Congenital varicella. Am J Dis Child 96730,1958. 101. Odessky L, Newman B, Wein GB. Congenital varicella. N Y State J Med 54:2849, 1954. 102. Harris LE. Spread of varicella in nurseries. Am J Dis Child 105:315, 1963. 103. Matseoane SL, Abler C. Occurrence of neonatal varicella in a hospital nursery. Am J Obstet Gynecol92:575, 1965. 104. Lipton S, Brunell PA. Management of varicella exposure in a neonatal intensive care unit. JAMA 261:1782,1989. 105. Patou G, Midgley P, Meurisse EV, Feldman RG. Immunoglobulin prophylaxis for infants exposed to varicella in a neonatal unit. J Infect 20:207, 1990. 106. Gold WL, Boulton J, Goldman C, et al. Management of varicella exposures in the neonatal intensive care unit. Pediatr Infect Dis J 12:954, 1993. 107. Friedman CA, Temple DM, Robbins KK, et al. Outbreak and control of varicella in a neonatal intensive care unit. Pediatr Infect Dis J 13:152, 1994. 108. Apert ME. Une epidemic de varicelle dans une maternite. Bull Med (Paris) 9:827, 1985. 109. Gold E. Serologic and virus-isolation studies of patients with varicella or herpes zoster infection. N Engl J Med 274181,1966. 110. Myers MG. Viremia caused by varicella-zoster virus: association with malignant progressive varicella. J Infect Dis 140:229,1979. 111. Nelson A, St. Geme J. On the respiratory spread of varicella-zoster virus. Pediatrics 371007, 1966. 112. Trlifajova J, Bryndova D, Ryc M. Isolation of varicella-zoster virus from pharyngeal and nasal swabs in varicella patients. J Hyg Epidemiol Microbiol Immunol28:201,1984. 113. Ozaki T, Ichikawa T, Matsui Y, et al. Lymphocyte-associated viremia in varicella. J MedVirol 19249,1986. 114. Asano Y, Itakura N, Hiroishi Y, et al. Viremia is present in incubation period in nonimmunocompromised children with varicella. J Pediatr 106:69, 1985. 115. Feldman S, Epp E. Isolation of varicella-zoster virus from blood. J Pediatr 88265,1976. 116. Feldman S, Epp E. Detection of viremia during incubation period of varicella. J Pediatr 94746, 1979. 117. Moffat JF, Stein MD, Kaneshima H, Arvin AM. Tropism of varicdazoster virus for human CD4+ and CD8+ T lymphocytes and epidermal cells in SCID-hu mice. J Virol69:5236,1995. 118. Koropchak C, Graham G, Palmer J, et al. Investigation of varicellazoster virus infection by polymerase chain reaction in the immunocompetent host with acute varicella. J Infect Dis 163:1016, 1991. 119. Ozaki T, Miwata H, Asano Y, et al. Varicella-zoster virus DNA in throat swabs of vaccinees. Arch Dis Child 267328,1993. 120. Grose CH. Variation on a theme by Fenner. Pediatrics 68:735, 1981. 121. Arvin AM, Pollard RB, Rasmussen L, Merigan T. Selective impairment in lymphocyte reactivity to varicella-zoster antigen among untreated lymphoma patients. J Infect Dis 137531,1978.


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122. Hardy IB, Gershon A, Steinberg S, et al. The incidence of zoster after immunization with live attenuated varicella vaccine: a study in children with leukemia. N Engl J Med 325:1545,1991. 123. Rand KH, Rasmussen LE, Pollard RB, et al. Cellular immunity and herpesvirus infections in cardiac transplant patients. N Engl J Med 2961372,1977. 124. Ruckdeschel JC, Schimpff SC, Smyth AC, Mardiney MR. Herpes zoster and impaired cell-associated immunity to the varicella-zoster virus in patients with Hodglun’s disease. Am J Med 62:77, 1977. 125. Friedman-Kien A, Lafleur F, Gendler F, et al. Herpes zoster: a possible early clinical sign for development of acquired immunodeficiency syndrome in high-risk individuals. J Am Acad Dermatoll4 1023,1988. 126. Feldman S, Chaudhary S, Ossi M, Epp E. A viremic phase for herpes zoster in children with cancer. J Pediatr 91:597, 1977. 127. Gershon A, Steinberg S, Silber R. Varicella-zoster viremia. J Pediatr 92:1033, 1978. 128. Stevens D, Ferrington R, Jordan G, Merigan T. Cellular events in zoster vesicles: relation to clinical course and immune parameters. J Infect Dis 131:509, 1975. 129. Szanton E, Sarov I. Interaction between polymorphonuclear leukocytes and varicella-zoster infected cells. Intervirology 241 19, 1985. 130. Ihara T, Starr S, Ito M, et al. Human polymorphonuclear leukocytemediated cytotoxicityagainst varicella-zostervirus-infected fibroblasts. JVirol51:110, 1984. 131. Ihara T, Ito M, Starr SE. Human lymphocyte, monocyte and polymorphonuclear leucocyte mediated antibody-dependent cellular cytotoxicity against varicella-zoster virus-infected targets. Clin Exp Immunol63:179, 1986. 132. Garcia AGP. Fetal infection in chickenpox and alastrim, with histopathologic study of the placenta. Pediatrics 325395, 1963. 133. Erlich RM, Turner JAP, Clarke M. Neonatal varicella. J Pediatr 53:139, 1958. 134. Lucchesi PF, LaBoccettaAC, Peale AR. Varicella neonatorum. Am J Dis Child 73:44, 1947. 135. Oppenheimer EH. Congenital chickenpox with disseminated visceral lesions. Bull Johns Hopkins Hosp 74240,1944. 136. Pearson HE. Parturition varicella-zoster. Obstet Gynecol23:2 1, 1964. 137. Steen J, Pederson RV. Varicella in a newborn girl. J Oslo City Hosp 936,1959. 138. Ranney EK, Norman MG, Silver MD. Varicella pneumonitis. Can Med Assoc J 96445,1967. 139. Triebwasser JH, Harris RE, Bryant RE, Rhodes ER. Varicella pneumonia in adults: report of seven cases and a review of the literature. Medicine (Baltimore) 46409,1967. 140. Bradley JS, Schlievert PM, Sample TG. Streptococcal toxic shock-like syndrome as a complication of varicella. Pediatr Infect Dis J 1077, 1991. 141. Brogan W,Niozet V, Waldhausen JHT, et al. Group A streptococcal necrotiziig fasciitis complicating primary varicella: a series of fourteen patients. Pediatr Infect Dis J 14588, 1995. 142. Centers for Disease Control. Outbreak of invasive group A Streptococnrs associated with varicella in a childcare center-Boston, MA, 1997. MMWR Morb Mortal Wkly Rep 46944,1997. 143. Davies HD, McGeer A, Schwarts B, et al. Invasive group A streptococcal infections in Ontario, Canada. N Engl J Med 335:547, 1996. 144. Doctor A, Harper MB, Fleischer GR. Group A beta-hemolytic streptococcal bacteremia: historical review, changing incidence, and recent association with varicella. Pediatrics 96:428, 1995. 145. Gonzalez-Ruiz A, Ridgway GL, Cohen SL, et al. Varicella gangrenosa with toxic shock-like syndrome due to group A Streptococcus infection in an adult. Clin Infect Dis 2 0 1058, 1995. 146. Mills WJ, Mosca VS, Nizet V, et al. Invasive group A streptococcal infections complicating primary varicella. J Pediatr Orthop 16522, 1996. 147. Peterson CL, Vugia D, Meyers H, et al. Risk factors for invasive group A streptococcal infections in children with varicella: a case-control study. Pediatr Infect Dis J 15:151, 1996. 148. Wilson G, Talkington D, Gruber W, et al. Group A streptococcal necrotizing fasciitis following varicella in children: case reports and review. Clin Infect Dis 20:1333, 1995. 149. Bullowa JGM, Wishik SM. Complications of varicella. I. Their occurrence among 2,534 patients. Am J Dis Child 49923, 1935. 150. Johnson R, Milbourn PE. Central nervous system manifestations of chickenpox. Can Med Assoc J 102:831,1970. 151. Jenkins RB. Severe chickenpox encephalopathy. Am J Dis Child 110137,1965.

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Viral Infections

152. Minkowitz S, Wenk R, Friedman E, et al. Acute glomerulonephritis associated with varicella infection. Am J Med 44:489,1968. 153. Yuceoglu AM, Berkovich S, Minkowitz S. Acute glomerular nephritis as a complication of varicella. JAMA 202:113, 1967. 154. Morales A, Adelman S, Fine G. Varicella myocarditis. Arch Pathol 91:29, 1971. 155. Moore CM, Henry J, Benzing G, et al. Varicella myocarditis. Am J Dis Child 118:899,1969. 156. Priest JR, Groth KE, Balfour HH. Varicella arthritis documented by isolation of virus from joint fluid. J Pediatr 93:990, 1978. 157. Ward JR, Bishop B.Varicella arthritis. JAMA 212:1954, 1970. 158. Gershon A. Varicella-zoster virus: prospects for control. Adv Pediatr Infect Dis 10:93, 1995. 159. Jura E, Chadwick E,Josephs SH, et al. Varicella-zoster virus infections in children infected with human immunodeficiency virus. Pediatr Infect Dis J 8:586, 1989. 160. Feldman S, Hughes W, Daniel C. Varicella in children with cancer: 77 cases. Pediatrics 80388, 1975. 161. Ihara T, Kamiya H, Starr SE, et al. Natural killing of varicella-zoster virus (VZV)-infected fibroblasts in normal children, children with VZV infections, and children with Hodgkm’s disease. Acta Pediatr Jpn 31:523, 1989. 162. Arvin A, Sharp M, Smith S, et al. Equivalent recognition of a varicellazoster virus immediate early protein (IE62) and glycoprotein I by cytotoxic T lymphocytes of either CD4+ or CD8+ phenotype. J Immunol 146257,1991. 163. Cooper E, Vujcic L, Quinnan G. Varicella-zoster virus-specific HLArestricted cytotoxicity of normal immune adult lymphocytes after in vitro stimulation. J Infect Dis 158:780, 1988. 164. Krugman S, Goodrich C, Ward R. Primary varicella pneumonia. N Engl J Med 257843,1957. 165. Mermelstein RH, Freireich AW. Varicella pneumonia. Ann Intern Med 55456, 1961. 166. Weber DM, Pellecchia JA.Varicella pneumonia: study of prevalence in adult men. JAMA 192572,1965. 167. Sargent EN, Carson MJ, Reilly ED.Varicella pneumonia: a report of 20 cases with postmortem examination in 6. Calif Med 107:141, 1967. 168. Bocles JS, Ehrenkranz NJ, Marks A. Abnormalities of respiratory function in varicella pneumonia. Ann Intern Med 60183, 1964. 169. Fish SA. Maternal death due to disseminated varicella. JAMA 173:978, 1960. 170. Hackel DB. Myocarditis in association with varicella. Am J Pathol 29369,1953. 171. Harris RE, Rhoades ER. Varicella pneumonia complicating pregnancy: report of a case and review of the literature. Obstet Gynecol25:734,1965. 172. Brunell PA. Varicella-zoster infections in pregnancy. JAMA 199315, 1967. 173. Baren J, Henneman P,Lewis R. Primary varicella in adults: pneumonia, pregnancy, and hospital admission. Ann Emerg Med 28165, 1996. 174. Siegel M, Fuerst HT. Low birth weight and maternal virus diseases: a prospective study of rubella, measles, mumps, chickenpox, and hepatitis. JAMA 197:88, 1966. 175. Harger JH, Ernest JM, Thurnau GR, et al. Risk factors and outcome of varicella-zoster virus pneumonia in pregnant women. J Infect Dis 185:422,2002. 176. Harger JH, Ernest JM, Thurnau GR, et al. Frequency of congenital varicella syndrome in a prospective cohort of 347 pregnant women. Obstet Gynecol 100260,2002. 177. Abler C. Neonatal varicella. Am J Dis Child 107:492, 1964. 178. Siegel M, Fuerst HT, Peress NS. Comparative fetal mortality in maternal virus diseases: a prospective study on rubella, measles, mumps, chickenpox, and hepatitis. N Engl J Med 274:768, 1966. 179. Pickard RE. Varicella pneumonia in pregnancy. Am J Obstet Gynecol 101:504, 1968. 180. Mendelow DA, Lewis GC. Varicella pneumonia during pregnancy. Obstet Gynecol 33:98, 1969. 181. Geeves RB, Lindsay DA, Robertson TI. Varicella pneumonia in pregnancy with varicella neonatorum: report of a case followed by severe digital clubbing. Aust N Z J Med 1:63, 1971. 182. Paryani SG, Arvin AM. lntrauterine infection with varicella-zoster virus after maternal varicella. N Engl J Med 314:1542,1986. 183. Esmonde TF, Herdman G, Anderson G. Chickenpox pneumonia: an association with pregnancy. Thorax 44:812,1989. 184. Figueroa-Damian R, Arrendondo-Garcia JL. Perinatal outcome of pregnancies complicated with varicella infection during the first 20 weeks of gestation. Am J Perinatol 14:411, 1997.

185. Cox SM, Cunningham FG, Luby J. Management ofvaricella pneumonia complicating pregnancy. Am J Perinatol7:300,1990. 186. Smego RA, Asperilla MO. Use of acyclovir for varicella pneumonia during pregnancy. Obstet Gynecol 78:1112,1991. 187. Landsberger EJ, Hager WD, Grossman JH. Successful management of varicella pneumonia complicating pregnancy: a report of 3 cases. J Reprod Med 31:311,1986. 188. Lotshaw RR, Keegan JM, Gordon HR. Parented and oral acyclovir for management of varicella pneumonia in pregnancy: a case report with review of literature. W V Med J 87:204, 1991. 189. Hockberger RS, Rothstein RJ. Varicella pneumonia in adults: a spectrum of disease. Ann Emerg Med 115931,1986. 190. Hollingsworth HM, Pratter MR, Irwin RS. Acute respiratory failure in pregnancy. J Intensive Care Med 4:11, 1089. 191. Hankins GDV, Gilstrap LC, Patterson AR. Acyclovir treatment of varicella pneumonia in pregnancy. Letter. Crit Care Med 15:336,1987. 192. Glaser JB, Loftus J, Ferragamo V, et al. Varicella in pregnancy. Letter. N Engl J Med 315:1416,1986. 193. Boyd K, Walker E. Use of acyclovir to treat chickenpox in pregnancy. BMJ 296393, 1988. 194. White RG. Chickenpox in pregnancy. Letter. BMJ 196864,1988. 195. Broussard OF, Payne DK, George RB. Treatment with acyclovir of varicella pneumonia in pregnancy. Chest 991045,1991. 196. Eder SE, Apuzzio JA,Weiss G. Varicella pneumonia during pregnancy: treatment of 2 cases with acyclovir. Am J Perinatol5:16,1988. 197. Andrews EB, Tilson HH, Hurn BAL, Corder0 JF. Acyclovir in pregnancy registry. Am J Med 85:123, 1988. 198. Centers for Disease Control. Acyclovir registry. MMWR Morb Mortal Wkly Rep 42S06.1993. 199. Pearse BM. Characterization of coated-vesicle adaptors: their reassembly with clathrin and with recycling receptors. Methods Cell Biol31:229, 1989. 200. Centers for Disease Control. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 45:1, 1996. 201. Enders G, Miller E, Cradock-Watson J, et al. Consequences of varicella and herpes mster in pregnancy: prospective study of 1739 cases. Lancet 343:1548, 1994. 202. Benyesh-Melnick M, Stich HF, Rapp F, et al. Viruses and mammalian chromosomes. 111. Effect of herpes zoster virus on human embryonal lung cultures. Proc SOCExp Biol Med 117546,1964. 203. Ada P. Chromosomes and virus infections. Lancet 1:720,1964. 204. Massimo I, Vianello MG, Dagna-Bricarelli F, et al. Chickenpox and chromosome aberrations. BMJ 2:172, 1965. 205. Collier E. Congenital varicella cataract. Am J Ophthalmol86:627,1978. 206. Cuthbertson G, Weiner CPW, Giller RH, Grose C. Prenatal diagnosis of second-trimester congenital varicella syndrome by virus-specific immunoglobulin M. J Pediatr 111:592, 1987. 207. Hardmg B, Bonner JA. Congenital varicella-zoster: a serologically proven case with necrotizing encephalitis and malformations. Acta Neuropathol 76:311, 1988. 208. Hammad E, Helin 1, Pasca A. Early pregnancy varicella and associated congenital anomalies. Acta Paediatr Scand 78:963, 1989. Malignant disease in children whose 209. Adelstein AM, Donovan JW. mothers had chickenpox, mumps, or rubella in pregnancy. BMJ 2:629 1972. 210. Fox MJ, Krumpiegel ER, Teresi JL. Maternal measles, mumps, and chickenpox as a cause of congenital anomalies. Lancet 1:746,1948. 211. Jones KL, Johnson KA, Chambers CD. Offspring of women infected with varicella during pregnancy: a prospective study. Teratology 4929, 1994. 212. Pastuszak A, Levy M, Schick B, et al. Outcome after maternal varicella infection in the first 20 weeks of pregnancy. N Engl J Med 330:901 1994. 213. Michie CA, Acolet D, Charlton R, et al. Varicella-zoster contracted in the second trimester of pregnancy. Pediatr Infect Dis J 101050,1992. 214. Connan L, Ayoubi J, Icart J, et al. Intra-uterine fetal death following maternal varicella infection. Eur J Obstet Gynecol68:205, 1996. 215. Sauerbrai A, Muller D, Eichhorn U, Wutzler P. Detection of varicellazoster virus in congenital varicella syndrome: a case report. Obstet Gynecol 88:687 1996. 216. Mouly F, Mirlesse V, Meritet JF, et al. Prenatal diagnosis of fetal varicella-zoster virus infection with polymerase chain reaction of amniotic fluid in 107 cases. Am J Obstet Gynecol 177894, 1997. 217. Ussery XT, Annunziato P,Gershon A, et al. Congenital varicella-zoster infection and Barrett’s esophagus. J Infect Dis 178:539, 1998.

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404. Rota PA, Rota JS,Bellini WJ. Molecular epidemiology of measles virus. Semin Viol 6379, 1995. 405. Centers for Disease Control. MeaslesUnited States, 2000. MMWR Morb Mortal Wkly Rep 51:120,202. 406. Weigle K, Murphy D, Brunell P. Enzyme-linked immunosorbent assay for evaluation of immunity to measles virus. J Clin Microbiol 19376, 1984. 407. Mayo DR, Brennan T, C o r d e r DP, et al. Evaluation of a commercial measles virus immunoglobulin M enzyme immunoassay. J Clin Microbiol292865. 1991. 408. Lievens A, Bruneu PA. Specific immunoglobulin M enzyme-linked immunosorbent assay for confuming the diagnosis of measles. J Clin Microbiol24391, 1986. 409. Papp K. Experiences prouvant que la voie d'infection de la rougeole est la contamination de la musqueuse conjunctivale. Rev Immunol 20:27, 1956. 410. Morley DC, Woodland M, Martin WJ. Measles in Nigerian children: a study of the disease in West Africa, and its manifestations in England andothercountriesduringdifferentepochs.] Hyg(Lond) 61:113,1963. 411. Babbott FL Jr, Gordon JE. Modern measles. Am J Med Sci 225:334, 1954. 412. Centers for Disease Control. Measles, mumps, and rubella-vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps. MMWR Morb Mortal Wkly Rep 47:1, 1998. 413. Frank J, Orenstein W, Bart K, et al. Major impediments to measles elimination. Am J Dis Child 139881, 1985. 414. Markowitz LE, Preblud SR, Fine PE, et al. Duration of live measles vaccine-induced immunity. Pediatr Infect Dis J 9:101, 1990. 415. Krugman S. Further-attenuated measles vaccine: characteristics and use. Rev Infect Dis 5:477, 1983. 416. Mathias RG, Meekison WG, Arcand TA, et al. The role of secondary vaccine failures in measles outbreaks. Am J Public Health 79:475,1989. 417. Berg RB, Rosenthal MS. Propagation of measles virus in suspensions of human and monkey leukocytes. Proc SOCExp Biol Med 106581, 1961. 418. Suringa DWR, Bank LJ, Ackerman AB. Role of measles virus in skin lesions and Koplik's spots. N Engl J Med 283:1139, 1970. 419. Debre R, Celers J. Measles: pathogenicity and epidemiology. In Debre R, Celers J (eds). Clinical Virology. Philadelphia, WB Saunders, 1970, p 336. 420. Enders J, McCarthy K, Mitus A, et al. Isolation of measles virus at autopsy in cases of giant cell pneumonia without rash. N Engl 1 Med 261:875, 1959. 421. Mitus A, Enders J, Crair JM, et al. Persistence of measles virus and depression of antibody formation in patients with giant cell pneumonia after measles. N Engl J Med 261982, 1959. 422. Lachmann P. Immunopathology of measles. Proc R SOCMed 67:12, 1974. 423. Stillerman M, Thalhimer W. Attack rate and incubation period of measles. Am J Dis Child 6715, 1944. 424. Baugess H. Measles transmitted by blood transfusion. Am J Dis Child 27:256, 1924. 425. Littauer 1, Sorensen K. The measles epidemic at Umanak in Greenland in 1962. Dan Med Bull 12:43, 1965. 426. Warthin AS. Occurrence of numerous large giant cells in ionsils and pharyngeal mucosa in prodromal stage of measles: report of four cases. Arch Pathol 112364, 1932. 427. Moroi K, Saito S, Kurata T, et al. Fetal death associated with measles virus infection of the placenta. Am J Obstet Gynecol 1641107, 1991. 428. La Boccetta AC, Tornay AS. Measles encephalitis: report of 61 cases. Am J Dis Child 107247,1964. Hauser GH. Encephalitis as a complication of measles. 429. Musser JH, JAMA 90:1267, 1928. 430. Pearl PL. Abu-Farsakh H, Starke JR, et al. Neuropathology of two fatal cases of measles in the 1988-1989 Houston epidemic. Pediatr Neurol 6126,1990. 431. Jahnke U, Fischer EH, Alvord EC. Hypothesis-certain viral proteins contain encephalitogenic and/or neuritogenic sequences. J Neuropathol Exp NeurolM320, 1985. 432. Kipps A, Dick G, Moodie W.Measles and the central nervous system. Lancet 2:1406, 1983. 433. Gremillion DH, Crawford GE. Measles pneumonia in young adults: an analysis of 106 cases. Am J Med 71:539,198 1. 434. Centers for Disease Control. Measles surveillance. MMWR Morb Mortal Wkly Rep 9:"'. 1973.

435. Christensen PE, Schmidt H, Bang HO, et al. An epidemic of measles in southern Greenland, 1951. Acta Med Scand 1M430,1953. 436. Krasinski K, Borkowsky W. Measles and measles immunity in children infected with human immunodeficiency virus. JAMA 261:2512,1989. 437. Embree JE, Datta P, Stackiw W, et al. Increased risk of early measles in infants of human immunodeficiency type 1-seropositive mothers. 1 Infect Dis 165:262, 1992. 438. Angel JB, Walpita P, Lerch RA, et al. Vaccine-associated measles pneumonitis in an adult with AIDS. Ann Intern Med 129:104,1998. 439. Kaplan LJ, Daum RS, Smaron M, McCarthy C. Severe measles in immunocompromised patients. JAMA 2671237,1992. 440. Kernahan J, McQuillin J, Craft A. Measles in children who have malignant disease. BMJ 295:15, 1987. 441. Breitfeld V, Hashida Y, Sherman FE, et al. Fatal measles infection in children with leukemia. Lab Invest 28:279, 1973. 442. Greenhill JP. Acute (extragenital) infections in pregnancy, labor, and the puerperium. Am J Obstet Gynecol25:760, 1933. 443. Nouvat JR. Rougeole et Grossesse. Bordeaux, xxxx, 1904. 444. Dyer I. Measles complicating pregnancy: report of 24 cases with three instances of congenital measles. South Med J 33:601,1940. 445. Packer AD. The influence of maternal measles (morbilli) o n the newborn child. Med J Aust 1:835,1950. 446. Atmar RL,Englund JA, Hammill H. Complications of measles during pregnancy. Clin Infect Dis 14217, 1992. 447. Eberhart-Phillips JE, Fredrick PD, Baron RC, Mascola L. Measles in pregnancy: a descriptive study of 58 cases. Obstet Gynecol 82:797, 1993. 448. Nichols WW, Levan A, Hall B, et al. Measles-associated chromosome breakage. Preliminary communication. Hereditas 48:367, 1962. 449. Miller ZB. Chromosome abnormalities in measles. Lancet 2:1070,1963. 450. Higurashi M, Tarnura T, Nakatake T. Cytogenic observations in cultured lymphocytes from patients with Down's syndrome and measles. Pediatr Res 7582,1973. 451. Jespersen CS, Littauer J, Sigild U. Measles as a cause of fetal defects. Acta Pediatr Scand 66:367, 1977. 452. Gazala E, Karplus M, Sarov I. The effect of maternal measles on the fetus. Pediatr Infect Dis 4:202, 1985. 453. Rones B. The relationship of German measles during pregnancy to congenital ocular defects. Med Ann DC 13:285,1944. 454. Swan C, Tostevin AL, Moore B, et al. Congenital defects in infants following infectious diseases during pregnancy, with special reference to relationship between German measles and cataract, deaf mutism, heart disease and microcephaly, and to period in pregnancy in which occurrence of rubella was followed by congenital abnormalities. Med J Aust 2:201, 1943. 455. Canelli AF. Sur le comportement normal et pathologique de l'immunity antimorbilleuse chez le nourison jeune. Rev Fr Pediatr 5:668, 1929. 456. Ronaldson GW. Measles at confinement with subsequent modified attack in the child. Br J Child Dis 23:192, 1926. 457. Narita M, Togashi T, Kikuta H. Neonatal measles in Hokkaido, Japan. Pediatr Infect Dis J 16908, 1997. 458. Kohn JL. Measles in newborn infants (maternal infection). J Pediatr 23:192, 1933. 459. Richardson DL. Measles contracted in utero. R I Med J 3:13, 1920. 460. Muhlbauer B, Berns LM, Singer A. Congenital measles-1982. Isr J Med Sci 19:987, 1983. 461. Noren GR,Adams P Jr, Anderson RC. Positive skin reactivity to mumps virus antigen in endocardial fibroelastosis. J Pediatr 62:604,1963. 462. Abreo F, Bagby 1. Sputum cytology in measles infection: A case report. Acta Cytol35:719, 1991. 463. Lightwood R, Nolan R. Epithelial giant cells in measles as an aid in diagnosis. J Pediatr 77:59, 1970. 464. Llanes-Rodas R, Liu C. Rapid diagnosis of measles from urinary sediments stained with fluorescent antibody. N Engl J Med 275:516, 1966. 465. Minnich LL, Goodenough F, Ray CG. Use of immunofluorescence to identify measles virus infections. J Clin Microbiol29:1148, 1991. 466. Smaron MF, Saxon E, Wood L, et al. Diagnosis of measles by fluorescent antibody and culture of nasopharyngeal secretions. J Virol Methods 33:223,1991. 467. Rossier E, Miller H, McCulloch B, et al. Comparison of immunofluorescence and enzyme immunoassay for detection of measlesspecific immunoglobulin M antibody. J Clin Microbiol29:1069, 1991. 468. Arrieta C, Zaleska M, Stutman H, Marks M. Vitamin A levels in children with measles in Long Beach, California. J Pediatr 121:75,1992.

Chapter 22 469. Frieden TR, Sowell AL, Henning K, et al. Vitamin A levels and severity of measles. Am J Dis Child 146182, 1992. 470. Hussey GD, Klein M. A randomized, controlled trial of vitamin A in children with severe measles. N Engl J Med 323:160, 1990. 471. Forni AL,Schluger NW, Roberts RB. Severe measles pneumonitis in adults: evaluation of clinical characteristics and therapy with intravenous ribavirin. Clin Infect Dis 19454, 1994. 472. Mustafa MM, Weitman SD, Wmick NJ, et al. Subacute measles encephalitis in the young immunocompromised host: report of two cases diagnosed by polymerase chain reaction and treated with ribavirin and review of the literature. Clin Infect Dis 16654, 1993. 473. Gudnadottir M, Black FL. Measles vaccination in adults with and without complicating conditions. Arch Gesamte Virusforsch 16521, 1965. 474. Chui LW-L, Marusyk RG, Pabst HF. Measles virus specific antibody in infants in a highly vaccinated society. J MedVirol33:199, 1991. 475. Lennon J, Black F. Maternally derived measles immunity in sera of vaccine-protected mothers. J Pediatr 108671,1986. 476. Wakefield AJ. Enterocolitis, autism and measles virus. Mol Psychiatry 7(Suppl2):S44,2002. 477. Fombone E. Chakrabarti S. No evidence for a new variant of MMRinduced autism. Pediatrics 108: E58,2001 478. Taylor B, Lingam R, Simmons A, et al. Autism and MMR vaccination in North London; no causal relationship. Mol Psychiatry 7(Suppl 2): s7,2002. 479. Taylor B, Miller E, Lingam R, et al. Measles, mumps, and rubella vaccination and bowel problems or developmental regression in children with autism: population study. BMJ 324393,2002. 480. Coughlan S, Connell J, Cohen B, et al. Suboptimal measles-mumpsrubella vaccination coverage facilitates an imported measles outbreak in Ireland. Clin Infect Dis 3584,2002. 481. Krugman S, Giles JP, Friedman H. Studies on immunity to measles. J Pediatr 66471, 1965. 482. Stillerman M, Marks HH, Thalhimer W. Prophylaxis of measles with convalescent serum. Am J Dis Child 621,1944. 483. Orvell C. The reactions of monoclonal antibodies with structural proteins of mumps virus. J Immunol 132:2622, 1984. 484. Lennette E. Laboratory Diagnosis of Viral Infections. New York, Marcel Dekker, 1992. 485. Garcia A, Periera J,Vidigal N, et al. Intrauterine infection with mumps virus. Obstet Gynecol56756,1980. 486. Connolly NK. Mumps orchitis without parotitis in infants. Lancet 1:69, 1953. 487. Bowers D. Mumps during pregnancy. West J Surg Obstet Gynecol 61:72, 1953. 488. Greenberg MW, Beilly JS. Congenital defects in the infant following mumps during pregnancy. Am J Obstet Gynecol57:805,1949. 489. Hardy JB.Viral infection in pregnancy: a review. Am J Obstet Gynecol 93:1052, 1965. 490. Homans A. Mumps in a pregnant woman. Premature labor, followed by the appearance of the same disease in the infant, twenty-four hours after its birth. Am J Med Sci 29:56, 1855. 491. Moore JH. Epidemic parotitis complicating late pregnancy: report of a case. JAMA 921625,1931. 492. Philip RN, Reinhard KR, Lackman DB. Observations on a mumps epidemic in a “virgin” population. Am J Epidemiol6991, 1959. 493. Schwartz HA. Mumps in pregnancy. Am J Obstet Gynecol60875,1950. 494. Siddall RS. Epidemic parotitis in late pregnancy. Am J Obstet Gynecol 33:524, 1937. 495. Ylinen 0,Jervinen PA. Parotitis during pregnancy.Acta Obstet Gynecol Scand 32:121,1953. 496. Kilham L. Mumps virus in human milk and in milk of infected monkey. Am J Obstet Gynecol33:524, 1951. 497. Dutta PC. A fatal case of pregnancy complicated with mumps. J Obstet Gynaecol Br Emp 422369, 1935. 498. Swan C. Congenital malformations associated with rubella and other virus infections. In Banks HS (ed). Modern Practice in Infectious Fevers. New York, PB Hoeber, 1951, p 528.


737

499. Hyatt H. Relationship of maternal mumps to congenital defects and fetal deaths, and to maternal morbidity and mortality. Am Pract Dig Treat 12:359, 1961. 500. Kurtz J, Tomlinson A, Pearson J. Mumps virus isolated from a fetus. BMJ 284471,1982. 501. Robertson GG, Williamson AP, Blattner RJ. Origin and development of lens cataracts in mumps-infected chick embryos. Am J Anat 115:473, 1964. 502. St. Geme JW Jr, Davis CWC, Peralta HJ, et al. The biologic perturbations of persistent embryonic mumps virus infection. Pediatr Res 2541, 1973. 503. Johnson RT, Johnson KP, Edmonds CJ. Virus-induced hydrocephalus: development of aqueductal stenosis in hamsters after mumps infection. Science 157:1066, 1967. 504. Holowach J, Thurston DL, Becker B. Congenital defects in infants following mumps during pregnancy: a review of the literature and a report of chorioretinitis due to fetal infection. J Pediatr 50:689, 1957. 505. Grenvall H, Selander P. Some virus diseases during pregnancy and their effect on the fetus. Nord Med 37:409, 1948. 506. Baumann B, Danon L, Weitz R, et al. Unilateral hydrocephalus due to obstruction of the foramen of Monro: another complication of intrauterine mumps infection? Eur J Pediatr 139:158, 1982. 507. Timmons G, Johnson K. Aqueductal stenosis and hydrocephalus after mumps encephalitis. N Engl J Med 283:1505, 1970. 508. Manson MM, Logan WPD, Loy RM. Rubella and Other Virus Infections During Pregnancy. London, Her Majesty’s Stationery Office, 1960. 509. St. Geme JW Jr, Noren GR, A d a m P. Proposed embryopathic relation between mumps virus and primary endocardial fibroelastosis. N Engl J Med 275:339, 1966. 510. Finland M. Mumps. In Charles D, Finland M (eds). Obstetric and Perinatal Infections. Philadelphia, Lea & Febiger, 1973, p 333. 511. Calabrese F, Rigo E, Milanese 0, et al. Molecular diagnosis of myocarditis and dilated cardiomyopathy in children: clinicopathologic features and prognostic implications. Diagn Mol Pathol 11:212,2002. 512. Ni J, Bowles NE, Kim YH, et al. Viral infection of the myocardium in endocardial fibroelastosis. Molecular evidence for the role of mumps virus as an etiologic agent. Circulation 95:133, 1997. 513. Zardini V. Eccezionale casso di parotite epidemica in neonato da madre convalescente della stessa malattia. Lattante 33:767, 1962. 514. Shouldice D, Mintz S. Mumps in utero. Can Nurse 51:454, 1955. 515. Jones JF, Ray G, Fulginiti VA. Perinatal mumps infection. J Pediatr 96:912, 1980. 516. Reman 0, Freymuth F, Laloum D, et al. Neonatal respiratory distress due to mumps. Arch Dis Child 61230, 1986. 517. Yamauchi T, Wilson C, St. Geme JWJr. Transmission of live, attenuated mumps virus to the human placenta. N Engl J Med 290:710, 1974. 518. Chiba Y, Ogra PA, Nakao T. Transplacental mumps infection. Am J Obstet Gynecol 122:904, 1975. 519. Monif GR. Maternal mumps infection during gestation: observations on the progeny. Am J Obstet Gynecol 121:549, 1974. 520. Meyer MB. An epidemiologic study of mumps: its spread in schools and families. Am J Hyg 75:259, 1962. 521. Hoen E. Mumpsinfektion beim jungen Sugling. Kinderprtzl 36:27, 1968. 522. Harris RW, Turnball CD, Isacson P, et al. Mumps in a Northeast metropolitan community: epidemiology of clinical mumps. Am J Epidemiol88:224, 1968. 523. Hodes D, Brunell P. Mumps antibody: placental transfer and disappearance during the first year of life. Pediatrics 45:99,1970. 524. Sanford HN, Shmigelsky 11. Purulent parotitis in the newborn. J Pediatr 26149, 1945. 525. Wharton M, Cochi S, Hutcheson RH, Schaffner W. Mumps transmission in hospitals. Arch Intern Med 150:47, 1990. 526. Brunell PA, Brickman A, O’Hare D, et al. Ineffectivenessof isolation of patients as a method of preventing the spread of mumps. N Engl 1 Med 279:1357,1968.

Chapter 23 CYTO MEGALOVIRUS INFECTIONS Sergio Stagno

William Britt

TheVirus 740 Cytomegalovirus Replication Cytomegalovirus Cellular Tropism

Epidemiology 743 Overview Breast-feeding Young Children as a Source of Cytomegalovirus Maternal Infection and Vertical Transmission Sexual Transmission Nosocomial Transmission Transmission to Hospital Workers

Pathogenesis 749 Cytomegalovirus Infection and Cell- Associated Viremia Virus-Encoded Pathogenic Functions Host Immunity and the Pathogenesis of Cytomegalovirus Infections Modulation of the Host Immune Response to Cytomegalovirus Pathogenesis of Acute Infections Pathogenesis of Central Nervous System Infections in Congenitally Infected Infants Pathogenesis of Hearing Loss Associated with Congenital Cytomegalovirus Infection Nature of Maternal Infection Perinatal Infection Persistent Viral Excretion

Pathology 757 Overview Commonly Involved Organ Systems

Clinical Manifestations 758 Congenital Infection Perinatal Infection

Diagnosis 764 Detection of Virus Tissue Culture DNA Hybridization Polymerase Chain Reaction Amplification Antigenemia Detection of Immune Response Diagnosis of Cytomegalovirus Infection during Pregnancy Prenatal Diagnosis Diagnosis of Perinatally Acquired Infections

Differential Diagnosis 768 Congenital Rubella Syndrome Congenital Toxoplasmosis Congenital Syphilis Neonatal Herpes Simplex Virus Infections

Treatment 769 Chemotherapy Passive Immunization Vaccines

Prevention 770 Pregnant Women Nosocomial Infection

Cytomegaloviruses (CMVs) comprise a group of agents in the herpesvirus family known for their ubiquitous distribution in humans and in numerous other mammals. In vivo and in vitro infections with CMVs are highly species specific and result in a characteristic cytopathology of greatly enlarged (cytomegalic) cells containing intranuclear and cytoplasmic inclusions.' The strikingly large, inclusionbearing cells with a typical owl's-eye appearance were first reported by Ribber? in 1904 from the kidneys of a stillborn infant with congenital syphilis. Subsequently, Jesionek and Kiolemenoglo~~ reported similar findings for another stillborn infant with congenital syphilis. In 1907, Lowenstein4 described inclusions in 4 of 30 parotid glands obtained from children 2 months to 2 years old. Goodpasture and Talbot5 observed the similarityof these cells to the inclusion-bearing cells (giant cells) found in cutaneous lesions caused by varicella virus, and they postulated that cytomegaly was the result of a similar agent. The observation of a similar cytopathic effect after infection with herpes simplex virus led Lipschutz6and then others to suggest that these characteristiccellular changes were a specific reaction of the host to infection with a virus. The observation by Cole and Kuttner7that inclusion-bearing salivary glands from older guinea pigs were infectious for younger animals after being passed through a Berkefeld N filter in a highly species-specific manner led to the denomination of these agents as salivary gland viruses. The cellular changes observed in tissue sections from patients with a fatal infection led to the use of the term cytomegalic inclusion diseuse (CID) years before the causative agent was identified. In 1954, Smith' succeeded in propagating murine CMV in explant cultures of mouse embryonic fibroblasts. Use of similar techniques led to the independent isolation of human CMV (unless otherwise noted, CMV refers to human cytomegalovirus) shortly thereafter by Smith: Rowe and coworkers," and Weller and associates." Smith' isolated the agent from two infants with CID. Rowe and associates" isolated three strains of CMV from adenoidal tissue of children undergoing adenoidectomy. The term AD1 69, used to designate a common laboratory-adapted strain of CMV, comes from these studies. Weller and associates" isolated the virus from the urine and liver of living infants with generalized CID. The term cytornegaZovirus was proposed in 1960 by Weller and colleagues" to replace the names CID and salivary gland virus, which were misleading because the virus usually involved other organs and because the name salivary gland virus had been used to designate unrelated agents obtained from bats. The propagation of CMV in vitro led to the rapid development of serologic methods such as neutralization and complement fixation. Using such antibody assays and viral isolation, several investigators quickly established that CMV was a significant pathogen in humans. This ancient virus, like other members of the herpesvirus family, infects almost

740

Section I11

Viral Infections

all humans at some time during their live^.'^^'^ Evidence of infection has been found in all populations tested. The age at acquisition of infection differs in various geographic groups and socioeconomic settings, which results in major differences in prevalence among groups. The natural history of human CMV infection is very complex. After a primary infection, viral excretion, occasionally from several sites, persists for weeks, months, or even years before the virus becomes latent. Episodes of recurrent infection with renewed viral shedding are common, even years after the primary infection. These episodes of recurrent infection are caused by reactivation of latent viruses or reinfections with an antigenically diverse strain of CMV. In immunocompetent hosts, CMV infections are generally subclinical. However, when infection occurs during pregnancy without consequences for the mother, it can have serious repercussions for the fetus. Even though most immunocompromised hosts tolerate CMV infections relatively well, in some instances, such as acquired immunodeficiency syndrome (AIDS) and bone marrow transplantation, CMV can cause disease of diverse severity, and the infection can be life threatening. Because of a longstanding and close host-parasite relationshp, many-probably thousands-genetically different strains of CMV have evolved and circulate in the general p0pu1ation.l~ THE VIRUS CMV (human herpesvirus 5) is the largest and structurally most complex member of the family of human herpesviruses. It has been classified as a betaherpesvirus based on several biochemical criteria such as the genome size, guanosine and cytosine content, slow replicative cycle, and restricted in vivo and in vitro tropism. Other members of this subfamily of viruses include other mammalian CMVs and the agents associated with the exanthem roseola, human herpesviruses 6 and 7.I6-l8Early estimates of its size based on electron microscopic studies indicated that the CMV particle was approximately 200 nm in diameter, a finding consistent with its measurement by more contemporary technique^.^^.^^ Intracellular and extracellular particles are heterogeneous in size, which is probably a reflection of the variabilityof envelope glycoprotein content. The virus genome consists of more than 250 kilobase pairs of linear double-stranded DNA, making CMV almost 50%larger than the alphaherpesviruses, herpes simplex virus and varicella-zoster virus.21In contrast to other betaherpesviruses, including other CMVs, CMV contains terminal and internal repeated nucleotide sequences that enable the genome to exist in four isomeric forms, similar to herpes simplex virus and other alphaherpesviruses.22The biologic advantages that favor four isomeric forms of the genome of this virus have not been determined but clearly depend on replication of the genome in a permissive cell.23 The nucleotide sequence of several clinical isolates of CMV has been determined, and from the analysis of these strains, it is estimated that CMVs could encode more than 250 open reading frames (ORFs). Individual viral genes and ORFs are designated by their location in the unique long (UL) region, unique short (US) region, or the internal or terminal repeat regions (IRS, IRL, TRS, TRL) of the prototypic genome of CMV.” In addition to the massive size of the genome, other post-transcriptional modifications can

increase the complexity of the coding sequence of CMV. A limited number of CMV genes represent spliced transcripts, primarily those encoding immediate-early gene products. In some cases, multiple proteins can arise from a single gene by use of internal translational initiation sites. Although in most cases experimental verification of virus-specific proteins arising from predicted ORFs has not been accomplished, it is nevertheless obvious from this analysis that the proteomes of the virus and of the virus-infected cell are exceedingly complex. Consistent with this observation has been the complexity of the proteome of the virion revealed by mass spe~ trometr y.Organization ~~ of the CMV genome is similar to that of other herpesviruses in that conserved gene blocks that encode replicative and virion structural proteins can be found in similar locations. This organization of the genome has allowed assignment of positional homologues between members for different subfamilies of herpesviruses, an approach that has been instrumental in the identification of genomic coding sequences of CMV proteins. Outside of these conserved gene blocks are genes or gene families that are specificfor individual betaherpesvirus.These genes are thought to impart specific in vivo tropism and the species-restricted growth of these viruses. The CMV virion consists of three identifiable regions: the capsid containing the double-stranded DNA viral genome, the tegument, and the envelope. The CMV capsid consists of six proteins that have functional and structural homologues in other herpesviruses. These proteins and their counterparts found in herpes simplex virus are listed in Table 23-1. The capsid of CMV has been studied by high-resolution cryoelectron microscopy, and its structure is almost identical to that of herpes simplex virus, with the exception that it has slightly different internal dimensions because it must incorporate a genome that is about 60% larger than herpes simplex virus. The capsid consists of 162 capsomere subunits consisting of 150 hexons and 12 pentons arranged in icosahedral symmetry.” The subunits of the capsid are thought to be partially assembled in the cytoplasm of the infected cell, followed by self-assembly using products of the UL80a

Table 23-1

Cytomegalovirus Proteins and Their Homologues in Herpes Simplex Virus

Protein

Herpes Simplex Virus

Major capsid protein Small capsid protein Minor capsid protein Minor capsid protein Assembly protein

Vp5 (UL119 ) Vp26 (UL35) Vp23(UL18) Vpl9c (UL38) VpZZa(UL26.5)

Assembly protein precursor

Vp21 (UL26)

Assembly protein precursor Portal protein

Vp24(UL26) UL6

Cytomegalovirus

MCP (UL86)a SCP (UL48-49)a MnCP (UL85)” MnCP-bp (UL46)” Assembly protein (UL80.5) Assemblin precursorcOOH (UL80a) Assemblin (UL80a)a UL104

%dicates capsid proteins that have been demonstrated in infectious virions. Data from Gibson W. Structure and assembly of the virion. Intervirology 39:389-400. 1996.

Chapter 23 Proteins encoded by this ORF serve as a scaffold for the assembly of the individual caps om ere^.^^ After the shell is assembled, newly replicated concatemeric viral DNA enters the capsid shell through a portal generated by the portal protein and the action of a virus-encoded protein complex called the terminase complex, generating the intranuclear ~ a p s i d . ~ ~ , ~ ’ Several steps in the assembly of the viral DNA-containing capsid are unique to CMV, including the cleavage of unit length DNA and the formation of the capsid portal. At least one of these steps in virus replication have been demonstrated to be the target of antiviral drugs.**Capsids containing infectious DNA leave the nucleus by poorly understood pathways and are enveloped in the cytoplasm. The tegument of CMV is the most complex and heterogeneous structure in the virion. An undetermined number of viral proteins and viral RNAs can be found in the tegument of infectious particles.29Although it is generally argued that the tegument has no identifiable structure and is usually described as an amorphous layer between the envelope and

Table 23-2

Functions of Selected Cytomegalovirus Tegument Proteins

ORF

Protein

Proposed Function

UL25 UL26 UL32 uL47 UL48 UL50 UL53 UL76 UL82 UL83 UL84 UL94 UL99

ppUL25 ppUL26 PP150 ppUL47 PP200 P35 ppUL53

Structurala Regulatoryb Structural Regulatory, structural Structural Assem blf Assembly, structural Regulatory, structural Regulatory, structural Regulatory, structural Regulatory 5tructural Structural

PP71 PP65 ppUL94 PP28

Tegument proteins are considered structural if they are considered essential for assembly of an infectious particle. bTegurnent proteins with identified regulatory activities in the replicative cycle of the virus. The proteins are considered essential for assembly of an infectious particle, but in some cases, they have not been demonstrated to be in the particle. ORF, open reading frame; UL, unique long region.

Table 23-3

Cytomegalovirus Infections

the capsid, some studies have argued that at least the innermost region of the tegument assumes the structure of the underlying icosahedral capsid.” Proteins within the tegument are characteristically phosphorylated and in many cases serve regulatory functions for virus replication. Some tegument proteins appear to have a primary role in maintenance of the structural integrity of the virion. Tegument proteins have a variety of functions in the infected cell, including direct stimulation of cell cycle progression from Goto GI by degradation of the retinoblastoma (Rb) protein and blocking progression at the GI-S junction of the cell Other tegument proteins enhance transcription from the immediateearly genes and accelerate the replication of viral DNA.34 Some tegument proteins are thought to modify cellular structures such as the infected cell nucleus to facilitate nuclear egress of capsids containing viral DNA (Table 23-2).35 These examples illustrate the functional complexity of CMV tegument proteins and suggest that it will be difficult in some cases to assign a unique function to an individual protein in the replicative cycle of CMV. The tegument contains the most immunogenic proteins of the virions, including the immunodominant targets of T lymphocyte responses and antibody responses.364oIn the case of one of the most abundant tegument proteins, pp65 (UL83 OW), studies have shown that approximately 2% to 5% of peripheral blood CD8’ lymphocytes from CMV-infected hosts are specific for this single protein.40It remains unclear why the normal host has devoted such a large percentage of peripheral CD8* lymphocyte reactivity to a single CMV antigen. The envelope of CMV rivals the tegument in terms of the number of unidentified proteins and the limited amount of information on the function of many envelope proteins. Sequence analysis of the CMV genome indicates that more than 50 ORFs exhibit predicted amino acid motifs found in glyc~proteins.~~.~~ The number of glycoproteins in the envelope of CMV is unknown, but eight glycoproteins have been defined experimentally (Table 23-3). Results of studies have suggested that the gM/gN complex represents the most abundant proteins in the virion envelope, with gB and the gH/gL/gO complex being the second and third most abundant group of glycoproteins in the envelope, respectively. There appears to be a redundancy in function for several of these glycoproteins (see Table 23-3); however, it also is llkely that these redundancies are a function of in vitro assays and that each of these proposed functions is essential for virus infectivity in vivo. The envelope glycoproteins induce a readily detectable

Cytomegalovirus Envelope Glycoproteins

Glycoprotein

ORF

gB gH gL go gM gN gpTRLl0 gpUL132

UL55 UL75 UL115 UL74 ULlOO UL73 TRLlO UL132

741

Complex Formation

ORF, open reading frame; TRL, terminal repeat location; UL, unique long region.

Essential for infectivity

Proposed Function

Yes Yes Yes Yes Yes Yes No No

AttachmenVfusion Fusionlpenetration Fusion/penetration Fusion/penetration Unknown Unknown Unknown Unknown

742

Section I11

Viral Infections

temporal expression of viral genes and the coordinated antibody response in the infected hosts and neutralizing inhibition of viral gene expression. This allows regulated antibodies directed against gB, gH, and the gM/gN complex of the viral genome. The next set of viral genes, ~~ can be demonstrated in human CMV immune s e r ~ m . ~ -expression the early or p genes, primarily encode viral proteins that are Moreover, considerable amounts of data from human and animal studies have indicated that antiviral antibodies required for replication of viral DNA or alteration of cellular directed at proteins of the envelope are a major component responses such as progression through the cell cycle or of,the host protective response to this virus. These and other cellular apoptotic responses.22These include the viral DNA findings further demonstrate that envelope glycoproteins polymerase, alkaline exonuclease, ribonucleotide reductase, play a key role in the early steps of viral infection. and other replicative enzymes. Some virion structural proteins are also made during this interval. The final set of viral genes, the late or y genes, are expressed approximately Cytomegalovirus Replication 24 hours after infection. These genes encode virion structural Virus replication begins when CMV attaches to the cell proteins and are required for the assembly of an infectious surface. The initial engagement of virion glycoproteins with particle. The entire replicative cycle is estimated to take cell surface proteoglycans is followed by more specific between 36 and 48 hours in permissive cells. Abortive infections receptor interaction^.^^-^^ Suggested cellular receptors for in nonpermissive cells have also been characterized, and CMV include the epidermal growth factor receptor and viral gene expression usually is limited to the immediatei n t e g r i n ~Regardless .~~ of the specific receptor used by CMV, early genes and possibly to a limited number of early genes. several studies have shown that CMV attachment and likely After viral DNA replication in the nucleus of infected fusion with the host cell membrane result in a cascade of cells, concatemeric DNA is cleaved during packaging into cellular responses mediated by signaling pathway^.^^-'^ the procapsid by mechanisms that closely resemble the pathSignaling pathways can be activated by the attachment of way of bacteriophage assembly. of the assembly of alphaherpesviruses have provided a better understanding ultraviolet light-inactivated, noninfectious virus and by a of the mechanisms and pathways of viral capsid assembly single envelope glycoprotein, indicating that the process of binding and fusion with the cell membrane is sufficient to and DNA packaging. The viral capsid leaves the nucleus by induce these cellular response^.^^^^^^^^ After infection with undetermined mechanisms and enters the cytoplasm as a CMV, more than 1400 cellular genes are induced or repressed, partially tegumented, subviral particle. Assembly of the suggesting that infection with this virus elicits myriad mature particle takes place in the cytoplasm of the infected host cell responses.56 Included in these early responses are cell in a specialized compartment that has been called the activation of transcription factors such as nuclear factorassembly compartmenr.68It is believed that this is a modified kappa B ( N F - a ) , increases in levels of second messengers secretory compartment close to the tran~-Golgi.6~*~~ Virion structural proteins are transported to this compartment, and such as phosphoinositide-3 (PI3) kinase, inhibition of cellular presumably through a series of protein interactions, the virus innate responses that block virus infection (e.g., RNAis assembled and enveloped. The latter step is of considerable activated protein kinase [PKR]), and progression to apoptosis complexity because of the large number of virion glycoof the infected cell.22,55,56,58-60 CMV infection prepares the proteins that constitute the envelope of infectious virion. host cell for virus replication and inhibits host cell responses Virus is presumably released by cell lysis in cells such as that can block virus infection. After attachment and penetration, the DNA-containing fibroblasts and by poorly defined exocytic pathways in certain viral capsid is rapidly transported to the nucleus, probably other cell using the microtubular network of the cell. Once in the Latency is a common theme of herpesviruses, particularly nucleus, the immediate-early genes of the virus are expressed of the betaherpesviruses. The concept of CMV latency is in the absence of any de novo viral protein synthesis, somewhat controversial in that viral persistence in the host suggesting that host or virion proteins are responsible for is more likely associated with chronic, low-level productive their induction. The replication cycle is divided into three infection and intermittent excretion. However, latent CMV classes according to time of synthesis after infection: infection has been demonstrated in macrophages obtained immediate early, early, and late. The immediate-early genes from infected nonimmunocompromised donors and in are the first set of viral genes to become active within infected vitro models of infection with CMV.71-74 The mechanisms cells, usually within the first 4 hours after infection, and the that favor the establishment of latent infections are not most abundantly expressed products of these genes are the known, but the viral genome is thought to be maintained as immediate-early 1 (IE1) and 2 (IE2) proteins. Both gene closed circular viral DNA that persists as an episome in latently products arise from the same region of the genome and infected cells, not by integration into the host DNA.75More share some amino acid sequences. IE1 is a 72-kDa phosphodefinitive information is available on the signals that induce protein (pp72) that is readily detectable throughout infection reactivation from latent infection. They include proin permissive cells and is the target of antibody assays for inflammatory cytokines such as tumor necrosis factor-a detection of CMV-infected cell^.^'.^^ IE2 is a promiscuous (TNF-a) and possibly interferon-? (IFN-y).73,74876 It has been trans-activating protein that probably is responsible for argued that latently infected cells of the monocytic lineage activating many of the early and late genes of CMV and some can become activated and replicate CMV after exposure to cellular genes.22IE 1, IE2, and additional immediate-early these cytokines in vivo, such as in the setting of rejection of genes encode inhibitors of cellular apoptotic an allograft. This mechanism may explain aspects of the pathogenesis of CMV infection in uninfected allograft The remaining replication program of CMV is similar to recipients transplanted with an organ from a CMV-infected that initially described for bacteriophages and for herpes donor.77978 simplex virus. It involves the coordinated and sequential

Chapter 23

Cytomegalovirus Cellular Tropism CMV can be detected in a wide variety of cell types in vivo.77.79-84 Studies using tissue from autopsies or biopsies have demonstrated virus in almost every cell type, including epithelial cells, endothelial cells, smooth muscle cells, neuronal cells and supporting cells in the central nervous system (CNS), retinal epithelium, dermal fibroblasts, and cells of the monocyte-macrophage lineage. There appears to be a very limited restriction of the host cellular tropism in vivo. Routine virus isolation and propagation in vitro requires that the host cell be permissive for CMV replication. Primary cells derived from a variety of organs such as primary astrocytes,primary endothelial cells, primary smooth muscle cells, primary macrophages, and primary fibroblasts are permissive for CMV replication in vitro. However, the yield of infectious virus from these various cell types is highly variable, ranging from very low (macrophages) to high (fibroblasts). Primary human fibroblasts are the most commonly employed cells for the recovery and propagation of CMV and if adequately maintained can yield up to lo6to lo7 infectious particles per milliliter of supernatant from cultures infected with laboratory strains of CMV. In contrast, recent clinical isolates often yield a fraction of this amount of virus, and almost all of the progeny virions are cell associated. The explanation for the differences in replication phenotype is unknown. Clinical isolates often exhibit an extended tropism and infect primary endothelial cells, macrophages, and primary smooth muscle cells, whereas commonly used laboratory strains of CMV do not infect these cell types. Although not fully understood, studies have provided clues about possible mechanisms that lead to extended cellular tropisms of some recent clinical viral isolates. It has been argued that these clinical isolates contain a number of genes that facilitate their in vivo replication and spread. These genes are not required for in vitro replication in fibroblasts and perhaps even inhibit replication, particularly the production of extracellular They are selected against, and over time, viral mutants with deletions of genomic material can be isolated from these cultures. Loss of these viral genes restricts host cell tropism for cells such as


743

endothelial cells and macrophages. The in vivo phenotype of these viral genes and their importance to in vivo replication and spread are not understood, but they are assumed to be essential because they are conserved in recent virus isolates.

EPIDEMIOLOGY Overview Human CMV is highly species specific, and humans are believed to be its only reservoir.’ CMV infection is endemic and has no seasonal variation. l 4 Seroepidemiologic surveys have found CMV infection in every human population that has been tested.”,14 The prevalence of antibody to CMV increases with age, but accordingto geographic and ethnic and socioeconomic backgrounds, the patterns of acquisition of infection vary widely among populations (Fig. 23- 1).15 In general, the prevalence of CMV infection is higher in developing countries and among the lower socioeconomic strata of the more developed nations. These differences are particularly striking during childhood. For instance, in subSaharan Africa, South America, and South Pacific, the rate of seropositivity was 95% to 100% among preschool children studied, whereas surveys in Great Britain and in certain populations in the United States have generally found that less than 20% of children of similar ages are seropositive. The level of immunity among women of childbearing age, which is an important factor in determining the incidence and significance of congenital and perinatal CMV infections, varies widely among different populations. Several reports indicate that seropositivity rates in young women in the United States and Western Europe range from less than 50% to 85%.13,14In contrast, in sub-Saharan Africa, Central and South America, India, and the far East, the rate of seropositivity is greater than 90% by the end of the second decade of life. More important, from the point of view of congenital infection, prospective studies of pregnant women in the United States indicate that the rate of CMV acquisition for childbearing-aged women of middle to higher socioeconomic background is approximately 2% per year, whereas

SEROEPIDEMIOLOGY OF CYTOMEGALOVIRUS INFECTION 100

$ ..-c

Kansas City (USA)” Birmingham (USA)* Leningrad, Russia

90 -

:: 8 0 - 0 u,

5

70-

0

B c m >

-

H

50 40

ea

3 0 - f

I?

20-

0 c c

Melbourne, Australia

60-

10

I

I

I

I

I

I

I

I

Figure 23-1 Age-related prevalence of antibody t o cytornegalovirus (CMV) in various populations. (From Alford CA, Stagno S, Pass RF, et al. Epidemiology of cytornegalovirus. In Nahmias Al, Dowdle WR, Schinazi RE [edsl. The Human Herpesviruses. New York, ElsevierNorth-Holland, 1981, p 161.)

74.4

Section I11

Viral Infections

Table 23-4 Breast-feeding Patterns and Prevalence of Cytomegalovirus Infections in Young Children of Various Nations Breast-feeding Rate

Percent Seropositive

Nation

Ever

At 3 Months

Mothers

Children (Age)

Solomon Islands India Vel lore Pondicherry Barbados Guatemala Chile Japan Sapporo Sendai Finland (Helsinki) United States Houston, Texas Birmingham, Alabama France (Paris) Canada (Nova Scotia) U.K. (Manchester)

100

97

100

100 (5 mo-4 yr)

96

64

96 95 89

? ? ?

98 97 77 98 92

80 (1 yr) 67 (1-5 yr) 62 (1-5 yr) 47 (6 mo-1 yr) 42 (1 -2 yr) 42 (6 mo-2 yr) 38 (1 yr) 28 (1 yr)

15 (1 yr) 8 (1 yr) 10 (10 mo) 12 (6 mo-1 yr) 12 (3-1 1 mo)

?

95

50

67 85 55

46 8 85 49 51

? ? ? 26 13

48 85 56 34 59

56

Data from Pass RF. Transmission of viruses through human milk. In Howell RR, Morris FH Jr, Pickering K (eds). Role of Human Milk in Infant Nutrition and Health. Springfield, 111, Charles C Thomas, 1986, pp 205-224.

it is 6% per year among women of lower socioeconomic background.86 The modes of transmission from person to person are incompletely understood. Several features of CMV infection make it difficult to study the modes of acquisition. In most individuals, CMV infections are subclinical, including those acquired in utero and during the perinatal period. Infected persons continue to expose other susceptible people to CMV. Virus excretion persists for years after congenital, perinatal, and early postnatal infections. Prolonged viral shedding, which lasts more than 6 months in most individuals, is also a feature of primary infection in older children and adults. Because recurrent infections are fairly common, intermittent excretion of virus can be anticipated in a significant proportion of seropositive adults. Regardless of whether CMV is maintained as a latent infection with periodic reactivation or as a chronic, persistent infection yielding low titers of infectivity, the virus readily spreads within a population. A large reservoir of CMV exists in the population at all times. Transmission occurs by direct or indirect person-toperson contact. Sources of virus include urine, oropharyngeal secretions, cervical and vaginal secretions, semen, milk, tears, blood products, and organ allograft^.^^.^' CMV is not very contagious because the spread of infection appears to require close or intimate contact with infected secretions. The prevalence of CMV infection is higher for populations of low socioeconomic status, presumably reflecting factors that account for increased exposure to CMV, such as crowding, sexual practices, and increased exposure to infants and toddlers. Sexual contact contributes to the spread of CMV. Higher rates of seropositivity have been observed among males and females with multiple sex partners and histories of sexually transmitted disease^.^^-^^

Breast-feeding CMV is commonly excreted in milk collected post partum from seropositive The rates of excretion range from 13% to 32% by isolation of virus in tissue cultures to an excess of 70% when tested by polymerase chain reaction (PCR) methods. Peak excretion occurs between 2 weeks and 2 months post partum. The risk of transmission of CMV infection to the infants is 39% to 59%. The risk of transmission by lactating mothers correlates with viral loads of 7 x lo3 genome equivalents/mL. CMV can be detected in different components of breast milk. There is consensus that milk whey is the material of choice to detect the virus during lactation. Fractions of milk containing milk cells are less likely to show the virus by culture or PCR methods. This may explain why rates of viral isolation are lower in colostrum than in mature milk. Most infected infants begin to excrete CMV between 22 days and 3 months after birth. Conservatively, it is estimated that almost 40% of all infants nursed for at least 1 month by CMV-seropositive mothers become infected postnatally. Most of these infants become chronic excreters of CMV in urine and saliva, creating a large pool of infected infants. Because in most populations of the world the seroprevalence of CMV infection in women of childbearing age is high (80% to 100%) and most women breast-feed their infants for more than 1 month, the rate of transmission of CMV is quite high (Table 23-4). Trends in infant feeding practices have undergone major changes in the industrialized world. In the United States, breast-feeding in the hospital setting declined progressively during the 20th century to reach a nadir in the early 1970s, when exclusive breast-feeding was reported by 19% of white and 9% of black mothers.

Chapter 23

Table 23-5


745

Prevalence of Cytomegalovirus Excretion among Children in Daycare Centers

Investigator

Year

Location

Percent infected (n/N)

Stangert Strom Pass Adler Hutto MMWR Jones Murph Adler

1976 1979 1982 1985 1985 1985 1985 1986 1987

Stockholm, Sweden Stockholm, Sweden Birmingham, Alabama, USA Richmond, Virginia, USA Birmingham, Alabama, USA Birmingham, Alabama, USA San Francisco, California, USA Iowa City, Iowa, USA Richmond, Virginia, USA

35 72 51 24 41 29 22 22 53

(7/20) (13/18) (36/70) (16/66) (77/188) (66/231) (31/140) (9/41) (55/104)

Data from Adler St? Cytomegalovirus transmission among children in day care, their mothers and caretakers. Pediatr Infect Dis J 7:279-285, 1988. MMWR, Morbidity and Mortality Weekly Report.

Young Children as a Source of Cytomegalovirus Certain child-rearing practices influence the spread of CMV among children. In 1971,Weller' suggested that the high rate of seropositivity among Swedish children probably was caused by the frequent use of daycare centers. Swedish children had a rate of infection that was three to four times higher than that observed in London or in Rochester, New York. As shown in Table 23-5, high rates of CMV infection among children attending daycare centers were later confirmed in Sweden and have been reported in several studies in the United state^.^'-'^' The studies, which included a control group of children, confirmed that the rate of CMV infection was substantially higher among those in daycare than in those who stayed at home.97398 In the study of Pass and c o - ~ o r k e r of s ~ a~ group of 70 children of middle- to upper-income background whose ages ranged from 3 to 65 months, the rate of CMV excretion in urine and saliva was 51%. The lowest rate of excretion (9%) occurred in infants younger than 1 year, and the highest rate (88%) was among toddlers in their second year of life. Twelve infants whose mothers were seronegative excreted CMV, which indicated that their infection was not congenitally or perinatally acquired. These findings have been corroborated by other investigators. Similar results were reported by Adler and colleagues,"' who found that more than 50% of initially seronegative children acquired daycare-associated strains of CMV as determined by restriction fragment length polymorphism analysis of viral DNA. The findings of Adler, which have been confirmed by others, demonstrate that CMV is very efficiently transmitted from child to child in the daycare setting and that it is not unusual to find excretion rates as high as 20% to 40% in young toddler~?~.''~ In many instances, these rates of infection are substantially higher than the seroprevalence rates for the parents of the children and young adults in the cities where the studies were done.lo3 There is compelling evidence that the high rate of CMV infection among children in group daycare is caused by horizontal transmission from child to child. The route of transmission that appears most likely is the transfer of virus that occurs through saliva on hands and toy^.'^^^'^^ CMV can retain infectivity for hours on plastic surfaces and has been isolated from randomly selected toys and surfaces in a daycare center. No data have indicated CMV transmission through respiratory droplets.

These observations in daycare centers indicate that transmission of CMV between young children is very efficient. Once infected, these children excrete CMV in large quantities and for extended periods. With the changes in child-rearing practices occurring in the United States and the resurgence of breast-feeding, significant changes in the epidemiology of CMV can be expected within the next few decades.Io3 An important issue is whether children excreting CMV can become a source of infection for serosusceptible childcare personnel and parents, particularly women who may become pregnant. This type of transmission has been confirmed by restriction endonuclease mapping of CMV DNA.'06,'07 Seroepidemiologic studies suggest that parents often acquire CMV from their children who became infected outside the family. For instance, Yeager'" reported that 7 (47%) of 15 seronegative mothers of premature infants who acquired CMV in a nursery seroconverted within 1 year. Dworsky and colleagues'09reported that the rate of seroconversion for women with at least one child living at home was 5.5%, significantly higher than the 2.3% rate for women from the same clinic who were pregnant for the first time or the rates for susceptible nursery nurses and for physicians in training. Taber and associates showed a significant association between seroconversion among children and seroconversion among susceptible parents and showed that, in most cases, the infection in a child preceded seroconversion in the parents.466There is also compelling evidence linking the acquisition of CMV by children in daycare with subsequent infection in their mothers and caregivers.'02~'06"10~'13Several studies have demonstrated that CMV-seronegative parents have a significant risk of acquiring CMV infection if their infants and children attend daycare. The highest risk of seroconversion is approximately 20% to 45% for parents with a child shedding CMV at 18 months old. On average, parents acquire infection within 4.2 months (range, 3 to 7 months) after their children become infected. As determined by restriction fragment length polymorphism analysis of viral DNA, many of the strains isolated from the children, their parents, and their caretakers are epidemiologically related. For caretakers working with young children in daycare centers, the annual rate of seroconversion is approximately lo%, which is significantly higher than the 2% annual rate occurring in hospital employees matched for age, race, and marital status. These observations provide compelling evidence that serosusceptible parents and women who work with children in daycare centers have an occupational risk of

746


Table 2 3 6 Rate of Congenital Cytomegalovirus Infection in Relation to Rate of Maternal Immunity in Various Locations Location and Date Manchester, England, 1978 Aarhus-Viborg, Denmark, 1979

Hamilton, Canada, 1980 Halifax, Canada, 1975 Birmingham, Alabama (upper SES), 1981 Houston, Texas (upper SES), 1980 London, England, 1973 Houston, Texas (low SES), 1980 Abidjan, Ivory Coast, 1978 Sendai, Japan, 1970 Santiago, Chile, 1978 Helsinki, Finland, 1977 Birmingham, Alabama (low SES), 1980

No. of

Rate of Congenital CMV Infection (%)

Infants

605 1 3060 15,212 542 2698 46 1 720 493 2032 132 118 200 1412

Rate of Maternal

Seropositivity (%)

0.24 0.4 0.42 0.55 0.6 0.6 0.69 1.2 1.38 1.4 1.7 2.0 2.2

25 52 44 37 60 50 58 83 100 83 98 85 85

cytornegalovirus; SES, socioeconomic status. Data from Stagno 5, Pass RF, Dworsky ME, et al. Maternal cytornegalovirus infection and perinatal transmission. Clin Obstet Gynecol 25:564, 1982.

CMV,

acquiring CMV. It is reasonable to expect that as many as 50% of susceptible children between the ages of 1 and 3 years who attend daycare will acquire CMV from their playmates and become an important source of infection for susceptible parents and caregivers. Of particular concern is the risk to seronegative women who become pregnant.

Maternal Infection and Vertical Transmission Because maternal CMV infection is the origin of congenital infections and of most perinatal infections, it is important to review the relevant issues that pertain to vertical transmission. As used here, vertical transmission implies transmission from mother to infant.

Congenital Infection Congenital infection is assumed to be the result of transplacental transmission. In the United States, congenital CMV infection occurs in 0.2% to 2.2% (average, 1%) of all newborns. However, as shown in Table 23-6, the incidence of congenital infection is quite variable among different populations. The natural history of CMV during pregnancy is particularly complex and has not been fully explained. Infections such as rubella and toxoplasmosis cannot serve as models. With these infections, in utero transmission occurs only as a result of a primary infection acquired during pregnancy, whereas the in utero transmission of CMV can occur as a consequence of primary and recurrent infections (i.e., reinCongenital infection resulting fection or reacti~ation).”~”’~ from recurrent CMV infection is common, especially in highly immune populations. The initial clue was provided by three independent reports of congenital CMV infections that occurred in consecutive In all three instances, the first infant was severely affected or died and the second born in each case was subclinicallyinfected. More convincing evidence came from a prospective study of women known to be seroimmune before conception.”’ As shown in Table 23-7, the rate of congenital CMV infection was 1.9% among 541 infants born to these seropositive women. The 10 congenitally infected infants were not

Table 23-7

Incidence of Congenital Cytomegalovirus Infection in a Low-Income Population

Parameter

Total

No. Infected (%)

Incidence in general infant population Incidence with recurrent

1412

31 (2.2)

457 58

8 (1.8)

26 541

1 (3.8) 10 (1.9)

maternal infection Previously seropositive Prior cytomegalovirus excretion Prior intrauterine transmission

Total

1 (1.7)

Data from Stagno S, Pass RF, Dworsky ME, et at. Maternal cytomegalovirus infection and perinatal transmission. Clin Obstet Gynecol 25:567, 1982.

infected as a result of primary maternal CMV infection because all mothers were known to have been infected with CMV 1 year to several years before the onset of pregnancy. Shortly after our studies were published, Schopfer and associate^"^ found that in an Ivory Coast population in which virtually all inhabitants are infected in childhood, the prevalence of congenital CMV infection was 1.4%. This remarkable phenomenon of intrauterine transmission that occurs in the presence of substantial immunity has been attributed to reactivation of endogenous virus in some cases and to reinfection with different strains of CMV in other instances. In support of reactivation is our observation that the viruses isolated from each of three pairs of congenitally infected siblings were identical when examined by restriction endonuclease analysis.”’ In two of these three pairs, the first-born infant was severely affected, whereas the secondborn sibling was subclinically infected, which suggested that virulence of infection was not related to strain and that maternal immunity in some way attenuated the fetal infection. Another studyI2’ indicates that women who are CMV seropositive can become reinfected with a different strain of CMV, leading to intrauterine transmission and symptomatic

Chapter 23 congenital infection. This study assessed maternal humoral immunity to strain-specific epitopes of CMV glycoprotein H. Serum specimens from women with preconceptional immunity were obtained during the previous and the current pregnancy. Of the 16 mothers with congenitally infected infants, 10 had acquired new antibody specificities against glycoprotein H, compared with only 4 of the 30 mothers of uninfected infants. The women participating in this study were from a group that is predominantly characterized by low socioeconomic rank, young age, unmarried status, high seroprevalence of CMV, and a strong background of sexually transmitted diseases, including high rates of CMV excretion. Whether the observations of this study can be extrapolated to other populations remains to be defined. Intrauterine transmission in immune women accounts for the direct relationship between the incidence of congenital CMV infection and the rate of seropositivity shown in Table 23-6. It is extremely difficult to define by virologic or serologic markers which patient may undergo a reactivation of CMV, and it is almost impossible to define the time of intrauterine transmission with such reactivations or reinfections during pregnancy. The sites from which CMY reactivates to produce congenital infection are unknown and probably are inaccessible to sampling during pregnancy. Although CMV excretion is a relatively common event during and after pregnancy, the simple isolation of virus during pregnancy is a poor indicator of the risk of intrauterine infection. Virus can be shed at variable rates from single or multiple sites after primary or recurrent infections in women whether pregnant or not. Sites of excretion include the genital tract, cervix, urinary tract, pharynx, and breast. In pregnant women, virus is excreted most commonly, in decreasing order, from the cervix, urinary tract, and the throat. In the immediate postpartum period, the frequency of viral shedding into breast milk can reach 40% of seropositive women. The rates of cervical and urinary tract shedding in nonpregnant women are comparable to those found in pregnant cohorts of similar demographic and socioeconomic characteristics. In general, rates of cervical shedding range from 5.2% for nonpregnant women drawn from private practice or family planning clinics to 24.5% among women attending a sexually transmitted disease c l i n i ~ . ~ ~ ' ~ ~ Pregnancy per se has no discernible effect on the overall prevalence of viral shedding. However, the prevalence of excretion is lower (2.6%) in the first trimester than near term (7.6%).'19This rate is comparable to the prevalence of genital excretion in nonpregnant women. The rates of CMV excretion in the genital and urinary tracts of women are inversely related to age after puberty. In one study, the rate of genital CMV excretion fell from 15% in girls between 1 1 and 14 years old to undetectable levels in women 31 years old or older.'lg From a peak of 8% for the younger group, urinary excretion fell to zero among women 26 years old or older. No CMV excretion occurred from either site in postmenopausal women. The transient depression of cellular immune responses to CMV antigens during the second and third trimesters is another peculiar aspect of the relationship between CMV and the pregnant human host.'21 In one study, there was no generalized depression of cellular immunity because numbers of T lymphocytes, T cell proliferative responses to other mitogens, and serum antibody titers remained


747

unchanged. None of these mothers shed virus during the period of depressed cellular immune response, nor did they transmit the infection to their infants. It has been shown that antibody responses to glycoprotein B are significantly higher at the time of delivery in women with primary CMV infection who transmitted the infection in utero compared with those who did not, suggesting that the amount of antiviral antibody is not reflective of protection from transmission. 122 However, analysis of the qualitative antibody response revealed lower neutralizing antibody titers in transmitters, suggesting an association between neutralizing activity and intrauterine transmission. In this study, a significant correlation was found between neutralizing titers and antibody avidity, indicating that antibody avidity maturation is critical for production of high levels of neutralizing antibodies during primary CMV infection.lZ2In a separate study, higher levels of transplacentally acquired maternal antibodies against glycoprotein B and neutralizing antibodies were observed in infants with symptomatic infection at birth and who went on to develop ~eque1ae.l'~ Perinatal Infection In contrast to the poor correlation that exists between CMV excretion during pregnancy and congenital infection, there is a good correlation between maternal shedding in the genital tract and milk and perinatal acquisition. As shown in Table 23-8, in one study,g0the two most efficient sources of transmission in the perinatal period were infected breast milk, which resulted in a 63% rate of perinatal infection, and the infected genital tract, particularly in late gestation, which was associated with transmission in 26% and 57% of cases (i.e., natal infection). Viral shedding from the pharynx and urinary tract of the mother late in gestation and during the first months post partum has not been associated with perinatal transmission. As shown in Table 23-4, there is considerable variability in perinatal transmission of CMV throughout the world. lZ4 The age of the mother and her prior experience with CMV,

Table 23-8

Association between Maternal Excretion of Cytomegalovirus from Various Sites and Subsequent Infection of the Infant

Only Site of Maternal Excretion Breast milk Breast-fed infant Bottle-fed infant Cervix Third trimester and post partum Third trimester First and second trimesters Urinea Sa Iiva Nonexcreting women Bottle-fed infant Breast-fed infant

No. of Infants Infected1 No. Exposed (%) 19130 (63) 019 (0) 8114 (57) 18/68 (26) 118 (12) 0111 (0) 0115 (0) 01125 (0) 0111 (9)

aLatethird trimester. bExcretion 1 day post partum. Data from Stagno S, Reynolds DW, Pass RF, et al. Breast milk and the risk of cytomegalovirus infection. N Engl J Med 302:1073, 1980.

748


2.5% to 12%. In a study of seronegative children receiving blood for cardiac surgery, the risk of acquiring CMV was calculated to be 2.7% per unit of blood.128There is a significant correlation between the risk of acquisition of CMV by patients labeled seronegative and the number of units of blood (total volume) transfused. In one study, the incidence of primary infection increased from 7% among patients receiving 1 unit of blood to 21% among those receiving more than 15 units.'29 For seronegative marrow transplant recipients who receive standard blood products, the risk of CMV infection is between 28% and 57%.'32 Under Sexual Transmission conditions found in blood banks, CMV inoculated in whole Many epidemiologic studies support the classification of blood persisted for 28 days and in fresh-frozen plasma for CMV as a sexually transmitted infection. This is consistent 97 days. The observation that two newborns who received large with excretion of this virus in cervical secretions, vaginal fluid, volumes of fresh blood subsequently developed symptomatic and semen. In general, in developing areas of the world, 90% CMV infections led McCracken and associate^'^^ to suggest to 100% of the population is infected during childhood, an association between blood transfusion and clinically even before they are 5 years old. Sexual transmission in these apparent postnatal CMV infection. A subsequent report populations plays a minor role as a source of primary CMV indicated an association between postnatal CMV infection infection, but its importance in reinfection is unclear. In developed countries, the infection is acquired at a lower rate, and exchange transfusion^.'^^ With exchange transfusions, the risk of infection can reach 50%, which is probably the and in some population groups, there is a burst in the preresult of the much larger volume (150 to 200 mL/kg) received valence of infection after puberty. Several lines of evidence indicate that sexual transmission of CMV is at least partly by these infants.'34 Intrauterine transfusions have also been implicated in CMV infection of mothers and their infants. responsible for this increase in seroprevalence. Increased CMV infections resulting from transfusion of blood seroprevalence of CMV and excretion of virus have been products can cause significant disease in newborn infants, found in women attending sexually transmitted disease clinics and in young male h o r n o s e ~ u a l s . ~Ha~ndsfield ~ ~ ~ ~ ' ~ ~particularly in premature infants and infants born to women without immunity to CMV. Extremely premature infants demonstrated that previously infected individuals could be born to seropositive mothers are also at increased risk because reinfected by a different strain of CMV as assessed by the transplacental transfer of specific antibodies does not restriction fragment length p~lymorphism.'~~" Evidence has occur until the later stages of gestation. Infected infants with also been provided for sexual transmission in less propassively acquired anti-CMV antibodies develop milder miscuous populations.94395Among the many variables disease than infected infants without passively acquired antiinvestigated, a significant correlation was found among bodies. This observation is a compelling argument for the seropositivity to CMV, greater numbers of lifetime sexual role of antiviral antibodies in protecting the host against partners, and past or present infection with other sexually severe disease. transmitted diseases. Transmission of CMV by transplantation of an allograft from donors previously infected with CMV represents a major Nosocomial Transmission clinical problem in allograft transplantation. Transplantation of a kidney from a seropositive donor into a seronegative Nosocomial CMV infection is an important hazard of blood recipient results in primary CMV infection in 80% of the transfusion and organ transplantation. In compromised patients. The clinical manifestations of the infection vary hosts such as small premature newborns and bone marrow widely, depending principally on immunosuppressive transplant recipients, transfusion-acquired CMV infection regimens. Most investigators have found that CMV infection has been associated with serious morbidity and even fatal has an adverse effect on the survival of the allograft. CMV is infection. The association between the acquisition of CMV also a major cause of morbidity and mortality in bone marrow infection and blood transfusion was first suggested in 1960 re~ipients.'~~-'~' Interstitial pneumonitis is the most significant by keel and co-workers,'26who described a syndrome characmanifestation of the infection; the mortality rate approaches terized by fever and leukocytosis occurring 3 to 8 weeks after 100% in some series. Between 70% and 100% of heart transopen heart surgery. The reports that followed soon after plant recipients excrete CMV.'3s8139 Primary CMV infection expanded the syndrome to include fever, atypical lymphooccurs in a high proportion (60%) of patients who are cytosis, splenomegaly, rash, and lymphadenopathy.'27-13'The seronegative before surgery. Severe disease is more likely to term postperfusion mononucleosis was then proposed. be associated with primary than with reactivated infection, Prospective studies incriminated blood transfusion as the but primary infection is not associated with an increased major risk factor and demonstrated that although the clinical risk of rejection of the transplant.'40s141 The demonstration syndrome occurred in approximately 3% of the patients of CMV nucleic acid in kidneys of infected donors and of undergoing transfusion, inapparent acquisition of CMV latent CMV in cells of macrophage-monocyte lineage indicates infection ranged from 9% to 58% as determined by seroconthat the transplanted organs and hematopoietic allografts version, a fourfold rise in complement-fixing antibody titers can serve as the source of virus in transplant recipients. or viral excretion, or both, occurring between 3 and 12 weeks Nosocomial transmission is possible in the nursery after surgery. It has been estimated that the percentage of setting, which suggests that workers' hands or contaminated blood donors capable of transmitting CMV ranges from

which influence the frequency of viral excretion into the genital tract and breast milk, are important factors. Younger seropositive women who breast-feed are at a greater risk for transmitting virus in early infancy, especially in lower socioeconomic groups.'o3It is remarkable that in Japan, Guatemala, Finland, and India, where the rates of CMV excretion within the first year of life are extremely high (39% to 56%), the practice of breast-feeding is h o s t universal,and most women of childbearing age are seroimmune for CMV.



749

Rates of Primary Cytomegalovirus Infection among Health Care Workers and Others

Study

Group

Yeager 197514

Non-nurses Neonatal nurses Pediatric nurses Medical students Pediatric residents Neonatal nurses High risk: pediatric intensive care unit, blood/ intravenous fluids team Low risk: pediatric ward nurses, noncontact Pediatric residents Pediatric nurses Neonatal nurses Pediatric nurses Pediatric "therapists" Transplantldialysis nurses Neonatal intensive care unit nurses Nursing students Blood donors Middle-income pregnant women Low-income pregnant women

Dworsky et al, 1983'" Friedman et al,a 198414' Brady et al, 1985'45a Adler et al, 1986'" Demmler e t al, 19861aa Balfour and Balfour, 19861ab

Stagno et al, 198686

No. in Group

27 34 31 89 25 61 57 151 122 31 40 43 76 117 96 139 167 4692 507

Seroconversions (%/yr)

0 4.1 7.7 0.6 2.7 3.3 12.3 3.3 3.8 4.4 1.8 0 0 1.04 2.28 2.25 1.57 2.5 6.8

aOnlystudy in a children's hospital reporting a statistically significant difference in relation to occupational contact. Data from Pass RF, Stagno S. Cytomegalovirus. In Donowitz LG (ed). Hospital Acquired Infection in the Pediatric Patient. Baltimore, Williams & Wilkins, 1988.

fomites might be i n v o l ~ e d . ' ~CMV ~ - ' ~ ~has been recovered from objects used in the care of an infected newborn and from surfaces in a daycare center, with recovery of virus for up to 8 However, the very low rate of CMV infection in newborn infants of seronegative mothers who are not exposed to other important sources such as banked human milk or seropositive blood products indicates that transmission of CMV by means of fomites or workers' hands is rare.

Transmission to Hospital Workers Because hospital workers are often women of childbearing age, there has been concern about occupational risk through contact with patients shedding CMV. As illustrated in Table 23-9, most studies carried out during the past decade indicate that the risk is not significantly different from the general pop~1ation.l~~ The studies showing differences in the rate of seroconversion between health care workers and controls did not show that the risks were statistically ~ignificant.'~,'~~ The risk for hospital personnel is a function of the prevalence of CMV excretion among patients, the prevalence of seronegativity in health care workers, and the degree of their exposure to infected patients. In general, among hospitalized infants and children, viruria occurs in approximately 1% of newborns and 5% to 10% of older infants and toddlers. Working with hospitalized children inevitably leads to contact with a child shedding CMV; however, it is important that workers who develop a primary infection not assume that their occupational exposure or contact with a specific patient is the source of infection. Three reports illustrate this point well. Yow and c o - ~ o r k e r s , Wilfert '~~ and associate^,'^^ and Adler and colleag~es'~'described health care workers who acquired CMV while pregnant and after attending patients known to be excreting CMV. In each of these reports, assays

of restriction fragment length polymorphisms from CMV isolates demonstrated that the source of CMV for the workers were not the patients under suspicion. With the implementation of universal precautions in the care of hospitalized patients, the risk of nosocomial transmission of CMV to health care workers is expected to be much lower than the risk of acquiring the infection in the community.

PATHOGENESIS The disease manifestations that are associated with CMV infections can be conveniently divided into those associated with acute infection and those associated with chronic infections. considerably more is known about acute infectious syndromes, because acute CMV infections can be temporally related to specific symptoms and associated with specific laboratory abnormalities. Infrequently,acute CMV syndromes can occur in presumably normal individuals and in these cases manifest as an infectious mononucleosis that is indistinguishable clinically from the infectious mononucleosis associated with Epstein-Barr virus infection.'493150 Normal individuals with symptomatic infections often have increased viral burdens as measured by serologic responses compared with individuals with asymptomatic infection^.'^' More commonly, acute CMV infections that result in symptomatic disease occur in immunocompromised hosts. In general, acute CMV syndromes that are associated with clinical disease often share several common characteristics, including occurrence in hosts with depressed cellular immunity, uncontrolled virus replication, multiorgan involvement, end-organ disease caused by direct viral cytopathic effects, and clinical manifestations of disease correlated with virus burden. In patients with invasive CMV infections, such as those in allograft recipients, organ dysfunction and often disease course can be correlated with increasing virus

750


b ~ r d e n . ' ~ ' -There ' ~ ~ is usually not an absolute level of After infection, local replication, and amplification of viral replication as measured by viral genome copy number virus titer in regional sites, the spread of CMV within an infected host is likely to be cell associated based on findings in the peripheral blood that is predictive of the onset of from immunocompromised patients and experiments using an invasive infection and end-organ disease. It appears animal models. In mucosal surface infection and blood-borne that increasing levels of virus replication (i.e., genome copy number) is more useful in the identification of infections, the mode of spread and dissemination probably is the same, albeit with different kinetics and quantity of inindividuals at risk for invasive disease and presumably fected cells in the vasculature and infected organs. In all but reflects ongoing viral replication with an increasing risk the most severely immunocompromised patients, infectivity of dissemination. that can be demonstrated in the blood compartment is most Chronic disease syndromes associated with CMV include frequently associated with endothelial cells and polymorphoa variety of chronic inflammatory diseases of older popunuclear leukocytes (PMNs) from the buffy coat fraction of lations such as atherosclerotic vascular disease and vascular b l ~ o d . ' ~PMNs ~ - ' ~cannot ~ support virus replication ~ processes associated with chronic allograft r e j e ~ t i o n . ' ~ ~ - 'peripheral but have been shown to carry infectious virus and viral gene The progressive and late-onset hearing loss associated with p r o d u ~ t s . ' ~It~ has ~ ' ~ been ~ proposed that CMV-infected congenital CMV infection can be considered in this same endothelial cells or fibroblasts can transfer infectious virus ~ a t e g o r y . ' ~The ~ - ' ~characteristicsof populations experiencing to PMNs, and these cells can transmit virus by a microfusion these manifestations of CMV infection are different from event between virus-containingvesicles and susceptible cells.'78 those described previously and do not include hosts with This mechanism has not been experimentally verified in global immune dysfunction. Most individuals have normal animal models of CMV infection, but the role of PMNs in immunity and allograft recipients undergoing chronic graft transmission of infectious CMV in vivo is accepted, and the rejection may have increased immune responsiveness within correlation between CMV antigen-positive PMNs (antithe allograft. Viral replication appears to be a prerequisite for genemia assay) and disseminated infection provides a diagdisease, but the level of virus replication has not been related nostic tool for the identification of patients at risk for invasive to disease. The course of the disease in animal models of infection with CMV.'80-'87Antigen-positive PMNs can be CMV-associated vascular disease is that of ongoing inflamdetected in normal hosts infected with CMV, although with mation that is enhanced and prolonged by the presence of a drastically reduced frequency compared with immunoCMV.169-'72 Inhibition of virus replication early in the course compromised patients, suggesting that even in normal hosts of infection in animal models has been shown to dramatically that PMNs may be a common mode of virus dissemination. alter the course of disease, suggesting that virus must seed Other cells within the leukocyte fraction of peripheral blood these areas and establish a persistent i n f e ~ t i 0 n . I The ~~ cells support CMV persistence and transmit infectious virus, presence of the virus in areas of inflammation increases the including monocyte and macrophages derived by differenexpression of soluble mediators of inflammation such as tiation of blood monocytes. 188-197 Granulocyte-monocyte cytokines and chemokines and in some cases, virus-infected progenitor cells have been proposed as sites of latency based cells actively recruit inflammatory cells, including monocytes, on in vitrn infections and can be detested as antigen coninto the area of disease.'"*173 The bidirectional interactions taining cells in immunocompromised patients with disbetween CMV and the host inflammatory response are unique and appear to favor virus persistence, viral gene expression, seminated CMV infect~on.72~73~~89-"'92''9s Macrophages and likely virus dissemination. derived from peripheral blood monocytes have been shown to harbor infectious CMV on stimulation with specific cytokines, including TNF-a.7'*7697R Viral replication and Cytomegalovirus Infection and expression of a variety of early and late proteins can be Cell-Associated Viremia demonstrated in macrophages after infection with recently derived CMV clinical isolates. Another cell lineage believed An important aspect of the pathogenesis of CMV infection to be critical for the in vivo spread of CMV is endothelial is the route of infection and spread within the host. It is cells in a variety of microvascular beds. Endothelial cells have believed that virus is acquired at mucosal sites (i.e., community been shown to support CMV replication in vitro and infection exposures) or by blood-borne transmission, such as after of these cells results in a variety of cellular responses, inblood transfusion or transplantation of an infected allograft. cludmg the release of cytokines and chemokines.7°~79~80~'9'*'~~2~ Understanding the pathogenesis of these types of infections Lytic and nonlytic productive infections have been requires an understanding of the mode of virus transmission described, suggesting that endothelial cells can respond very and virus dissemination. It is believed that cell-free virus is differently to infection.70~200~207'208 Virus infection of endoresponsible for community-acquired CMV infection based on recovery of virus from saliva and from cell-free genital thelial cells is thought to be an initial step for infection of various tissues during CMV dissemination, and endothelial tract secretions, but only limited data directly support this claim. The most convincing evidence comes from studies in cell infection appears to be critical for the hematogenous spread from infected t i s s ~ e . ' ~ Early ~ ~ ' ~studies ' ~ ~ ~in~transbreast-feeding women that have demonstrated that infectious plantation populations described viral antigen-containing virus exists in the cell-free fraction of breast milk.'74 This endothelial cells circulating in the blood of viremic transplant finding suggests that cell-free virus can infect a mucosal recipients?01.2w92'o These cells are believed to be infected surface. Animal models of CMV infection have most commonly used intraperitoneal or subcutaneous inoculations; endothelium that slough into the circulation, presumably because of local infection or inflammation. A similar role for however, oral infection with cell-free murine CMV has been endothelial cells in spread of CMV in the murine model and accomplished (S. Jonjic, University of Rijeka, Rijeka, Croatia, guinea pig CMV model has been pr~posed."~ personal communication, 2000).

Chapter 23

Virus-Encoded Pathogenic Functions


75 1

influences in vivo tropism and replication of CMV is the MCMV gene M45. Endothelial cell tropism of MCMV can Specific CMV-encoded virulence factors have not been be linked to this single viral gene (M45), and it is believed identified. Early studies attempted to correlate restriction that expression of this gene limits resistance of endothelial fragment length polymorphism of viral isolates from cells to MCMV-induced a p o p t o ~ i s . ' ~Deletion ~ of the congenitally infected infants with clinical outcome. This homologous reading frame in CMV (UL45) was not genetic analysis proved too crude to allow identification of associated with the loss of endothelial tropism.235 subtle changes in the viral genome. Numerous studies have Other genes in MCMV encode functional chemokines, reported a possible linkage between polymorphisms in a such as the murine cytomegalovirus chemokine 1 (MCK-1) gene encoding the major envelope glycoprotein gB and that exhibits activity similar to that of interleukin-8 d i ~ e a s e . ~ " Most - ~ l ~ studies have failed to demonstrate any (IL-8).232,234 Studies in mice have suggested that the capacity specific linkage between different gB genotypes and disease, of this gene product to recruit inflammatory cells into a site and studies using other polymorphisms in several viral genes of virus replication is important for cell-associated virus (UL73, UL74, UL144) have failed to establish any genetic spread within infected animals.232In the absence of this linkage between a specific genotype and d i ~ e a s e . ~ ' ~ - ~virus-encoded '~ function, virus replication remains localized Although the explanation for the vast polymorphisms in to the site of infection because of a failure to recruit and CMVs is unclear, several characteristics of CMV infections, infect infiltrating inflammatory cells, limiting viral dissemiincluding frequent reinfections with new strains of virus in nation.232A functionally homologous viral gene in CMV exposed populations and recombination between strains of '~ (UL146) may influence the spread of CMV in v ~ v o . ~The virus, are likely reasons for the variability in the nucleotide protein encoded by UL146 is a secreted protein that appears sequences of different viral isolates.'20'213'219'220 However, there to function as a CXCL chemokine (CXCL1) and can induce appear to be differences in the biologic behavior of CMVs, chemotaxis and degranulation of PMNs.~'~It has been such that some strains exhibit extended tropism and can postulated that this viral chemokine could recruit PMNs in infect endothelial cells, macrophages, and epithelial cells in vivo and promote CMV dis~emination.~'~ In severely addition to permissive primary fibroblast cells. This extended immunocompromised hosts such as AIDS patients with tropism is found only in very recently derived isolates of gastrointestinal and retinal disease from disseminated CMV CMV, and after these viruses are repeatedly passaged through infection, neutrophil infiltration can be observed in the fibroblast cells, their extended tropism is quickly lost. It is lamina propria and in the retina.237-240 Infection of lamina believed that one or more viral genes are responsible for propria macrophages with CMV in vitro results in the their extended tropism in vivo and that without the selective induction of IL-8 release from these cells, suggesting that pressure of replication in vivo, these genes are lost or mutated. CMV can induce IL-8 release and encode a viral IL-8-like Specific genes that permit extended tropism in vitro have molecule.241Such findings are consistent with the proposed not been identified, but the presence of large numbers of mechanism of chemokine expression and CMV dissemination genes that modify the immune response to CMV point to from sites of virus replication. This mechanism of dissemithe possibility that these genes can encode a function that nation is consistent with the histopathologic findings in inhibits an innate response from cells such as macrophages. severely immunocompromisedpatients. However, a neutrophil Other viral genes encode functional chemokine receptors, infiltrate is not an invariant feature of the histopathology of viral cytokine-like molecules (vIL-10, vIL-~),and viral antinaturally acquired CMV infections, and interactions between apoptotic functions (vICA, UL37), all of which have been other virus-encoded chemokines and chemokine receptors proposed to contribute to the in vivo replication and virulence and peripheral blood leukocytes may contribute to virus dissemination. Research findings have demonstrated that of CMV infection^.^^'^^'-^^' Although defining the function of viral genes in the in CMV engages toll-like receptors with resultant induction of pro-inflammatory cytokines and chemokines cascades.242 vivo replication and spread of CMV has been difficult This observation raises the possibility that virus infection because of the restricted tropism of CMV to cells of human origin, much information has been gathered from studies in alone can recruit cells such as monocytes and PMNs to sites of infection without the requirement of a specific viral animal models. Using the mouse model of murine CMV infection, several laboratories have identified specific viral ~ h e r n o k i n e Other . ~ ~ ~ viral genes probably induce host cell genes that appeared to be required for efficient replication genes that facilitate virus replication. Microarray and difand spread in vivo.'95*224-229 Three viral genes encoded by ferential display experiments have demonstrated that CMV m139, m140, and m141 OFGs of murine CMV (MCMV) infection induces the expression of cyclooxygenase 2 (COX-2), an enzyme required for prostaglandin synthesis and initiation have been shown to play a critical role in viral replication in monocytes and macrophages but have little or no effect on of early steps of inflammati~n.~~ Subsequent experiments the replication of the virus in mouse fibroblast^.^^^-^^^ The in have shown that when COX-2 activity is blocked, CMV vivo phenotype of viruses that lacked these genes indicated replication was Together, these experiments these genes were required for in vivo dissemination and demonstrated that a CMV-encoded gene could induce a cellular enzyme that facilitated its replication possibly by spread of MCMV.232s234 The mechanism that accounts for restricted replication in monocytes of MCMV with deletions increasing the inflammatory response to the infection. This in these specific genes is unknown. The CMV genes that host response presumably leads to the recruitment of permit replication in monocyte-macrophages has not been inflammatory cells into the site of virus replication, thereby definitively identified, but the MCMV genes M139, M140, promoting infection of infiltrating cells and virus spread. and M141 are homologous to a family of CMV genes (US22 CMV encodes four G-coupled protein receptor (GPCR)gene family). Another example of a viral gene that directly like molecules in ORFs UL33, UL78, US 27, and US28.'73s244-246

752


marrow allograft recipients who received ex vivo expanded CMV-specific CD8' CTL and were protected from invasive CMV infection compared with historical control patients.262 Another interesting finding from this study was that patients that failed to generate CMV-specific CD4' lymphocyte responses failed to generate long-term protection from CMV and developed invasive infections late in the course of This observation predated studies that showed that a CD4' response is required for maintenance of long-term immunity to an infectious agent.265*266 Effector cells and mediators of the innate immune response have also been shown to be critical for control of CMV infections. Although most studies have used murine models of CMV infections, loss of natural killer (NK) cell activity and invasive CMV infection have been reported.267s268 In murine models, NK cells and interferons have been shown to play a critical role in resistance to MCMV infection and appear to represent an initial host response that can limit virus replication and spread during the development of a more efficient effector function of the adaptive immune system.255In contrast to the role of antiviral antibodies in limiting dissemination of MCMV, the importance of antiviral antibodies in protective responses to CMV remains unclear. Several studies have demonstrated a correlation between antiviral antibody responses, particularly virus-neutralizing antibodies, and Host Immunity and the Pathogenesis of patient o u t ~ o m e . ~ Studies ~~-~'~ in solid organ transplant Cytomegalovirus Infections recipients given intravenous immunoglobulins containing In normal hosts, innate and adaptive cellular immune anti-CMV antibodies have suggested that virus-specific antiresponses can limit but not prevent the spread of CMV from bodies can provide some degree of protection from invasive secondary sites such as the liver and spleen. The roles of infection^.^^^.'^^ In other transplantation populations, such innate and adaptive cellular immune responses in the control as bone marrow allograft recipients, the efficacy of antiof virus replication and spread to other sites have been clearly CMV immunoglobulins has not been proved, and its use shown in experimental animal models of CMV i n f e c t i ~ n . ~ ~varies ~ - ~ ~among ~ transplant center^.^^^'^^^'^^^^^^^ Animal models Increased levels of virus replication follow the loss of either other than mice have also indicated that antiviral antibodies class of cellular immune responses.253v255 The loss of viruscould provide some degree of protection. This is most specific CD4' or CD8' cytotoxic T lymphocyte (CTL) convincing in a guinea pig model of congenital CMV responses is associated with uncontrolled virus replication infection in which passive transfer of anti-guinea pig CMV and lethal disease in these models.255The role of virus(gpCMV) antibodies limited maternal disease and disease in specific antibodies has also been defined in these models and infected offspring.28032s' Available data argue for a role of antiviral antibodies in limiting disease caused by CMV, and appears to contribute minimally to control of local virus replication but plays a key role in limiting blood-borne in the case of intrauterine infections, antiviral antibodies dissemination of the This finding is of some interest could freely pass into the fetal circulation and, if protective, because in this model of CMV infection, virus spread is could alter the outcome of intrauterine infections. almost entirely by cell-associatedvirus and not cell-free virus, raising several interesting questions, including the mechanisms Modulation of the Host Immune Response to by which antiviral antibodies restrict virus dissemination.226 Cytomeg a lovirus Consistent with the findings in experimental animal models, studies in immunocompromised human hosts have repeatedly Over the past 10 years, several laboratories have identified demonstrated that loss of normal T lymphocyte responses multiple viral genes whose products interfere with immune predisposes the host to CMV infection and, depending on recognition and destruction of virus-infected cells. A the severity of the immune deficit, can lead to invasive disease description of these genes and their modes of action is resulting in considerable morbidity and m ~ r t a l i t y . ~ ~provided ~ - ~ ~ in Table 23-10. Several striking examples of the relationship between The importance of these genes in the biology of CMV in immunity and invasive CMV disease have been documented. vivo is not completely understood; however, animal models These include the development of pneumonitis in bone of CMV infection have allowed investigators to determine marrow and cardiac allograft recipients, prolonged CMV the importance of homologous genes during virus replication. viremia and end-organ disease such as retinitis in AIDS The results from these studies have indicated that these viral patients with high viral (i.e., human immunodeficiency virus functions actively interfere with virus clearance during acute infection in experimental animals.258'282v283 Although a [HIV]) burdens and low CD4' lymphocyte counts, and in fetuses infected in utero. Perhaps the most convincing complete discussion of these viral genes and their mechanisms evidence for the critical role of T lymphocyte responses in of immune evasion is outside the scope of this chapter, host resistance to invasive CMV infection were studies in bone several pertinent observations can be made about the

The US28 gene encodes a GPCR that is constitutively activated and that can also signal after interaction with chemokines, Reports including RANTES, MCP- 1, and have detailed possible roles for this molecule in the spread of CMV in vivo, including as a chemokine sink to limit host cell chemotaxis to CMV-infected cells, providing an anti-apoptotic function, recruitment of infected mononuclear cells to the sites of inflammation leading to dissemination of virus, and perhaps even binding of virus or virus-infected cells to chemokine expressing endothelial cell^.^^.^^' Arterial smooth muscle cells expressing US28 have been shown to migrate down chemokine gradients, thereby providing a mechanism for the localization of CMV-infected cells to sites containing inflammatory cellular infiltrate^.'^^ Although the role of US28 in CMV-induced vascular disease has been well described and supported by in vitro models of smooth muscle cell migration, the importance of US28 in virus dissemination from local site of infection remains to be more completely defined. Together, these and other studies suggest that the large coding sequence of CMV encodes proteins that are essential for efficient replication and for spread within the infected animal but probably have little or no function in the in vitro replication of virus.

Chapter 23

Table 23-1 0


753

Mechanisms of Cytomegalovirus Modulation of Host Immune Responses

Responses Innate Immune responses I Interferon responses

1 NK cell activity Adaptive Immune Responses 1 CD8'. MHC restricted CTL 1 CD4' responses

1 Antibody activity Antigenic variation Cytokines, Chemokine Responses Chernokine receptors (GPCRs) Cytokine

Viral Gene ORFsa

Mechanism

UL83 (pp65) TRS 1 UL18 UL40

1 IRFs, ~NF-KB 1 PKR activity

us2, us3, us11 us2 US6 TRLll UL73, UL55, UL75

1 Class I expression HLA-DR degradation Blocks TAP transport Viral Fc receptor Loss of antibody binding

US28, US27 ULllla

GPCR acts as a sink for extracellular chernokines Viral IL-10

MHC class I decoy THLA-E expression

aGenes and ORFs are designated by their locations in the unique long region (UL), unique short region (US), or the internal or terminal repeat regions (IRS, IRL, TRS, TRL) of the prototypic genome of cytomegalovirus. GPCRs, G-coupled protein receptors; HLA, human leukocyte antigen; IL, interleukin; IRFs, interferon regulatory factors; MHC, major histocompatibilitycomplex; NF-KB, nuclear factor of kappa light polypeptide gene enhancer in B cells; ORFs, open reading frames, PKR, protein kinase activated by double-stranded RNA; TAP, transporter associated with antigen presentation. Data from references 282, 475, 476, 477, 478, 479, 480, 481.

importance of these viral genes in the pathogenesis of CMV infections. These genes do not prevent recognition and control of CMV infections in normal hosts, as evidenced by the limited pathogenicity of this virus in normal individuals and in experimental animal models. Some investigators have argued that the phenotype of these viral genes can only be appreciated in the immunocompromised hosts. Moreover, vast amounts of literature describe the function of immune evasion genes in experimental animals and during acute infection. In most studies, the function of these viral genes has only been evaluated in a limited number of target organs, raising the question of whether some of these genes could be tissue specific. Other investigators have raised the question of whether these genes function to focus the immune response to a limited number of viral antigens, restricting the available antigens for immune recognition. However, these viruses have committed a large amount of their genome to immune evasion functions, the genes are conserved in animal and human CMVs, and experiments using animals have demonstrated that immune evasion functions facilitate a tissue-specific virus replication advantage in v ~ v o . ~These '~ observations suggest that these genes likely play a critical role in the biology of these viruses. Immune evasion functions encoded by CMVs interfere with innate immune responses and adaptive immune responses to virus-infected cells. Mutations that result in mutation in viral structural proteins and in viral proteins recognized by the immune system also appear to allow escape from immunologic control. Mutations in CMV viral genes encoding targets of dominant CD8' CTL responses have been reported.284One of the more interesting findings has been the observation that one MCMV gene, M157, previously shown to activate NK responses through NK receptor Ly49H in strains of mice that were genetically resistant to MCMV infection, can develop mutations within weeks of infecti0n.2'~Viruses with mutations in M157 were shown to replicate to higher titers in strains of resistant mice.

This mutational event appears to be caused by immune selection because genetically susceptible strains of mice that do not use this NK cell activation pathway do not generate viruses with mutations in the m157 gene.285Antigenic variation in virion envelope glycoproteins that are targets of virus neutralizing antibodies have been well described. Strain-specificneutralizing antibody responses to the envelope glycoprotein B have been One study'' of the polymorphic envelope glycoprotein N suggested that immune selection was responsible for the variation in amino acid sequence of gN derived from different virus isolates. CMVs, including human CMV, can evade immune recognition by a variety of active mechanisms such as immune evasion genes and by more conventional strategies, such as loss of antigenic determinants or loss of key antigens required for activation and recognition by immune cells.

Pathogenesis of Acute Infections Very early in the study of CMV infections, disease manifestations associated with congenital and perinatal CMV infections were related to the level of virus excretion, a marker for virus replication.288Subsequent studies in allograft recipients and in patients with AIDS have confirmed these findings and have consistently demonstrated that increased levels of CMV replication in these patients are a key predictor of invasive disease. Unchecked virus replication and dissemination leads to multiorgan disease as illustrated by autopsy studies of neonates with congenital CMV infections, allograft recipients, and AIDS patients. Studies using rhesus macaques infected with rhesus CMV (RhCMV) have yielded results consistent with the proposed pathogenesis of human infection and provided a more detailed view of infection with this virus.'" In these studies, virus given intravenously or by a mucosal route resulted in blood-borne dissemination and widespread infection of a number of organs, including the liver and spleen?" The kinetics of the

754

Section I11

Viral Infections

virus replication were different in the two groups, with a lag is poorly understood for several reasons, including the lack in peak virus titers and liver infection occurring in animals of a sufficiently large number of autopsy studies. There are inoculated by a mucosal route. This result suggested that a no well-developed animal models of CNS infection associlocal or regional amplification of virus was required after ated with congenital CMV infection. The MCMV model is mucosal infection before blood-borne dissemination to the useful for the study of many aspects of CMV infection, but liver and spleen. This finding is consistent with experimental congenital infection with MCMV does not occur in mice. findings in guinea pigs and mice infected with their The other widely employed small animal model, the guinea respective CMVs.22832w~292 The rhesus macaques that were pig, can be used to study intrauterine infections, and early reports suggested that CNS infections developed in these inoculated by mucosal exposure remained asymptomatic and failed to exhibit the clinical and laboratory abnormalities anhals.305,306 However, the usefulness of this model for that were observed in animals given virus intravenou~ly.~~~ studying CNS infection has not been defined, and because Together, these findings parallel clinical and laboratory findings only a limited number of observational studies have been in humans infected with CMV, and human infections that reported, it has been difficult to assign its value as a model. follow parented exposure to virus can exhibit clinical and The rhesus macaque offers perhaps the most relevant model laboratory abnormalities similar to those described in these for the study of CMV CNS infections for several reasons, experimental animal models. including the similarities in brain development shared The dissemination of CMV from the liver and spleen to between macaques and humans. The rhesus CMV is more distal sites probably occurs in the normal immunocompetent closely related to CMV than are the rodent and guinea pig CMVs. However, this model is expensive, and these individual and in the immunocompromised host. However, it is also quite likely that the quantity and duration of the experimental animals are in limited supply because of their viral dissemination is quantitatively different in these two use in studies of HIV. For these reasons, our understanding of CNS infection with CMV is limited. populations. In contrast to community-acquired CMV infections in normal adults, persistent viral DNAemia as Infection of the developing CNS is associated with a number of structural abnormalities, depending on the age of detected by PCR is characteristic of populations with disseminated CMV infections, such as AIDS patients or infants fetus at the time of CNS infection. Imaging studies of living with symptomatic congenital CMV i n f e c t i ~ n . ' ~ It ~ ~ ~ infants ~ ~ - ' ~and ~ children with congenital CMV infections and appears that the natural history of CMV infection includes clinical findings consistent with CNS disease have been local replication at mucosal sites followed by amplification informative. Commonly observed abnormalities include periventricular calcifications, ventriculomegaly, and loss of of virus, locally and presumably in regional lymphoid tissue, and spread to the viscera such as liver and spleen. Virus white-gray matter demar~ation.~'~-~'~ More refined imaging studies have detailed loss of normal brain architecture with replication in these organs further increases the quantity of loss of normal radial neuronal migrati~n.~" Limited autopsy viruses, and virus then spreads to distal organs and sites of persistence such as the salivary glands and renal tubules. studies have confirmed these imaging abnormalities and have demonstrated the presence of inflammatory infiltrates in the From observations in humans and in experimental models of infection, symptomatic infection appears to be related to parenchyma of the The latter finding is consistent the level of virus replication in sites seeded by the primary with the presence of increased protein and inflammatory viremia, such as the liver and spleen. It follows that parented cells in spinal fluid obtained from congenitally infected infants with CNS disease. Together these findingsargue for a exposure from sources such as contaminated blood are associated with symptomatic infections because a larger pathogenic spectrum that likely includes lytic infection of viral inoculum is delivered to the organs such as the liver, neuronal progenitor cells in the subventricular gray area, often in the absence of a developing immune response that vasculitis with loss of supporting vessels in the developing would normally be present after infection of a mucosal surface. brain, and meningoencephalitis with release of inflammatory mediators. It is unclear why the fetal and newborn brains are more susceptible to CMV infection compared with the adult Pathogenesis of Central Nervous System brain; however, findings from experimental models suggest Infections in Congenitally Infected Infants that the developing cells of the CNS are particularly susceptible to the lytic or possibly the apoptotic effects of The disease manifestations of congenital CMV infections include manifestations seen in adult immunocompromised CMVs. In animal models, including mice and rhesus hosts with disseminated CMV infections and include visceral macaques, infection of the developing CNS results in wideorgan involvement, such as hepatitis and, infrequently, spread lytic virus replication, including neuronal progenitor pneumonitis and adrenaliti~.~"-~O~ Unique to congenital cells of the subventricular gray area and e n d ~ t h e l i u m . ~ " - ~ ~ ~ CMV infection is the presence of CNS disease, a manifestation Lytic virus replication in this area would lead to loss of rarely seen even in the most immunocompromised allograft normal neuronal development, radial migration, and vascurecipients. CMV encephalitis has been reported in patients larity of the developing brain. Extravasation of blood from with AIDS, but this disease is distinctly different clinically damaged microvasculature would lead to calcifications that and pathologically from CMV infection of the CNS associare prominent findings in imaging studies of CMV-infected ated with intrauterine infection. CNS involvement in infants newborn infants. The more severe manifestations of CMV with congenital CMV infections often is associated with CNS infection can be explained by lytic virus infection ongoing disease, such as progressive hearing loss during the of neuronal progenitor cells, glial cells in the CNS, and destruction of supporting vasculature. Intracerebral inocufirst few years of life, at a time when there is no apparent lation of fetal rhesus macaques with RhCMV results in progression of structural damage in the CNS.165-'68s3" The pathogenesis of CMV CNS infection in the developing fetus findings similar to those described in severely affected human

Chapter 23 infants, suggesting that if CMV enters the CNS early in development, significant structural damage will ensue. Other infants infected in utero with CMV exhibit clinical findings consistent with CNS involvement,including developmental delays and loss of perceptual functions, but do not have structural damage of the brain that can be detected by routine imaging techniques. At least one autopsy series has suggested that affected infants without calcifications can have neuronal migration deficits manifest as pachygyria and other abnormalities such as cerebellar hypopla~ia.~"The mechanisms leading to loss of normal architecture are unknown but could be related to ongoing inflammation in the CNS because of intrauterine meningoencephalitis. Various inflammatory mediators have been shown to cause loss of neuron and supporting cell function and can modify vascular permeability and endothelial function. Evidence from experimental animal models has suggested that cytokines and chemokines may directly influence neuronal radial m i g r a t i ~ n . " ~Ongoing , ~ ~ ~ inflammation may result in loss of normal brain architecture from delayed or absent radial migration of neurons destined for the cerebral cortex.

Pathogenesis of Hearing Loss Associated with Congenital Cytomegalovirus Infection Hearing loss represents one of the most common long-term sequelae of congenital CMV infection, and its pathogenesis is perhaps the least understood of any manifestation of CMV infection. As discussed in preceding sections, the hearing loss can vary between mild and profound and be unilateral or bilateral, and it can develop or progress after the perinatal period.'65-'683304B316 Hearing impairment may represent the common outcome of CMV infections in different parts of the auditory apparatus or result from infection at different stages in the development of the auditory system. Besides the potential complexity of the disease, several other reasons probably contribute to the lack of understanding of the pathogenesis of hearing loss that follows congenital CMV infection. One of the most apparent is the lack of adequate histopathologic examinations of affected tissue from infected infants. A literature review revealed that only 12 temporal bones from congenitally infected infants have been studied and described in the medical literature. Most of the studies were done without the aid of modern techniques of virus and viral antigen detection and relied almost entirely on conventional histologic examinations. These limitations, together with the lack of adequate information on the maternal and fetal infection, have resulted in the lack of solid clues to the possible mechanisms of virus-induced damage to the auditory system. Hearing loss in CNS infections in adults with AIDS or transplant-related infections is rare and not well described, presumably because these infections differ significantly from congenital CMV infection in the extent of CNS involvement, the underlying diseases, and type of treatment in these immunocompromised patients. Animal models of CMV-induced hearing loss have been developed and have provided some information regarding selected aspects of the hearing loss associated with CMV. In general, however, they have failed to recapitulate the disease, and in some cases, early findings have been difficult to reproduce. Investigators have attempted to combine the limited data from histopathologic studies with natural history


755

studies of hearing loss from congenitally infected infants with findings from animal studies to develop a model of the pathogenesis of hearing loss associated with congenital CMV infections. A comprehensive review of temporal bone pathology in infants with congenital CMV infection was published by S t r a ~ s s . ~The ~ ' , specimens ~~~ in this series were from infants who died between the ages of 3 weeks and 5 months. A single case report of a 14-year-old patient with severe neuromuscular sequelae resulting from congenital CMV can be found.31y Findings in the inner ear, cochlea, vestibular system, and auditory or vestibular neural structures were described in all patients. Five of the original nine specimens had evidence of endolabyrinthitis,and virus was isolated from the endolymph in three of the nine specimen^.^'^ Viral antigen was detected by immunofluorescence in two cases in which routine histology failed to demonstrate viral inclusion^.'^^ Cochlear and vestibular findings were variable and ranged from rare inclusion bearing cells in or adjacent to the sensory neuroepithelium of the cochlea or vestibular system to more extensive involvement of the nonsensory epithelium. Routine histologic analysis failed to detect viral inclusions in the auditory or vestibular neural structures, but viral antigens were detected in the spiral ganglion when specimens were examined by immunofluorescence.165 Inflammatory infiltrates were minimal and reported in only three patients in this series.318Perhaps the most interesting results were those reported in the examination of tissue from the 14-year-old patient with extensive sequelae from congenital CMV infection. In this patient, extensive cellular degeneration, fibrosis, and calcifications were observed in the cochlea and vestibular systems.319Several generalizations can be made from these limited data. First, in all but two of these cases, virus, viral antigens, or histopathologic findings consistent with virus infection were detected in the cochlea or vestibular apparatus. These findings indicate that virus replication could have occurred in the sensory neuroepithelium and nonsensory epithelium and that cellular damage could have resulted from a direct viral cytopathic effect. Virus-induced damage can also result from bystander effects from immunemediated cytopathology. CMV could induce loss of sensory neuroepithelium in the absence of direct infection of the sensory neuroepithelium but from infection of supporting epithelium followed by host immunopathologic responses. However, an inflammatory infiltrate was seen in only three of nine specimens, an unexpected finding based on the role that the inflammatory response is thought to play in CMV end-organ disease in other patient populations. However, it is well documented that infants with congenital CMV have a delay in the development of immunologic responses to CMV, and it can be argued that findings in the cochlea and vestibular apparatus are consistent with the ineffectual immune responses of congenitally infected infants. An alternative and not exclusive possibility is that infection of the inner ear structures is a late or, in some cases, a postnatal event. The relationship between susceptibility of cells of the sensory neuroepithelium and supporting epithelium to infection with CMV and their developmental status is unknown.These cells could be resistant to CMV infection until late in development. In this case, findings from specimens of the autopsy series described previously may reflect recent infection before host inflammatory responses. Such an

756


explanation is, however, inconsistent with the course of fetal CMV infection in other parts of the CNS in most of the patients included in autopsy studies. The findings of extensive degenerative changes together with fibrosis and calcifications in the temporal bones from the oldest patient presumably reflect the natural history of CMV labyrinthitis and, depending on the rate at which these changes develop, may explain the progressive nature of hearing loss associated with congenital CMV infection. The loss of neuroepithelium from direct virus-mediated damage or from host-derived inflammation followed by fibrosis is consistent with the profound hearing impairment that develops in some children with congenital CMV infection. Findings in experimental animal models indicate that exaggerated deposition of extracellular matrix is part of the inflammatory response in the inner ear and that this host response possibly leads to the ossification that is observed in animals inoculated in the labyrinth with CMV.320,321 Studies in animal models have provided some limited insight into the pathogenesis of hearing loss after congenital CMV infection. Small animal models have provided some information and have mirrored findings in humans. Both virus and inflammation are required for the development of pathology in the inner ear. A study in guinea pigs demonstrated that virus infection in immunocompromised animals was not associated with the typical pathologic findings in virus-infected normal animals.322Similarly, blocking virus replication with antiviral compounds or pretreating the animals with virus-neutralizing antibodies limited the development of inner ear p a t h ~ l o g y . ~From ’ ~ - ~the ~ ~ available studies the pathogenesis of hearing loss associated with congenital CMV infection requires virus replication and a host immune response. Interrupting virus replication or the local host inflammatory response could offer some therapeutic benefit to these patients.

Nature of Maternal Infection

The risk of congenital CMV infection resulting from a recurrence of infection during pregnancy ranges from a high of 1.5% for a U.S. population of low socioeconomic background to 0.19% for women of middle or upper socioeconomic background from the United States,86 Great Britain,328or Sweden.334 In recurrent infection, it is likely that preexisting immunity inhibits the occurrence of viremia, at least to some extent. Cellular immunity may be more important than humoral immunity; however, maternal IgG antibodies are transmitted to the fetus, although their precise role has not been elucidated. Several cases of symptomatic congenital infection have been reported after therapeutic immune suppression, in women with lupus or AIDS, and even in women with intact immune system^.^^^-^^'

Perinatal Infection Naturally acquired perinatal CMV infections result from exposure to infected maternal genital secretions at birth or to breast milk during the first months of postnatal life.89,90 The presence of CMV at these two sites may be the result of primary or recurrent maternal infection. Iatrogenic CMV infections are acquired predominantly from transfusions of blood or blood products and breast milk from CMVinfected donors. Exposure to CMV in the maternal genital tract has resulted in a 30% to 50% rate of perinatal infection. The transmission from mother to infant through breast milk occurs in 30% to 70% if nursing lasts for more than 1 month~96.124.174.342-344 After ingestion of the virus, CMV infection is presumably established at a mucosal surface (i.e., buccal, pharyngeal, or esophageal mucosa) or in the salivary glands, for which CMV is known to have a special tropism. Occasionally, perinatal CMV infection and, rarely, congenital CMV infections are associated with pneumonitis. Although it is not proved, it is conceivable that CMV replicates in respiratory mucosa after aspiration of infected secretions or breast milk. Transmission of CMV by blood transfusion is more likely to occur when large quantities of blood are transfused. The failure to isolate CMV from the blood or blood elements of healthy seropositive blood donors suggests that the virus exists in a latent state, presumably within leukocytes. It has been suggested that CMV becomes reactivated after transfusion, when infected cells encounter the allogeneic stimulus. CMV genomes are activated when transfused to a recipient, particularly if immunologically immature or deficient. Chou and colleagues345reported that if the recipient is human leukocyte antigen (HLA) matched with the donor, activation is more likely to occur, presumably because of better survival * of ~ infected ~ ~ ~ cells. ~ ~ ~

The nature of the maternal infection is a major pathogenetic factor for congenital CMV infection. Primary infections are more likely to be transmitted to the fetus and are likely to cause more fetal injury than recurrent infections.326With primary CMV infection, as in other infections during pregnancy, there appears to be some innate barrier against vertical t r a n ~ m i s s i o n . ~ ~Intrauterine ’ ~ ~ ~ - ~ ) ’ transmission after primary infection occurs in 30% to 40% of cases. How the placenta contains the infection is poorly defined. There have been a few reports of isolated placental involvement in the absence of fetal infection. Current information suggests that gestational age has no apparent influence on the risk of transmission of CMV in ~ t e r o . ~However, ~ * ~ with ~ ~ regard to the role of gestational age on the expression of disease in the fetus and offspring, infection at an earlier gestational age produces the worst O U ~ C O ~ ~ . ~ ~ * Congenital infection may also result from recurrences of The term recurrence is used here to represent reactivation of infection or reinfection with the same or a different strain of CMV during pregnancy. Evidence indicates that despite the inability of maternal immunity to prevent transmission of this virus to the fetus, congenital infections that result from recurrent infections are less likely to affect the offspring than those resulting from primary infections.326

Persistent Viral Excretion

~ ~ ~ * ~ ~ ~

Congenitally and perinatally acquired CMV infections are characterized by chronic viral excretion.301Virus is consistently shed into the urine for up to 6 years or longer and into saliva for 2 to 4 years. Not only does excretion persist much longer in these patients than in infected older children and adults, but the quantity of virus excreted is also much greater. Even asymptomatic congenitally or perinatally infected infants excrete quantities of virus that usually exceed those

Chapter 23


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detectable in seriously ill immunocompromised older patients. As shown in Figure 23-2, the highest quantities of virus are excreted during the first 6 months of life. Infants with symptomatic congenital CMV infection excrete significantly larger amounts than those with asymptomatic congenitally or perinatally acquired infections.

PATHOLOGY

Overview Early reports of histopathologic changes associated with CMV infections relied on a demonstration of classic changes characterized by cytomegaly and nuclear and cytoplasmic inclusion^.^^^^^^ The distinctive features include large cells 20 to 35mm in diameter with a large nucleus containing round, oval, or reniform inclusions. These large inclusions are separated from the nuclear membrane by a clear zone, which gives the inclusion the so-called owl's-eye appearance. The inclusions within the nucleus show DNA positivity by histochemical staining, whereas the cytoplasmic inclusions contain carbohydrates, as evidenced by periodic acid-Schiff positivity. The cytoplasmic inclusions vary from minute dots to distinct rounded bodies 3 to 4 mm in diameter. The cytoplasmic inclusions are usually aggregated opposite to the eccentricallyplaced inclusion-bearing nucleus. Unfortunately, the classic CMV inclusion-bearing cell may be only scattered throughout involved tissue and missed by routine sectioning. This finding has been confirmed when more refined techniques such as in situ DNA hybridization and immunofluorescence using CMV-specific monoclonal antibodies have been used to define the extent of infection with CMV in immunocompromised patients. Disseminated disease can occur in the infected fetus and congenitally infected infant. CMV can cause a multisystem disease in which almost all major organ systems are involved?OO

84

96

108

120

Figure 23-2 Quantitative assessment of cvtomeaalovirus excretion in subjectsvkh congenital symptomatic (triangles) and congenital asymptomatic (circles) infections:

of the pathology of CNS infection are relevant only to infants with severe CID, which is occasionally fata1.347-349 The infection can be described grossly as focal encephalitis and periependymitis. The encephalitis can involve cells of the gray matter and white matter and cells within the choroid plexus. Inclusion-bearing cells have been identified in neurons, glia, ependyma, choroid plexus, meninges, and vascular endothelium, and in cells lying free in the ventricles. Rarely, inclusion-bearing cells have been identified in the cerebrospinal Resolution of acute encephalitis leads to gliosis and calcification. Previous descriptions have emphasized the periventricular location of calcifications; however, these lesions can be located anywhere in the brain.3513352 CMV has been isolated on a few occasions from cerebrospinal Viral inclusion-bearing cells and viral antigen-containing cells can also be found within structures of the inner ear, including the organ of Corti, and in epithelial cells of striae vascularis of the cochleae.'65s354-356 Involvement of the eye, including chorioretinitis, optic neuritis, cataract formation, colobomas, and microphthalmos, has been demonstrated. The histopathologic changes associated with retinitis begin as an acute vasculitis that spreads into the choroid through the vascular basement membrane. CMV has been isolated from fluid of the anterior chamber of the eye.357 '659349

Liver

Commonly Involved Organ Systems

Involvement of the liver is common in congenital CMV infections. Clinical evidence of hepatitis as manifested by hepatomegaly, elevated levels of serum transaminases, and direct hyperbilirubinemia is frequently seen in infants with symptomatic congenital infections. Pathologic descriptions of hepatic involvement include mild cholangitis with CMV infections of bile duct cells, intralobular cholestasis, and obstructive cholestasis caused by extramedullary hematop ~ i e s i sLiver . ~ ~ calcification has been detected radiologically in infants with congenital infections.35sp359 Clinical and laboratory evidence of liver disease eventually subsides in surviving infants.

Central Nervous System

Hematopoietic System

Involvement of the CNS is perhaps the most important consequence of fetal infection with CMV. Most descriptions

Hematologic abnormalities, including thrombocytopenia, anemia, and extramedullary hematopoieses, are common in

758


symptomatically infected infants, but these abnormalities almost invariably resolve within the first year of life. The exact mechanism accounting for these disturbances is not certain, although congestive splenomegaly resulting in platelet and red blood cell trapping must play some part in the overall process. Major splenomegaly is common, and congestion, extramedullary hematopoiesis, and diminished size of lymphoid follicles can be seen histologically. In congenital C W infections, thrombocytopenia may persist for several months, even years, with or without petechiae. At least in animal models, direct infection of megakaryocytes has been found and postulated as a possible r n e c h a n i ~ m Anemia .~~ is another feature of symptomatic congenital CMV infection. The presence of indirect hyperbilirubinemia, extramedullary hematopoiesis, and erythroblastemia indicates active hemolysis, but mechanisms for these effects have not been elucidated.

which may be found in endothelial cells, in cells attached to the capillary walls, or in Hofbauer’s or stromal ce11s.364,365 Other lesions include focal necrosis, which in early gestation shows sparse infiltration by lymphocytes, macrophages, and a few plasma cells. The early lesions manifest as foci of necrosis of the stroma and occasionally of the vessels of the villi. The focus of necrosis is later invaded by inflammatory cells, histiocytes, and fibroblasts. At later gestational ages, these focal lesions become densely cellular, with plasma cells predominating over lymphocytes. Deposition of intracellular and extracellular hemosiderin can be found in stem and terminal villi and is presumably the result of fetal hemorrhage during the necrotizing phase or of maternal intervillous thrombosis. Calcification within villi or on basement membranes has been described as a late manifestation of placental CMV infection.

Kidneys

CLINICAL MANIFESTATIONS

Macroscopically, the kidneys show no alterations. Microscopically, inclusion-bearing cells are commonly seen, especially in the cells lining the distal convoluted tubules and collecting Affected cells may desquamate into the lumina of the tubules and appear in the urine sediment. Inclusions can be found occasionally in Bowman’s capsules and proximal tubules. Mononuclear cell infiltration may be present in the peritubular zones of the kidney.

Endocrine Glands Secretory cells of endocrine glands commonly contain typical CMV inclusions. In the pancreas, the endocrine and exocrine cells are affected.300Some reports describe intralobular or periductal mononuclear infiltration, suggesting focal pancreatitis. There is no indication of an association between congenital CMV infection and diabetes mellitus. CMV inclusion-bearing cells have been documented in follicular cells of the thyroid, the adrenal cortex, and the anterior pituitary.

Gastrointestinal Tract The salivary glands are commonly involved in congenital and perinatal CMV infections. However, there are no reliable figures on the frequency of involvement because the examination of the salivary glands is not always part of autopsies.362CMV inclusions have also been described in the mucosal surfaces of the esophagus, stomach, and intestine and in the vessels of ulcerative intestinal lesions.363

Lungs Pulmonary CMV lesions are similar in the newborn and the adult. Microscopically, most inclusion-bearing cells are alveolar cells that lay free in terminal air spaces. In general, there is little inflammatory reaction; however, in the more severe cases, focal interstitial infiltration by lymphocytes and plasma cells can be found.

Placenta Abnormalities occur in the placentas of most patients with symptomatic CMV infection and are uncommon with subclinical infection^.^^ Placentas are not remarkable in size or macroscopic appearance. The most specific feature histologically is the presence of inclusion-bearing cells,

Congenital Infection Approximately 10% of the estimated 44,000 infants (1% of all livebirths) born annually with congenital CMV infection in the United States have signs and symptoms at birth that would lead the physician to suspect a congenital infection. Only one half of these symptomatic infants have typical generalized CID, characterized mainly by the clinical manifestations given in Table 23-9.303,366 Another 5% of these infants present with milder or atypical involvement, and 90% are born with subclinical but chronic infection. Because early studies emphasized symptomatic infections, congenital CMV was considered a rare and often fatal disease. In the early reports, many patients were referred to the investigators because of developmental problems; this might have automatically highlighted a group of patients at a higher risk for persistent abnormalities and neurologic damage. The use of more sensitive and specific methods of diagnosis, particularly viral isolation,has allowed prospective longitudinal study of newborns with symptomatic and asymptomatic congenital CMV infections. This has resulted in a better understanding of the infection and its clinical spectrum.

Symptomatic Infection ACUTE MANIFESTATIONS

Clinically apparent infections or CID is characterized by involvement of multiple organs, particularly the reticuloendothelial system and CNS, with or without ocular and auditory damage. Weller and Hanshad66defined the abnormalities found most frequently in infants with symptomatic congenital infection as hepatomegaly, splenomegaly, microcephaly, jaundice, and petechiae. As shown in Table 23-11, petechiae, hepatosplenomegaly, and jaundice are the most common presenting signs. The magnitude of the prenatal insult is demonstrated by the occurrence of microcephaly with or without cerebral calcification, intrauterine growth retardation, and prematUrity.86.303,307.309,327,367- 370 Inguinal hernia in males and chorioretinitis with or without optic atrophy are less common. Clinical findings occasionallyinclude hydrocephalus,hemolytic anemia, and pneumonitis. Among the most severely affected infants, the mortality rate may be as high as 30Y0.~~’ Most

Chapter 23 Table 23-1 1


759

Clinical and Laboratory Findings for 106 Infants with Symptomatic Congenital Cytomegalovirus infection in the Newborn Period

Abnormality Prematurity (80U/L) Thrombocytopenia

120mg/dL)a

aDeterminationsin the first week of life. From Bomana 5, Pass RF, Britt WS, et al. SvmDtomatic conqenital cytomegalovirus infection: neonatal morbidi'ty and mortal&. Pediatr Infect Dis J 11:93-99, 1992.

Figure 23-3 Symptomatic congenital cytomegalovirusinfection is manifested by microcephaly and petechiae.

deaths occur in the neonatal period and usually are caused by multiorgan disease with severe hepatic dysfunction, bleeding, disseminated intravascular coagulation, and secondary bacterial infections. When death occurs after the first month but during the first year, it typically is caused by progressive liver disease with severe failure to thrive. Death after the first year usually is restricted to severely neurologically handicapped children and is caused by malnutrition, aspiration pneumonia, and overwhelming infections.

Jaundice.Jaundice is a common manifestation of congenital CID. The pattern of hyperbilirubinemia may take several forms, ranging from high levels on the first day to undetectable jaundice on the first day with gradual elevation of the bilirubin level to clinically apparent jaundice. The level of jaundice in the early weeks of life may fluctuate con~iderably.~'~.~'~ In some instances, jaundice is a transient phenomenon, beginning on the first day and disappearing by the end of the first week. More often, however, jaundice tends to persist beyond the time of physiologic jaundice. Transient jaundice may occasionally occur in early infancy with pronounced elevation of bilirubin levels during the third month. Bilirubin levels are high in the direct and the indirect components. Characteristically,the direct component increases after the first few days of life and may constitute as much as 50% of the total bilirubin level. It is rare for the indirect bilirubin component to rise high enough to require an exchange transfusion, but this has been reported.

Hepatomegaly. This sign, along with splenomegaly, is probably the most common abnormality found in the newborn period in infants born with a symptomatic congenital CMV infection.370The liver edge is smooth and nontender and usually measures 4 to 7 cm below the right costal margin. Liver function tests are often abnormal but usually not markedly so. The persistence of hepatomegaly is variable. In some infants, liver enlargement disappears by the age of 2 months. In others, significant enlargement persists throughout the first year of life. However, massive hepatomegaly extending beyond the first 12 months of life is uncharacteristic of CID. Splenomegaly. Enlargement of the spleen exists to a greater or lesser degree in all the common human congenital infections and is especially frequent in congenital CMV infections.3033370 It may be the only abnormality present at birth. In some instances, splenomegaly and a petechial rash coexist as the only manifestations of the disease. Occasionally, the enlargement is such that the spleen may be felt 10 to 15 cm below the costal margin. Splenomegaly usually persists longer than hepatomegaly does.

Petechiae and hupura. There is evidence that CMV has a direct effect on the megakaryocytes of the bone marrow that results in a depression of the platelets and a localized or generalized petechial In some patients, the rash is purpuric (Fig. 23-3), not unlike that observed in the expanded rubella syndrome. Unlike the latter infection, however, pinpoint petechiae are a more common manifestation. These petechiae are rarely present at birth but often appear within a few hours thereafter; they may be transient, disappearing within 48 hours. The petechiae may be the only clinical manifestation of CMV infection. More often, however, enlargement of the spleen and liver is associated.The petechiae

760


may persist for weeks after birth. Crying, coughing, the application of a tourniquet, a lumbar puncture, or restraints of any kind may result in the appearance of petechiae even months after birth. Platelet counts in the first week of life range from less than 10,000 to 125,000, and most counts are in the 20,000 to 60,000 range. Some infants with petechial rashes do not have associated thrombocytopenia.

matic congenital CMV than in congenital toxoplasmosis, lesions caused by CMV and Toxoplasma cannot be differenToxoplasma tiated on the basis of location or appearan~e.'~'.~~~ gondii and CMV can induce central retinal lesions. Occasionally, the appearance of strabismus with subsequent referral to an ophthalmologist is the means by which chorioretinitis is detected. Any infant with suspected CMV infection or strabismus in early life should be examined carefully for retinal lesions. Chorioretinitis caused by CMV differs from that caused by Toxoplasma in that postnatal progression is

Microcephaly. Microcephaly, usually defined as a head circumference of less than the fifth percentile, affected 14 of 17 patients with CID in the early studies of Medearis in 1964?71As tissue culture methods became more widely used and clinical awareness of the infection increased, microcephaly Fetal Growth Retardation. Intrauterine growth retardation, became a less prominent symptom in subsequent series that occasionally severe, was reported in 50% of 106 patients included mainly infants born with less severe disease. In an with symptomatic congenital CMV infection, whereas preexamination of 106 surviving patients who were born with maturity occurred in 34% (see Table 23-1 l).303 Infants with symptomatic CMV infection, 53% were micro~ephalic.~~~ asymptomatic congenital infection in general show no intraNot all infants with microcephaly continue to have head uterine growth retardation or prematurity, and CMV cannot circumferences of less than the third percentile.370Microbe considered an important cause of either condition. cephaly is the most specific predictor of mental retardation hemnonitis. Pneumonitis, a common clinical manifestation (this is especially true if the head measurement is close to the of CMV infection after bone marrow and renal transfifth percentile in an infant of low birth weight). Intracranial plantation in adults, is not usually a part of the clinical calcifications are an indication that the infant will have at presentation of congenital CMV infection in newborns. least moderate and probably severe mental retardation. Diffuse interstitial pneumonitis occurs in less than 1% of Ocular Defects. The principal abnormality related to the eye congenitally infected infants, even when the most severely in CMV infection is chorioretinitis, with strabismus and affected cases are considered. As is discussed in greater detail optic atrophy.303,367s370 Microphthalmos, cataracts, retinal later, CMV-associated pneumonitis is more likely to develop necrosis and calcification, blindness, anterior chamber and in infants with perinatally acquired CMV infections.372 optic disk malformations, and pupillary membrane vestiges have also been described in association with generalized Dental Defects. Congenital CMV infection is also associated congenital CID. Despite these findings, the presence of with a distinct defect of enamel, which seems to affect mainly abnormalities such as microphthalmos and cataracts is primary dentition.373This defect is more severe in children strong presumptive evidence that the disease process is not with the symptomatic form of the infection than in those caused by CMV. Chorioretinitis occurs in approximately 14% born with asymptomatic infections (Fig. 23-4). of infants born with symptomatic congenital i n f e c t i ~ n . ~ ~ ~ .Clinically, ~~~ this defect appears on all or most of the teeth Although chorioretinitis occurs less frequently in symptoand is characterized by generalized yellowish discoloration.

Figure!23-4 Cytomegalovirus (CMVtaffected teeth. This patient had a clinically severe congenital CMV infection. Notice the fractured borders and opaque and hypocalcified enamel.

Chapter 23 The enamel is opaque and moderately soft and tends to chip away from dentin. Affected teeth tend to wear down rapidly, leading to dental caries frequently seen in these children. In our longitudinal studies, this defect of enamel was documented in 27% of 92 children born with symptomatic congenital CMV infection and in 4% of 267 who were born with the subclinical form and who were observed for at least 2 years.373These patients usually require extensive orthodontic therapy. It is evident that these defects do not involve permanent teeth to the same degree.


761

intrauterine growth retardation are independent predictors of hearing loss. LONG-TERM OUTCOME

The likelihood of survival with normal intellect and hearing after symptomatic congenital CMV infection is 133,303,316,367,368,371,375-377,382,383 As shown in Table 23-12, in our prospective studies, one or more handicaps have occurred in almost 90% of the patients with symptomatic congenital infection who survived.303 Psychomotor retardation, usually combined with neurologic complications and microcephaly, occurred in almost Deafness. Sensorineural deafness is the most common handicap caused by congenital CMV infection. M e d e a r i ~ ~ ~ l70% of the patients. Sensorineural hearing loss was seen in was the first investigator to call attention to the presence 50%. The hearing loss is bilateral in 67% of patients with of deafness in symptomatic congenitally infected infants. hearing loss and is progressive in 54%. Chorioretinitis or Subsequent reports confirmed this association and prooptic atrophy occurred in 20% of cases. Expressive language delays independent from hearing loss and mental impairvided evidence that CMV can also cause sensorineural ment have also been described. Several studies have searched hearing loss in children with subclinical congenital infection.133,165-168,304,309,316,374-381 CMV is now one of the for clinical predictors of intelligence and developmental outcome and found that microcephaly at birth, development most important causes of deafness in childhood. CMV can of neurologic problems during the first year of life, ocular replicate in many structures of the inner ear, as demonlesions (e.g., chorioretinitis), and microcephaly that became strated by typical CMV-induced cytopathology in Reissner's apparent after birth were significantly associated with a low membrane, stria vascularis, and semicircular canals or by IQ and developmental quotient. The best predictor of adverse CMV-specific immunofluorescence in the organ of Corti and neurons of the eighth nerve.'6533173318*354-356 neurodevelopmental outcome is the presence of cranial The districomputed tomographic (CT) abnormalities detected within bution of viral antigens is far more extensive than viral the first month of life.3o9 In infants with symptomatic cellular cytolysis. The presence of an inflammatory response congenital CMV infection, abnormal CT findings, particularly suggests the possibility that immune damage in the inner ear intracerebral calcifications, are common (70%).Almost 90% may also be a contributing factor. of children with abnormal newborn CT scans develop at The frequency and severity of the hearing impairment are least one sequela compared with 29% among those with a worse in patients with symptomatic infection (58%) normal In this particular study, which included 56 compared with asymptomatic infection at birth (7.4%). In children with symptomatic congenital CMV, only 1 child general, hearing loss is progressive in 50%, is bilateral in with a normal CT scan had an IQ of less than 70, in contrast 50%, and has a late onset in 20% of cases. The predictors of to 59% of those with imaging abnormalities. Newborn CT hearing loss in children with symptomatic congenital CMV abnormalities were also associated with an abnormal infection are intrauterine growth retardation, petechiae, hearing screen at birth and hearing loss on follow-up. None hepatosplenomegaly, thrombocytopenia, and intracerebral of the neonatal neurologic findings was predictive of an calcifications. The presence of microcephaly and other abnormal CT finding.309Overall, it can be anticipated that neurologic abnormalities does not predict hearing loss. between 90% and 95% of infants with symptomatic Using logistic regression analysis, only petechiae and

Table 23-1 2

Sequelae in Children after Congenital Cytomegalovirus Infection

Sequelae

Percent Symptomatic (n/N)

Percent Asymptomatic (n/N)

Sensorineural hearing loss Bilateral hearing loss Speech threshold moderate to profound (60-90 dB)" Chorioretinitis IQ c70 Microcephaly, seizures, or paresidparalysis Microcephaly Seizures Paresis/paralysis Deathb

58 (58/100) 37 (37/100) 27 (27/100) 20.4 (19/93) 55 (33/60) 51.9 (54/104) 37.5 (39/104) 23.1 (24/104) 12.5 (13/104) 5.8 (6/104)

7.4 (22/299) 2.7 (81299) 1.7 (5/299) 2.5 (7/281) 3.7 (6/159) 2.7 (9/330) 1.8 (6/330) 0.9 (3/330) 0 (01330) 0.3 (1/330)

"For the ear with better hearing. bAfter the newborn period. Data from Pass RF, Fowler KB, Boppana S. Progress in cytomegalovirus research. In Landini MP (ed). Proceedings of the Third International Cytomegalovirus Workshop, Bologna, Italy, June 1991. London, Excerpta Medica, 1991, pp 3-10.

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congenital infections who survive will develop mild to severe handicaps.

Asymptomatic Infection

As indicated in the previous section, almost 90% of infants with congenital CMV infections have no early clinical manifestations, and their long-term outcome is much better. Nevertheless, there is solid evidence derived from controlled, prospective studies that at least 10% of these infants, and perhaps as many as 15%, are at risk of developing a multitude of developmental abnormalities, such as sensorineural hearing loss, microcephaly, motor defects (e.g., spastic diplegia or quadriplegia), mental retardation, chorioretinitis, dental defects, and others. These abnormalities usually become the first 2 years of 1ife.165J67,324,374,3759378$79,384-386 apparent Table 23-12 shows results based on our prospective longitudinal study of 330 patients with asymptomatic congenital infection who were followed by using serial clinical, psychometric, audiometric, and visual Follow-up studies of patients with inapparent congenital CMV infection have also been done by Kumar and colleagues?78Saigal and associates?75Melish and H a n ~ h a w ?Pearl ~ ~ and co-workers,'" Williamson and colleagues?MPreece and associates,"' Harris and c o - ~ o r k e r s ?Conboy ~~ and colleague^,'^' Ivarsson and associate^,"^ Fowler and colleague^,'^' Kashden and coworkers?86 and Noyola and associates.387In general, their findings resemble the results of our study presented in Table 23-12. Most patients in these studies and their controls were from a low socioeconomic background. The most significant abnormality in children born with subclinical congenital CMV infection is hearing loss. Fowler and associate^'^^ evaluated 307 children with documented asymptomatic congenital CMV infection and compared their audiometric assessments with 76 uninfected siblings of children with asymptomatic congenital CMV infection and 201 children whose neonatal screen for this infection showed negative results. Sensorineural hearing loss occurred only in children with congenital CMV infection. Among them, 22 (7.2%) had hearing loss. In 11 (50%) of the 22 children, the hearing loss was bilateral. Among the children with hearing loss, further deterioration of hearing occurred in 50% with a medial age at first progression of 18 months (range, 2 to 70 months). Delayed onset of sensorineural hearing loss occurred in 18% of the children with the medial age of detection at 27 months (range, 25 to 62 months). Fluctuating hearing loss was documented in 22.7% of the children with hearing loss. These results are very similar to those obtained by Williamson and co-workers in Houston.384 A study in Sweden of more than 10,000 newborns screened for hearing loss and congenital CMV infection found that this congenital infection was the leading cause of sensorineural hearing loss accounting for 40% of the cases with hearing In our group, Hicks and c o - w o r k e r ~found ~ ~ ~ 14 cases of congenital CMV infection with sensorineural hearing loss in 12,371 neonates screened for CMV, a rate of approximately 1.1 per 1000 livebirths. The rate was 0.6 per 1000 livebirths when only cases with bilateral loss of 50 dB or greater were considered. These results suggest that CMV infection accounts for at least one third of sensorineural hearing loss in young children.388Taken together, these studies indicate that the universal screening for hearing loss in vogue in the United States will detect less than one half of all the cases of

sensorineural hearing loss caused by congenital CMV infection. Because most of these infants are asymptomatic at birth, they are not recognized as being at high risk for hearing loss and are not being further tested to detect late onset hearing loss. The universal screening of neonates for hearing loss needs to be combined with a screening for congenital CMV infections. Prospective studies of children with subclinical congenital CMV infections have revealed a wide but significant spectrum of neurologic complication^.^^^ It has been estimated that within the first 2 years of life, 2% to 7% of the infants in this group develop microcephaly with various degrees of mental retardation and neuromuscular defects. How often milder forms of brain damage, such as learning or behavioral difficulties, will occur as these patients grow older is unknown. Studies of the intellectual development of children with asymptomatic congenital CMV infections have shown conflicting results. However, one study evaluated 204 prospectively followed children with asymptomatic congenital CMV infections and 177 uninfected siblings ranging in age from 6 to 203 months.38' Parents were administered the Developmental Profile, and the children were administered an objective intelligence measure. Results showed that children with asymptomatic congenital CMV infection do not demonstrate intellectual impairment and that they perform similarly to uninfected siblings. Children with asymptomatic congenital CMV infections are at low risk for developing chorioretinitis. The current estimate is that it occurs in 2% of these children, and like hearing loss, it may not exist at birth. In summary, these observations underscore the need for longitudinal follow-up of patients with congenital CMV infection regardless of the initial clinical presentation. Careful assessments of perceptual functions (e.g., hearing, visual acuity), psychomotor development, and learning abilities must be made to recognize the full impact of CMV. With early identification of a problem, corrective measures can be instituted to reduce psychosocial and learning problems.

Effect of Type of Maternal Infection on Symptoms and long-Term Outcome Studies have clearly demonstrated that preexisting maternal immunity does not prevent CMV from reactivating during pregnancy and cannot reliably prevent transmission in utero nor symptomatic infeaions.~'4-~18.'20~326.334-341.389,39 A prospective study of young, predominantly African American women with one or more previous deliveries were evaluated to quantify the protection conferred by preconception maternal immunity.391For the almost 3500 multiparous women who had previously delivered newborns screened for congenital CMV infection and who subsequently became part of this study, the overall rate of congenital CMV infection was 1.3%. Congenital infection occurred in 18 (3.0%) of 604 newborns (95% CI, 1.8% to 4.7%) born to initially seronegative mothers compared with 29 (1.O%) among the 2857 births (95% CI, 0.7% to 1.4%) to immune mothers. Of the initially seronegative women, 23.5% seroconverted for an annualized seroconversion rate of 7.8% per year with 12.7% of these seroconversions resulting in congenital CMV infection. Only 1% of infants born to mothers immune to CMV before conception had congenital infection. These results show that young women who have

Chapter 23


763

immunity to CMV from naturally acquired infections are year, and almost 2160 of the survivors develop handicaps. Another 5580 or so among the subclinically infected develop 69% less likely to have a baby with congenital CMV infections in the future than are those who are initially seronegative. significant hearing and mental deficits. In addition to the This study also demonstrated a strong relationship between personal and family suffering associated with these conan increased rate of congenital CMV infection and short ditions, the cost to society for caring for all these children interval from initial CMV antibody test to subsequent birth must amount to millions of dollars annually. among seropositive women. This observation indicates that some of the initially seropositive women had recently Perinatal Infection experienced primary infection and therefore had increased risk for congenital CMV infection. Perinatal infections can be acquired from exposure to virus It is generally recognized that primary infection has a in the maternal genital tract at delivery, from breast milk, or higher risk of symptomatic infection; however, data that To through multiple blood transfusions.89~90~96~342’344~394’395 have emerged in recent years, including our own prospective establish the diagnosis of perinatal CMV infection, the studies, raise the possibility that recurrent maternal infection examiner must first exclude congenital infection by showing may result in adverse outcome more frequently than an absence of viral excretion during the first 2 weeks of life. previously thought. In 1999, prospective studies carried out The incubation period of perinatal CMV infection ranges in Sweden392and the United States393reported the presence between 4 and 12 weeks. Although the quantity of virus of symptomatology at birth and the development of longexcreted by infants with perinatal infection is less than that term sequelae in children born with congenital CMV seen with intrauterine acquisition, the infection is also infection after a recurrence of maternal infection. Our s t ~ d 3 ~chronic, ~ with viral excretion persisting for years.301 included 246 children (1.18%) with congenital CMV Most infants with naturally acquired perinatal infections infection from the screening of 20,885 neonates. Of the 246 remain asymptomatic. Most of these infections result from infants, 47 were symptomatic at birth, and 8 (17%) of the 47 reactivation of maternal virus, and infants therefore are born were born to mothers with recurrent CMV infection as with variable levels of maternal antibody. Asymptomatic defined by seropositive status at the time of a previous perinatal CMV infection in full-term and otherwise healthy pregnancy. Demographically, the women in this study have infants does not appear to have an adverse effect on growth, been characterized as predominantly black (93%), single perceptual functions, or motor or psychosocial development. (96%), young (46% 520 years old), and without private CMV has been incriminated as a cause of pneumonitis in insurance. A study of this population concluded that in In a study infants younger than 4 months.90,344,372,396,397 women who are seropositive for CMV, reinfection with undertaken to define the possible association of CMV and different strains of CMV rather than reactivation of the other respiratory pathogens with pneumonitis in young endogenous strain could lead to intrauterine transmission infants, CMV was isolated in 21 (21%) of 104 patients enand symptomatic congenital infection. In contrast, the study rolled.372Only 3% of 97 hospitalized controls were infected. of women who are predominantly white, married, of middle CMV-associated pneumonitis occurs throughout the year in to high socioeconomic background, and somewhat older has contrast to the common respiratory virus infections, which not revealed the occurrence of symptomatic congenital CMV occur most often in winter and early spring. infection as a result of a recurrence of maternal infection. CMV-associated pneumonitis is clinically and radiographically indistinguishable from other types of afebrile Public Health Significance pneumonia caused by agents such as Chlamydia trachomatis The public health impact of congenital CMV infection in the and respiratory syncytial virus. Clinically, patients with United States is significant, as shown in Table 23-13. With an CMV-associated pneumonitis have an afebrile course with average incidence of 1% and a birth rate of 4 million per tachypnea, cough (sometimes paroxysmal), occasional annum, approximately 40,000 infants are born each year episodes of apnea, coryza, nasal congestion, intercostal with congenital CMV infections. Of these, as many as 2800 retractions, and radiographic evidence of diffuse lower airway present with signs and symptoms of infection (e.g., CID). obstruction (e.g., air trapping, thickened bronchial walls About 336 of them can be expected to die within the first with prominent pulmonary markings and various degrees of atelectasis). Expiratory wheezing is unusual. Laboratory findings include elevated levels of one or more serum immunoglobulins (especially IgM, in 66% of patients), Table 23-1 3 Public Health Impact of leukocytosis of more than 12,000 white blood cells/mm3 Congenital Cytomegalovirus (59%), and absolute eosinophilia. The median time of Infection in the United States hospitalization is 17 days. Some infants require oxygen therapy Parameter Estimate and ventilatory assistance. Long-term follow-up of patients with pneumonitis associated with CMV and other respiratory No. of live births per year 4,000,000 pathogens provides evidence that significant mortality and Rate of congenital CMV infection (average) 1% morbidity do occur irrespective of the etiologic agent.397 No. of infected infants 40,000 In premature and ill term infants, Yeager and colleagues398 No. of infants symptomatic at birth (5%-7%) 2800 336 No. with fatal disease (+12%) found that naturally acquired CMV infection may pose a 2160 No. with sequelae (90% of survivors) greater risk. They found that premature infants weighing less 37,200 No. of infants asymptomatic at birth (93%-95%) than 1500g at birth who acquired CMV from a maternal 5580 No. with late sequelae (15%) source often developed hepatosplenomegaly, neutropenia, a076 Total no. with sequelae or fatal outcome lymphocytosis, and thrombocytopenia, coinciding with the

764

Section I11

Viral Infections

onset of virus excretion. Frequently, infected patients required longer treatment with oxygen than uninfected patients. In a later study, Paryani and c o - w o r k e r ~from ~ ~ ~the same group reported a prospective study of 55 premature infants, including controls, and suggested that there might be a propensity for an increased incidence of neuromuscular impairments, particularly in premature infants with the onset of CMV excretion during the first 2 months of life. However, sensorineural hearing loss, chorioretinitis, and microcephaly occurred with similar frequency in both groups. Similar findings were reported by V ~ c h e m ~ and ~* Ma~chmann.~~ Transfusion-acquired perinatal CMV infection can cause significant morbidity and mortality, particularly in premature infants with a birth weight of less than 1500 g born to CMVseronegative The syndrome of posttransfusion CMV infection in premature newborns was characterized by Ballard and c o - w o r k e r ~ They . ~ ~ isolated CMV from 16 of 51 preterm infants of a mean birth weight of 1000 g and found that 14 of the 16 virus-positive infants had a constellation of symptoms that resembled CID. This recognizable, self-limited syndrome consisted of deterioration of respiratory function, hepatosplenomegaly, unusual gray pallor with disturbing septic appearance, an atypical and an absolute lymphocytosis, thrombocytopenia, and hemolytic anemia. The syndrome was more severe in low-birth-weight infants and occurred 4 to 12 weeks after the transfusion, when the infants were progressing satisfactorily. Although the course of the disease was generally self-limited (lasting 2 to 3 weeks), death occurred in 20% of the dl infants. Subsequent work by Yeager and associates269and Adler4" confirmed these observations. The risk of infection is greater with an increasing number of units of blood transfused. Yeager and associates269demonstrated that the risk of infection is related to the serologic status of the donor and that these infections could be prevented by transfusing seronegative newborns with blood from seronegative donors.

Table 23-14

DIAGNOSIS Detection of Virus The diagnosis of congenital CMV infection should be entertained in any newborn with signs of congenital infection or if there is a history of maternal seroconversion or a mononucleosis-like illness during pregnancy. The best test is virus isolation in tissue culture, which is generally accomplished with urine or saliva or with demonstration of CMV genetic material by PCR (Table 23- 14).295,299,3463402-405 CMV-IgM serology does not have adequate sensitivity or specificity for the diagnosis of congenital CMV infection. With diagnostic methods that detect the virus, viral antigens, and nucleic acids, it is possible to confirm the diagnosis from blood, cerebrospinal fluid, and biopsy material. Of particular interest is the possibility of diagnosis by PCR on blood stored on filter paper.404To confirm a congenital CMV infection, demonstration of virus must be attempted in the first 2 weeks of life because viral excretion after that time may represent an infection acquired at birth (natal) by exposure to an infected birth canal or one acquired in the neonatal period by exposure to breast milk or blood products. Although isolation of CMV during the first 2 weeks of life proves a congenital CMV infection, it does not necessarily confirm an etiologic relationship with an existing disease. Urine and saliva are the preferred specimens for culture because they contain larger amounts of virus. The viability of CMV is surprisingly good when specimens are properly stored. For instance, when positive urine specimens (without preservatives) are stored at 4'C for 7 days, the rate of isolation drops to 93%; it drops to only 50% after 1 month of storage.404However, storage and transport at ambient temperature or freezing should never be used because infectivity is rapidly and significantly reduced.

Diagnostic Methods for Identification of Infants with Congenital Cytomegalovirus Infection

Method

Advantages

Disadvantages

Detection of Virus or Viral Antigens Standard tube culture method

Standard reference method

Shell vial assay83 Microtiter plate immunofluorescent antibody a s ~ a y ~ . ~ ~ CMV antigenemiaE6

Rapid, sensitive, commercially available Rapid, sensitive, reliable, simple, inexpensive Rapid and simple

Takes 2-4 weeks, not suitable for screening Expensive, not suitable for screening Cell culture based, not commercially available Unknown sensitivity and utility t o screen newborns, expensive

Nucleic Acid Amplification Methods DNA hybridization assaf'

Sensitive and reliable

PCR amplification method^^.^^ Serologic Methods Anti-CMV IgM antibody assay

Simple and can be used t o screen large numbers Simple and widely available

CMV, cytomegalovirus; PCR, polymerase chain reaction. Data from Boppana and Fowler, personal communication, 2004.

Complicated, need for a radiolabeled probe Utility as a screening assay not proved

Low sensitivity and not reliable for screening

Chapter 23

Tissue Culture Standard tissue culture based viral isolation requires inoculation of specimen into monolayers of human fibroblasts. Typically, 2 to 4 weeks may be required for the appearance of the characteristic cytopathic effect. Since 1980, methods for rapid viral diagnosis have become available. Several modifications of the standard tissue culture method combined with immunologic detection of immediate-early CMV-induced antigens have maintained high specificity and sensitivity but allowed the confirmation of diagnosis within 24 hours of inoculation of the clinical ~ p e c i m e n . 4 ~ ~ ~ ~ ' ' Typically, tissue culture includes the use of monoclonal antibodies to CMV-specific early antigens with low-speed centrifugation of the clinical specimens onto the monolayer of fibroblasts growing on coverslips inside shell vial^.^^"^'^ When this method was evaluated with clinical specimens (i.e., blood; urine; bronchoscopy lavage; lung, liver, and kidney biopsy samples; sputum; and others) obtained primarily from immunosuppressed patients, the sensitivity approached 80%, and the specificity ranged from 80% to 100%. Subsequently, another adaptation of this rapid immunofluorescent assay used 96-well microtiter plates and a monoclonal antibody that is reactive with the major immediate-early human CMV protein polypeptide 72.411This rapid assay detected all but 1 of 19 specimens identified by standard virus isolation method from 1676 newborn urine specimens, achieving a sensitivity of 94.5% and a specificity of 100%. This test retained high sensitivity and specificity when saliva instead of urine was tested.403This microtiter plate method using saliva or urine samples is the most rapid, simple to perform, and inexpensive alternative to the standard virus isolation method. It is perfectly suitable for mass screening, and there is no drop in sensitivity for Specimens at 4" C for up to 3 days. This study also showed that the sensitivity of the microtiter plate method declined rapidly for specimens from older infants and children with congenital CMV infection and from virus-infected children attending daycare centers. It is not recommended for screening or diagnosing CMV infections in older infants and children.

DNA Hybridization Rapid diagnosis of CMV can also be accomplished by DNA hybridizatior~?'~-~'~ However, the methodology is cumbersome because of the need to concentrate virus at high speed centrifugation and the need to extract DNA and hybridize it with a DNA probe labeled with phosphorus 32. The sensitivity and specificity of this method is good when the specimens contain lo3or more tissue culture infective doses per milliliter.


765

from a total of 44 specimens positive by tissue culture. No positive PCR results were found in 27 urine specimens that were negative by tissue culture.402Warren and c o - w ~ r k e r s ~ ~ ~ used the PCR technique to detect CMV in saliva from children who were between the ages of 1 month and 14 years and who had congenital or perinatal CMV infection and compared the results with a standard tissue culture method and microtiter plate detection of early antigen with tissue culture results as a reference. The sensitivity of PCR was 89.2%, and the specificity was 95.8%. Reproducibility was excellent. If primer selection and amplification conditions are carefully chosen, PCR can give results comparable to standard tissue culture test. Some advantages include the minute amount of specimen and the fact that infectious virus is not required, allowing for retrospective diagnosis of CMV infection if the appropriate specimens are a ~ a i l a b l e . ~ ~ Nelson and colleagues295showed that PCR detection of CMV DNA in serum was a sensitive, specific, and rapid method for diagnosis of infants with symptomatic congenital CMV infection. The PCR detected CMV DNA in the serum of 18 infants with symptomatic infection, 1 of 2 with asymptomatic infection, and 0 of 32 controls. An exciting new development is the use of real-time PCR to detect and quantitate CMV DNA in dried blood spots obtained from a drop of neonatal blood applied to the IsoCode card (Schleicher and Schuell, Inc., Keene, NH) at the time of the newborn metabolic screen. IsoCode cards are preferred for this application because of ease of isolation of DNA from peripheral blood without the use of a lysis Swedish investigators were able to detect CMV DNA in dried blood specimens of 13 (81%) of 16 infants with congenital CMV infe~tion.~" Italian investigators using a similar method obtained a sensitivity of 100% and a specificityof 98.5% in a study of 205 neonates, including 14 with congenital infections.4'' Both groups of investigators used a nested PCR method to detect CMV DNA in dried blood specimens, which adds to the complexity of the assay, reducing its potential use as a screening assay. Advantages of PCR-based methods to screen newborn infants include no need for tissue culture facilities and a minute amount of specimens. Once dried, the samples on filter paper are no longer infectious, reducing the biohazard risk. They are easy to ship and transport without occupational exposure to infectious material. They offer the possibility to quantitate CMV DNA in PCR-positive samples and the possibility for automation. They are available for retrospective diagnosis when appropriate specimens are available, and they can be stored at room temperature for many years.

Antigenemia

An assay to detect CMV antigenemia by means of monoclonal antibodies to pp65 in PMNs has shown good sensitivity compared with conventional methods (e.g., serology,culture) for the diagnosis of CMV disease in immunocompromised Polymerase Chain Reaction Amplification adult subjects.'83,299~4'8-420Revello and colleagues299342' examined pp65 antigenemia, viremia, and DNAemia in Detection of viral DNA by PCR amplification has proven peripheral blood leukocytes from 75 infants born to mothers extremely sensitive for the detection of CMV genetic material in a variety of clinical samples, including urine, cerebrospinal who had primary CMV infection during pregnancy. The fluid, blood, plasma, saliva, and biopsy material~93~295J99~402,404-405 results of this study showed that compared with virus Using primers directed at major immediate-early protein isolation from newborn urine, the sensitivity of PCR, antiand late antigen genes, the initial report from Demmler and genemia, and viremia were loo%, 42.5%, and 28%, respectively. The specificity of the three assays was 100%. colleagues402found 41 urine specimens positive by PCR

766


Detection of Immune Response With congenital CMV infection, antibody production begins in utero and is continued probably during the life span of the host. Antibodies are also produced for prolonged periods after postnatally acquired infections.

are better perfected for general use, clinicians should not rely solely on one of these assays to diagnose congenital CMV infection. Continued research in this area may provide a simple and generally available method for rapid, definitive diagnosis of congenital infections in ill and asymptomatic neonates.

Detection of IgG Antibodies Serologic tests that measure IgG antibody are readily available and are easier to perform than are most virologic methods. However, their correct interpretation is complicated by the presence of antibodies (IgG class) that are normally transmitted from the mother to the fetus.28sA negative antibody titer in cord and maternal sera is sufficient evidence to exclude the diagnosis of congenital CMV infection. In uninfected infants born to seropositive mothers, IgG antibodies serially decrease with a half-life of approximately 1 month and disappear when the children are between 4 and 9 months old. In contrast, in infected infants, IgG antibody levels persist for long periods at comparable or sometimes higher levels than in their mothers. CMV infections are commonly acquired during the neonatal period mostly from maternal sources (e.g., milk, genital secretions) and blood or blood products. When neonatal infections are transmitted from the mother, the distinction from congenital involvement is not possible by routine serologic means. In both situations, IgG antibody titers tend to remain stable for many months. A neonatal infection in the face of a negative maternal IgG antibody titer should point to transmission from other sources, such as a blood transfusion or nosocomial infection. Many serologic assays have been described and evaluated for the detection of CMV IgG antibodies. Among these, complement fixation, enzyme-linked immunosorbent assay (ELISA), anticomplement immunofluorescence, radioimmunoassay, and indirect hemagglutination are adequate.

Detection of IgM Antibodies Infected fetuses usually produce specific IgM antibodies. IgM antibodies are not transferred by the placenta, and their presence in cord or neonatal blood represents a fetal antibody response. There are a number of different means to test for IgM antibodies,but before deciding on the use of any particular test, it is important to know its specificity, sensitivity, and reproducibility. None has reached a level of specificity and sensitivity to match the virologic assays described in the previous section. The solid-phase radioimmunoassay RIA described by Griffiths and Kang1-0~~~ is among the best, with a reported sensitivity of 89% and a specificity of 100% for diagnosis of congenital CMV infections. With the IgM ELISA, the specificity was almost 95% with a sensitivity of approximately 70% when evaluating congenitally infected infants.423 The IgM capture ELISA and radioimmunoassay have not fared much better when testing for congenital CMV infection. Modifications of the IgM tests yet to be appropriately tested in newborns include an ELISA test that uses purified recombinant CMV polypeptides shown to be highly immunogenic as the antigens for the assay.424Another version with proven greater sensitivity in blood donors, pregnant women, and transplant recipients with active CMV infection is a Western blot test for IgM antibodies against viral structural polypeptides pp150 and ~ ~ 5 2 . Until 4 ’ ~ IgM antibody tests

Diagnosis of Cytomegalovirus Infection during Pregnancy Clinical Signs and Symptoms Most primary CMV infections in immunocompetent hosts are subclinical and infections occurring in pregnant women are no exception. Less than 5% of pregnant women with proven primary CMV infections are symptomatic with an even smaller percentage manifesting mononucleosis-like syndrome. No clinical manifestations are expected with recurrent infections (i.e., reactivations or reinfections).

Laboratory Markers The diagnosis of primary CMV infection can be easily confirmed by documenting seroconversion (i.e., the de novo appearance of virus-specific IgG antibodies in a pregnant woman who was seronegative). In the absence of serologic screening, this is seldom available in clinical practice. The presence of IgG antibodies denotes past infection from 2 weeks to many years in duration.

IgM Assays Of the several tests that have undergone evaluation, the ELISA-IgM capture method seems to provide the best specificity (95%) and sensitivity (100%). The IgM antibody response varies widely from one patient to another. Seropositivity can be detected up to 16 weeks, but it is unusual to last more than 1 year. It is typical to see sharp drops in titers within the first 2 to 3 months of infection. Recombinant IgM assays have been developed based on recombinant CMV proteins and peptides. Structural and nonstructural CMV-encoded proteins react with IgM antibodies. The detection of specific IgM antibodies can be accomplished by Western blot, immunoblot, or microparticle enzyme i m m u n o a ~ s a y . ~With ~ ~ ’ ~the ~ ’immunoblot assay, the sensitivity was loo%, and the specificity was 98%.426The microparticle enzyme immunoassay had sensitivity and specificity of greater than 95Y0.~~’

IgG Avidity Assay The IgG avidity assay is based on the observation that IgG antibodies of low avidity are present during the first months after the onset of infection. With time, IgG antibodies of increasingly higher avidity are produced and eventually only IgG of high avidity is detected in individuals with longstanding CMV infection. The results of the avidity test are reported as an index representing the percentage of IgG antibody bound to the antigen after denaturation treatment Similar approaches have been reported with 6M urea?*34283429 for other infectious agents. In one study, an avidity index value of approximately 20% was obtained in serum samples collected within 3 months after onset of primary infection, in contrast to an avidity index of 78% in sera from individuals with remote infection (Fig. 23-5).430

Chapter 23


767

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80

h

$?

x

0)

60

.

0 0 0

0.0.

.$

z

0

.

0 I .

.7

0

40

20 Figure 23-5 Kinetics of IgG avidity index. (From Revello MG. Gerna G. Diaanosis and manaaement of

0

Days after onset of infection

In determining the risk of congenital CMV, a moderate to high avidity index obtained before the 18th week of has a negative predictive value of 100%.When the avidity index is determined between 21 and 23 weeks' gestation, the negative predictive value dropped to 91%.431 The explanation for this observation is that some of the women who transmitted the infection in utero had acquired the infection at a very early gestational age. One important limitation of the IgG avidity test is the lack of standardization. In one study, the ability of these IgG avidity assays to identify primary CMV infection almost reached loo%, whereas the ability to exclude a recent infection ranged from 20% to 96%.

viral Cultures CMV excretion from multiple sites such as urine, saliva, and genital secretions is common and can last weeks to several months after a primary infection. Unfortunately, the same occurs with reinfections and reactivations, making this diagnostic approach useless. Viremia, as determined by conventional tissue culture methods, is too insensitive to confirm the diagnosis of primary infection in immunocompetent hosts.

Other Viral Tests Other diagnostic methods with greater sensitivity and specificity include the determination of antigenemia (number of pp65-positive peripheral blood leukocytes); quantification of CMV DNA in whole blood (DNAemia),leukocytes (leukoDNAemia),or plasma; and determination of immediate-early and late mRNA (RNAemia) in blood.299*432 Some of these assays are commercially available. The data supporting their diagnostic value are derived largely from studies in immunosuppressed patients with primary CMV infections, reactivations, and dissemination of infection and evaluation of antiviral treatments. One study of immunocompetent adults, including a large proportion of pregnant women with primary CMV infection, showed that pp65 antigenemia was detected in 57% of patients examined within the first month after the onset of primary infection.433The rate of positive results dropped to 25% a month later and to 0% 5 months later. Viremia was detected in 26% of patients during the first month only. Leuko-DNAemia (by PCR test) was detected in 100% of patients tested during the first

2002.)

month, in 89% of those tested on the second month, and in 47% of those tested 3 months after the onset of primary infection. DNAemia lasted 4 to 6 months in 26% of patients, and no patient remained positive beyond 6 months from the onset of infection. None of these three assays was positive for patients with old CMV infection, including nine subjects with proven recurrences. The results of this indicate that antigenemia and DNAemia when run on blood specimens can rapidly and specifically diagnose and provide an approximate date of onset for primary infection in pregnant women. The detection of immediate-early mRNA has been evaluated as a diagnostic tool for primary CMV infection in healthy i n d i v i d ~ a l s . 4 ~This ~ 9 ~ test ~ ~ was consistently negative in all subjects with old or recurrent CMV infection. In contrast, all subjects within the first month of a primary infection tested positive. The proportion of positive results declined over time with all patients testing negative after 6 months of the onset of CMV infection. The kinetics of this test resemble that of DNA detection and, in at least one comparison, the immediate-early mRNA test was slightly more sensitive in the early phase of primary CMV infecti0n.4~~

Maternal Laboratory Tests of Fetal Infection In utero transmission of CMV infection occurs in approximately 40% of primary infections acquired during pregnancy. No reliable tests can define transmission of infection to the fetus. Moreover, there are no maternal prognostic markers of fetal infection with a recurrence of maternal infection. One study showed that reinfection with a different strain of CMV, as measured by new antibody specificity against epitopes of glycoprotein H, was capable of causing symptomatic congenital CMV infection. The methodology used in this study is far from becoming a standard laboratory assay.

Prenatal Diagnosis The prenatal diagnosis of CMV is possible by testing fetal blood obtained by cordocentesis and amniotic fluid obtained by amniocentesis. Fetal blood can be used for determination of specific IgM antibodies and direct viral markers. IgM antibodies can be detected only after 20 weeks' gestation, but because of low sensitivity (approximately So%), the test has very limited diagnostic va1ue.436-438 However, studies of viral

768


load in fetal blood show that the sensitivity of antigenemia was approximately 58%; of viremia, 55%; and of leukoDNAemia, 82%. The specificity is 100% for the three assays.299In one study, PCR in fetal blood had a sensitivity of 41%, but viral culture had a sensitivity of only 7%. With the use of fetal blood, even the most sensitive assays miss almost 15% to 20% of infected fetuses. Results in amniotic fluid are far better, and this method is the standard for prenatal diagnosis. Viral isolation in tissue culture has a sensitivity of approximately 60%, whereas the sensitivity of PCR can reach 100%. The specificity of both assays is A quantitative PCR method has shown that when the amniotic fluid contains 10’ or more genome equivalents of CMV DNA, the risk of symptomatic congenital CMV infection is significantly higher than when the viral load is lo3genome equivalents or l e ~ s . ~ ~ - ~ ’ A confounding factor in prenatal diagnosis is the gestational age at the time of amniocentesis or cordocentesis. After a primary maternal infection, it may take weeks to months for transplacental transmission of CMV to occur. An interval of 7 weeks between maternal onset of infection and diagnostic tests for fetal infection has been suggested as a reasonable interval by some investigator^?^^^^^^ Gestational age at the time of testing is important, because the sensitivity can be as low as 30% when amniotic fluid is obtained before the 21st week of gestation, and it can be 100% if the test is performed after 2 1 weeks‘ gestation.437,4389442.447-452 When counseling pregnant women, it is important to remember that 80% to 90% of children with congenital CMV infection escape CNS sequelae. In the absence of specific antiviral treatment, the only alternatives available after a prenatal diagnosis of congenital CMV infection are to terminate the pregnancy or do nothing. The presence or absence of ultrasonographic evidence of fetal abnormalities should be taken into consideration during counseling of women at risk.

Diagnosis of Perinatally Acquired Infections For perinatally acquired infections, viral culture and CMV DNA detection by PCR using urine and saliva are the preferred diagnostic methods, but CMV excretion does not begin until 3 to 12 weeks after e x p o s ~ r e . For ~ ~ diagnostic *~~~ specificity, it is imperative to have a negative result from urine or saliva specimens collected within the first 2 weeks of life. In early infancy, antibody assays have the same limitations described earlier for infants with congenital CMV infection. The desire to differentiatebetween congenital and perinatal CMV infections stems from the fact that their risks for acute morbidity and for long-term sequelae are very different.

DIFFERENTIAL DIAGNOSIS During the newborn period, the constellation of hepatosplenomegaly,petechiae, and direct hyperbilirubinemia with or without pneumonitis, microcephaly, and ocular and neurologic abnormalities that characterize CID is common to several disease entities, including other congenital infections such as congenital rubella syndrome, toxoplasmosis, syphilis, neonatal herpes simplex virus infections, and less likely,

hepatitis B and varicella virus infections.370The differential diagnosis of symptomatic congenital CMV infection also includes bacterial sepsis and noninfectious disorders such as hemolytic diseases related to Rh or ABO incompatibilities or red blood cell defects, metabolic disorders such as galactosemia and tyrosinemia, immune thrombocytopenia, histiocytosis X, congenital leukemia, and others. The list of diseases that must be considered in the differential diagnosis becomes broader as the clinical manifestations diminish in severity. Infections may coexist in the same patient. Consequently, the laboratory workup for differential diagnosis must be thorough.

Congenital Rubella Syndrome Congenital rubella has been virtually eliminated in the United States after the successful immunization program adopted years ago. Although symptomatic congenital rubella and CMV infections share many signs and symptoms, central cataracts, congenital heart defects, raised purpuric rather than petechial rash, salt-and-pepper lesions as opposed to chorioretinitis, and the absence of cerebral calcifications are more likely to occur with congenital rubella syndrome than with CID.370

Congenital Toxoplasmosis Almost all of the manifestations observed in CID have been described for symptomatic congenital toxoplasmosis. Some differences merit discussion.370For instance, the calcifications of toxoplasmosis are generally scattered throughout the cerebral cortex, whereas the calcifications of CID tend to occur in the periventricular areas. The rash associated with toxoplasmosis is usually maculopapular but is not petechial or purpuric. Chorioretinitis in the two diseases cannot be differentiated on the basis of appearance or distribution. However, it is more likely that chorioretinitis related to CMV is associated with other major clinical manifestations, such as microcephaly. Not uncommonly, the chorioretinitis of toxoplasmosis is an isolated finding.

Congenital Syphilis The most consistent signs of early congenital syphilis are osteochondritis and epiphysitis on the radiograph of the long bones.370These occur in approximately 90% of infected patients and are more likely to appear in patients who become symptomatic in the first week of life. Rhinitis, sometimes associated with laryngitis, is another common manifestation of congenital syphilis; it is often followed by a dark red maculopapular, spotted rash. Lesions of the skin and mucous membranes are also seen. Hepatosplenomegaly occurs but is less common in early syphilis than in CID. Calcifications of the brain are not characteristic of congenital syphilis. However, choroiditis may be seen.

Neonatal Herpes Simplex Virus Infections Congenital herpes simplex virus infections are less common than neonatal herpes simplex virus infections, but they are more likely to pose a diagnostic dilemma because they may

Chapter 23 resemble CID. Microcephaly, intracranial calcifications, chorioretinitis with and without optic atrophy and hepatosplenomegaly are common clinical manifestations of intrauterine herpes simplex virus infections. The presence of skin vesicles or scarring present at birth is valuable for the differential diagnosis. The more common form of herpes simplex virus infection, neonatal infection, is acquired during parturition and does not usually manifest as an acute disease until the infants are 5 to 2 1 days old. Unlike the situation in typical CID, the infant is well during most of the first week of life. When dlness does occur, it may be accompanied by seizures, encephalitis, respiratory distress, bleeding disorders, and vesicular lesions that tend to cluster. The presence of skin and mucous membranous lesions is valuable for the differential diagnosis of CID.

TREATMENT

Chemotherapy A small number of systemically administered antiviral agents have been used in therapeutic trials of serious, lifethreatening or sight-threatening CMV disease. Two antiviral agents, ganciclovir and foscarnet, are licensed for this purpose in immunocompromised patients. Foscarnet inhibits viral replication by inhibiting viral DNA polymerase, and ganciclovir acts as a chain terminator during elongation of the newly synthesized viral DNA>53-457 The Collaborative Antiviral Study Group (CASG) under the auspices of the National Institute of Allergy and Infectious Diseases first conducted a phase I1 pharmacokineticpharmacodynamic study that established the safe dose of ganciclovir to be used in young infants and demonstrated an antiviral effect with suppression of ~ i r u r i a . 4A~phase ~ 111, randomized, controlled study followed in newborn infants with symptomatic congenital infection involving the CNS.456 A total of 100 patients were enrolled. Those in the ganciclovir treatment arm received doses of 6 mg/kg administered intravenously every 12 hours for 6 weeks of treatment. The primary end point was improved hearing (as assessed by brain-stem-evoked response) between baseline and 6 months of follow-up or, for those with normal hearing at enrollment, preservation of normal hearing at follow-up. Twenty-one (84%) of 25 ganciclovir-treated patients had hearing improvement or maintained normal hearing at 6 months, compared with 10 (59%) of 17 in the no-treatment group (P = .06).At 6 months of follow-up, none (0 of 25) of the ganciclovir-treated infants had hearing deterioration, compared with 7 (41%) of 17 in the no-treatment group (P < .01). Alternatively, 5 (21%) of 24 of ganciclovir recipients had worsening in hearing in their best ear between baseline and 1 year or longer, compared with 13 (68%)of 19 in the no-treatment group ( P < .01). As in the previous phase I1 study, the most significant toxicity in the treated group was neutropenia, with 29 (63%) of 46 patients developing moderate to severe neutropenia compared with 9 (21%) of 43 of the no-treatment group (P< .01). One half of the patients with neutropenia required dosage adjustment and 12%had discontinuation of therapy. This study demonstrates that 6 weeks of intravenous ganciclovir in symptomatic congenital CMV-infected infants


769

prevents worsening of hearing loss at 6 months and 1 year of follow-up. Treated patients had a more rapid resolution of their liver function abnormalities and improvements in short-term growth and head circumference compared with controls. There are no reports on the therapeutic efficacy of combined therapy (i.e., foscarnet-ganciclovir). The CASG is conducting a phase 1/11pharmacokinetic-pharmacodynamic study of valganciclovir, the orally bioavailable prodrug of ganciclovir, to determine the dose necessary to achieve a safe and effective concentration of ganciclovir in the bloodstream. Intravenous ganciclovir treatment at a dose of 6 mg/kg that is administered every 12 hours for 42 days can be recommended for infants with proven symptomatic congenital CMV infection, particularly for those with no evidence of hearing loss. Although the phase I11 study sponsored by the CASG did not include infants without CNS involvement, the data suggest that treatment may speed the resolution of liver abnormalities. The decision to treat should be carefully discussed with parents and caregivers because treatment often requires a substantial commitment, including 42 days of intravenous therapy (preferably in the hospital), the use of secure intravenous access, and frequent blood sampling to check for ganciclovir toxicity. Anecdotal reports do not support the use of hyperimmune immunoglobulin or antiviral treatment with ganciclovir or foscarnet for treating the fetus in utero.

Passive Immunization Hyperimmune plasma and immunoglobulin have been used with some success as prophylaxis for primary CMV infections in immunosuppressed transplant recipients. A meta-analysis of randomized, controlled trials of immunoglobulin as prophylaxis for CMV disease in adult transplant recipients found a significant beneficial e f f e ~ t . 4Studies ~~ are being conducted to determine if a humanized monoclonal antibody, such as the one that binds to gH of CMV, is more efficacious for the prevention or treatment in patients at high risk for CMV infecti0n.4~~ It is unlikely that passive immunoprophylaxis will ever work for treatment of congenital infections because the cases are identified weeks and months after infection occurred in utero. However, it might be a means of preventing primary CMV infection and disease associated with transfusion-acquired infections in premature infants. No controlled studies are available.

Vaccines In the United States, congenital CMV infection is a significant public health problem. It is the leading cause of sensorineural hearing loss and the leading infectious cause of brain damage in Not surprisingly, the Institute of Medicine of the National Academy of Sciences concluded that a vaccine to prevent congenital CMV infection should be a top priority. Despite 30 years of research efforts, no such vaccine is available. The prevailing thought is that both neutralizing antibodies and cell-mediated immunity are necessary for prevention. Of the CMV proteins, gB, gH, pp65, and pp150 can induce neutralizing and CTL response^.^^'-^^^ The strategies for vaccine development include liveattenuated vaccine (i.e., Towne strain). This vaccine induces

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a significant antibody response and cell-mediated immunity, as determined by lymphoproliferative response. In CMVseronegative recipients of kidneys from seropositive donors, this vaccine reduced disease severity but did not prevent infection!61 It also protected against a low-dose virulent CMV challenge in normal volunteers. In a later trial, this vaccine failed to decrease the rate of acquisition of CMV in parents of children in daycare. The magnitude of the induced immune response was 10-fold lower than that generated by natural infection.&' The Towne vaccine is not excreted by vaccinees.

Recombinant Virus Vaccine The genome of the virulent Toledo strain of CMV, divided into four fragments, was inserted in the genetic background of the attenuated Towne strain, creating four chimeras. The ability of these four recombinant virus strains to generate antibody and cell-mediated immune responses in the absence of clinical side effects is being evaluated in a phase I study.&'

Subunit Vaccines A CMV vaccine based on the envelope glycoprotein gB combined with a novel adjuvant (MF59) was tested in a double-blind, placebo-controlled trial of seronegative adult volunteers.& Results showed that after three doses, the antibody responses to gB and neutralizing antibodies exceeded the levels in seropositive control subjects. Cellmediated immunity was not evaluated. The major target of the cell-mediated immune response is pp65. In an effort to elicit this response, a made use of the nonreplicating canarypox expression vector in which CMV pp65 has been inserted. A phase I trial on seronegative volunteers found that pp65-specific CTLs were elicited after only two vaccinations. An antibody response to pp65 was also demonstrated. In this preliminary study, the canarypox CMV pp65 recombinant vaccine seems to generate an immune response similar to that provided by natural i n f e ~ t i o nA. ~canarypox ~ CMV recombinant that contained gB did not induce neutralizing antibodies. It is possible to explore the immunogenicity of a vaccine combining canarypox CMV (pp65) with gB with an appropriate adjuvant such as MF59. This combination may generate sufficient CTLs and neutralizing antibodies to protect against CMV disease. Other potential avenues for the development of CMV vaccine include peptide vaccines and DNA vaccines. All candidate vaccines must demonstrate that immunogenicity provides protection.

PREVENTION CMV usually is not very contagious, and its horizontal transmission requires direct contact with infected material, such as secretions that contain the virus and, less likely, f~mites.~~.' ''466 With the exception of a few small studies that were designed to prevent infection through blood and blood products and grafted organs, no broad-based strategies for preventing the transmission of this virus have been tested.269,395,467,468Although there are still no effective means of preventing congenital CMV infections or most perinatally acquired CMV infections, a few common sense recommendations can be made.

Pregnant Women An average of 2% of susceptible pregnant women acquire CMV infection during pregnancy in the United States; most of them have no symptoms, and only 40% of the episodes result in fetal infection (Fig. 23-6).469Because there is no effective drug therapy and the risk of fetal morbidity is low, several investigators have concluded that routine serologic screening of pregnant women for primary CMV infections during pregnancy is of limited However, reliable and inexpensive serologic tests are available, and women of childbearing age can be informed of their immune status.471 Those who are seronegative should be able to make informed decisions about the risks of CMV. Primary CMV infection should be suspected in pregnant women with symptoms compatible with a heterophil-negative, mononucleosis-like syndrome. To more precisely define a recent asymptomatic primary CMV infection, serologic tests such as Igh4 capture ELISA, IgG avidity index, and DNAemia (PCR) could be used. There are no reliable means to determine whether intrauterine transmission has occurred after symptomatic or subclinical primary infection in early gestation or to assess the relatively small number of fetuses at risk of disease. The sensitivity and specificity of prenatal diagnosis by testing fetal blood obtained by cordocentesis or amniotic fluid PCR and viral culture are good after 20 weeks' gestation. There is still limited information to serve as a basis for recommendations regarding termination of pregnancy after a primary CMV infection acquired in early gestation. Similarly, there is no conclusive information regarding how long conception should be delayed after documented primary infection is acquired in a woman of childbearing age. Viral excretion is not a good indicator because virus is shed into saliva for weeks or months after infection and into urine and the cervix for months or years. The data on which to base recommendations for prevention of congenital CMV infection after recurrent maternal infection are even more inadequate. Preexisting immunity does not prevent the virus from reactivating or reinfection, nor does it effectively control the occasional spread to the fetus.326Preexisting maternal immunity affords significant protection to the fetus. However, evidence that in some high-risk populations reinfections with antigenically different virus can cause fetal disease and long-term sequelae may temper this statement. There are no techniques for identifylng women with reactivation of CMV that result in intrauterine transmission. Because the risk of transmission is very low (see Fig. 23-6) and the risk of fetal disease even lower, women known to be seropositive before conception do not need to be virologically or serologically tested, nor do they need to be unduly worried about the very low risk of adverse effects on the fetus. The principal sources of CMV infection among women of childbearing age are exposure to children excreting CMV and sexual contacts. Recommendations for prevention of sexual transmission of CMV are beyond the scope of this review. Suffice it to say that they are similar to those advocated for the prevention of other, more common sexually transmitted infections. As for the risk from exposure to children, at greater risk are susceptible pregnant mothers of CMVinfected children who attend daycare centers~7,98,102,106-108,110-113 Hand washing and simple hygienic measures that are routine

Chapter 23


771

CONSEQUENCES OF CMV IN PREGNANCY

Immune

r

1-4%

Congenital infection (recurrent maternal infection) L

I

0-1 Yo Infected infants may have clinically apparent disease or sequelae

10% Develop normally

90% Develop sequelae

5-1 5% Develop sequelae

85-95% Develop normally

1 Figure 23-6 Characteristics of cytomegalovirus infection in pregnancy. (From Stagno 5, Whitley RJ. Herpesvirus infection of pregnancy. N Engl J Med 313:1270-1274, 1985.)

for hospital care can be recommended, but it is unrealistic to infected children and children excreting this virus in the expect all mothers to comply. workplace so that seronegative workers and parents can Because CMV has been found to be endemic in the dayavoid contact with them pose serious logistic problems and would require frequent periodic testing. care setting and is found everywhere in hospitals, questions often arise about the occupational risks to pregnant personnel in these facilities. Although hospital workers do Nosocomial Infection not appear to be at increased risk for CMV infection,109,143,145,148 personnel who work in daycare centers are.97~98,102,1043105,110 In Hospitalized patients who receive blood products and organ transplants are at risk for nosocomial CMV infection. the hospital, routine procedures for hand washing and infection control should make nonparenteral acquisition of Because the role of organ transplantation in transmission of CMV infections less likely than in the community. Although CMV is insignificant in the newborn period, it is not most patients who shed CMV are asymptomatic and go discussed here. Transfusion of blood products can be an important source of perinatal CMV infections. The use unrecognized, when caring for known CMV-excreting of blood products from seronegative donors prevents patients, these routine measures should be combined with a special recommendation that pregnant caretakers be especially the transmission of CMV and the subsequent risk of disease.132,269,395,401 However, this method is not practical in careful in handling such patients.143In the daycare setting, where hygiene is difficult at best, these preventive measures areas where most of the donor population is seropositive. The availability of seronegative donors and the additional may be more difficult to implement. Although there is still cost involved in serologic screening and processing the blood debate about the need for routine serologic screening of female personnel and daycare workers, I believe that it must be evaluated by regional blood banks. The use of deglycerolized, frozen red blood cells and the should be recommended for potentially childbearing women use of filters to remove leukocytes are also effective means of whose occupation exposes them to CMV. Knowing their immune status can be helpful in counseling pregnant women eliminating post-transfusion CMV infection in adult dialysis at risk. Those found to be seropositive can be strongly patients and in newborns, even in low-birth-weight reassured. Those found to be serosusceptible should be infants.132,468472 Both methods result in a significant disprovided with information on prevention measures and ruption and depletion of leukocytes. Many hospitals are using one of these three approaches to reassured that common sense steps such as hand washing and avoiding contact with secretions should prevent acquisition prevent transfusion-acquired perinatal CMV infections.473It is up to the local hospital and blood bank to determine of infe~ti0n.I~~ Attempts to identify all congenitally CMV-

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whether transfusion-associated CMV disease is a problem and which method to choose. However, many nurseries have adopted the policy that all transfusions of blood or blood products should be with seronegative blood, irrespective of the infant’s birth weight and maternal immune status. The absence of CMV infection in premature infants born to seronegative mothers and who receive only seronegative blood products suggests that spread of CMV from hands of personnel or from fomites must be rare. Until more information is available, the only logical recommendation is hand washing and routine infection control measures. Rarely is perinatal infection through breast milk a cause for concern, at least for full-term newborns who receive their mother’s milk?0396Premature infants, who generally do not receive sufficient quantities of specific transplacental antibodies, are at higher risk for m ~ r b i d i t y .We ~ ~must ~ , ~also ~ be cautious with expressed banked milk and wet nurses because CMV-infected milk might inadvertently be given to infants born to seronegative women. Storage of naturally infected breast milk at -20’ C (freezer temperature) significantly reduces but does not eliminate infectivity>74Heat treatment of breast milk at 72’ C for 10 seconds eliminates all infectious viruses without affecting the nutritional and immunologic properties of milk.342 REFERENCES 1. Weller TH. The cytomegaloviruses: ubiquitous agents with protean clinical manifestations. N Engl J Med 285:203-214, 1971. 2. Ribbert H. Uber protozoenartigen Zellen in der Nueeines syphilitischen Neugeboren und in der Parotis von Kindren. Zentralbl Allg Pathol 15:945-948,1904. 3. JesionekA, KiolemenoglouB. Ober einen Befund von protozoenartigen Gebilden in den Organen eines hereditarleustiochen Fotus. MMW Munch Med Wochenschr 51:1905-1907, 1904. 4. Lowenstein C. Ober protozoenartigen Gebilden in den Organen von Dindern. Zentralbl AUg Pathol 18:513-518.1907. 5. Goodpasture E, Talbot FB. Concerning the nature of “protozoanWceh in certain lesions of infancy. Am J Dis Child 2~415-425,1921. 6. Lipschutz B. Untersuchungen uber die Aetiologic der Krankheiten d. herpes genitalis, usw. Arch Derm Syph 136428-482, 1921. 7. Cole R, Kuttner AG. Filterable virus present in the salivary glands of guinea pigs. J Exp Med 44:855-873,1926. 8. Smith MG. Propagation of salivary gland virus of the mouse in tissue culture. Proc SOCExp Biol Med 8643540,1954. 9. Smith MG. Propagation in tissue cultures of a cytopathogenic virus from human salivary gland virus (SGV) disease. Proc SOCExp Biol Med 92:424-430,1956. 10. Rowe WP, Hartley JW, Waterman S, et al. Cytopathogenic agent resembling salivary gland virus recovered from tissue cultures of human adenoids. Proc SOCExp Biol Med 92:418-424,1956. 11. Weller TH, Macauley JC, Craig JM, et al. Isolation of intranuclear inclusion-producing agents from infants with illnesses resembling cytomegalic inclusion disease. Proc SOCExp Biol Med 944-12, 1957. 12. Weller TH, Hanshaw JB, Scott DE.Serologic differentiation of viruses responsible for cytomegalic inclusion disease. Virology 12: 130-132, 1960. 13. Krech U, Jung M, Jung F. Cytomegalovirus Infections of Man. Basel, S Karger, 1971, p 28. 14. Gold E, Nankervis GA. Cytornegalovirus. In Evans AS (ed). Viral Infections of Humans: Epidemiology and Control. New York, Plenum, 1982, pp 167-186. 15. Alford CA, Stagno S, Pass RF, et al. Epidemiology of cytomegalovirus. In Nahrnias A, Dowdle W, Schinazi R (eds). The Human Herpesviruses: An Interdisciplinary Perspective. New York, Elsevier, 1981, pp 159-171. 16. Black JB, Pellett PE. Human herpesvirus 7. Rev Med Virol9:245-262, 1999. 17. Campadelli-Fiume G, Mirandola P, Menotti L. Human herpesvirus 6: an emerging pathogen. Emerg Infect Dis 5:353-366, 1999.

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447. 448. 449. 450. 451. 452. 453.

454.

women at risk of transmitting congenital CMV infection. Clin Diagn Lab Immunol6127-129, 1999. Revello MG, Gerna G. Diagnosis and implications of human cytomegalovirus infection in pregnancy. Fetal Matern Med Rev 11:117-134, 1999. Maine GT, Lazzarotto T, Landini MP. New developments in the diagnosis of maternal and congenital CMV infection. Expert Rev Mol Diagn 1:19-29,2001. Boeckh M, Boivin G. Quantitation of cytomegalovirus: methodologic aspects and clinical applications. Clin Microbiol Rev 11:533-554,1998. Revello MG, Zavattoni M, Sarasini A, et al. Human cytomegalovirus in blood of immunocompetent persons during primary infection: prognostic implications for pregnancy. J Infect Dis 1721170-1175, 1998. Revello MG, Lilleri D, Zavattoni M, et al. Human cytomegalovirus immediate-early messenger RNA in blood of pregnant women with primary infection and of congenitally infected newborns. J Infect Dis 184:1078-1081,2001. Gerna G, Baldanti F, Lilleri D, et al. Human cytomegalovirus immediate-early mRNA detection by nucleic acid sequence-based amplification as a new parameter for preemptive therapy in bone marrow transplant recipients. J Clin Microbiol38:1845- 1853,2000. Donner C, Liesnard C, Content J, et al. Prenatal diagnosis of 52 pregnancies at risk for congenital cytomegalovirus infection. Obstet Gynecol82:481-486,1993. Lamy ME, Mulongo KN, Gadisseux JF, et al. Prenatal diagnosis of fetal cytomegalovirus infection. Am J Obstet Gynecol 16691-94,1992. Lynch L, Daffos F, Emanuel D, et al. Prenatal diagnosis of fetal cytomegalovirus infection. Am J Obstet Gynecol 165:714-718,1991. Liesnard C, Donner C, Brancart F, et al. Prenatal diagnosisof congenital cytomegalovirus infection: prospective study of 237 pregnancies at risk. Ohstet Gynecol95:881-888,2000. Lipitz S, Yagel S, Shalev E, et al. Prenatal diagnosis of fetal primary cytomegalovirus infection. Obstet Gynecol89763-767, 1997. Revello MG, Baldanti F, Furione M, et al. Polymerase chain reaction for prenatal diagnosis of congenital human cytomegalovirus infection. J Med Viol 47:462-466,1995. Ruellan-Eugene G, Bajot P, Bajot P, et al. Evaluation of virological procedures to detect fetal human cytomegalovirus infection: avidity of IgG antibodies, virus detection in amniotic fluid and maternal serum. J Med Virol509-15,1996. Ahlfors K, Ivarsson SA, Nilsson H. On the unpredictable development of congenital cytomegalovirus infection. A study in twins. Early Hum Dev 18:125-135,1988. Guerra B, Lazzarotto T, Quarta S, et al. Prenatal diagnosis of symptomatic congenital cytomegalovirus infection. Am J Obstet Gynecol 183:476-482,2000. Lazzarotto T, Varani S, Guerra B, et al. Prenatal indicators of congenital cytomegalovirus infection. J Pediatr 137:90-95,2000. Bodeus M, Hubinont C, Bernard P, et al. Prenatal diagnosis of human cytomegalovirus by culture and polymerase chain reaction: 98 pregnancies leading to congenital infection. Prenatal Diagn 19314- 17, 1999. French MLV, Thompson JR, White A. Cytomegalovirus viremia with transmission from mother to fetus. Ann Intern Med 86748-749, 1977. Huikeshoven FJM, Wallenburg HCS, Jahoda MGJ. Diagnosis of severe fetal cytomegalovirus infection from amniotic fluid in the third trimester of pregnancy. Am J Obstet Gynecol 142:1053-1054, 1982. Yambao TJ, Clark D, Weiner L, Aubry RH. Isolation of cytomegalovirus from the amniotic fluid during the third trimester. Am J Ohstet Gynecol 141:937-938,1981. Grose C, Weiner CP. Prenatal diagnosis of congenital cytomegalovirus infection: two decades later. Am J Obstet Gynecol 163:447-450,1990. Grose C, Meehan T, Weiner CP. Prenatal diagnosis of congenital cytomegalovirus infection by virus isolation after amniocentesis. Pediatr Infect Dis J 11:605-608, 1992. Pass RF. Commentary: is there a role for prenatal diagnosis of congenital cytomegalovirus infection? Pediatr Infect Dis J 11:608-609, 1992. Collaborative DHPG Treatment Study Group. Treatment of serious cytomegalovirus infections with 9-( 1,3-dihydroxy-2-propoxymethyl) guanine in patients with AIDS and other immunodeficiencies. N Engl J Med 314801-805,1986. Chrisp P, Clissold SP. Foscarnet: a review of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocom-

455. 456.

457. 458. 459. 460. 461. 462. 463.

464. 465.

466. 467. 468. 469. 470. 471. 472. 473. 474. 475. 476. 477. 478. 479. 480.

481.


781

promised patients with cytomegalovirus retinitis. Drugs 41:104-129, 1991. Faulds D, Heel RC. Ganciclovir: a review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infections. Drugs 39:597-638, 1990. Kimberlin DW, Lin CY, Sanchez PJ, et al. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr 16-25,2003. Michaels MG, Greenberg DP, Sabo DL, et al. Treatment of children with congenital cytomegalovirus infection with ganciclovir. Pediatr Infect Dis J 22:504-508,2003. Glowacki LS, Smaill FM. Meta-analysis of immune globulin prophylaxis in transplant recipients for the prevention of symptomatic cytomegalovirus disease. Transplant Proc 25: 1408-1410, 1993. Hamilton AA, Manuel DM, Grundy JE, et al. A humanized antibody for prophylaxis against human cytomegalovirus(CMV) gp UL 75 (gH) or treatment of CMV infections. J Infect Dis 176:59-68, 1997. Pass RF, Burke RL. Development of cytomegalovirus vaccines: prospects for prevention of congenital CMV infection. Semin Pediatr Infect Dis 13:196-204,2002. Gonczol E, Plotkin S. Development of a cytomegalovirus vaccine: lessons from recent clinical trials. Exp Opin Biol Ther 1:401-412,2001, Britt WJ. Vaccines against human cytomegalovirus: time to test. Trends Microbiol434-38, 1996. Adler SP, Hempfling SH, Starr SE, et al. Safety and immunogenicity of the Towne strain cytomegalovirus vaccine. Pediatr Infect Dis J 12200-206,1998. Pass RF, Duliege AM, Boppana S, et al. A subunit cytomegalovirus vaccine based on recombinant envelope glycoprotein B and a new adjuvant. J Infect Dis 180:970-975, 1999. Berencsi K, Gyulai 2, Gonczol E, et al. A canarypox vector-expressing cytomegalovirus (CMV) phosphoprotein 65 induces long-lasting cytotoxic T cell responses in human CMV-seronegative subjects. J Infect Dis 183:1171-1179,2001. Taber LH, Frank AL, Yow MD, et al. Acqu infections in families with young children: a serological study. J Infect Dis 151:948-952, 1985. Onorato IM, Morens DM, Martone WJ, et al. Epidemiology of cytomegalovirus infections: recommendations for prevention and control. Rev Infect Dis 2479-497,1985. Brady MT, Milam JD, Anderson DC, et al. Use of deglycerolized red blood cells to prevent posttransfusion infection with cytomegalovirus in neonates. J Infect Dis 150:334-399, 1984. Stagno S, Whitley RJ. Herpesvirus infection of pregnancy. N Engl J Med 313:1270-1274,1327-1329, 1985. Peckham CS, Chin KS, Coleman JC, et al. Cytomegalovirus infection in pregnancy: preliminary findings from a prospective study. Lancet 1:1352-1355,1983. Yow MD. Congenital cytomegalovirus disease: a NOW problem. J Infect Dis 159163-167,1989. Gilbert GL, Hayes K, Hudson IL, et al. Prevention of transfusionacquired cytomegalovirus infection in infants by blood filtration to remove leukocytes. Lancet 1:1228-1231, 1989. Holland PV, Schmitt PJ. Standards for Blood Banks and Transfusion Services, 12th ed. Arlington, Va, Committee on Standards, American Association of Blood Banks, 1987, pp 30-3 1. Dworsky ME, Stagno S, Pass RF, et al. Persistence of cytomegalovirus in human milk after storage. J Pediatr 101:440-443, 1982. Ploegh HL. Viral strategies of immune evasion. Science 280:248-253, 1998. Hengel H, Reusch U, Gutermann A, et al. Cytomegaloviral control of MHC class I function in the mouse. h m u n o l Rev 168:167-176,1999. Tomazin R, Boname J, Hegde NR, et al. Cytomegalovirus US2 destroys two components of the MHC class I1 pathway, preventing recognition by CD4+ T cells. Nat Med 5:1039-1043, 1999. Alcami A, Koszinowski UH. Viral mechanisms of immune evasion. Immunol Today 21:447-455,2000, Tortorella D, Gewurz BE, Furman MH, et al. Viral subversion of the immune system. Annu Rev Immunol 18:861-926,2000. Gewurz BE, Gaudet R, Tortorella D, et al. Antigen presentation subverted structure of the human cytomegalovirus protein US2 bound to the class I molecule HLA-A2. Proc NatI Acad Sci U S A 98:6794-6799,2001. Mocarski ES Jr. Immunomodulation by cytomegaloviruses: manipulative strategiesbeyond evasion. Trends Microbiol 10332-339,2002,

Chapter 24 ENTEROVIRUS AND PARECHOVIRUS INFECTIONS James D. Cherry

as well as shared features in their epidemiology and pathogenesis and the many disease syndromes that they cause. Congenital and neonatal infections have been linked with Morphology and Classification Characteristics and Host Systems many different enteroviruses and parechoviruses. RepresenAntigenic Characteristics tatives of all four major enterovirus groups, as well as parechoviruses 1 and 2, have been associated with disease in Epidemiology and Transmission 787 the ne~nate.'-'~"'-~' General Considerations Poliomyelitis,the first enteroviral disease to be reco nized Transplacental Transmission Ascending Infection and Contact Infection during Birth and the most important one, has had a long historyj3 The Neonatal Infection earliest record is an Egyptian stele of the 18th dynasty (1580 Host Range to 1350 BC), which shows a young priest with a withered, Geographic Distribution and Season shortened leg, the characteristic deformity of paralytic polioPathogenesis 792 myelitis.34v35 Underwood, 36 a London pediatrician, published Events during Pathogenesis the first medical description in 1789 in his Treatise on Diseases Factors That Affect Pathogenesis of Children. During the 19th century, many reports appeared Pathology 793 in Europe and the United States describing small clusters of cases of "infantile paralysis." The authors were greatly General Considerations Polioviruses puzzled about the nature of the affliction; not until the 1860s Coxsackieviruses A and 1870s was the spinal cord firmly established as the seat Coxsackieviruses B of the pathologic process. The contagious nature of polioEchoviruses myelitis was not appreciated until the latter part of the 19th Clinical Manifestations 795 century. Medin, a Swedish pediatrician, was the first to Abortion describe the epidemic nature of poliomyelitis (1890), and Congenital Malformations his pupil Wickman3' worked out the basic principles of the Prematurity and Stillbirth epidemiology. Neonatal Infection The virus was first isolated in monkeys by Landsteiner Diagnosis and Differential Diagnosis 810 and Popper in 19OtL3' The availability of a laboratory animal Clinical Diagnosis assay system opened up many avenues of research that in the Laboratory Diagnosis ensuing 40 years led to the demonstration that an unrecogDifferential Diagnosis nized intestinal infection was common and that paralytic Prognosis 811 disease was a relatively uncommon event. Polioviruses Coxsackieviruses and echoviruses have had a shorter Nonpolio Enteroviruses history. Epidemic pleurodynia was first clinically described in Therapy 812 northern Germany in 1735 by H a n n a e ~ smore ~ ' ~ ~than 200 years before the coxsackieviral cause of this disease was Specific Therapy Nonspecific Therapy discovered. In 1948, Dalldorf and Sickles4' first reported the isolation of a coxsackievirus by using suckling mouse Prevention 813 inoculation. Immunization In 1949, Enders and associates4' reported the growth of Other Measures poliovirus type 2 in tissue culture, and their techniques paved the way for the recovery of a large number of other cytopathic viruses. Most of these "new" viruses failed to produce illness in laboratory animals. Because the relationships of Enteroviruses (i.e., coxsackieviruses, echoviruses, newer many of these newly recovered agents to human disease were enteroviruses, and polioviruses) and parechoviruses are unknown, they were called orphan viruses." Later, several responsible for significant and frequent human illnesses, agents were grouped together and called enteric cytopathowith protean clinical manifestation^.'-'^ Enteroviruses and parechoviruses are two genera of the Pi~ornaviridae.'~-'~ genic human orphan viruses, or echoviruses.Some ~tudies'~.'~ of the viral genome of echoviruses 22 and 23 found that they Enteroviruses were first categorized together and named in were distinctly different from other enteroviruses, and they 1957 by a committee sponsored by the National Foundation have been placed in the new genus, parechovirus. for Infantile Paraly~is'~; the human alimentary tract was Live-attenuated oral poliovirus vaccines (OPV) became believed to be the natural habitat of these agents. Enteroavailable 40 years ago, and the most notable advance during viruses and parechoviruses are grouped together because of the past 20 years has been the dramatic reduction in worldsimilarities in physical, biochemical, and molecular properties, The Viruses

784

784


wide poliomyelitis because of immunization with OPV and efforts of the global immunization The last case of confirmed paralytic polio in the Western Hemisphere occurred in 1991*! Aside from the polio immunization successes, there have been few major advances or new modes of treatment for enteroviral diseases. However, the use of nucleic acid detection systems for enteroviral diagnosis has progressed over the past 15 years, and rapid diagnosis of meningitis and other enteroviral illnesses has become p o ~ s i b l e . ~ ’There , ~ ~ - ~has been pro ress in the development of specific anti-enteroviral drugs.6 5 - 8

THE VIRUSES

Morphology and Classification The enteroviruses are single-stranded RNA viruses belonging to the Picornaviridae (from pico, meaning “small”). They are grouped together because they share certain physical, biochemical, and molecular properties.’ 1 ~ ’ 3 ~ 1 5 In electron micrographs, the virus is seen as a 30-nm particle consisting of a naked protein capsid that constitutes 70% to 75% of the mass; each particle has a dense central core (nucleoid) of RNA. Enterovirus capsids are composed of four structural proteins: VP1, VP2, VP3, and VP4. The capsid shell has icosahedral symmetry with 20 triangular faces and 12 vertices. The shell is formed by VP1, VP2, and VP3; VP4 lies on its inner surface. The three surface proteins (VP1, VP2, VP3) have no sequence homology, but they have the same top~logy.’~ They form an eight-stranded, antiparallel p barrel that is wedge shaped and composed of two antiparallel p sheets. The amino acid sequences in the loops that connect the p strands and the N- and C-terminal sequences that extend from the P-barrel domain ofVPl,VP2, and VP3 give each enterovirus its distinct antigenicity. The coat proteins protect the RNA genome from nucleases and are important determinants of host range and tropism. They determine antigenicity, and they deliver the RNA genome into the cytoplasm of new host cells. The genome of enteroviruses is a single-stranded, positivestrand RNA m~lecule.~’ It contains a 5’ noncoding region, which is followed by a single long open reading frame, a

Table 24-1

short 3’ noncoding region, and a poly(A) tail. The four capsid proteins (VP 1 through VP4) and seven nonstructural proteins (2A, 2B, 2C, 3A, 3B, 3C, and 3D) result from a cleaved, long polyprotein that was translated from genomic RNA. Viral components and complete virions are formed in the cytoplasm of infected cells. If the rate of virus assembly is rapid and many particles are formed in one area, crystallization may occur. The original classification of human enteroviruses is shown in Table 24- 1. The enteroviral subgroups were differentiated from each other by their different effects in tissue cultures and in animals. Although these differentiating factors are still useful, many strains have been isolated that do not conform to such rigid specificities. For example, several coxsackievirus A strains grow and have a cytopathic effect in monkey kidney tissue cultures, and some echovirus strains cause paralysis in mice. Since 1974, newly identified enteroviral types were assigned enterovirus type numbers instead of coxsackievirus or echovirus numbers. Prototype enteroviral strains Fermon, Toluca-1, J670/71, and BrCr were assigned enteroviral numbers 68 through 7 1, respectively. Sequencing studies of the VP1 protein of “untypeable” strains have identified at least six new enteroviral types.78 Definitive identification of enteroviral types is made by neutralization with type-specific antiserum. Because studies of the viral genomes of echoviruses 22 and 23 found that they were distinctly different from other enteroviruses, they were placed in the new genus, parechovirus; they are parechoviruses types 1 and 2.14-16The parechoviruses contain only three capsid polypeptides:VP1, VP2, and VPO, which is the uncleaved precursor to VP2 plus VP4. Complete or partial genetic sequence data are available from all enteroviruse~.~~-~’ In general, sequence comparisons partially support the classic subgrouping of enteroviruses as provided in Table 24- 1. However, in many instances, genetic relationships do not correlate with the original subdivisions.13,64.71,77 All prototype human enterovirus strains fall into one of five genomically identified cluster^.'^^^"^^^^^^^ Presented in Table 24-2 is the species designation by genetic analysis for the original enteroviral types. The cellular receptors and co-receptors for attachment in the replication cycle for selected enteroviruses and parechoviruses are presented in Table 24-3. After attachment, the replication cycle takes 5 to 10 hours and occurs in the cytoplasm.

Human Enteroviruses: Animal and Tissue Culture Spectrum Cytopathic Effect

Virus’ Polioviruses Coxsackieviruses A Coxsackieviruses B Echoviruses

Illness and Pathology

Antigenic Typesb

Monkey Kidney Culture

Human Tirsue Culture

1-3 1-24‘ 1-6 1-34d

+

+

+ +

f

+

Suckling Mouse

+ +

Monkey

+

aMany enteroviral strains have been isolated that do not conform to these categories. bNew types, beginning with type 68, were assigned enterovirus type numbers instead of cowackievirus or echovirus numbers. Types 68 through 71 were identified. Type 23 was found to be the same as echovirus 9. dEchovirus 10 was reclassified as a reovirus; echovirus 26 was reclassified as a rhinovirus; echoviruses 22 and 23 have been reclassified as parechoviruses.

Chapter 24

Characteristics and Host Systems Enteroviruses are relatively stable viruses in that they retain activity for several days at room temperature and can be stored indefinitely at ordinary freezer temperatures (-200 (-).I 1,13,35,69,70 They are rapidly inactivated by heat (>56' C), formaldehyde, chlorination, and ultraviolet light but are resistant to 70% alcohol, 5% Lysol, quaternary ammonium compounds, ether, deoxycholate, and detergents that are effective against lipid-containing viruses. Enteroviral strains grow rapidly when adapted to susceptible host systems and cause cytopathology in 3 to 7 days. The typical tissue culture cytopathic effect is shown in Figure 24-1; characteristic pathologic findings in mice are shown in Figures 24-2 and 24-3. Final titers of virus recovered in the laboratory vary markedly among different viral strains and the host systems employed; usually, concentrations of lo3to lo7infectious doses per 0.1 mL of tissue culture fluid or tissue homogenate are obtained. Unadapted viral strains frequently require long periods of incubation in tissue cultures or suckling mice before visible evidence of growth is observed.

Table 24-2

Genomic Classification of Enteroviruses

Species Designation

Original Enteroviral Type

Poliovirus types 1, 2, 3 Enterovirus type 71, Coxsackievirus A types 2-8, 10, 12, 14, 16 Human enterovirus B (HEV-B) Coxsackievirus type A9 Coxsackievirus types 81-6 Echovirus types 1-9, 11-21, 24-27, 29-33 Enterovirus type 69 Human enterovirus C (HEV-C) Coxsackievirus A types 1, 11, 13, 15, 17-22, 24 Human enterovirus D (HEV-D) Enterovirus types 68, 70 Poliovirus (PV) Human enterovirus A (HEV A)

Data from lshiko H, Shimada Y, Yonaha M, et al. Molecular diagnosis of human enteroviruses by phylogeny-basedclassification by use of the VP4 sequence. J Infect Dis 185:744-754, 2002, and from Pallansch MA, Roos RP. Enteroviruses: polioviruses, coxsackieviruses, and newer enteroviruses.In Knipe DM, Howley PM (eds). Fields Virology, vol. 1. Philadelphia, Lippincott Williams & Wilkins, 2001, pp 723-775.

Table 24-3

Enterovirus and Parechovirus Infections

785

Blind passage is occasionally necessary for cytopathic effects to become apparent. Although many different primary and secondary tissue culture systems support the growth of various enteroviruses, it is generally accepted that primary rhesus monkey kidney cultures have the most inclusive spectrum. Other simian kidney tissue cultures, although less commonly used, also have the same broad spe~trum.'~ Tissue cultures of human origin have a more limited spectrum, but several echovirus types have had more consistent primary isolation in human embryonic lung fibroblastic cell strains than in monkey kidney cultures.8°-82 Most coxsackievirus A types do not grow and produce a cytopathic effect in simian kidney tissue cultures. However, most coxsackievirus A types (except Al, A19, and A22) replicate in the RD cell line derived from a human rhabdomyosar~oma.8~ A satisfactory system for the primary recovery of enteroviruses from clinical specimens would include primary rhesus, cynomolgus, or African green monkey kidney tissue cultures; a diploid, human embryonic lung fibroblast cell strain; the RD cell line; and the intraperitoneal and intracerebral inoculation of suckling mice younger than 24 hours old. Optimally, blind passage should be carried out in the tissue culture systems.

Antigenic Characteristics Although some minor cross-reactions exist between several coxsackievirus and echovirus types, common group antigens of diagnostic importance are not well d e f i ~ ~ e d . " He . ' ~at~ ~ ~ ~ ~ ~ treatment of virions and the use of synthetic peptides have produced antigens with broad enteroviral reactivity.84385 These antigens have been used in enzyme-linked immunosorbent assay (ELISA) and complement fixation tests to determine IgG and IgM enteroviral antibodies and for antigen detection. In one study, Terletskaia-Ladwig and colleagues8' identified patients infected with enteroviruses with the use of an IgM enzyme immunoassay (EIA). This test employed heat-treated coxsackievirus B5 and echovirus 9 as antigens, and it identified patients infected with echoviruses 4,11, and 30. The sensitivity of the test was 35%. In another study using heat-treated virus or synthetic peptides, the respective sensitivitieswere 67% and 62%.84However, both tests lacked specificity. Intratypic strain differences are common occurrences, and some strains (i.e., prime strains) are neutralized

Cell Receptors and Co-receptors for Selected Enteroviruses and Parechoviruses

Virus Type

Receptor

Polioviruses 1-3 Coxsackievirus A13, A18 Coxsackievirus A21 Coxsackievirus A9 Coxsackievirus B 1-6

Poliovirus receptor (PVR, CD155) lntercellular adhesion molecule-1 (ICAM-1) Decay-accelerating factor (CD55) a& (vitronectin receptor) Coxsackievirus-adenovirusreceptor (CAR) or decay-accelerating factor (CD55) a$, integrin (Vla-2) Decay-accelerating factor (CD55) Decay-accelerating factor (CD55) a$,, (vitronectin receptor)

Echoviruses 1, 8 Echoviruses 3, 6, 7, 11-13, 20, 21, 29, 33 Enteroviruses 70 Parechovirus 1

Co-receptor

ICAM-1

sPSintegrin P,-microglobulin P,-microglobulin

Data from Racaniello VR. Picornaviridae:the viruses and their replication. In Knipe DM, Howeley PM (eds). Fields Virology, vol. 1. Philadelphia, Lippincott Williams & Wilkins, 2001, pp 685-722.

786

Section I11 Vkal Infections

A

Figure 24-1 Fetal rhesus monkey kidney tissue culture (HL-8). A, Uninoculated tissue culture. B, Echovirus 11 cytopathic effect.

A

B

Figure 24-2 Suckling mouse myocardium. A, Normal suckling mouse myocardium. B, Myocardium of suckling mouse infected with coxsackievirus E l .

poorly by antiserums to prototype viruses. In animals, however, these prime strains induce antibodies that neutralize the specific prototype viruses. Identification of polioviral, coxsackieviral, and echoviral types by neutralization in suckling mice or tissue cultures with antiserum pools is relatively well defined. Neutralization is induced by the epitopes on structural proteins VP1, VP2, and VP3; in particular, several epitopes are clustered on VP1. Prime strains do cause diagnostic difficulties because frequently they are not neutralized by the reference antiserums, which is a particular problem with echoviruses 4,9,

and 11 and with enterovirus 71. If these types or other possible prime strains are suspected, this problem sometimes can be overcome by employing antiserums in less-diluted concentrations or using antiserums prepared against several different strains of problem viruses. Kubo and associates” were able to type enteroviral isolates not identified by neutralization by nucleotide sequence analysis of the VP4 gene. They specifically identified prime strains of echovirus 18 and enterovirus 71. Sequence analysis of the VP1 gene also is useful for typing enteroviral prime strains not identified by neutralization.86

Chapter 24 A


787

B

Figure 24-3 Suckling mouse skeletal muscle. 4 Normal suckling mouse skeletal muscle. B, Skeletal muscle of a suckling mouse infected with coxsackievirus A1 6.

EPIDEMIOLOGY AND TRANSMISSION

General Considerations

the placenta and the fetus after a spontaneous abortion in a 24-year-old woman with poliomyelitis. Although attenuated poliovirus vaccines have been given to pregnant women, there has never been a search for the transplacental passage of vaccine v i r ~ s . ~ ' ' Viremia ~"~ occurs after oral administration of polio vaccine, and occasionally, this virus probably is passed transplacentally to the f e t u ~ . l ~ ' - ' ~ ~

Enteroviruses are spread from person to person by fecal-oral and possibly by oral-oral (respiratory) routes. 1-11,87 Swimming and wading pools may serve as a means of spread of enteroviruses during the summer.88Oral-oral transmission by way Coxsackieviruses of the contaminated hands of health care personnel and transmission by fomites have been documented on a longSeveral investigators have studied coxsackievirus infections in pregnant animals and the transplacental passage of virus term care pediatric ward.89Enteroviruses have been recovered from trapped flies, and this carriage probably contributes to to the fetus. Dalldorf and Gifford'" studied two strains of coxsackievirus B1 and one of coxsackievirus A8 in gravid the spread of human infections, particularly in lower socioeconomic populations that have poor sanitary f a c i l i t i e ~ ? ~ - ~ mice. ~ In only one instance (coxsackievirus B1) were they able to recover virus from a fetus. They thought that this result Children are the main susceptible cohort; they are was inconclusive because they were unable to recover virus immunologically susceptible, and their unhygienic habits in five other instances. Berger and Roulet12' observed muscle facilitate spread. Spread is from child to child (by feces to lesions in the young of gravid mice infected with coxsackieskin to mouth) and then within family groups. Recovery studied several viruses in gravid viruses A1 and B1. Sel~er'~' of enteroviruses is inversely related to age; the prevalence of mice; coxsackievirus A9 was found in the placentas of two specific antibodies is directly related to age. The incidence of mice but in no fetuses, and coxsackievirus A18 was not infections and the prevalence of antibodies do not differ recovered from fetuses or placentas. Selzer13' found that between boys and girls. coxsackieviruses B3 and B4 passed the placental barrier. S ~ i k e also ' ~ ~observed that in the last week of pregnancy, coxsackievirusB3 reached fetal mice transplacentally. Modlin Transplacental Transmission and Cr~rnpacker'~' reported that infection in late gestational Polioviruses mice was more severe than that occurring in early pregnancy and that transplacental infection of the fetus occurred Poliovirus infections in pregnancy can result in abortion, transiently during the maternal infection. Flamm'33observed stillbirth, neonatal disease, or no evidence of fetal involvethat coxsackievirusA9, when injected intravenously in rabbits, ment.93Gresser and associates94have shown that the human reached the blastocyst early in pregnancy and the amniotic amniotic membrane in organ culture can be infected, resulting fluid later in pregnancy. He also demonstrated congenital in a persistent low-grade infection. It has been observed on infection in mice with coxsackievirus A1.'34 many occasions that maternal poliomyelitis occurring late in Palmer and c o - ~ o r k e r s studied '~~ the gestational outcome pregnancy has resulted in transplacental transmission of the in pregnant mice inoculated intravenously with Theiler's virus to the fetus in ~ t e r o . ~ ~The - " ~evidence that transmurine encephalomyelitis virus, a murine enterovirus. In placental passage of virus occurs in early pregnancy is meager. early gestational infections they found a high rate of placental Schaeffer and colleagues9*were able to recover virus from

788

Section I11

Viral Infections

and fetal abnormalities. The rates of fetal abnormalities and placental infection were greater than the rate of fetal viral infection, suggesting that the adverse effects of the viral infections were direct and indirect. Gestational infection could result in virus passage to the fetus and fetal damage or in placental compromise with indirect fetal damage. In another study using the same murine model with Theiler's murine encephalomyelitisvirus, A b ~ u gfound ' ~ ~ that maternal factors (i.e., compromised uteroplacental blood flow, concomitant infection, and advanced age) increased the risk of transplacental fetal infection. In humans, the transplacental passage of coxsackieviruses at term has been documented on several occasions. Benir~chke'~~ studied the placentas in three cases of congenital coxsackievirus B disease and could find no histologic evidence of infection. In 1956, Kibrick and Benir~chke'~' reported the first case of intrauterine infection with coxsackievirus B3. In this instance, the infant was delivered by cesarean section and had clinical evidence of infection several hours after birth. Brightman and colleague^'^^ recovered coxsackievirus B5 from the placenta and rectum of a premature infant. No histologic abnormalities of the placenta were identified. Other evidence of intrauterine infection has been presented for coxsackieviruses A4 and B2 through B6.'40-148 Evidence for intrauterine infection during the first and second trimesters of pregnancy with coxsackieviruses is less clear. Burch and c o - ~ o r k e r s reported '~~ the results of immunofluorescent studies of two fetuses of 5 months' gestation and one fetus of 6 months' gestation; the 6-monthold fetus had evidence of coxsackievirus B4 myocarditis, one 5-month-old fetus showed signs of coxsackievirus B3 infection, and the other 5-month-old fetus showed evidence of coxsackievirus B2, B3, and B4 infections. Basso and associa t e ~ recovered '~~ coxsackievirus B2 from the placenta, liver, and brain of a fetus after a spontaneous abortion at 3 months' gestation. Plager and co-workers found no evidence of intrauterine viral transmission of coxsackievirus B5 infections during the first and second trimesters of ~regnancy.'~' Euscher and associates"' detected coxsackievirus RNA in placental tissue from six of seven newborn infants with respiratory difficulties and other manifestations at birth. Of these infants, one died shortly after birth, and the other six suffered neurodevelopmental delays. The placentas of 10 normal infants were examined for coxsackievirus RNA, and results of these studies were negative. Three of the placentas from the affected infants showed focal chronic villitis, two showed focal hemorrhagic endovasculitis, and one showed focal calcifications. In addition to respiratory distress, two neonates had rashes, two had seizures, two had thrombocytopenia, and one had intraventricular hemorrhage. Echoviruses, Enteroviruses, and Parechoviruses Less is known about transplacental passage of echoviruses than about that of coxsackieviruses and polioviruses. Echovirus infections are regular occurrences in all populations. Women in all stages of pregnancy are frequently infected, and viremia is commonly seen in these infection^.'^' In particular, epidemic disease related to echovirus 9 has been studied epidemiologically and serologically.153-155 In these studies, a search for teratogenesis has been made, but no definitive virologic investigations have been carried out; asymptomatic transplacental infection might have occurred.

Cherry and colleague^'^' cultured samples from 590 newborns during a period of enteroviral prevalence without isolating an echovirus. Antepartum serologic study of a group of 55 mothers in this study showed that 5 (9%) were actively infected with echovirus 17 during the 6-week period before delivery. In two other large nursery studies, there was no suggestion of intrauterine echovirus infection~.'~~"'~ Berkovich and Smithwick"' described a newborn without clinical illness who had specific IgM parechovirus 1antibody in the cord blood, suggesting intrauterine infection with this virus. Hughes and colleag~es''~reported a newborn with echovirus 14 infection who had a markedly elevated level of IgM (190 mg/dL) on the sixth day of life. It seems likely that this infant was also infected in utero. Echoviruses 6,7,9, 11, 19,27, and 33 have been identified in cases of transplacentally acquired infection^.'^^"^^-'^* Chow and associate^'^^ described a 1300-g fetus, which was stillborn after 26 weeks' gestation, with unilateral hydrocephalus, hepatosplenomegaly, fibrotic peritonitis, and meconium staining. Enterovirus 71 was isolated from the amniotic fluid, and the same virus was identified by polymerase chain reaction (PCR) in the cord blood and by immunohistochemical staining in the fetal midbrain and liver. Otonkoski and coworkers'70reported the occurrence of neonatal type 1 diabetes after a possible maternal echovirus 6 infection.

Ascending Infection and Contact Infection during Birth Definitive evidence is lacking for ascending infection or contact infection with enteroviruses during birth. In prospective studies of genital herpes simplex and cytomegaloviral infections, there have been no enteroviral isolation^.'^'"^^ These results suggest that ascending infections with enteroviruses, if they occur at all, are rare. However, Reyes and a~sociates'~~ recovered coxsackievirus B5 from the cervix of four third-trimester pregnant women. Three of the four positive cultures were obtained 3 weeks or more before delivery. In the fourth case, the cervical culture was obtained the day before delivery,and the child was delivered by cesarean section. All of the infants were healthy, but unfortunately, culture for virus was possible only from the infant delivered by cesarean section; the result was negative. In an earlier study, Reyes and colleagueslMreported a child who died of a disseminated echovirus 11 infection. The illness had its onset on the third day of life, and the virus was recovered from the mother's cervix at that time. Enteroviral infection during the birth process seems probable. The fecal carriage rate of enteroviruses in asymptomatic adult patients varies between 0% and 6% or higher in different population group^.'^^-'^^ Cherry and associate^'^' found that in 2 (4%) of 55 mothers, enteroviruses were present in the feces shortly after delivery. K a t ~ , in ' ~a~discussion of a child with neonatal coxsackievirus B4 infection, suggested that the infant might have inhaled maternally excreted organisms during birth. The fact that this child had pneumonia tends to support the contention. Infections occurring 2 to 7 days after birth could have been acquired during passage through the birth canal.

Chapter 24

Neonatal Infection Neonatal infections and illnesses from enteroviruses are relatively common.178 Transmission of enteroviruses to newborns is similar to that for populations of older people. The main factor in the spread of virus is human-to-human contact. During the summer and fall of 1981 in Rochester, New York, 666 neonates were cultured for enteroviruses within 24 hours of birth and then weekly for 1 month.la The incidence of acquisition of nonpolio enteroviral infections during this period was 12.8%.Two risk factors were identified: lower socioeconomic status and lack of breast-feeding. Polioviruses Clinical poliomyelitis is rare in neonates, but the infection rate before the vaccine era was never determined. It is probable that the rarity of neonatal poliomyelitis was not related to lack of viral transmission but reflected the protection from disease offered by specific, transplacentally transmitted polioviral antibodies. From experience gained in vaccine studies, it is apparent that infants with passively acquired antibody can be regularly infe~ted.’~~-’~l In 1955, Bates”’ reviewed the literature on poliomyelitis in infants younger than 1 month. He described six infants who apparently were not infected by their mothers and who had had other likely contacts. A neighbor was the contact in one case, siblings in two cases, nursery nurses in two cases, and an uncle in the sixth case. In most other infants, the mother had had poliomyelitisshortly before the child was born and probably was the contact. The mode of transmissionintrauterine, during birth, or postnatal contact-is unknown. Bergeisen and colleague^'^' reported a case of paralytic poliomyelitis from a type 3 vaccine viral strain. They suggested that the source of this virus might have been the child of the neonate’s baby sitter, who was vaccinated about 2 weeks before the onset of the illness. Coxsackieviruses Several epidemics with coxsackieviruses B in newborn nurseries have been studied. Brightman and ~o-workers’~~ observed an epidemic of coxsackievirus B5 in a premature nursery. Their data suggested that the virus was introduced into this nursery by an infant with a clinically inapparent infection who had been infected in utero. Secondaryinfections occurred in 12 infants and two nurses. The timing of the secondary cases suggested that three generations of infection had occurred and that the nurses had been infected during the second generation. The investigators suggested that the infection had spread from infint to infant and from infant to nurse. Javett and colleagues’93documented an acute epidemic of myocarditis associated with coxsackievirus B3 infection in a Johannesburg maternity home. Unfortunately, no epidemiologic investigation or search for asymptomatic infected infants was performed. However, analysis of the onset dates of the illnesses indicated that single infections occurred for five generations and then five children became ill within a 3-day period. Kipps and colleague^'^^ carried out epidemiologic investigations in two coxsackievirus B3 nursery epidemics. In the first epidemic, the initial infection was probably transmitted from a mother to her child; this infant was then the source


789

of five secondary cases in newborns and one illness in a nurse. Infants with four of the five secondary cases were located on one side of the nursery, but only one cot was close to the cot of the index patient, and this cot did not adjoin the cots of the three other infants with contact cases. In the second outbreak, an infant who also was infected by his mother probably introduced the virus into the nursery. Infants with the three secondary cases were geographically far removed from the one with the primary case of infection. There have been many other instances of isolated nursery infections and small outbreaks with coxsackieviruses,and it seems that the most consistent source of original nursery infection is transmission from a mother to her ~ h i l d , ’ ~ ~ - ~ ~ ~ but introduction of virus into the nursery by personnel also O C C U ~ S . ~ ~ ~ , ~ ~ ~

Echoviruses and Parechoviruses Although many outbreaks of echovirus infections have been observed in newborn nurseries, information on viral transmission is i n c ~ m p l e t e . ~ ’ .Cramblett ~ ~ ~ - ~ ~ ~and c o - w o r k e r ~ ~ ~ ~ reported an outbreak of echovirus 11 disease in four infants in an intensive care nursery. All infants were in enclosed incubators, and three patients became ill within 24 hours; the fourth child became ill 4 days later. Echovirus 11 was recovered from two members of the nursery staff. These data suggest that transmission from personnel to infants occurred because of inadequate hand washing. In another outbreak in an intensive care unit, the initial patient was transferred to the nursery because of severe echovirus 11 disease.250After transfer, infection occurred in the senior house officer and a psychologist in the unit. It was inferred by the investigators that spread by respiratory droplets to nine other infants occurred from these infected personnel. In a maternity unit outbreak of echovirus 11 involving six secondary cases?57 infection spread through close contact between the infected newborns and the nurses. In another reported nosocomial echovirus 11 outbreak, infants in an intermediate care unit for more than 2 days were more likely to become infected than those who were there for less than 2 days. Illness was also associated with gavage feeding, mouth care, and being a twin.z58 Modlin260reviewed reports of 16 nursery outbreaks involving206 ill infants. In only 4 of the 16 outbreaks was the source identified, and in all 4, the primary case was an infant who acquired infection vertically from its mother. After introduction of an infected newborn into a nursery, spread to other infants by personnel is common.z6z~z65 Risk factors for nursery transmission as described by Rabkin and coworkers26zwere “lower gestational age or birth weight; antibiotic or transfusion therapy; nasogastric intubation or feeding; proximity in the nursery to the index patient; and care by the same nurse during the same shift as the index patient.” Wilson and associatesza reported an intensive care nursery epidemic in which respiratory syncytial virus and echovirus 7 infections occurred concurrently. This epidemic persisted from January to June 1984 despite an aggressive isolation cohorting program. A major factor in persistence was asymptomatic infections with both viruses. Sat0 and associates266reported a point-source outbreak of echovirus 33 infection in nine newborns related to one nursery over a 10-day period. The primary case was born to

790


Epidemics of poliomyelitis first began to appear in a mother who was febrile and who had a high echovirus 33 Europe and the United States during the latter part of the neutralizing antibody titer in a convalescent-phase serum 19th century; they continued with increasing frequency in specimen. the economically advanced countries until the introduction Jack and colleagues236observed the endemic occurrence of effective vaccines in the 1950s and 1960s.33,34,288,289 The of asymptomatic infection with parechovirus 1 in a nursery evolution from endemic to epidemic follows a characteristic during an 8-month period. A total of 44 infants were infected pattern, beginning with collections of a few cases, then during this time, and nursery infection occurred when there endemic rates that are higher than usual, followed by severe was no known activity of parechovirus 1 in the community epidemics with high attack rates. at large. The investigators believed that the endemic viral The age group attacked in endemic areas and in early infection was spread by fecal contamination of hands of epidemics is the youngest one; more than 90% of paralytic nursery personnel. Nakao and colleagues246and Berkovich and P a r ~ g a n ~ ~cases ~ begin in children younger than 5 years. After a pattern of epidemicity begins, it is irreversible unless preventive also documented parechovirus 1 infections in nurseries. Like vaccination is carried out. Because epidemics recur over a Jack and colleagues?36 they observed that the infections period of years, there is a shift in age incidence such that seemed to be endemic to the nurseries rather than related to relatively fewer cases are in the youngest children; the peak community epidemics. often occurs in the 5- to 14-year-old group, and an increasing proportion is in young adults. These changes are correlated Host Range with socioeconomic factors and improved standards of hygiene; when children are protected from immunizing inIt is the general opinion that humans are the only natural hosts of entero~iruses.8~ However, enteroviruses have been fections in the first few years of life, the pool of susceptible recovered in nature from sewage?' f l i e ~ , ~swine,267,268 .~~ persons builds up, and introduction of a virulent strain often d o g ~ , a~ calf?71 ~ ~ s a~ budgerigar ~ ~ (i.e., small Australian is followed by an epidemic.290Extensive use of vaccines in mussels,274and oysters.275Serologic parakeet)?72 a the past 4 decades has resulted in elimination of paralytic poliomyelitis from large geographic areas, but the disease evidence of infection with enteroviruses similar to human remains endemic in various parts of the world. Although strains has been found in chimpanzees,276cattle:77 rabbits:78 seasonal periodicity is distinct in temperate climates, some a a and a marmot.251It is probable that viral activity does take place during the winter?" Infection infection of these animals was the result of their direct and acquisition of postinfection immunity occur with greater contact with an infected human or infected human excreta. Although enteroviruses do not multiply in flies, they appear intensity and at earlier ages among crowded, economically to be a possible significant vector in situations of poor deprived populations with less efficient sanitation facilities. sanitation and heavy human infection. The contamination Molecular techniques have allowed the study of enotypes of specific viral types in populations over time!92-295 For of shellfish is also intrig~in$74,275,279-~~~ because in addition example, Mulders and colleagues295studied the molecular to their possible role in human infection, they offer a source epidemiology of wild poliovirus type 1in Europe, the Middle of enteroviral storage during cold weather. Contaminated foods are another possible source of human infection.284 East, and the Indian subcontinent. They found four major genotypes circulating. Two genotypes were found predominantly in Eastern Europe, a third genotype was circulating Geographic Distribution and Season mainly in Egypt, and the fourth genotype was widely Enteroviruses have a worldwide distrib~tion.'~''~~~~~~~~'~~ dispersed. All four genotypes were found in Pakistan. Neutralizing antibodies for specific viral types have been The epidemiologic behavior of coxsackievirusesand echofound in serologic surveys throughout the world, and most viruses parallels that of polioviruses; unrecognized infections strains have been recovered in worldwide isolation studies. In far outnumber those with distinctive symptoms. The agents any one area, there are frequent fluctuations in predominant are disseminated widely throughout the world, and outbreaks types. Epidemics probably depend on new susceptible persons related to one or another type of virus occur regularly. These in the population rather than on reinfections; they may be outbreaks tend to be localized, with different agents being localized and sporadic and may vary in cause from place to prevalent in different years. In the late 1950s, however, place in the same year. Pandemic waves of infection also occur. echovirus 9 had a far wider circulation, sweeping through a Intemperate climates,enteroviral infections occur primarily large part of the world and infecting children and young in the summer and fall, but in the tropics, they are prevalent adults. This behavior has been repeated occasionally with A basic concept in understanding their all year.''*87~287 other enteroviruses; after a long absence, a particular agent epidemiology is the far greater frequency of unrecognized returns and circulates among the susceptible persons of difinfection than that of clinical disease. This is illustrated by ferent ages who have been born since the previous epidemic poliomyelitis, which remained an epidemiologic mystery occurred. Other agents remain endemic in a given area, until it was appreciated that unrecognized infections were the surfacing as sporadic cases and occasionally as small outmain source of contagion. Serologicsurveys were instrumental breaks. Multiple types are frequently active at the same time, in elucidating the problem. In populations living in conalthough one agent commonly predominates in a given locality. ditions of poor sanitation and hygiene, epidemics do not There are no available data on the incidence of symptooccur; but wide dissemination of polioviruses has been confirmed by demonstrating the presence of specific antimatic congenital and neonatal enteroviral infections. From bodies to all three types in nearly 100% of children by the the frequency of reports in the literature, it appears that severe neonatal disease caused by enteroviruses decreased age of 5 years.

Chapter 24

Table 24-4


791

Predominant Types of Nonpolio Enteroviral Isolations in the United States, 1961-1999 Five Most Common Viral v p e s per Year"

Year

First

Second

Third

Fourth

Fifth

1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999

Coxsackievirus B5 Coxsackievirus B3 Coxsackievirus B1 Coxsackievirus B4 Echovirus 9 Echovirus 9 Coxsackievirus B5 Echovirus 9 Echovirus 30 Echovirus 3 Echovirus 4 Coxsackievirus B5 Coxsackievirus A9 Echovirus 11 Echovirus 9 Coxsackievirus B2 Echovirus 6 Echovirus 9 Echovirus 11 Echovirus 11 Echovirus 30 Echovirus 11 Coxsackievirus B5 Echovirus 9 Echovirus 11 Echovirus 11 Echovirus 6 Echovirus 11 Coxsackievirus 85 Echovirus 30 Echovirus 30 Echovirus 11 Echovirus 30 Coxsackievirus B2 Echovirus 9 Coxsackievirus B5 Echovirus 30 Echovirus 30 Echovirus 11

Coxsackievirus B2 Echovirus 9 Coxsackievirus A9 Coxsackievirus B2 Echovirus 6 Coxsackievirus B2 Echovirus 9 Echovirus 30 Echovirus 9 Echovirus 9 Echovirus 9 Echovirus 4 Echovirus 9 Echovirus 4 Echovirus 4 Echovirus 4 Coxsackievirus B1 Echovirus 4 Echovirus 7 Coxsackievirus 83 Echovirus 9 Echovirus 30 Echovirus 30 Echovirus 11 Echovirus 21 Echovirus 4 Echovirus 18 Echovirus 9 Echovirus 9 Echovirus 6 Echovirus 11 Echovirus 30 Coxsackievirus 85 Coxsackievirus B3 Echovirus 11 Echovirus 17 Echovirus 6 Echovirus 9 Echovirus 16

Coxsackievirus 84 Coxsackievirus B2 Echovirus 9 Coxsackievirus A9 Coxsackievirus B2 Echovirus 6 Coxsackievirus A9 Coxsackievirus A16 Echovirus 18 Echovirus 6 Echovirus 6 Echovirus 6 Echovirus 6 Echovirus 6 Echovirus 6 Coxsackievirus 84 Coxsackievirus B3 Coxsackievirus A9 Echovirus 30 Echovirus 30 Echovirus 11 Echovirus 5 Echovirus 20 Coxsackievirus B5 Echovirus 6, 7b Echovirus 7 Echovirus 11 Coxsackievirus B4 Echovirus 11 Coxsackievirus B2 Coxsackievirus B1 Echovirus 9 Coxsackievirus A9 Echovirus E6 Coxsackievirus A9 Echovirus 6 Echovirus 7 Echovirus 11 Echovirus 9

Echovirus 11 Echovirus 4 Echovirus 4 Echovirus 4 Coxsackievirus 85 Coxsackievirus 85 Echovirus 6 Coxsackievirus 83 Echovirus 6 Echovirus 4 Coxsackievirus B4 Echovirus 9 Coxsackievirus B2 Echovirus 9 Coxsackievirus A9 Cowackievirus A9 Echovirus 9 Echovirus 30 Coxsackievirus B2 Coxsackievirus B2 Echovirus 3 Echovirus 9 Echovirus 11 Echovirus 30

Echovirus 9 Coxsackievirus 85 Coxsackievirus B4 Echovirus 6, Coxsackievirus B1 Coxsackievirus B4 Coxsackievirus A9, A16 Coxsackievirus B2 Coxsackievirus 84 Coxsackievirus 84 Coxsackievirus 84 Coxsackievirus B2 Coxsackievirus 83 Coxsackievirus 85, echovirus 5 Echovirus 18 Coxsackievirus 84 Coxsackievirus B3, echovirus 6 Coxsackievirus A9 Coxsackievirus B4 Coxsackievirus 84 Coxsackievirus A9 Coxsackievirus A9, echovirus 5 Coxsackievirus B 5 Echovirus 24 Coxsackievirus B2, A9 Coxsackievirus B2 Coxsackievirus 85 Coxsackievirus B2 Echovirus 6 Echovirus 6 Echovirus 11 Echovirus 7 Coxsackievirus A9 Echovirus 7 Coxsackievirus A9 Echovirus 30 Coxsackievirus 84 Echovirus 18 Echovirus 6 Echovirus 25

Echovirus 18 Coxsackievirus A9 Coxsackievirus B2 Coxsackievirus B2 Coxsackievirus A9 Coxsackievirus B2 Coxsackievirus B1 Coxsackievirus B1 Echovirus 30 Coxsackievirus B2 Coxsackievirus A9 Echovirus 11 Coxsackievirus 83 Echovirus 14

aMost patients from whom viruses were isolated had neurologic illnesses. bThird and fourth place tie. Data from Cherty JD. Enteroviruses and parechoviruses. In Feigin RD, Cherry JD, Demmler GJ, Kaplan SL (eds). Textbook of Pediatric Infectious Diseases, 5th ed. Philadelphia, WB Saunders, 2004, p 1989.

slightly during the late 1960s and early 1970s and then became more common again. Shown in Table 24-4 are the five most prevalent nonpolio enterovirus isolations per year in the United States from 1961 through 1999. Most patients from whom viruses were isolated had neurologic illnesses. It is possible that other enteroviruses were also prevalent but did not produce clinical disease severe enough to cause physicians to submit specimens for study. Many coxsackievirus A infections, even in the epidemic situation, probably went undiagnosed because suckling mouse inoculation was not performed. Although 62 nonpolio enteroviral types and 2 parechovirus types have been identified, in the 39 years covered in Table 24-4, only 24 different virus types have been reported. In the earlier years, echovirus 9 was the most common type; echoviruses 6 and 1 1 and coxsackievirusesB2 and B4 were the next most common types. Since 1990, echoviruses 30 and 11 have been the most common circulating

viral types. In 1999, three of the five most common viral types (echoviruses 14, 16, and 25) were new to the list. Similar data are available for the most common enteroviral isolates in Spain from 1988 to 1997 and Belgium from 1980 to 1994?96*297 The most common enterovirus isolated in both countries was echovirus 30. In 1997 and 1998, major epidemic disease caused by enterovirus 71 occurred in Taiwan, Malaysia, Australia, and Japan?98-302 An analysis of the Centers for Disease Control and Prevention nonpolio enterovirus data for 14 years found that early isolates in a particular year were predictive of isolates for the remainder of that year.303The six most common isolates during March, April, and May were predictive of 59% of the total isolates during July through December of the same year. Although the use of live polioviral vaccine has eliminated epidemic poliomyelitis in the United States, it is hard to

792

Section I11

Viral Infections

Infection during birth or

Portal of entry

-during neonatal period

-Oral (possible congenital infection secondary to virus containing amniotic fluid)

and /or respiratory

I

Pharynx and lower alimentary tract

I

Direct spread to

Tonsils, deep cervical nodes, Peyer's patches and mesenteric lymph nodes

Central newous

Heart

Liver.

ResDiratorv

Skin and

Central nervous system Antibody appears, viremia ceases, viral content in secondary infection sites diminishes

Figure 24-4

The pathogenesis of congenital and neonatal

enteroviral infections.

2 weeks earlier, at 33 weeks' gestation, had coxsackievirus A9 determine what the effect of polio vaccine viruses has been meningitis. The woman was delivered of a macerated, stillon enteroviral ecology. In 1970, polioviruses accounted for born infant. At birth, virus was recovered from the placenta only 6% of the total enteroviral isolations from patients with neurologic i l l n e s ~ e sAlthough .~~ the figures are not directly but not from the stillborn infant. comparable, more than one third of the enteroviral It is assumed that infection in the fetus results from isolations in 1962 from similar patients were p o l i o v i r u ~ e s . ~ ~hematogenous ~ dissemination initiated in the involved placenta. It is also possible that some in utero infection results from However, Horstmann and associates306studied specimens the ingestion of virus contained in amniotic fluid; in this from sewage and asymptomatic children during the vaccine situation, primary fetal infection involves the pharynx and era and found that the number of yearly polioviral isolations lower alimentary tract. The portal of entry of infection during (presumably vaccine strains) was greater than the number of the birth process and the neonatal period is similar to that nonpolio enteroviruses. The prevalence of vaccine viruses for older children and adults. did not seem to affect the seasonal epidemiology of other Figure 24-4 shows a schematic diagram of the events of enteroviruses. pathogenesis. After initial acquisition of virus by the oral or respiratory route, implantation occurs in the pharynx and the lower alimentary tract. Within 1 day, the infection extends PATHOGENESIS to the regional lymph nodes. On about the third day, minor viremia occurs, resulting in involvement of many secondary Events during Pathogenesis infection sites. In congenital infections, infection is initiated Congenital infections with enteroviruses result from transduring the minor viremia phase. Multiplication of virus in placental passage of virus to fetus. The method of transport secondary sites coincides with the onset of clinical symptoms. from mother to fetus is poorly understood. Maternal viremia Illness can vary from minor to fatal infections. Major viremia occurs during the period of multiplication of virus in the during enteroviral infections is common, and because virus secondary infection sites; this period usually lasts from the has been recovered from the placenta on several occasions, it third to the seventh days of infection. In many echovirus and is probable that active infection of the placenta also occurs. Benir~chke'~~ found no histologic evidence of placental coxsackievirusinfections, central nervous system involvement disease in three cases of established transplacentally acquired apparently occurs at the same time as other secondary organ coxsackievirus B infections. Batcup and associates307found involvement. This occasionally appears to happen with polioviral infections; however, more commonly, the central diffuse perivillous fibrin deposition with villous necrosis and nervous system symptoms of poliomyelitis are delayed, inflammatory cell infiltration of the placenta in a woman who

Chapter 24 suggesting that seeding occurred later in association with the major viremia. Cessation of viremia correlates with the appearance of serum antibody. The viral concentration in secondary infection sites begins to diminish on about the seventh day. However, infection continues in the lower intestinal tract for prolonged periods.

Factors That Affect Pathogenesis The pathogenesis and pathology of enterovirus infections depend on the virulence, tropism, and inoculum concentration of virus, as well as on many specific host factors. Enteroviruses have marked differences in tropism and virulence. Although some generalizations can be made in regard to tropism, there are marked differences even among strains of specific viral types. Differences in virulence of specific enteroviral types may be the result of recombination among enteroviruses or point mutation^.^^^"^^ Enterovirus infections of the fetus and neonate are thought to be more severe than similar infections in older individuals. This is undoubtedly true for coxsackievirus B infections and probably also true for coxsackievirus A, echovirus, and poliovirus infections. Although the reasons for this increased severity are largely unknown, several aspects of neonatal immune mechanisms offer clues. The similarity of coxsackievirus B infections in suckling mice to those in human neonates has provided a useful animal model. Heineberg and co-workers3" compared coxsackievirus B 1 infections in 24-hour-old sudding mice with similar infections in older mice. They observed that adult mice produced interferon in all infected tissues, whereas in suckling mice, only small amounts of interferon were identified in the liver. They thought that the difference in outcome of coxsackievirus B1 infections in suckling and older mice could be explained by the inability of the cells of the immature animal to elaborate interferon. Others thought that the increased susceptibility of suckling mice to severe coxsackievirus infections was related to the transplacentally acquired, increased concentrations of adrenocortical hormone^.^^'^^'^ Kunin3I4suggested that the difference in age-specific susceptibility might be explained at the cellular level. He showed that a variety of tissues of newborn mice bound coxsackievirus B3, whereas tissues of adult mice were virtually inactive in this regard.314,315 It has been suggested that the progressive loss of receptor-containing cells or of receptor sites on persisting cells with increasing age might be the mechanism that accounts for infections of lesser severity in older animals. Teisner and Haahr316 suggested that the increased susceptibility of suckling mice to severe and fatal coxsackievirus infections might be from physiologic hypothermia and poikilothermia during the first week of life. In the past, it was assumed that specific pathology in various organs and tissues in enteroviral infections was caused by the direct cytopathic effect and tropism of a particular virus. However, a large number of studies using murine myocarditis model systems have suggested that host immune responses contribute to the pathology.'3~308,317-332 These studies suggest that T cell-mediated processes and virus-induced autoimmunity cause acute and chronic tissue damage. Other studies suggest that the primary viral cytopathic effect is


793

responsible for tissue damage and that various T cell responses are a response to the damage, not the cause.333From my review of various murine myocarditis model systems, it is apparent that the genetics of the hosts and of the viral strains determine the likelihood of autoimmune, cell-mediated cellular dmage~308,317-320.322-325,327.329,331 However, none of the model systems is appropriate for the evaluation of the pathogenesis of neonatal myocarditis. Although available studies suggest that enterovirus-induced myocarditis in older children and adults occasionally may have a delayed cellmediated component, the short incubation period and fulminant nature of neonatal disease, as well as the similar infection in suckling mice, suggest that autoimmune factors are not major in the pathogenesis of myocarditis in neonates. During the past 40 years, the clinical manifestationscaused by several enteroviral serotypes have changed. For example, echovirus 11infections initially were associated with exanthem and aseptic meningitis in children. They later were found to cause severe sepsis-like illnesses in neonates. These phenotypic changes in disease expression may be the result of recombination among e n t e r o v i r u ~ e s . ~ ' ~ ~ ~ ~ ~

PATHOLOGY

General Considerations Great variations in the clinical signs of congenital and neonatal enterovirus infections are paralleled by wide variations in pathology. Because pathologic material usually is available only from patients with fatal illnesses, the discussion in this section considers only the more severe enteroviral manifestations. It is worth emphasizing, however, that these fatal infections account for only a small portion of all congenital and neonatal enterovirus infections. The pathologic findings in infants with milder infections, such as nonspecific febrile illness, have not been described.

Polioviruses The pathologic findings in fatal neonatal poliomyelitis are similar to those seen in disease of older children and a~~ts~19,102,108.109,1 11 The major findings have involved the central nervous system, specifically the anterior horns of the spinal cord and the motor nuclei of the cranial nerves. Involvement is usually irregularly distributed and asymmetric. Microscopically, the anterior horn cells show neuronal destruction, gliosis, and perivascular small round cell infiltration. Myocarditis has also been observed,"' characterized by focal necrosis of muscle fibers and various degrees of cellular infiltration.

Coxsackieviruses A Records of neonatal illnesses associated with coxsackieviruses A are rare.335-337 Gold and c o - ~ o r k e r sin , ~a~study ~ of sudden unexpected death in infants, recovered coxsackievirus A4 from the brains of three children. Histologic abnormalities were not identified in the brains or spinal cords of these patients. Baker and Phillips337reported the death of twins in association with coxsackievirus A3 intrauterine infections; the first twin was stillborn, and the second twin died when 2 days old of viral pneumonia.

794

Section I11

Viral Infections

Figure 24-5 Coxsackievirus 84 myocarditis in a 9-day-old infant. Notice the myocardial necrosis and mononuclear cellular infiltration.

Figure 24-6 Coxsackievirus 84 encephalitis in a 9-day-old infant. Notice the focal infiltrate of mononuclear and glial cells.

Eisenhut and associates338described a full-term neonate with coxsackievirusA9 infection with meningitis, myocarditis, and disseminated intravascular coagulation who died on the seventh day of life.

Brain and Spinal Cord

Coxsackieviruses B Of the enteroviruses, coxsackieviruses B have been most frequently associated with severe and catastrophic neonatal disease. The most common findings in these cases have been myocarditis or meningoencephalitis, or both. Involvement of the adrenals, pancreas, liver, and lungs has occurred. Heart

Grossly, the heart is usually enlarged, with dilatation of the chambers and flabby musculature.~38~147”93”95’204 M‘icroscopically,the pericardium frequently contains some inflammatory cells; and thickening, edema, and focal infiltrations of inflammatory cells may be found in the endocardium. The myocardium (Fig. 24-5) is congested and contains infiltrations of inflammatorycells (i.e., lymphocytes, mononuclear cells, reticulum cells, histiocytes, plasma cells, and polymorphonuclear and eosinophil leukocytes). Involvement of the myocardium is often patchy and focal but occasionally is diffuse. The muscle shows loss of striation, edema, and eosinophilic degeneration. Muscle necrosis without extensive cellular infiltration is common.

The meninges are congested, edematous, and occasionally mildly infiltrated with inflammatory cells.138~’473177~195~201~204 Lesions in the brain and spinal cord are focal rather than diffuse but frequently involve many different areas. The lesions consist of areas of eosinophilic degeneration of cortical cells, clusters of mononuclear and glial cells (Fig. 24-6), and perivascular cuffing. Occasionally, areas of liquefaction necrosis unassociated with inflammation are seen. Other Organs

The lungs commonly have areas of mild focal pneumonitis with peribronchiolar mononuclear cellular infiltrations.138,177,195.201,340-342 Massive pulmonary hemorrhage has been observed. The liver is frequently engorged and occasionally contains isolated foci of liver cell necrosis and mononuclear cell infiltrations. A neonate with a coxsackievirus B 1 infection developed a sepsis-like illness on the fourth day of life with severe hepatitis and subsequently developed progressive liver calcification^.^^' In the pancreas, infiltration of mononuclear cells, lymphocytes, and plasma cells has been observed, and occasional focal degeneration of the islet cells occurs. Congestion has been observed in the adrenal glands, with mild to severe cortical necrosis and infiltration of inflammatory cells.

Chapter 24

Echoviruses In an earlier period, although frequently responsible for neonatal illnesses, echoviruses were rarely associated with fatal infections. During the past 30 years, however, there have been many reports of fatal illnesses in newborns from echovirus type 1 1 .30,'62,165,257,343-348 In virtually all cases, the major pathologic finding was massive hepatic necrosis; other findings included hemorrhagic necrosis of the adrenal glands, hemorrhage in other organs, myocardial necrosis, and acute tubular necrosis of the kidneys. Wang and coll e a g u e ~ ~studied ~' four neonates (three with echovirus 11 and one with echovirus 5 infections) with fulminant hepatic failure and observed two histopathologic patterns associated with minimal inflammation but extensive hemorrhagic necrosis. One pattern indicated ongoing endothelial injury with endotheliitis and fibrinoid necrosis. The second pattern, which was seen in the two neonates who initially survived, was that of veno-occlusive disease. Virus has not been identified in hepatocytes. Extensive myositis of the strap muscles of the neck occurred in one case.347Massive hepatic necrosis has also occurred in infections with echoviruses 3, 5, 6, 7, 9, 14, 19, 20, and 21.'59,'60,254*343,349-353 Wreghitt and associate^'^^ described a neonate with a fatal echovirus 7 infection. This infant was found to have massive disseminated intravascular coagulation, with bleeding in the adrenal glands, renal medulla, liver, and cerebellum. At autopsy, one infant with echovirus 6 infection was found to have cloudy and thickened leptomeninges, liver necrosis, adrenal and renal hemorrhage, and mild interstitial p n e ~ m o n i t i s .One ~ ~ ~infant with echovirus 9 infection had an enlarged and congested liver with marked central necrosis?50 and another with this virus had interstitial pneumonitis without liver involvement.'61 Three infants with echovirus 1 1 infections had renal and adrenal hemorrhage and smallvessel thrombi in the renal medulla and in the medulla and the inner cortex of the adrenal glands.250In these patients, the livers were normal. Two infants, one with echovirus 6 and the other with echovirus 31 infection, had only extensive pne~monias.'~~~~~~


Abortion Polioviruses Poliomyelitis is associated with an increased incidence of abortion. Horn93reported 43 abortions in 325 pregnancies complicated by maternal poliomyelitis. Abortion was directly related to the severity of the maternal illness, including the degree of fever during the acute phase of illness. However, abortion also was associated with mild, nonparalytic poliomyelitis. Schaeffer and colleagues9' studied the placenta and abortus 12 days after the onset of illness in a mother. Poliovirus type 1 was isolated from the placenta and the fetal tissues. Other investigator^^^^"^^ have reported an increased incidence of abortions in cases of maternal poliomyelitis. Siegel and Greenberg"' noticed that fetal death occurred in 14 (46.7%) of 30 instances of maternal poliomyelitis during the first trimester. Kaye and colleagues3@' reviewed the literature


795

in 1953 and found 19 abortions in 101 cases of poliomyelitis in pregnancy. In a small study in Evanston Hospital in Illinois, the abortion rate associated with maternal poliomyelitis was little different from the expected rate.357In a study of 310 pregnant women who received trivalent oral poliovirus vaccine, there was no increase in abortions above the expected rate.'I8 In a later study in Finland that involved about 9000 pregnant women immunized with oral poliovirus vaccine, there was no evidence of an increase in stillbirths.361 Coxsackieviruses Although in the late 1950s and early 1960s there were extensive outbreaks of illness caused by coxsackievirusA16, there was no evidence of adverse outcomes of pregnancy related to this virus. Because infections with other coxsackieviruses rarely involve large segments of the population, rate studies have not been performed. Frisk and D i d e r h ~ l m ~found ~ ' that 33% of women with abortions had IgM antibody to coxsackieviruses B, whereas only 8% of controls had similar antibody. In a second, larger study, the same research group confirmed their original findings.363 Echoviruses There is no available evidence suggesting that echovirus infections during pregnancy are a cause of spontaneous abortion. Landsman and associates'55studied 263 1 pregnancies during an epidemic of echovirus 9 and could find no difference in antibody to echovirus 9 between mothers who aborted and those who delivered term infants. A similar study in Finland revealed no increase in the abortion rate among mothers infected in early pregnancy with echovirus 9.153

Congenital Malformations Polioviruses The congenital malformation rate associated with poliovirus infection as determined in the NIH-sponsored Collaborative Perinatal Research Project of 45,000 pregnancies was 4.1%.364 Although isolated instances of congenital malformation and maternal poliomyelitis have been reported, there is little statistical evidence demonstrating that polioviruses are teratogens. In their review of the literature, Kaye and coll e a g u e ~identilied ~ ~ ~ six anomalies in 101 infants born to mothers with poliomyelitis during pregnancy. In the reviews of Bates,110and Siegel and Greenberg,"' there was no evidence of maternal poliovirus infection-induced anomalies. The possibility of congenital anomalies associated with attenuated oral poliovirus vaccine has also been 17,118,361,365-367 Pearson and co-~orkers"~ studied the fetal malformation rate in a community in which a large vaccine field trial had been carried out; although it is probable that pregnant women became infected with vaccine virus by secondary spread, there was no community increase in fetal malformations. Prem and associates"' studied the infants of 69 women who received attenuated vaccine before 20 weeks' gestation and found that none had anomalies. In contrast, the rate of congenital defects in Blackburn, England, increased coincident with mass vaccination with trivalent poliomyelitis vaccine.365However, there is no evidence of cause and effect related to this observation. Connelly and

796


colleague^^^ commented on a child with a unique renal disease acquired in utero. The child’s mother had received oral polio vaccine during the second month of pregnancy. In February 1985, a mass vaccination program with live oral poliovirus vaccine was carried out in Finland.”7 Although pregnant women received vaccine, there was no evidence that vaccine virus had a harmful effect on developing fetuses.

Gauntt and associates375studied the ventricular fluids from 28 newborn infants with severe congenital anatomic defects of the central nervous system. In four infants (two with hydranencephaly, one with an occipital meningocele, and one with aqueductal stenosis), neutralizing antibody to one or more coxsackievirus B types was found in the fluid. In one case, IgM-neutralizing antibody to coxsackievirus B6 was found. The investigators concluded that their data Coxsackieviruses suggested the possibility of an association between congenital In a large prospective study, B r o ~ n and ~ ~colleagues ~ - ~ ~ ~ infections with coxsackievirusesB and severe central nervous (E~ans~”’~’* and Karuna~’~~) made a serologic search for system defects. selected maternal enteroviral infections in association with Echoviruses congenital malformations. In one serum samples from 22,935 women had been collected. From this group, In the large prospective study of Brown and K a r ~ n a s ?the ~~ serum samples from 630 mothers of infants with anomalies possible association of maternal infections with echoviruses and from 1164 mothers of children without defects were 6 and 9 and congenital malformations was examined. carefully studied. Specifically, serologic evidence was sought Maternal infection with these selected echoviruses apparently for infection during the first trimester and last 6 months of was not associated with any anomaly. In three other pregnancy with coxsackieviruses B1 through B5 and A9 and st~dies,’~’’~~ no association was found between maternal with echoviruses 6 and 9. In this study, infants were examined echovirus 9 infection and congenital malformation. for 113 specific abnormalities; these anomalies were grouped into 12 categories for analysis. The investigators demonstrated a positive correlation between maternal infection and infant Prematurity and Stillbirth anomaly with coxsackieviruses B2 through B4 and A9. The Polioviruses overall first-trimester infection rate with coxsackievirus B4 was significantly higher in patients with anomalies than that In the study by Horn93of 325 pregnancies, nine infants died in controls. Maternal coxsackievirus B2 infection throughout in utero. In each instance, the mother was critically ill with pregnancy, coxsackievirus B4 infections during the first poliomyelitis. Horn93also observed that 45 infants weighed trimester of pregnancy, and infection with at least one of the less than 6 pounds, and 17 of these had a birth weight of less five coxsackieviruses B during pregnancy were all associated than 5 pounds. These low-birth-weight infants were born with urogenital anomalies. Coxsackievirus A9 infection was predominantly to mothers who had had poliomyelitis early associated with digestive anomalies, and coxsackieviruses B3 in pregnancy. A similar finding was reported by and B4 were associated with cardiovascular defects. When In New York City, Siege1 and Greenberg’I2 also documented coxsackievirusesB were analyzed as a group (B1 to B5), there an increase in prematurity after maternal poliomyelitis was an overall association with congenital heart disease; the infection. This was specifically related to maternal paralytic likelihood of cardiovascular anomalies was increased when poliomyelitis. There has been no observation of stillbirth or maternal infection with two or more coxsackieviruses B prematurity in relation to vaccine admini~tration.~~’ occurred. In this study, the mothers had been instructed to keep illness diary sheets. There was no correlation between Coxsackieviruses reported maternal clinical illnesses and serologic evidence of Bates reported a fetus of 8 months’ gestational age who was infection with the selected enteroviruses. This suggests that stillborn and had calcific pancarditis and hydrops fetalis at many infections that may have been causally related to the autopsy.’@ Fluorescent antibody study revealed coxsackievirus anomalies were asymptomatic. A disturbing finding in this B3 antigen in the myocardium. Burch and colleague^'^^ study was the lack of seasonal occurrence of the births of described three stillborn infants who had fluorescent antichildren with specificdefects. Because enteroviraltransmission body evidence of coxsackievirus B myocarditis, one each with is most common in the summer and fall, the birth rate of coxsackievirusesB2, B3, or B4. They also reported a premature children with malformations should have been greatest in boy who had histologic and immunofluorescent evidence of the spring and summer if coxsackieviruses were a major cardiac infection with coxsackieviruses B2 through B4; he cause of malformation. lived only 24 hours. A macerated stillborn girl was delivered In the NIH-sponsored Collaborative Perinatal Research 2 weeks after the occurrence of aseptic meningitis caused Project, Elizan and c o - w o r k e r ~were ~ ~ ~unable to find any by coxsackievirus A9 in a 27-year-old woman.3o7Virus was relationships between maternal infections with coxsackierecovered from the placenta but not from the infant. viruses B and congenital central nervous system malformations. Coxsackievirus B6 has been recovered from the brain, liver, Scattered case reports in the literature describe congenital and placenta of a stillborn infant.’43 anomalies associated with maternal coxsackievirus infections. Makower and colleagues’40reported a child with congenital Echoviruses and Enteroviruses malformations who was born at 32 weeks’ gestation and from whom a coxsackievirus A4 strain was recovered from Freedman377reported the occurrence of a full-term, fresh the meconium. The child’s mother had been well throughstillbirth in a woman infected with echovirus 11. Because the out pregnancy, except for a febrile illness during the first infant had no pathologic or virologic evidence of infection, month. The relationship of the viral infection to the he attributed the event to a secondary consequence of congenital malformations or to the prematurity is uncertain. maternal infection from fever and dehydration rather than

Chapter 24

Table 24-5

Enterovirus a n d Parechovirus Infections

797

Major Manifestations of Neonatal Nonpolio Enteroviral and Parechoviral Infections

Specific Involvement

Common

Rare

Inapparent infection

Par 1

Mild, nonspecific, febrile illness

Cox 85 Echo 5, 11, 33 Cox B2, B3, 84, B5 Echo 5, 11, 15

Cox A9, B1, B2, B4, 65 Echo 3, 5, 9. 11, 13, 14, 20, 30, 31 Cox B1, B2, 63, B4, A9, A16 Echo 4, 7. 9, 17 Cox B 1, A9 Echo 2, 3, 4, 6, 9, 14, 19, 21 Par 1 Cox B1, B4, 85, A9 Echo 9, 17 Cox A5 Cox A9 Echo 11, 17, 19 Par 1 Cox 84 Echo 11, 17, 18 Cox B1, B4 Echo 11 Cox B4, A9 Echo 6, 9, 11, 17, 31 Par 1 Echo 20

Sepsis-Iike illness Respiratory illness (general)

Echo 11 Par 1

Herpangina Coryza Pharyngitis Laryngotracheitis or bronchitis Pneumonia Cloud baby Gastrointestinal Vomiting or diarrhea

Hepatitis

Echo 5, 17, 18

Echo 11, 19

Pancreatitis Necrotizing enterocolitis Cardiovascular Myocarditis and pericarditis Skin Neurologic Aseptic meningitis Encephalitis

Cox B1, B2, B3, 84 Cox 85 Echo 5, 17 Par 1 Cox B2, 83, 84, 85 Echo 3, 9, 11, 17 Cox B1, B2, 83, B4

ParaIysis Sudden infant death

Cox B1, B2, 85 Echo4, 6,8, 9, 11, 16, 19, 21 Par 1 Entero 71 Cox B1, B3, 84, A9 Echo 5, 6, 7, 9, 14, 20, 21 Cox 83, B4, 85 Cox B2, B3 Par 1 Cox 85, A9 Echo 11, 19 Cox B1 Echo 4, 7, 9, 11, 18 Entero 71 Cox B1, A9, A14 Echo 1, 5, 13, 14, 21, 30 Entero 71 Cox 85 Echo 6, 9, 23 Par 2 Entero 71 Cox B2 Cox B1, 83, 84, A4. A5, A8 Par 1

Cox, coxsackievirus; echo, echovirus; entero, enterovirus; par, parechovirus. Data from Cherry JD. Enteroviruses and Parechoviruses. In Feigin RD, Cherry JD, Dernrnler GJ, Kaplan SL (eds). Textbook of Pediatric Infectious Diseases, 5th ed. Philadelphia, WB Saunders, 2004.

p r i m a r y transplacental infection. Echovirus 27 has been associated with intrauterine death on two occasion^.^^^,'^^ In a n extensive study of neonatal enteroviral infections in Milwaukee in 1979, P i r a i n o a n d associate^'^^ found that 12 of 19 stillbirths occurred from July through October coincident with a major outbreak of enterovirus disease. Echovirus 11 was the m a i n agent isolated during this period. A 1300-g fetus, stillborn after 26 weeks’ gestation, h a d hydrocephalus, fibrotic peritonitis, a n d hepatosplenomegaly a n d was found to have an enterovirus 71 infection by P C R a n d immunohistochemical

Neonatal Infection Nonpolio Enteroviruses and Parechoviruses Illnesses caused by nonpolio enteroviruses a n d parechoviruses are discussed by clinical classification (Table 24-5) in the following sections. INAPPARENT INFECTION A l t h o u g h it is probable that inapparent infections in neonates occasionally occur with m a n y different enteroviruses, there i s l i t t l e documentation of this assumption. C h e r r y a n d

798


~o-workers’~~ studied 590 normal newborns during a 6-month period and found only one infection without clinical signs of illness. This was a child infected in utero or immediately thereafter with coxsackievirus B2. The mother had an upper respiratory illness 10 days before delivery. In a similar but more comprehensive study, Jenista and associate^'^^ failed to isolate any enteroviruses from cultures from 666 newborns on the first postpartum day. However, during weekly cultures during the month after birth, 75 enteroviruses were isolated. Symptomatic enteroviral disease occurred in 21% (16 of 75). During a survey of perinatal virus infections, 44 infants were found to be infected with parechovirus 1 during the study period from May to December 1966.236The virus prevalence and the incidence of new infections during this period were fairly uniform. No illness was attributed to parechovirus 1 infection, and the virus disappeared from the nursery in mid-December 1966. Inapparent infections with parechovirus 1 have been reported on two other occasions?37246 Infections without evidence of illness have occurred with coxsackievirusesA9, B1, B4, and B5 and with echoviruses 3, 5, 9, 11, 13, 14, 20, 30, and 31~9~156~157~178,210,250~256.340.378-381 MILD, NONSPECIFIC FEBRILE ILLNESS

In a review of 338 enterovird infections in early infancy, 9% were classified as nonspecific febrile illnesses.378Illness may be sporadic in nature or part of an outbreak with a specific viral type. In the latter situation, clinical manifestations vary depending on the viral type; some infants have aseptic meningitis and other signs and symptoms, and some have only nonspecific fever. Coxsackievirus B5 and echovirus types 5, 11, and 33 have been those found most commonly in nonspecific fevers; other agents identified have included coxsackieviruses A9, A16, and B1 through B4 and echoviruses 4,7,9, and 17.* Mild, nonspecific febrile illness occurs most commonly in full-term infants after uneventful pregnancies and deliveries without complications. Illness can occur at any time during the first month of life. When the onset occurs after the infant is 7 days old, a careful history frequently reveals a trivial illness in a family member. The onset of illness is characterized by mild irritability and fever, which is usually in the range of 38” C to 39” C, but higher temperatures occasionally occur. Poor feeding is frequently observed. One or two episodes of vomiting or diarrhea, or both, may occur in some infants. The usual duration of illness is 2 to 4 days. Routine laboratory study is not helpful, but cerebrospinal fluid (CSF) examination may reveal an increased protein concentration and leukocyte count indicative of aseptic meningitis. Although, by definition, illness in this category is mild, the degree of viral infection may be extensive. When looked for, virus may be isolated from the blood, urine, and spinal fluid of infants with mild illnes~es.~’ 1,379 SEPSIS-LIKE ILLNESS

The major diagnostic problem in neonatal enteroviral infections is differentiation of bacterial from viral disease. Even in the infant with mild, nonspecific fever, bacterial

*See references 29, 141, 165, 196,207,211,229,230,238,240-242, 249-251,379,382,384.

disease must be strongly considered. The sepsis-like illness described here is always alarming. This illness is characterized by fever, poor feeding, abdominal distention, irritability, rash, lethargy, and h y p o t ~ n i a . ~ ~ ~ , ~ er ~ ~findings ” ~ ’ O tinclude h diarrhea, vomiting, seizures, shock, disseminated intravascular coagulation, thrombocytopenia, hepatomegaly, jaundice, and apnea. The onset of illness is introduced by irritability, poor feeding, and fever and followed within 24 hours by other manifestations. In a group of 27 neonates, Lake and associates286observed that 54% had temperatures of 39’ C or higher. The duration of fever varies from 1 to 8 days, most commonly 3 to 4 days. Barre and colleagues388reported a 3-day-old boy with an enterovirus-associatedhemophagocytic syndrome. This neonate presented with a typical sepsislike picture with fever, hepatosplenomegaly, coagulopathy, thrombocytopenia, and anemia. This child recovered and had no hemophagocytic relapses. Sepsis-like illness is common. M o r e n ~ ~described ~’ its occurrence in one fifth of 338 enteroviral infections in infants. In an attempt to differentiate bacterial from viral disease, Lake and c o - w o r k e r ~studied ~ ~ ~ 27 infants with enteroviral infections. White blood cell counts were not helpful because the total count, the number of neutrophils, and the number of band form neutrophils were elevated in most instances. Of most importance were historical data. Most mothers had evidence of a recent febrile, viral-like illness. Other factors often associated with bacterial sepsis, such as prolonged rupture of membranes, prematurity, and low Apgar scores, were unusual in the enteroviral infection group. Sepsis-like illness has been identified most often with coxsackieviruses B2 through B5 and echovirus types 5, 11, and 16; other viruses detected include coxsackieviruses A9 and B1; echoviruses 2,3,4,6,9,14,19, and 21; and parechovirus 1.* Since the early 1980s, echovirus 11 has been associated most frequently with fatal septic events, with hepatic necrosis, and disseminated intravascular coagulation.30~163~165~257.344”48.354 RESPIRATORY ILLNESS

Respiratory complaints are generally overshadowed by other manifestations of neonatal enteroviral disease. Only 7% of 338 enteroviral infections in early infancy were classified as respiratory illness.378Except for echoviruses 11 and parechovirus 1, respiratory illness associated with enteroviruses has been s p o r a d i ~ . ~ ~ ~ , ’ ~ ~ Hercik and c o - w o r k e r ~reported ~ ~ ~ an epidemic of respiratory illness in 22 newborns associated with echovirus 11 infection. All of these infants had rhinitis and pharyngitis, 50% had laryngitis, and 32% had interstitial pneumonitis. Berkovich and Pangan237studied respiratory illnesses in premature infants and reported 64 with illness, 18 of whom had virologic or serologic evidence of parechovirus 1 infection. Many had high but constant levels of serum antibody to parechovirus 1. Some of the 18 infants were probably also infected with parechovirus 1. The children with proven parechovirus 1 infections could not be clinically differentiated from those without evidence of parechovirus 1 infection. Ninety percent of the infants had coryza, and 39% had radiographic evidence of pneumonia. ‘See references 28-30,160, 161, 163-165,168,214,234,235,243,247,250, 251,257,338,340,342,344-346,348,350,351,354,383,385,389-394.

Chapter 24

Herpangina. Chawareewong and associates396described several infants with herpangina and coxsackievirus A5 infection. A vesicular lesion on an erythematous base on a tonsillar pillar in a 6-day-old infant with coxsackievirus B2 meningitis has also been reported.397Two 1-month-old infants were described in an outbreak of herpangina due to coxsackievirus B3 in a welfare home in Japan.398 Coryza. Several agents have been associated with coryza: coxsackievirus A9 and echoviruses 11, 17, 19, and 22.158,239,243,246,399 Pharyngitis. Pharyngitis is uncommon in neonatal enteroviral infections. In more than 50 infants with enteroviral infections studied by Linnemann and colleagues383and Lake and a~sociates,3~~ pharyngitis did not occur. Suzuki and cow o r k e r ~observed ~ ~ ~ pharyngitis in 3 of 42 neonates with echovirus 1 1 infections. In contrast, in the same study, 67% of children 1 month to 4 years old had pharyngitis. Pharyngitis has been associated with coxsackievirus B4 and with echoviruses 11, 17, and 18.207p239~2537400,40' Laryngotracheobromhitisor Bronchitis. A few enteroviruses have been identified in cases of laryngotracheobronchitisor bronchitis: coxsackieviruses B1 and B4 and echovirus 11.239,402 Specific clinical descriptions of laryngotracheobronchitis or bronchitis associated with enteroviral infections are scanty. Hercik and c o - w o r k e r ~observed ~ ~ ~ laryngitis in 11 and croup in 4 of 22 neonates during an echovirus 1 1 outbreak. All of the affected infants had upper respiratory tract findings, vomiting, and lethargy. Many were also cyanotic and had hepatosplenomegaly. Pneumonia. Pneumonia as the main manifestation of neonatal enteroviral infection is rare. M o r e n documented ~~~~ only seven instances of pneumonia in 338 neonatal enteroviral infections. Outbreaks of pneumonia in neonates have been reported with echovirus 11 and parechovirus 1.237,239 Pneumonia resulting from other enteroviruses is a sporadic event and has been reported for the following nonpolio enteroviruses: coxsackieviruses A9 and B4 and echoviruses 9, 17, and 31. During a nursery echovirus 11 outbreak, 7 of 22 neonates had pneumonia.239All infants had signs of upper respiratory infection and general signs of sepsis-like illness. In infants with pneumonia associated with an echovirus 22 nursery epidemic, coryza, cough, and dyspnea were early signs?37The illnesses tended to be protracted, with radiographic changes persisting for 10 to 100 days. Cloud Baby. Eichenwald and associates248recovered echovirus 20 from four full-term infants younger than 8 days. Although these infants apparently were well, it was found that they were extensively colonized with staphylococci and that they disseminated these organisms into the air around them. Because of this ability to disseminate staphylococci, they were called cloud babies. The investigators believed that these cloud babies contributed to the epidemic spread of staphylococci in the nursery. Because active staphylococcal dissemination occurred only during the time that echovirus 20 could be recovered from the nasopharynx. it was theorized that viral-bacterial synergism occurred. GASTROINTESTINAL MANIFESTATIONS

Significant gastrointestinal illness occurs in about 7% of enteroviral infections during infancy.378


799

Vomiting or Diarrhea. Vomiting and diarrhea are common but usually just part of the overall illness complex and not the major manifestations. In 1958, Eichenwald and colleagues2@described epidemic diarrhea associated with echovirus 18 infections. In 22 infants with epidemic respiratory disease caused by echovirus 11, all had vomiting as a manifestation of the illness.239Linnemann and colleagues383reported vomiting in 36% and diarrhea in 7% of neonates with echoviral infections. In another study, Lake and associates340found diarrhea in 81% and vomiting in 33% of neonates with nonpolio enteroviral infections. Vomiting and diarrhea in neonates have been associated with coxsackieviruses B1, B2, and B5; echoviruses 4 through 6,8,9,11, 16, 17, 18, 19, and 21; parechovirus 1; and enterovirus 71.* Hepatitis. M o r e n ~observed ~ ~ ~ that 2% of neonates with clinically severe enteroviral disease had hepatitis. Lake and colleagues340found that 37% of neonates with enteroviral infections had hepatomegaly, and hepatosplenomegaly was observed by Hercik and associates239in 12 of 22 newborns with echovirus 11 respiratory illnesses. Severe hepatitis, frequently with hepatic necrosis, has been associated with echoviruses 5,6,7,9, 11,14,19,20, and 2 1.159,160,263,343,344,347-350,353,406,407 In 1980, M ~ d l i n ~reported '~ four fatal echovirus 11 illnesses in premature infants. All had hepatitis, disseminated intravascular coagulation, thrombocytopenia, lethargy, poor feeding, and jaundice. Since 1980, there have been many reports of sepsis-like illness with fatal hepatitis related to echovirus 1 1.30,163,165,257,345,347~348,351 Coxsackieviruses B1, B4, and other B types have been Abzug408 associated with neonatal hepatitis.'2,29,203v216,342,393-395 reviewed medical records of 16 neonates with hepatitis and coagulopathy and found a case-fatality rate of 31%. All of the five patients who died had myocarditis, and three had encephalitis. Pancreatitis. Pancreatitis was recognized in three of four newborns with coxsackievirus B5 meningitis"' and in coxsackievirus B3 and B4 infections at autopsy.'97In other fatal coxsackievirus B infections, pancreatic involvement has been identified, but clinical manifestations have rarely been observed. Necrotizing Enterocolitis. Lake and associates340described three infants with necrotizing enterocolitis. Coxsackievirus B3 was recovered from two of these infants and coxsackievirus B2 from the third. Parechovirus 1 was associated with a necrotizing enterocolitis outbreak.409 CARDIOVASCULAR MANIFESTATIONS

In contrast with enteroviral cardiac disease in children and adults, in which pericarditis is common, neonatal disease virtually always involves the heart muscle.+ Most cases of neonatal myocarditis are related to coxsackievirusB infections, and nursery outbreaks have occurred on several occasions. In 1961, %brick2' reviewed the clinical findings in 45 cases of neonatal myocarditis; his findings are summarized in

*See references 157,211,214,234,238-240,242-244,247,383,385,403-405. 'See references 6,12,28,29, 138,144,147-149,163,165,193-196,201-206, 208-210,213,215,218,220,221,223,225,227-229,341,345,346,393-395, 410-414,416.

800


Table 24-6

Findings in Neonatal Coxsackievirus B Myocarditis

Finding

Feeding difficulty Listlessness Cardiac signs Respiratory distress Cya nosis

Fever Pharyngitis Hepatosplenomegaly Biphasic course Central nervous system signs Hemorrhage Jaundice Diarrhea

Frequency (%)

84 81 81 75 72 70 64 53

35 27

13 13 8

Modified from Kibrick 5.Viral infections of the fetus and newborn Perspect Vtrol 2:140, 1961.

Linnemann and co-worker~~’~ reported exanthem in 4 of 14 neonates with echoviral infections. Cutaneous manifestations usually have their onset between the third and fifth day of illness. The rash is usually macular or maculopapular, and petechial lesions occasionally are seen. Surprisingly, vesicular lesions have been reported only once with coxsackievirus B3 infection and once with enterovirus 71 infection in neonates. Theodoridan and associates4I7 described a full-term newborn boy with vesicular lesions at birth. PCR revealed coxsackievirus B3. A 1-month-old infant with enterovirus 71 infection and hand-foot-and-mouth syndrome has been reported.418 Hall and associates385 reported two neonates with echovirus 16 infections in which the illnesses were similar to roseola. The patients had fevers for 2 and 3 days, defervescence, and then the appearance of maculopapular rashes. NEUROLOGIC MANIFESTATIONS

Exanthem as a manifestation of neonatal enteroviral infection has occurred with coxsackieviruses B1, B3, and B5; echoviruses 4,5,7,9, 11, 16, 17, 18, and 21; and parechovirus 1.* In most instances, rash is just a minor manifestation of moderate to severe neonatal disease. Of 27 infants studied by Lake and colleagues, 41% had e~anthem.’~’Similarly,

Meningitis and Meningoencephalitis. As shown in Table 24-5, meningitis and meningoencephalitishave been associated with coxsackieviruses B1 through B5 and with many echoviruses.* In most instances, the differentiation of meningitis from meningoencephalitis is difficult in neonates. Meningoencephalitis is common in infants with sepsis-like illness, and autopsy studies reveal many infants with disseminated viral disease (e.g., heart, liver, adrenals) in addition to central nervous system involvement. In the review of M ~ r e n s , ~ ’ ~ 50% of the neonates with enteroviral infections had encephalitis or meningitis. The initial clinical findings in neonatal meningitis or meningoencephalitisare similar to those in nonspecific febrile illness or sepsis-like illness. Most often, the child is quite normal and then becomes febrile, anorectic, and lethargic. Jaundice frequently affects newborns, and vomiting occurs in neonates of all ages. Less common findings include apnea, tremulousness, and general increased tonicity. Seizures occasionally occur. CSF examination reveals considerable variation in protein, glucose, and cellular values. In seven newborns with meningitis related to coxsackievirus B5 studied by Swender and associates?34the mean CSF protein value was 244 mg/dL, and the highest value was 480 mg/dL. The mean CSF glucose value was 57 mg/dL, and one of the seven had pronounced hypoglycorrhachia (12 mg/dL). The mean CSF leukocyte count for the seven infants was 1069cells/mm3, with 67% polymorphonuclear cells. The highest cell count was 4526 cells/mm3, with 85% polymorphonuclear cells. In another study involving 28 children younger than 2 months in whom coxsackievirus B5 was the implicated pathogen, 36% of the infants had CSF leukocyte counts of 500 cells/mm3 or more.391In this same study, only 13% of the infants had CSF protein values of 120 mg/dL or more; 12% of the infants had glucose values of less than 40 mg/dL. The CSF findings in cases of neonatal nonpolio enteroviral infections are frequently similar to those in bacterial disease. In particular, the most consistent finding in bacterial disease, hypoglycorrhachia, affects about 10% of newborns with enteroviral meningitis.234*340~382~3g1~419

‘See references 28,29, 147, 158,161, 165, 198,212,224,235,238,240,243, 383,385-387,393,399,412,415,417,

‘See references 28-30, 149, 157, 165, 212,228,234,235,238,242,247,257, 259,338,339,346,380,386,387,391,395,397,403,405,409,412,415-437.

Table 24-6. Many of the early experiences, particularly in South Africa, involved catastrophic nursery epidemics. Since the observation in 1972 of five newborns with echovirus 11 infections and myocarditis, there have been no further reports of nursery epidemic^.^" The illness as described by Kibrick” most commonly had an abrupt onset and was characterized by listlessness,anorexia, and fever. A biphasic pattern was observed in about one third of the patients. Progression was rapid, and signs of circulatory failure appeared within 2 days. If death did not occur, recovery was occasionally rapid but usually occurred gradually during an extended period. Most patients had cardiac findings, such as tachycardia, cardiomegaly, electrocardiographic changes, and transitory systolic murmurs. Many patients showed signs of respiratory distress and cyanosis. About one third of the infants had signs suggesting neurologic involvement. Of the 45 patients analyzed by Kibrick, only 12 survived. In the echovirus 11 nursery outbreak reported by Drew:14 5 of 10 infants had tachycardia out of proportion to their fevers. Three of these infants had electrocardiograms, supraventricular tachycardia occurred in all, and ST segment depression was observed in two of the records. Supraventricular tachycardia has also been seen in patients with coxsackievirus B infections.*’”Echovirus 19 has been associated with rnyo~arditis.3~~ Neonatal myocarditis related to enteroviruses has been less common than it was 4 decades ago. In his review, Morens3” reported only two instances among 248 severe neonatal enteroviral illnesses. EXANTHEM

Chapter 24 Paralysis. Johnson and as~ociates~~' reported a 1-month-old boy with a right facial paralysis and loss of abdominal reflexes. The facial paralysis persisted through convalescence; the reflexes returned to normal within 2 weeks. The boy was infected with coxsackievirus B2. A 1-month-old boy with hand-foot-and-mouth syndrome and bilateral lower limb weakness due to enterovirus 71 infection has been described.418 SUDDEN INFANT DEATH

Balduzzi and G r e e n d ~ k erecovered ~ ~ ~ coxsackievirusA5 from the stool of a 1-month-old child after sudden infant death. In a similar investigation of sudden infant death, Gold and c o - w o r k e r ~recovered ~~~ coxsackievirus A4 from the brains of three infants. Coxsackievirus A8 was recovered from the stool of a child in whom anorexia was diagnosed on the day before death. Coxsackievirus B3 was recovered at autopsy from an infant who died suddenly on the eighth day of life.335Morens and associates6reported eight cases of sudden infant death associated with enteroviral infection; parechovirus 1 was found on two occasions. In five instances of cot death in one study, echovirus 11 was isolated from the lungs in two children, from the myocardium in one, and from the nose or feces in the other Grangeot-Keros and c o - w o r k e r ~looked ~ ~ ~ for evidence of enteroviral infections using PCR and an IgM immunoassay in cases of sudden and unexplained infant deaths. They divided their infant death population into two groups. One group had clinical, biologic, or histologic signs of viral infection, and the other group had no indicators of an antecedent infection. Fifty-four percent of infants with evidence of a preceding infection had PCR evidence of an enterovirus in samples from the respiratory tract or lung, or both, whereas none of those without evidence of a prior infection had similar positive PCR findings. Their IgM antibody studies supported their PCR findings.

Manifestations of Polioviruses


these data show that more than one half of the cases resulted from maternal disease. Because others have identified congenital infection without symptomatic maternal infection, it is probable that infection in the mothers was the source for an even greater percentage of the neonatal illnesses. Because the incubation period of neonatal poliomyelitis has not been determined, it is difficult to know how many infants were infected in utero. Most illnesses occurring within the first 5 days of life probably were congenital. Most neonates had symptoms of fever, anorexia or dysphagia, and listlessness. Almost one half the infants described in this review died, and of those surviving, 48% had residual paralysis. INAPPARENT INFECTION

Shelokov and Habe197followed a virologically proven infected newborn without signs of illness. The infant was normal when 1 year old. Wingate and co-workers'07studied an infant deliveredby cesarean section from a woman with poliomyelitis who died 1 hour after delivery. Her infant was treated with gamma globulin intramuscularly at the postnatal age of 21 hours. He remained asymptomatic; poliovirus 1 was recovered from a stool specimen on the fifth day of life. INFECTION ACQUIRED IN UTERO

Elliott and colleagues"' described an infant girl in whom "complete flaccidity" was observed at birth. This child's mother had had mild paralytic poliomyelitis, with the onset of minor dlness occurring 19 days before the infant's birth. Fetal movements had ceased 6 days before delivery, suggesting that paralysis had occurred at this time. On examination, the infant was severely atonic; when supported under the back, she was passively opisthotonic. Respiratory efforts were

Table 24-7

Clinical Findings in 58 Cases of Neonatal Poliomyelitis

GENERAL CONSIDERATIONS

Polioviral infection in children classically results in a spectrum of clinical illness. As described by Paul439and accepted by others, 90% to 95% of infections in non-neonatal children are inapparent, 4% to 8% are abortive, and 1% to 2% are frank cases of poliomyelitis. Whether neonatal polioviral infection is acquired in utero, during birth, or after birth, it appears that the more severe manifestations of clinical illness are similar to those of older children. However, the available reports in the literature suggest that the frequencies of occurrence of inapparent, abortive, and frank cases are quite different from those in older children. Most reports describe severely affected l6 Asymptomatic infection does occur, In the excellent review by Bates"' in 1955, 58 cases of clinically overt poliomyelitis in infants younger than 1 month were described. Although complete data were not available on many of the cases, 51 had paralysis or died from their disease, or both. Of the total number of infants for whom there were clinical data, only one had nonparalytic disease. Because follow-up observation was recorded for only a short time in many infants, the evaluation of residual paralysis (presence or absence) may not be reliable. Pertinent clinical data from the study by Bates are presented in Table 24-7, and

801

Finding

No. o f Cases with a Particular FindinglNo. of Cases Evaluated (%)

Time o f Onset after Birth 55 days 6-14 days 21 5 days

13/55 (24) 25/55 (45) 17/55 (31)

Infection Source for Symptomatic

Illness Mother Other contact Unknown Acute Illness Fever Anorexia or dysphagia Listlessness lrrita bi Iity Diarrhea Paralysis Outcome Death Residual paralysis Recovery without paralysis

22/42 (52) 6/42 (14) 14/42 (34) 17/29 (59) 16/24 (67) 24/33 (73) 3/33 (9) 2/11 (18) 43/44 (98) 21/44 (48) 12/44 (27) 11/44 (25)

Adapted from Bates T. Poliomyelitis in pregnancy, fetus, and newborn. Am J Dis Child 90:189, 1955.

802

Section I11

Viral Infections

abortive and confined to accessory muscles, and laryngoscopy revealed complete flaccidity in the larynx. Johnson and Sti ms~n''~reported a case in which the mother's probable abortive infection occurred 6 weeks before the birth of the infant. The newborn was initially thought to be normal but apparently had no medical examination until the fourth day of life. At that time, the physician diagnosed a right hemiplegia. On the next day, a more complete examination revealed a lateral bulging of the right abdomen accompanied by crying and the maintenance of the lower extremities in a frog-leg position. Adduction and flexion at the hips were weak, and the knee and ankle jerks were absent. Laboratory studies were unremarkable except for the examination of the CSF, which revealed 20 lymphocytes/mm3 and a protein concentration of 169 mgldL. During a 6-month period, this child's paralysis gradually improved and resulted in only residual weakness of the left lower extremity. Paresis of the left arm occurred in another child with apparent transplacentally acquired poliomyelitis shortly after The 2-day-old infant was quadriplegic, but patellar reflexes were present, and there were no respiratory or swallowing difficulties. This child had pneumonia when 3 weeks old, but general neurologic improvement occurred. Examination when the infant was 8 weeks old revealed bilateral atrophy of the shoulder girdle muscles. The CSF in this case revealed 63 leukocytes/mm3, with 29% of them polymorphonuclear cells, and a protein value of 128 mg/dL. All three of the infants previously discussed were apparently infected in utero several days before birth. Their symptoms were exclusively neurologic; fever, irritability, and vomiting did not occur. POSTNATALLY ACQUIRED INFECTION

In contrast to infections acquired in utero, those acquired postnatally are more typical of classic poliomyelitis. Shelokov and Weinstein" described a child who was asymptomatic at birth. Onset of minor symptoms in the mother occurred 3 weeks before delivery, and major symptoms occurred 1 day before delivery. On the sixth day of life, the infant became suddenly ill with watery diarrhea. He looked grayish and pale. On the next day, he was irritable, lethargic, and limp and had a temperature of 38" C. Mild opisthotonos and weakness of both lower extremities developed. He was responsive to sound, light, and touch. The CSF had an elevated protein level and an increased number of leukocytes. His condition worsened during a total period of 3 days, and then gradual improvement began. At 1 year, he had severe residual paralysis of the right leg and moderate weakness in the left leg. Baskin and associates''2 described two infants with neonatal poliomyelitis. The first child, whose mother had severe poliomyelitis at the time of delivery, was well for 3 days and then developed a temperature of 38.3" C. On the fifth day of life, the boy became listless and cyanotic. CSF examination revealed a protein level of 300 mg/dL and 108 leukocytes/mm3. His condition worsened, and extreme flaccidity, irregular respiration, and progressive cyanosis developed; he died on the seventh day of life. The second infant was a boy who was well until he was 8 days old, but he then became listless and developed a temperature of 38.3" C. During the next 5 days, he developed flaccid quadriplegia; irregular, rapid, and shallow respirations; and an inability to swallow. The child died on

the 14th day of life. His mother had developed acute poliomyelitis 6 days before the onset of his symptoms. Abramson and colleagues'" reported four children with neonatal poliomyelitis, two of whom died. In three of the children, the illnesses were typical of acute poliomyelitis seen in older children; they were similar to the cases of Baskin and associateslo2described previously. The fourth child died at 13 days of age with generalized paralysis. The onset of his illness was difficult to define, and he was never febrile. Swarts and Kercher''' also described a child whose illness had an insidious onset. When 10 days old, the child gradually became lethargic and anorectic and regurgitated formula through his nose. On the next day, flaccid quadriplegia developed. Winsser and associate^"^ and Bates"' reported infants with acute poliomyelitis with clinical illnesses similar to those that occur in older individuals. VACCINE VIRAL INFECTIONS

Administration of oral polio vaccines to newborns has been carried out in numerous ~ t u d i e s . ~ Vaccine ' ~ ~ ' ~ viral ~ ~ ' infection ~~ occurs in newborns with all three types of poliovirus, although the rate of infection is less than that for immunized older children. This rate is governed by the dose of virus, transplacentally acquired maternal antibody, and antibody acquired from colostrum and breast milk. Although clinical illness rarely has resulted from attenuated polioviral infections in older children and adults, there is only one specific report of paralytic poliomyelitis in a newborn associated with infection with a vaccine viral strain.Ig2 In that case, the possible source for the infection was the recently vaccinated child of the baby-sitter. In a review of 118 cases of vaccineassociated paralytic poliomyelitis in the United States between 1980 and 1992, the age of patients ranged from 1 month to 69 years, but details about neonates were not presented.-

Manifestations of Specific Nonpolio Enteroviruses COXSACKIEVIRUSES

CoxsackievirusA. There have been few reports of neonatal coxsackievirus A infections. Baker and Phillips337reported a small-for-gestational-age infant with pneumonia and a sepsislike illness with disseminated intravascular coagulation. This newborn died on the second day of life, and when cultured, the CSF grew coxsackievirus A3. Balduzzi and G r e e n d ~ k e ~ ~ ' recovered a coxsackievirus A5 from the stool of a 1-monthold child with sudden infant death. In a similar investigation of sudden infant death, Gold and c o - ~ o r k e r srecovered ~~~ coxsackievirusA4 from the brains of three infants. Coxsackievirus A8 was also recovered from the stool of a child in whom anorexia was observed on the day before death. Berkovich and reported a 3-day-old neonate with nonspecific febrile illness (38.3" C) who was infected with coxsackievirus A9. Coxsackievirus A9 was also recovered from an 11-day-old infant with rhinitis, lethargy, anorexia, and fever.243This illness lasted 3 days. Jack and associates236 described a 3-day-old newborn with fever, cyanosis, and respiratory distress who died on the seventh day of life; an autopsy revealed bronchopneumonia. CoxsackievirusA9 was isolated from the feces on the fourth and sixth days of life. Lake and associate^^^' reported two neonates with coxsackievirus A9 infections, but no clinical details were

Chapter 24

803

nuclear cells. Coxsackievirus B1 was recovered from the throat, stool, urine, and serum. Wright and colleagues216 reported an infant fatality associated with coxsackievirus B1 infection. This premature boy was well until he was 4 days old, when he had two episodes of cyanosis and apnea. After this, he became anorexic and listless and lost the Moro reflex. On the ninth day of life, he had shallow respirations,hepatomegaly,jaundice, petechiae, and thrombocytopenia. He was edematous and lethargic, and he had a temperature of 34.5” C, a pulse rate of 130 beats per minute, and a respiratory rate of 20 breaths per minute. He became weaker, unresponsive, and apneic and died. Positive laboratory findings included the following values: less than 10,000 platelets/mm3, 283 mg of CSF protein/dL; 20.5mg of serum bilirubin/dl; and 100 units of serum aspartate aminotransferase.Autopsy revealed hepatic necrosis, meningoencephalitis,and myocarditis. Coxsackievirus B 1 was recovered from the throat, urine, liver, lung, kidney, and brain. Twin boys with a sepsis-like illness with hepatitis and disseminated intravascular coagulation have been reported?’ The first twin died on the 16th day of life, and the second twin survived. Another set of twins had coxsackievirus B1 infections shortly after birth; one twin had myocarditis, and the other had hepatitis with subsequent progressive liver calcification^.^^^ A third set of twins had coxsackievirus B 1 infections with illness that began when they were 5 days old.395One twin had disseminated intravascular coagulation, and the other had meningitis. Three other newborns with fatal sepsis-like illnesses with hepatitis have been described.3933394 Isa~sohn’~~ described four severe cases of neonatal illnesses due to coxsackievirus B1; three of the four neonates died. Of the three fatalities, one was caused by myocarditis, and the other two resulted from multiorgan dysfunction.The surviving

presented. Jenista and co-~orkers”~ recovered coxsackievirus A9 strains from seven nonhospitalized neonates who were thought to be well. In the Netherlands, a neonate with coxsackievirus A9 illness had pericarditis, meningitis, pneumonitis, and hepatitis; he recovered completely.410Krajden and Middleton2’described a neonate with a sepsis-like illness who died. Coxsackievirus A9 was recovered from the liver and lung. Morens3” also reported a death associated with this same virus type. Eisenhut and colleagues338reported an outbreak that included four neonates with coxsackievirusA9 infections. One infant who had meningitis, myocarditis, and disseminated intravascular coagulation died. A second neonate had vomiting, rhinitis, and abdominal distention, and two neonates had asymptomatic infections. Forty-eight of 598 neonates admitted to a regular nursery in Bangkok, Thailand, in the spring of 1977 had herpar~gina.~’~ Coxsackievirus A5 was isolated from nine specimens from the afflicted infants, and a rise in the serum antibody titer was identified in 10 instances. Helin and colleagues424described 16 newborns with aseptic meningitis caused by coxsackievirusA14. During a 2.5-year follow-up period, they all developed normally, and no sequelae were identified. CoxsackievirusA16 was recovered from one newborn with nonspecific illness; his mother had had hand-foot-and-mouth syndrome 4 days previously.23o

CoxsacldevinrS B1. Coxsackievirus B 1 has only occasionally been recovered from newborns (Table 24-8). Eckert and cow o r k e r ~ ~recovered ~* a coxsackievirus B1 strain from the stool of a 1-month-old boy with bronchitis. Jahn and CherrJ” described a 4-day-old infant who became febrile and lethargic. This illness persisted for 5 days without other signs or symptoms. An examination of the CSF showed a slight increase in the number of leukocytes, and most were mono-

Table 24-8


Clinical and Pathologic Findings in Coxsackievirus B infection of Newborns References for Coxsackievirus

Finding

81

Exanthern

224, 393

Nonspecific febrile illness Sepsis-like illness Paralysis Diarrhea Sudden infant death Pneurnothorax Aseptic meningitis, rneningoencephalitis, encephalomyelitis

29, 215, 233, 393-395 394

82

84

85

229 28. 233

196, 207 163. 337

147, 198, 212, 415 384 29

335.438

438

83 148

142 29 420 404

438 211, 214, 216, 395

149, 199, 209, 222, 337, 339, 382, 397,434,435

28, 29, 138, 145, 201, 212, 223

29, 198, 203, 204, 212, 227, 339

Myocarditis

214, 216-218, 233, 342, 393, 394

29, 149, 199, 209, 210, 219, 220, 337, 382,431

28, 29, 138, 148, 207, 208, 21 5, 222, 243, 247, 376

Hepatitis

216, 233, 342, 393, 396

28, 149, 165, 196, 198, 203, 204, 206, 213, 227, 337, 411, 416, 43 1 203, 213

Pancreatitis Adrenocortical necrosis Bronchitis

233

197 201 402

236 28, 139, 147, 149, 200, 202, 210, 231, 232, 234, 380, 391, 413, 423, 432 28, 147, 202, 380, 423

200

804

Section I11

Viral Infections

infant had hepatitis, congestive heart failure, thrombocytopenia, and residual neurologic damage. McLean and colleague^"^ described a male newborn who had a temperature of 39’ C, vomiting, and diarrhea on the fourth day of life. When 6 days old, he appeared gray and mottled and developed shallow respirations. He died on the seventh day of life after increased respiratory distress (90 breaths per minute), hepatomegaly, generalized edema, and cardiac enlargement. Coxsackievirus B 1 was recovered from the heart and brain. Gea817studied an extensive epidemic of Bornholm disease related to coxsackievirus B1 in Johannesburg in the summer of 1960 to 1961. After the first coxsackievirus B1 isolations, the medical officers of the area were on the alert for nursery infections and the prevention of nursery epidemics. Despite careful isolation procedures, Gear’” reported that infection “was introduced into all the large maternity homes in Johannesburg.”About 20 cases of neonatal myocarditis were documented, as were three deaths. The isolation procedures apparently prevented secondary nursery cases. Volakova and Jandasek2I8reported epidemic myocarditis related to coxsackievirus B1. Cherry and JahnzZ4 described a child with a mild febrile exanthematous illness, which had its onset within 10 minutes of birth. CoxsackievirusB2. The reported instances of coxsackievirus

B2 infections in neonates are provided Table 24-8. In most instances, the infants had myocarditis or neurologic manifestations. Eleven of 12 of the infants with myocarditis died. The one child with myocarditis who survived was reexamined when 2 years old and was found to be n ~ r r n a l . ”This ~ child’s mother became ill with sore throat, coryza, and malaise on the day after delivery. When 3 days old, the child became febrile (38.9’ C) and had periods of apnea and cardiac irregularities. The cry was “pained.” The electrocardiogram showed a left-sided heart pattern in the V leads and T wave abnormalities. The child’s symptoms lasted less than 48 hours. Coxsackievirus B2 was isolated from the nose, urine, throat, and CSF of the child and from the mother’s stool. The mother breast-fed the infant (while she wore a mask) during her illness. A later specimen of breast milk was cultured for virus without successful recovery of an agent. P~schak’~’ reported a child who became febrile (39.5’ C) 8 hours after birth. During the next 9 days, the infant’s temperature fluctuated between 36.7’ C and 38.9’ C. The patient had no other symptoms. Serologic evidence of coxsackievirus B2 infection was found. Johnson and associates420described a 1-month-old infant with aseptic meningitis who developed a persistent right facial paralysis. In a study of undifferentiated diarrheal syndromes, Ramos-Alvarez4” observed a child with coxsackievirus B2 infection. Eilard and associates382reported a nursery outbreak in which 12 infants were infected. All had aseptic meningitis, and 2 also had myocarditis. One of the two infants died on the 13th day of life. One child with thrombocytopenia and respiratory failure died.340 Coxsackievirus B3. Neonatal infections with coxsackievirus B3 are summarized in Table 24-8. Most reported cases have been severe illnesses with myocarditis or meningoencephalitis, or both. One case involved sudden infant death,335in which coxsackievirus B3 was recovered from a pool of organs from an infant who died on the eighth day of life.

Tuuteri and c o - ~ o r k e r s studied * ~ ~ a nursery outbreak of coxsackievirus B3 infection. Seven children had mild disease characterized by anorexia, listlessness, and fever, and two infants had fatal myocarditis. Of the 57 reported neonatal infections with coxsackievirus B3, 30 deaths occurred, and most were associated with myocarditis and sepsis-like illness. Three infants had febrile illnesses with meningitis and were reported to have suffered no residual effects; long-term follow-up is not available, however.145s212 Isacsohn and colleagues233reported two neonates with multiorgan dysfunction who survived. A full-term boy delivered by caesarean section had scattered vesicular lesions at birth.417 New lesions appeared over a 5-day period, and the rash lasted for 10 days. The child had no other symptoms, and the mother had no febrile illness during pregnancy. Chesney and associate^^'^ studied a 3-week-old girl with meningoencephalitis. This child had hypoglycorrhachia; the CSF glucose value on the sixth day of illness was 23 mg/dL, with a corresponding blood glucose level of 78mg/dL. As described in another review,340two infants who died had thrombocytopenia and respiratory failure; a clinical picture suggestive of necrotizing enterocolitis also was observed. During a 5-year period in Toronto, Krajden and MiddletonZ8 assessed 24 neonates with enteroviral infections who were admitted to the Hospital for Sick Children. Nine children were infected with coxsackievirus B3; of these, two infants had meningitis, three had myocarditis, and four had a sepsislike illness. Of this group, one infant with meningitis, one with myocarditis, and all with sepsis-like illness died. All the neonates with sepsis-like illness had clinical evidence of multiorgan involvement;they had respiratory distress, hepatomegaly, hemorrhagic manifestations, and congestive heart failure. Two neonates with herpangina and coxsackievirus B3 infections were described in an outbreak involving 25 infants.398

Coxsackievirus B4. Table 24-8 summarizes coxsackievirus B4 neonatal infections. Most were severe and frequently were fatal illnesses with neurologic and cardiac involvement. An infant with less severe disease was described by Sieber and associates.207 This child was well until 6 days after delivery, when he developed pharyngitis, diarrhea, and gradually increasing lethargy. This was followed by fever for 36 hours. No other signs or symptoms were observed, and the child was well when 11 days old. He had virologic and serologic evidence of coxsackievirus B4 infection. Winsser and AltieriI9’ studied an infant who suddenly became cyanotic and convulsed and died at 2 days of age. At autopsy, the only findings were bronchopneumonia, congestive splenomegaly, and chronic, interstitial pancreatitis. Coxsackievirus B4 was isolated from the spleen. Barson and associates4” reported the survival of an infant with myocarditis. Cardiac calcification was revealed on radiographs when the child was 4 weeks old, and the electrocardiogram revealed a left bundle branch block. When the child was 7 months old, the conduction defect remained, but the myocardial calcification had resolved. Coxsackievirus B5. The spectrum of neonatal infection with coxsackievirus B5 is greater than that with the other coxsackieviruses B. Studies are summarized in Table 24-8. Meningitis and encephalitis are common neonatal mani-

Chapter 24 festations of coxsackievirusB5 infection.* Nursery epidemics have been observed. Rantakallio and associates231studied 17 infants in one nursery with aseptic meningitis. None of the infants was severely ill. All had fever, with a temperature of 38' C to 40' C. Eleven of the 17 neonates were boys. Signs included irritability, nuchal rigidity, increased tone, anorexia, opisthotonos, whimpering, loose stools, and diminution of alertness. In another nursery outbreak, Farmer and Patten380 found 28 infected infants. Of the group of 28,15 had aseptic meningitis, 4 had diarrhea, and 9 had no signs of illness. Six years later, the 65 children who had had meningitis were studied. Thirteen were found to be physically normal and to have normal intelligence. Two children had intelligence levels below the mean for the group and had residual spasticity. At the time of the initial illness, these two infants and one additional child were twitching, irritable, or jittery. Swender and associates234studied seven cases of aseptic meningitis in an intensive care nursery during a 6-week period during the summer of 1972. Two of the infants had apnea. One of the infants had a CSF glucose level of 12 mg/dL. During a community outbreak of coxsackievirus B5 infections, Marier and colleagues39'studied 32 infants with aseptic meningitis. In this group, 36% had CSF leukocyte counts of 500 cells/mm3or higher, and in 19%, neutrophils accounted for 50% or more of the count. In 12% of patients, the CSF glucose level was less than 40mg/dL. Thirtyeight percent of the infants had blood leukocyte counts of 15,000 cells/mm3or higher values. Of particular interest is the observation of exanthem in four reports. Cherry and co-worker~~'~ described a 3-weekold boy with fever, a maculopapular rash, and enlarged cervical and postauricular lymph nodes. Examination of the CSF revealed 141 leukocytes/mm3, of which 84% were lymphocytes, and a protein value of 100 mg/dL. An electrocardiogram was normal. In this child, the rash appeared before the fever. Coxsackievirus B5 was isolated from the pharynx and the CSF. Nogen and Lepou\412 reported an infant with a similar illness. This child had a nonspecific erythematous papular rash on the face and scalp. One week later, he became febrile and irritable. The CSF contained 440 white blood cells/mm3,and 96% of them were mononuclear. Virus was isolated from the feces, throat, and CSF. Artenstein and associate^'^^ reported a 23-day-old girl with a fever and an erythematous macular rash that spread from the scalp to the entire body, except the palms and soles, and lasted 4 days. Coxsackievirus B5 was recovered from the stool, but no evidence of serum antibody to this virus was found. McLean and c o - ~ o r k e r s also ' ~ ~ described a child with a papular rash on the trunk and limbs that was present at birth. On the fourth day of life, the rash had disappeared, but the patient then developed a temperature of 39.4' C. Irritability, twitching, and fullness of the anterior fontanelle were observed, and CSF examination showed meningitis. During an &day period, the child had repeated episodes of vomiting and diarrhea. On the 1lth day of life, the infant had hyperpnea, tachycardia, and an enlarging liver. The child died on the 13th day of life. Autopsy revealed extensive encephalitis and focal myocardial necrosis. Virus was recovered from the brain, heart, lungs, and liver. 'See references 28, 139, 147, 149, 200,202,231,232,234,380,391,and 423.


805

It appears that neonatal infection with coxsackievirus B5 is less likely to be fatal than infection with the other coxsackieviruses B. Only 6 of 36 infants described in Table 24-8 died. In contrast to coxsackievirusesB2, B3, and B4, coxsackievirus B5 appears to be more neurotropic than cardiotropic. ECHOVIRUSES

Echovirus 1. Domok and Molnar228described aseptic meningitis related to echovirus 1.

Echovirus2. Krajden and Middleton" described three infants with echovirus 2 infections. Two of the neonates had meningitis and recovered. The third child, who died, had a sepsis-like illness. Virus was isolated from the CSF, lung, liver, and urine. One other neonate with echovirus 2 infection has been observed, but no details are available.340 Echovirus 3. In the summer of 1970, Haynes and cow o r k e r ~studied ~ ~ ~ an epidemic of infection caused by echovirus 3. Three infected neonates were observed, all of whom had meningitis. One child, a full-term girl, developed tonic seizures and an inability to suck on the third day of life. The serum bilirubin level was 28 mg/dL. Shortly thereafter, the child became cyanotic, flaccid, and apneic and developed a bulging anterior fontanelle; she was in shock. She received assisted ventilation with a respirator for 3 days. When the child was 1 month old, severe neurologic damage with developing hydrocephalus was obvious. Echovirus 3 was recovered from the CSF, and the CSF protein level was 880 mg/dL on the sixth day of life. The other two infants in this study apparently had uncomplicated aseptic meningitis. The CSF findings in one child revealed 1826 white blood cells/mm3,and 91% of them were polymorphonuclear cells. The other child had 320 cells/mm3,98% of which were polymorphonuclear cells. A 4-day-old infant from whom echovirus 3 was recovered from the CSF has been reported.2sThis child had fewer than 3 white blood cells/mm3 in the CSF. Other neonates with echovirus 3 infection have been observed, but no details are a~ailable."~*~~~

Echovirus4. Linnemann and associates383studied 11 infants with echovirus 4 infections. All infants had fevers, and most were irritable. Four infants had a fine maculopapular rash, which was located on the face or abdomen, or both. In two children, the extremities were also involved. Other neonates with echovirus 4 infections have been reported, but details of their illness are not a ~ a i l a b l e . ' ~ ~ ~ ~ ~ ~ Echovirus 5. There have been six reports of neonatal illnesses associated with echovirus 5 infections.340'348,3792432 In one nursery epidemic, six infants were in~olved?~' All infants had fever (38.3' C to 39.7' C) that lasted 4 to 8 days. Two neonates had tachycardia that was disproportionately rapid when compared with the degree of fever, but in neither was there evidence of myocarditis. Four infants had splenomegaly and enlarged lymph nodes; these findings persisted for several weeks. In 1966 (July to October), an epidemic of echovirus 5 infection involved 23% of the infants in the maternity unit Fiftyat the Royal Air Force Hospital in Chargi, Singapore.240 six infants were symptomatically infected, and 10 were asymptomatically infected. Those who were ill were 2 to 12 days old at the onset of disease. All 56 symptomatic infants

806

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had fever; 87% of them had a temperature of 38.3OC or greater. The mean duration of fever was 3.5 days, with a range of 2 to 7 days. Twenty infants had a faint erythematous macular rash that was most prominent on the limbs and buttocks but also occurred on the trunk and face. The rash, which began 24 to 36 hours after the beginning of fever, lasted 48 hours. Diarrhea occurred in 17 infants, 4 of whom passed blood and mucus. Vomiting was observed in about one half the neonates. All infants apparently recovered completely. One newborn girl had a nonspecific, biphasic febrile illness.327Echovirus 5 was recovered from the CSF, but the cell count, protein level, and glucose value were normal. Another study included a 9-day-old infant with aseptic meningitis!32 During an epidemiologic investigation in Rochester, New York, 13 of 75 enteroviral isolates were echovirus 5.178Six of the infants were asymptomatic; no clinical details of the other seven patients were presented. A neonate with sepsis-like illness and hepatic failure died 9 days after birth.348

Echovirus 6. Sanders and Cramblett243reported a boy who was well until 9 days old, when he developed a fever (38’ C), severe diarrhea, and dehydration. His white blood cell count was 27,900 cells/mrn3,and virologic and serologic evidence of echovirus 6 infection was found. Treatment consisted of intravenous hydration, to which there was a good response. Krous and colleagues343described an infant who died on the ninth day of life with a sepsis-like illness. The child had meningitis, disseminated intravascular coagulation, hepatic necrosis, and adrenal and renal hemorrhage. Ventura and associates348reported the death of a full-term neonate with sepsis-like syndrome who at postmortem examination had massive hepatic necrosis, adrenal hemorrhagic necrosis, renal medullary hemorrhage, hemorrhagic noninflammatory pneumonia, and severe encephalomalacia. Yen and coworkers’68reported a premature boy who developed a sepsislike illness on the fifth day of life. This infant had hepatic failure and was treated with intravenous immune globulin. He recovered gradually, but on the 62nd day of life, he died of a nosocomial Enterobacter cloacae infection. Echovirus type 6 has been associated with neonatal illness on two other occasions, but no clinical details are a ~ a i l a b l e . ~ ~ ’ . ~ ~ ~ Echovirus 7. Piraino and colleagues165reported three infants

with echovirus 7 infections. All three had fever, one had respiratory distress and exanthem, and one had irritability and loose stools. Two neonates with fatal sepsis-like illnesses with massive disseminated intravascular coagulation have been r e p ~ r t e d . ’ ~ ~One , ~ ’ ~neonate with severe hepatitis was treated with pleconaril and survived.407 Echovirus 8. In a search for etiologic associations in infantile diarrhea, Ramos-Al~arez~~ identified one neonate from whom echovirus 8 was recovered from the stool. The antibody titer to this virus rose fourfold.

Echovirus 9. Echovirus 9 is the most prevalent of all the enteroviruses (see Table 24-4). From 1955 to 1958, epidemic waves of infection spread throughout the world.@’ Since that time, echovirus 9 has been a common cause of human illness. Despite its prevalence and its frequent association with epidemic disease, descriptions of neonatal illness are uncommon. Unlike experiences with several other enteroviruses, new-

Table 24-9

Neonatal Infection with Echovirus 9

Study

Finding

Asymptomatic infection Meningitis (4 cases) Gastroenteritis (2 cases) Pneumonia (1 case) Hepatic necrosis Rawls e t Severe, generalized disease Cho et Mild febrile illness Jahn and Cherry’” Eichenwald and Koste~alov’~’ Aseptic meningitis Gastroenteritis (2 cases) Meningoencephalitis Haynes et aI.42’ Fatal interstitial pneumonia Cheeseman et a1.16’ Meningitis Krajden and Middleton” Moscovici and M a i ~ e l ’ ~ ~ Mirani et aL4O3

born nursery epidemics caused by echovirus 9 have not often been described. Neonatal echovirus 9 experiences are provided in Table 24-9. Moscovici and MaiselIs6 described an asymptomatic infant with echovirus 9 infection. When echovirus 9 was prevalent in Erie County, New York, during the summer of 1971, seven neonatal cases were 0bserved.4’~Four children had aseptic meningitis, but only moderate elevations of CSF protein values and white blood cells were observed. One child, a 15-day-old infant, had radiologic evidence of bronchopneumonia, and two infants had gastroenteritis. Rawls and co-workers3’’ described an infant who was well until the seventh day of life, when progressive lethargy, anorexia, and irritability developed. The child became moribund, and jaundice, scattered petechiae, and hypothermia were observed. The pulse rate was 90 beats per minute, the respiratory rate was 40 breaths per minute, and the liver was enlarged. The infant died 3 days after the onset of symptoms. Echovirus 9 was recovered from the lung, brain, and CSF. Cho and coll e a g u e ~described ~~~ a similar severe neonatal illness in a child from whom echovirus 9 was recovered from the CSF. This child was hypothermic and hypotonic on the third day of life. He had bilateral pneumonia and leukopenia. After a stormy course, which included an exchange transfusion for suspected sepsis and mechanical ventilation for apnea, he eventually recovered. A child who became febrile (38.3’ C), irritable, and anorectic on the sixth day of life was described by Jahn and Cherry.’” This child became asymptomatic within 2 days; echovirus 9 was recovered from the throat, feces, serum, and CSF. Eichenwald and Ko~tevalov’~’reported two children with mild irritability, fever, and diarrhea and a third child with diarrhea and convulsions in whom laboratory findings showed aseptic meningitis. Haynes and colleagues422studied a large outbreak of meningoencephalitis caused by echovirus 9 and described nine children who were 2 weeks to 2 months old. Cheeseman and associatesI6’ studied a neonate with fatal interstitial pneumonia, and Krajden and Middleton28 reported a 4-day-old infant from whom echovirus 9 was recovered from the CSF. This child had fewer than 3 white blood cells/mm3 in the CSF. Echovirus 11. Neonatal illness associated with echovirus 11 infection has been interesting and varied. Reported cases are

Chapter 24

Table 24-1 0


Neonatal Infection with Echovirus 11

Study

Finding

Miller e t al.238

Exanthern and pneumonia (1 case) Nonspecific febrile illness (1 case) Aseptic meningitis (1 case) Gastroenteritis (2 cases) Gastroenteritis (1 case) Meningitis (1 case) Meningitis (3 cases, 1 with rash) Severe, nonspecific febrile illness (1 case) Respiratory illness (22 cases) Fever (31 cases) Stomatitis (4 cases) Fever and stomatitis (6 cases) Encephalopathy (1 case) Nonspecific febrile illness ( 1 case) Sepsis-like illness with cardiac failure (1 death) Lower respiratory infection (1 case) Sepsis-like illness with hepatitis and rash (1 case) Aseptic meningitis (4 cases) Gastroenteritis andlor respiratory distress (3 cases) Sepsis-like illness with shock, diffuse bleeding, and renal hemorrhage (3 deaths) Fever (100%); pharyngitis (7%) (42 cases) Sepsis-like illness with disseminated intravascular coagulation, hepatic necrosis (1 death) Sepsis-like illness with apnea, lethargy, poor feeding, jaundice, hepatitis, disseminated intravascular coagulation (4 deaths) Myocarditis (5 cases) Meningitis and rash (2 cases) Meningitis (4 cases) Fatal case with cardiac failure, interstitial pneumonia, and interventricular cerebral hemorrhage Meningitis Fever (2 cases) Meningitis (4 cases) Fatal sepsis-like illness Sepsis-like illness (1 1 deaths) Sudden death Sepsis-like illness (5 deaths) Sepsis-like illness (1 death, 1 survived) Meningitis (34 infants 24 months old) Sepsis-like illness (2 deaths) Sepsis-like illness with meningitis and apnea (5 cases) Meningitis (4 cases) Gastroenteritis (3 cases) Sepsis-like illness with hepatic necrosis (4 deaths) Meningitis (8 cases with 1 death) Mild illness (4 cases) Inapparent infection (2 cases) Sepsis-like illness (9 cases, 5 with meningitis) Inapparent infection (1 case) Meningitis (2 cases, 1 with myocarditis) Pneumonia (1 case) Inapparent infection (7 cases) Apnea (1 case) Sepsis-like illness with hepatic failure Bone marrow failure

Sanders and Cramblett243 Berkovich and K i b r i ~ k ~ ~ ~ Cramblett et al.235 Hercik et Ha~egawa’~* Davies et al.251

Jones et Lapinleimu and H a k ~ l i n e n ‘ ’ ~ Nagington et al.250 Suzuki et al.400 Krous et a1.343 M~dlin’~~ Drew414 Piraino et aI.16’

Krajden and Middleton28 Mertens et al.257 Reyes et Berry and N a g i n g t ~ n ~ ~ ~ Gh et a1.345 Bose et al.163 Bowen et al.429 Halfon and S p e ~ t o r ~ ~ ~ Steinmann and A l b r e ~ h t ~ ~ ’ Gitlin et a1.347 Kinney et Rabkin et a1.262 lsaacs et

Wang et Tarcan et a1.433

807

listed in Table 24-10. Eleven of the reports involved nursery outbreaks, and in five reports, the neonatal cases were part of a larger community epidemic. Miller and associates23*studied an epidemic of aseptic meningitis and other acute febrile illnesses in New Haven, Connecticut, in the summer of 1965. This epidemic was unique in that one half of the patients with meningitis from whom virus was isolated were younger than 6 months. The echovirus 11 in this epidemic was a prime strain. Three neonatal illnesses were reported. One of the patients, a 1-month-old infant, was initially irritable and feverish and had diarrhea. Chest radiographs revealed bilateral

pneumonitis. A generalized, discrete maculopapular rash, which lasted 24 hours, was seen on the third day of illness. Fever persisted for 6 days. A 12-day-oldgirl had fever (39.4’ C) lasting 1day but no other findings. Echovirus 11 was recovered from her throat. Another 1-month-old infant had aseptic meningitis. Sanders and Crarnblet~’~~ described two infants with diarrhea. Both infants were acutely ill; one was jaundiced and irritable and had feeding difficulty. In another study, two infants with echovirus 11 infections had diarrhea.242One infant had a temperature of 39.3’ C and a “stuffy nose,” and

808

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Viral Infections

the other had a temperature of 39.8"C and aseptic meningitis. Cramblett and co-worker~'~~ observed an outbreak of nosocomial infections caused by echovirus 11 in a neonatal intensive care unit. In a 1-month-old, premature infant with frequent apneic episodes, the CSF contained 2200 white blood cells/mm3,89% of them polymorphonuclear cells, and the protein level was 280 mg/dL. The infant made a gradual recovery. Echovirus 11 was isolated from the CSF and stool. In another premature infant, apneic episodes and bradycardia suddenly began on the 20th day of life. Fever developed, the apneic spells continued, and digitalis therapy was necessary because of congestive heart failure. Examination of the CSF revealed aseptic meningitis, and echovirus 11 was recovered from the CSF, throat, and stool. A third child with aseptic meningitis had an exanthem. The disease began suddenly, and the child had shallow respirations and poor skin color. On the next day, generalized seizures occurred, and a maculopapular rash developed on the trunk, extremities, and face. The patient made a gradual recovery. A fourth child had a severe, nonspecific febrile illness. A particularly noteworthy finding in neonatal echovirus 11 infection has been severe sepsis-like illness with hepatitis or hepatic necrosis, disseminated intravascular coagulation, and extensive hemorrhagic manifestations.162-161,250,251,254,343-348.351 During the past 15 years, more than 40 such cases have been described, and most of the illnesses have been fatal. Hercik and c o - w o r k e r ~ *reported ~~ an epidemic of respiratory illness in 22 newborns. Six of the infants were severely ill, and one subsequently died. The incubation period varied from 17 hours to 9 days, with an average of 3 days. Seven infants had an interstitial pneumonia, and all had rhinitis, pharyngitis, and vomiting. Toce and KeenanI6' reported two newborns with respiratory distress and pneumonia at birth. Both infants died of their echovirus 11 infections. Tarcan and colleagues433described a 5-day-old boy who developed fever and diarrhea. He developed a maculopapular rash on the face, generalized petechiae and hemorrhagic bullae, and pancytopenia due to bone marrow failure. This infant was treated with intravenous immune globulin and recovered.

Echovirus 13. Before 2000, infection with echovirus 13 was rare in neonates. The virus was isolated from one asymptomatic infant in a neonatal surveillance In 2001 in the United States, echovirus 13 was the leading cause of aseptic meningitis, and during 2001 and 2002, aseptic meningitis outbreaks with this agent occurred in a number of c o ~ n t r i e s . ~A' - substantial ~~ number of cases were infants who were 3 months old or younger.-' A 28-day-old boy in Tennessee had aseptic meningitis and hepatitkM1Neonatal cases were reported in Israel and Spain, but details were not Echovirus 14. Hughes and colleagues159reported an infant boy who became febrile (38O C) and had cyanotic episodes on the third day of life. When 4 days old, his temperature was 38.9" C, and he experienced recurrent apneic spells. Liver enlargement, hypothermia, bradycardia, periodic breathing, and spontaneous ecchymoses developed, and the infant died on the seventh day of life. Laboratory studies revealed the presence of leukopenia and thrombocytopenia, and autopsy showed severe hepatic necrosis. DrouhetM6described a child with aseptic meningitis and echovirus 14 infection, and

Hinuma and associates381reported four newborns with apparent asymptomatic echovirus 14 infections.

Echovirus 16. In 1974, Hall and colleagues385studied five neonates with echovirus 16 infections. All five infants were admitted to the hospital because sepsis was suspected. Four of five were febrile, all were lethargic and irritable, and two had abdominal distention. Three of the neonates had erythematous maculopapular exanthems, and in two, the rash appeared after or with defervescence. Leukocyte counts in four infants revealed an increased percentage of band form neutrophils. Two neonates had aseptic meningitis. Lake and associates340observed three infants with echovirus 16 infections. In their study, clinical findings were not itemized by virus type, but it is inferred that sepsis-like illnesses occurred.

Echovirus 17. Neonatal infection with echovirus 17 has been observed by three investigators. Cherry and co-worker~'~~ reported two ill infants. A 19-day-old infant developed otitis media 5 days after his mother had a flulike illness. Echovirus 17 was isolated from his feces, and serologic evidence of echovirus 17 infection was found in the infant and the mother. The second child had a nonspecific febrile illness at the age of 4 weeks, which was severe enough to require hospitalization. Virus was isolated from the infant's throat, feces, and serum. Sanders and Cramblett243described two neonates with exanthem associated with echovirus 17. The first child, a 3-week-old girl, became drowsy, anorectic, and febrile. She had a fine maculopapular rash on the trunk, a slightly injected pharynx, and a few petechiae on the soft palate. She remained febrile for 5 days. Echovirus 17 was recovered from the CSF and the feces. The second infant became ill when 3 weeks old. His symptoms were mild rhinitis and cough followed by lethargy and refusal to eat. Four days after the onset of symptoms, his temperature was 39" C, and his respiratory rate was 60 breaths per minute. A fine maculopapular rash appeared on the trunk, and radiographs revealed an infiltrate in the right lung. The patient's course was uneventful, and he was much improved 12 days after the onset of symptoms. Faulkner and van R ~ o y e n *described ~~ an outbreak of echovirus 17 infection with illness in a nursery in mid-August of 1971. Seven infants were involved, including one with aseptic meningitis who was 7 weeks old. AU the infants had fever, four had central nervous system signs, three had abdominal distention, four had diarrhea, and three had a rash. One other infant from another community was also studied by the investigators. This child had a febrile pneumonitis when 3.5 weeks old. The findings abated in 5 days, but the child suddenly died 6 days later. Autopsy revealed interstitial pneumonitis with extensive edema and scattered petechial hemorrhages of the viscera. Echovirus 17 was isolated from the liver, lung, spleen, and kidney.

Echovirus 18. In 1958,Eichenwald and colleagues2@described epidemic diarrhea associated with echovirus 18 infections. In a nursery unit of premature infants, 12 of 21 were mildly ill. Neither temperature elevation nor hypothermia occurred. Six infants were lethargic and listless, and two developed moderate abdominal distention. The diarrhea lasted 1 to 5 days; there were five or six watery, greenish stools per day, occasionally expelled explosively. In two

Chapter 24 infants, a small amount of blood was seen in the stools, but there was no mucus or pus cells. Five other infants in another nursery had similar diarrheal illness. Echovirus 18 was recovered from all ill infants. Medearis and c o - w ~ r k e r s ~reported ~’ a 3-week-old girl with fever, irritability, lethargy, pharyngitis, and postnasal drainage. Admitted to the hospital because of apneic spells, she developed a generalized erythematous blotchy macular rash and had frequent stools. The illness lasted about 7 days. Echovirus 18 was recovered from the blood, throat, and feces. Berkovich and found echovirus 18 in the stool of a 12-day-old twin infant with fever and a red throat. The relationship of echovirus 18 to the illness is uncertain because the patient’s twin was infected with echovirus 11, and the patient also had serologic evidence of echovirus 11 infection. The fever and red throat may have been caused by echovirus 11 rather than echovirus 18 infection. Wilfert and associates425observed a 9-day-old infant with aseptic meningitis.

Echovirus 19. Cramblett and c o - ~ o r k e r described s ~ ~ ~ two neonates with echovirus 19 infections. One child had an upper respiratory infection, cough, and paroxysmal atrial tachycardia. The other child also had an upper respiratory infection, but in addition to echovirus 19 infection, coxsackievirus B4 was recovered from the throat of this infant. Butterfield and associates245 isolated echovirus 19post mortem from the brain, lung, heart, liver, spleen, lymph nodes, and intestine of a premature infant who had cystic emphysema. The relationship between the generalized viral infection and the pulmonary disease is not understood. Philip and LarsonI6’ reported three catastrophic neonatal echovirus 19 infections, which resulted in hepatic necrosis and massive terminal hemorrhage. One infant, infected in utero, was symptomatic at birth. The Apgar score was 3, and multiple petechiae were observed. The infant had generalized ecchymoses and apneic episodes and died when 3.5 hours old. Thrombocytopenia was identified, and echovirus 19 was isolated from the brain, liver, spleen, and lymph nodes. The other two infants who died of echovirus 19 infection were twins. They were normal during the first 3 days of life but then became mildly cyanotic and lethargic. Shortly thereafter, apneic episodes occurred, and jaundice and petechiae developed. Both twins became oliguric, and they died on the eighth and ninth days of life, with severe gastrointestinal bleeding. Both twins were thrombocytopenic, and virus was recovered from systemic sites in both. Two similar catastrophic cases have been described.406 Purdham and associates255reported an outbreak of echovirus 19 in a neonatal unit in which 12 infants were affected. Eleven infants were febrile, 10 were irritable, 7 had marked abdominal distention with decreased bowel sounds, and 5 had apneic episodes. Bacon and described two neonates with sepsis-like illness. The infants were cyanotic with peripheral circulatory failure. In another study involving the same echovirus 19 epidemic, five infants younger than 3 months were reported.3w All had sepsis-like illness with hypotonia and peripheral circulatory failure. Two infants had aseptic meningitis, and two others had diarrhea.

Echovirus 20. Eichenwald and Koste~alov’~~ recovered echovirus 20 from four asymptomatic infants younger than 8 days (see “Cloud Baby”). Five neonates with severe illness


due to echovirus 20 have also been hepatitis,andtwodied.

809

All had

Echovirus 21. Jack and c o - ~ o r k e r srecovered ~~~ echovirus 21 from the feces of a 7-day-old infant with jaundice and diarrhea. No other details of the child’s illness are available. Chonmaitree and associates4I2studied a 19-day-old infant with aseptic meningitis and rash, and Georgieff and coll e a g u e ~reported ~ ~ ~ a newborn with fulminant hepatitis. Lake and colleagues340also mentioned one infected infant but presented no specific details.

Echovirus 25. Linnemann and colleagues3s3reported one neonate with echovirus 25 infection. They gave no virusspecific details except that fever and irritability occurred. Echovirus 30. Matsumoto and associates42sdescribed a nursery outbreak involving 11 infants during a 2-week period. All the neonates had aseptic meningitis, and all recovered. Two symptomatic and six asymptomatic neonates were reported in the Rochester, New York, surveillance Echovirus 31. McDonald and associates256described three neonates in an intensive care nursery with echovirus 31 infections. One infant had a fatal encephalitis-like illness, with hypertonicity, hyperreflexia, and apneic spells. The other two infants also experienced apneic spells, and in addition, one had pneumonia and meningitis. Echovirus 33. In a study of epidemic illness related to echovirus 33 disease in the Netherlands, K a p ~ e n b e r gstated ~~~ that 7- to 8-day-old neonates in a maternity ward had a febrile illness. No further data were presented. ENTEROVIRUS71 Schmidt and colleagues426mentioned one 3-week-old infant with meningitis and enterovirus 71 infection. Chonmaitree and colleaguesM5described one 9-day-old neonate with aseptic meningitis and one 14-day-old infant with gastroenteritis from enterovirus 71. Chen and associate^^'^ reported a child with bilateral lower limbs weakness in association with the hand-foot-and-mouth syndrome. PARECHOVIRUSES

Parechovirus 1. Parechovirus 1 has been associated with three epidemics of nursery infections. During a survey of perinatal virus infections, 44 infants were found to be infected with parechovirus 1 during a study period from May to December 1966.236The virus prevalence and the incidence of new infections during this period were fairly uniform. No illness was attributed to parechovirus 1 infection, and the virus disappeared from the nursery in mid-December of 1966. Berkovich and P a ~ ~ g a nstudied ’~~ respiratory illnesses in premature infants and reported 64 infants with illness, 18 of whom had virologic or serologic evidence of parechovirus 1 infection. Many had high but constant levels of serum antibody to parechovirus 1. Some of these infants were probably also infected with parechovirus 1. The children with proven parechovirus 1 infections could not be clinically differentiated from those without evidence of parechovirus 1 infection. Of 18 infants with documented parechovirus 1 infections, 90% had corna, 39% had vneumonia, and 11% had morbilliform rash o r conjunctivks, or both. In contrast to the studies of Jack and ~o-workers?~~ only 3 of 35 asymptomatic infants were found to be infected

810

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Viral Infections

with parechovirus 1. Nakao and associates246recovered parechovirus 1 from 29 premature infants. Many of the infected infants were asymptomatic, and those who were ill had only mild symptoms of coryza, cough, and diarrhea. Jenista and colleague^'^^ described 17 parechovirus 1 infections in nonhospitalized neonates. Clinical details were not presented, but it appears that all of these infants were asymptomatic. Parechovirus 1 infection was associated with a nosocomial necrotizing enterocolitis outbreak.409 Parechovirus 2. Ehrnst and E r i k s ~ o nreported ~ ~ ~ a 1-monthold girl with encephalopathy resulting from a nosocomial parechovirus 2 infection. No further details of this case were provided.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

Clinical Diagnosis The clinical differentiation of neonatal infectious diseases frequently seems to be an impossible task. Although it is true that treatable bacterial and viral illnesses should always be considered and treated first, it is also true that when all the circumstances of a particular neonatal illness are considered, enterovirus diseases can be suspected on clinical grounds. The most important factors in clinical diagnosis are season of the year, geographic location, exposure, incubation period, and clinical symptoms. In temperate climates, enteroviral prevalence is distinctly seasonal, and disease is usually seen in the summer and fall. Neonatal enterovirus disease is unlikely in the winter. In the tropics, enteroviruses are prevalent throughout the year, and the season therefore is not helpful diagnostically. As with all infectious illnesses, knowledge of exposure and incubation time is important. A careful history of maternal illness is vital, particularly the symptoms of maternal illness. For example, nonspecific mild febrile illness in the mother that occurs in the summer and fall should warn of the possibility of more severe neonatal illness. More specific findings in the mother (e.g., aseptic meningitis, pleurodynia, herpangina, pericarditis, myocarditis) should alert the clinician to look for more specific enteroviral illnesses. Minor illness in nursery personnel during enteroviral seasons and the short incubation period of enteroviral infections should be taken into consideration. Manifestations of neonatal nonpolio enteroviral infections are given in Table 24-5.

Laboratory Diagnosis Virus Isolation Most viral diagnostic laboratories have facilities for the recovery of most enteroviruses that cause congenital and neonatal illness. Three tissue culture systems-primary rhesus, cynomolgus, or African green monkey kidney tissue culture; a diploid, human embryonic lung fibroblast cell strain; and the RD cell line-allow the isolation of all polioviruses, coxsackieviruses B, echoviruses, newer enteroviruses, parechoviruses, and many coxsackieviruses A. In a 1988study in which Buffalo green monkey kidney cells and subpassages of primary human embryonic kidney cells were used in addition to primary monkey kidney and human diploid

fibroblast (MRC-5) cells, the enterovirus recovery rate was increased by 1l%.447 For a complete diagnostic isolation spectrum, suckling mouse inoculation should also be performed. Optimally, at least one blind passage should be carried out in each of the culture systems. Proper selection and handling of specimens are most important in the isolation of viruses from ill neonates. Because infection in neonates tends to be generalized, collection of material from multiple sites is important. Specimens should be taken from any or all of the following: nasopharynx, throat, stool, blood, urine, CSF, and any other body fluids that are available. Swabs from the nose, throat, and rectum should be placed in a transport medium. Transport medium provides a protective protein, neutral pH, and antibiotics for control of microbial contamination and, most importantly, prevents desiccation. Many viral transport and storage media are commercially available or are prepared readily in the laboratory; their utility has been reviewed elsewhere.448Convenient and practical collection devices, such as the Culturette (Becton-Dickinson, Cockeysville, Md) or Virocult (Medical Wire and Equipment Co.,Victory Gardens, NY),consist of a swab, usually Dacron or rayon, on a plastic or aluminum shaft accompanied by a self-contained transport medium (Stuart or h i e s ) and are routinely available in most hospitals for bacteriologic culture. Calcium alginate swabs, which are toxic to herpes simplex virus, and wooden shafts, which may be toxic for viruses and the cell culture system itself, should not be used. Saline or holding media that contain serum also should be avoided. Useful liquid transport media (2-mL aliquots in screw-capped vials) consist of tryptose phosphate broth with 0.5% bovine albumin; Hanks’ balanced salt solution with 5% gelatin or 10% bovine albumin; or buffered sucrose which has been used as a phosphate (0.2 M, 2-SP),M83M9 combined transport for viral, chlamydial, and mycoplasmal culture requests and is appropriate for long-term frozen storage of specimens and isolates.450 Fluid specimens should be collected in sterile vials. Specimens of autopsy material are best collected in vials that contain transport medium. In general, specimens should be refrigerated immediately after collection and during transportation to the laboratory. Specimens should not be exposed to sunlight during transportation. If an extended period is likely to elapse before a specimen can be processed in the laboratory, it is advisable to ship and store it frozen. Contrary to popular belief, evidence of enteroviral growth from tissue cultures takes only a few days in many cases and less than a week in most.451The use of the spin amplification, shell vial technique, and monoclonal antibodies has significantly reduced the time for detection of enteroviral ~ u l t u r e sAfter . ~ ~isolation ~ ~ ~ ~ of an enterovirus, identification of its type is conventionally done by neutralization, which is unfortunately an expensive and lengthy process.

Rapid Virus Identification Because of the number of different serotypes of enteroviruses, the use of immunofluorescence, agglutination, counterimmunoelectrophoresis, and ELISA techniques for the direct detection of antigen in suspected enteroviral infections has not been useful. Nucleic acid techniques with cDNA and RNA probes have been useful for the direct identification of enteroviruses. 76,453-456 Of most importance has been the

Chapter 24


811

development of numerous PCR techniques. Since 1990, ations, it is not necessary to carry out serologic tests on the innumerable reports have described enteroviral PCR collected serum because demonstration of an antibody titer methods and their use in identifjmg enterovirus RNA in rise in the serum of an infant from whom a specific virus has clinical specimens.49-62*457-465 PCR has proved most useful for been isolated from a body fluid is obviously superfluous. the direct identification of enteroviruses in the CSF of patients However, collected serum can be useful diagnostically if the with meningitis. Compared with culture of CSF specimens, prevalence of specific enteroviruses in a community is known. PCR is more rapid and sensitive, and the specificity is equal. In this situation, it is relatively easy to look for antibody titer PCR also has proved useful in the identification of enterochanges to a selected number of viral types. More rapid viruses in blood, urine, and throat specimens.31751,56,58,459,460 diagnosis using a single serum sample is possible if a search Particularly impressive are the findings of Byington and for specific IgM enteroviral antibody is made.207v468‘476 associate^.^' Using PCR on specimens of blood and CSF, they Unfortunately, enterovirus IgM antibody tests are not found that more than 25% of infants admitted to the hospital commercially available. Commercial laboratories do offer for suspected sepsis in 1997 had nonpolio enterovirus enteroviral complement fixation antibody panels. However, infections. Based on this study and the work of Adrkoletti these tests are expensive, and their results in the clinical and co-workers:2 I believe the general workup for febrile setting are almost always meaningless unless acute-phase neonates hospitalized for possible sepsis should include PCR and convalescent-phase sera are analyzed. for enteroviruses in blood and CSF. This is most important Histology during enterovirus season (summer and fall in temperate climates), but because enteroviral circulation continues all There are no specific histologic findings in enteroviral year, it is reasonable to also perform PCR in the off seasons. infections, such as those seen in cytomegalovirus or herpes Although PCR detects enterovirus RNA, the specific enterosimplex viral infections. However, tissues can be examined viral type is not identified. Because of this shortcoming, I for specific enteroviral antigens by immunofluorescent study and by pCR.I49,457,477,478 recommend that conventional culture should be performed along with PCR. PCR has also identified enteroviruses in frozen and Differential Diagnosis formalin-fixed biopsy and autopsy specimens of myo5 I ,56,58,459,460 I The differential diagnosis of congenital and neonatal enteron one study, enteroviruses were virus infections depends on the clinical manifestations. In identified in myocardial tissue from four neonates who died general, the most important illness categories are generalized of rnyo~arditis.~~~ In one case, the specimen was obtained bacterial sepsis or meningitis, congenital heart disease, and during life by a right ventricular endomyocardial biopsy, and congenital and neonatal infections with other viruses. in the other three, frozen or formalin-fixed autopsy samples Hypothermia and hyperthermia associated with nonwere used. Most PCR methods can detect one tissue culture specific signs such as lethargy and poor appetite are common infective dose of enterovirus in CSF, stool, or throat in neonatal enteroviral infections; they are also the presenting specimen.459Polioviruses can be separated from other manifestations in bacterial sepsis. Proper bacterial cultures enteroviruses, and poliovirus vaccine strains can be rapidly are essential. Differentiation between congenital heart disease identified by PCR.461-466 and neonatal myocarditis is frequently difficult. However, Enteroviral RNA has been identified in numerous tissue the occurrence of fever or hypothermia, generalized lethargy specimens from patients with chronic medical conditions, and weakness, and characteristic electrocardiographicchanges such as idiopathic dilated cardiomyopathy. However, the should suggest a viral cause. possibility of lack of specificity (false-positive results) is a Congenital infections with rubella virus, cytomegalovirus, concern. Toxoplasma gondii, or Treponema pallidurn are frequently Serology associated with intrauterine growth retardation; this is not usual with enterovirus infections. Generalized herpes simplex Except in special circumstances, the use of serologic infections are clinically similar to severe infections with techniques in the primary diagnosis of suspected neonatal several enteroviruses; in herpes infections, skin lesions are enterovirus infections is impractical. Standard serologic common, and a scraping of a lesion and a culture should study depends on the demonstration of an antibody titer rise allow a rapid diagnosis. In infants with signs of central to a specific virus as an indication of infection with that nervous system involvement, it is particularly important to agent. Although hemagglutination inhibition, ELISA, and consider herpes simplex virus infection as a possible cause complement fixation tests take only a short time to perform, because infection with this agent is treatable and early these tests can be done only after the collection of a second, treatment is essential. In infants with meningitis, proper convalescent-phase blood specimen. These tests are also cultures and PCR testing are essential because the CSF impractical in searching for the cause of a specific illness in findings in bacterial and viral illnesses are frequently similar. a child because there are so many antigenically different enteroviruses. As discussed in “Antigenic Characteristics,” group antigens can be produced that allow serologic diagnosis by IgM EIA and complement fixation, but these tests PROGNOSIS lack s p e ~ i f i c i t y . ~ ~ . ~ ~ , ~ ~ In the evaluation of an infant with a suspected enteroPolioviruses virus infection, serum should be collected as soon as possible after the onset of illness and then again 2 to 4 weeks later. As substantiated in the review by Bates”’ and the summary in Table 24-7, poliovirus infections in neonates are generally This serum should be stored frozen. In most clinical situ-

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severe. Of the 44 cases with available follow-up data, there were 21 deaths; of the survivors, 12 had residual paralyses. Because infant survivors of poliomyelitis are susceptible to infection by the other two types of poliovirus, they should receive polio vaccine.

Nonpolio Enteroviruses

The most alarming report is that of Ei~henwald:’~ who gave details of a 5-year follow-up study of infants who had had neonatal diarrhea associated with echovirus 18 infedion?@ Thirteen of 16 infants who had had an echovirus 18 infection during the neonatal period showed neurologic damage; these children had an IQ of less than 70, spasticity, deafness, blindness, or a combination of these effects. In most instances, the antibody response of neonates after enterovirus infection is good. It is therefore to be expected that one attack of infection with a particular viral type provides immunity to the specific agent in the future. From the evidence derived from polio vaccine studies, it is probable that reinfection with all enteroviruses is common, but that after an initial antibody response, a secondary inapparent infection occurs and is confined to the gastrointestinal tract.

It is apparent that the immediate prognosis for patients with coxsackievirus and echovirus infections is related to the specific manifestations. Mortality rates are highest for infants with myocarditis, encephalitis, or sepsis-like illness with liver involvement. Differences in the severity of illness depend on viral type and strain variations. In general, infections with coxsackievirusesB1 to B4 and with echovirus 11 appear to carry the most ominous initial prognoses. There is a surprising dearth of information related to long-term sequelae of neonatal coxsackievirus and echovirus infections. Gear,’95 in a 4-year follow-up study, found no THERAPY evidence of permanent cardiac damage in several children who had coxsackievirus B myocarditis. For children with Specific Therapy aseptic meningitis, there is little available evidence of neuroNo specific therapy for any enterovirus infection is approved logic damage. One of five infants studied by Nogen and Lepow?” from whom virus was recovered from the CSF, was for use in the United States. In severe, catastrophic and suspected of having brain damage. Cho and colleagues389 generalized neonatal infection, it is likely that the infant received no specific antibody for the particular virus from reported that a child who had had severe neonatal echovirus the mother. In this situation, it is probably advisable to 9 disease was developing normally at 1 year of age. Tuuteri administer human immune serum globulin to the infant. and associates229reported that two children who had had clinically mild neonatal coxsackievirus B3 infections were Dagan and associates480examined three lots of human serum thriving when seen at 1 year of age. After an epidemic of globulin and found the presence of neutralizing antibodies mild febrile disease related to echovirus 5, 51 children were to several commonly circulating and infrequently circulating examined at 1 year of age and found to be normal.240 enteroviruses.Although there is no evidence that this therapy Farmer and colleagues423did a careful follow-up study of is beneficial in treating acute neonatal infections, there is evidence of some success in the treatment of chronic entero15 children who had meningoencephalitis related to coxsackievirus B5 during the neonatal period. When 6 years old, two viral infections in agammaglobulinemic patients.481Because it was found by Hammond and c o - w o r k e r ~that ~ ~ ~a single of the children were found to have developed spasticity, and dose of intramuscular immunoglobulin resulted in little change their intelligence was below the mean for the study group as in circulating neutralizing antibodies to coxsackievirus B4 a whole and below the mean of a carefully selected control and echovirus 11 in seven infants, it seems advisable when group. Three children who had myocarditis and meningotherapy is decided on to use high-dose intravenous immune encephalitis had no cardiac sequelae at the age of 6 years. Sells globulin. One neonate with disseminated echovirus 11 inand associates427described neurologic impairment at later fection with hepatitis, pneumonitis, meningitis, disseminated follow-up study of some children who had central nervous intravascular coagulation, decreased renal function, and system enteroviral infections during the first year of life. In a study in which nine children with enteroviral anemia survived after receiving a large dose of intravenous immune globulin and supportive care?83 meningitis during the first 3 months of life were compared Abzug and colleagues484performed a small but controlled with nine matched control children, Wilfert and associates432 study in which nine enterovirus-infected neonates received found that the receptive language functioning of patients was significantly less than that of the controls. Head circumintravenous immune globulin and seven similarly infected infants received supportive care. In this study, there was no ference, hearing, and intellectual function were similar for patients and controls. Bergman and colleagues4” reported an significant difference in clinical scores, antibody values, or extensive study in which 33 survivors of enteroviral meningitis magnitude of viremia and viruria in those treated compared during infancy were compared with their siblings. In this with the control infants. However, five infants received intracomprehensivestudy, none of the survivors had major neurovenous immune globulin with a high neutralizing antibody logic sequelae, and they performed as well as their siblings titer (21:800) to their individual viral isolates, and they had on a large number of cognitive, achievement, perceptuala more rapid cessation of viremia and viruria. motor skills, and language tests. Rantakallio and co-worker~~’~ Jantausch and associates485reported an infant with a disfound that 16 of 17 patients with neonatal meningitis related seminated echovirus 11 infection who survived after maternal plasma transfusions. The role, if any, of these transfusions in to coxsackievirus B5 had normal neurologic development on follow-up. The one exception was a child with suspected the infant’s recovery is unknown, and this form of therapy intrauterine myocarditis. In another study, 16 newborns cannot be recommended. A neonate with an echovirus 11 with meningitis related to coxsackievirus A14 were normal infection-induced fulminant hepatitis survived after orthotopic liver t r a n ~ p l a n t a t i o n . ~ ~ ~ 2.5 years later.

Chapter 24 Many antipicornavirus drugs and biologicals have been studied during the past 30 y e a r ~ . 6 ~The . ~ ~antiviral drug pleconaril offers promise for the treatment of enteroviral infections.65,395,407,487-4S9 This drug is a novel compound that integrates into the capsid of enteroviruses. It prevents the virus from attaching to cellular receptors and therefore prevents uncoating and subsequent release of viral RNA into the host cell. In a double-blinded, placebo-controlled study of 39 patients with enteroviral meningitis, a statistically significant shortening of the disease duration was noted from 9.5 days in controls to 4.0 days in drug re~ipients.6~ Pleconaril also has been used on a compassionate-release basis in the treatment of patients with life-threatening infe~tion."'~Several categories of enteroviral illnesses have been treated: chronic meningoencephalitis in patients with agammaglobulinemia or hypogammaglobulinemia,neonatal sepsis, myocarditis, poliomyelitis (wild-type or vaccine associated), encephalitis, and bone marrow transplant patients. Favorable clinical responses were observed in 22 of 36 treated patients, including 12 of 18 patients with chronic meningoencephalitis. However, in the absence of controls, the extent to which the favorable outcomes can be attributed to pleconaril is unknown. In severe illnesses, such as neonatal myocarditis or encephalitis, it is frequently tempting to administer corticosteroids. Although some investigators thought this approach was beneficial in treating coxsackievirus myocarditis, I believe that corticosteroids should not be given during acute enterovirus infections. The deleterious effects of these agents in coxsackievirus infections of mice490 are particularly persuasive. Immunosuppressive therapy for myocarditis of unknown origin with prednisone and cyclosporine or azathioprine was evaluated in a controlled trial of 11 1 adults, and no beneficial effect was observed.491 Because the possibility of bacterial sepsis cannot be ruled out in most instances of neonatal enteroviral infections, antibiotics should be administered for the most likely potential pathogens. Care in antibiotic selection and administration is urged so that drug toxicity is not added to the problems of the patient. In neonates with meningitis or meningoencephalitis and in some infants with sepsis-like illnesses, the possibility of herpes simplex virus infections should be strongly considered, and empirical treatment with intravenous acyclovir should be instituted after obtaining appropriate herpesvirus studies.

Nonspecific Therapy Mild, Nonspecific Febrile Illness In infants in whom fever is the only symptom, careful observation is most important. Many infants who eventually become severely ill have 2 to 3 days of fever initially without other localized findings. Care should be taken to administer adequate fluids to febrile infants, and excessive elevation of temperature should be prevented, if possible.

Sepsis-like Illness In infants with severe sepsis-like illness, the major problems are shock, hepatitis and hepatic necrosis, and disseminated intravascular coagulation. For shock, attention should be directed toward treating hypotension and acidosis and ensuring adequate oxygenation.


813

For hepatitis, oral neomycin (25 mg/kg every 6 hours) or other nonabsorbable antibiotics to suppress intestinal bacterial flora may be helpful. The administration of blood (i.e., exchange transfusion) and vitamin K may be useful when bleeding occurs because of liver dysfunction. Heparin therapy should be considered when disseminated intravascular coagulation occurs.

Myocarditis There is no specific therapy for myocarditis. However, congestive heart failure and arrhythmias should be treated by the usual methods. In administering digitalis preparations to infants with enteroviral myocarditis, careful attention to the initial dosage is most important because the heart is often extremely sensitive; frequently, only small amounts of digoxin are necessary.

Meningoencephalitis In patients with meningoencephalitis, convulsions, cerebral edema, and disturbances of fluid and electrolyte balance occur frequently and respond to treatment. Seizures are best treated with phenobarbital, phenytoin (Dilantin), or lorazepam. Cerebral edema can be treated with urea, mannitol, or large doses of corticosteroids. However, it seems unwise to use corticosteroids in active enterovirus infections because the potential benefits may be outweighed by deleterious effects. Fluids should be monitored closely, and frequent determinations of serum electrolyte levels should be made because inappropriate antidiuretic hormone secretion is common.

Paralytic Poliomyelitis Infants should be observed carefully for evidence of respiratory paralysis. If respiratory failure occurs, the early use of a positive-pressure ventilator is essential. In newborns, this is better performed without tracheotomy. Careful attention to pooling of secretions is important. Blood gas levels should be monitored frequently. Passive exercises of all involved extremities should be started if the infant has been afebrile for 3 days.

PREVENTION

Immunization Congenital and neonatal poliomyelitis should be illnesses of historical interest only. However, because segments of populations in a few regions of the world have not been adequately immunized with polioviral vaccines, clinical poliomyelitis will continue to occur. In adequately immunized populations, congenital and neonatal poliomyelitis has been eliminated. Attenuated viral vaccines for other enteroviruses are not available. However, if a virulent enteroviral type became prevalent, it is probable that a specific vaccine for active immunization could be developed. Passive protection with intramuscular immune globulin (0.15 to 0.5 mWkg) or perhaps intravenous immune globulin can be useful in preventing disease.482~492~494 In practice, however, this approach seems to be worthwhile only in sudden and virulent nursery outbreaks. For example, if several cases

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of myocarditis occurred in a nursery, it would seem wise to administer immune globulin to all infants in the nursery. Pooled human immune globulin in most instances can be expected to contain antibodies against coxsackievirus types B1 through B5 and echovirus 11. This procedure could offer protection to infants without transplacentally acquired specific antibody who had not yet become infected.

Other Measures Careful attention to routine nursery infection control procedures is important in preventing and controlling epidemics of enteroviral diseases. Nursery personnel should exercise strict care in washing their hands after handling each infant. It is also important to restrict the nursery area to personnel who are free of even minor illnesses. Nursery infection, when it occurs, is best controlled in units that follow a cohort system. When illness occurs, the infant in question should be immediately isolated, and the nursery should be closed to all new admissions. REFERENCES 1. Cherry JD, Nelson DB. Enterovirus infections: their epidemiology and pathogenesis. Clin Pediatr 5:659, 1966. 2. Bodian D, Horstmann DM. Polioviruses. In Horsfall FL Jr, Tamm I (eds). Viral and Rickettsial Infections of Man, 4th ed. Philadelphia, 1B Lippincon, 1965, p 430. 3. Dalldorf G, Melnick JL. Coxsackie viruses. In HorsfaU FL Jr, Tamm I (eds). Viral and Rickettsial Infections of Man, 4th ed. Philadelphia, JB Lippincott, 1965, p 474. 4. Melnick JL. Echoviruses. In Horsfall FL Jr, Tamm 1 (eds). Viral and Rickettsial Infections of Man, 4th ed. Philadelphia, JB Lippincott, 1965, p 513. 5. Kibrick S. Current status of coxsackie and ECHO viruses in human disease. Prog Med Virol627,1964. 6. Morens DM, Zweighaft RM, Bryan JM. Nonpolio enterovirus disease in the United States, 1971-1975. Int J Epidemiol849, 1979. 7. Wenner HA, Behbehani AM. Echoviruses. I n Gard S, Hallaner C, Meyer KF (eds). Virology Monographs, vol. 1. New York, SpringerVerlag, 1968, p 1. 8. Scott TFM. Clinical syndromes associated with entero virus and RE0 virus infections. AdvVirus Res 8165,1961. 9. Cherry JD. Enteroviruses and Parechoviruses. In Feigin RD, Cherry JD (eds). Textbook of Pediatric Infectious Diseases, 5th ed. Philadelphia, WB Saunders, 2003, p 1984. 10. Grist NR, Bell EJ,Assaad F. Enteroviruses in human disease. Prog Med Virol24114, 1978. 11. Melnick JL. Enteroviruses. I n Evans AS (ed).Viral Infections of Humans: Epidemiology and Control, 3rd ed. New York, Plenum Publishing, 1989,p 191. 12. Gear JHS, Measroch V. Coxsackievirus infections of the newborn. Prog Med Virol 15:42, 1973. 13. Pallansch MA, Roos RP. Enteroviruses: polioviruses, coxsackieviruses, echoviruses, and newer enteroviruses. In Knipe DM, Howley PM (eds). Fields Virology, vol. 1. Philadelphia, Lippincott Williams & Wdkins, 2001, p 723. 14. Stanway G, Joki-Korpela P, Hyypia T. Human parechovirusesbiology and clinical significance. Rev Med Virol 10:57,2000. 15. RacanieUo VR. Picornaviridae: the viruses and their replication. In Knipe DM and Howley PM (eds). Fields Virology,vol. 1, Philadelphia, Lippincott Williams & Wilkins, 2001, p 685. 16. Stanway G, Hyypia T. Parechoviruses. J Virol73:5249, 1999. 17. Melnick JL,Dalldorf G, Enders JF,et al. The enteroviruses. Am J Public Health 47:1556, 1957. 18. Overall JC Jr, Glasgow LA. Virus infections of the fetus and newborn infant. J Pediatr 77:315, 1970. 19. MonifGRG.Viral Infections of the Human Fetus. Toronto, Macmillan, 1969. 20. Kibrick S. Viral infections of the fetus and newborn. Perspect Virol 2:140, 1961.

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84329,1966. 123. Cabasso VJ, Jungherr EL, Moyer AW, et al. Oral poliomyelitis vaccine, Lederle: thirteen years of laboratory and field investigation. N Engl J Med 263:1321,1960. 124. Katz SL. Efficacy, potential and hazards of vaccines. N Engl J Med 270884,1964. 125. Payne AMM. Summary of the conference. In Second International Conference on Live Poliovirus Vaccines, Washington, DC, June 6-10, 1960. Washington, DC, Pan American Sanitary Bureau, 1960. 126. White LR. Comment. In Viral Etiology of Congenital Malformations, May 19-20, 1967. Washington, DC, U.S. Government Printing Office, 1968. 127. Horstmann DM. Epidemiology of poliomyelitis and allied diseases1963. Yale J Biol Med 36:5, 1963. 128. Dalldorf G, Gifford R. Susceptibility of gravid mice to coxsackie virus infection. J Exp Med 99:21, 1954. 129. Berger E, Roulet F. Beitrage zur Ausscheidung und Tierpathogenitut des Coxsackie-virus. Schweiz Z AUg Pathol 15:462, 1952. 130. Selzer G. Transplacental infection of the mouse fetus by Coxsackie viruses. Israel J Med Sci 5:125, 1969. 131. Soike K. Coxsackie B-3 virus infection in the pregnant mouse. J Infect Dis 117:203,1967. 132. Modlin JF, Crumpacker CS. Coxsackievirus B infection in pregnant mice and transplacental infection of the fetus. Infect Immun 32222, 1982. 133. Flamm H. Some considerations concerning the pathogenesis of prenatal infections. In Eichenwald HC (ed). The Prevention of Mental

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Section I11

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392. Bacon CJ, Sims DG. Echovirus 19 infection in infants under six months. Arch Dis Child 51:631,1976. 393. Grossman M, Azimi P. Fever, hepatitis and coagulopathy in a newborn infant. Pediatr Infect Dis J 11:1069, 1992. 394. Wong SN, Tam AYC, Ng THK, et al. Fatal coxsackie B1 virus infection in neonates. Pediatr Infect Dis J 8:638, 1989. 395. Bauer S, Gottesman G, Sirota L, et al. Severe coxsackie virus B infection in preterm newborns treated with pleconariL Eur J Pediatr 161:491,2002. 396. Chawareewong S, Kiangsiri S, Lokaphadhana K, et al. Neonatal herpangina caused by coxsackie A-5 virus. J Pediatr 93:492, 1978. 397. Murray D, Altschul M, Dyke J. Aseptic meningitis in a neonate with an oral vesicular lesion. Diagn Microbiol Infect Dis 3:77, 1985. 398. Nakayama T, Urano T, Osano M, et al. Outbreak of herpangina associated with coxsackievirus B3 infection. Pediatr Infect Dis J 8:495,1989. 399. Cramblett HG, Moffet HL, Middleton GK Jr, et al. ECHO 19 virus infections. Arch Intern Med 110:574, 1962. 400. Suzuki N, Ishikawa K, Horiuchi T, et al. Age-related symptomatology of ECHO 11 virus infection in children. Pediatrics 65:284, 1980. 401. Medearis DN Jr, Kramer RA. Exanthem associated with ECHO virus type 18 viremia. J Pediatr 55:367, 1959. 402. Eckert HL, Portnoy B, Salvatore MA, et al. Group B Coxsackie virus

infection in infants with acute lower respiratory disease. Pediatrics 39526,1967. 403. Mirani M, Ogra PL, Barron AL. Epidemic of echovirus type 9 infection: certain clinical and epidemiologic features. N Y J Med 73:403, 1973. 404. Ramos-Alvarez M. Cytopathogenic enteric viruses associated with undifferentiated diarrheal syndromes in early childhood. Ann N Y Acad Sci 62326,1957. 405. Chonmaitree T, Menegus MA, Schervish-Swierkosz EM, et al. Enterovirus 71 infection: report of an outbreak with two cases of paralysis and a review of the literature. Pediatrics 67:489, 1981. 406. Arnon R, Naor N, Davidson S, et al. Fatal outcome of neonatal echovirus 19 infection. Pediatr Infect Dis J 10788, 1991. 407. Aradottir E, Alonso E, Shulman S. Severe neonatal enteroviral hepatitis treated with pleconaril. Pediatr Infect Dis J 20e457,2001. 408. Abzug MJ. Prognosis for neonates with enterovirus hepatitis and coagulopathy. Pediatr Infect Dis J 20:758,2001. 409. Boccia D, Stolfi I, Lana S, et al. Nosocomial necrotising enterocolitis outbreaks: epidemiology and control measures. Eur J Pediatr 160:385, 2001. 410. Talsma M, Vegting M, Hess J. Generalised coxsackie A9 infection in a neonate presenting with pericarditis. Br Heart J 52:683, 1984. 411. Barson WJ, Craenen J, Hosier DM, et al. Survival following myocarditis and myocardial calcification associated with infection by coxsackie virus B4. Pediatrics 68:79, 1981. 412. Chonmaitree T, Menegus MA, Powell KR. The clinical relevance of “CSF viral culture.” A two-year experience with aseptic meningitis in Rochester, N.Y. JAh4A 247:1843, 1982. 413. Rantakallio P, Saukkonen AL, Krause U, et al. Follow-up study of 17 cases of neonatal coxsackie B5 meningitis and one with suspected myocarditis. Scand J Infect Dis 2:25, 1970. 414. Drew JH. ECHO 11 virus outbreak in a nursery associated with myocarditis. Aust Paediatr J 9:90, 1973. 415. Cherry ID, Lerner AM, Klein 10, et al. Coxsackie B5 infections with exanthems. Pediatrics 3 1:445, 1963. 416. Chan SH, Lun KS. Ventricular aneurysm complicating neonatal coxsackie B4 myocarditis. Pediatr Cardiol22247,2001. 417. Theodoridou M, Kakourou T, Laina I, et al. Vesiculopapular rash as a single presentation in intrauterine coxsackie virus infection. Eur J Pediatr 161:412, 2002. 418. Chen CY, Chang YC, Huang CC, et al. Acute flaccid paralysis in infants and young children with enterovirus 71 infection: MR imaging findings and clinical correlates. Am J Neuroradiol22:200,2001. 419. Chesney PI, Quennec P, Clark C. Hypoglycorrhachia and coxsackie B3 meningoencephalitis. Am J Clin Pathol70947, 1978. 420. Johnson RT, Shuey HE, Buescher EL. Epidemic central nervous system disease of mixed enterovirus etiology. I. Clinical and epidemiologic description.Am 1 Hyg 71:321, 1960. 421. Haynes RE, Cramblett HG, Hilty MD, et al. ECHO virus type 3 infections in children: clinical and laboratory studies. J Pediatr 80589, 1972. 422. Haynes RE, Cramblett HG, Kronfol HJ. Echovirus 9 meningoencephalitis in infants and children. JAMA 208:1657, 1969. 423. Farmer K, MacArthur BA, Clay MM. A follow-up study of 15 cases of neonatal meningoencephalitis due to coxsackie virus B5. J Pediatr 87:568, 1975.

Chapter 24 424. Helin I, Widell A, Borulf S, et al. Outbreak of coxsackievirus A-14 meningitis among newborns in a maternity hospital ward. Acta Paediatr Scand 76234,1987. 425. Wilfert CM, Lauer BA, Cohen M, et al. An epidemic of echovirus 18 meningitis. J Infect Dis 131:75, 1975. 426. Schmidt NJ, Lennette EH, Ho HH. An apparently new enterovirus isolated from patients with disease of the central nervous system. J Infect Dis 129304,1974. 427. Sells CJ, Carpenter RL, Ray CG. Sequelae of central-nervous-system enterovirus infections. N Engl J Med 293:1,1975. 428. Matsumoto K, Yokochi T, Matsuda S, et al. Characterization of an echovirus type 30 variant isolated from patients with aseptic meningitis. Microbiol Immunol30333,1986. 429. Bowen GS, Fisher MC, Deforest A, et al. Epidemic of meningitis and febrile illness in neonates caused by echo type 11 virus in Philadelphia. Pediatr Infect Dis 2:359, 1983. 430. Sumaya CV, Corman LI. Enteroviral meningitis in early infancy: significance in community outbreaks. Pediatr Infect Dis 1:151, 1982. 431. Bergman I, Painter MJ, Wald ER, et al. Outcome in children with enteroviral meningitis during the first year of life. J Pediatr 110:705, 1987. 432. Wilfert CM, Thompson RJ Jr, Sunder TR, et al. Longitudinal assessment of children with enteroviral meningitis during the first three months of life. Pediatrics 62811, 1981. 433. Tarcan A, Ozbek N, Giirakan B. Bone marrow failure with concurrent enteroviral infection in a newborn. Pediatr Infect Dis J 20e719, 2001. 434. Schurrnann W, Statz A, Mertens T, et al. Two cases of coxsackie B2 infection in neonates: clinical, virological, and epidemiological aspects. Eur J Pediatr 140:59, 1983. 435. Barson WJ, Reiner CB. Coxsackievirus B2 infection in a neonate with incontinentia pigmenti. Pediatrics 77:897, 1986. 436. Blokziji ML, Koskiniemi M. Echovirus 6 encephalitis in a preterm baby. Lancet 2:164,1989. 437. Ehrnst A, Eriksson M. Echovirus type 23 observed as a nosocomial infection in infants. Scand J Dis 28205,1996. 438. Grangeot-Keros L, Broyer M, Briand E, et al. Enterovirus in sudden unexpected deaths in infants. Pediatr Infect Dis J 15:123,1996. 439. Paul JR. Epidemiology of poliomyelitis. Monogr Ser World Health Organ 269,1955. 440. MuUins JA, Khetsuriani N, Nix WA, et al. Emergence of echovirus type 13 as a prominent enterovirus. Clin Infect Dis 38:70,2004. 441. Kirschke DL, Jones TF, Buckingham SC, et al. Outbreak of aseptic meningitis associated with echovirus 13. Pediatr Infect Dis J 21:1034, 2002. 442. Somekh E, Cesar K, Handsher R, et al. An outbreak of echovirus 13 meningitis in central Israel. Epidemiol Infect 130257,2003. 443. Trallero G, Casas I,Avell6n CA,et al. First epidemic of aseptic meningitis due to echovirus type 13 among Spanish children. Epidemiol Infect 130251,2003. 444. Weibel RE, Benor DE. Reporting vaccine-associated paralytic poliomyelitis: concordance between the CDC and the National Vaccine Injury Compensation Program. Am J Public Health 86:734,1996. 445. Sabin AB, Krumbiegel ER, Wigand R. ECHO type 9 virus disease. Am J Dis Child 96197,1958. 446. Drouhet V. Enterovirus infection and associated clinical symptoms in children. Ann Inst Pasteur 98:562,1960. 447. Chonmaitree T, Ford C, Sanders C, et al. Comparison of cell cultures for rapid isolation of enteroviruses. J Clin Microbiol262576, 1988. 448. Johnson FB. Transport of viral specimens. Clin Microbiol Rev 3:120, 1990. 449. Howell CL, Miller MJ. Effect of sucrose phosphate and sorbitol on infectivity of enveloped viruses during storage. J Clin Microbiol 18: 658,1983. 450. August MJ, Warford AL. Evaluation of a commercial monoclonal antibody for detection of adenovirus antigen. J Clin Microbiol 25:2233, 1987. 451. Herrmann EC Jr.Experience in providing a viral diagnostic laboratory compatible with medical practice. Mayo Clin Proc 42:112, 1967. 452. Trabelsi A, Grattard F, Nejmeddine M, et al. Evaluation of an enterovirus group-specific anti-VPI monoclonal antibody, 5-D8/1, in comparison with neutralization and PCR for rapid identification of enteroviruses in cell culture. J Clin Microbiol33:2454, 1995. 453. Carstens JM, Tracy S, Chapman NM, et al. Detection of enteroviruses in cell cultures by using in situ transcription. J Clin Microbiol 3025, 1992.


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454. De L, Nottay B, Yang CF, et al. Identification of vaccine-related polioviruses by hybridization with specific RNA probes. J Clin Microbiol 33:562, 1995. 455. Rotbart HA. Nucleic acid detection systems for enteroviruses. Clin Microbiol Rev 4156, 1991. 456. Petitjean J, Freymuth F, Kopecka H, et al. Detection of enteroviruses in cerebrospinal fluids: enzymatic amplification and hybridization with a biotinylated riboprobe. MoI Cell Probes 8:15B22, 1994. 457. Redline RW, Genest DR, Tycko B. Detection of enteroviral infection in paraffin-embedded tissue by the RNA polymerase chain reaction technique. Am J Clin Pathol96568, 1991. 458. Muir P, Nicholson F, Jhetam M, et al. Rapid diagnosis of enterovirus infection by magnetic bead extraction and polymerase chain reaction detection of enterovirus RNA in clinical specimens. J Clin Microbiol 31:31, 1993. 459. Muir P, Ras A, Klapper PE, et al. Multicenter quality assessment of PCR methods for detection of enteroviruses. J Clin Microbiol321409,1999. 460. Martin AB, Webber S, Fricker FJ, et al. Acute myocarditis: rapid diagnosis by PCR in children. Circulation 90330, 1994. 461. Abraham R, Chonmaitree T, McCombs J, et al. Rapid detection of poliovirus by reverse transcription and polymerase chain amplification: application for the differentiation between poliovirus and nonpoliovirus enteroviruses. J Clin Microbiol 31:295, 1993. 462. Chezzi C. Rapid diagnosis of poliovirus infection by PCR amplification. J Clin Microbiol341722,1996. 463. Egger D, Pasamontes L, Ostermayer M, et al. Reverse transcription multiplex PCR for differentiation between polio and enteroviruses from clinical and environmental samples. J Clin Microbiol 33:1442, 1995. 464. Gorgievski-Hrisoho M, Schumacher JD, Vilimomovic N, et al. Detection by PCR of enteroviruses in cerebrospinal fluid during a summer outbreak of aseptic meningitis in Switzerland.J Clin Microbiol 36:2408, 1998. 465. Ramers C, Billman G, Hartin M, et al. Impact of a diagnostic cerebrospinal fluid enterovirus polymerase chain reaction test on patient management. JAMA 283:2680,2000. 466. Yang CF, De L, Holloway BP, et al. Detection and identification of vaccine-related polioviruses by the polymerase chain reaction. Viral Res 20:159B179,1991. 467. Samuelson A, Glimaer M, Skoog E, et al. Diagnosis of enteroviral meningitis with IgG-EL4 using heat-treated virions and synthetic peptides as antigens. J Med Virol40271,1993. 468. Chan D, Hammond GW. Comparison of serodiagnosis of group B coxsackievirus infections by an immunoglobulin M capture enzyme immunoassay versus microneutralization. J Clin Microbiol 21 330, 1985. 469. Chomel JJ, Thouvenot D, Fayol V, et al. Rapid diagnosis of echovirus type 33 meningitis by specific IgM detection using an enzyme linked immunosorbent assay (ELISA). J Virol Methods 1 0 11, 1985. 470. Gong CM, Ho DWT, Field PR, et al. Immunoglobulin responses to echovirus type 11 by enzyme linked immunosorbent assay: singleserum diagnosis of acute infection by specific IgM antibody. J Virol Methods 9209,1984. 471. Pozzetto B, LeBihan JC, Gaudin OG. Rapid diagnosis of echovirus 33 infection by neutralizing specific IgM antibody. J Med Virol 18:361, 1986. 472. McCartney RA, Banatvala JE, Bell EJ. Routine use of mu-antibodycapture ELISA for the serological diagnosis of Coxsackie B virus infections. J Med Virol 19:205,1986. 473. Dorries R, Ter Meulen V. Specificityof IgM antibodies in acute human coxsackievirus B infections, analysed by indirect solid phase enzyme immunoassay and immunoblot technique. J Gen Virol64:159,1983. 474. Bell EJ, McCartney RA, Basquill D, et al. Mu-antibody capture ELISA for the rapid diagnosis of enterovirus infections in patients with aseptic meningitis. J Med Virol 19213, 1986. 475. Glimaker M, Ehrnst A, Magnius L, et al. Early diagnosis of enteroviral meningitis by a solid-phase reverse immunosorbent test and virus isolation. Scand J Infect Dis 22:519, 1990. 476. Gaudin 0-G, Pozzetto B, Aouni M, et al. Detection of neutralizing IgM antibodies in the diagnosis of enterovirus infections. J Med Virol 28:200, 1989. 477. Martin AB, Webber S, Fricker FJ, et al. Acute myocarditis. Rapid diagnosis by PCR in children. Circulation 90:330, 1994. 478. Chambon M, Delage C, Bailly JL, et al. Fatal hepatic necrosis in a neonate with echovirus 20 infection: use of the polymerase chain reaction to detect enterovirus in liver tissue. Clin Infect Dis 24:523, 1997.

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479. Eichenwald HC (ed). The Prevention of Mental Retardation Through

487. Kearns GL, Bradley JS, Jacobs RF,et al. Single dose pharmacokinetics

Control of Infectious Diseases. Washington, DC, U.S. Government Printing Office,1966, p 31. 480. Dagan R,Prather SL,Powell KR, et al. Neutralizing antibodies to nonpolio enteroviruses in human immune serum globulin. Pediatr Infect Dis 2454,1983. 481. McKinney RE Jr, Katz SL, Wilfert CM. Chronic enteroviral meningoencephalitis in agammaglobdinemic patients. Rev Infect Dis 9334,

of pleconaril in neonates. Pediatric Pharmacology Research Unit Network. Pediatr Infect Dis J 19833,2000. 488. Pevear DC, T d TM, Seipel ME, et al. Activity of pleconaril against enteroviruses. Antimicrob Agents Chemother 439109,1999. 489. Rotbart HA, Abzug MJ, Levin MJ. Development and application of RNA probes for the study of picornaviruses. Mol Cell Probes 2:65,

1987. 482. Hammond GW, Lukes H, Wells B, et al. Maternal and neonatal

neutralizing antibody titers to selected enteroviruses. Pediatr Infect Dis 432,1985. 483. Johnston JM, Overall JC Jr. Intravenous immunoglobulin in disseminated neonatal echovirus 11 infection. Pediatr Infect Dis J 8254, 1989. 484. Abzug MJ, Keyerling HL, Lee ML, et al. Neonatal enterovirus

infection: virology, serology, and effects of intravenous immune globulin. Clin Infect Dis 201201,1995. 485. Jantausch BA, Luban NLC, Duffy L, et al. Maternal plasma transfusion in the treatment of disseminated neonatal echovirus 11 infection. Pediatr Infect Dis J 14154, 1995. 486. Chuang E, Maller ES, Hoffman MA, et al. Successful treatment of fulminant echovirus 11 infection in a neonate by orthotopic liver transplantation. J Pediatr Gastroenterol Nutr 1721 1, 1993.

1988. 490. Kilbourne ED, Wilson CB, Perrier D. The induction of gross myo-

cardial lesions by a Coxsackie (pleurodynia) virus and cortisone. J Clin Invest 35:367, 1956. O’Connell JB, Herskowitz A, et al. A clinical trial of 491. Mason JW, immunosuppressive therapy for myocarditis. N Engl J Med 333969, 1995. 492. Carolane DJ, Long AM, McKeever PA, et al. Prevention of spread of echovirus 6 in a special care baby unit. Arch Dis Child 60674, 1985. 493. Nagington 1, Walker J, Gandy G, et al. Use of normal immunoglobulin in an echovirus 11 outbreak in a special-care baby unit. Lancet 2443, 1983. 494. Pasic S, Jankovic B, Abinun M, et al. Intravenous immunoglobulin prophylaxis in an echovirus 6 and echovirus 4 nursery outbreak. Pediatr Infect Dis J 16718, 1997.

Chapter 25 HEPATITIS John 5 . Bradley

Hepatitis A

823

The Virus Pathogenesis ’l’rmsmissiot i Clinical Illnes> I.ahorJtory Diagnosis Therapy Pre\~entionof Infection

Hepatitis B

826

The Virus Pathogentis Tr,insmission Clinic,il Illness L‘iborJtory lli,ignosis Therapy Prevention of Infection

Hepatitis C

832

The I’irua Pathogenesis Transmission Clinical Illness I.aboratorv Iliagnosis Therapy Prcvcntion of Infection

Hepatitis D

837

The Viriij Pathogenesis Tr.in\m i\\ion Clinicd lllrics\ Lihirat~iryL)isignosi\ T’her‘ipy Prevention of Intection

Hepatitis E

838

The \’irus Pathogenesis Tr.insmission (:linic‘il Illness I.ahoratory Diagnosis ‘l‘herap); I’reveiition of Infection

Hepatitis G

hepatitis C virus (HCV); hepatitis D virus (HDV), an agent found to infect only patients simultaneously infected with HBV; hepatitis E virus (HEV); and hepatitis G virus (HGV), also known as GB virus type C (GB being the initials of the patient from whom the prototype virus in this group was first isolated). Fortunately, these viruses rarely cause transplacental in utero infection. As a result of the almost universal inoculation of the vaginally born infant with maternal blood, vaginal secretions, and stool, however, most of these agents may be transmitted perinatally (at the time of labor and delivery) when present in the mother. This chapter reviews the characteristics of each of these viruses, pathogenesis and transmission of the disease, nature of the clinical illness, and diagnosis, therapy, and prevention of the infection.

839

The \’irus I’d thogenesis Transinission Clinical Illness Laboratory IXagnosis

Scientific and medical knowledge about the genetic composition, molecular structure, pathogenesis, and natural history of infection has dramatically increased over the past decade for the hepatotropic viruses (Table 25-1). Six viral agents have been documented or suspected to cause hepatitis as the primary clinical manifestation of infection in children and adults: hepatitis A virus (HAV); hepatitis B virus (HBV);

HEPATITIS A

The Virus HAV was first identified in the stool of a patient with the acute phase of hepatitis A (Fig. 25-1).8Although the size (27 nm in diameter), density, and structure (genetic organization, absence of lipid envelope) are similar to those of enteroviruses, HAV does not share any cross-reactive antigens, nucleic acid, or protein sequences with the enterovir~ses.~”~ It is classified as a picornavirus within the genus Hepatovirus.4 The positive-sense, single-stranded RNA is 7.5 kilobases long and is composed of a single open reading frame, coding for at least four structural (W1,W2, W 3 , and VP4) and seven nonstructural proteins (including an RNA polymerase and a pr~tease).~ The structural proteins are cleaved from a single precursor protein by the viral protease, with the capsid proteins VP1 and VP3 representing the antigenic structure against which neutralizing antibody is d i r e ~ t e d . ~ Although only one serotype is known to exist, genetic variability derives from isolates around the world, which have been categorized into four human genotype^.^ HAV has been cultured in a variety of human and nonhuman primate cells in ~ i t r o . ~ *

Pathogenesis Virus is ingested, enters the gastrointestinal tract, and is transported from the gut to the liver where hepatocyte entry occurs: The cellular receptor involved in viral uptake is a membrane glycoprotein of unknown function.26The pathogenesis of HAV-mediated liver injury is not well understood. HAV can be detected in the liver, bile, blood, and stool as early as 2 weeks after exposure following release of virions from hepatocytes into both bile and blood. HAV replication may occur within the hepatocyte without evidence of cell

824

Section I11

Table 25-1

Viral Infections

Hepatitis Viruses

Virus

Virus Structure

Primary Route o f Neonatal Infection

Transmission in Children and Adults

HAV (picornavirus, genus Hepatovirus) HBV (Hepadnavirus) HCV (flavivirus, genus Hepacivirus) HDV (Deltavirus) HEV (provisionally togavirus) HGV (flavivirus)

SS RNA, nonenveloped

Perinatal

Fecal-oral

DS circular DNA, enveloped

Perinatal Perinatal Not reported In utero; perinatal In utero; perinatal

Blood-borne Blood-borne Blood-borne Fecal-oral Blood-borne, sexual

SS RNA, enveloped SS, circular RNA (HBV envelope) SS RNA, nonenveloped

SS RNA, nonenveloped

DS, double-stranded; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV, hepatitis E virus; HGV, hepatitis G virus (GB virus type C); SS, single-stranded.

anti-HAV immunoglobulin M (IgM) and total anti-HAV antibody also were measured, in addition to liver function testing. A correlation was found between peak serum virus and peak serum aminotransferase levels; however, peak antiHAV IgM levels did not correlate with a decreasing viral load. Instead, viral loads decreased with increasing total anti-HAV antibody, suggesting a greater role for anti-HAV IgG, or specific antibody in the context of an ongoing cellular response, which was not assessed in these patients. Primate model evidence suggests that virus particles excreted into the bile and intestine may again be absorbed through the gut and transported back to the liver in an enterohepatic circulation, providing a mechanism for autoinoculation: The biochemical and histologic changes in hepatitis occur with the onset of the anti-HAV immune response. The histopathologic findings in HAV infection are nonspecific and include focal hepatocellular necrosis with balloon degeneration and hepatocyte regeneration, accompanied by a predominantly mononuclear inflammatory infiltrate. The areas of most marked inflammation are periportal.

Transmission Figure 25-1 Hepatitis A virus (HAV) particles. Electron micrograph of the 27-nm HAV virions in a stool specimen. (Reprinted with permission from Feinstone SM, Kapikian AZ, Purcell RH. Hepatitis A: detection by immune electron microscopy of a viruslike antigen associated with acute illness. Science 182:1026. Copyright 1973 by the American Association for the Advancement of Science.)

injury; most tissue-cultured strains of HAV are not cytotoxic. Some clinical or environmental isolates are clearly cytopathic, however.’ The role of the immune system in clearing the infection is poorly understood. The anti-HAV immune response in adults consists of specific cellular and humoral response^.'^^^^ Hepatocyte injury is thought to be a result of of cytotoxic T cell responses.34 In one study of 11 acutely infected adults,’’ for the first 70 days after the appearance of jaundice, virus titers in serum were detectable in the range of 1 x lo3 to 3 x lo4 genome equivalents per mL. During the subsequent 4 months, the viral load generally decreased, although in 4 patients, the load increased after an apparent earlier decline, despite the presence of circulating antibody. In 3 patients, virus could be detected in blood for longer than 6 months. In these patients,

Hepatitis A is spread by the fecal-oral route. Transmission occurs by direct contact with a person with an acute HAV infection, such as an infected infant in a daycare center environment, or by ingestion of contaminated food and ~ a t e r . ~ The ” ~ ’stool ~ ~ is highly contagious; in prospective evaluations of fecal excretion in symptomatic older children and adults, as well as in experimental animals, investigators found stool containing up to lo8 HAV genome equivalents per mL.16.3’Following infection, children may excrete virus for a more prolonged period than has been noted in adults; investigators unexpectedly also found HCV DNA in the stool during the second week of illness more often in children than in adult^.^' Excretion in the stool may be particularly prolonged in neonates. HAV RNA was detected in neonatal stool samples for 4 to 5 months in 23% of babies diagnosed with HAV infection.22 In addition to prolonged excretion in clinically silent infection, transmission is facilitated by the fact that the quantity of virus in stool is highest before HAV-mediated illness becomes clinically detectable in children and adults, before the development of elevated serum concentrations of transaminases or bilirubin.””’ To further facilitate transmission, HAV is known to be stable in stool specimens for prolonged periods, as documented by animal infection following inoculation by

Chapter 25 HAV-containing stool that had been dried and stored at 77°F for 30 days.” In addition to fecal-oral transmission, parented transmission of HAV also is possible, both by blood transfusion and by injection drug use, because viremia has been well documented to occur with acute HAV With respect to maternal-infant transmission of HAV, an early study of acute icteric hepatitis during pregnancy assessed six women with acute hepatitis A. All six women were symptomatic with jaundice at the time of hospitalization for delivery and had markedly increased serum alanine aminotransferase (ALT)levels. Clinical or laboratorysigns of hepatitis did not develop in any of the infants born to mothers with acute hepatitis A during pregnancy, presumably owing to the fact that viral shedding had decreased substantially by the time clinical symptoms appeared.33Perinatal transmission, however, was documented in a neonate in the course of an investigation of a nursery outbreak of HAV, finding that the infant’s mother had been diagnosed with an acute HAV infection 10 days before delivery.35Perinatal transmission also has been documented in infants born to mothers diagnosed with infection at 4 months before delivery7or at the time of deli~ery.~’ In both of these reports, the infants were asymptomatic for the first weeks of life, with documentation in one report3’ of the absence of HAV RNA in cord blood. Other reports have documented intrauterine transmission with fetal infection associated with polyhydramnios and ascites at 27 weeks of gestation, following maternal infection at 20 weeks of ge~tation.’~ Prospectively collected epidemiologic data on the true incidence of neonatal HAV infection following maternal infection, acquired either in utero or perinatally at the time of delivery, are not available. Although a neonate may become infected from transfusion or from vertical transmission as outlined, spread within nurseries to other infants and health care workers also has been documented. Outbreaks of HAV infection once the virus was introduced into the nursery have been rep~rted.’~’~~~~~ No cases of transmission from breast milk as the sole means of exposure of the neonate to infectious virus have been reported.

Clinical Illness Although biopsy-proven clinical HAV infection in a neonate has been r e p ~ r t e d the , ~ true incidence of clinical disease in HAV-infected neonates is unknown, because no prospective evaluation in exposed neonates has been possible. In infants and children, particularly those younger than 3 years of age, less than 20% are clinically symptomatic following i n f e c t i ~ n ~-far ~ ’ ~ ~lower ’ ~ than in adults, of whom between 76% and 97% have clinical illness, with icterus in 40% to 70%?14 The average incubation period from exposure to onset of symptoms is 30 days, with a range of 15 to 50 days. Nonspecific signs and symptoms associated with infection include fever, anorexia, nausea, myalgia, diarrhea, and abdominal discomfort. In adults, these symptoms may be present 5 to 7 days before the onset of jaundice. Duration of disease varies considerably, averaging 30 days in adults, but is shorter in children. Elevated values on liver function tests and abnormalities on liver biopsy, however, may persist in

Hepatitis

825

some cases for several month^.^ Approximately 100 cases of fulminant HAV infection with liver failure occur each year in the United States, representing less than 1% of cases of HAV infection. Acute liver failure occurs more often in older adults or in those with underlying liver disease but has been reported in children as well.6,23327 Chronic, lifelong infection, as has been documented for HBV and HCV, has not been shown to occur with HAV infection.

Laboratory Diagnosis Hepatitis A is diagnosed in the laboratory by demonstration of serum antibodies to HAV (anti-HAV) by a number of different enzyme immunoassays or radioimmunoassays. The most commonly used test to diagnose HAV infection is the determination of anti-HAV IgM, which is virtually always present at the first sign of clinical disease and persists for 4 to 6 months. The sensitivity and specificity of anti-HAV IgM assay were reported to be 100% and 99%, respectively, in one community ~utbreak,’~ but similar data are not available for the accuracy of the test in the neonate. Anti-HAV IgG remains detectable for years following infection. Research laboratories also can detect virus in blood or stool by means of reverse transcriptase-polymerase chain reaction (RT-PCR) tests or by in situ hybridization techniques on biopsy samples.

Therapy No approved antiviral agents are available for treatment of hepatitis A infection. This state of affairs is likely to be a consequence of the widespread availability of effective vaccines and the self-limited nature of this infection.

Prevention of Infection For infants born to mothers whose symptoms began between 2 weeks before to 1 week after delivery, current recommen-

dations are to administer a single intramuscular injection of immune serum globulin (ISG), 0.02 mL/kg, to the infant, although the efficacy of ISG in this situation has not been documented.’ Prevention of infection in infants and health care workers in a nursery outbreak consists of strict infection control measures to prevent fecal-oral transmission of virus from infected infants to susceptible infants. For health care workers, previous immunization with one of the U.S.Food and Drug Administration (FDA)-approved HAV vaccines should be protective for those who are inadvertently exposed to an infected neonate, parent, or sibling and should prevent further nosocomial transmission within the nursery. If an outbreak of hepatitis A is documented in the nursery, postexposure prophylaxis with ISG (0.02 mL/kg) should provide sufficient anti-HAV antibody to prevent or modify illness in non-HAV-immunized, exposed health care workers, or in neonates who may have had close exposure to infectious secretions. No data are available to support the use of vaccine alone for postexposure prophylaxis.’ Because HAV vaccines have not been tested in the neonate, immune prophylaxis is the only available preventive measure for this population following documented exposure.

826

Section I11

Viral Infections

HEPATITIS B The Virus HBV is a hepadnavirus, an enveloped virus that contains a partially double-stranded DNA molecule approximately 3200 nucleotides in length.96Although viruses with genetic organization and morphologic structure similar to those of HBV have been identified in birds and other mammals, the host range of HBV is limited to humans, gorillas, and chimpanzees. The life cycle of HBV is largely understood because of extensive studies in animal models with species-specific hepadnaviruses. Early after infection, the virus infects primarily hepatocytes but also may infect cells of the kidney and pancreas and mononuclear cells. Although the hepatocyte cell surface receptor for HBV remains unknown, several possibilities are under investigation.64Following membrane fusion, the virus nucleocapsid ultimately arrives in the nucleus, where the partially double-stranded DNA molecule becomes covalently closed, circular DNA through the action of host cellular DNA repair enzymes, which not only complete the DNA strand but also release the attached viral This double-stranded DNA may then be associatedwith cellular histone proteins to form stable minichromosomes, which may represent a feature of intracellular stability of the virus, with implications for viral latency.@ The double-stranded DNA also serves as the template for host RNA polymerase 11, which provides the RNA required for translation to viral proteins and creates the pregenomic RNA destined for encapsidation in the process of forming new viral progeny. The HBV DNA genome codes for four families of polypeptides (correspondingto overlapping open reading frames): the pre-S/S region proteins, the pre-C/C/e-antigen proteins, the P gene polymerase product, and the X gene product, HBx protein. The pre-S/S region codes for three envelope proteins that exist as both glycosylated and nonglycosylated forms: the large L (pre-S1) protein, the medium (middle) M (pre-S2) protein, and the small S ( S , or major) protein.5 1.54,64,91,96,103 Th e serum of patients with acute hepatitis B contains three morphologically distinct forms of virus or viral antigen (Fig. 25-2). These forms are distinct particles that can be readily aggregated by reaction with serum containing specific antibody against the hepatitis B surface antigen (HBsAg). The first particle to be described, and the most common form in the serum, is a spherical 22-nm particle composed of multiple subunits of the S envelope protein." In addition, long microfilaments with the same 22-nm diameter as for the spherical particles can be seen scattered throughout an electron microscopic field. The third particle is a large spherical particle, 42 nm in diameter, with an outer shell and a dense inner core, which represents the complete infectious virus particle. The 22-nm particles are formed from HBsAg composed of 90% S (major) protein, with minor components of the medium and large proteins. About 70% of HBsAg protein on the filamentous and 42-nm particles consists of the S protein." The pre-CIC open reading frame provides the genetic material for the core protein (P21), which is serologically recognized by the host as HBcAg and is the major protein in the core, or nucleocapsid. The pre-C region also codes for a soluble antigen, detected in the blood as HBeAg.

Figure 25-2 Hepatitis B virus (HBV) particles. Electron micrograph from a patient with acute HBV infection demonstrates three circulating particles: 20-nm structures and filamentous structures containing HBsAg envelope proteins (primarily the 5, or major protein, but no HBV viral genome); and the 47-nm infectious virion structures containing both envelope proteins and nucleocapsid containing genomic HBV DNA. HBSAg, hepatitis B surface antigen. (Courtesy of Dr. June Almeida.)

The pol gene is the longest-segment open reading frame, coding for a multifunctional 90-kilodalton ( m a ) polymerase protein, which has the ability to act as reverse transcriptase (creating double-stranded DNA, which is present in infectious virions), an RNase, and a DNA polymerase. The X open reading frame leads to the formation of the 154-amino-acid-long nonstructural, regulatory HBx protein. The function of HBx is not well but it appears to be involved as a transactivator for a number of viral and cellular gene promoters, possibly in events that lead to dysregulation of cellular functions. These occurrences over time are believed to be factors leading to the development of hepatocellular carcinoma. The core protein self-assembles into capsids in the cytoplasm, incorporating pregenomic single-stranded HBV RNA. Following assembly of the caspsid, however, the RNA is transcribed back into DNA by the multifunctional pol gene polymerase (also called the Pol protein, or P protein), exhibiting reverse transcriptase activity. Within the nucleocapsid, the pregenomic RNA is then degraded by this enzyme, and the viral polymerase subsequently completes the formation of the final double-stranded HBV DNA, and then attaches covalently to the 3' end of the minus-strand DNA, to complete the formation of the nucleocapsid. These completed nucleocapsids are then capable of associating with cell membranes, binding to envelope proteins, and subsequent release.@ Possibly because of the extensive worldwide distribution of HBV, some diversity exists in its DNA sequences and the

Chapter 25

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827

antigenicity of HBsAg.1'2Classically,three antigenic epitopes 20% chance of developing cirrhosis with their chronic HBV on HBsAg have been distinguished: a, d/y, and ~ / r . ~ ~ ~ " " , "infection. ' The a antigen is common to HBsAg molecules derived from In general, circulating HBeAg in adults denotes a higher load of circulating virus, with less host control of the inall strains of HBV and is a major neutralizing epitope. Because fection and less host-mediated damage to hepatocytes. Over vaccination with HBsAg usually results in the development of time, a certain percentage of adults will revert from HBeAg antibodies to the a epitope, any form of HBsAg can be used seropositivity to anti-HBe seropositivity,usually accompanied to produce neutralizing antibodies. HBsAg usually is acutely by increased liver inflarnmation.Io6One study showed exclusively d or y and w or r, leading to serologic designations that the vertical transmission rate of HBV infection was of ayw, ayr, adw, and adr. With the development of monoclonal increased in women who were HBeAg positive, suggesting a antibodies to HBsAg and genetic sequencing data, more correlation between yiral load and transmission rates.77Of subtle differences in serotypes of HBsAg have become those with perinatal infection, the period of immune tolerance apparent; for example, four distinct subgroups have been may last for the first 2 decades or longer.'" Although HBeAg identified within the ayw group."' The antigenic differences positivity may correlate with less inflammation, the risk of among viral isolates are of epidemiologic interest, although hepatocellular carcinoma is highest in those who are HBeAg clinical outcomes of HBV infection as they relate to strain positive, suggesting that altered molecular control of cellular differences are currently under study. function in HBV infected hepatocytes may correlate with the development of cancer:' In addition to being present as extrachromosomal, Pathogenesis covalently closed, double-stranded DNA, HBV DNA also may become integrated into host chromosomes and can be HBV is noncytopathic to the hepatocyte. The pathogenesis found within the chromosomes of most hepatocellular of disease is closely associated with the appearance of the tumors. The viral DNA usually has been severely rearranged, host immune response, most prominently that of circulating with deletions, duplications, inversions, and insertion^.^^ HBV-specific cytotoxic T cell^.^',^^^^^ The breadth and The role of HBV in carcinogenesis is not well defined and intensity of the response to the HBV antigenic epitopes have may be a function of random genetic integration events that been correlated with the ability to clear the virus. In addition to direct cytotoxic mechanisms, HBV-specific T cells have facilitate the development of uncontrolled tumor growth through genetic expression of HBV enhancers or promoters the ability to decrease viral replication by noncytolytic mechanisms, primarily involving IFN-y, which leads to an within critical human genes, or may reflect a biologic effect enhanced immune response both within the hepatocyte and of one of the HBV proteins, such as HBx, which may prevent with respect to recruitment of additional immune-competent mechanisms of cell homeostasis from operating normally. As the chronic infection progresses over many years, the Accumulating (CD4' and natural killer [ NK]) lifetime risk of the development of hepatocellular carcinoma evidence suggests that even in adults who recover clinically is estimated to be 40% to 50%.38,61 from the infection, persisting, perhaps lifelong HBV infection, is the rule, accompanied by a strong and continuing T cell Following inoculation of a susceptible host with infectious virions, HBsAg appears in the bloodstream within 1 to response.s6The actual immune parameters that are respon6 months during the acute phase of infection, correlating with sible for the persistent, chronic infection seen in neonates, high levels of circulating virus and contagiousness. A high however, have not been investigated in detail. risk of vertical transmission of HBV from mother to infant Acute infection in adults may be either asymptomatic or is present during the acute infection. In older children and symptomatic, in the latter case accompanied by biochemical adults, HBV-specific CD8' and CD4' lymphocytes clear the and histologic evidence of hepatitis. The pathogenesis of production of virus by both cytolytic and noncytolytic infection has been broadly separated into four categories: mechanisms.88In the neonate, the most common response immune tolerance, immune/active clearance, nonreplicative, following perinatal exposure is a chronic asymptomatic and reactivation.lo8 Greater than 90% of neonatal infections hepatitis with the histologic features of unresolved or result in chronic infection, whereas only 5% of infections in persistent hepatitis. adults become persistent. Immune tolerance in the neonate Limited data exist on the hepatocellular characteristics of may result either from cellular immune system immaturity infection in the newborn or during the first year of life. Early or from suppression of immune responses. Immune supstudies by Schweitzer and colleagues demonstrated that in pression leading to chronic infection may either be specific 13 of 17 HBsAg-positive infants, no signs of acute clinical to HBV, possibly linked to the transplacental passage of soluble hepatitis were present.93Physical findings for 12 infants with HBeAg, or be a nonspecific function of the fetal immune persistent antigenemia remained normal. In one child, hepasuppression that normally occurs during gestation. tomegaly and splenomegaly were detected at 15 months of The serum concentration of HBV DNA varies markedly age. Liver biopsy specimens were obtained from 10 HBsAgfrom patient to patient with different states of chronic HBV positive infants between 3 and 27 months of age; results from disease. Asymptomatic HBsAg-positivechronic carriers with 8 of the 10 infants documented intact lobular architecture little or no hepatocellular injury usually have very high with no suggestion of nodular regeneration or fibrosis. Some concentrations of serum HBV DNA, validating the concept liver cells were hydropic and polyhedral, giving a cobblestone of immune tolerance, with poor host regulation of viral appearance to the liver lobule. Liver cell nuclei were slightly replication and minimal host-mediated injury to hepatocytes. enlarged, and small foci of liver cell necrosis were present. On the other hand, persons who remain HBsAg positive but Only one liver biopsy specimen had increased amounts of have ongoing evidence of hepatocellular injury, as assessed fibrosis, but no bridging between portal areas was apparent. by serum aminotransferases and liver biopsy, will have a

828

Section I11

Viral Infections

Transmission Transmission to the neonate most often occurs at the time of delivery, but some evidence suggests that some neonates may already be infected in utero, with virus present in cord blood at birth.84 In Taiwan, where the prevalence of HBsAg positivity in the population is 5% to 20%, a high frequency of vertical transmission of HBsAg from asymptomatic carrier mothers was documented before the routine use of hepatitis B immune globulin (HBIG) and HBV vaccines. In natural history studies by Stevens and co-workers, HBsAg antigenemia was eventually documented in 6 3 infants born to 158 carrier mothers.'"" Fifty-one of these infants became HBsAg positive within the first 6 months of life. Furthermore, within this group, 21 of 103 infants born to carrier mothers had a positive cord blood sample for HBsAg, suggesting a high rate of in utero transmission. A relationship also was documented in this study between the level of the mother's viremia and the development of infection in the infant. This strikingly high frequency of transmission of the hepatitis virus noted in Taiwan also has been observed in other Asian and African populations. A high incidence of maternal transmission of HBV from asymptomatic carrier mothers to infants also was reported in 1975 by investigators in Japan.76In a study of 5993 mothers in five municipal hospitals in Tokyo, 139 (2.3%) were positive for HBsAg. These women were judged to be asymptomatic carriers by three criteria: (1) HBsAg was present in a high titer (1:512 or greater) as determined by the immune adherence hemagglutination method; (2) the women were free of clinical liver disease; and (3) no laboratory-tested abnormalities of liver function were present. Of the infants born to the 139 HBsAg-positive mothers, none had congenital malformations. Of note, none of 59 cord blood specimens tested by the technique of immune adherence hemagglutination were positive for HBsAg. Outcomes in 11 infants of HBsAg-positivemothers were studied in follow-up evaluations. In 8 of these 1 1 , HBsAg appeared in the serum within 6 months; 3 remained HBsAg negative for 7 to 14 months. In view of the lack of HBsAg in cord blood in this study, perinatal transmission, rather than in utero transmission appears to have been the major route of neonatal infection in this population studied in Japan. Another early report from Japan77 documented the presence of e antigen (a marker of higher viral load and less vigorous host response to HBV) in the blood of 10 asymptomatic carrier mothers, all 10 of whose infants became HBsAg positive. The infants born to mothers whose sera contained antibodies to e antigen (anti-e) did not become HBsAg positive. The importance of e antigen as a determinant in the transmission of HBV was confirmed in a prospective trial of pregnant women who were chronic carriers of HBsAg. Of the 70 pregnant women who delivered, 38 were HBeAg positive. --seven of the 38 HBeAg-positive mother-infant pairs were followed for 5 months or more. By 5 months, 26 of the 37 infants (70.3%) born to HBeAg-positive mothers were HBsAg p0sitive.6~Another study from Taiwan further supported the correlation between the presence of HBeAg in the serum of HBsAg carrier mothers and infection in their newborns: 85% of infants born to HBeAg-positive women became infected with HBV during the first year of life, and no vertical transmission was documented in HbeAg-

negative mothers."' Circulating HBV DNA was measured during pregnancy in chronically infected pregnant women in Sweden, both HBeAg positive (n = 9) and HbeAg negative (n = 46)?9 Not unexpectedly, viral load was higher in HbeAg-positive women than in those who were HbeAg negative; the three infants who acquired the infection all were born to HbeAg-positive mothers. In the United States, the rate of transmission of HBsAg from asymptomatic carrier mothers to their children appears to be lower. Schweitzer and colleagues found that only 1 of 21 infants born to HBsAg-positive mothers became positive for H B s A ~In . ~this ~ study, HBsAg was found in the cord blood in 9 of 18 specimens, but none of these infants became HBsAg positive. The authors concluded that the presence of HBsAg in the cord blood bore no relationship to the development of antigenemia in the infant of an asymptomatic carrier mother. In Denmark, Skinhoj and c o - ~ o r k e r sfound ~ ~ no infections among 28 infants studied for 3 to 5 months after birth to asymptomatic carrier mothers. In a recent study from China, a high rate of in utero transmission was again suggested in the population studied."' Among 59 infants born to HBV chronic carrier mothers, in utero transmission was documented in 40% by HBV DNA detected in peripherally drawn venous blood shortly after birth. A fetal pulmonary or gastrointestinal route of infection in utero is theoretically possible in infants who may not be infected through a hematogenous route. Investigators in one study found HBsAg in 33% of amniotic fluid samples and in 95% of gastric aspirates from the newborn infants.63HBV DNA was found by PCR assay of amniotic fluid from 48% of chronic carrier mothers, although contamination of amniotic fluid from maternal blood may have been p~ssible."~ Thus, in Taiwan, Japan, and China, the risk of infants acquiring hepatitis B from asymptomatic carrier mothers by perinatal as well as in utero routes appears to be high, whereas in the United States and other countries, the risk of acquiring neonatal hepatitis from HBsAg carrier mothers appears to be lower. It is not clear what role genetically determined immune responses, or socioeconomic or cultural conditions, may play in the epidemiology of transmission from mother to infant. No evidence is available to suggest that the clinical course in the pregnant woman in whom acute hepatitis B develops during pregnancy is different from that in women who are not ~regnant.~' With acute infection during the first part of pregnancy, however, clearance of HBV virions usually occurs by the time of delivery. For those women with infection later in pregnancy who are HBsAg positive at the time of delivery, the rate of perinatal acquisition of infection in the infant is similar to the rate found in infants born to mothers with chronic infection. In the United States, Schweitzer and coworkers assessed the presence of HBsAg in 56 mother-infant pairs; the mothers had acute viral hepatitis during pregnancy or within 6 months after delivery?2394 This study indicated that HBsAg was transmitted from mother to infant by 10 of 26 mothers who had HBsAg-positive hepatitis. Of interest, infection was transmitted from 8 of 17 mothers whose hepatitis developed within 2 months after delivery. The investigators demonstrated that the frequency of HBV transmission from mother to infant is high (76%) when

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hepatitis with variable elevations of ALT and abnormalities on liver biopsy were reported.95In the study carried out in Taiwan, however, in which 158 women who were carriers of HBsAg gave birth to 63 antigen-positive infants (40%), all of the infants remained healthy, without signs or symptoms of hepatitis.’” Although the vast majority of infants have benign clinical disease, fulminant hepatitis has been reported, particularly in infants born to HBeAg-negative mothers, although it may also occur in infants born to mothers who are HBeAg positive.43,45S9,60 Neonatal infection with HBV has been suggested to play a dominant role in the development of primary hepatocellular carcinoma in later life.38A progression of events from vertical HBV transmission leading to chronic infection, resulting in cirrhosis and hepatocellular carcinoma in adult life, has been implicated to explain findings in Senegal, West Clinical Illness Africa, where primary hepatocellular carcinoma is a major A majority of infants who become positive for HBsAg after cause of death among young adult men.62The finding that mothers of patients with hepatocellular carcinoma were mother-to-infant transmission remain anicteric, show no signs positive for HBsAg four times more frequentlythan the fathers of acute clinical hepatitis, and remain HBsAg positive for an suggested that the virus was acquired from the mother by extended period. The natural history of neonatal infection is vertical transmission. The development of hepatocellular best described by studies in which ongoing exposures to carcinoma also may relate to an associated high incidence of HBV from the community are minimal, giving the best insight HBeAg positivity in HBsAg carriers in particular geographic into the evolution of virus-child interactions. A natural regions. In the United States, only 3% to 5% of HBsAg carriers history study was recently published from England in which also are HBeAg positive, and hepatocellular carcinoma is 73 infants diagnosed with perinatal infection were born to uncommon, whereas 30% of HBsAg carriers also are HBeAg HBsAg-, HBeAg-positive mothers (comprising53 women from the Indian subcontinent and 9 Asian, 6 African-Caribbean, positive in Taiwan, Japan, and Uganda; these countries have These infants either were born before and 5 white a very high incidence of hepatocellular carcinoma. In several the era of routine perinatal prophylaxis ( n = 51) or were studies, between 37% and 90% of patients with hepatocellular prophylaxis failures (n = 22). The mean duration of followcarcinoma were HBsAg positive; these rates were 10 times up was 10 years (range 2 to 20 years). All children were higher than that in matched controls living in the same area.Io5Furthermore, preliminary data from Taiwan suggest clinically we& none had evidence of liver enlargement by that perinatal HBV prophylaxis programs, now in their third palpation or ultrasound examination. All were of normal decade, have been associated with the decrease in hepatoheight and weight. Of the 73 children, 3 had cleared HBsAg cellular carcinoma in the age groups immunized.46 and had become seropositive for anti-HBs at follow-up testing. In summary, it is evident that a majority of infants who Sixty-five percent of children were seropositive for HBeAg, become HBSAg positive by mother-to-infant transmission and 30% had seroconverted to become anti-HBe positive by are clinically healthy, but they may have persistently elevated an average of 10 years of age (range 4 to 19 years). Four of values on liver function tests, and approximately 5% will the five (80%) white children seroconverted, compared with have moderately severe histopathologic changes on liver 18 of the 50 (36%) children from the Indian subcontinent, biopsy. These changes are not well predicted by the clinical with no seroconversions noted in the 9 Asian children. This or HBV serologic status, or by liver function testing. Late finding of different rates of HBeAg seroreversion in different ethnic groups also has been reported by other in~estigat0r.s.~~complications include cirrhosis and hepatocellular carcin ~ m a . ~ Clinical ~ , ~ ’ illness in adults has recently been Half of the Indian subcontinent children and two thirds of the Asian children had normal values for serum ALT. Elevated aminotransferase values tended to be stable over the period of follow-up evaluation. Liver biopsy samples Laboratory Diagnosis were available in 48% of the children. In these children, 30% The availability of reliable, reproducible methods for a variety of biopsy specimens showed minimal or no inflammation, of antigens and antibodies associated with HBV infection 63% showed mild hepatitis, and 6% demonstrated moderately severe hepatitis, as graded by Ishak scoring. Two children has played a major role in the accumulation of knowledge on with moderately severe changes had “incomplete cirrhosis.” the epidemiology and clinical relevance of HBV. These tests are widely available from both hospitals and regional No association was found between the severity of the historeference laboratories. The patterns of HBV viral products pathologic changes and age, gender, or ethnic origin. A weak and host responses in both acute, resolved infection and in association was found between elevation of liver function chronic infection are summarized in Figure 25-3.96 tests and the degree of inflammation present.Children who HBsAg was one of the first detected virus-associated were HBeAg positive also were shown to have the highest antigens. At present, most clinical laboratories use variations levels of circulating HBV DNA. of the enzyme-linked immunoassay (EIA) methods or Although none of the children in this series became radioimmunoassay (RIA) and to detect HBsAg. HBsAg is clinically symptomatic, in earlier reports mild, self-limited acute hepatitis B occurs in the third trimester or early in the postpartum period and low (10%) when hepatitis occurs in the first two trimesters of pregnancy. Although infants may theoretically be infected through breast milk, which is known to contain virus,41,67,104 this mode of transmission does not appear to add additional risk for the infant beyond other exposures from a chronically infected mother.55s84 Infants who receive appropriate prophylaxis following delivery should be allowed to breast-feed.’ For parents who refuse appropriate prophylaxis, or in situations in which prophylaxis is not available, the added risks of neonatal infection beyond those from exposures to HBV during the pregnancy and birth are minimal, particularly when balanced with the nutritional and immunologic benefits from breast milk.

830


Anti-HBq,.

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1

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Years Years Time afler exposure Figure 25-3 Viral and host serologic markers and clinical correlates of hepatitis B virus (HBV) infection. A, Acute infection with appropriate host response and resolution of infection. B, Chronic infection. (Data from Servoss JC, Friedman LS. Serologic and molecular diagnosis of hepatitis B virus.Clin Liver Dis 2004;8[2]:267-81.) Months afler exposure

Months

are predominantly of the IgM class and have been used to synthesized during viral replication and also may be synthesized from HBV DNA sequences integrated into the diagnose acute infection in adults. Symptomatic adults are chromosomes of hepatocytes in the absence of viral proanti-HBc positive 2 weeks after symptoms begin, and virtually d~ction."~ In general, the presence of HBsAg is an indication all patients with asymptomatic HBV infections are anti-HBc of active viral infection. Approximately 90% of adults will be positive at the time when other virus-associated antigens are detectable and the ALT rises. With time, the titer of anti-HBc HBsAg positive using a conventional enzyme-linked immunosorbent assay (ELISA) for HBsAg during the first 2 weeks of IgM declines as the titer of anti-HBc IgG rises. At 6 months following infection, a majority of patients' anti-HBc antisymptomatic acute viral hepatitis B. A single negative assay result early in the course of infection may represent a falsebodies are IgG, although a minority may have detectable negative result, because the antigen concentration may be anti-HBc IgM for up to 2 years. The anti-HBc antibody titer below the sensitivity of the immunoassays. Repeating the slowly declines but remains detectable for many years after assay several weeks later may yield a positive result. In acute self-limited infection. The anti-HBc titer usually remains high infection, the levels of HBsAg begins to fall 4 t o 6 months during the course of chronic infection. During recovery from after expo~ure.'~ In the neonate, HBsAg may be present at an acute infection, the anti-HBc IgM may be detected in birth, as a consequence of in utero infection, or may not be serum several weeks after infection at a time when the HBsAg is decreasing and no longer detectable in serum, and detectable for several months following perinatal or while anti-HBs is increasing but is not yet detectable in postnatal inoculation. For infants born to chronically serum. The newborn infant's anti-HBc response following infected mothers who are provided immunoprophylaxis, HBsAg (and anti-HBs) should be checked at 9 to 15 months perinatal infection has not been prospectively studied. Of of age, or 1 to 3 months following completion of the primary note is the fact that immunized infants born to mothers not immunization series.' infected by hepatitis B may be transiently positive for HBsAg Anti-HBs antibody testing is widely available, usually from the vaccine but should not be positive for anti-HBc. In performed by EIA or RIA techniques. This circulating antiinfants born to mothers with chronic infection, transplacental, maternal anti-HBc should be detectable for up to the first body is directed against epitopes on the S protein of the preseveral months of life. In addition, in infants born to S/S OW gene product. In self-limited HBV infections, it usually is assumed that the patient is no longer infectious chronically infected mothers, passive immunization with after anti-HBs is detectable. With the development of more hepatitis B immune globulin also may provide anti-HBc sensitive assays for HBsAg and anti-HBs, patients with selfdetectable in the infant's serum. Continued presence of antilimited infection may be transiently HBsAg and anti-HBs HBc at 12 to 18 months in these infants, however, should positive simultane~usly.~~ Most patients with chronic HBV raise the suspicion of perinatal infection with HBV. infections will never be anti-HBs positive. Conversely, less Both HBeAg and anti-HBe are detectable by both EIA than 10% of chronic carriers have anti-HBs a n t i b o d i e ~ . ~ ~and RIA. The HBeAg usually is detectable in adults when Anti-HBs positivity usually implies that an HBV infection viral replication is occurring with little host response to limit has resolved or that the patient has mounted an antibody the production of virions. Later in the course of infection, response to the hepatitis B vaccine. In persons with natural particularly in certain ethnic groups, a seroconversion from infection, anti-HBc also is positive. Evidence that an adult HBeAg to anti-HBe may be accompanied by decreasing viral may both have anti-HBs and be intermittently positive for titers, or even the eventual clearance of virus. The concensmall amounts of HBV DNA suggests that anti-HBs is a marker tration of virus usually is higher in HBeAg-positive sera than for clinical cure, rather than for sterilizing immunity.52s88 in HBeAg-negative sera. The absence of HBeAg positivity, Anti-HBc is formed against the nucleocapsid core protein however, does not exclude the potential infectivity of during the course of infection. It is most commonly detected HBsAg-positive sera in patients with HBV infections either by EM or RIA. Early in the infection, anti-HBc antibodies caused by standard strains or caused by those with mutations

Chapter 25

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831

response than lamivudine alone, and the in the precore region in which HBeAg is not p r o d u ~ e d . 6 ’ , ~ ~ ,antiviral ~~ combination of lamivudine plus peginterferon-a did not At present, although the immunoassays for HBeAg and antisignificantly improve the outcome of infection beyond that HBe are readily available to the practitioner, the clinical use achieved by peginterferon-a alone.” In two smaller studies of these assays is limited to guiding antiviral therapy in involving 19 and 20 children, respectively, interferon-a plus helping to identify an HBeAg-to-anti-HBe seroconversion in the chronic HBV carrier. No other management decisions lamivudine was used for treatment in ( 1 ) children who were can be reliably based on these tests at this time. The decision noted to be interferon-a nonresponders, demonstrating a of whether to perform immunoprophylaxis of a newborn of response rate of 37%;’ and (2) those who were treatment an HBsAg-positive mother with HBIG and HBV vaccine naive, resulting in a response rate of 5 5 ~ 0 . ~ ’ The decision of which child to treat is still evolving, and should not depend on her HBeAdanti-HBe status, because vertical transmission may occur in either setting. incorporates both the safety, side effects, tolerability, as well HBV DNA can be measured in commercial reference as efficacy in children who usually are asymptomatic with laboratories by a variety of techniques, either qualitative their HBV infection^.'^'^^ assays that detect the presence or absence of HBV DNA or quantitative HBV DNA assays. Techniques include signal Prevention of Infection amplification following molecular hybridization (including hybrid capture and branched-DNA methods) or nucleic acid Prophylaxis for the HBV-exposed neonate may consist of target amplification (PCR and transcription-mediated passive immunization with hepatitis B immune globulin amplification [TMA] techniques) .79,80 These tests most often (HBIG),active immunization with HBV vaccines, or antiviral therapy with lamivudine, or a combination of these treatare used to monitor response to antiviral therapy, rather ments. The role of HBIG in preventing vertical transmission than to diagnose an HBV infection. of HBV to infants born to HBV carrier mothers has been HBV genotypes also can be determined in reference well documented, but HBIG is currently being replaced by laboratories by using immunoassay and nucleic acid vaccine in some countries, particularly in infants born to sequencing techniques. These assays most often are interpreted mothers considered at low risk of transmitting the inin conjunction with a pretreatment laboratory assessment, fe~tion.6”~~”’~ HBIG is used routinely with vaccine for all because different genotypes may respond differently to various antiviral and immune therapies. infants born to HbsAg-positive mothers in the United States.’ Many other tests for hepatitis B virus and other techHBIG is derived from plasma collected from persons who niques to measure HBV antigens, HBV antibody, and specific have recovered from HBV infection and is processed to lymphocyte responses to various HBV epitopes have existed eliminate risk of infection from HIV or HCV.44The success for several years. New molecular techniques are being used of HBIG alone in preventing vertical transmission was docuto provide more insight into the pathogenesis of infection, mented in Taiwan by demonstrating a decrease in neonatal and to allow investigators to track response to antiviral therapy HBV infection from 92% in infants born to HBSAg- and HBEAg-positive mothers to 26% in infants given 0.5 mL of more closely. HBIG at birth, 3 months, and 6 months.36 In an effort to further decrease transmission, subsequent studies employed Therapy both passive protection (HBIG) and active immunization with HBV vaccine. Immune serum globulin (ISG) is not Therapy for HBV infection has not been studied systematically considered to have sufficient antibody to HBV to be a in the neonate. In older children, therapy is undertaken in reasonable substitute for HBIG for passive prophylaxis in the those with biopsy evidence of liver di~ease.4~ Therapy for newborn. hepatitis B includes interferon-a (including pegylated The first hepatitis B vaccines were originally approved in formulations) and lamivudine and adefovir, the nucleoside the United States in 1981. They were composed of purified analogues that act as polymerase inhibitors. In children, HBsAg from plasma of chronic carriers and were documultiple studies have been conducted using interferon-a, mented to be immunogenic and protective in infants born to with overall encouraging results. Response rates as high as chronic carrier mothers.37,57,68,72,73,1 14,116 These vaccines were 58% were noted in some In adults and children replaced a few years later by the currently available vaccines, with chronic hepatitis B infection, lamivudine treatment has all of which use recombinant DNA technology in Saccharobeen associated with a rapid and profound decrease in serum myces cerevisiae to produce HBsAg and are safer than but HBV DNA levels, normalization of aminotransferase levels, just as effective as previously available vaccines.69~74~82~10z and in adults, reversal of some histologic changes seen in Currently available data on long-term protection suggest liver biopsy specimens, with reduction in fibrosis and that booster doses of HBV vaccines may not be necessary for ~ i r r h o s i s ? ~ ,Unfortunately, ~ ~ * ~ ~ , ~ ~ emergence of lamivudine children who received either plasma-derived or recombinant resistance may occur within 6 months of therapy, linked to vaccines, although the relevant studies were conducted largely nucleic acid mutations in the HBV Adefovir has been studied in both HbeAg-negativeS3and HbeAg-po~itive~’ in countries in which hepatitis B is endemic. Current recommendations to achieve protection of the adults. Limited data exist on adefovir therapy in children with infant from vertically transmitted infection begin with chronic HBV infection, but no recommendations can yet be universal screening of all pregnant women for the HBV made. Other nucleotide analogues are currently investigational. carrier state. For infants born in the United States to women The concept of multiple drug therapy to decrease the risk of who are identified as chronic carriers (regardless of HBeAg the development of resistance also has been suggested. serologic status), both HBIG (0.5 mL) and an initial dose of In addition, pegylated interferon-a, used alone or in one of the FDA-approved hepatitis B vaccines (Recombivax combination with lamivudine in adults, provided a better

832

Section I11

Viral Infections

HB [Merck], 5 pg; or Engerix-B [GSK], 10 pg) should be administered at different sites, within 12 hours of birth. For premature infants born at less than 2000g whose mothers are HbsAg positive, the initial dose of vaccine at birth should not be considered as part of the immunizing series and should be regarded as just an additional dose. For infants born to women who are not HBV carriers, the first dose of vaccine should be provided in the neonatal period, not necessarily within 12 hours of birth. For women who have not been screened, vaccine should be administered within the first 12 hours of life while maternal testing is under way. If maternal testing indicates that the mother is a chronic HBV carrier, then HBIG should be administered as quickly as possible, preferably within 48 hours of birth, but may be given within 7 days of birth. For infants born at less than 2000g whose mothers did not undergo screening or were screened too late for results to be available within 12 hours of birth, a dose of HBIG should be given in addition to vaccine, rather than waiting for the maternal HBV status to be determined. For infants born to HBSAg-positive mothers, follow-up testing should be performed for HBsAg and anti-HBs at 9 to 15 months of age, after completion of the series of immunizations for HBV. Testing of the infant shortly after vaccine administration may yield a positive result for HBsAg as a result of vaccination, rather than of infection. Detailed recommendations for immunization of neonates are available from the American Academy of Pediatrics’ and the ACIP? In situations in which a chronic carrier mother has premature rupture of the membranes, the delivery management should not be altered in order to deliver the infant to provide prophylaxis, because no data are available to support an increased risk of HBV infection to the infant before delivery in this situation.” Mutations in the viral genome responsible for the production of HBsAg with an altered antigenic structure are known to exist. These relatively rare mutations create HBV virions that are not neutralized by the immunity created with HBV i r n r n u n i z a t i ~ n ~the ~ ’ ~clinical ~; consequences in persons infected by these altered HBV virions are therefore not altered with available HBV vaccines. The current recommendation to prevent HBV infection in infants born to mothers with chronic hepatitis also should apply to infants born to mothers who become infected by HBV in the last trimester of pregnancy and are HBsAg positive at the time of delivery, because risk of vertical transmission appears to be similar in both situations. Largescale trials to document efficacy of HBIG and HBV vaccine in these infants do not exist, however. In addition to providing immune prophylaxis with HBIG and vaccine to infants, lamivudine also has been used for treatment in mothers with high viral loads during the last month of pregnancy in an effort to reduce the risk of vertical transmission. Although the average viral load decreased in women who received lamivudine, one of eight infants who also received immune prophylaxis became infected with HBV.’09 At this time, antiviral therapy during the last month of pregnancy cannot be routinely recommended. Intervention strategies with hepatitis vaccine and HBIG for the newborn infant, based on maternal screening for HBV infection and the gestational age of the infant, are summarized in Table 25-2.

HEPATITIS C

The Virus After the development of definitive assays for both HAV and HBV in the mid- WOs, it became clear that other agents also were responsible for post-transfusion hepatitis, sporadic hepatitis, and occasional epidemics of maternally transmitted hepatitis.”’ Following the discovery of the virus by means of a “blind” recombinant immunoscreening approach, HCV was recognized as the agent most commonly responsible for parenterally transmitted non-A, non-B virus infection.’22 HCV is a single-stranded enveloped RNA virus approximately 9600 nucleotides long, belonging to the Flaviviridae family.’’46*’49 The single strand of positive-sense RNA codes for a single open reading frame, producing a single polyprotein of approximately 3000 amino acids that is cleaved into three structural proteins-core, El, E2-and seven nonstructural proteins-p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B. Structural proteins El and E2 are involved in the viral envelope and are likely to be involved in cell receptor binding. Nonstructural proteins provide various intracellular functions, including a protease used to cleave a portion of the polyprotein into active components, a helicase, and an RNAdependent RNA polymerase. Entry into the cell follows attachment of the virus by means of the E2 envelope protein to CD81, a cell surface protein expressed on hepatocytes and other cells.’47Following entry, events of viral replication and release are not well understood. Viral uncoating occurs, with release of viral RNA into the cytoplasm and subsequent translation into the polyprotein as well as the production of negative-sense RNA, from which further copies of RNA for virus production can be made. Core protein, formed from the first 191 amino acids of the polyprotein, polymerizes to form the icosahedral HCV nucleocapsid, which combines with positive-sense RNA to form virions, which then incorporate the envelope proteins E l and E2 before release. The E2 protein genome contains a hypervariable region (HVR-1) that permits ongoing change in antigenic structure of the E2 protein, providing a mechanism by which HCV may continually elude targeted host defenses,’56similar to that seen in HIV infections. The viral RNA polymerase lacks the “proofreading” capabilities normally found in mammalian polymerases, thereby facilitating ongoing base replacement and altered tertiary structure of the E2 protein. Worldwide, six major genotypes exist, although each genotype comprises hundreds to thousands of subtypes resulting from the high mutation rates during virus replication. These subtypes are called quasispecies and provide some insight into the unique ability of this virus to continually alter its immunologically recognizable epitopes. In general, the genotypes of HCV are used as epidemiologic tools, but they also appear to respond differently to antiviral therapies.

Pathogenesis Most of the information gathered on the pathogenesis of disease is based on primate models of infection, because cell culture systems and small animal models do not currently exist.13’ Following infection, the virus primarily enters

Chapter 25

Table 25-2

Hepatitis

833

Hepatitis B Neonatal Intervention Strategies Based on Maternal HBV Screening Status ~~~

Laboratory Evaluation at Birth and during Infancy

Maternal HBV Status

Interpretation

HBsAg negative

Mother is not considered infectious; no risk t o the neonate

None required

HBsAg positive

Mother is infectious; significant risk o f neonatal infection

HBsAg on peripheral venous blood sampling t o diagnose intrauterine infection (and less likely benefit from perinatal intervention); test infant for anti-HBs and HBsAg at 9-15 months of age for outcome o f intervention

HBsAg status unknown

Mother's infectious status unknown; do maternal HBsAg testing as soon as possible

None required at birth In infants whose mothers are subsequently found t o be HBsAg positive, testing for anti-HBs and HBsAg at 9-15 months of age is recommended

Infant Treatment A l l newborn infants: standard 3-dose immunization regimen with hepatitis B vaccine recommended: dose 1 given soon after birth, up t o 2 months of age; dose 2 given at least 4 weeks after dose 1; dose 3 given at least 16 weeks after dose 1, and at least 8 weeks after dose 2, with last dose no earlier than 24 weeks of age A l l infants: HBlG 0.5 mL within 12 hours of birth, i n addition t o the first dose of hepatitis I3 vaccine, also given within 12 hours of birth; second and third doses of vaccine for infants with birth weight 2000 g or greater, as above Preterm infants less than 2000 g birth weight: initial birth dose should not be counted as one of immunizing series because of an immature response t o vaccine; subsequent 3 immunizations in primary immunizing series for these infants should start at age 1 month Full-term infants: give first dose of hepatitis B vaccine within 12 hours of birth; if maternal HBsAg is positive, give HBlG 0.5 mL as soon as possible, within 7 days of age; if maternal HBsAg is negative, HBlG is not needed; subsequent doses as for HBsAg negative Preterm infants less than 2000 g birth weight: if maternal HBsAg status cannot be determined within 12 hours of birth, give HBlG in addition t o hepatitis vaccine within 12 hours of birth; provide subsequent 3 hepatitis B immunizations for primary series, starting at 1 month of age, as above for preterm infants

HBIG, hepatitis B immune globulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.

hepatocytes, although viral replication also may occur in other cell types, including dendritic cells and B cells. The virus is not cytopathic, similar to HBV. Within 10 to 14 weeks following inoculation, acute hepatitis develops, although virus can be detected in the liver many weeks before clinically evident disease. At the onset of illness, liver function test results become abnormal, and HCV-specific T cells appear in the li~er."','~~,'~~,'~~,'~~ In a study of outcome in five persons following needlestick exposure, viremia could first be detected within 1 to 2 weeks after exposure.'58Clearance of virus occurred in only

one subject in this study and was not seen until after the appearance of HCV-specific CD8' T cells accompanied by a strong HCV-specific CD4' response. Clinical hepatitis occurred at the time of appearance of CD8' T cells, although elevation of liver enzymes occurred as early as 2 weeks after exposure in persons who remained asymptomatic. In persons in whom persistent infection did not develop, no CD8+-specific response was detected, although in some, strong CD4' T cell responses initially developed that subsequently faded during the 23 to 92 weeks of follow-up evaluation. Of note, the production of IFN-y led to a

834


100,000-fold drop in circulating virus titer, suggesting that the noncytolytic mechanisms of T cell control of intracellular virus replication in HBV infections may be similar in HCV. Other studies have documented strong CDS+ T cell responses to multiple different epitopes of HCV among human subjects with resolution of infe~ti0n.I~’ The responses differed in the specific HCV epitopes recognized, suggesting that no single neutralizing epitope exists, and that a response to multiple epitopes simultaneously is more likely to lead to clearance of virus. Persons with persisting infection had responses that were weaker and more narrowly focused. Similar data exist in the chimpanzee model, suggesting that CD8+T cell responses, seen in cells resident within the liver, constitute an important component of the immune response.121,149,155,159 Within the liver, complex interactions between virally infected cells and HCV-specific CD8’ and CD4’ T cells occur, leading to both cytolytic, destructive changes in hepatocytes and interferon production, With an extremely high replication rate of greater than 10” virions per day, as well as rapid rates of mutation, the ever-changing antigenic structure provides a moving target for the immune system. The HCV-specific antibody, which is used to diagnose infection, recognizes epitopes on the various quasispecies of HCV virions, many of which may no longer exist in the circulation at the time antibody is detected. Likewise, epitopes that elicit a cellular immune response also are changing, providing a difficult challenge to the cellular immune system to find and neutralize virally infected cells. It is not difficult to understand that chronic infection develops in 80% of infected adults.

Transmission

to viremic mothers; the viral load in the mother has been a significant factor in transmission in most studies in which viral load was determined, with the presence of greater than lo6 genome equivalents per mL resulting in greater risk of transmis~ion.‘~~,’~~ HIV co-infection has been associated with increased rates of HCV transmission four to five times higher than in women who are not also HIV infected.126~’29,142*154.’60 Some investigators also have noted infantile hypoxia and intrapartum exposure to maternal blood as assessed by a history of perineal or vaginal laceration as additional risk fa~t0rs.I~’ At present, universal screening during pregnancy for HCV is not r e ~ o m m e n d e d l l ~however, ”~~; pregnant women at high risk for infection should be screened. Risk factors include HIV or HBV infection, parented drug abuse, transfusion or transplantation before 1992, presence of chronic infection with HCV/HBV/HIV in a sexual partner, attendance at a chronic dialysis unit or assocaition with staff of such units, elevated values on liver function tests, and history of body piercing.133Although most authorities do not advocate cesarean section for delivery in cases of maternal infection, some studies suggest a higher rate of transmission with vaginal de1i~ery.I~~ One analysis predicted the cost-effectiveness of cesarean section if the perinatal transmission rate in a group of HCV-positive pregnant women is at least 7.7%, estimating a reduction in transmission of more than 77Y0.l~~ Although breast milk may contain HCV DNA, breastfeeding does not appear to carry additional risk to the term infant born to a mother with HCV infection. Therefore, no restrictions should be placed on routine breast-feeding by the HCV-positive mother.139B153 Recommenations for testing the infant for evidence of vertical transmission, based on maternal laboratory screening tests for HCV infection, are summarized in Table 25-3.

HCV is primarily transmitted parenterally: by needlestick exposure (from reused needles in medical settings from the past decades, or in intravenous drug abuse) and by blood Clinical Illness transfusion before screening of donated blood beginning in 1992. The infection may be transmitted vertically from HCV infection most often is asymptomatic in infants with chronically infected mother to infant, although the rate of perinatally acquired HCV.134,151 Most infections in children infection in newborns is only about 3% to 7%.152Infection are either found by screening those with exposure to HCV appears to be most often acquired perinatally, although some (receipt of blood products prior to 1992 or born to mothers with chronic HCV infection) or noted incidentally on controversy exists as about what proportion of neonates might be infected in utero. The assessment of in utero inexaminations and laboratory testing unrelated to hepatitis. fection usually is made by confirming the presence of HCV Long-term follow-up evaluation of 62 perinatally infected RNA by RT-PCR assay in cord blood. Inapparent contamininfants, defined by presence of HCV RNA in serum and ation of the cord with maternal blood, however, may lead presence of anti-HCV antibody beyond 18 months of age, to false-positive results. In some of these situations, suggests that chronic infection will develop in greater than contamination is supported by follow-up studies in infants 80%.15’ Elevated values on liver function tests were present that failed to detect either HCV RNA by RT-PCR assay, or in 93%, and liver biopsies performed in 11 asymptomatic evidence of productive infection as assessed by the later children all demonstrated only mild abnormalities. Thereappearance of anti-HCV antibody. In some studies, a rare fore, it is likely that a majority of infants will have not overt infant who is negative for HCV by PCR assay at birth may manifestations of infection, and that the first clinical become transiently positive during the first year of life symptoms attributable to HCV infection will appear in the without evidence of anti-HCV antibody at that time, or third and fourth decades of life, when cirrhosis begins to when tested later at follow-up evaluation. These observations produce clinical symptoms.136Unlike in HBV infections, in of transient viremia may be explained either by false-positive which the degree of abnormality of liver function tests test results or by inoculation and subsequent clearance of correlates roughly with the degree of liver damage, the HCV in the infant without evidence of productive infection. fluctuating host response in HCV infection suggests that Many studies of vertical transmission have recently been liver function tests are not helpful in assessing the developpublished describing the rate of infection in the newborn ment of aggressive hepatitis and cirrhosis. Normal findings and factors that may influence transmission.123~126”50”52’157’160 on these tests may simply reflect a period in which the child’s immune surveillance has not yet recognized new quasiThe vast majority of infants who develop infection are born

Chapter 25

Table 25-3

835

Hepatitis C Management Strategy for Infants Born to Mothers Screened for HCV Due to Risk Factors

Maternal HCV Status ~~

Hepatitis

Interpretation

Laboratory Evaluation at Birth and during Infancy

Infant Treatment

~

Anti-HCV negative

Anti-HCV positive

Mother n o t considered infectious; no risk t o neonate unless mother was infected within 6 months before testing and had not yet seroconverted at time of screening; for recent high-risk exposures for mother, request additional plasma HCV RT-PCR testing on mother at delivery Mother has been previously infected and has an 80% chance o f being chronically infected and persistently viremic with HCV Check maternal plasma HCV by RT-PCR assay; if result is positive, mother i s infectious (5% risk of HCV vertical transmission), particularly if she also is HIV positive (30% risk of HCV vertical transmission)

None required for infants born t o mothers who are anti-HCV negative (or with negative result on HCV RT-PCR assay if obtained)

None

No routine testing at birth; infant should be tested for anti-HCV antibody at 1 2 to 18 months of age Maternal, transplacental antibody should be reliably cleared by the infant at that time if no neonatal infection has occurred; if anti-HCV is present at age 12 t o 18 months, do plasma HCV RT-PCR testing in infant; if result is positive, infant has been infected If anti-HCV test result is positive at age 18 months, and plasma HCV RT-PCR assay result is negative, repeat anti-HCV and HCV PCR testing every 6 months until both are negative (no infection) or both are positive (infection)

No HCV vaccine available; no effective immune globulin t o prevent HCV transmission t o neonate

anti-HCV, antibody to hepatitis C virus, HCV, hepatitis C virus, HIV, human immunodeficiency virus, RT-PCR, reverse transcriptase-polymerase chain reaction

species within hepatocytes, and no acute inflammatory host response is present at that moment. Yet significant damage to the liver may have already occurred. Similarly, highly elevated liver function test values may reflect an ongoing immunologic response, with a liver that previously incurred minimal inflammatory changes. Of perinatally infected children, about 20% have been documented to clear their infection during childhood-a higher proportion than in children who acquired infection through tran~fusi0n.I~~ Of perinatally infected children who cleared their infection, liver inflammation as assessed by liver function tests was greater than in those who remained chronically infected. This finding suggests that greater host recognition of viral infection accompanied by liver damage may be a predictor of subsequent cure.15' Routine liver biopsy in children with HCV is not currently re c ~mmended. '~ '~ ~ In adults, jaundice will develop as part of the clinical presentation in only 20% of those with acute HCV inf e c t i o n ~ . Some ' ~ ~ patients will have a nonspecific prodrome of fatigue, lethargy, low-grade fever, nausea and vomiting, and abdominal discomfort beginning approximately2 months

following exposure ( 2 to 12 weeks), and lasting from 2 to 12 weeks. Of those adults who are clinically symptomatic, approximately 50% will clear the infection; of those who have clinically asymptomatic infection, the infection will become chronic in 80%.l4OThe interval from acute infection to the development of cirrhosis may be 30 years or longer. Severe complications of cirrhosis will occur in 15% to 20% of chronically infected p e r ~ 0 n s .With I ~ ~ HCV infection outbreaks associated with contaminated blood products, longterm follow-up evaluation suggests that the great majority of chronically infected adults have minimal cirrhosis as confirmed by biopsy performed 20 years after infection. Alcohol use and co-infection with other viruses causing hepatitis are associated with an acceleration of the inflammatory process. The genotype of HCV causing the infection does not appear to play a major role in the clinical course or progression of infe~ti0n.l~' Chronic HCV infection in adults also is a risk factor for the development of hepatocellular carcinoma. An HCVattributable risk of 1% to 4% per year has been reported for persons in whom cirrhosis also developed."'

836


The status of HCV viral infection in pregnancy has been studied. Published reports suggest a decrease in the level of aminotransferases as the pregnancy progresses, as well as some variability in the viral l ~ a d . ' ~ ~ ~ ' ~ '

Laboratory Diagnosis The diagnosis of an HCV infection is based on the detection of anti-HCV antibodies, which reflect a host humoral response to a wide range of HCV viral antigens as measured by enzyme immunoassay (EM). Unlike in HAV or HBV infection, however, the presence of antibody does not document recovery from infection, or lack of contagiousness. As in HIV infection, the EIAs are very sensitive, but serologic confirmation of infection also is available with the more specific recombinant immunoblot assay (RIBA), which detects the host response to specific viral products within infected cells. Current-generation EIA and RIBA tests are more sensitive and specific than previous tests, allowing more accuracy in diagnosis. The third-generation EIA tests detect antibodies to recombinant and synthetic peptides representing the core and NS3, NS4, and NS5 regions and are 99% RIBAs also are highly specific in measuring host antibody reactions to each of a number of specific HCV antigens, including two synthetic peptides, 5- 1- 1(p) and c 100(p), from the NS4 region of the HCV genome; c33-c recombinant antigen derived from the NS3 region; c22(p) from the core portion of HCV; and the product of the NS5 region of the HCV genome. Routine confirmation of positive third-generation EL4 results with RIBA usually is not required to document i n f e ~ t i 0 n .Antibodies l~~ to HCV antigens develop as early as 2 to 4 weeks after infection; however, some HCV-infected persons, including neonates, may not seroconvert for up to 6 months or longer following the assumed time of exposure. The diagnosis of active, chronic infection also relies on detection of HCV RNA, because the virus cannot be cultured. Both qualitative (nonquantitative) and quantitative assays are commercially available, Qualitative systems generally are more sensitive and include RT-PCR or TMA techniques, which can detect as few as 50 HCV genome copies per mL of blood. Quantitative assays, useful in following response to antiviral therapy, include PCR, TMA, and branched-DNA amplification technique^.'^^ The quantity of HCV nucleic acid detected in serum in chronic infection appears to wax and wane, probably in response to the state of immunologic recognition by the host. When the host recognizes specific HCV epitopes and produces specific antibody and cellular immunity against that particular strain of circulating virus (quasispecies),it often will disappear from the circulationonly to be replaced by other quasispecies of HCV as the hypervariable genes continue to mutate to produce antigenically distinct epitopes, which then are no longer recognized by the host. At certain times during a chronic infection, the viral load of organisms detected in the serum may drop below the level of detection, producing a falsenegative result. With time and further mutation during viral replication, however, new quasispecies will appear and will again be detected by assays for HCV RNA in chronically infected patients.

Additional tests that generally are not helpful in management of patients include FWA sequencing assays, to determine the genotype of infecting strain of HCV, and HCV core antigen levels (which correlate with HCV RNA levels). Transplacentally acquired antibody in babies who are not documented to have chronic infection usually becomes undetectable during the first year of life. Antibody has not been detected in infants at 18 months of age but has been found in some infants up to 15 months of age.'20"26Diagnosis of transplacental infection can be made by detecting persisting anti-HCV antibody at 18 months of age, with infection confirmed by qualitative PCR testing for HCV RNA. Although the presence of antibody before the age of 18 months may still represent maternal antibody, the presence of HCV RNA at any age suggests inoculation, if not infection. Clinicians may wish to test for HCV RNA (qualitative) in infants born to mothers with chronic HCV infection as early as 6 months of life, but if the result is positive, the test should be repeated at the age of 9 to 12 months to confirm vertical transmission.

Therapy As with HBV infection in the newborn, the infection is clinically benign during the first years of life; therapy with either interferon-a or specific anti-HCV antivirals in the infant is more likely to cause unacceptable adverse reactions in these asymptomatic babies than it is to provide any longterm benefit in preventing cirrhosis or hepatocellular carcinoma. In general, therapy is not necessary during infancy. In view of the variability in clinical progression of disease during childhood, however, a liver biopsy in the school-aged child may help the clinician in assessing the risks versus benefits of anti-HCV therapy during childhood. Interferon-a has been FDA approved for use in children with hepatitis C infection in children from 3 to 16 years of age. All children in pediatric clinical trials were biopsied before enrollment; all trials required some histologic evidence of hepatitis. Virologic response rates in children varied, ranging from 33% to 45%, with a consistently lower response rate for genotype 1 Interferon-a in combination with ribavirin also has received FDA approval125for the same age group based on data from 118 children, with virologic response to genotype 1 (n = 92) of 36% and a response to non- 1 genotypes of 8 1% ( n = 26). In adults, pegylated interferon-a in combination with ribavirin has produced the best overall virologic response among FDA-approved therapies, with response rates of about 55%.14 Clinical trials of peginterferon are under way in children.

Prevention of Infection No HCV vaccines have been approved for use in humans. No therapeutic trials in pregnancy have been undertaken during the last trimester to reduce the viral load at the time of delivery in an attempt to decrease the rate of vertical transmission. No immune globulins or antivirals have been used for the newborn infant to prevent the development of infection in those perinatally exposed to HCV.

Chapter 25

HEPATITIS D

The Virus

Hepatitis

837

appear to confer additional risk of hepatocellular carcinoma, h0~ever.l~~ Overall, approximately 5% of persons infected chronically with HBV worldwide are co-infected with HDV, resulting in a public health burden of 15 million cases of HDV infection. As the epidemiology of hepatitis D is better understood, the worldwide distribution and clinical significance of HDV are becoming appreciated. HDV is present in 40% to 60% of all cases of hlminant HBV infection.

Rizzetto and colleagues first noted that clinical deterioration of chronic HBV infection was associated with the appearance of a new (delta) antigen in the liver and antibody in the serum to this antigen.17' This delta agent was subsequently isolated and analyzed and its nucleic acid cloned and sequenced.162~165~171HDV (delta agent) is a 37-nm negativesense single-stranded RNA agent that requires co-infection with HBV. The unique circular RNA genome is only 1700 Transmission nucleotides long. HDV is unrelated to known animal RNA viruses but shares some similarities with plant v i r ~ s e s . ~ ~ ~ , HDV ' ~ ~ , 'infection ~~ in adults in the developed world occurs Reclassification of HDV as a new genus, Deltavirus, has been primarily in association with parenteral drug abuse, although proposed. sexual transmission and intrafamilial transmission also may occur.166In underdeveloped areas within Africa and South America, the seroprevalence of HDV is much higher, Pathogenesis although it may vary considerably even within regions of a Little is known about HDV infection. Cell entry is thought single country. In these areas, identified risk factors include to be mediated by an HBsAg-associated cellular receptor. living in a household with an index case, sexual contact, and Once inside the cell, host cell RNA polymerase transcribes spread through open skin lesions in children.'69 In utero or viral RNA by mechanisms that are poorly understood, because vertical transmission of HDV from mother to neonate has no RNA-dependent RNA polymerase activity usually exists not been reported. for host enzymes.16' HDV has multiple open reading frames, but only one, ORF5, leads to the production of a single, identifiable HDV protein. This protein can take two formsClinical Illness HDAg-S (short) and HDAg-L (long), which contains an additional 19 amino acids and serves a different function. HDV infections occur in three clinical settings: (1) acute HDAg-S is involved in HDV RNA replication by stimulating HDV hepatitis with acute HBV hepatitis, (2) acute HDV transcription of viral nucleic acid b the host enzyme; hepatitis with chronic HBV hepatitis, and (3) chronic HDV HDAg-L is involved in virion Genetic heterohepatitis with chronic HBV hepatitis. The incidence, geneity is well documented with HDV Three genotypes, as transmission, and clinical consequence of HDV infection in well as numerous quasispecies within each genotype, have newborns and young children have not been defined. been de~cribed.'~~ The RNA genome is capable of selfcleavage and self-ligation in the process of creating circular RNk therefore, it is classified as a ribozyme. The virus uses Laboratory Diagnosis the HBV S protein (HBsAg) as a coat protein, packaging the HDV RNNHDAg within infectious virions. The virus may Commercial anti-HDV EIA tests are widely available, including an anti-HDV IgM test. In acute self-limited HDV be directly cytotoxic to the hepatocyte. Investigation of the immunologic response to HDV acute hepatitis, the IgM anti-HDV antibody is only transiently infection in patients chronically infected by HBV suggests positive; therefore, serial samples may be necessary to conclearance of HDV by CD4' helper T cells, which have been firm the diagnosis. In any HBsAg-positive, anti-HBc IgM documented to respond to at least four specific viral antibody-negative patient who has acute hepatitis, a epitopes.'68 Patients with HDV hepatitis in whom chronic screening test for IgM anti-HDV antibody may help rule out HDV infections subsequently developed lacked these concurrent HDV superinfection. In chronic HDV hepatitis, specific cellular responses. Recently, a set of HDV epitopes anti-HDV IgM or high-titer anti-HDV IgG antibodies are eliciting specific anti-HDV CD8' T cell responses were found detectable. Serial samples that are positive for anti-HDV in patients with evidence of past HDV infection, suggesting antibody confirm that the infection is chronic and not acute. that cellular immune responses to HDV may be similar to In addition to detection of antibody, HDV antigen (HDAg) these seen with HBV infection.'@ can be detected in serum by immunoblot technique in a The histopathology of hepatitis delta virus infection has majority of patients with chronic HDV infection. The most sensitive test for HDV infection is an assay for HDV RNA been studied in carriers of HBsAg with serial biopsies in adults with acute HDV hepatitis associated with chronic using RT-PCR, which also is commercially available. infection. No feature distinguished HDV histopathology from other types of viral hepatitis. Portal and periportal Therapy inflammation with piecemeal necrosis was documented, often accompanied by cirrhosis. Biopsies also documented The only treatment that proved effective in HDV/HBV cofocal, confluent, and bridging necrosis. In patients with infection in adults is high-dose, prolonged therapy with chronic HBV infection who are co-infected with HDV, more interfer0n-1x.I~~Courses of interferon longer than 1 year rapid progression to cirrhosis may occur, particularly in have been used in some patients.'63 No treatment has been certain population groups.'69 HDV co-infection does not used in children.

838


Prevention of Infection The prevention of hepatitis D is accomplished through the prevention of hepatitis B, because available evidence does not suggest that HDV can infect a person who is HBsAg negative. Perinatal transmission has not yet been documented; accordingly, the need for intervention during pregnancy has not yet been defined.

HEPATITIS E

The Virus HEV is a 7500-base, positive-sense, single-stranded RNA whose sequence is unique among those of other known viruses, most closely resembling that of togaviruses. The viral genome consists of three open reading frames, which code for at least five nonstructural and capsid proteins, including a protease, a helicase, and an RNA-dependent RNA polymerase. This virus is 27 to 32 nm in diameter and can be found in stool by immune electron microscopy during the acute phase of the infection. The virus does not have a lipid membrane and is labile to high salt concentrations and freezing but appears to be able to persist in sewage.'86,188

Pathogenesis HEV infection is found worldwide. Llke HAV, this virus is a major cause of waterborne epidemics of acute hepatitis under conditions of poor sanitation. Infections occur predominantly in Asia, Africa, and Mexico. Recently developed EIAs for anti-HEV have detected antibodies to HEV-related antigens in 1% to 2% of U.S. volunteer blood donors, indicating that HEV also may be endemic in the United States. Most people infected with HEV are older than those infected with HAV, with seroepidemiologic investigations suggesting a peak incidence of infection between the ages of 15 and 40 years. Published data suggest negligible intrafamilial transmission from index cases identified during outbreaks of HEV infection, providing support for a more prominent role in exposure from contaminated water supplies.17*Early childhood transmission,presumably through direct contact, also has been documented to Very little is known about the pathophysiology of HEV infection in humans, although primate models have successfully been used to study productive infections. The virus first appears in the liver, followed by viremia, and subsequently by shedding of the virus in feces. Liver injury occurs with elevated serum aminotransferases and develops at the time of appearance of anti-HEV IgM antibody. Evidence of liver inflammation is accompanied by biopsy evidence of injury, but without the presence of significant clinical illness in the primate model. No chronic infection has been described in humans. In animal models and in humans, the severity of the disease may be genotype dependent. Passively administered neutralizing antibody to HEV capsid antigens is successful in preventing infection following challenge in the cynomolgus primate m0de1.I'~ Little is known about the human cellular immune response to HEV infection.

A number of studies of the natural history of hepatitis in pregnancy have documented HEV to play a dominant role in the progression to fulminant hepatic failure and death.18'*'84*'R5 The pathogenesis of aggressive infection in pregnancy is not well understood.

Transmission Hepatitis E virus (HEV) usually is transmitted to children and adults by the fecal-oral With respect to the neonate, limited data point to in utero infection as suggested by the presence of specific HEV IgM in cord blood, as well as by the detection of virus by PCR a ~ s a y . ' ~ *In~one ' ~ ~ report from India of a series of eight infants born to mothers with evidence of acute HEV infection in the third trimester, five infants had PCR evidence of in utero infection"'; of these, four had elevated values of liver aminotransesterases, and three had anti-HEV IgM. Two of these five neonates died, with postmortem examination in one infant documenting hepatic necrosis. In another report, also from India, three of six neonates born to mothers with acute HEV infection during the third trimester of pregnancy were PCR positive for HEV. Two of these three infants also were anti-HEV I@ positive in cord blood. One of these infants had intrauterine growth retardation and elevated values on liver function tests at the time of birth but recovered clinically from the illness.lE5 Prospectively collected, uncontrolled data on HEV transmission from mothers to infants in Saudi Arabia documented HEV RNA in colostrum of infected mothers. Of 57 pregnant women documented to be HEV seropositive for viral RNA during the last trimester, 6 experienced symptomatic liver disease in the perinatal period. Clinical hepatitis developed in 4 infants born to these 6 women by 6 to 8 weeks of age. None of these infants were breast-fed, because of maternal illness. All other infants born to HEV RNA-positive mothers were breast-fed for a mean of 3.6 months. Hepatitis did not develop in any of these infants. Therefore, available data suggest that breast-feeding does not increase the transmission of virus from mother to infant.176

Clinical IIlness The incubation period following exposure in children and adults is between 15 and 60 days. The clinical manifestations of illness usually are mild, with nausea, vomiting, and epigastric pain, followed by the onset of jaundice. Clinical symptoms and aminotransferase elevation usually resolve within 1 to 6 week^.'^^*'^^ In the animal model, clinical symptoms are dependent on the inoculum of Excretion generally continues for a few weeks following onset of i1lne~s.l~~ Chronic HEV infection has not been documented.

Laboratory Diagnosis Acute infection may be diagnosed by the presence of antiHEV IgM, whereas past infection may be documented by the presence of anti-HEV IgG. Assays for both immunoglobulins are available commercially in reference

Chapter 25

Therapy Clinical studies of antiviral therapy in animal models or humans have not been reported. Nevertheless, antiviral therapy might provide benefit to specific populations, including pregnant women, in whom more serious disease may develop.

Prevention of Infection Postexposure, passive administration of immune globulin does not appear to reduce the incidence of disease.Is3Based on the ability to passively neutralize virus and to prevent infection in animal models, vaccines have been developed for HEV infection.A vaccine that contains an epitope spanning all genotypes is now in clinical trials in Nepal.I7'

HEPATITIS G

The Virus HGV, also known as GB virus type C (GBV-C),was identified in 1995 from the blood of hepatitis patients who had no other identifiable causes of viral hepatitis.192Since its discovery, however, no further association has been found with hepatitis as a clinical syndrome attributable to this virushence the preference of some experts for the name GBV-C.'97 The virus is classified as a flavivirus,containing a 9.4-kilobase single strand of positive-sense RNA. The single polyprotein encoded by the single open reading frame in the genome has approximately 30% homology with HCV. The polyprotein is cleaved into at least eight proteins, including two envelope proteins (El, E2) and six nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B), analogous to HCV. Unlike the genes that code for the HCV E2 protein, however, a hypervariable region does not appear to exist in HGV.Ig7

Pathogenesis In an attempt to define the HGV-attributable liver infection in patients known to be chronically infected with the virus because of persistent serum HGV RNA, investigators assayed HGV RNA in both liver and serum from patients undergoing liver transplantation (for a variety of underlying disorders) who were known to be infected either with HGV alone, infected with HCV alone, or coinfected with both viruses.193The investigators found a mean liver-to-serum ratio of HCV, known to be hepatotropic, of greater than lo2, whereas the mean liver-to-serum ratio in HGV patients was only 0.3, leading to the conclusions that HGV was not hepatotropic and that HGV RNA found in the liver was related to blood circulation rather than to hepatocyte infection. Indeed, HGV has not been found to be pathogenic in any study in which patients were known to be infected.'96AntiHGV antibody was found in 13% of blood donors in the midwestern United States who passed the standard laboratory and questionnaire screening tests to permit donation. Furthermore, in 2% of these donors, HGV RNA was detected. In epidemiologic studies worldwide, the prevalence of antibodies to HGV E2 protein varies, ranging from 20% in South Africa to 3% in the phi lip pine^.'^^ In studies in which

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both HGV RNA and anti-HGV antibody directed against the E2 protein are assayed, both are never found together in the same patient.194,197

Transmission HGV has been shown to be transmitted by exposure to infected blood and blood products, by sexual exposure, and from mother to newborn infant.'96 In Sweden, three studies investigated vertical transmission, including one study of HN-infected mothers. Of seven infants born to mothers not infected with HIV, one infant became HGV RNA positive in serum at 3 months, with persisting viremia during 42 months of follow-up and no evidence of liver disease."' In another investigation, 16 of 20 mothers (80%) with HGV viremia transmitted the infection, as documented by the presence of HGV RNA in their infants.Ig8 The time to acquisition of viremia in the infants was not well defined, but occurred in a majority of infants by 3 to 6 months of age. Symptomatic hepatitis did not develop in any of the infants. In mothers with HGV and HIV coinfection, the vertical transmission rate of HGV was assessed in the era prior to maternal antiretroviral antenatal prophylaxis. Of 17 mothers identified with HGV infection, 3 were viremic with HGV at the time of delivery, and 14 had anti-HGV antibody. None of the anti-HGVantibody positive women had detectable serum HGV RNA. Only one of the infants born to the mothers with HGV viremia transmitted the infection to her infant; HIV was not co-transmitted to this infant.'" HGV did not appear to influence the rate of transmission of HIV, noted to be 20% in this study. The role of breast-feeding in transmission was investigated in one study, documenting the lack of detectable HGV RNA in the breast milk of 15 viremic women.'95Nevertheless, the vertical transmission rate in this study was 20%, as assessed by HGV RNA in the infants. Because breast milk may not play a significant role in vertical transmission of HGV, and the consequences of neonatal chronic infection are not defined, breast-feeding should not be discouraged in women known to be HGV infected.

Laboratory Diagnosis Most commercial laboratories do not offer routine testing for HGV. An EIA for antibody to the E2 protein has been developed to detect past infection, however, and is used in epidemiologic investigation^.'^^ HGV RNA can be detected by RT-PCR assay, which is available in some reference laboratories. Because the virus is not known to cause disease, recommendations for routine screening for HGV infection in any population, including blood donors, have not been made. REFERENCES Hepatitis A 1. American Academy of Pediatrics. The 2003 Report of the Committee on Infectious Diseases. Elk Grove, Ill, American Academy of Pediatrics, 2003. 2. Baroudy BM, Ticehurst JR, Miele TA, et al. Sequence analysis of hepatitis A virus cDNA coding for capsid proteins and RNA polymerase. Proc Natl Acad Sci U S A 822143-2147, 1985.

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148. Plunkett BA, Grobman WA. Elective cesarean delivery to prevent perinatal transmission of hepatitis C virus: a cost-effectiveness analysis. Am J Obstet Gynecol 191:998-1003,2004. 149. Racanelli V, Rehermann B. Hepatitis C virus infection: when silence is deception. Trends Immunol24456-464,2003. 150. Resti M, Azzari C, Mannelli F, et al. Mother to child transmission of hepatitis C virus: prospective study of risk factors and timing of infection in children born to women seronegative for HIV-1. Tuscany Study Group o n Hepatitis C Virus Infection. BMJ 317437-441,1998. 151. Resti M, Jara P, Hierro L, et al. Clinical features and progression of perinatally acquired hepatitis C virus infection. J Med Virol 70: 373-377,2003. 152. Roberts EA, Yeung L. Maternal-infant transmission of hepatitis C virus infection. Hepatology 36(5 Suppl 1):S106-S113,2002. 153. Ruiz-Extremera A, Salmeron J, Torres C, et al. Follow-up of transmission of hepatitis C to babies of human immunodeficiency virusnegative women: the role of breast-feeding in transmission. Pediatr Infect Dis J 19:511-516,2000. 154. Schuval S, Van Dyke RB, Lindsey JC, et al. Hepatitis C prevalence in children with perinatal human immunodeficiency virus infection enrolled in a long-term follow-up protocol. Arch Pediatr Adolesc Med 158: 1007-1013.2004. 155. Shoukry NH, Grakoui A, Houghton M, et al. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J F q Med 1971645-1655,2003. 156. Simmonds P. Genetic diversity and evolution of hepatitis C virus15 years on. J Gen Virol85:3173-3188,2004. 157. Steininger C, Kundi M, Jatzko G, et al. Increased risk of mother-toinfant transmission of hepatitis C virus by intrapartum infantile exposure to maternal blood. J Infect Dis 187:345-351,2003. 158. Thimme R, Oldach D, Chang KM, et al. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med 194 1395-1406,2001. 159. Thimme R, Bukh J, Spangenberg HC, et al.Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc Natl Acad Sci U S A 9915661-15668,2002. 160. Thomas SL, Newell ML, Peckham CS, et al. A review of hepatitis C virus (HCV) vertical transmission: risks of transmission to infants born to mothers with and without HCV viraemia or human immunodeficiency virus infection. Int J Epidemiol 27:108-117,1998. Hepatitis D 161. Casey JL. Hepatitis delta virus: molecular biology, pathogenesis and immunology. Antivir Ther 3(Suppl3):37-42, 1998. 162. Denniston KJ, Hoyer BH, Smedile A, et al. Cloned fragment of the hepatitis delta virus RNA genome: sequence and diagnostic application. Science 232373-875, 1986. 163. Farci P. Delta hepatitis: an update. J Hepatol39(Suppl 1):S212-S219, 2003. 164. Huang YH, Tao MH, Hu CP, et al. Identification of novel HLAA'O201-restricted CD8' T-cell epitopes on hepatitis delta virus. J Gen Virol 85:3089-3098,2004. 165. Kos A, Dijkema R, Arnberg AC, et al. The hepatitis delta virus possesses a circular RNA. Nature 323:558-560,1986. 166. Niro GA, Casey JL, Gravinese E, et al. Intrafamilial transmission of hepatitis delta virus: molecular evidence. J Hepatol30:564-569, 1999. 167. Niro GA, Rosina F, Rizzetto M. Treatment of hepatitis D. J Viral Hepat 12~2-9,2005. 168. Nisini R, Paroli M, Accapezzato D, et al. Human CD4' T-cell response to hepatitis delta virus: identification of multiple epitopes and characterization of T-helper cytokine profiles. J Virol71:2241-2251, 1997. 169. Polish LB, Gallagher M, Fields HA, HadIer SC. Delta hepatitis: molecular biology and clinical and epidemiological features. Clin Microbiol Rev 6 2 1 1-229, 1993. 170. Rizzetto M, Canese MG, Gerin JL, et al. Transmission of the hepatitis B virus-associated delta antigen to chimpanzees J Infect Dis 141: 590-602, 1980. 171. Wang KS, Choo QL, Weiner A], et al. Structure, sequence and expression of the hepatitis delta viral genome. Nature 323:508-514, 1986. Hepatitis E 172. Arankalle VA, Chadha MS, Mehendale SM, Tungatkar SP. Epidemic hepatitis E serological evidence for lack of intrafamilial spread. Indian J Gastroenterol 19:24-28,2000. 173. Balayan MS, Adnjaparidz AG, Savinskaya SS, et al. Evidence for a virus in non-A, non-B hepatitis transmitted via the fecal-oral route. Intervirology 20:23-31, 1983.

Chapter 25 174. Balayan MS. HEV infection: historical perspectives, global epidemiology,

and clinical features. In Hollinger FB, Lemon SM, Margolis HS (eds). Viral Hepatitis and Liver Disease. Baltimore, Williams & Wilkins, 1991, pp 498-501. 175. Bradley DW. Hepatitis E virus: a brief review of the biology, molecular virology, and immunology of a novel virus. J Hepatol 22( 1 Suppl): 140-145,1995. 176. Chibber RM, Usmani MA,Al-Sibai MH. Should HEV infected mothers breast feed? Arch Gynecol Obstet 27015-20,2004. 177. Emerson SU, Purcell RH. Hepatitis E virus. Rev Med Virol 13:145-154, 2003. 178. Emerson SU, Purcell RH. Running like water-the omnipresence of hepatitis E. N Engl J Med 351:2367-2368,2004. 179. Favorov MO, Fields HA, Purdy MA, et al. Serologic identification of hepatitis E virus infections in epidemic and endemic settings. J Med Virol36:246-250, 1992. 180. Fix AD, Abdel-Hamid M, Purcell RH, et al. Prevalence of antibodies to hepatitis E in two rural Egyptian communities. Am J Trop Med Hyg 62~519-523,2000. 181. Jaiswal SP, rain AK, Naik G, et al. Viral hepatitis during pregnancy. Int J Gynaecol Obstet 72:103-108,2001. 182. Khuroo MS, Kamili S, Jameel S. Vertical transmission of hepatitis E virus. Lancet 22:1025-1026, 1995. 183. Krawczynski K, Aggarwal R, Kamili S. Hepatitis E. Infect Dis Clin North Am 14669-687.2000. 184. Kumar A, Beniwal B, Kar P, et al. Hepatitis E in pregnancy. Obstet Gynecol Surv 607-8,2005. 185. Singh S, Mohanty A, Joshi YK, et al. Mother-to-child transmission of hepatitis E virus infection. Indian J Pediatr 7037-39,2003, 186. Ticehurst J. Identification and characterization of hepatitis E virus. In Hollinger FB, Lemon SM, Margolis HS (eds).Vial Hepatitis and Liver Disease. Baltimore, Williams & Willtins, 1991, pp 501-513. 187. Tsarev SA, Tsareva TS, Emerson SU, et al. Successful passive and active immunization of cynomolgus monkeys against hepatitis E. Proc Natl Acad Sci U S A 91:10198-10202, 1994.

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188. Worm HC, van der Poel WH, Brandstatter G. Hepatitis E an overview. Microbes Infect 4:657-666,2002. 189. Yarbough PO. Hepatitis E virus. Advances in HEV biology and HEV vaccine approaches. Intenirology 42:179-184, 1999.

Hepatitis G 190. Barqasho B, Naver L, Bohlin AB, et al. GB virus C coinfection and vertical transmission in HIV-infected mothers before the introduction of antiretroviral prophylaxis. HIV Med 5:427-430,2004. 191. Fischler B, Lara C, Chen M, et al. Genetic evidence for mother-toinfant transmission of hepatitis G virus. J Infect Dis 176:281-285,1997. 192. Linnen J, Wages J Jr, Zhang-Keck ZY, et al. Molecular cloning and disease association of hepatitis G virus: a transfusion-transmissible agent. Science 271:505-508,1996, 193. Pessoa MG, Terrault NA, Detmer J, et al. Quantitation of hepatitis G and C viruses in the liver: evidence that hepatitis G virus is not hepatotropic. Hepatology 27:877-880, 1998. 194. Ross RS, Viazov S, Schmitt U, et al. Distinct prevalence of antibodies to the E2 protein of GB virus C/hepatitis G virus in different parts of the world. J MedVirol54:103-106,1998. 195. Schroter M, Polywka S, Zollner B, et al. Detection of TT virus DNA and GB virus type Clhepatitis G virus RNA in serum and breast milk: determination of mother-to-child transmission. J Clin Microbiol 38~745-747,2000. 196. Stapleton JT. GB virus type C/hepatitis G virus. Semin Liver Dis 23:137-148,2003. 197. Stapleton JT, Williams CF, Xiang J.GB virus type C a beneficial infection? J Clin Microbiol42:3915-3919,2004. 198. Wejstal R, Manson AS, Widell A, Norkrans G. Perinatal transmission

of hepatitis G virus (GB virus type C) and hepatitis C virus infectionca comparison. Clin Infect Dis 28916-821, 1999.

Chapter 26 HERPES SIMPLEX VIRUS INFECTIONS Ann M. Arvin

Richard J. Whitley

Historical Background

845

Herpes Simplex Virus

845

St r tic t Lire Kcplication I.atency and R e d v a t i o n

Epidemiology 847 N ~ t u r eof Infection hl&rii‘il Infcction Fxtors Influencing Transmission of Infection to the Fetus Iiicidence of Newhorii Infection Times of Trmmission o f Infection

Immunologic Response Neonatal Infection

851

851

Bxkground Clinical Presentations

Diagnosis 856 (:linical Evaluation 1.aboratorv Assessment

Treatment

857

Background Antiviral Ilrugs Other lsaueb in Acute hlanagement I.ong-Terni hlanagement o t Infected Infants

Prevention

861

Ihckground hlmagement ot Pregnant Women with Known Genital Herpes hlan,igt.ment ot Inlants of hlothers with Genital Herpes

Conclusions 862

HISTORICAL BACKGROUND Infections caused by herpes simplex viruses (HSVs) were recognized by the ancient Greeks. The word herpes, meaning “to creep or crawl,” was used to describe skin lesions. Herodotus associated mouth ulcers and lip vesicles with fever’ and called this event herpes febrih. Genital herpetic infections were first described by Astruc, a physician to French royalty.* The transmissibility of these viruses was established unequivocally by passage of virus from lip and genital lesions of humans to the cornea or the scarified skin of the rabbit.3 During the early 20th century, diseases associated with HSV infections became more clearly defined by numerous clinical and pathologic case reports. Neonatal HSV infection was identified as a distinct disease 70 years ago. The first written descriptions of neonatal HSV infections were attributed to Hass, who described the histopathologic findings of a fatal case, and to Batignani, who described a newborn child with HSV keratiti~.~.’During subsequent decades, our understanding of neonatal HSV

Kathleen M. Gutierrez

infections was based on histopathologic descriptions of the disease, which indicated a broad spectrum of organ involvement in infants. An important scientific breakthrough occurred in the mid-l960s, when Nahmias and Dowdle6 demonstrated two antigenic types of HSV. The development of viral typing methods provided the tools required to clarify the epidemiology of these infections. HSV infections “above the belt,” primarily of the lip and oropharynx, were found in most cases to be caused by HSV type 1 (HSV-1). Infections “below the belt,” particularly genital infections, were usually caused by HSV type 2 (HSV-2). The finding that genital HSV infections and neonatal HSV infections were most often caused by HSV-2 suggested a cause-and-effect relationship between these two disease entities. This causal relationship was strengthened by detection of the virus in the maternal genital tract at the time of delivery, indicating that acquisition of the virus by the infant occurs by contact with infected genital secretions during birth. During the past 25 years, our knowledge of the epidemiology, natural history, and pathogenesis of neonatal HSV infections has been enhanced greatly. The development of antiviral therapy represents a significant advance in the management of infected children, providing the opportunity to decrease mortality and reduce the morbidity associated with these infections. Neonatal HSV infection is more amenable to prevention and treatment than many other pathogens because it is acquired most often at birth rather than during gestation. As our understanding of the epidemiology of HSV infections has improved, postnatal acquisition of HSV- 1 has been documented from nonmaternal sources, and more cases caused by HSV-1 infections of the maternal genital tract have been identified. New perspectives on the changing presentations of neonatal HSV infection, the obstacles to diagnosis, and the value of antiviral therapy are topics addressed in this chapter.

HERPES SIMPLEX VIRUS Structure The biologic, molecular, antigenic, and epidemiologic characteristics of HSV-1 and HSV-2 have been the subject of numerous publications. Reviews highlight the importance of these organisms as models for viral replication and as pathogens in human infe~tion.”~ The HSVs are members of a family of large DNA viruses that contain centrally located, linear, double-stranded DNA. Other members of the herpesvirus family include cytomegalovirus, varicella-zoster virus, Epstein-Barr virus, and human As a family, these viruses are herpesviruses 6A, 6B, 7, and virtually indistinguishable from each other by electron

846

Section 111 Vial Infections

microscopy. The viral DNA is packaged inside a protein structure, the capsid, which confers icosahedral symmetry to the virus. The capsid consists of 162 capsomers and is surrounded by a tightly adherent membrane known as the tegument. An envelope consisting of glycoproteins, lipids, and polyamines loosely surrounds the capsid and tegument. The glycoproteins mediate attachment of the virus to cells. The HSV genome consists of about 150,000 base pairs.7 The DNA encodes for more than 80 polypeptides.The genome consists of two components, L and S, each of which contains unique sequences that can invert, which leads to four isomers. Viral DNA extracted from virions or infected cells consists of four equal populations differing solely with respect to the relative orientation of these two unique components. The DNAs of HSV-1 and HSV-2 are colinear with respect to the order of genes encoding viral proteins. The percent homology of base pairs that constitute each gene varies from higher to lesser degrees of conservation. There is considerable overlap in the cross-reactivitybetween HSV- 1 and HSV-2 glycoproteins, although unique regions of these gene products exist for each The two viral types can be distinguished by using restriction enzyme analysis of viral DNA, which allows precise epidemiologic investigations of virus transmission.

Replication Replication of HSV is characterized by the expression of three gene classes: alpha, beta, and gamma. These genes are expressed temporally and in a cascade sequence.' Although herpesvirus genes carry transcriptional and translational signals similar to those of other DNA viruses that infect higher eukaryotic cells, the messenger RNAs arising from most genes are not spliced. The information density is lower than that encoded in the genes of smaller viruses. This relatively low density of genetic information is important in that it permits insertion and deletion of genes in the HSV genome without significant alteration of the genomic architecture. This point is relevant because it provides an opportunity for the use of genetically engineered herpesviruses as vaccines or vectors for antigen delivery." Alpha genes are expressed at immediate-early times after infection and are responsible for the initiation of replication. These genes are transcribed in infected cells in the absence of viral protein synthesis. Products of the beta genes, or early genes, include the enzymes necessary for viral replication, such as HSV thymidine kinase, and the regulatory proteins. These genes require functional alpha gene products for expression. The onset of expression of beta genes coincides with a decline in the rate of expression of alpha genes and an irreversible shutoff of host cellular macromolecular protein synthesis. Structural proteins are usually of the gamma, or late, gene class. The gamma genes are heterogeneous and are differentiated from beta genes solely by their requirement for viral DNA synthesis for maximal expression. Most glycoproteins are expressed as late genes. In addition to its regulatory and structural genes, the virus encodes genes that allow initial evasion of the host response, including gene products that block interferon-a and interferon+ responses. HSV- 1 and HSV-2 also express an immediate-early protein, ICP47, that mediates the downregulation of major histocompatibility complex class I molecules.12

Replication of viral DNA occurs in the nucleus of the cell. Assembly of the virus begins with formation of nucleocapsids in the nucleus, followed by acquisition of the envelope at cytoplasmic locations. Virus is transported through the cytoskeleton to the plasma membrane, where progeny virions are released. HSV specifies at least 11, and probably several more, glycoproteins. The glycoproteins have been designated as B, C, D, E, G, H, I, J, K, L, and M.9 Glycoprotein D (gD) is required for infectivity and is the most potent inducer of neutralizing antibodies; glycoprotein B (gB) is required for infectivity and also induces neutralizing antibodies; glycoprotein C (gC) binds to the C3b component of complement; and glycoprotein E (gE) binds to the Fc portion of IgG. The amino acid sequences of the glycoprotein G (gG) produced by HSV-1 and HSV-2 are sufficiently different to elicit antibody responses that are specific for each virus type. The fact that the antibody response to the two G molecules exhibits minimal cross-reactivity has provided the basis for serologic methods that can be used to detect recent or past HSV-2 infection in individuals who have also been infected with HSV-1.I3-I6 The close antigenic relatedness between HSV-1 and HSV-2 interferes with the serologic diagnosis of these infections using standard serologic assays. These methods do not distinguish between individuals who have had past infection with HSV-1 only, past infection with HSV-2 only, or dual infection. Although laboratory reports often indicate antibody titers to each virus, the methods used by some commercial laboratories are based on use of crude antigen and do not eliminate the detection of cross-reactive antibodies. Commercial type-specific tests based on glycoprotein G are available in some laboratories and must be used for diagnosis of HSV-2 infe~ti0n.I~ Clinicians must be knowledgeable regarding the type of testing performed by their referral laboratory to correctly interpret results.

Latency and Reactivation All of the herpesviruses have a characteristic ability to establish latency, by mechanisms that remain unidentified, to persist in this latent state for various intervals of time and to reactivate, causing virus excretion at mucosal or other sites. After infection, the viral DNA persists in the host for the entire lifetime of the individual. The biologic phenomenon of latency has been recognized and described since the beginning of the 20th century, particularly the association of HSV latency with neurons. In 1905,Cushing17observed that patients treated for trigeminal neuralgia by sectioning a branch of the trigeminal nerve developed herpetic lesions along the innervated areas of the sectioned branch. This specific association of HSV with the trigeminal ganglion was suggested by Goodpasture." Past observations have demonstrated that microvascular surgery of the trigeminal nerve tract to alleviate pain associated with tic douloureux resulted in recurrent lesions in more than 90% of seropositive individual^.'^^^^ Accumulated experience in animal models and from clinical observations suggests that inoculation of virus at the portal of entry, usually oral or genital mucosal tissue, results in infection of sensory nerve endings, and the virus is transported to the dorsal root ganglia. Replication at the site of

Chapter 26 inoculation enhances access of the virus to ganglia but is usually not associated with signs of mucocutaneous disease. Only a fraction of new infections with HSV-1 and HSV-2 are associated with clinically recognizable disease. When reactivation is triggered at oral or genital sites, the virus is transported back down axons to mucocutaneous sites. Replication and shedding of infectious virus occur at these sites. Recognizing that excretion of infectious virus during reactivation is not usually associated with clinical signs of recurrent herpes lesions is essential for understanding the transmission of HSV to newborns. Clinically silent reactivations are much more common than recurrent lesions. Reactivation, with or without symptoms, appears in the presence of humoral and cell-mediated immunity. Reactivation is spontaneous, although symptomatic recurrences have been associated with physical or emotional stress, exposure to ultraviolet light, tissue damage, and suppression of the immune system. Persistence of viral DNA has been documented in neuronal tissue of animal models and humans.7'8-21'23 Animal model studies indicate that the transport of virus to the ganglia is by retrograde axonal After transport, virus replicates for several days in sensory ganglia that innervate the sites of inoculation. After latency is established in sensory ganglia, virus cannot be eradicated from the infected cells. Because the latent virus does not multiply, it is not susceptible to drugs, such as acyclovir, that affect viral DNA synthesis. Our understanding of the mechanisms by which HSV establishes a latent state and persists in this form remains limited, and this is a subject of intense research interest.

EPIDEMIOLOGY

Nature of Infection Although many routes of infection have been suggested, transmission of HSV most often occurs as a consequence of intimate, person-to-person contact. Virus must come in contact with mucosal surfaces or abraded skin for infection to be initiated. Infection with HSV- 1, generally limited to the oropharynx, can be transmitted by respiratory droplets or through direct contact of a susceptible individual with infected secretions. Acquisition often occurs during childhood. Primary HSV-1 infection in the young child is usually asymptomatic, but clinical illness is associated with HSV gingivostomatitis. Primary infection in young adults has been associated with only pharyngitis or with a mononucleosislike syndrome. Seroprevalence studies have demonstrated that acquisition of HSV- 1 infection, like that of other herpesvirus infections, is related to socioeconomic factors. Antibodies, indicative of past infection, are found early in life among individuals of lower socioeconomic groups, presumably reflecting the crowded living conditions that provide a greater opportunity for direct contact with infected individuals. As many as 75% to 90% of individuals from lower socioeconomic populations develop antibodies to HSV-1 by the end of the first decade of life.8,25-27 In middle and upper middle socioeconomic groups, only 30% to 40% of individuals are seropositive by the middle of the second decade of life.' A change in seroprevalence rates of HSV-1 has been recognized in the past few decades, which reflects a

Herpes Simplex Virus Infections

847

delay in acquisition of infection until later in life. The increase in the reported number of cases of genital herpes caused by HSV-2 may be related to a lower prevalence of prior HSV- 1 infection in young adults. These individuals would not have the partial protection against HSV-2 infection that is probably conferred by cross-reactive HSV- 1 immunity. Investigators have found that a substantial percentage of cases of genital HSV infection are caused by HSV-1 in certain populations.28 Because infections with HSV-2 are usually acquired through sexual contact, antibodies to this virus are rarely found until the age of onset of sexual activity.26A progressive increase in infection rates with HSV-2 in all populations begins in adolescence. Until recently, the precise seroprevalence of antibodies to HSV-2 had been difficult to determine because of cross-reactivity with HSV- 1 antigens. During the late 1980s, seroepidemiologic studies performed using typespecific antigen for HSV-2 (glycoprotein G-2) identified antibodies to this virus in approximately 25% to 35% of middle-class women in several geographic areas of the United S t a t e ~ . ' ~ *Based ~ ~ - ~on l national health surveys, the seroprevalence of HSV-2 in the United States from 1988 to 1994was 21.9% for individuals 12 years old or 01der.~'Among those with serologic evidence of infection, fewer than 10% had a history of genital herpes symptoms. This seroprevalence represented a 30% increase compared with data collected from 1976 to 1980. HSV seroprevalence is highly variable and depends on geographic region, sex, age, race, and high-risk behavior^.^' The increasing prevalence of genital HSV- 1 infection in some countries suggests that use of type-specific tests for HSV-1 and HSV-2 may be helpful in determining the true incidence of genital HSV infections." The molecular epidemiology of HSV infections can be determined by restriction enzyme analysis of viral DNA obtained from infected individuals. Viruses have identical profiles when they are from the same host or are epidemiologically related.33In a few circumstances, however, it has been demonstrated that superinfection or exogenous reinfection with a new strain of HSV is possible. Such occurrences are uncommon in the nonimmunocompromised host with recurrent genital HSV i n f e ~ t i o n . ~Differences ~'~~ in the restriction endonuclease patterns of viral DNAs, indicating exogenous infections, are more common in immunocompromised individuals who are exposed to different HSVs, such as patients with acquired immunodeficiency syndrome (AIDS).

MaternaI Infection Infection with HSV-2, which reactivates and is shed at genital sites, is common in the pregnant woman. Using assays to detect type-specific antibodies to HSV-2, seroepidemiologic investigations have demonstrated that approximately one in five pregnant women has had HSV-2 Given the capacity of HSV to establish latency, the presence of antibodies is a marker of persistent infection of the host with the virus. The incidence of infection in women of upper socioeconomic class was 30% or higher in three large s t ~ d i e s . ~ ~ * ~ ~ , ~ ' These investigations have demonstrated that most women with serologic evidence of HSV-2 infection have no history of symptomatic primary or recurrent disease. New HSV-2 infections also appear to be acquired during pregnancy with a frequency that is comparable to seroconversion rates among

848

Section 111

Viral Infections

known history of genital herpes. These women represent a nonpregnant women, and these infections usually occur subset of the population of women with HSV-2 infection without clinical signs or because they had characteristic genital lesions from which Evaluation of pregnant women and their partners has virus was isolated. In a predominantly white, middle-class demonstrated that women can remain susceptible to HSV-2 population, symptomatic recurrent infection occurred during despite prolonged sexual contact with a partner who has pregnancy in 84% of pregnant women with a history of known genital herpes.39One in 10 women in this study were symptomatic disease.48Vial shedding from the cervix occurred found to be at unsuspected risk for acquiring HSV-2 infection in only 0.56% of symptomatic infections and 0.66% of during pregnancy as a result of contact with a partner whose asymptomatic infections. These data are similar to those HSV-2 infection was asymptomatic. Most maternal infections are clinically silent during obtained for other p o p ~ l a t i o n s The . ~ ~ incidence of cervical gestation. However, infection during gestation may manifest shedding in asymptomatic pregnant women has been reported in several clinical syndromes. An uncommon problem ento vary from 0.2% to 7.4%, depending on the numbers of cultures that were obtained between symptomatic episodes. countered with HSV infections during pregnancy is that of Overall, these data indicate that the frequency of cervical widely disseminated disease. As first reported by Flewett and shedding is low, which may reduce the risk of transmission co-worker~~~ in 1969 and by subsequently, infection of virus to the infant when the infection is recurrent. The has been documented to involve multiple visceral sites in frequency of shedding does not appear to vary by trimester addition to cutaneous ones. In a limited number of cases, during gestation. No increased incidence of premature onset dissemination after primary oropharyngeal or genital infection has led to severe manifestations of disease, including of labor was apparent in these prospective studies of women necrotizing hepatitis with or without thrombocytopenia, with reactivation of HSV-2 infection. leukopenia, disseminated intravascular coagulopathy, and The most important fact about maternal transmission is encephalitis. Although only a few patients have suffered from that most infants who develop neonatal disease are born to disseminated infection, the mortality rate for these pregnant women who are completely asymptomatic for genital HSV women is more than 50%. Fetal deaths were described infections during the pregnancy and at the time of delivery. in more than 50% of cases, although mortality did not These women usually have neither a past history of genital necessarily correlate with the death of the mother. Surviving herpes nor a sexual partner reporting a genital vesicular rash fetuses were delivered by cesarean section during the acute and account for 60% to 80% of all women whose infants illness or at term, and none had evidence of neonatal HSV become infe~ted.~'.~' Among women delivering children who infection. developed neonatal HSV infection, only 27% had a history Earlier studies described an association of maternal primary of or evidence of recurrent lesions indicative of HSV infection infection before 20 weeks' gestation with spontaneous during the current pregnan~y.~'One half of these women reported genital HSV infection in their sexual partners. abortion in some w0men.4~Although the original incidence of spontaneous abortion after a symptomatic primary infection during gestation was thought to be as high as 25%, Factors Influencing Transmission of Infection this estimate was not substantiated by prospective studies to the Fetus and was erroneous because of the small number of women followed. More precise data obtained from a prospective The development of serologic assays that distinguish analysis of susceptible women demonstrated that 2% or antibodies to HSV- 1 from those elicited by HSV-2 infection has allowed an accurate analysis of risks related to perinatal more acquired infection but that acquisition of infection was transmission of HSV.'3-'6 The category of maternal genital not associated with a risk of spontaneous ab~rtion.'~ With the exception of rare case reports:' primary infection that infection at the time of delivery influences the frequency of develops later in gestation is not generally associated with neonatal acquisition of infection. Maternal infections are premature rupture of membranes or premature termination classified as caused by HSV-1 or HSV-2 and as newly of pregnancy.47 acquired or recurrent. These categories of maternal infection Localized genital infection, whether it is associated with status are based on laboratory criteria and are independent lesions or remains asymptomatic, is the most common form of clinical signs. Women with recurrent infections are those of HSV infection during pregnancy. Overall, prospective who have preexisting antibodies to the virus type that is investigations using cytologic and virologic screening isolated from the genital tract, which is usually HSV-2. Most indicate that genital herpes occurs with a frequency of about women classified as having recurrent infection have no history of symptomatic genital herpes. Infections that are 1% in women tested at any time during Most of these infections were classified as recurrent when newly acquired, which have been referred to as first-episode HSV-2-specific serologic evaluation was done concurrently. infections, are further categorized as primary or first episode, Transmission of infection to the infant is most frequently nonprimary based on type-specific serologic testing. This differentiation is made whether clinical signs are present or related to the actual shedding of virus at the time of delivery. Because HSV infection of the infant is usually the connot. Primary infections are those in which the mother is sequence of contact with infected maternal genital secretions experiencing a new infection with HSV- 1 or HSV-2 and has at the time of delivery, the incidence of viral excretion at this not already been infected with the other virus type. These point has been of particular interest. The reported incidence mothers are seronegative for any HSV antibodies (i.e., HSV-1 of viral excretion at delivery is 0.01% to 0.39% for all or HSV-2 negative) at the onset of infection. Nonprimary women, regardless of their history of genital h e r p e ~ . ~ ~ ? ~ ' infections are those in which the mother has a new infection Several prospective studies have evaluated the frequency with one virus type, usually HSV-2, but has antibodies to the and nature of viral shedding in pregnant women with a other virus type, usually HSV-1, because of an infection that

Chapter 26 was acquired previously. As transmission has been studied using type-specific serologic methods, it has become obvious that attempts to distinguish primary and recurrent disease by clinical criteria are not reliable. Serologic classification is an important advance because many “new” genital herpes infections in pregnancy represent the first symptomatic episode of infection acquired at some time in the past. In one study designed to evaluate acyclovir therapy, pregnant women who were thought to have recent acquisition of HSV-2 based on symptoms had all been infected previously. These women were experiencing genital symptoms, caused by the reactivation of latent virus, for the first time.52 A hierarchy of risk of transmission has emerged using laboratory tools to classify maternal infection. Infants born to mothers who have true primary infections at the time of delivery are at highest risk, with transmission rates of 50% or higher.4635’ Those born to mothers with new infections that are first episode but nonprimary appear to be at lower risk; transmission rates are estimated to be about 30%. The lowest risk of neonatal acquisition occurs when the mother has active infection caused by shedding of virus acquired before the pregnancy or at stages of gestation before the onset of labor. The estimated attack rate for neonatal herpes among these infants is less than 2%. This estimate is reliable because it is based on the cumulative experience from large, prospective studies of pregnant women in which viral shedding was evaluated at delivery, regardless of the mother’s history of genital herpes or contact with a partner with suspected or documented genital herpes. The reasons for the higher risk of transmission to the infant when the mother has a new infection can be attributed to differences in the quantity and duration of viral shedding in the mother and in the transfer of passive antibodies from the mother to the infant before delivery. Primary infection is associated with larger quantities of virus replicating in the genital tract (>lo6 viral particles per 0.2mL of inoculum) and a period of viral excretion that may persist for an average of 3 weeks.53Many women with new infections have no symptoms but shed virus in high titers. In some mothers, these infections cause signs of systemic illness, including fever, malaise, and myalgias. In a small percentage of cases, significant complications, such as urinary retention and aseptic meningitis, occur. In contrast, virus is shed for an average of only 2 to 5 days and at lower concentrations (approximately 10’ to lo3 viral particles per 0.2 mL of inoculum) in women with symptomatic recurrent genital infections. Asymptomatic reactivation is also associated with short periods of viral replication, often less than 24 to 48 hours. One of the most important observations about HSV infections that has emerged from the evaluation of pregnant women is that new HSV-1 and HSV-2 infections often occur without any of the manifestations that were originally described as the classic findings in primary and recurrent genital herpes. In parallel with the classification of maternal infection, the mother’s antibody status to HSV at delivery appears to be an additional factor that influences the likelihood of transmission and probably affects the clinical course of neonatal herpes. Transplacental maternal neutralizing antibodies appear to have a protective, or at least an ameliorative, effect on acquisition of infection for infants inadvertently exposed to virus.%Maternal primary infection late in gestation


849

may not result in significant passage of maternal antibodies across the placenta to the fetus. Based on available evidence, the highest risk of transmission from mothers with newly acquired genital herpes is observed when the infant is born before the transfer of passive antibodies to HSV-1 or HSV-2, when the infant is exposed at delivery or within the first few days of life?635o355 The duration of ruptured membranes has also been described as an indicator of risk for acquisition of neonatal infection. Observations of a small cohort of women with symptomatic genital herpes indicated that prolonged rupture of membranes (>6 hours) increased the risk of acquisition of virus, perhaps as a consequence of ascending infection from the ~ervix.4~ It is recommended that women with active genital lesions at the time of onset of labor be delivered by cesarean section.56 Isolation of HSV from the genital tract at the time of delivery is a major risk factor for neonatal herpes infection. One study found that cesarean section significantly reduced the rate of HSV infection in infants born to women from whom HSV was isolated at the time of delivery (1.2% versus 7.7%, P = .047).57However, this effect of cesarean delivery was established by postdelivery analysis of data on viral shedding at delivery for a large cohort of pregnant women. In the absence of a reliable rapid test for HSV in the birth canal, it is difficult at this time to apply this information in clinical practice. The benefit of cesarean section beyond 6 hours of ruptured membranes has not been evaluated. Although some protection may be expected, infection of the newborn has occurred despite delivery by cesarean ~ e c t i o n . ~ ~ ’ ~ ’ Certain forms of medical intervention during labor and delivery may increase the risk of neonatal herpes if the mother has active shedding of the virus, although in most instances, viral shedding is not suspected clinically. For example, fetal scalp monitors can be a site of viral entry through kin.^^^^^,^^ The benefits and risks of these devices should be considered for women with a history of recurrent genital HSV infections. Because most women with genital infections caused by HSV are asymptomatic during labor and have no history of genital herpes, it is usually not possible to make this assessment.

Incidence of Newborn Infection A progressive increase in the number of cases of neonatal HSV infection to a rate of approximately 1 in 1500 deliveries was reported in King County, Washington, during the period from 1966 to 1983, when adult infection rates were also increasing6’ Overall, the United States, with approximately 4 million deliveries each year, has an estimated 11 to 33 cases of neonatal infection per 100,000 livebirths. This estimate has been confirmed by a review of comprehensive hospital discharge data recorded in California for the years 1985, 1990, and 1995. The diagnosis of HSV infection in infants 6 weeks old or younger was made in 11.7, 11.3, and 11.4 infants, respectively, per 100,000 livebirths in each of these years6’ In studies where maternal serologicstatus during pregnancy and virologic status at the time of delivery are evaluated prospectively, the rate of transmission leading to neonatal HSV infection varies from 12 to 54 newborn infections per

850

Section I11

Viral Infections

100,000 livebirths. Higher rates of transmission are seen in babies born to seronegative mothers and those infected with HSV-1.57 Neonatal HSV infection occurs far less frequently than might be expected given the high prevalence of genital HSV infections in women of childbearing age in the United States. Some countries do not report a significant number of cases of neonatal HSV infection despite a similar high prevalence of antibodies to HSV-2 in women. In the United Kingdom, genital herpes infection is relatively common, but very few cases of neonatal HSV infection are recognized. Although serologic studies in central Africa indicate that women have a high frequency of antibodies to HSV-2, the first case of neonatal herpes was reported less than 25 years ago. Neonatal HSV infection in the Netherlands occurs in only 2.4 of 100,000 newb0rns.6~ Although underreporting of cases may explain some differences between countries, there may be unidentified factors that account for these differences. The interpretation of incidence data must also include the potential for postnatal acquisition of HSV infection. Not all cases of neonatal herpes are the consequence of intrapartum contact with infected maternal genital secretions, which alters the overall estimate of delivery-associated infections.

Times of Transmission of Infection HSV infection of the newborn can be acquired in utero, intrapartum, or postnatally. The mother is the most common source of infection for the first two of these routes of transmission of infection. With regard to postnatal acquisition of HSV infection, the mother can be a source of infection from a genital or nongenital site, or other contacts or environmental sources of virus can lead to infection of the child. A maternal source is suspected when maternal herpetic lesions are discovered shortly after the birth of the child or when the infant's illness is caused by HSV-2. Although intrapartum transmission accounts for 85% to 90% of cases, in utero and postnatal infection must be recognized for public health and prognostic purposes. Some infants acquire infection in utero, but this mode of transmission is Although it was originally presumed that in utero acquisition of infection resulted in a totally normal infant or premature termination of ge~tation;~ it has become apparent that intrauterine acquisition of infection can lead to the clinical signs of congenital infection. By using stringent diagnostic criteria, more than 30 infants with symptomatic congenital disease have been described in the literature. These criteria include identification of infected infants with lesions present at birth, virologic confirmation of infection, and the exclusion of other infectious agents whose pathogenesis mimics the clinical findings of HSV infections, such as congenital cytomegalovirus infection, rubella, syphilis, or toxoplasmosis. Virologic diagnosis is a necessary criterion because no standard method for detection of IgM antibodies is available and infected infants often fail to produce IgM antibodies detectable by research The manifestations of disease in this group of children range from the presence of skin vesicles at the time of delivery to the most severe neurologic a b n o r m a l i t i e ~ . ~ ~ . ~ In utero infection can result from transplacental or ascending infection. The placenta can show evidence of

necrosis and inclusions in the trophoblasts, which suggests a transplacental route of infe~tion.~' This situation can result in an infant who has hydranencephaly at the time of birth, or it may be associated with spontaneous abortion and intrauterine HSV viremia. Virus has been isolated from the products of conception under such circumstances. Histopathologic evidence of chorioamnionitis suggests ascending infection as an alternative route for in utero infection.68Risk factors associated with intrauterine transmission are not known. Primary and recurrent maternal infections can result in infection of the fetus in utero. HSV DNA has been detected in the amniotic fluid of two women experiencing a first-episode nonprimary infection and in one woman during a symptomatic recurrent infection. All three infants were healthy at birth and demonstrated no clinical or serologic evidence of HSV infection during follow-up? The second and most common route of infection is intrapartum contact of the fetus with infected maternal genital secretions. Intrapartum transmission is favored by delivery of the infant to a mother with newly acquired infection. Postnatal acquisition is the third route of transmission. Postnatal transmission of HSV-1 has been suggested as an increasing risk. Data from the National Institute of Allergy and Infectious Diseases (NIAID) Collaborative Antiviral Study Group indicate that the frequency of infants with neonatal HSV- 1 infection ranges from approximately 25% HSV-1 infections appear to account for only to 30%.49,73 about 5% to 17% of all genital HSV infections in the United States,28creating greater concern about postnatal acquisition of HSV- 1 infection from nonmaternal sources. Relatives and hospital personnel with orolabial herpes may be a reservoir of virus for infection of the newborn. The documentation of postnatal transmission of HSV- 1 has focused attention on such sources of v i r ~ s ? Postpartum ~-~~ transmission from mother to child has been reported as a consequence of nursing on an infected brea~t.7~ Transmission from fathers and grandparents has also been d o c ~ m e n t e d . ~ ~ When the infant's mother has not had HSV infection, the infant may be inoculated with the virus from a nonmaternal contact in the absence of any possible protection from maternally derived passive antibodies. Because of the prevalence of HSV- 1 infections in the general population, many individuals have intermittent episodes of asymptomatic excretion of the virus from the oropharynx and therefore can provide a source of infection for the newborn. The occurrence of herpes labialis, commonly referred to as fever blisters or cold sores, has ranged from 16% to 46% in various groups of adults." Population studies conducted in two hospitals indicated that 15% to 34% of hospital personnel had a history of nongenital herpetic In both hospitals surveyed, at least 1 in 100 individuals documented a recurrent cold sore each week. As is true of genital herpes, many individuals have HSV-1 infection with no clinical symptoms at the time of acquisition or during episodes of reactivation and shedding of infectious virus in oropharyngeal secretions. Prospective virologic monitoring of hospital staff increased the frequency with which infection was detected by twofold; however, no case of neonatal HSV infection was documented in these nurseries. The risk of nosocomial infection in the hospital environment is a concern. The demonstration of identity by restriction

Chapter 26


851

endonuclease analysis of virus recovered from an index case the number of antibody bands to defined polypeptides. and a nursery contact leaves little doubt about the possibility Children with a more limited infection, such as infection of of spread of virus in a high-risk nursery p o p ~ l a t i o n .The ~ ~ , ~ ~the skin, eye, or mouth, have fewer antibody bands possible vectors for nosocomial transmission have not been compared with those children with disseminated disease. A defined. Whether personnel with herpes labialis should vigorous antibody response to the ICP4 alpha gene product, avoid working in the nursery while lesions are active remains which is responsible for initiating viral replication, has been a matter of debate. No cases of transmission of HSV from correlated with poor long-term neurologic outcome, suggesting personnel to infants have been documented. Vigorous handthat these antibodies reflect the extent of viral replication. A washing procedures and continuing education of personnel regression analysis that compared neurologic impairment in newborn nurseries can be expected to contribute to the with the quantity of antibodies to ICP4 identified the child low frequency of HSV transmission in this environment. at risk for severe neurologic im~airment.~’ Herpetic whitlow in a health care provider should preclude Adaptive cellular immunity is a critical component of the direct patient contact, regardless of the nursing unit. Because host response to primary herpetic infections. Newborns with more infants are born to seronegative women now, our HSV infections have a delayed T lymphocyte proliferative nursery practice is to exclude personnel with active herpes response compared with older i n d i v i d ~ a l s . ~Most ~ , ~infants ~,~~ labialis from direct patient care activities until the lesion is have no detectable T lymphocyte responses to HSV when crusted. evaluated 2 to 4 weeks after the onset of clinical symptoms.55 Because most mothers have antibodies to HSV and these The delayed T lymphocyte response to viral antigens in antibodies are transferred to their infants, exposures to the infants whose initial disease is localized to the skin, eye, or virus in the newborn period may not often result in neonatal mouth may be an important determinant of the frequent disease. However, if the mother was seronegative,nosocomial progression to more severe disease in Lack of exposure may pose a more significant risk to the infant. cell-mediated immunity is likely to permit viremia and dissemination in infants, which is otherwise controlled by the host response in older children and adults with new HSV IMMUNOLOGIC RESPONSE infections. Infected newborns have decreased interferon-a and The host response of the newborn to HSV is impaired interferon-y production in response to HSV antigen when compared with older children and adults.55~70~82-86 There is no compared with adults with primary HSV The evidence for differences in virulence of particular HSV importance of interferon-a may be related to its effect on strains. The severity of the manifestations of HSV-1 and the induction of innate immune mechanisms, such as natural HSV-2 infections in the newborn, as described in “Neonatal killer cell Other mechanisms of the innate Infection,” can be attributed to immunologic factors. The immune system of the newborn that may be deficient in relevant issues are protection of the fetus by transplacental controlling HSV include other nonspecific cytokine responses antibodies, the innate immune response of the exposed infant and complement-mediated effects. T lymphocytes from infected infants have decreased interferon-y production and the acquisition of adaptive immunity by the infected during the first month of life. This defect can be predicted newborn. to limit the clonal expansion of helper and cytotoxic Passive antibodies to HSV influence the acquisition of T lymphocytes specific for herpes viral antigens, allowing infection and its severity and clinical signs.40,51,55’70 Transmore extensive and prolonged viral replication and failure to placentally acquired antibodies from the mother are not totally establish latency. protective against newborn infection, but transplacentally acquired neutralizing antibodies correlate with a lower Antibody-dependent cell-mediated cytotoxicity has been attack rate in exposed newborn^.^',^^.^^ Although the absence demonstrated to be an important component of adaptive of any detectable antibodies has been associated with disimmunity to viral infection.82Antibodies and lymphocytes, monocytes, macrophages or polymorphonuclear leukocytes, semination, the presence of antibodies at the time that clinical signs appear does not predict the subsequent 0utcome.4~”~ as well as antibodies and complement, lyse HSV-infected cells in ~ i t r o However, .~~ newborns appear to have fewer The most important example of the failure of passive antibodies to alter progression is the occurrence of encephalitis effector lymphocytes than older individuals do. The immaturity of neonatal monocytes and macrophage function in untreated infants whose initial symptoms were limited to cutaneous lesions. Most infected newborns eventually against HSV infection has been demonstrated in vitro and in produce IgM antibodies, but the interval to detection is animal model^.^^*^^ Adhesion defects may be responsible for prolonged, requiring at least 2 to 4 weeks.55 This method suboptimal antibody-mediated target-cell binding of neonatal natural killer cells.” Additional information regarding the cannot be used for diagnostic purposes to determine the immune response to HSV is provided in Chapter 4. need for antiviral therapy. These antibodies increase rapidly during the first 2 to 3 months, and they may be detectable for as long as 1 year after infection. The quantity of neutralizing antibodies and antibodies that mediate antibody-dependent NEONATAL INFECTION cellular cytotoxicity in infants with disseminated infection is lower than that in those with more limited disease.55s82 Background Humoral antibody responses to specific viral proteins, especially glycoproteins, have been evaluated by assays for After direct exposure, replication of HSV is presumed to antibodies to gG and by i m m u n ~ b l o t .Immunoblot occur at the portal of entry, which is probably the mucous ’~~~~ studies membranes of the mouth or eye, or at sites where the skin indicate that the severity of infection correlates directly with

852

Section I11

Viral Infections

has been damaged. Factors that determine whether the infection causes symptoms at the site of inoculation or disseminates to other organs are poorly understood. Sites of replication during the incubation period have not been defined, but the virus evades the host response during this early stage, probably by mechanisms such as blocking cellmediated immune recognition of viral peptides by preventing major histocompatibility complex class I molecules from reaching the surface of infected cells. Intraneuronal transmission of viral particles may provide a privileged site that is inaccessible to circulating humoral and cell-mediated defense mechanisms, facilitating the pathogenesis of encephalitis. Transplacental maternal antibodies may be less effective under such circumstances. Disseminated infection appears to be the consequence of virernia. HSV DNA has been detected in peripheral blood mononuclear cells, even in infants who appear to have localized infection.” Extensive cell-to-cell spread could explain primary HSV pneumonia after aspiration of infected secretions. After the virus has adsorbed to cell membranes and penetration has occurred, viral replication proceeds, leading to release of progeny virus and cell death. The synthesis of cellular DNA and protein ceases as large quantities of HSV are produced. Cell death in critical organs of the newborn, such as the brain, results in devastating consequences, as reflected by the long-term morbidity of herpes encephalitis. Cellular swelling, hemorrhagic necrosis, development of intranuclear inclusions, and cytolysis all result from the replicative process. Small, punctate, yellow-to-gray areas of focal necrosis are the most prominent gross lesions in infected organs. When infected tissue is examined by microscopy, there is extensive evidence of hemorrhagic necrosis, clumping of nuclear chromatin, dissolution of the nucleolus, cell fusion with formation of multinucleate giant cells, and ultimately, a lymphocytic inflammatory re~ponse.’~Lymphocytic perivascular cuffing is particularly prominent in organs that exhibit extensive hemorrhagic necrosis, especially in the central nervous system.y3Irreversible organ damage results from ischemia and direct viral destruction of cells.

Clinical Presentations Pediatricians must be prepared to consider the diagnosis of neonatal herpes in infants who have clinical signs consistent with the disease regardless of the maternal history of genital herpes. Only about 30% of mothers whose infants develop neonatal herpes have had symptomatic genital herpes or sexual contact with a partner who has recognized HSV infection during or before the pregnancy. The clinical presentation of infants with neonatal HSV infection depends on the initial site and extent of viral replication. In contrast to human cytomegalovirus, neonatal infections caused by HSV-1 and HSV-2 are almost invariably symptomatic. Case reports of asymptomatic infection in the newborn exist, but they are uncommon, and long-term follow-up of these children to document absence of subtle disease or sequelae was not described. Classification of newborns with HSV infection is used for prognostic and therapeutic consideration^.^^ Historically, infants with neonatal HSV infection were classified as having localized or disseminated disease, with the former group being subdivided into those with skin, eye, or mouth disease

versus those with central nervous system infection. However, this classification system understates the significant differences in outcome within each ~ategory.’~ In a revised classification scheme, infants who are infected intrapartum or postnatally are divided into three groups, including those with disease localized to the skin, eye, or mouth; encephalitis, with or without skin, eye, or mouth involvement; and disseminated infection that involves multiple organs, including the central nervous system, lung, liver, adrenals, skin, eye, or mouth. A few infants with intrauterine infection constitute a fourth category. Knowledge of the patterns of clinical disease caused by HSV-1 and HSV-2 in the newborn is based on prospectively acquired data obtained through the NIAID Collaborative Antiviral Study Group. These analyses have employed uniform case record forms from one study interval to the next. Of 186 infants enrolled in the NIAID Collaborative Antiviral Study Group studies of neonatal herpes virus infections between 1981 and 1997,34% were classified with skin, eye, or mouth disease; 34% with central nervous system disease; and 32% with disseminated infection.73 This analysis of the natural history of neonatal herpes infections likely underestimates the proportion of infants who present with skin, eye, or mouth disease. Patients with central nervous system or disseminated HSV infection were disproportionately enrolled in a high-dose acyclovir study conducted from 1989 to 1997. The presentation and outcome of infection, including the effect of antiviral therapy on prognosis, varies significantly according to the clinical ~ategories.~~ Table 26-1 summarizes disease classification and outcome of 291 infants with neonatal herpes simplex virus infections enrolled in NIAID Collaborative Antiviral Study Group protocols. Intrauterine Infection Intrauterine infection is rare. The manifestations are seen in approximately 3 of every 100 infected infar1ts.6~ When infection occurs in utero, severe disease follows acquisition of infection at virtually any time during gestation. In the most severely afflicted group of infants, evidence of infection is apparent at birth and is characterized by a triad of findings, including skin vesicles or scarring, eye damage, and the severe manifestations of microcephaly or hydranencephaly. Central nervous system damage is caused by intrauterine encephalitis. Infants do not have evidence of embryopathy. Often, chorioretinitis in combination with other eye findings, such as keratoconjunctivitis, is a component of the clinical presentation. Serial ultrasound examination of the mothers of infants infected in utero has demonstrated the presence of hydranencephaly, but cases are seldom diagnosed before delivery. Chorioretinitis alone should alert the pediatrician to the possibility of this diagnosis, although it is a common sign for other congenital infections. A few infants have been described who have signs of HSV infection at birth after prolonged rupture of membranes. The infants may have no other findings of invasive multiorgan involvement-no chorioretinitis, encephalitis, or evidence of other diseased organs-and can be expected to respond to antiviral therapy. Antiviral therapy is not effective for infants who are born with hydranencephaly. Intrauterine HSV infection has been reported as a cause of hydrops fetali~.~’



853

Demographic and Clinical Characteristics of Infants Enrolled in the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Disease Classification

Demographic Characteristics

Disseminated

No. of infants (‘YO) No. malelno. female

93 (32) 54/39

95 (33) 50/46

60133 33 (35) 36.5 i 0.4 11.6 i 0.7 21.7 i 0.5

73/23 20 (21) 37.9 i 0.4 17.4 i 0.8 23.1 i 0.5

76/26 24 (24) 37.8 2 0.3 12.1 i 1.1 22.8 i 0.5

72 (77) 69 (74) 46 (49) 56 (60)

60 (63) 96 (100) 4 (4) 13 (14)

86 (84)

15/34 (44) 13/26b (50) 1/6b(17) l/Zb (50)

45/81 (56) 25/51 (49) 18/27b (67) 2/3b (67)

10/93” ( 1 1 ) 3/34’ (9) 4/51’ (8) 3/8b (38)

Central Nervous System

Skin, Eye, or Mouth 102 (35) 51/51

Race

No. whitelno. other No. premature, c36 wk (%)

Gestational age (wk) Enrollment age (wk) Maternal age (yr) No. of clinical findings (%) Skin lesions Brain involvement Pneumonia Deaths a t 1 yrb (‘YO) No. of survivors with neurologic impairmentltotal no. (%)

Total Adenine arabinoside Acyclovir

Placebo

0 (0)

3 (3) 0 (0)

aRegardlessof therapy. bDenominatorsvary according to number with follow-up available. fluorescence methods are useful for rapid diagnosis of herpesvirus-infected cells in skin lesion specimens but must not be used to test oropharyngeal or other secretions. When Infants whose initial diagnosis is disseminated herpes have discrete lesions are not available for obtaining infected cells, the worst prognosis for mortality. Many of these infants are the virus can also be detected in the peripheral blood of born to mothers who are experiencing a new HSV-1 or HSV-2 some infants by viral culture or PCR, but confirmation of infection and may lack any passively acquired antibodies viremia is not necessary for clinical management. against the infectingvirus type.13,51,y8 Infants with disseminated Evaluation of the extent of dissemination is imperative to infection have signs of illness within the first week of life, provide appropriate supportive interventions early in the although the diagnosis may be delayed until the second clinical course. Infants should be assessed for hypoxemia, week. The onset of symptoms may occur less than 24 hours acidosis, hyponatremia, abnormal hepatic enzyme levels, after birth, but most infants appear well at delivery. The direct hyperbilirubinemia, neutropenia, thrombocytopenia, short incubation period of disseminated herpes reflects an and bleeding diathesis. Chest radiographs should be obtained, acute viremia, which allows transport of the virus to all and depending on signs and whether the infant is stable organs; the principal organs involved are the adrenals and the liver, causing fulminant hepatitis in some cases.y4,yy-101 enough, abdominal radiography, electroencephalography,and computed tomography or magnetic resonance imaging of Viremia is associated with infection of circulating mononuclear cells in these Infection can affect the head should be used be to further determine the extent multiple organs, including the central nervous system, larynx, of disease. The radiographic picture of HSV lung disease is characterized by a diffuse, interstitial pattern, which progresses trachea, lungs, esophagus, stomach, lower gastrointestinal to a hemorrhagic pneumonitis and on rare occasions, a tract, spleen, kidneys, pancreas, and heart. Initial signs and significant pleural Not infrequently, necrotizing symptoms are irritability, seizures, respiratory distress, enterocolitis with pneumatosis intestinalis can be detected jaundice, coagulopathy, and shock. The characteristicvesicular when gastrointestinal disease is present. Meningoencephalitis exanthem is usually not present when the symptoms begin. Untreated infants may develop cutaneous lesions resulting appears to be a common component of disseminated infection, occurring in about 60% to 75% of children. Usual from viremia. More than one third of children with disexaminations of cerebrospinal fluid, including viral culture seminated infection do not develop skin vesicles during the and PCR, should be performed along with noninvasive course of their Disseminated infections caused neurodiagnostic tests to assess the extent of brain disease. by HSV-1 and HSV-2 are indistinguishable by clinical criteria. The mortality rate for disseminated HSV in the absence The diagnosis of disseminated neonatal herpes is exceedof therapy exceeds 80%, and many survivors are impaired. ingly difficult because the clinical signs are often vague and The most common causes of death of infants with disnonspecific, mimicking those of neonatal enteroviral disease seminated disease are intravascular coagulopathy or HSV or bacterial sepsis. The diagnosis of disseminated herpes pneumonitis. There is evidence that the long-term neurologic should be pursued by obtaining specimens of oropharyngeal outcome is better for infants who survive disseminated and respiratory secretions and a rectal swab to be tested by HSV-1 involving the central nervous system than for those viral culture and by polymerase chain reaction (PCR) testing who are infected with HSV-2.96,’05 if a qualified reference laboratory is available.Direct immunoDisseminated Infection

854

Section I11

Viral Infections

Encephalitis Almost one third of all infants with neonatal HSV infection have encephalitis only as the initial manifestation of disease.””” These infants have clinical manifestations distinct from those who have central nervous system infection associated with disseminated HSV. The pathogenesis of these two forms of brain infection is probably different. The virus is likely to reach brain parenchyma by a hematogenous route in infants with disseminated infection, resulting in multiple areas of cortical hemorrhagic necrosis. In contrast, neonates who present with only encephalitis are likely to develop brain disease because of retrograde axonal transport of the virus to the central nervous system. The evidence for this hypothesis is twofold. First, newborns with disseminated disease have documented viremia. Second, infants with encephalitis are more likely to have received transplacental neutralizing antibodies from their mothers, which may allow only intraneuronal transmission of virus to the brain. Infants with localized HSV encephalitis as their initial manifestation of infection usually develop signs more than a week after birth, typically presenting in the second or third week but sometimes as late as 4 to 6 weeks. Clinical manifestations of encephalitis include seizures (focal and generalized), fever, lethargy, irritability, tremors, poor feeding, temperature instability, bulging fontanelle, and pyramidal tract signs. Similar signs are observed when disseminated herpesvirus is associated with encephalitis. As in cases of disseminated herpesvirus, many infants with encephalitis do not have skin vesicles when signs of illness begin. Some infants have a history or residual signs of lesions of the skin or eye that were not recognized as herpetic. If untreated, infants with encephalitis may develop skin vesicles later in the disease course. Anticipated findings on cerebrospinal fluid examination include a mononuclear cell pleocytosis, moderately low glucose concentrations, and elevated protein. A few infants with central nervous system infection, proven by brain biopsy done immediately after the onset of seizures, have no abnormalities of their cerebrospinal fluid, but most infants have some pleocytosis and mild reduction of the glucose level. The hemorrhagic nature of the encephalitis may result in an apparent “bloodytap.” Although initial protein concentrations may be normal or only slightly elevated, infants with localized brain disease usually demonstrate progressive increases in protein (21000 mg/dL). The importance of cerebrospinal fluid examinations in all infants is underscored by the finding that even subtle abnormalities have been associated with significant developmental ~ e q u e l a e . ~ ~ Electroencephalography and computed tomography or magnetic resonance imaging can be very useful in defining the presence and extent of central nervous system abnormalities and should be done before discharge of all infants with this d i a g n o s i ~ . ’ ~These ~ ~ ’ ~abnormalities ~ may also be detected by ultrasound examination.Io8Typical abnormalities seen by neuroimaging include localized or multifocal areas of abnormal parenchymal attenuation, atrophy, edema, and hemorrhage involving the temporal, frontal, parietal, and subcortical regions of the brain”’ (Fig. 26-1). Localized central nervous system disease is fatal in approximately 50% of infants who are not treated and is usually related to involvement of the brain stem. With rare exceptions, survivors are left with neurologic impairment.94The long-term

Figure 26-1

Herpes simplex encephalitis. Computed tomographic scan of an infant with herpes simplex virus type 2 infection and severe sequelae.

prognosis is poor. As many as 50% of surviving children have some degree of psychomotor retardation, often in association with microcephaly, hydranencephaly, porencephalic cysts, spasticity,blindness, chorioretinitis, or learning disabilities. Quantitative PCR methods show a greater amount of HSV-2 DNA in cerebrospinal fluid from patients with more extensive neurologic impairment.’ l o There is evidence that progressive neurologic damage occurs after neonatal HSV encephalitis, although many infants have obvious severe sequelae within a few weeks after onset of HSV encephalitis.”’*112 Despite the presumed differences in pathogenesis, clinical manifestations of disease in children with encephalitis alone are virtually identical to the findings for brain infection in disseminated cases. For infants with encephalitis, approximately 60% develop evidence of a vesicular rash characteristic of HSV infection. A newborn with pleocytosis and proteinosis of the cerebrospinal fluid but without a rash can easily be misdiagnosed as having another viral or bacterial infection unless HSV infection is considered. Skin, Eye, and Mouth Infections Infection localized to the skin, eye, or mouth or some combination of these sites appears benign at the onset, but it is associated with a high risk of progression to serious disease. When infection is localized to the skin, the presence of discrete vesicles remains the hallmark of disease (Fig. 26-2). Vesicles occur in 90% of children with skin, eye, or mouth infection. The skin vesicles usually erupt from an erythematous base and are usually 1 to 2 mm in diameter. The formation of new lesions adjacent to the original vesicles is typical, creating a cluster that may coalesce into larger,

Chapter 26 irregular vesicles. In some cases, the lesions progress to large bullae larger than 1 cm in diameter. Clusters of vesicles may appear initially on the presenting part of the body, presumably because of prolonged contact with infected secretions during birth, or at sites of trauma (e.g., scalp monitor sites). Nevertheless, first herpetic lesions in infants with localized cutaneous disease have been described on the trunk, extremities, and other sites. Children with disease localized to the skin, eye, or mouth or some combination of these sites typically have symptoms within the first 7 to 10 days of life. Although discrete vesicles are usually encountered, crops and clusters of vesicles are described, particularly before antiviral treatment was available or when the cause of the first lesions is not recognized. In these cases, the rash can progress to involve other cutaneous sites, presumably by viremia and hematogenous spread. The scattered vesicles resemble varicella.Although progression is expected without treatment, a few infants have had infection of the skin limited to one or two vesicles,with no further evidence of cutaneous disease. These infants may be identified after the newborn period and should have a careful evaluation because many are likely to have had neurologic disease that was not detected. A zosteriform eruption is another manifestation of herpetic skin disease reported in infants.'13

Figure 26-2 Cutaneous herpes simplex virus infection. Initial vesicular lesion in a premature infant with herpes simplex type 2

infection.

Table 26-2


Infections involving the eye may manifest as keratoconjunctivitis. Ocular infection may be the only site of involvement in the newborn. When localized eye infection is observed in infants who also have microphthalmos and retinal dysplasia, intrauterine acquisition should be suspected, and a thorough neurologic evaluation should be done. Before antiviral therapy was available, persistent ocular disease resulted in chorioretinitis caused by HSV-1 or HSV-2.'14 Keratoconjunctivitis can progress to chorioretinitis, cataracts, and retinal detachment despite therapy. Cataracts have been detected as a long-term consequence in infants with perinatally acquired HSV infections. Localized infection of the oropharynx involving the mouth or tongue occurs, but newborns do not develop the classic herpetic gingivostomatitis caused by primary HSV- 1 infection in older children. Overall, approximately 10% of patients have evidence of HSV infection of the oropharynx by viral culture. Unfortunately, many of these children did not undergo a thorough oral examination to determine whether the detection of infectious virus in oropharyngeal secretions was associated with lesions. Long-term neurologic impairment has been encountered in children whose disease appeared to be localized to the skin, eye, or mouth during the newborn p e r i ~ d . ~ ~ The ~~~~"* significant findings include spastic quadriplegia, microcephaly, and blindness. Important questions regarding the pathogenesis of delayed-onset neurologic debility are raised by these clinical observations. Despite normal clinical examinations in these children, neurologic impairment became apparent between 6 months and 1 year of life. At this stage of the disease, the clinical presentation may be similar to that associated with congenitally acquired toxoplasmosis or syphilis. Newborns who have skin lesions invariably suffer from recurrences for months or years. Continued recurrences are common, particularly when the infecting virus is HSV-2, whether or not antiviral therapy was administered. Historically, although death was not associated with disease localized to the skin, eye, or mouth, approximately 30% of these children eventually developed some evidence of neurologic i m ~ a i r m e n t .Table ~ ~ 26-2 shows morbidity and mortality 12 months after infection by HSV viral type and disease classification in patients enrolled in two studies

Morbidity and Mortality among Patients after 12 Months by Viral Type, 1981-1997 Number of Patients by Disease Classification (O/O)~

Skin, Eye, or Mouth HSV- 1

HSV-2

HSV- 1

Normal

24 (100) 0 (0) 0 (0)

19 (95) 0 (0) 1 (5) 0 (0) 0 (0)

4 (75) 0 (0) 1 (14) 2 (29) 0 (0)

Unknown

0 (0) 0 (0)

Total of 20

Disseminated

CNS

Outcome

Mild impairment Moderate impairment Severe impairment Death

HSV-2

7 (17.5) 7 (17.5) 7 (17.5) 13 (32.5) 6 (15) Total of 16

HSV-1

3 (23) 0 (0) 0 (0) 1 (8) 9 (69)

HSV-2

14 (41) 1 (3) 0 (0) 3 (9) 16 (47) Total of 16

aSurvival rate (by Cox regression analysis)of patients infected with HSV-2 was higher compared with that of patients infected with HSV-1; however, the difference was not statistically significant. Patients infected with HSV-2 were more likely to have neurologic abnormalities compared with those infected with HSV-1 (borderlinesignificance, P = . I 0). CNS, central nervous system; HSV, herpes simplex virus. Data from Kimberlin DW, Lin CY, Jacobs RF, et al. Natural history of neonatal herpes simplex virus infections in the acyclovir era. Pediatrics 108:223-229. 2001.

855

856


conducted by the NIAID CollaborativeAntiviral Study Group between 1981 and 1997. With parenteral acyclovir therapy, virtually all children with HSV-1 and most children with HSV-2 disease of the skin, eye, or mouth who enrolled and who were available for follow-up at 12 months had normal development.73

Subclinical Infection A few cases of apparent subclinical infection with HSV proven by culture isolation of virus in the absence of symptoms have been de~cribed."~It has been difficult to document such cases in the course of prospective evaluations of several thousand infants from many centers around the United States. Conversely, infants who were exposed to active maternal infection at the time of delivery and who did not develop symptoms have been followed for the first year of life and did not have immunologic evidence of subclinical infection?' HSV-1 or HSV-2 may be recovered from the infant's oropharyngeal secretions transiently, without representing true infection. Because of the propensity of the newborn to develop severe or life-threateningdisease, laboratory evidence of neonatal HSV infection requires careful follow-up for clinical signs and the administration of antiviral therapy.

DIAGNOSIS Clinical Evaluation The clinical diagnosis of neonatal HSV infection is difficult because the appearance of skin vesicles cannot be relied on as an initial component of disease presentation. Enteroviral sepsis is a major differential diagnostic possibility in infants with signs suggesting neonatal HSV. Bacterial infections of newborns can mimic neonatal HSV infection. Skin lesions may resemble those seen with bullous or crusted impetigo. Some infants infected by HSV have been described who had concomitant bacterial infections, including group B Streptococcus, Staphylococcus aureus, Listeria monocytogenes, and gram-negative bacteria. A positive culture for one of these pathogens does not rule out HSV infection if the clinical suspicion for neonatal herpes infection is present. Many other disorders of the newborn can be indistinguishable from neonatal HSV infections, including acute respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, and various ocular or cutaneous diseases. When vesicles are present, alternative causes of exanthems should be excluded. Other diagnoses include enteroviral infection, varicella-zoster virus infection, and syphilis. Laboratory methods are available to differentiate these causes of cutaneous lesions in the newborn. Cutaneous disorders such as erythema toxicum, neonatal melanosis, acrodermatitis enteropathica, and incontinentia pigmenti often confuse physicians who suspect neonatal HSV infections. HSV lesions can be distinguished rapidly from those caused by these diseases using direct immunofluorescencestain of lesion scrapings or other methods for rapid detection of viral proteins and confirmed by viral culture. HSV encephalitis is a difficult clinical diagnosis to make, particularly because many children with central nervous system infection do not have a vesicular rash at the time of clinical presentation. Infection of the central nervous system

is suspected in the child who has evidence of acute neurologic deterioration, often associated with the onset of seizures, and in the absence of intraventricular hemorrhage and metabolic causes. PCR to detect the viral DNA in cerebrospinal fluid has become an important diagnostic method, largely replacing the need for diagnosis by brain biopsy.' l6 Infants with localized encephalitis usually have serial increases in cerebrospinal fluid cell counts and protein concentrations and negative bacterial cultures of the cerebrospinal fluid. Noninvasive neurodiagnostic studies can be used to define the sites of involvement.

Laboratory Assessment The appropriate use of laboratory methods is essential if a timely diagnosis of HSV infection is to be achie~ed.''~ Virus isolation remains the definitive diagnostic method. If skin lesions are present, a swab of skin vesicles, done vigorously enough to obtain cells from the base of the lesion, should be made and transferred in appropriate virus transport media to a diagnostic virology laboratory. Rapid diagnosis should be attempted by preparing material from skin lesion scrapings for direct immunofluorescence testing to detect the presence of virus-infected cells or for testing by enzyme immunoassays for viral proteins. Because of the possibility of falsepositive results using immunofluorescence or other antigen detection methods, specimens should also be obtained for confirmation by viral isolation. Direct immunofluorescence staining for virus-infected cells is not reliable unless the specimen is obtained from a skin lesion. Cells from oropharyngeal swabs or from cerebrospinal fluid should not be tested using this method. Clinical specimens should be transported to the diagnostic virology laboratory without being frozen and their processing expedited to permit the rapid confirmation of the clinical diagnosis. In addition to skin vesicles, other materials or sites from which virus may be isolated include the cerebrospinal fluid, stool, urine, throat, nasopharynx, and conjunctivae. The isolation of virus from swabs of superficial sites, such as the nasopharynx, may represent transient presence of the virus in secretions, when the culture is obtained within the first 24 hours after birth, and particularly when the specimen is taken immediately after birth. Typing of an HSV isolate may be done by one of several techniques. Because the outcome of antiviral treatment and risk of late sequelae may be related to the virus type, typing is of prognostic and epidemiologic i m p ~ r t a n c eResults . ~ ~ of viral cultures of the cerebrospinal fluid may be positive for infants with disseminated HSV infections but are usually negative for those who have localized encephalitis. Detection of HSV DNA in cerebrospinal fluid by PCR can allow a rapid presumptive diagnosis of HSV encephalitis in the newborn.''6-'20 PCR was used in the retrospective analysis of materials collected from 34 infants enrolled in the NIAID Collaborative Antiviral Study Group antiviral studies."' HSV was detected by PCR assay of cerebrospinal fluid in 71% of infants before antiviral therapy was initiated. At least one specimen was positive in 76% of infants, and all samples that were positive by viral culture were positive by PCR. Similar findings were reported by Swedish investigators when stored cerebrospinal fluid specimens obtained from infants with neonatal HSV infection were tested for HSV by

Chapter 26 PCR. HSV DNA was detected from cerebrospinal fluid in the acute phase of illness from 78% of patients with central nervous system disease.’” Use of HSV PCR methods on cerebrospinal fluid can potentially decrease the duration of time to diagnosis of some cases of HSV encephalitis; however, there are reports in older patients of initial negative HSV PCR results early in the course of illness. Cerebrospinal fluid obtained 4 to 7 days after the initial cerebrospinal fluid samples were obtained was subsequently positive for HSV DNA in a small number of patients.’22 PCR tests of cerebrospinal fluid were positive in 7 (24%) of 29 infants enrolled in the NIAID Collaborative Antiviral Study Group antiviral studies whose clinical disease was limited to mucocutaneous lesions. Five of the six infants who were evaluated when 1 year old were developmentally normal.”’ The significance of this observation for disease classification and prognosis remains to be determined in prospective studies. Most studies of PCR for the diagnosis of HSV central nervous system infections indicate the test is sensitive in approximately 75% to 100% of cases in small cohorts of infants.”8-’2’Specificity of the test ranges from 71% to 100%. The broad range of values for sensitivity and specificity of HSV PCR probably results from different study methods and disease classifications.lZ3 Some studies have shown that HSV PCR may be used to detect HSV DNA in peripheral blood mononuclear cells and plasma of infants with proven neonatal HSV infection. Using a sensitive and well-standardized PCR method, investigators found HSV DNA in peripheral blood mononuclear cells of 6 of 10 infants tested and in plasma of 4 of 6 infants tested.” Other investigators have reported the presence of HSV DNA in serum of 67% (20 of 30) infants with neonatal HSV infection.’” Whether HSV PCR testing of peripheral blood mononuclear cells or plasma can be used to accurately diagnose neonatal HSV infection in the absence of positive cultures is unknown. In clinical practice, there is considerable interlaboratory variability in HSV PCR test performance. Many clinical laboratories employ user-developed (“home-brew”)protocols, further complicating interpretation of PCR results. Diagnostic laboratories that perform HSV PCR testing must be able to validate their test and participate in national and in-house proficiency testing pr~grarns.”~ Until more information regarding the reliability of HSV PCR results obtained in clinical diagnostic laboratories has been determined, interpretation of negative or positive HSV PCR results must depend on clinical findings. A negative PCR result for HSV in cerebrospinal fluid in the setting of clinical, laboratory, or radiologic findings consistent with central nervous system infection does not rule out HSV infection. It is important to continue to use standard clinical and laboratory diagnostic methods for the evaluation of infants with possible neonatal HSV (Table 26-3). Every effort should be made to confirm HSV infection by viral isolation. Cytologicexamination of cells from the infant’s lesions should not be used to diagnose HSV infection because reliable specific methods are available. Cytologic methods, such as Papanicolaou, Giemsa, or Tzanck staining, have a sensitivity of only approximately 60% to 70%. A negative result therefore must not be interpreted as excluding the


857

diagnosis of HSV, and a positive result should not be the sole diagnostic determinant for HSV infection in the newborn. Intranuclear inclusions and multinucleated giant cells may be consistent with, but not diagnostic of, HSV infection. In contrast to some other neonatal infections, serologic diagnosis of HSV infection has little clinical value. The interpretation of serologic assays is complicated by the fact that transplacentally acquired maternal IgG cannot be differentiated from endogenously produced antibodies, making it difficult to assess the neonate’s antibody status during acute infection. Serial type-specific antibody testing may be useful for retrospective diagnosis if a mother without a prior history of HSV infection has a primary infection late in gestation and transfers little or no antibody to the fetus. Therapeutic decisions cannot await a diagnostic approach based on comparing acute-phase and convalescent-phase antibody titers. IgM production is delayed or does not occur in infected infants because of inherent immunodeficiencies in the response to systemic viral infections in the newborn, and commercially available assays for IgM antibodies to HSV have limited reliability. The results of specific laboratory tests for HSV should be used in conjunction with clinical findings and general laboratory tests, such as platelet counts, cerebrospinal fluid analysis, and liver function tests, to establish a disease classification.

TREATMENT

Background The cumulative experience of the past 2 decades demonstrates that perinatally acquired HSV infections are amenable to Table 26-3

Initial Diagnostic Evaluation for Suspected Neonatal Herpes Simplex Virus Infection

A. Microbiologic studies 1. Skin lesion: viral culture and direct viral examination 2. Cerebrospinal fluid: viral culture and HSV PCRa 3. Conjunctivae: viral culture 4. Nasopharynx: viral culture 5. Rectum: viral culture 6. Urine: viral culture B. Ancillary studies 1. Cerebrospinal fluid cell count, glucose and protein levels 2. Complete blood cell count with differential and platelet counts 3. Liver function studies 4. Coagulation studies 5. Electroencephalogram 6. Computed tomography or magnetic resonance imaging of head 7. Chest radiograph C. Not recommended 1. Direct viral examination of samples from conjunctivae, nasopharynx, rectum, urine, or cerebrospinal fluid 2. Herpes antibody from serum 3. Tzanck smear ”The diagnostic reliability of herpes simplex virus polymerase chain reaction (HSV PCR) results from blood or skin lesions performed outside of the research setting IS unknown

858

Section I11

Viral Infections Skin, eyes, or mouth, vidarabine (n = 31) or acyclovir (n = 54)

treatment with antiviral agents. Acyclovir is the drug of choice?6 Because most infants acquire infection at the time of delivery or shortly thereafter, antiviral therapy has the potential to decrease mortality and improve long-term outcome. The benefits that antiviral therapy can provide are influenced substantially by early diagnosis. The likelihood of disease progression in infants who acquire HSV infections is an established fact. Without treatment, approximately 70% of those presenting with disease localized to the skin, eye, or mouth develop involvement of the central nervous system or disseminated infection. Treatment initiated after disease progression is not optimal because many of these children die or are left with significant neurologic impairment. Regardless of the apparently minor clinical findings in some cases, the possibility of HSV infection in the newborn requires aggressive diagnostic evaluation and likely or proved infection mandates the immediate initiation of acyclovir therapy, which must be given intravenously.

Antiviral Drugs Historically, four nucleoside analogues have been used to treat neonatal herpes: idoxuridine, cytosine arabinoside, vidarabine, and acyclovir. Of these compounds, the first three are nonspecific inhibitors of cellular and viral replication, and the fourth, acyclovir, is selectively activated by HSV thymidine kinase. Acyclovir acts as a competitive inhibitor of HSV DNA polymerase and terminates DNA chain e10ngation.l~~ Idoxuridine and cytosine arabinoside have no value as systemic therapy for any viral infection because of toxicity and equivocal efficacy. Vidarabine was the first drug demonstrated to be efficacious; it decreased mortality and improved morbidity in cases of neonatal HSV infections.'26 A comparison of vidarabine with acyclovir suggests that these compounds have a similar level of activity for this disease; however, vidarabine is no longer available for clinical use.112Acyclovir is safe for use in newborns and is familiar to pediatricians from its other clinical uses. Acyclovir has been established as efficacious for the treatment of primary genital HSV infection when administered by intravenous, oral, and topical route^.'^^"^^ Oral and intravenous administration of acyclovir to the immunocompromised host decreases the frequency of reactivation after immunosuppression and the duration of disease.I2' Acyclovir has been established to be superior to vidarabine for the treatment of HSV encephalitis in older children and adults.I3' Because this compound is a selective inhibitor of viral replication, it has a low frequency of side effects. After pharmacokinetic and tolerance evaluations of acyclovir were done in infant^,'^'"^^ the NIAID Collaborative Antiviral Study Group compared vidarabine and acyclovir for the treatment of neonatal HSV infection in a randomized trial.'12 The dose of vidarabine used was 30 mg/kg/day, and acyclovir was given at a dose of 10 mg/kg every 8 hours. The duration of therapy was 10 days. There were no significant differences in survival between the two treatment groups (Fig. 26-3). There were no differences in adverse effects or laboratory evidence of toxicity. Survival with antiviral therapy depended on classification of the extent of disease at diagnosis (Fig. 26-4). Mortality and morbidity were also influenced by clinical status at the time of diagnosis and the virus type, Among infants with

l.0)h

m

CNS. vidarabine (n = 36)

*

CNS, acyclovir (n = 35)

0.8

0.7

111 Disseminated, vidarabine (n = 28)

Disseminated; acyclovir (n = 18)

0.3. 0.2.

1 I

0.1

o i . . . . . , . . . . .......................... 0

60

120

240

180

360

300

Survival (days) Figure 26-3 Survival of babies with neonatal herpes simplex virus infection according to treatment and the extent of disease. The infection was classified as confined to the skin, eyes, or mouth; affecting the central nervous system (CNS); or producing disseminated disease. After adjustment for the extent of disease with the use of a stratified analysis, the overall comparison of vidarabine with acyclovir was not statistically significant (P = .27)by a log-rank test. No comparison of treatments within disease categories was statistically significant. (From Whitley R, Arvin A, Prober C, et al. A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. N Engl 1 Med 324444,1991.)

8

a

0.4-

Disseminated disease

(n = 46)

5! 0.3-

n

0.2 . 0.1

1

04 0

,

,

1

1

1

,

1

1

1

100 200 300 400 500 600 700 800 900 lo00

Survival (days) Figure 26-4 Survival of babies with neonatal herpes simplex virus infection according to the extent of disease (P < ,001 for all comparisons). (From Whitley R, Arvin A, Prober C, et al. Predictors of morbidity and mortality in neonates with herpes simplex infections. N Engl J Med 324:450,1991.)

skin, eye, or mouth disease, those with HSV-1 infections were all normal developmentally at 1 year compared with 86% of those with HSV-2 infections. Infants who were alert or lethargic when treatment was initiated had a survival rate of 91%, compared with 54% for those who were semicomatose or comatose; similar differences in survival rates related to neurologic status were observed in infants with

Chapter 26


859

Figure 26-5 Mortality rates for patients with disseminated disease (A) and central nervous system disease (B) depending on the dose of acyclovir. (Data from Kimberlin DW, Chin-Yu L, Jacobs RF, et al. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics 108:230-238, 2001.)

disseminated infection. Prematurity, pneumonitis, and disseminated intravascular coagulopathy were poor prognostic ~igns.9~ The improved outcome compared with historical data probably reflects earlier diagnosis and institution of antiviral therapy, thereby preventing progression of disease from skin, eye, or mouth to more severe disease. The mean duration of symptoms before treatment for all participants, regardless of disease classification, was 4 to 5 days, indicating that therapy might have been instituted even sooner. These observations suggested that further advances in therapeutic outcome might be achieved by earlier intervention. Unfortunately, despite advances in laboratory diagnosis and treatment of neonatal HSV infection, the mean time between onset of disease symptoms and initiation of antiviral therapy has not changed.73 Despite the proven efficacy of antiviral therapy for neonatal HSV infection, the mortality rate remains high, and many infants who survive disseminated or central nervous system disease have serious sequelae. This circumstance dictated the need to evaluate high doses of acyclovir and longer treatment regimens. Infants were enrolled in an NIAID Collaborative Antiviral Study Group assessment of acyclovir given at an intermediate dose (45 mg/kg/day) or

high dose (60 mg/kg/day). Mortality rates for infants with disseminated or central nervous system disease were lower for infants given high-dose acyclovir than observed in the earlier studies (Fig. 26-5).’33There was no significant difference in morbidity status at 12 months of follow-up between high-dose and standard-dose acyclovir recipients for each of the three disease categories. Transient and reversible neutropenia occurred more frequently during high-dose therapy but resolved during or after cessation of treatment. The dose of acyclovir used had no impact on the duration of viral ~hedding.”~ The current recommendation for treatment of neonatal HSV infection is acyclovir, 60mg/kg/day in three doses (20 mg/kg/dose) given intravenously. Disseminated and central nervous system infections are treated at least 21 days. Duration of treatment for skin, eye, and mucous membrane infection, after disseminated and central nervous system infection have been ruled out, is a minimum of 14 days.’34 The use of oral acyclovir is contraindicated for the treatment of acute HSV infections in newborns. Its limited oral bioavailability results in plasma and cerebrospinal fluid concentrations of drug that are inadequate for therapeutic effects on viral replication. The high risk of progression from localized mucocutaneous infections requires the administration of

860

Section I11

Viral Infections

intravenous acyclovir to these infants, regardless of how well ration, despite appropriate therapy and supportive care, can they appear at the time of diagnosis. In addition to intrabe attributed to virus-induced destruction of cells comprising venous therapy, infants with ocular involvement caused by infected organs, such as liver or brain, or irreversible changes, HSV should receive one of the topical ophthalmic agents such as disseminated intravascular coagulopathy. The observation of an association between late sequelae approved for this indication. Topical acyclovir is not and frequent recurrences of s h n lesions in infants who were necessary for treatment of mucocutaneous lesions caused by treated for localized HSV-2 infections during the newborn HSV because parented drug reaches these sites. Acyclovir treatment is based on a laboratory diagnosis of period has raised questions about the potential efficacy of neonatal HSV infection. Rapid methods, including direct suppressive therapy with oral acyclovir. The NIAID Collaboantigen detection and PCR, should be used to facilitate early rative Antiviral Study Group has undertaken an assessment of the safety and efficacy of suppression as an adjunct after laboratory confirmation of suspected cases. Acyclovir prophylaxis is not recommended. Presumptive treatment the recommended treatment of mucocutaneous disease with may be a reasonable option when circumstances prevent intravenous acycl~vir.”~ Infants were given 300 mg/m’ twice or three times per day for 6 months. Of 16 infants given the rapid laboratory diagnosis and the clinical manifestations three daily doses, 13 (81%) had no recurrences of lesions are those described for mucocutaneous infections, dissemiwhile receiving therapy, compared with 54% of infants from nated disease, or HSV encephalitis. In all cases, specimens earlier studies who received intravenous acyclovir only. should be obtained for laboratory testing to guide the decision to continue treatment. During the course of therapy, careful Forty-six percent of the 26 infants developed neutropenia. In monitoring is important to assess the therapeutic response. one infant, suppressive therapy was associated with a transient Even in the absence of clinical evidence of encephalitis, recurrence of infection due to an acyclovir-resistant isolate evaluation of the central nervous system should be done for of HSV-2; subsequent recurrences were caused by susceptible prognostic purposes. Serial evaluations of hepatic and isolates. Whether this effect on cutaneous recurrences, which hematologic parameters may indicate changes caused by the was limited to periods of active oral suppressive therapy, has viral infection or by drug toxicity. any effect on late neurologic sequelae is unknown. Oral Intravenous acyclovir is tolerated well by infants. Adequate acyclovir prophylaxis is not recommended for routine use, hydration is necessary to minimize the risk of nephrotoxicity, pending results from a larger NIAID Collaborative Antiviral Study Group trial of efficacy against this end point. and dosage adjustments are necessary if renal clearance is impaired. As for all drugs, the possibility of acute toxicity should be considered in any child receiving parented antiOther Issues in Acute Management viral therapy and should be assessed by serially evaluating Isolation of the newborn with HSV infection is important to bone marrow, renal, and hepatic functions. The potential for long-term harm from these drugs remains to be defined. decrease the potential for nosocomial transmission. Many infants with this infection have life-threatening problems, Acyclovir resistance has been reported in an infant with including disseminated intravascular coagulation, shock, and acute HSV infection of the larynx in the newborn period; in respiratory failure, and they require supportive care that is this case, the initial isolate was not inhibited by acyclovir, although the source of this infection could not be e~p1ained.l~~ available only at tertiary medical centers. Acyclovir resistance has also been reported in a premature There is no indication that administration of immune infant with cutaneous and central nervous system disease globulin or hyperimmune globulin is of value for the treatcaused by an initially acyclovir-susceptible HSV. The infant ment of neonatal HSV infection. Although a series of studies developed recurrent disseminated HSV infection 8 days after have suggested that the quantity of transplacental neutralizing antibodies affects the attack rate among exposed infants and a 21-day course of acyclovir. The virus isolated at the onset may influence the initial disease manifestations, the presence of recurrent symptoms was found to lack thymidine b a s e activity on the basis of a frame-shift mutation in the of antibodies may or may not influence the subsequent course thymidine kinase gene.136Another infant born to a mother of infection.49,51,54,55,82 The administration of standard prewith severe systemic primary HSV-2 infection developed an parations of intravenous immune globulin does not enhance acyclovir resistant mutant during acyclovir therapy for the titers of functional antibodies against HSV in low-birthdisseminated HSV infection and eventually died. The use of weight infants.14’ The evaluation of virus-specific monoclonal steroids to treat blood pressure instability may further have antibodies in combination with antiviral therapy may hampered this baby’s immune response to infe~ti0n.l~’ become feasible as new technologies for deriving human or Isolates of HSV recovered from infants who received humanized antibody preparations are de~eloped.’~’ intravenous acyclovir for cutaneous disease in the newborn No other forms of adjunctive therapy are useful for treating period and had subsequent recurrent cutaneous lesions neonatal HSV infections. Various experimental modalities, typically remain sensitive to acyclovir.”* Emergence of viral including bacille Calmette-Gukrin, interferon, immune resistance to acyclovir has been described in patients requiring modulators, and immunization, have been attempted, but prolonged or repeated treatment with this drug. One infant none has produced demonstrable effects. who was given long-term oral acyclovir for suppression of recurrences during the first 6 months of life had a resistant Long-Term Management of Infected Infants HSV isolated from a lesion after therapy was discontinued, but subsequent isolates were s~sceptible.’~~ With the advent of antiviral therapy, an increasing number Antiviral resistance does not generally explain the failure of newborns who suffered from HSV infection are surviving of infants with the disseminated or encephalitic form of the and require careful long-term follow-up. The most common complications of neonatal HSV infection include neurologic disease to respond well to antiviral therapy. Clinical deterio-

Chapter 26 and ocular sequelae that may be detected only on long-term follow-up. It is therefore necessary that these children receive serial long-term evaluation from qualified pediatric specialists in these areas, which should include neurodevelopmental, ophthalmologic, and hearing assessments. Recurrent skin vesicles are present in many children, including those who did not have obvious mucocutaneous disease during the acute phase of the clinical illness. Skin vesicles provide a potential source for transmission of infection to other children or adults who have direct contact with these infants. The increasing use of daycare for children, including those surviving neonatal HSV infections, stimulates many questions from daycare providers about these children. There is some risk that children with recurrent HSV skin lesions will transmit the virus to other children in this environment. The most reasonable recommendation in this situation is to cover the lesions to prevent direct contact. It is much more likely that HSV-1 will be present in the daycare environment in the form of asymptomatic infection or gingivostomatitis. In both cases, virus is present in the mouth and pharynx, and the frequent exchange of saliva and other respiratory droplets that occurs among children in this setting makes this route of transmission more likely. Education of daycare workers and the general public about herpesvirus infections, their implications, and the frequency with which they occur in the population as a whole can calm fears and correct common misconceptions. Parents of children with neonatal HSV infection often have significant guilt feelings. Parents often require support from psychologists, psychiatrists, or counselors. The family physician or pediatrician can provide a supportive role of great value to the family in this situation. Most parents and many physicians are unaware of the high prevalence of HSV-2 infection in the United States and of the lifelong persistence and subclinical nature of these infections. Concern about the risk of fetal and neonatal infection during subsequent pregnancies is often a major issue that can be addressed effectively based on the low risks as proved from large, prospective studies.

PREVENTION

Background Despite the progress that has been made in antiviral treatment of neonatal HSV infection, the ideal approach is to prevent the exposure of infants to active maternal infection at the time of delivery. Unfortunately, genital infections caused by HSV are often clinically silent when they are acquired as new infections and when the virus reactivates. The high prevalence of HSV-2 infections in the U.S. population means that women are at risk for acquiring new genital infections during pregnancy and that at least one in five will become infected before pregnancy. The problem of asymptomatic genital HSV infection means that the transmission of HSV from mothers to infants cannot be eliminated even with the best obstetric management. It is futile to obtain sequential genital cultures during the last weeks of gestation in women with a history of genital herpes in an effort to identify those who will have asymptomatic infection at the onset of labor.48These cultures do not predict the

Table 26-4


861

Projected Risk of Transmission of HSV-2 from Mothers to Infants at Delivery in a Cohort of 100,000 Pregnant Women

25% with Past HSV-2

Infection 25,000 women 1.5% reactivation at delivery 375 women with reactivation lo%) from B19 have been Both were isolated from patients with a transient red cell aplasia indistinguishable clinically from the typical B19-induced aplastic crisis. The clinical significance of these variants and whether they represent different genotypes or merely geographic variants of B19 remains a topic of debate.27330 The B19 genome is very small ( ~ 5 . 6kb) and contained within an icosahedral protein capsid. The capsid structure and lack of an envelope make the virus very resistant to heat and detergent inactivation, features that appear to be important in transmission. The genome appears to encode only three proteins. Two are capsid proteins, designated VP1 and VP2. VP2 is smaller but more abundant and makes up approximately 96% of the capsid protein. VP1 is larger and constitutes about 4% of the capsid but contains a unique

Chapter 27 region that extends out from the capsid surface and serves as the attachment site for the cellular receptor?l VP2 has the unique ability to self-assemble into capsids that are morphologically and antigenically similar to B19 viruses when expressed in cell culture systems in v i t r ~ . ~ When ’ , ~ ~ present with VP1, the capsids incorporate both proteins, but VP1 alone does not self-as~emble.~~ The third gene product is a nonstructural protein designated NS1. The function of this protein is not entirely clear, but it is involved in regulation of the viral promoter and appears to have a role in DNA repli~ation.’~ Studies of NS1 have been hampered by the observation that it appears to be toxic to cells by an unknown mechanism.34 Studies have further suggested that production of NS1 can lead to programmed cell death (i.e., apoptosis) mediated by stimulation of cytokine p r o d ~ c t i o n . ~ ~ . ~ ~ Because of its limited genomic complement, B19 requires a mitotically active host cell for replication. It can replicate only in certain erythroid lineage cells stimulated by erythropoietin, such as erythroid precursors found in bone marrow, fetal liver, umbilical cord blood, and a few erythroleukemic cell line^.'^,^'-^^ B19 cannot be propagated in standard cell cultures,4’ a fact that previously limited the availability of viral products for development of diagnostic assays. Much of this limitation has been overcome by the development of molecular methods for the detection of viral nucleic acid, but reliable commercial serologic assays are still somewhat limited. The cellular receptor for the virus has been identified as globoside, a neutral glycosphingolipidfound on erythrocytes, where it represents the P blood group antigen.43This receptor is necessary for viral infection to occur, and individuals who lack this antigen (p phenotype) are naturally immune to B19 infection.44The P antigen is present on other cells such as endothelial cells, fetal myocardial cells, placenta, and megakaryocyte~.~~ The tissue distribution of this receptor may explain some of the clinical manifestations of infection with this virus (discussed later). Although the P antigen is necessary for B19 viral infection, it is not sufficient, because some cells, particularly nonerythroid tissues, that express the receptor are not capable of viral infection!’ A co-receptor has been described on cells that are permissive for B19 infection!6 The hypothesis is that the globoside receptor is necessary for viral attachment but that the co-receptor somehow allows for viral entry into the cell, where viral replication can occur. If confirmed, this may provide an alternative explanation of the pathogenesis of infection in nonerythroid tissues that express globoside without the co-receptor.

PATHOGENESIS: GENERAL ASPECTS Parvovirus B19 requires a mitotically active host cell to complete its full replicative life cycle. The primary target for B19 infection appears to be erythroid progenitor cells that are near the pronormoblast stage of development. The virus can be propagated only in human erythroid progenitor cells from bone marrow, umbilical cord blood, fetal liver, peripheral blood, and a few erythroid leukemic cell lines.47 B19 lytically infects these cells, with progressive loss of targeted cells as infection proceeds. In vitro hematopoietic

Human Parvovirus Infections

869

assays demonstrate that B19 suppresses formation of erythroid colony-forming units and this effect can be reversed by addition of serum containing anti-B19 immunoglobulin G (IgG) antibodies!8 The virus has little to no effect on the myeloid cell line in vitro, but it inhibits megakaryocytopoiesis in vitro without viral replication or cell l ~ s i s . * ~ Clinically, this situation is best illustrated in the transient aplastic crisis of sickle cell disease. Patients have fever, weakness, and pallor on presentation, with a sudden and severe drop in their reticulocyte counts. This cessation of red blood cell production, coupled with shortened red blood cell survival because of hemolysis, produces a profound anemia. Examination of the bone marrow typically reveals hypoplasia of the erythroid cell line and a maturational arrest; giant pronormoblasts are often seen with intranuclear viral inclusion^.^^ With development of specific antibodies, viral infection is controlled, and reticulocyte counts begin to rise. Evaluation of infection in normal volunteers has shown similar hematologic changes, but because of the longer life of red blood cells, these changes are clinically insignificant.” Adult volunteers inoculated intranasally with B 19 developed viremia after 5 to 6 days with a mild illness. Their reticulocyte counts fell to undetectable levels, and this was accompanied by a modest fall in hemoglobin and hematocrit levels. Platelets and granulocyte counts also declined. Specific antibody production with immunoglobulin M (IN) was followed by IgG, and viremia was cleared rapidly. A second-phase illness developed at 17 to 18 days with rash and arthralgias but without fever, and hematologic indices had returned to normal. The tissue distribution of the cellular receptor for the virus (P antigen) may explain the predominance of hematologic findings associated with B19 infection. Its presence on other tissues may help to explain other clinical manifestations, such as myocardial disease, congenital infection, and vasculitis syndromes. Although the cellular receptor is present and the virus can attach, unlike erythroid cells, these cells are nonpermissive for viral replication; the virus is unable to undergo a complete life cycle with the resultant lysis of the host cells. Instead, interaction in these tissues leads to accumulation of the nonstructural protein NS1. This protein is essential for viral replication and has a variety of proposed functionsz3but appears to be toxic to most mammalian cell lines when present in excess.34NS1 has been associated with apopt~sis.~ NS1 ~ , ~also ~ has been linked to production of tumor necrosis factor-a and interleukin-6, a potent proinflammatory c y t ~ k i n e . ~ ”This ~ ~ ” ~may lead to cellular injury through cytokine pathways and provide another mechanism aside from lytic infection for some of the clinical manifestations. Chronic infections in immunocompromised patients develop when patients are unable to mount an adequate neutralizing antibody response. These infections are characterized by viral persistence in serum or bone marrow and lack of detectable circulating antibody. Clinical manifestations include chronic anemia or red cell aplasia and may include granulocytopenia and thrombocytopenia. The mechanism for the leukopenia and thrombocytopenia is not known, although it has been shown49that B19 causes disturbances in megakaryocytic replication when infected in vitro.

870


EPIDEMIOLOGY AND TRANSMISSION B19 is a highly contagious and common infection worldwide. In the United States, 60% or more of white adults are seropositive (i.e., have IgG antibodies to B19 in their sera). This indicates a previous infection, usually one acquired in childhood. Among African Americans, the rate of seropositivity is lower, about 30%.19 Transmission of B19 from person to person probably occurs by droplets from oral or nasal secretions. This is suggested by the rapid transmission among those in close physical contact, such as schoolmates or family members, and from a study of healthy volunteers experimentally infected with B19, in whom virus was found in blood and nasopharyngeal secretions for several days beginning 1 or 2 days before symptoms a~peared.~’ In the volunteer study, no virus was detected in urine or stool. Given the highly contagious nature of B19 infections, it is not surprising that most outbreaks occur in elementary schools and occasionally child-care centers. Susceptible (seronegative) adult school personnel are at high risk for acquiring the infection from students.” Some outbreaks in schools may be seasonal (often late winter and spring) and epidemic, with many children and staff acquiring the infection and developing symptoms of EI. At other times, the infection is often endemic, with transmission occurring slowly and with only a few persons manifesting symptoms.

Global Distribution B19 infections occur worldwide. Serologic evidence of B19 infection has been found everywhere studied, including developed countries, undeveloped countries, urban and rural areas, and isolated island population^.^^-^^ The diseases and associated signs and symptoms are the same worldwide. No important strain or antigenic differences have been detected, and serologic assays are independent of the source or location of patient serum. Disease caused by B 19 appears to be unrelated to specific viral genotypes, although analysis of the antigenic variation or nucleotide sequences of widely dispersed B19 isolates shows some heterogeneity of unknown ~ignificance.~~*~~*~~-~’

Seasonality and Periodicity Transmission of B 19 continues throughout the year, but there are seasonal variations in transmission rates. Outbreaks of EI most often occur in winter and spring in temperate climates and less frequently in fall and summer.62-64 In schools or daycare centers, outbreaks of EI may persist for months, usually starting in late winter or early spring and ending with summer vacation. Figure 27- 1 highlights multiyear outbreaks of B19 exposure among pregnant women and the associated seasonal variation in Pittsburgh, Pennsylvania. Most cases occurred in late spring and summer of each year. In Jamaica, an island nation, careful studies of those with sickle cell disease show that epidemics of transient aplastic crises occurred about every 5 years, with little disease occurring inside this interval.65Epidemics of B 19 infections at 5-year intervals were also observed in Rio de Janeiro, Brazil.” In Japan, age-related serologic evaluation of stored serum samples showed no evidence for B19 epidemics over a 10-year peri0d.6~The prevalence of IgG antibodies to B19 among three tribes of South American Indians living in remote regions of Brazil was very low (< 1l%), and was zero for those younger than 30 years in one tribe?5 However, school nursing records in Iowa over 14 years identified cases of EI every year but

Seroprevalence by Age In numerous studies of B19 infection based on serologic testin the seroprevalence of B 19 infection increases with 8v69, .74 Figure 27-2 shows the age-dependent increase in age.436 seroprevalence in Richmond, Virginia.75 Transplacentally acquired maternal antibodies are undetectable by 1 year of age. In children younger than 5 years, the prevalence of IgG antibodies to B19 is usually less than 5%. The greatest increase in seroprevalence and B19 infection occurs between 5 and 20 years of age. By age 20 years, the seroprevalence of B19 infection rises from about 5% to almost 40%. Afterward, without regard to risk factors, B19 seroprevalence increases slowly. In adult blood donors, the seroprevalence of IgG antibodies to B19 ranges from 29% to 79% with a median of 45%.76-82 By age 50, the seroprevalence may be greater than

Figure 27-1 Seasonal variation in reported parvovirus 619 exposures in pregnant women. Each month is indicated by its first letter. (Data from Harger J, Koch W, Harger GF.Prospective evaluation of 618 pregnant women exposed to parvovirus 619: risks and symptoms. Obstet Gynecol 91:413, 1998.)

Chapter 27


871

Incidence

Age (Y)

Figure 27-2 Percentage of family subjects positive for IgG antibody to B19 by age. The sample includes 283 subjects from 11 1 families. Subjects were one twin of each twin pair, nontwin parents, and the oldest child of each family. (Data from Adler SP, Koch W. Human parvovirus B19 infections in women of childbearing age and within families. J Pediatr Infect Dis 8233, 1989.)

75%. Similar results on the age-related seroprevalence of B19 infections were observed in India.83

Seroprevalence by Gender In most studies, the prevalence of antibodies to B19 in sera obtained from men and women is similar.” At least four studies, however, have reported that women have a higher rate of 1319 infection than men.19,75,77,84 In one study of adult blood donors, the proportion of women who were seropositive, 47.5%, was 1.5 times higher than for men. The prevalence of IgG antibodies averaged 51% for women of all ages, compared with 38% for males in one of two family studies in Richmond, Virginia, and 64% for women and 50% for men in the ~ t h e r . ’ In ~ . Taiwan, ~~ the prevalence of IgG antibodies to B19 among females was significantly higher than among males (36.4% versus 29.4%, P < .001).85The most likely explanation for the higher rates of B19 infection among women compared with men is that women are likely to have more frequent contact with children, especially schoolaged children, who are the major sources of B19 transmission because of school attendance. For adults, contact with schoolaged children is the major risk factor for B19 infection.”

Seroprevalence by Race In the United States, there are significant differences in the seroprevalenceto B19 between blacks and whites. For example in Richmond, Virginia, approximately 60% of whites are seropositive, compared with 45% of bla~ks.’~ The reasons for the lower rate of infection among blacks are unknown, but may reflect the fact that students in Richmond schools are predominantly African American.

In tests of serum from random blood donors for evidence of recent B19 infection using detection of viral antigens or DNA, the rate using antigen detection of infection is 0 to 2.6 cases per 10,000 individuals tested, with a median of 1 per 10,000; using DNA detection, the rate is 0 to 14.5 per 10,000, with a median of 2 per 10,000.86-91 When IgM antibodies to B19 are used to detect recent infection, the rate has been zero, but all studies included fewer than 1000 As for seroprevalence, women may have a greater risk for infection during outbreaks of EI. During an epidemic of EI in Port Angeles, Washington, the attack rate for women was 15.6%, more than twice the rate of 7.4% for men.” In Spain and Chile, children have the highest rates of B19 infection, which is true for groups of children 0 to 4 years old and for those 5 to 9 years A study of 633 children with sickle cell disease followed at the Children’s Hospital in Philadelphia between 1996 and 2001 found that 70% were seronegative (i.e., susceptible), and during this period, 110 patients developed B19 infections, for an incidence of 11.3 per 100 patients per year.96Among the 110 patients infected, there were 68 episodes of transient aplastic crisis, characterized by an acute exacerbation of anemia, acute chest syndrome, pain, and fever. The high incidence of disease among these patients emphasizes the need for a vaccine against a parvovirus B19.

Risk Factors for Acquisition B19 is efficiently transmitted among those residing in the same home, with attack rates based on the development of signs and symptoms of EI ranging from 17% to 30%.’0,97 Using serologic testing to identify asymptomatic infection and to exclude immune individuals, the secondary attack rate for susceptible household contacts is 50%. Most secondary cases of EI or aplastic crisis in the home occur 6 to 12 days after the index case.’O’ 97-100 A serologic study of pregnant Danish women indicated that seropositivitywas significantly correlated with increasing number of siblings, having a sibling of the same age, number of own children, and occupational exposure of children.’” During epidemics, B19 transmission is widespread among school-aged children. Studies of school or classroom outbreaks of EI with at least one serologically confirmed case of acute B19 infection revealed student infection rates ranging from 1% to 62% based on the occurrence of a rash illness. The median rate for all studies was 23%.’02-’09 Because asymptomatic infections are common and other signs and symptoms of EI may be mild and overlooked, these studies undoubtedly underestimate the true incidence of infection. Studies of students using serologic assays to identify B19 infection during outbreaks report infection rates of between 34% and 72%, with most not associated with a rash illness.103,108J09 The higher rates of infection occur in elementary schools and daycare centers compared with secondary schools and in boarded school students compared with nonboarded student^.'^^-'^^ During school epidemics, employees in contact with children have the highest rates of infection compared with community controls. The attack rate based on detection of rash illness or arthropathy may be relatively low (12% to

872


25%).lo3,Io7However, the seroprevalence of B19 IgG antibodies to B19 in school employees is greater than adult community controls and ranges between 50% and 75%.'9,'09,'10 When serologic testing is used to identify employees with asymptomatic infection and to exclude immune employees, the attack rate among the susceptibles is usually very high. In four school outbreaks where serologic testing was used, the attack rate varied from 19% to 84%, and the frequency of asymptomatic infection was greater than 50% in all but one o u ~ ~ r e ~ ~ 1 0 3 ~ 1 0 6 ~ 1 0 9The . " 0 highest infection rates occurred among susceptible elementary school teachers compared with middle and high school teachers, and this may reflect exposure to more infected children or a greater likelihood of contact with respiratory secretions in younger ~hi"ren.'~'*''~ During a community-wide outbreak of EI in Connecticut in 1988, the infection rate among susceptible women was 16% for school teachers, 9% for daycare workers and homemakers, but only 4% for other women working outside the home."' The risk of infection may be increased for school employees even in the absence of recognized epidemics of EI. In a study of 927 susceptible school employees conducted during a 3.5-year period when no community outbreaks were detected, the annual incidence of specific IgG seroconversion was 2.9%, compared with 0.4% for a control population of 198 hospital employees.'' The rate of 3.4% was higher for school employees with jobs involving direct contact with children compared with only 0.6% observed for persons with other job classifications. Most of the individuals who seroconverted did not recall an illness characterized by rash or arthropathy. Salivary antibodies can be used to detect IgG and IgM antibodies to B19 because serum antibodies passively diffuse into saliva. Testing saliva for antibodies to B19 was useful in documenting outbreaks in schools and households. In an outbreak in England, school attack rates varied from 8% to 50%, including an attack rate of 45% for the teaching staff.'" The household transmission attack rate was 45% for 11 susceptible individuals. These rates are similar to what has been previously observed."' Crowding and low socioeconomic status are not proven risk factors for B19 infection. However, these factors are suggested by the observation that in Rio de Janeiro, the seroprevalence of IgG antibodies to B19 is 35% in children age 5 years or younger, but in Niger, it was 90% by 2 years of age.54,70

Hospital Transmission B19 can be transmitted from infected patients to hospital workers."' Most investigations reveal that hospital transmission of B19 is common and includes direct patient-topatient transmission and indirect transmission from materials or specimens known to contain B19 to laboratory p e r s ~ n n e l . " ~ ~One " ~ patient with sickle cell anemia became ill with aplastic crisis 9 to 11 days after contact in the hospital with a patient with hereditary spherocytosis hospitalized for aplastic crisis; B19 infection was confirmed in both.L16An outbreak of EI occurred on a pediatric ward where 13 (26%) of 50 children developed a rash illness.'I7 B19 seroconversion occurred in 5 (71%) of 7 children with rash illness and in 9 (35%) of 26 children who were asymptomatic. Transmission from patient to health care worker occurred twice in one hospital after admission of patients with aplastic crisis."' In

the first case, 4 (36%) of 11 susceptible employees with close contact had IgM antibodies to B19, indicating recent infection; in the second case, 10 (48%) of 21 employees had specific IgM antibodies to B19 or seroconverted from IgG negative to positive. Eleven (79%) of 14 were symptomatic with rash or arthropathy. Another study of an outbreak of EI among health care workers on a pediatric ward found that 10 (33%) of 30 susceptible health care workers had serologic evidence of acute B19 infection, along with 2 (17%) of 12 immunocompromised patients being cared for on the ~ a r d . " ~ *The " ~two infected patients were not symptomatic, but analysis of preexisting sera showed they acquired B19 while hospitalized. Onset of symptoms among the employees was temporally clustered, indicating a chronic source such as an immunocompromised patient or person-to-person transmission. Studies in Hong Kong identified three immunocompromised patients who appeared to transmit genetically identical strains of B19 from patient to patient."' At least one of these three patients appeared to be able to transmit the virus over many months. Immunocompromised patients often have chronic infections and therefore may be infectious for long periods. DNA sequence analysis was also used in Japan to document B19 transmission between hospital staff members, including nursing staff, office workers, and a physiotherapist.12' Other investigations have observed little or no risk for hospital transmission. No evidence of patient-to-employee transmission was found among 10 susceptible health care workers with frequent contact with a chronically infected patient hospitalized for 24 days before institution of isolation precautions.12' Transmission to hospital employees did not occur after exposure to a parvovirus B19-infected mother, her infected stillborn fetus, and contaminated objects in the hospital room.'22 During a community outbreak of B19, none of 17 susceptible pregnant health care workers with possible exposure had serologic evidence (IgM antibodies to B19) of a recent infecti~n."~Ina case-control study of hospital transmission, serologic testing was used to determine the infection rates among personnel exposed to patients with sickle cell disease and transient aplastic crisis before the subjects being placed in is01ation.l~~ Only 1 of 32 susceptible exposed hospital workers acquired a B 19 infection, compared with 3 of 37 susceptible workers not exposed. Results of this study suggested that hospital workers who cared for patients with aplastic crisis were not at an increased risk for B19 acquisition. Two prospective studies from one institution determined the incidence of infection in health care workers during endemic (nonepidemic) periods. The first study found the annual seroconversion rate to be 1.4% for 124 susceptible female health care workers followed for an average of 1.7 years. In a subsequent study of 198 susceptible hospital employees, the annual rate was 0.4%, compared with 2.9% for school employees." Taken as a whole, the evidence indicates that B19 may be highly contagious in the hospital, although perhaps not in every circumstance. Many potential variables may affect rates of transmission from patients to staff, including the type of patient (immunocompromised or not), the duration of B19 infection at the time of hospitalization, and potentially, the viral load of the infected patient. Patients with erythrocyte

Chapter 27 aplasia or others with suspected EI or B19 infection should be presumed to have a B19 infection until proved otherwise. These patients should receive respiratory and contact isolation while hospitalized.

Routes of Viral Spread Person-to-person spread of B19 probably occurs through contact with respiratory secretions. Viral DNA is present in saliva50.108,L?4,125at levels similar to those in blood, and in a volunteer study, infection was initiated by intranasal inoculation of B19.50,’26 B19 cannot be detected in columnar epithelial cells of the large airways.’27 Indirect evidence suggests B19 is not transmitted by aerosols. Viruses such as measles and influenza that are transmitted by aerosols are rapidly spread during outbreaks, but new cases of EI are spread out over many months during school outbreaks, suggesting that B19 transmission is inefficient. B19 DNA may be found in the urine, but it is unlikely that this is associated with infectious virus. The only well-documented routes of spread for B19 are vertically from mother to fetus and from parented transfusion with contaminated blood products or needles. Vertical transmission is discussed later. Transmission of B19 by transfusion occurs but is rare because of the low prevalence of B19 viremia among donors of blood and blood products; however, the risk increases for pooled blood products. 1’8-131 For example, B19 DNA is frequently found in clotting factor concentrates, including products treated with solvents and detergents, steam, or monoclonal antibodies, and even treated products may be i n f e c t i ~ u s . ~ ~ S”eroprevalence ’ ~ ” ~ ~ ~ ~ ~of~ IgG antibodies to B19 is high among hemophiliacs compared with age-matched controls and is higher for those who received frequent infusions of clotting factors prepared from large donor pools compared with those prepared from small donor P O O ~ S . ~ ~ ~ Parvoviruses are resistant to chemical inactivation. In one hospital, B19 transmission occurred without recognized direct patient contact, suggesting possible transmission by fomites or environmental contamination.”’ That B19 is transmitted by fomites has not been directly established,but considering the stability of related animal parvoviruses, this possibility exists. B 19 DNA, not infectious virus, was found in a study of a suspected nosocomial outbreak in a maternity ~ a r d . ’ B19 ’ ~ DNA was detected by polymerase chain reaction (PCR) on the hands of the mother of a stillborn fetus infected with B19 and on the sink handles in her hospital room. Samples from countertops, an intravenous pump, and telephone were also positive by a sensitive nested-PCR DNA technique. PCR is so sensitive that minute quantities of DNA can be detected by this technique, and the presence of B19 DNA on surfaces does not imply that these surfaces are sources of infection. Infected fetal tissues and placental or amniotic fluids are more likely sources of infection for health care workers than fomites.

Risk of B19 Acquisition for Women of Childbearing Age We completed a large epidemiologic study” to determine the relative risk of B19 acquisition for women of childbearing age in daily contact with children, including nurses, daycare


873

employees, and teachers at all levels. We identified risk factors for B19 infections for hospital and school employees during an endemic period. We monitored by serologic testing 2730 employees of 135 schools in three school systems and 75 1 employees of a hospital, all in Richmond, Virginia. Sixty percent were initially seropositive. After adjusting for age, race, and gender, risk factors for seropositivity were contact with children 5 to 18 years old at home or at work and employment in elementary schools. Over 42 months, only 1 of 198 susceptible hospital employees seroconverted (0.42% annual rate), compared with 62 of 927 (2.93% annual rate) school employees (relative risk = 6.9). Four factors associated with seroconversionwere employment at elementary schools, contact with children 5 to 11 years of age at home, contact at work with children 5 to 18 years old; and age younger than 30 years. Those in daily contact with school-aged children had a fivefold increased annual occupational risk for B19 infection.l9 Several observations indicate that B 19 infections were endemic but not epidemic or pandemic in the Richmond area during the 42-month prospective evaluation.” First, few cases of B19 infection were reported by the school nurses, and no cluster of cases was observed at any single school or group of schools. Second, the seroconversion rates during each of three consecutive study periods were the same for all groups or subgroups. Third, for employees, B19 infections were not clustered at individual schools or groups of schools. Fourth, the infection rates we observed among employees, even for those teaching elementary school, were less than those observed for the 1988 Connecticut epidemic, in which 46 infections occurred among 236 susceptible individuals exposed in the schools, for a minimum annual infection rate of 19%.‘09In a study of secondary B19 infections among exposed household members, rates ranged from 30% to Persons with B19 infections are often asymptomatic or have no rash, and low-level endemics can go unnoticed. We observed that 28 of 60 infected employees were asymptomatic and that only 20 knew of a specific exposure. In a study of 52 household contacts of patients with B19 infections during an Ohio epidemic, infections without a rash occurred in 15 (94%) of 16 blacks and 17 of 35 (47%) whites, and completely asymptomatic infections occurred in 11 (69%) of 16 blacks and 6 (20%) of 30 whites.98During the Connecticut outbreak, 5 (8%) of 65 teachers who were never exposed to a child with a rash became infected.’09Observations of high secondary attack rates during epidemics and the high rates of rashless or asymptomatic infections provide strong evidence that even during periods when EI is inapparent in the community, school or hospital personnel in contact with children have a significant occupational risk for B19 infections. Contact with elementary school-aged children, whether at home or at work, may be the most important risk factor for B19 acquisition. When seropositivity for those with children at home was stratified by the child’s age, the association between seropositivity and children at home was significant (P < .05) when all children between 5 and 18 years old were included, and for seroconversion, the significant association was with elementary school-aged children at home.” The low seroprevalence and seroconversion rate among hospital employees without known contact with

874

Section I11

Viral Infections

children indicates that this group has a low occupational risk for acquiring B19 infections. The major conclusions from these studies were that when EI is inapparent in the community, school or hospital personnel in contact with children still have a significant occupational risk for B19 infections and that school employees have an approximately twofold greater risk of acquiring B19 from children at work than from elementary school-aged children at home. We also found that hospital employees without contact with children have a low risk for acquiring B19. Using the Richmond data and assuming that on average 50% of pregnant women are immune, we estimate that 1% to 4% of susceptible women will become infected during pregnancy during endemic periods. If the rate of fetal death after maternal infection is as high as 5% to 10% (discussed later), the occupational risk of fetal death for a pregnant woman with unknown serologic status wdl be between 1 in 500 and 1 in 4000. These rates are so low that during endemic periods, they do not justrfy intervention such as serologic testing for pregnant women, furloughing workers, or temporary transfer of pregnant seronegative employees to administrative or other positions without child contact. Knowing B19 infection rates during endemic periods may be more important than knowing rates during epidemic periods. In the United States, B19 infections are endemic most of the time. Because more than 75% of B19 infections are inapparent, most women who acquire B19 infection during pregnancy do so during endemic periods, not during epidemics. For establishing public health policy and assessing the potential importance of immunizing against B19, knowing that for seronegative women the endemic rate is between 1% and 4% is more important than knowing epidemic rates.

CLINICAL MANIFESTATIONS OTHER THAN INTRAUTERINE INFECTION

Erythema lnfectiosum The most common clinical manifestation of infection with parvovirus B19 is EI, or fifth disease, a well-known rash illness of children. EI begins with a mild prodromal illness consisting of low-grade fever, headache, malaise, and upper respiratory tract symptoms. This prodrome may be so mild as to go unnoticed. The hallmark of the illness is the characteristic exanthem. The rash usually occurs in three phases, but these are not always disting~ishable.'~~'"~~~~~ The initial stage consists of an erythematous facial flushing described as a slapped-cheek appearance. In the second stage, the rash spreads quickly to the trunk and proximal extremities as a diffuse macular erythema. Central clearing of macular lesions occurs promptly, giving the rash a lacy, reticulated appearance. Palms and soles are usually spared, and the rash tends to be more prominent on the extensor surfaces. Affected children at this point are afebrile and feel well. Adolescents and adult patients often complain of pruritus or arthralgias concurrent with the rash. The rash resolves spontaneously, but it typically may recur over the course of 1 to 3 weeks in response to a variety of environmental stimuli such as sunlight, heat, exercise, and stress.136

Lymphadenopathy is not a consistent feature but has been reported in association with E197and as sole manifestations of i n f e ~ t i o n . ' ~A~ mononucleosis-like .'~~ illness associated with confirmed B19 infections has occasionally been reported, but B19 does not typically cause a mono-like illness. Atypical rashes not recognizable as classic EI have also been associated with acute B19 infections; these include morbilliform, vesiculopustular, desquamative, petechial, and purpuric rashes.' Asymptomatic infection with B19 also occurs commonly in children and adults. In studies of large outbreaks, asymptomatic infection is reported in approximately 20% to 30% of serologically proven case^.^^'^^

Transient Aplastic Crisis Transient aplastic crisis was the first clinical illness to be definitively linked to infection with B19. An infectious origin had been suspected for this condition because it usually occurred only once in a given patient, had a well-defined course and duration of illness, and tended to occur in clusters within families and comrnunitie~.'~~ Attempts to link it to infection with any particular agent had repeatedly failed until 1981, when Pattison and colleagues6 reported six positive tests for B19 (seroconversion or antigenemia) among 600 admissions to a London hospital. All six were children with sickle cell anemia admitted with aplastic crisis. This association was confirmed by studies of an outbreak of aplastic crisis in the population with sickle cell disease in J a m a i ~ a . ~ In contrast to EI, patients with a transient aplastic crisis are ill at presentation with fever, malaise, and signs and symptoms of profound anemia (e.g., pallor, tachypnea, tachycardia). These patients rarely have a rash.1007140 The acute infection causes a transient arrest of erythropoiesis with a profound reticulocytopenia. Given the short half-life of these patients' red cells and their dependence on active erythropoiesis to counterbalance their increased red cell turnover, this leads to a sudden and potentially life-threatening decline in serum hemoglobin. Children with sickle hemoglobinopathies may also develop a concurrent vaso-occlusive pain crisis, which may further complicate the clinical picture. Although such transient aplastic crises are most commonly associated with sickle cell anemia, any patient with a condition of increased red cell turnover and accelerated erythropoiesis can experience a similar transient red cell aplasia with B19 infection. B19-induced aplastic crises have been described in many hematologic disorders, including other hemoglobinopathies (e.g., thalassemia, sickle-C hemoglobin); red cell membrane defects (e.g., hereditary spherocytosis, stomatocytosis); enzyme deficiencies (e.g., pyruvate kinase deficiency, glucose-6-phosphate dehydrogenase deficiency); antibody-mediated red cell destruction (e.g., autoimmune hemolytic anemia); and decreased red cell production (e.g., iron deficiency, blood ~ O S S ) .B19 ~ ~ is, 'not ~ ~ a significant cause of transient erythroblastopenia of childhood, another condition of transient red cell hypoplasia that usually occurs in younger, hematologically normal children and follows a more indolent course.47 Leukopenia and thrombocytopenia may occur during a transient aplastic crisis, but the incidence varies with the underlying condition. In a French study of 24 episodes of aplastic crisis (mostly in individuals with hereditary spherocytosis),35% to 40% of patients were leukopenic or thrombo-

Chapter 27 cytopenic, compared with 10% to 15% reported in a large U.S. study of mostly sickle cell These transient declines in leukocyte count or platelets follow a time course similar to that for reticulocytopenia, although they are not as severe and recovery occurs without clinical sequelae. The relative preservation of leukocyte and platelet counts in sickle cell anemia compared with other hereditary hemolytic anemias presumably is caused by the functional asplenia associated with sickle cell disease:' As observed in experimental infection in human volunteers, B19 infection in normal subjects does result in a fall in the reticulocyte count, but because of the normal red cell half-life, this is not clinically significant or noticeable. Various degrees of leukopenia and thrombocytopenia also occur after natural B 19 infection in hematologically normal patients." Some cases of idiopathic thrombocytopenic purpura (ITP) and cases of childhood neutropenia have been reported in association with acute B19 Aside from these few anecdotal reports, larger studies have not confirmed B19 as a common cause of ITP or chronic neutropenia in ~hildren.4~


875

but may be one of several viral triggers capable of initiating joint disease in genetically predisposed indi~idiua1s.l~~

Infection in the lmmunocompromised Host

Patients with impaired humoral immunity are at risk for developing chronic and recurrent infections with B 19. Persistent anemia, sometimes profound, with reticulocytopenia is the most common manifestation of such infections, which may also be accompanied by neutropenia, thrombocytopenia, or compete marrow suppression.Chronic infections with B19 occur in children with cancer who receive cytotoxic ~hemotherapy,'~~,'~~ children with congenital immunodeficiency states,'57children and adults with acquired immunodeficiency syndrome (AIDS),'58and transplant recipient^,'^^ and they may even occur in patients with more subtle defects in immunoglobulin production who are able to produce measurable antibodies to B19 but are unable to generate adequate neutralizing antibodies. 16' B 19 has also been linked to viral-associated hemophagomore generally referred to as cytic syndrome (VAHS),'55*'61 infection-associated hemophagocytic syndrome (IAHS). This condition of histiocytic infiltration of bone marrow and Arthropathy associated cytopenias usually occurs in immunocompromised Joint symptoms are reported by up to 80% of adolescents patients. B19 is only one of several viruses that have been and adults with B19 infection, whereas joint symptoms are implicated as causingVAHS. IAHS is considered a nonspecific uncommon in children. " J'Arthritis ' or arthralgia may response to a variety of viral and bacterial insults rather than occur in association with the symptoms of typical EI or a specific manifestation of a single pathogen. be the only manifestation of infection. Females are more Infections in the immunocompromised host can lead to frequently affected with joint symptoms than males.'0"02 chronic infection. This is most often manifested as chronic The joint symptoms of B19 infection usually manifest as anemia (i.e., red cell aplasia), but various degrees of cytopenia the sudden onset of a symmetric peripheral polyarthropathy.'44 have been described, ranging from thrombocytopenia or The joints most often affected are the hands, wrists, knees, neutropenia to complete bone marrow failure.14' Patients and ankles, but the larger joints can also be i n v ~ l v e d . ' ~ ~ ~with ' ~ ~ an inability to produce neutralizing antibodies are at The joint symptoms have a wide range of severity, from mild greatest risk, and this complication of B19 infection has been morning stiffness to frank arthritis with the classic combidescribed in children with congenital immunodeficiency synnation of erythema, warmth, tenderness, and swelling. Like dromes, patients on cytoreductive chemotherapy, transplant the rash of EI, the arthropathy has been presumed to be recipients on immunosuppressive therapy, and adults and immunologically mediated because the onset of joint sympchildren with AIDS.'40 toms occurs after the peak of viremia and coincides with the Increased recognition of B19 infection in solid-organ development of specific IgM and IgG antibodies?' Rheumatoid transplant recipients led to several reports.'62-164 Although factor may also be transiently positive, leading to some diagmost such infections are manifested as the typical persistent nostic confusion with rheumatoid arthritis (RA) in adult anemia, an association of B19 viremia with acute graft patients.'46Fortunately, there is no joint destruction, and in rejection has been de~cribed.'~~ most patients, joint symptoms resolve within 2 to 4 weeks. For some patients, joint discomfort may last for months or, in rare individuals, for years. The role of B19 in these more Other Dermatologic Syndromes chronic arthropathies is not clear. Vasculitis and Purpura The arthritis associated with B19 infection may persist A variety of atypical skin eruptions has been associated with long enough to satisfy clinical diagnostic criteria for RA or B19 infections. Most of these are petechial or purpuric in juvenile rheumatoid arthritis (JRA).85'93,'45n 147~148This has led nature, often with evidence of vasculitis in those that report some to suggest that B19 might be the etiologic agent of skin biopsy results, and the eruptions may resemble the rash these conditiom2 This speculation has been supported by of other connective tissue diseases.','" There are reports of the detection of B19 DNA in synovial tissue from patients confirmed acute B19 infections associated with nonwith RA and reports of increased seropositivity among thrombocytopenic purpura and vasculitis, including several patients with these c ~ n d i t i o n s . ~Lat ~ ~er~findings ~ ~ ~ ' ~of' DNA cases clinically diagnosed as Henoch-Schonlein p~rpura!~~'~' from other viruses in addition to B19 in synovial tissue from an acute leukocytoclastic vasculitis of unknown origin in patients with arthritis and the finding of B19 DNA in synochildren. Chronic B19 infection has also been associated with vium from persons without arthritis suggest that this may be necrotizing vasculitis, including cases of polyarteritis nodosa a nonspecific effect of inflarnmati~n.'~'"~~ A review of the and Wegener's granulomatosis.'68 These patients had no accumulated evidence on this topic has concluded that B19 underlying hematologic disorder and were generally not is unlikely to be a primary cause in these rheumatic diseases

876


and the possibility that the CSF PCR was positive because anemic at diagnosis. The pathogenesis is unknown, but these of contamination from blood could not be completely details may suggest an endothelial cell infection, as occurs excluded. with some other viruses such as rubella. Disorders of the peripheral nervous system have included Information from biopsy of rashes temporally associated brachial plexus neuropathy,18' extremity paresthesias and with B19 infection is limited, although several reports have dysesthesia~,'~~ myasthenia-like weakness,la4 and carpal appeared. B19 capsid antigens and DNA were found in a tunnel syndrome."' The onset of most of these peripheral skin biopsy from a patient with EI, and this observation lends support to a role for B19 in these vascular d i ~ o r d e r s . ' ~ ~nerve symptoms has been coincident with the onset of rash and or joint pain at a time when the patient should have a Rashes resembling those of systemic lupus erythematosus, brisk immune response, suggesting that the neurologic abnorHenoch-Schonlein purpura, and other connective tissue malities could be immunologically mediated? In the course disorders have been d e ~ c r i b e d . ' ~In . ' ~a~controlled study of of one well-described outbreak of EI among intensive care 27 children with Henoch-Schonlein purpura, B19 was not a nurses, numbness and tingling of the fingers were reported common cause.'" Only 3 of 27 children had detectable B19 by 54% of the 13 B19-infected nurses.'83 The neurologic IgM antibodies indicating a recent infection. The role of B19 in these conditions remains speculative. symptoms persisted for more than 1 year in three of the nurses, and one had low levels of B19 DNA in serum for Papular-Purpuric "Gloves and Socks Syndrome more than 3 years in association with recurrent episodes of Papular-purpuric "gloves and socks" syndrome (PPGSS) is a paresthesias. She was never anemic and had no demonstrable distinctive, self-limited dermatosis first described in the immunodeficiency.Ia6Although these cases are suggestive, dermatologic literature in 1990.'72The syndrome is characthe role of B19 in neurologic disease and CNS infection will terized by fever, pruritus, and painful edema and erythema remain unresolved until the pathogenesis of the viral localized to the distal extremities in a distinct glove and sock infection in these conditions can be distribution. The distal erythema is usually followed by petechiae, and oral lesions often develop. Resolution of all Renal Disease symptoms usually occurs in 1 to 2 weeks. A search for seroReports of renal disease after B19 infection, previously rare, logic evidence of viral infection led to the discovery of an have increased within the past few year^.'^^‘'^^ Most have association with acute B19 infection in many of these patients, been case reports of glomerulonephritis or focal glomerulobased on demonstration of specific IgM or seroconversion. sclerosis temporally related to an acute B19 infection. This association has been further confirmed with subsequent Immune complex deposition has been demonstrated in renal reports and demonstration of B19 DNA in skin biopsy tissue, and B19 DNA occasionally can be found in renal samples and sera from these patient^.""'^^ Initially described tissue by PCR.'" Renal failure is rarely reported. The virus is in adults, a number of children with this condition were not known to infect kidney cells in vitro, and its presence in subsequently de~cribed.'~~ There appears to be sufficient renal tissue may reflect filtration of the viremia of acute evidence to suggest that PPGSS is a rare but distinctive maniinfection. B19 DNA has been detected in urine in studies of festation of primary, acute infection with parvovirus B19, infants with evidence of intrauterine infections. B19 antigens occurring mainly in young adults but also affecting children. may trigger an immune complex-mediated nephritis, but this may be a nonspecific effect, and further study is necessary to Central Nervous System Infection and define the relationship between B19 infection and the potential Neurologic Disorders for renal disease. Although a variety of neurologic symptoms and disorders have been described in patients clinically diagnosed as having DIAGNOSIS: GENERAL APPROACH AND EI or laboratory-confirmed B19 infection: the issue of LABORATORY METHODS whether B19 causes central nervous system (CNS) infection or is etiologic for other neurologic conditions remains unThe diagnosis of EI is usually based on the clinical recogresolved. Cases of meningiti~,'~'*'~~ en~ephalitis,'~'and nition of the typical exanthem, a benign course, and exclusion en~ephalopathy'~'caused by B19 infection have been of similar conditions. Rarely is laboratory confirmation reported. Many of these cases were determined during outnecessary. A presumptive diagnosis of a B19-induced transient breaks of EI from older reports based on clinical diagnosis only, before reliable laboratory tests for B19 were available. aplastic crisis in a patient with known sickle cell disease (or In one study, headache was reported in as many as 32% of other condition associated with chronic hemolysis) is based on an acute febrile illness, a sudden and severe decline in the children with rash illne~s.'~' However, there are no controlled serum hemoglobin level, and an absolute reticulocytopenia. comparative studies to evaluate the frequency of signs or Likewise, a clinical diagnosis of PPGSS can be based on the symptoms suggestive of meningeal inflammation or CNS characteristic skin eruption in the distinct acral distribution. infection in B19 infection. Cerebrospinal fluid (CSF) abnorSpecific laboratory diagnosis depends on identification of malities such as pleocytosis and increased levels of CSF B19 antibodies, viral antigens, or viral DNA. In the immunoprotein have been reported in some patients with meningismus or altered level of consciousness associated logically normal patient, determination of anti-B19 IgM is with EL2 B19 DNA has been detected in CSF using PCR in the best marker of recent or acute infection on a single serum several cases of serologically confirmed acute B19 infection sample. IgM antibodies develop rapidly after infection and with meningoencephalitis or en~ephalopathy.'~~~''' However, are detectable for as long as 6 to 8 weeks.'92 Specific IgG most of these reported patients were also viremic at the time, antibodies become detectable a few days after I@¶ and It

Chapter 27 persist for years and probably for life. Seroconversion from an IgG-negative to IgG-positivestatus on paired sera confirms a recent infection. Anti-B19 IgG, however, primarily serves as a marker of past infection or immunity. Patients with EI or acute B 19 arthropathy are usually IgM positive, and a diagnosis usually can be made from a single serum sample. Patients with B19-induced aplastic crisis may present before antibodies are detectable; however, IgM will be detectable within 1 to 2 days of presentation, and IgG will follow within days.’O0 The availability of serologic assays for B19 had previously been limited by the lack of a reliable and renewable source of antigen for diagnostic studies. The development of recombinant cell lines that express B19 capsid proteins have provided more reliable sources of antigen suitable for use in commercial test kit^.'^^,'^^ Several commercial kits are available for detection of B19 antibodies, but they employ a variety of different antigens (e.g., recombinant capsid proteins, fusion proteins, synthetic peptides), and their performance in large studies has varied.’93Based on studies of the humoral immune response to the various B19 viral antigens, it appears to be important to have serologic assays based on intact capsids that provide conformational epitopes. Antibody responses to these antigens are more reliable and longer lasting than are responses to the linear epitopes used in some assays.’95Only one commercial assay based on such capsids has received Food and Drug Administration approval in the United States’96;other commercial assays for this purpose are considered research tests. Until serologic tests are more standardized and results more consistent, some knowledge of the assay and antigens used will be necessary for proper interpretation of B19 antibody test results. In immunocompromised or immunodeficient patients, serologic diagnosis is unreliable because humoral responses are impaired, and methods to detect viral particles or viral DNA are necessary to make the diagnosis of a B19 infection. Because the virus cannot be isolated on routine cell cultures, viral culture is not useful. Detection of viral DNA by DNA hybridization technique^'^^ or by PCR’983’99 is useful in these patients. Both techniques can be applied to a variety of clinical specimens, including serum, amniotic fluid, fresh tissues, bone marrow, and paraffin-embedded tissues.14 Histologic examination is also helpful in diagnosing B19 infection in certain situations. Examination of bone marrow aspirates in anemic patients typically reveals giant pronormoblasts or “lantern cells” against a background of general erythroid hypoplasia. However, the absence of such cells does not exclude B19 infection.2003201 Electron microscopy has proved useful and may reveal viral particles in serum of some infected patients and cord blood or tissues of hydropic infants (discussed later).

EPIDEMIOLOGY OF B19 INFECTIONS AND RISK OF ACQUISITION IN THE PREGNANT WOMAN

Prevalence and Incidence in the United States We have completed three studies” using complementary strategies to determine the incidence of human parvovirus B19 infection during pregnancy. First, using the data from a study of school personnel, we estimated the average B19


877

infection rate among pregnant school personnel. Of the 60 individuals who seroconverted during that study, 8 (13%) were pregnant. However, not all pregnant women in the school system participated in the study. Although we had data on the pregnancy rates for the female school personnel who participated, these volunteers may have been biased toward younger females, raising the possibility that their pregnancy rates may not have been representative of all school employees. Of approximately 11,637 total school employees in Richmond,Virginia, we enrolled 2730 (24%) in our study. To determine whether the sample enrolled was representative, we performed a random survey of 733 school employees at the schools studied. The results provided strong evidence that the seroprevalence and annual infection rates observed among study subjects were representative and applicable to the entire school employee population.” Assuming no seasonality to B19 infections (none was observed) and that pregnancy does not affect susceptibility, we predicted that without regard to risk factors, seronegative pregnant personnel have an average annual infection rate of 3%, for a rate of 2.25% per pregnancy.” Second, in Richmond from 1989 to 1991, we collected sera from 1650 pregnant women from a lower socioeconomic group who attended a high-risk pregnancy clinic for patients without medical insurance. This group was 80% African American, with an average maternal age of 24 years. We randomly selected a subset of 395 women for serotesting and monitoring, 35% of whom were seropositive. Of the 256 seronegative women, 2 (0.8%) seroconverted, for an annual rate of 1.7%. This rate was similar to the rate observed among low-risk and African American school personnel in Richmond.” We also obtained serial sera from a large number of private practice obstetric patients from Birmingham, Alabama.202 From this serum bank, we randomly selected 200 patients per year over 4 years (1987 to 1990). No significant differences were observed by year among the 800 patients (average age was 27 years and 88% were white), and 46% were seropositive overall. Of 413 seronegative women serially tested over the 4 years, 5 seroconverted. Overall, the annual seroconversion rate was 2%. Combining data from the studies of pregnant women done in Richmond and Birmingham, we observed that 7 of 669 seronegativewomen seroconvertedduring pregnancy, for a rate of 1% per pregnancy (95% CI, 0.3% to 21%).

Prevalence and Incidence in Other Countries In numerous studies conducted worldwide, for pregnant women and women of reproductive age, the seroprevalence of IgG antibodies to B19 has varied from 16% to 72%, with most estimates falling between 35% and 55%.69v74,753124 In Denmark, a serologic survey of 31,000 pregnant Danish women found 65% had evidence of past infection’”; the seroprevalenceof IgG antibody among 1610 pregnant women in Barcelona was 35.03%*03;81% of pregnant Swedish women had parvovirus a n t i b o d i e ~ and ; ~ ~in ~ ~Japan, ~ ~ the seroprevalence of IgG antibodies to B19 was 26% for women between the ages of 21 and 30, and 44% for women between the ages of 31 and 40?4 The prevalence of IgG antibodies to B19 in cord blood from normal newborns provides estimates of maternal immunity ranging from 50% to 75%.17%205p206

878

Section I11

Viral Infections

Without regard to maternal age or other potential risk factors, a South African study found that 64 (3.3%) of 1967 pregnant women acquired B19 infection during pregnancy, and another in Barcelona found that 60 (3.7%) of 1610 pregnant women became infected with B19 during pregnancy?0J03 Seroconversion rates among susceptible pregnant Danish women during endemic and epidemic periods were 1.5% and 13%, respectively. In Denmark, risk of infection increased with the number of children in the household and having children 6 to 7 years old resulted in the highest rate of seroconversion, and nursery school teachers had a threefold increased risk of acute infection.lOlExtrapolatingto a 40-week period places the infection rate during pregnancy among susceptiblewomen at approximately 1.1%,with a range of 1% to 4%, depending on risk factors. The Danish and Barcelona data are similar to those obtained in Richmond, Virginia.” A few studies have tried to estimate the infection rate based on the prevalence of IgM antibodies to B19 in pregnancy or in women of reproductive age. Although B19-specific IgM is an accurate diagnostic test for recent infection, it is a poor test for epidemiologic studies. B 19-specific IgM persists for only a few months and therefore underestimates the maternal infection rate because women who have had a B19 infection 6 to 9 months before testing are not detected. Another problem with IgM surveys is that most studies have surveyed high-risk populations such as women with rash illness, possible exposure to cases of EI, or recent diagnosis of adverse reproductive outcomes. Sampling high-risk populations biases the results toward rates higher than would be observed in population-based studies. A few studies used B19-specific IgM to test pregnant women or women of reproductive age who did not have risk factors. The observed range in these studies was 0% to 2.6%.’7*205,207 For susceptible women with B19-specific IgM in populations known to be at increased risk, the prevalence of IgM has ranged from 0% to 1 2 . 5 ~17,74,124,208,209 ~. In countries other than the United States, the prevalence of IgG antibodies to B19 among pregnant women and women of reproductive age varies widely and probably reflects exposure during prior epidemics. Studies of infections during pregnancy are fraught with potentially confounding variables such as IgM testing, which lacks sensitivity, and biases introduced by selection criteria for the population studied. Despite these problems, it is likely that the risk for B19 infection during pregnancy in other countries is similar to the risk observed in the United States.

CLINICAL MANIFESTATIONS OF B19 INFECTIONS IN THE PREGNANT WOMAN The symptoms reported by pregnant women with a proven recent B19 infection are usually vague and nonspecific, and serologic confirmation is essential to establish the diagnosis. The signs and symptoms of classic EI in children are significantly different in adults; the sunburned or slapped-cheek facial rash common in children rarely occurs in adults. Malaise is a common feature of B19 infection in children and in adults, but it is nonspecific. In pregnant women and adolescents, the most characteristic symptom is symmetrical arthralgias, occasionally with signs of arthritis and usually involving the small (distal) joints of hands, wrists, and feet.

The proportion of pregnant women with serologically proven B19 infection who are asymptomatic varies with the inclusion criteria in the few studies that address symptoms. In a cohort of 1610 pregnant women studied in Barcelona, the sera of 30 women had IgM antibodies to B19 at the first prenatal visit, and another 30 seroconverted during pregnancy.” Of these 60 women, only 18 (30%) reported any combination of fever, rash, and arthralgias, and 70% were asymptomatic. The investigators did not report when questions about symptoms were asked in relation to the serologic results, and no comment was made about the distribution of symptoms nor about which joints were affected by the arthralgias.20Similarly, during an epidemic of EI in Connecticut, fully 69% of nonpregnant adults with serologically proven B19 infection were asymptomatic. In this study, symptoms were assessed by mailed questionnaires after the women were provided their serologic result^.'^^"^^ In a British multicenter study, only 6 (3%) of 184 patients were asymptomatic,but the population was ascertained largely by recruiting women with typical symptoms, and this study therefore is not comparable to the others.” We studied 618 pregnant women in Pittsburgh with known exposure to someone with a rash illness highly suggestive of EI.’” Each exposed patient was questioned about symptoms before serologic testing. Only 33% of the 52 women with serologically proven B 19 infection reported no symptoms, and the remaining 67% reported rash, fever, arthralgias, coryza, or malaise, or some combination of these symptoms.*” Malaise, although a very vague and nonspecific findin was reported by 27 (52%) of the 52 infected women!” In contrast, only 5.5% of 307 exposed but not susceptible (IgGseropositive and IgM-seronegative) women reported this symptom. After malaise, symmetrical arthralgias were the second most common symptom reported. Of the 618 known exposures in pregnant women, 24 (46%) of the 52 infected pregnant women reported arthralgias, compared with 11 (3.6%) of 307 immune women and 12 (4.6%) of 259 susceptible but uninfected women (P < .0001).210Of the 24 women with arthralgias in this study, 23 also reported malaise, 16 had rash, 7 had coryza, and 7 had fever. Among the 24 IgM-positive women with arthralgias, the symmetrical joints most commonly affected by pain, swelling, and erythema were the knees (75%), followed by wrists (71%), fingers (63%), ankles (42%), feet (29%), elbows (29%), shoulders (17%), hips (13%), and back and neck (8%). Only 2 of the 24 had only one set of joints involved, and very few other women reported monarticular pain or swelling. In most women, the arthralgias were easily controlled by antiinflammatory drugs and lasted only 1 to 5 days. However, arthralgias occasionally lasted 10 to 14 days and, in some women, were so painful that they were incapacitated for 2 to 3 days. The high frequency of arthralgia in pregnant women with B 19 infection is consistent with reports that distal arthralgias and arthritis are the most frequent finding in adults with EI. The frequency of arthralgias among nonpregnant adults with proven B19 infection in the Torrington, Connecticut, epidemic was 24% (11 of 46 adults), compared with 12% (61 of 512 adults) in adults without B19 infection ( P < .05).’09In another Connecticut study, arthralgias occurred significantly more often (26%) in 19 adults with IgM antibodies to B19 than in 460 adults (7%) who lacked IgM antibodies to B19

Chapter 27

( P < .01).123Arthralgias were even more common during outbreaks in Ireland; they occurred in 79% of 47 recently infected women and men. Ninety-three percent of those with arthralgias reported that their knees were Rash is less frequent in pregnant women than in children with EI, and the rash in pregnant women is not characteristic. In one report of the Connecticut epidemic, rashes occurred in 6 (13%) of 46 infected adults, compared with 49 (10%) of 512 individuals who were uninfected. In another report, rashes occurred in 3 (16%) of 19 infected adults, compared with 33 (7%) of 460 uninfected individuals. This difference is not significant ( P = .16) and may represent random variation."' In contrast to the classic curtain lace rash in children, pregnant women (80%) often have a maculopapular rash that rarely involves the face and may even be urticaria1 or morbilliform. In adults, these rashes are rarely pruritic and usually resolve within 1 to 5 days. In the Pittsburgh series, coryza was reported by 23% of the 52 B19-infected pregnant women but was reported in only 6.8% of the 307 previously infected women and 5.8% of the 259 seronegative women?" This difference was significant (P < .0001), but the nonspecific nature of coryza in pregnant women means this symptom alone is not diagnostically helpful. In the Pittsburgh series, a temperature of 38.0"C or higher occurred in 19% of the 52 IgM B19-infected women, compared ( P < .0001) with 2.6% of 307 previously infected patients and 3.1% of 259 susceptible, noninfected patients.'" In 9 of 10 women with fever, at least one other symptom was present. No woman's temperature exceeded 38.9"C. In 16 uninfected women with fever, all had at least one other symptom, and they had temperatures up to 4O.O0C, suggesting that a temperature of more than 39.0" C in a pregnant woman indicates infections other than B19. In a London outbreak of B19 infection, 7 of 10 infected adults had a an elevated temperat~re."~In the Connecticut epidemic, fever was reported in 15% of the 46 infected individuals and in 16% of the 512 uninfected individual^.'^' Pregnant women with fever are likely to seek medical attention. Occasionally, pregnant women infected with B 19 develop rapidly increasing fundal height, preterm labor, or even preeclampsia. Such symptoms are nonspecific and rarely indicate B19 infection.


879

Fetal Death

B19 was first linked to fetal death in 1984.15As anticipated based on the epidemiology of B19 transmission, the percentage of fetal deaths attributable to B19 varies, probably depending on the frequency of B19 infections in the population being studied. Prospective studies report rates of intrauterine viral transInitial studies mission ranging from 25% to 50%.'8,216,217 indicated that the risk of an adverse fetal outcome after a recent maternal infection was less than 10% (probably much less) and greatest in the first 20 weeks of pregnancy.'44A large, prospective study in the United Kingdom identified 186 pregnant women with confirmed B19 infections during an epidemic and followed them to term." There were 30 (16%) fetal deaths, with as many as 17 (9%) estimated to be caused by B19 on the basis of DNA studies of a sample of the abortuses. Most of the fetal deaths occurred in the first 20 weeks, with an excess fetal loss occurring in the second trimester.'* The intrauterine transmission rate was estimated at 33% based on analysis of the abortuses, fetal IgM in cord blood, and persistence of B19 IgG at a 1-year follow-up assessment of the infants. A smaller study of 39 pregnancies complicated by maternal B19 infection and followed to term found two fetal deaths (fetal loss rate of 5%), one (3%) of which was attributable to B19 and occurred at 10 weeks' gestation.'I6 A prospective study conducted by the Centers for Disease Control and Prevention identified 187 pregnant women with B19 infection and compared their outcomes to 753 matched The overall fetal loss rate in the infected group was 5.9%, with 10 of 11 occurring before the 18th week of gestation, compared with a 3.5% fetal loss rate in the control group, suggesting a fetal loss rate of 2.5% attributable to B19 infection. In a prospective Spanish study during an endemic period, 1610 pregnant women were screened for B19 infection, and 60 (3.7%) were identified.20 There were five abortions among this group, but only one ( 1.7%) was caused by B 19 based on histologic and virologic analysis of fetal samples. The incidence of vertical transmission was estimated at 25% based on serologic evaluation of the infants at delivery and at 1 year of age. In a similar prospective study of an obstetric population, 1967 pregnant women were screened, and 64 (3.3%) identified as recently infected.203Among this group, no adverse effects were seen by serial ultrasound examinations, and no case of fetal INTRAUTERINE TRANSMISSION RATES, hydrops was identified; one abortion occurred, but the fetus CLINICAL MANIFESTATIONS, AND FETAL was not examined for evidence of B19 infection (maximal OUTCOMES fetal loss attributable = 1.6%). In a case-control study of 192 women with fetal deaths, with one half occurring before 20 weeks' gestation and one Primary maternal infection with B19 during gestation has half after, there was serologic evidence of acute B19 infection been associated with adverse outcomes such as nonimmune in 1% of both case and control groups." The prevalence of hydrops fetalis, intrauterine fetal death, asymptomatic IgG antibodies was similar. In this study, the percentage of neonatal infection, and normal delivery at term.14*15Initial fetal deaths attributed to B19 infection was unlikely to exceed reports of fetal hydrops related to maternal B19 infection 3% in cases not selected for parvovirus exposure. were anecdotal and retrospective, suggesting rates of adverse In another study, 5 (6.3%) of 80 women with spontaneous outcomes as high as 26% and generating concern that B19 may be more fetotropic than rubella or cytornegalo~irus.~'~~''~ abortions between 4 and 17 weeks' gestation had IgM antibodies to B19 compared with 2 (2%) of 100 controls, but Subsequent reports of normal births after documented this difference was not statistically significant.20' These maternal B19 infection made clear the need for better investigators studied the aborted fetuses of the five seroestimates of the rate of intrauterine transmission and the risk positive cases and found B19 DNA in only two. of adverse outcome^?'^^'^

880


In a prospective study of 39 pregnant women infected with B19 during a community-wide outbreak in Connecticut, there were two fetal deaths, and only one (3%) was attriAmong women followed butable to B19 prospectively and who acquired B19 infection during pregnancy, there was no evidence of fetal damage in 43 in Virginia and 52 in Pittsburgh, and one fetal loss among 56 pregnancies in women from Barcelona.20v2’.210 Two Chinese studies found fetal B19 infection frequently associated with fetal The first study in China found that of 116 spontaneously aborted fetuses tested for B19 DNA, 27.3% were positive for parvovirus B19, but only 4% ( 1 of 25) of nonaborted fetal tissues in the control group tested positive.’” This difference was significant. It was unknown when these samples were collected whether B19 was endemic or epidemic in the community. Similarly a second Chinese study examined 175 biopsy tissues from spontaneous abortions from 1994 to 1995 and found that 25% were positive for B19 DNA in the fetal ti~sues.2’~ A control group of 40 fetal tissues came from induced abortions, and only 2 (5%) were positive. This difference was not statistically significant but did support the observation that in China, B19 may be an important cause of fetal death, especially if B19 is epidemic in the community. In contrast to the Chinese studies, a study from the Netherlands of fetal and placenta tissue from 273 cases of first and second trimester fetal loss were tested for serologic or virologic evidence of B19 infection.220Of the 273 cases, 149 were from seronegative women, and the fetal deaths for these women were considered unrelated to B19 infection. In only two of the remaining 124 cases (0.7% of all 273 cases) did the mothers have IgM antibodies to B19 at the time of abortion. This study indicates that B19 infection was a rare cause of fetal loss during the first and second trimesters. No congenital anomalies were observed among the fetal tissues examined. A study of 1047 pregnant women in Kuwait obtained maternal blood samples in the first, second, and third trimesters and tested them for serologic evidence of the recent B19 Forty-seven percent of the mothers were seronegative, and among these, the incidence of seroconversion was 16.5%. Among the women who seroconverted to a B19-positive status, the rate of fetal loss was 5.4%. All the fetal deaths occurred in the first two trimesters, suggesting that fetal death after maternal B19 infection is common, particularly during the first and second trimesters. A report from Toledo, Ohio, describes five unexpected fetal deaths that occurred in the second trimester.”’ Only one of the fetuses was hydropic, but all five had viral inclusions in the liver, and all five women were seropositive for B 19. Third trimester fetal deaths have also been reported. A Swedish study of fetal deaths among 33,759 pregnancies found 93 cases of third-trimester fetal deaths, and of these, 7 (7.5%) had detectable B19 DNA in frozen placental tis~ue.’’~ None of the seven fetuses was hydropic. The investigators suggested B19 occasionally caused third-, second-, and firsttrimester fetal death. A study of 13 pregnant women who acquired B19 infection during pregnancy and in whom the time of acquisition was known was completed in Japan.224Nonimmune hydrops occurred in three fetuses whose mothers acquired B19 infection in the first half of pregnancy. Spontaneous abortion without hydrops and intrauterine growth retardation occurred in

two fetuses whose mothers also developed B19 infection

during the first half of pregnancy. The remaining eight fetuses, whose mothers acquired infection in the first or second half of pregnancy, were asymptomatic, although human parvovirus B19 DNA was detected in the immune serum of all of the infants. These results suggest that B19 transmission to the fetus is common and that death may occur in almost one half of the fetuses of infected mothers. A Swedish study of 92 pregnancies for which there was an unexpected fetal death occurring after 22 weeks’ gestation found B19 DNA in 13 (14%) of the 92 fetuses.225Only 2 of the 13 were hydropic. The Swedish study suggests that B19 can infect the fetus in the third trimester and result in fetal death or hydrops, or both. This observation was confirmed in a larger study from Sweden, in which 47 cases of fetal deaths occurring after 22 weeks’ gestation were identified and compared with 53 normal Seven of the 43 intrauterine fetal deaths were positive for parvovirus B19 DNA, whereas B19 DNA was not detected in any of the normal pregnancies. In summary, B19 is a likely cause of first-, second-, and third-trimester fetal death, and most infected infants are not hydropic. The estimates of fetal deaths attributable to B19 range from 0% to 27%, making it difficult to assess the precise increase in fetal mortality attributable to B19.

Asymptomatic Fetal Infection Although the published prospective studies of B19 infection in pregnancy have varied in their estimates of adverse fetal outcome and rates of vertical transmission, it is clear that most women infected during pregnancy deliver normalappearing infants at term. Some of these infants have asymptomatic infection^.^^' Results of a prospective study that combined serologic with virologic markers of infection suggest that the rate of intrauterine transmission is very high.” In this study, 43 pregnant women with a confirmed B19 infection were followed to delivery. The infants were tested at birth and at intervals throughout the first year of life for IgM and IgG to B19 and by PCR for viral DNA in serum, urine, or saliva. No fetal losses or cases of fetal hydrops were observed in this study, although the rate of intrauterine viral transmission was 51%.’l

Birth Defects There is circumstantial evidence that intrauterine B19 infection may occasionally cause birth defects. The first case was reported in 1987.’” A fetus aborted at 11 weeks’ gestation was described with striking ocular abnormalities, including microphthalmia, aphakia, and dysplastic changes of the cornea, sclera, and choroid of one eye and retinal folds and degeneration of the lens in the other eye.229,230 The mother had a history of a rash illness with arthropathy at 6 weeks that was serologically confirmed. There have been few additional reports of malformations or developmental abnormalities in aborted fetuses or liveborn infants after intrauterine infection, and most of these cases could not be unequivocally attributed to infection with ~19.231-238However, three live-born infants had severe CNS abnormalities after serologically confirmed maternal B19 infe~tion.’~~’’~~ Subsequent case reports have also identified

Chapter 27 CNS manifestations, including mild to moderate hydrocephalus with CNS scarring associated with fetal B19 infe~tion.’~’ These reports suggest possible long-term neurologic sequelae in surviving infants that may not be apparent at birth. There are no other data suggesting that B19 is an important cause of birth defects in live-born infants. In an uncontrolled study of 243 infants younger than 4 months with birth defects, none had IgM antibodies to B19 detected.’05 In a controlled study of 57 infants with structural abnormalities or stigmata of congenital infection, specific IgM was not detected in cord blood of any of the affected infants or of the matched normal newborn control^.'^ There are no data suggesting that structural defects are common in newborns after maternal B19 infection. During a large communitywide outbreak of EI, there was no increase in congenital malformations compared with the periods before and after the epidemi~.’~’In the British study of maternal infections during pregnancy, outcomes were available for 186 patients; anencephaly was reported in 1 of the 30 fatal cases but not attributed to B19 infection, and hypospadias was present in 2 of the 156 live-born infants.” No new anomalies or serious neurodevelopmental problems were detected in the 114 infants followed clinically for at least 1 year?” In another prospective, but uncontrolled study of 39 pregnancies with maternal B19 infection, hypospadias was reported in 1 of the 37 live-born infants, and no abnormalities were reported in the one fatal case for which tissues were available?16

Meconium lleus and Peritonitis Meconium ileus and peritonitis have been associated with maternal B19 infection in a few report~.’~’’’~~ Three infants with congenital anemia after maternal infection and intrauterine hydrops have been rep~rted.’~ All three had abnormalities identified on bone marrow examination and B19 DNA detected in bone marrow by PCR.

Fetal Hydrops Although parvovirus B19 infection in utero may cause nonimmune hydrops fetalis, it is one of many causes of this syndrome and probably accounts for only 10% to 15% of fetal hydrops cases.14oHydrops fetalis is rare, occurring in only 1 of 3000 births; and in 50% of cases, the cause is unknown. In a study of 50 fetuses, B19 DNA was detected by in situ hybridization in the tissues of 4 fetuses, but most cases were caused by chromosomal or cardiovascular abnormalitie~.’~~ In another study, B19 DNA was demonstrated in 4 of 42 cases of nonimmune hydrops fetalis.244 However, B 19 infection is frequently associated with nonimmune fetal hydrops during local epidemics of EI. Ten cases of B19-associated hydrops, representing 8% of all cases of nonimmune hydrops and 27% of anatomically normal cases of nonimmune hydrops, occurred over 17 years in a hospital series from England?32In a consecutive series of 72 patients with nonimmune hydrops from Germany, 3 (4.2%) had B19 infe~tion.2~’ In a series of 673 fetal and neonatal autopsies conducted over 6 years in Rhode Island, 32 (0.7%) cases of hydrops were identified, and 5 (16%) of these had histologic and laboratory evidence of B 19 infection.2463247 In the British study, 1 of the 156 live-born infants had been


881

diagnosed with intrauterine hydrops and recovered after intrauterine transfusion; and of the six fatal cases that were positive for B19 DNA, hydrops was identified in one of three fatal cases with laboratory confirmed intrauterine inf e c t i ~ n . ’ * Postmortem ’~~~ examination may not be able to identify hydrops in fetal death occurring in early pregnancy. In summary, published reports suggest that nonimmune hydrops is not a common manifestation of fetal infection with B19.

Fetal Outcome in Relation to Maternal Manifestations There are no data suggesting that the clinical manifestations of B19 infection in the mother influences the pregnancy outcome. There is evidence for an association between the B19-affected fetus and maternal hypertension. Pregnancyinduced hypertension, preeclampsia, and eclampsia have been reported for some women with B19-associated fetal hydrops, and there is a record of improvement with spontaneous resolution of hydrops in one case.16~232,245~260-262 Hypertension of pregnancy may be caused by poor fetoplacental perfusion, and there is an increased risk in pregnancies complicated by hydrops. It is unknown whether there is an increased frequency of hypertensive disorders among B19-infected women compared with uninfected women or whether more careful monitoring of B19-infected women to detect findings of preeclampsia would be useful in identifying women at increased risk of B19-associated fetal hydrops. Long-term outcomes of live-born infants infected in utero with B19 are discussed in the “Prognosis” section of this chapter.

PATHOGENESIS OF INFECTION IN THE FETUS Fetal Immune Responses to B19 When serologic and virologic markers of infection have been examined, fetal immune responses to B19 are ~ a r i a b l e ? ’ ~ ’ ~ ~ ~ ~ ~ B19-specific IgM in cord blood is a recognized marker of fetal infection, but sensitivity can be increased by adding other markers such as IgA, PCR positivity, and persistence of B19 IgG at 1 year of age.21*’44~252 Infants exposed to B19 earlier in gestation may be less likely to demonstrate a positive IgM response because of immaturity of the fetal immune system, whereas the IgM response of infants exposed late in gestation may be delayed because of interference by passively acquired maternal antibodies. In one study, only two of nine infected infants whose exposure occurred in the first 14 weeks of pregnancy were B19 IgM-positive at delivery, whereas all four infected infants exposed in the third trimester had B19-specific IgM in cord blood.*’ Serum IgA, like IgM, does not cross the placenta, and for some other congenital viral infections, such as rubella and human immunodeficiency virus (HIV), virus-specific IgA responses in cord blood has been used to provide evidence of intrauterine infection.253In the only study of B19 that examined this marker, B19 IgA in cord blood was associated with maternal infection with B19, and for a few infants, this was the only marker of intrauterine infection?’ The fetal immune response to B19 may be important for preventing B19-induced red cell aplasia in the fetus. This

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effect is suggested by the apparently decreased rates of fetal death after 20 weeks' gestation in concert with the detection of IgM specific to B19 as early as 18 weeks' gestation 254 and the neutralization of B19 virus in vitro by fetal serum collected at 21 weeks' ge~tation.2~~

Pathogenesis of B19 Hydrops Nonimmune hydrops is the best-characterized complication of fetal B19 infection. Several mechanisms have been proposed, and more than one may contribute.232Severe fetal anemia affects most cases. Hemoglobin levels below 2 g/dL are detected by cordocentesis of hydropic Hypoxic injury to tissues may result in increased capillary permeability. Severe anemia may also increase cardiac outFigure 27-3 Placenta from a case of B19-associated nonimmune put, as evidenced by increases in umbilical venous pressure, and subsequently result in high-output heart failure.259 hydrops shows fetal capillaries filled with erythroblasts, most with marginated chromatin and typical amphophilic intranuclear inclusions Alternatively, myocarditis may precipitate heart failure. (hematoxylin & eosin stain). Reduced fetal myocardial function as determined by echocardiography occurs in some cases of fetal h y d r o p ~ . ~ ~ ~ Regardless of the cause, congestive heart failure can increase capillary hydrostatic pressure. Decreased venous return caused by massive ascites or organomegaly may lead to further cardiac decompensation. Hepatic function may be compromised by the extreme levels of extramedullary hematopoiesis, and lysis of B19-infected erythrocytes in the liver may cause hemosiderin deposition, fibrosis, and esophageal v a r i ~ e s . Impaired ~ ~ ~ ~ ~ production ~' of albumin may lead to a decrease in colloid osmotic pressure with transfer of fluid to the extravascular compartment. Placental hydrops may further compromise oxygen delivery to the fetus. Considerable evidence demonstrates that non-red cells may be susceptible to B19 infection. Virus has been demonstrated in fetal myocytes, including myocardiocytes, along with inflammatory changes, and fetal myocarditis has occurred.'27*234,256 Histologic studies show vascular damage and perivascular infiltrates in some tissues. It is unknown whether this is caused by B19 infection in endothelial cells or Figure 2 7 4 Fetal liver from a case of B19-associated nonimmune a nonspecific effect related to hypoxic damage. hydrops shows extramedullary hematopoiesis, intranuclear inclusions in erythroblasts, and focal areas with hemosiderin and fibrosis (hematoxylin & eosin stain).

PATHOLOGY IN THE FETUS

Anatomic and Histologic Features The hallmarks of fetal infection with B19 are edema, anemia, and myocarditis, and these conditions are reflected in the pathologic finding at autopsy. Otherwise, reports of gross and histopathologic pathology postmortem reveal few features specific for intrauterine B19 infection.163232* 235*246*251,260-265 At postmortem examination, B 1!+infected fetuses are often described as pale with subcutaneous edema. Rashes typically are absent, but a blueberry muffin rash caused by extramedullary hematopoiesis in the skin may occur.266 Fetal anemia is common in fetal deaths due to B19, although not in all cases.234,237,250.251.257,258,263,267 Histologic findings suggesting B19 infection include erythroid hypoplasia and, occasionally,hyperplasia characteristic of recovery. Extramedullary hematopoiesis is common in many organs, especially the liver and spleen. Nucleated red cells with amphophilic intranuclear inclusions (Figs. 27-3 and 27-4) are highly suggestive of B19 infection. These nucleated red

cells are often found in the lumen of vessels and at sites of extramedullary hematopoie~is.'~~ When stained with hematoxylin and eosin stain, the nuclei have an irregular band of dark chromatin. The center of the nucleus is lighter and has a smooth texture. The specificity of intranuclear inclusions for fetal B19 infection is unknown, but it is probably high when associated with anemia and hydrops. Viral DNA or inclusions may also be seen in macrophages and myocytes. 127,256,268 PCR used for detecting B19 DNA is the best method to diagnosis B19 infection in a dead fetus. In one study, 6 of 34 cases of idiopathic nonimmune hydrops contained B 19 DNA in fetal or placental tissues, compared with no PCRpositive findings among 23 cases of hydrops that were n o n i n f e c t i o ~ s .Histologic ~~~ examination of these cases found no nucleated red cells with intranuclear inclusions.

Chapter 27

Placenta


883

of 30 matched controls. This difference was significant (P < .02). Other infections, including herpes simplex virus, cytomegalovirus,rubella, and toxoplasmosis, were excluded. Additional studies testing for B19 infection of congenital heart disease are appropriate.

B19 infection of the placenta probably precedes fetal infection. The placenta is usually abnormal when associated with fetal death due to B19. Grossly the placenta is often enlarged and edematous. Histologically, the placenta also contains nucleated red blood cells with typical intranuclear inclusions (see Fig. 27-4). Foci of red cell production also Other Organs occur in the placenta, as does vascular i n f l a m m a t i ~ n ? ~ ~ ' ~ ~ ~ ~ ~ ~ Numerous other anatomic abnormalities have been In one vasculitis of villous capillaries or stem arteries associated with B19 infection of the fetus. Their occurrences, occurred in 9 of 10 placentas. The tissues demonstrated however, are so infrequent that it is unlikely that they are swelling of endothelial cells, fragmentation of endothelial related to B19 infection. These associated abnormalities cell nuclei, and fibrin thrombi. B19 DNA occurs in endoinclude dystrophic calcification of the brain and adrenal thelial cells of patients with myocarditis and in patients with glands; anencephaly and ventriculomegaly; pulmonary cutaneous lesions but has not been sought in placental endohypoplasia; hypospadias; cleft lip; meconium peritonitis; thelial cells. The human placenta contains a B19 receptor, corneal opacification and an ioedema; and thymic abnorthe neutral glycosphingolipid (globoside), on the villous malities.16,18,127,23~-233, 235-239,264$81-283 trophoblast layer of the placenta, and the concentration of the globoside decreases with advancing pregnancy.270The highest concentration occurs in the first trimester, with diminished reactivity occurring in the second trimester. The DIAGNOSTIC EVALUATION AND presence of this globoside in the placenta provides a MANAGEMENT OF THE WOMAN AND mechanism by which the virus infects the placenta and fetus. FETUS EXPOSED TO OR INFECTED BY B19 It also may explain why there is a difference in fetal outcome DURING PREGNANCY associated with gestational age. Maternal infections in late pregnancy have a better prognosis than those occurring early Management of a pregnant woman exposed to B 19 requires in pregnancy. In addition to B19 receptors, there is a B19knowledge of the prevailing status of EI in the community, a induced inflammatory response in the placenta, characterized detailed history of the exposure, knowledge of characteristic by a significant number of CD3' T cells and the inflammatory symptoms and signs of maternal EI and B19 infection in the cytokine i n t e r l e ~ k i n - 2 . ~ ~ ~ fetus, appropriate laboratory tests needed to confirm maternal and fetal infection, knowledge of the methods for monitoring the fetus at risk for nonimmune hydrops, Heart knowledge of therapeutic approaches for treating the The anemia associated with B19 infection is caused by a hydropic fetus, and information about the prognosis of specificviral tropism for progenitor erythroid cells, specifically maternal and fetal infection and the expected outcomes for P antigen, which is found on these However, clinical the therapeutic intervention. and laboratory evidence suggests that B19 has a wider tropism than for e r y t h r ~ b l a s t s .Fetal ~ ~ ~ myocardial cells contain P antigen.273Direct infection of myocardial cells after fetal Prevalence of Erythema lnfectiosum B19 infection of extramedullary erythroid progenitor cells The community health or school health departments may has been demonstrated by in situ DNA hybridization or know ~ ~ ~ ' ~ ~ is~ ~also ~ ~ , ~ ~ ~ whether EI is epidemic in the community, increasing electron m i ~ r o s ~ o p y . ~B~19~ myocarditis the probability of primary infection in susceptible pregnant associated with acute lymphocytic infiltration. Case reports women. have described at least eight fetuses, five children, and four adults with myocarditis associated with a concurrent B 19 infection.274,276-278 History of Exposure B19 causes acute and chronic myocarditis in infants. Myocarditis and the cardiac enlargement found in some Pregnant women who are potentially exposed to someone B19-infected fetuses with hydrops suggest that B19 is with EI should be asked about the type of exposure, including In pathogenic for the myocar~~um~127~232-235~246~254~256~276~279 duration (brief or prolonged) and location (household or infected fetuses, the heart may be normal or symmetrically workplace, indoor or outdoor), and contact with respiratory enlarged, suggesting congestive heart failure. Pericardial secretions. Exposure to a child within the household effusions are common. Myocytes with intranuclear inclusions constitutes the highest risk. occur infrequently. Mononuclear cell infiltrates occur Did the contact have symptoms typical of EI, including a occasionally, and B19 DNA, not associated with cells, can be low-grade fever and a slapped-cheek rash that soon spread found in the lumen of large vessels. Focal areas with dystrophic to the trunk or limbs in a lacy pattern? Did the rash calcification or fibroelastosis have occurred as a response to disappear and then reappear when the child was warm from injury. exercise or bathing? Had the child been exposed to any One case-control study8' examined the relationship known source of EI, such as an outbreak in school, prebetween congenital heart disease and B19 infection. Five of school, a daycare center, a family gathering, a play group, 29 cases of congenital heart disease had parvovirus B19 DNA or church nursery? Was the child evaluated by a physician detected in cardiac tissue using PCR, compared with none familiar with viral exanthems?

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Clinical Features Suggesting B19 Infection in the Pregnant Woman The examiner should consider whether the mother's signs and symptoms are compatible with B19 infection in adults, including at least one or more of the following: malaise, arthralgia, rash, coryza, or fever higher than 38" C. Pregnant women with such symptoms, especially malaise with symmetrical arthralgias in the hands, wrists, knees, or feet, should be considered at high risk and tested for recent B19 infection. In Barcelona, however, Gratecos and colleagues" found that only 30% of 60 IgM-positive women recalled any such symptoms. Pregnant women without such systemic symptoms but with a rapidly enlarging uterus (i.e., fundal height exceeding dates by more than 3 cm), an elevated serum a-fetoprotein level, preterm labor, or decreased fetal movement should be asked about B 19 exposure. If ultrasonography reveals evidence of hydrops fetalis or the fetus has ascites, pleural or pericardial effusion, skin thickening, polyhydramnios, or placentomegaly, maternal B19 testing is appropriate.

Table 27-2 Infection to Death Interval (weeks) 1 10

13 4 4 4 9 7 8 1 3 6 10-19 5 (10)" (4) (11) (7) (4)

(3)

Laboratory Diagnosis in the Pregnant Woman With evidence of maternal B19 exposure or maternal disease, maternal serum should be tested for IgG and IgM antibodies to B19. If there is probable or possible exposure, the first serum sample should be drawn at least 10 days after the exposure. Because fetal morbidity is unlikely to occur within 2 weeks of exposure, immediate serologic testing is appropriate for a woman or fetus with symptoms or signs of B19 infection. An initial serum sample that is IgG positive but IgM negative indicates a previous maternal infection, and additional testing is unnecessary. The IgM assay is sensitive, with few false-negative reactions. An initial serum sample that is negative for IgM and IgG indicates no previous maternal infection, and B19 infection is not responsible for maternal symptoms and signs or for hydrops fetalis. If the IgM result is positive, a recent B19 infection is established regardless of the IgG titer. A concomitant negative IgG titer means an early B19 infection without time for IgG to be detectable. Detection of maternal viremia by PCR for B19 DNA is also diagnostic of B19 infection. Viremia may precede the development of IgM antibodies by 7 to 14 days and may persist for several months after a primary infection. With a positive maternal IgM result, the fetus must be examined for signs of hydrops fetalis by ultrasonography within 24 to 48 hours. If the gestational age is less than 18 weeks, the absence of hydrops may not be reassuring, because hydrops can appear later. Because several cases of severe hydrops fetalis spontaneously reverting to normal over 3 to 6 weeks have been reported, advice about pregnancy termination is d i f f i c ~ l t . ~ ~ ~ , ~ ~ ' , ~ ' ~

Fetal Monitoring For a fetal gestational age of more than 20 weeks, initial negative ultrasound results demand sonograms to be repeated weekly to detect hydrops. The number of weekly sonograms that should be performed is controversial. Rodis and associates233originally suggested continuing weekly scans for

(8)

Fetal Deaths from B19 Infection Gestational Age at Death (weeks)

Fetal Weight at Death (grams) 3810

NR 409 161 420 695 580 300 236 NR

NR NR NR NR Hydrops, 3320 Hydrops, 31 11 Hydrops fetalis Hydrops, 1495 Hydrops, 3550 Hydrops fetalis

Reference 15 298 16 16 299

300 300 301 286

302 302 302 303 303 289 290 291 158 158 303 140

aNumbers in parentheses refer to intervals between exposure or onset of symptoms and the diagnosis of hydrops fetalis. bNumbers in parentheses refer to gestational age at the time of diagnosis of hydrops fetalis. NR, not reported.

6 to 8 weeks after exposure, and they reported a fetal death as late as 23 weeks' gestation after maternal fever and arthralgias

in the first trimester.12' The interval between maternal B19 infection and fetal morbidity is uncertain. Based on this report, others recommended weekly sonograms for 14 weeks after maternal B19 infection.284This approach often appeals to pregnant women fearful about fetal death, but it is time consuming and expensive. The duration of monitoring for hydrops fetalis may be best determined by examination of the interval between maternal exposure or symptoms of B19 infection and the appearance of hydrops fetalis or fetal death. Table 27-2 summarizes reports with adequate information to evaluate the interval, which include 14 intervals between maternal B19 exposure or infection and fetal death and 7 intervals between maternal exposure or infection and the first diagnosis of hydrops fetalis. The intervals range from 1 to 19 weeks, with a median of 6 weeks. Seventeen (81%) of 21 cases developed between 3 and 11 weeks. Because 11 of the 21 cases developed between 4 and 8 weeks after maternal exposure or infection, this is the most common interval between infection and the detection of fetal hydrops. Based on these observations, weekly ultrasound monitoring of the fetus for 12 weeks after maternal exposure is optimal but cannot detect all delayed cases and may be expensive. Such frequent scanning may not be considered cost-effective because the incidence of hydrops after maternal B19 infection is low in many studies. In our study, none of the 52 fetuses born to B19-IgM-positive pregnant women developed hydrops fetalis; however, the 95% confidence interval based on our sample size ranged from 0% to 8.6% for the risk of hydrops fetalis.2'0Other studies using maternal symptoms as

Chapter 27 criteria for maternal B19 infection have suggested a 9% incidence of fetal death due to B19 in B19-IgM-positive women.I8 Serial maternal serum a-fetoprotein (MSAFP) measurements may monitor the fetus in B19-infected women.285One report found elevated MSAFP levels in five B19-IgM-positive pregnancies associated with fetal death, but no fetal deaths in 11 IgM-positive women with B19 infection but normal MSAFP values.286A fatal case of B19-associated fetal death, discovered because of an elevated MSAFP level at 16 weeks in a routine test in an asymptomatic woman, has been described.16In adding a seventh case of fetal death associated with elevated MSAFP levels in B19-IgM-positive women, Bernstein and C a p e l e ~ suggested s ~ ~ ~ using the MSAFP values to indicate a good fetal prognosis. A German study8’ found that neither MSAFP nor human gonadotropin levels were markers of B19-infected pregnancies, although both were frequently elevated when complications occurred. The study included 35 pregnant women with fetal complications associated with B19; significant elevations of MSAFP levels occurred in 13 of 35 women, and elevations of human gonadotropin concentrations occurred in 25 of 35. The investigators tested 137 sera from 65 pregnant women without acute parvovirus infection and no fetal complications. Of the 30 women without fetal complications, there were significant elevations of MSAFP levels in only 2 women, and elevations of human gonadotropin levels occurred in only 5 women. Neither protein was a marker for a poor pregnancy outcome early on, but levels were frequently elevated when complications developed. Despite these results, there is insufficient experience using MSAFP concentrations, and MSAFP measurements at any gestational age are relatively nonspecific indicators of fetal well-being. Electronic fetal monitoring is ineffective in detecting hydrops fetalis and predicting the outcome of pregnancy in B19-IgM-positive women. Contraction stress tests and “nonstress” tests are not accurate predictors of fetal well-being in cases of fetal anemia or hydrops fetalis. Similarly, fetal assessment with estriol measurements or other biochemical markers have no documented role in cases of hydrops fetalis. Because fetal sonograms are as readily available and provide rapid specific information about hydrops fetalis, ultrasound is the best method to monitor the fetus after maternal B19 infection.

Fetal Therapy If hydrops fetalis is detected before 18 weeks, there is no effective intervention. Other causes of hydrops, such as chromosomal disorders or anatomic abnormalities, should be assessed. If at 18 weeks‘ gestation the fetus is still viable as determined by ultrasound examination, consideration can be given to percutaneous umbilical blood sampling (PUBS), also called cordocentesis.At 18 weeks‘ gestation, the umbilical vein diameter is about 4 mm, which is the minimum size required for successful PUBS. Fetal blood should be obtained for the hematocrit, reticulocytecount, platelet count, leukocyte count, antiparvovirus B19 IgM, karyotype, and tests for B19 DNA by PCR. The hematocrit must be determined immediately, and if fetal anemia exists, intrauterine intravascular fetal transfusion is performed with the same needle puncture.


885

If the fetus is between 18 and 32 weeks’ gestation when hydrops fetalis is detected, fetal transfusion should be considered. Many successful cases of fetal transfusion for B19-induced hydrops fetalis have been reported, and some have long-term follow-up, but the success rate of the procedure remains unknown.288-294 Two or three separate transfusions are usually required before resolution of the fetal anemia and hydrops fetalis, increasing the 1% to 2% risk of each single PUBS procedure. Resolution of the hydrops usually occurs 3 to 6 weeks after the first transfusion. Although spontaneous resolution has been reported, it seems appropriate not to risk an uncertain outcome, because the longer the fetal transfusion is delayed, the less likely it is to be successful and the worse the potential harm to the fetus caused by continued fetal hypoxia.231,249,284,289-291 For fetuses of 32 weeks’ gestation or older when hydrops is discovered, immediate delivery with neonatal exchange transfusion, thoracentesis, and paracentesis as indicated usually is the safest management.

DIFFERENTIAL DIAGNOSIS Recalling that the hallmarks of fetal infection with B19 are anemia, hydrops, and myocarditis helps in compiling a differential diagnosis. For infants with anemia, the differential diagnosis includes all the known causes, including fetalmaternal transfusion, intracranial bleeding, blood group incompatibilities, congenital anemias such as DiamondBlackfan syndrome, nutritional deficiencies, and inborn metabolic errors. Fetal hydrops and fetal and placental edema may be associated with other congenital infections,particularly congenital syphilis, chromosomal abnormalities, immune hydrops associated with blood group incompatibilities, hypothyroidism, and heart or renal failure, or both.

PROGNOSIS Pregnant women can be reassured about the relatively low risk of fetal morbidity resulting from exposure to B19. About one half of women already are seropositive. The seronegative maternal B19 infection rate ranges from about 29% for exposures by the woman’s own children to about 10% to 18% for other exposures. The expected fetal morbidity and mortality risk is about 2% (1 of 50). The overall risk of fetal death varies from 0.3% ( Y2x Yl0 x 1/50 = 3/Iooo) to a mere 0.1% (1/2 x 1/10 x 1/50 = 1 / I ~ ~ ) . 2 1 0 Live-born infants infected in utero may die shortly after birth. Two infants born prematurely at 24 and 35 weeks’ gestation developed an illness characteristic of congenital viral infection, including placentomegaly, petechial rash, edema, hepatomegaly, anemia, thrombocytopenia, and respiratory insufficiency, and both died p~stnatally.’~~ Both infants had nuclear inclusions in erythroid precursor cells, and PCR confirmed the presence of parvoviral DNA in one of the infants. Data regarding the long-term outcomes of live-born children infected in utero or born of mothers infected during pregnancy are very limited. In one study, 113 pregnant women with B19 infection during pregnancy and a control

886


group of immune women were questioned about the health and development of their children when the median age of The incidence of the children was 4 years for both developmental delays in speech, language, information processing, and attention was similar between the study group and the controls (7.3% versus 7.5%). Two cases of cerebral palsy were found in the study group, compared with none in the controls. Although not statistically significant, this 2% incidence of cerebral palsy in the infected group is 10-fold higher than the reported national incidence.242 In a British study of 427 pregnant women with B19 infection and 367 of their surviving infants, 129 surviving infants were reassessed when 7 to 10 years old.296The followup included questionnaires to obstetricians and general practitioners about the outcome of pregnancy and health of surviving infants. Maternal infection was confirmed by B19-specific IgM assay or IgG seroconversion.An excess rate of fetal loss was confined to the first 20 weeks’ gestation and averaged 9%. There were seven cases of fetal hydrops with maternal infections between 9 and 20 weeks’ gestation. There were no abnormalities attributable to B19 infection found at birth in surviving infants. No late effects were observed when the children were 7 to 10 years old. This study concluded that approximately 1 in 10 women infected before 20 weeks‘ gestation would have a fetal loss due to B19, that the risk of an adverse outcome of pregnancy beyond this stage was unlikely, and that infected women could be reassured that the risk of congenital abnormality due to B19 is less than 1% and that long-term development would be normal. One study used IQ testing and standard neurodevelopmental tests to assess 20 children who had parvovirusinduced fetal hydrops and intrauterine transfusion of packed red cells?” Testing of the 20 children when they were between 13 months and 9 years old revealed that all of their results ranged within two standard deviations of a population norm. There was no significant developmental delay. This study concluded that children who survived successful intrauterine transfusion from B19 anemia and hydrops had a good neurodevelopmental prognosis.

PREVENTION General Measures Because B19 is usually endemic in most communities, what is appropriate management for pregnant women with daily contact with children? The prevalence of seropositivity (immunity) to B 19 among pregnant women varies according to geographic location, sex, age, and race. Assuming that on average 50% of pregnant women are immune; that during endemic periods, between 1% and 4% of susceptible women become infected during pregnancy; and that the rate of fetal death after maternal infection is 2%, the occupational risk of fetal death for a pregnant woman with unknown serologic status is between 1 in 1000 and 1 in 2500. These low rates do not justify intervention such as serologic testing for pregnant women, furloughing pregnant workers, or temporarily transferring pregnant seronegative employees to administrative or other positions without child contact. During epidemic periods in specific schools, when the infection rates may be 5- to 20-fold higher, serologic testing or temporary transfer

of pregnant employees may occasionally be appropriate, and some very anxious women may choose to leave the workplace. Given the low risk for individual pregnant women, seronegative women should not send their own children away, and schools and daycare centers cannot stop B19 outbreaks by excluding children with rash illnesses because B19 is transmissible before the rash appears. Whether B19 can be transmitted by breast-feeding is unknown.

Vaccine Development For most women, fetal B19 infections during pregnancy occur from exposure to school-aged children at home rather than from occupational exposure. Given the highly communicable and endemic nature of the infection, the broad spectrum of illness that B19 causes, and the large portion of population (30% to 50%) who are susceptible, an effective B19 vaccine, preferably administered in infancy, is appropriate, and at least one vaccine is being de~eloped.’~’This vaccine is composed of the major B19 capsid proteins VP1 and VP2 and administered with a squalene adjuvant, MF59. After testing in a limited number of subjects, the vaccine appears to be safe and induces neutralizing antibodies. Studies using volunteers challenged with wild-type B19 should be able to assess efficacy. A vaccine that induces sustained neutralizing antibody IgG levels to B19 should be effective given that prior immunity to B19 protects against reinfection. Acknowledgments We are grateful to Dr. James H. Harger for his years of collaboration and helpful assistance.

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Section I11

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Viral Infections

293. Soothill l? Intrauterine blood transfusion for non-immune hydrops fetalis due to parvovirus B19 infection. Lancet 356121,1990. 294. Sahakian V, Weiner CP, Naides SJ, et al. Intrauterine transfusion treatment of nonimmune hydrops fetalis secondary to human parvovirus B19 infection.Amer J Obstet Gynecol 164:1090, 1991. 295. Vogel H, Kornman M, Ledet SC, et al. Congenital parvovirus infection. Pediatr Pathol Lab Med 17903,1997. 296. Miller E, Fairley CK, &hen BJ, Seng C. Immediate and long term outcome of human parvovirus B19 infection in pregnancy. Br J Obstet Gynaecol 105:14, 1998. 297. Ballou WR, Reed JL, Noble W, et al. Safety and immunogenicity of a recombinant parvovirus B19 vaccine formulated with MF59C.1. J Infect Dis 187675,2003. 298. Bond PR, Caul EO, Usher I, et al. Intrauterine infection with human parvovirus. Letter. Lancet 1:448, 1986.

299. Woernle CH, Anderson LJ, Tattersall P, et al. Human parvovirus B19 infection during pregnancy. J Infect Dis 15617, 1987. 300. Maeda H, Shimokawa H, Satoh S, et al. Nonimmunologic hydrops fetalis resulting from intrauterine human parvovirus B19 infection: report of 2 cases. Obstet Gynecol71:482, 1988. 301. Samra JS, Obhrai MS, Constantine G. Parvovirus infection in pregnancy. Obstet Gynecol73:832,1989. 302. Mortimer PP, Cohen BJ, Buckley MM, et al. Human parvovirus and the fetus. Lancet 2:1012, 1985. 303. Weiner CP, Naides SJ. Fetal survival after human parvovirus B19 infection: spectrum of intrauterine response in a twin gestation. Am J Perinatol966, 1992.

Chapter 28 R UB E LLA Louis Z. Cooper

TheVirus

Charles A. Alford, Jr.

894

hlorphology 'ind Physical and Chemical Composition Classifiintion Antigen and Serologic Testing Growth in (:ell (:ulture Pathogenicity for Aniinals

Epidemiology 896 Transmission In Utero

898

Risk of Fetal Infection Risk of Congenital Defects

Natural History 900 Post na t.il 1t i fect ion (:ongenital Infection

Pathogenesis

904

t'ostnatd Infection Congenital Infection

Pathology

905

Post n.1 tal In fect ion Congenital Infection

Clinical Manifestations

906

I'ostn'ital Infection (:ongenital Infection

Laboratory Diagnosis

910

hlatertial Infection Congetii tnl Infect ion

Management Issues

912

Use of Immune Globulin Termination of Pregnancy Clinical hlanagement Chemotherapy Isolation

Prevention of Congenital Rubella 913 Rubella Vaccine and Immunization Strategies Outbre,ik Control 5urveill.ince Pi-obpects for the Future

The impact of rubella virus infection and the progress made toward controlling congenital rubella infection have been well chronicled.'" Rubella was first recognized in the mid18th century as a clinical entity by German researchers, who called it Rotheln. However, they considered it to be a modified form of measles or scarlet fever.' Manton" first described it as a separate disease in the English literature in 1815. In 1866,Veale" gave it a "short and euphonious" name, rubella. The disease was considered mild and self-limited. Rubella became a focus of major interest in 1941, only after Gregg, l 2 an Australian ophthalmologist, associated intrauterine acquisition of infection with production of

cataracts and heart disease. Although his findings were initially doubted, numerous reports of infants with congenital defects after maternal rubella infection soon appeared in the literature.' Subsequent investigations showed that the major defects associated with congenital rubella infection included congenital heart disease, cataracts, and deafness. Mental retardation and many defects involving almost every organ have also been r e p ~ r t e d . ~ - ~Before ~ ~ ~ 'the ~ * availability '~ of specificviral diagnostic studies, the frequency of fetal damage after maternal infection in the first trimester was estimated to be in excess of 20%, a figure now known to be much too low. Recognition of the teratogenic potential of rubella infection led to increased efforts to isolate the etiologic agent. The viral cause of rubella was suggested by experimental infections in humans and monkeys as early as 1938 but was not confirmed until reports of the isolation of the viral agent in cell cultures were made independently in 1962 by Weller and Neva at Harvard University School of Public Health and by Parkman, Buescher, and Artenstein at Walter Reed Army Institute for Re~earch.'~-~' This accomplishment paved the way for the development of serologic tests and a v a c ~ i n e . ~ - ~ , ~ ' ' ~ ~ Efforts to develop a vaccine were hastened by the tragic events associated with a worldwide rubella pandemic from 1962 through 1964, which in the United States resulted in approximately 12.5 million cases of clinically acquired rubella, 11,000 fetal deaths, and 20,000 infants born with defects collectively referred to as the congenital rubella syndrome; 2100 infants with congenital rubella syndrome died in the neonatal period.24The estimated cost to the U.S. economy was approximately $2 billion. Routine use of rubella vaccine, in a two-dose schedule as measles-mumps-rubella vaccine (MMR) has not prevented importation-related infection, but it has eliminated indigenous rubella in the United States (personal communication from the CDC, 2004). However, congenital rubella syndrome remains a problem in many countries, with current estimates of 100,000 new cases ann~ally.2~ In 1969, three strains of live-attenuated rubella vaccine were licensed in various countries: HPV-77 (high-passage virus, 77 times), grown in duck embryo for five passages (DE-5) or dog kidney for 12 passages (DK-12); Cendehill, grown in primary rabbit cells; and RA 27/3 (rubella abortus, 27th specimen, third explant), grown in human diploid fibroblast culture.26-28Although these and other strains of vaccine are now used globally, the RA 2713 vaccine has been used exclusively in the United States since 1979.2-437329 In addition to providing the impetus for vaccine research and development, the rubella pandemic provided the scientific community with a unique opportunity to gain knowledge about the nature of intrauterine and extrauterine infections and the immunity stimulated by both. The quest for more knowledge using the tools of molecular biology has

894

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to 18 weeks' gestation is small. Sensitive laboratory assays continued since vaccine licensure and serves as a tribute to have shown that subclinical reinfection after previous natural Gregg's historic contribution to our understandmg of intrainfection, as after vaccination, may be accompanied by an uterine infection. IgM response, making differentiation between subclinical Much interest has focused on the epidemiology of rubella reinfection and asymptomatic primary infection at times and congenital rubella syndrome in countries with immunidifficult.4I ,51353.55 IgG avidity testing may be helpful also in zation programs, the desirability of introducing vaccine in this situation. Although reinfection usually poses no threat countries without a program, and the optimal strategy to to the fetus, rare instances of congenital infection after control congenital rubella (i.e., universal immunization versus 61'-' maternal reinfection have been reported.41,43*45,47'51-53,55*1 selective immunization of females).3s5-7'30-35 Vaccination of Follow-up of patients with congenital rubella has provided all children and of susceptible adolescents and young adults, information about the pathogenesis, immune status, interplay particularly females, has had such a dramatic impact on the between congenital infection, and human leukocyte antigen occurrence of rubella and congenital rubella in the United (HLA) haplotypes and the long-term outcome associated States that efforts are now in progress to eliminate congenital rubella syndrome from the United state^.^"^^^'"^ Given the with congenital i n f e ~ t i o n . " ~ -These ' ~ ~ studies have documented that congenital infection is persistent, that virtually magnitude of international travel, this goal will remain every organ may be affected, and that autoimmunity and elusive until similar goals are adopted by other countries. immune complex formation are probably involved in many The Pan American Health Organization (PAHO) has of the disease processes, particularly in the delayed and adopted a resolution calling on all countries of the Western persistent clinical manifestations. They also confirm earlier Hemisphere to eliminate rubella by 20 However, among studies, noting an increased risk of diabetes mellitus and developing countries, rubella immunization has not yet been given priority. other endocrinopathies in patients with congenital rubella Duration and quality of vaccine-induced syndrome compared with rates for the general population. and adverse events associated with immunization, particularly arthritis and the risk of the vaccine to the f e t ~ ~ have , ~ , ~ ~ ~ ~ - ~ ~ been a concern, but the vaccine continues to confer longTHE VIRUS lasting immunity while placing the vaccinated person at minimal risk of adverse events. Success in eliminating indiMorphology and Physical and Chemical genous disease in the United States and the absence of Composition teratogenicity observed after massive immunization programs (2001-2002) in Latin America offer considerable assurance Rubella virus is a generally spherical particle, 50 to 70 nm in about the long-term efficacy and safety of rubella vaccine. In diameter, with a dense central nucleoid measuring 30 nm in Brazil, where 28 million women were immunized in mass diameter. The central nucleoid is surrounded by a 10-nmcampaigns, and in Costa Rica, more than 2400 susceptible thick, single-layered envelope acquired during budding of pregnant women were immunized. Although infants were the virus into cytoplasmic vesicles or through the plasma infected, none had evidence of congenital rubella syndrome. membrane.'35-'49Surface projections or spikes with knobbed Research on the characteristics of the rubella virus, its ends that are 5 to 6 nm long have been reported. The specific effect on the developing fetus, the host's immune response, gravity of the complete viral particle is 1.184 f 0.004 g/mL, and diagnostic methodology has yielded new information corresponding to a sedimentation constant of 360 f 50 about the structural proteins of the virus and about the Svedberg units.'35 difference in the immune response to these proteins after The wild-type virus contains infectious RNA (molecular congenital and acquired infections.66-86Differences in antiweight of 3 to 4 x lo6) within its core.'2oThe rubella virus body profile may be useful in diagnosing congenital infection envelope contains lipids that differ quantitatively from those retrospectively and may provide further information on the of the plasma membrane and are essential for infecti~ity.'~~"~~ pathogenesis of congenital i n f e ~ t i o n . " ~ ~Techniques ~~~' that Rubella virus is heat labile and has a half-life of 1 hour at detect rubella-specific antibodies within minutes have been 57" C.15' However, in the presence of protein (e.g., 2% serum developed by using latex agglutination and passive hemagglualbumin), infectivity is maintained for a week or more at t i n a t i ~ n . ~Studies ' - ~ ~ to examine the subclass distribution of 4" C and indefinitely at -60" C. Storage at freezer temperatures immunoglobulin G (IgG) and the kinetics of rubella-specific of -10" C to -20" C should be avoided because infectivity is immunoglobulins (including IgA, I@, and IgE) after acquired rapidly l o ~ t . ' ~ ' Rubella , ' ~ ~ virus can also be stabilized against rubella, congenital infection, and vaccination may eventually heat inactivation by the addition of magnesium sulfate to lead to the development of additional diagnostic tools.95-99 virus suspension^.'^^ Specimens to be examined virologically In particular, rubella IgG avidity testing can be helpful should be transported to distant laboratories packed in ice in distinguishing between recently acquired and remote rather than frozen, with the addition of stabilizer if possible. infection.Io0-lo2 Infectivity is rapidly lost at pH levels below 6.8 or above 8.1 Improved laboratory methods defined the risk of fetal and exhausted in the presence of ultraviolet light, lipidinfection and congenital damage in all stages of pregactive solvents, or other chemicals such as formalin, ethylene nancy.'03-''0 The risk of fetal infection after first-trimester oxide, and P-propiolact~ne.'~~*'~~-'~~ Infectivity of rubella in maternal infection and subsequent congenital anomalies cell culture is inhibited by amantadine, but the drug appears after fetal infection may be higher than previously reported to have no therapeutic effe~t.'~'-'~' (81% and 85%, respectively, in one study).lo5The fetus may Several laboratories have described the structural proteins be at risk of infection throughout pregnancy, even near term, of rubella virus and determined the nucleotide sequence of although the occurrence of defects after infection beyond 16 the genes coding for these Originally,

Chapter 28

Rubella

895

three structural proteins were identified and designated as Antigen and Serologic Testing VP-l,VP-2, andVP-3.'62These three major structural proteins now are designated El, E2, and C, with relative molecular Purified rubella virus has a number of antigenic components weights of 58,000,42,000 to 47,000, and 33,000, re~pectively.~~-~~ associated with the viral envelope and the ribonucleoprotein El and E2 are envelope glycoproteins and make up the core.157s163 These antigens and the ability of specific antiserum to neutralize virus form the basis for the wide variety of characteristic spikelike projections that are located on the serologic methods available to measure humoral immunity viral membrane. Structural protein C, which is not glycosylated, is associated with the infectious 40s genomic RNA to after natural and vaccine-induced infection. form the nucleocapsid?' The E2 glycopeptide has been shown The ability of antibodies to inhibit agglutination of on polyacrylamide gels to be heterogeneous with two bands, erythrocytes by the surface hemagglutinin (HA antigen) which are designated E2a (relative molecular weight of forms the basis for the HI test, which at one time was the 42,000) and E2b (relative molecular weight of 47,000).67 most popular rubella serologic test. The HA antigen was originally prepared from BHK tissue culture fluids and then Monoclonal antibody studies have begun to delineate the functional activities of these structural proteins. E l appears from alkaline extracts of infected BHK-21 cells.23~178 This antigen can agglutinate a variety of red blood cells, including to be the viral hemagglutinin and binds hemagglutinationinhibiting and hemolysis-inhibiting antibody; E2 does not newborn chick, adult goose, pigeon, and human group 0 erythrocyte^.'^^ Rubella hemagglutinin is unique in its Monoappear to be involved in hemaggl~tination.6~,~~~~'>~~-~~ dependency on calcium ions to attach to red blood cell clonal antibodies specific for El and E2 have neutralizing r e ~ e p t o r s . ' ~ ~After ~ ' ~ 'extraction from infected cells, rubella a ~ t i v i t y . ~ , ~Studies ' , ~ ~ , also ~ ~ 'indicate ~~ that there are multiple hemagglutinin is stable for months at -20" C, several weeks epitopes on the structural proteins that are involved in hemagglutination inhibition (HI) and neutralizing a ~ t i v i t i e s . ~ ~ 'at~ ~4OC, and overnight at 37°C but is destroyed within minutes after heating to 56" C.'78,'80The HA antigen can be Molecular analyses of rubella viruses isolated during the period of 1961 to 1997 from specimens obtained in North protected from ether inactivation by pretreatment with Tween America, Europe, and Asia have documented the remarkable 80. Cells and serum contain heat-stable beta-lipoproteins that can inhibit rubella hemagglutination and give rise to antigenic stability of the E l envelope glycoprotein.8' E l amino false-positive result^.*^,'^^ Although it has been reported that acid sequences have differed by no more than 3%, indicating nonspecific inhibitors do not interfere in the HI test if the no major antigenic variation over the 36-year period that HA antigen and erythrocytes are mixed before addition of spanned the major worldwide pandemic of 1962 to 1964 and serum, the recommended method is to pretreat the sera to the 30 years since introduction of rubella vaccine. However, remove these inhibitors.'57B181 Earlier test procedures used two genotypes were evident: genotype I isolated before 1970 kaolin adsorption for removal of these nonspecific inhibitors; grouped into a single diffuse clade, indicating intercontinental however, a number of faster and more specific methods are circulation, whereas most of the post-1975 viruses segregated now used, such as treatment with heparin-MnC1, or dextran into geographic clades from each continent, indicating evolusulfate-CaC1. 182*183 tion in response to vaccination programs. The availability of Cell-associated complement fixation antigen was first molecular analysis and the minor variations in amino acid derived from infected rabbit kidney (RK-13) and African sequences have provided an additional tool for monitoring green monkey kidney cell cultures and later prepared from the sources of infection in areas where indigenous rubella alkaline extracts of infected BHK-21 cell^?^,"^ There are two has been greatly reduced by high levels of immunization. As complement fixation antigens-ne is similar in size and discussed in more detail later, the complexity of the antigenic weight to the hemagglutinin and infectious virus, and the nature of the rubella virion affects the ability of the host to other is smaller and " s o l ~ b l e . " ' ~The ~ ~ 'antibody ~~ response respond to the full complement of antigens and affects the as measured by the soluble antigen develops more slowly than various antibody assays required to detect all the corresthat to the larger antigen, which parallels the HI response. In ponding antibody responses (see "Natural History"). contrast to the HA antigen, complement fixation antigens do not lose their antigenicity after either treatment.184"86 Classification A variety of precipitin antigens have been serologically demonstrated; two of these, the theta and iota antigens, are Rubella has been classified as a member of the togavirus associated with the viral envelope and core, re~pectively.'~~~'~' family (from the Latin word toga, meaning "cloak"), genus The antibody response to these two antigens is of interest. R ~ b i v i r u s . ' ~No ~ ~ serologic '~~ relationship exists between Antibodies to the theta antigen rise promptly and persist. rubella and other known viruses. Minor biologic differences Antibodies to the iota antigen are detectable later and for a identified in different passaged strains of rubella virus are shorter time.'" The RA 27/3 vaccine appears to be unique not reflected in the antigenic differences assessed by comamong vaccine strains in its ability to elicit a response to the paring protein composition or serologic reaction^.'^^"^^"^^''^^ iota antigen, making its immune response more like natural Differencesin the immune response after immunization with infection. The significance of this observation remains the various vaccines now in use are not caused by inherent ~nclear."~ differences in the viral strain but rather by modification of Rubella virus antigen-antibody complexes (involving the the viruses during their attenuation in cell ~ulture.2~ The envelope and the core antigens) cause aggregation of reported variation in the virulence of rubella epidemics does platelet^.'^^"^^ However, the main platelet aggregation activity not appear to be explained by the molecular analysesdescribed appears to reside with the viral envelope. earlier, but it may result from differences in population Antibody directed against the rubella virus can also be susceptibility and underreporting of cases of congenital measured by virus neutralization in tissue

896


Whereas the presence of neutralizing antibodies correlates best with protective immunity, neutralization assays are time consuming, expensive, and relatively difficult to perform. Laboratories have traditionally performed the complement fixation and HI tests. Because the complement fixation test is insensitive for screening purposes and cannot detect an early rise in antibody in acute acquired infection, the HI test has been the most widely used assay~-4~157~191~195.198,199 However, a number of more rapid, easily performed, reliable, and sensitive tests have replaced the HI test for routine use.88~199~200 These include passive (or indirect) hemagglutination; single radial hemolysis (also known as hemolysis in gel), which is used widely abroad; radioimmunoassay; immunofluorescence; and enzyme immunoassay tests, also referred to as enzyme-linked immunosorbent assays. 195,198-229 Rapid latex agglutination and passive hemagglutination assays can provide results in minutes for screening and diagnostic purpose^.^^-^^ The large number of assays now available and their greater sensitivity compared with the HI test have led to some confusion about the level of antibody that should be considered indicative of immunity (see "Update on Vaccine characteristic^").^*^^,^^^^^^*^^^ However, the HI test still remains the reference test against which other assays are compared. Immunoglobulin class-specific antibody can be measured in most of the serologic systems.157,206-210.213.215,224-227,230-238 This most frequently involves detection of IgM in whole or fractionated sera. A number of techniques are used to fractionate and then test the serum. An important consideration in any IgM assay is the possibility of false-positive results because of the presence of rheumatoid factor. Solidphase IgM capture assays, however, appear to be unaffected by rheumatoid factor.99-'023210,225,236

Growth in Cell Culture Rubella replicates in a wide variety of cell culture systems, primary cell strains and cell lines. 153~157239The time required for virus recovery varies markedly, depending in part on the culture system being employed. As a generalization,rubella growing in primary cell cultures (i.e., human, simian, bovine, rabbit, canine, or duck) produces interference to superinfection by a wide variety of viruses (especiallyenteroviruses,but also myxoviruses, papovaviruses, arboviruses, and to some extent, herpesviruses) but no cytopathic e f f e ~ t . ' ~In' ~contrast, ~ ~ ' ~ ~a cytopathic effect of widely varying natures results from infection of continuous cell lines (i.e., hamster, rabbit, simian, and human). Generally, primary cells, especially African green monkey kidney, have proved superior for isolation of virus from human material by the interference technique. However, the continuous RK-13 and Vero (vervet kidney) cell lines are also used because cytopathic effect is produced and there is no problem with adventitious simian agents.153Continuous cell lines, such as BHK-21 and Vero, are best suited for antigen production because of the higher levels of virus produced. All cell lines support chronic infection with serial propagation, but some are limited by the occurrence of cytopathic effect. These cells grow slowly and can be subcultivated fewer times than when not infected.153 The mechanisms of rubella-induced interference and persistent infection in cell cultures are not completely understood. Although interferon

production has been described after rubella infection of cell cultures, interference appears to be an intrinsic phenomenon. 153.1 57,240-242 As with other viruses, generation of defective interfering particles can be found in tissue culture.243However, these particles are thought to be nonessential for persistence. Rubella virus can be plaqued in RK-13,BHK-21, SIRC (i.e., rabbit cornea), and Vero cells.157Plaquing forms the basis of neutralization assays, and differences in plaquing characteristics can be used as markers to differentiate strains.21,157,169,195-197

Pathogenicity for Animals Rubella virus grows in primates and in various small laboratory animals. However, in no animal has the acquired or congenital disease been completely reproduced. Vervet and particularly rhesus monkeys are susceptible to infection by the intranasal, intravenous, or intramuscular r o ~ t e s . Although ~ ~ - ~ ~ no ~ rash develops, there is nasopharyngeal excretion of viruses in all of the inoculated monkeys and demonstrable viremia in 50%. Attempts to produce transplacental infection in pregnant monkeys have been partially successful. Rubella virus has been recovered from the amnion and the placenta, but the embryo itself has not been shown to be consistently i n f e ~ t e d . ~ ~ ~ ? ~ ~ ' The ferret is by far the most useful of the small laboratory animals in rubella studies. Ferret kits are highly sensitive to subcutaneous and particularly to intracerebral inoculations. Virus has been recovered from the heart, liver, spleen, lung, brain, eye, blood, and urine for a month or longer after inoculation, and neutralizing and complement fixation antibodies have developed.249Ferret kits inoculated at birth develop corneal clouding. Virus appears in fetal ferrets after inoculation of pregnant animals.250 Rabbits, hamsters, guinea pigs, rats, and suckling mice have all been infected with rubella virus, but none has proved to be a consistent and reliable animal model system for study of rubella i n f e c t i ~ n . ' ~ ~Studies " ~ ' ~indicating ~ ~ ' ~ ~ ~that Japanese strains of rubella virus were less teratogenic to offspring of infected rabbits than U.S. strains have not been ~onfirrned.'"~~~~ These experiments were conducted to examine further the hypothesis referred to earlier that there is a difference in the virulence among rubella virus strains circulating in Japan and other parts of the wor1d.'68~170-174,176

EPIDEMIOLOGY Humans are the only known host for rubella virus. Continuous cycling in humans is the only apparent means for the virus to be maintained in nature. Because rubella is predominantly a self-limited infection seen in late winter and spring, questions have arisen about how the virus persists throughout the remainder of the year. Person-to-person transmission probably occurs at very low levels in the general population throughout summer and winter and probably at much higher levels in closed populations of susceptible individual^.^^^-^^^ Congenitally infected infants can shed virus from multiple sites and can serve as reservoirs of virus during periods of low transmi~sion.'~~,~~~-~~~ This is of particular concern in the hospital ~ e t t i n g . ' Efficiency ~ ~ , ~ ~ ~ of

Chapter 28

Rubella

897

transmission may also vary among individuals, with some In childhood, the most common time of infection, 50% being better “spreaders”than others. This phenomenon may or more of serologically confirmed infections result in incontribute to continued circulation of the apparent illness. The ratio may rise as high as 6:l or 7:l in Rubella remains worldwide in distrib~tion?~.~~’ The virus adults, perhaps as a result of silent reinfection in naturally circulates almost continually, at least in continental popuimmune individuals who have lost detectable antibody.260~2y6 lations. In the Northern Hemisphere’s continental temperate The frequent occurrence of infections that clinically mimic zones, rubella is consistently more prevalent in the spring, rubella makes it even more difficult to determine attack rates with peak attack rates in March, April, and May; infection is in open populations.299Attack rates undoubtedly depend on much less prevalent during the remainder of the year, inthe number of susceptible individuals, which varies widely creasing or decreasing during the 2 months before or after in different locations. Before widespread rubella immunization, the peak Serologic assessments of rubella attack rates have been sizable epidemics occurred every 6 to 9 years in most of the performed in closed populations, such as military recruits, world, with major ones occurring at intervals ranging from isolated island groups with small populations, boarding 10 to 30 years. Epidemics usually built up and receded home residents, and household members.260-262~283~295~298~29y~3’ gradually over a 3- to 4-year interval, peaking at the midIn such situations, individual exposure to the virus is point .9,284,287,289 The apparent increased infectivity and more intense than that encountered in open populations. virulence of rubella as exemplified in the major epidemics Under these circumstances, 90% to 100% of children and adults who are susceptible may become infected. have been the subject of considerable speculation.One popular thesis has been the unproven emergence of a more virulent Attack rates in susceptible persons on college and strain of virus at widely separated interval^.'^^"^'-'^^''^^ HOW- university campuses and in other community settings range from 50% to 90%.9,291Like primary infection, reinfection ever, no convincing evidence exists concerning clinically probably is increased as exposure becomes more different strains of rubella, and molecular analysis of the E l intense.260,296,304.305 envelope glycoprotein does not support the hypothesis of an epidemic versus endemic strain difference?’ The apparent In most of the world, including the United States before severity of the epidemic appears to be related to the number the introduction of mass immunization of children in 1969, of susceptible adults, especially pregnant women, in any rubella was typically a childhood disease that was most given population at the outset of an e p i d e m i ~ . ” ’ ~ ~ , ~ ~ ~prevalent ~ ~ ’ ’ in the 5- to 14-year-old age g r o ~ p . ~It was , ~ ~ ~ ~ ~ ~ rare in infants younger than 1 year of age. The incidence Host factors, such as the differences in the ability to transmit for the first 4 years, rose steeply between 5 rubella, and still unknown factors may also be i n v ~ l v e d . ~ increased ~ ~ ~ ~ ~slowly ~ Attack rates in open populations have not been defined and 14 years, peaked around 20 to 24 years, and then leveled precisely for a number of reasons. Because rubella is such a off. In developed countries before mass immunization, the mild disease,it is underreported, even in areas where reporting incidence of infection did not reach 100% before the ages of 35 to 40 years; 5% to 20% of women of childbearing age has been mandatory for years. Mandatory reporting did not remain susceptible to infection. begin in the United States until 1966 (Fig. 28-1).287,292 The In the era before a rubella vaccine, in isolated or island high and variable rate of inapparent infection poses a major populations, such as in Trinidad, some areas of Japan,Panama, problem when attempting to interpret the recorded data, rural Peru, and Hawaii, a relatively high rate of susceptibility which are based usually on clinical

80 70

70,000 v)

60,000

8 m -

50,000 40.000

2

’ii 30,000

z

5

=

20,000 10,000 0

Figure 28-1 Incidence rates for reported cases of rubella and congenital rubella syndrome in the United States from 1966 to 2003. (Data from Centers for Disease Control and Prevention, courtesy of S. Reef, March 1, 2004.)

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Viral Infections

was found among young adults.285’286,288,289,302 Between 26% and 70% of women of childbearing age remained susceptible. This situation existed even though rubella was endemic with ample opportunity for multiple introductions of virus from the outside. Low population density, tropical climate, low concentration of effective spreaders, and genetic factors have all been invoked to explain these low attack rates, but none can adequately account for this peculiar epidemiologic phenomenon by itself.283,2883289,291 Later studies from 45 developing nations where rubella immunization efforts have been minimal have revealed a wide range of susceptibility (I 10% to 225%).303 In other areas, particularly in South America, infection began earlier in life and peak incidence occurs before puberty.288However, infection rates in most South American countries reach a plateau at approximately the same level as that seen in Europe and North America, leaving 10% or more of young women who are susceptible, based on serologic tests. Chile appeared to be an exception, with almost all persons being infected before puberty.288The impact of major immunization programs in the PAHO countries to reach a goal of eliminating rubella by 2010 will change these data. Initial mass vaccination of children, followed by routine vaccination of 1-year-old children and vaccination of susceptible adolescents and adults, has been extremely successful in controlling rubella and congenital rubella syndrome in the United States.5324*3L*36,258,292 The characteristic 6- to 9-year epidemic cycle has been interrupted, and the reported incidence of rubella that ranged from approximately 200 to 400 cases annually during the period 1992 through 2000 dropped to less than 25 between 2001 and 2004. For comparison, there were approximately 58,000 cases reported in 1969, the year of vaccine licensure in the United States (see Fig. 28-1). Age-specific declines in the occurrence of rubella have been greatest in children, who, because they were the major reservoir of the virus, have been the primary target of the U.S. immunization program. However, the risk of rubella decreased by 99% in all age groups after efforts to increase vaccination levels in older, susceptible persons, especially childbearing-aged females (see “Prevention of Congenital R ~ b e l l a ” ) .Nonetheless, ~~~.~~~ serologic surveys continue to document a 10% to 20% susceptibility rate in this population because of less-thanoptimal immunization coverage rate^.^^,^^^,^^^-^^^ Adolescents and young adults now account for most reported cases, with more cases reported among those older than age 15years than in children. Outbreaks are still reported in colleges, hospitals, cruise ships, and other settings in which Outbreaks no persons live or work in proximity.266-268*271-276 longer occur among military recruits because they receive rubella vaccine as soon as they arrive for basic training.263 Whereas the reported incidence of cases of congenital rubella syndrome has decreased dramatically, the number of cases of rubella and congenital rubella reported in the United States increased in 1989 to 1991, documenting that the potential for cases will continue as long as children and women of childbearing age remain unde rimmuni~ ed.The ~~ outbreak of rubella and congenital rubella among the Amish in Pennsylvania in 1991 and 1992 was a tragic reminder that there are still pockets of susceptible individuals in the United

TRANSMISSION IN UTERO In pregnant women with clinical or inapparent primary rubella, virus infects the placenta during the period of viremia and subsequently infects the f e t ~ ~ . ~ *Intrauterine ~ , ~ ~ ~ , ~ ~ ~ transmission of virus associated with maternal reinfection is rare. It is presumed that this difference is a reflection that viremia is absent or greatly reduced because of immunity induced by the primary infection (natural or vaccine induced).* Maternal infection may result in no infection of the conceptus, resorption of the embryo (seen only with infections occurring in the earliest stages of gestation), spontaneous abortion, stillbirth, infection of the placenta without fetal involvement, or infection of the placenta and fetus! Infected infants can have obvious multiorgan system involvement or, as is frequently observed, no immediately evident disease.6,13,107,330-337 However, after long-term followup, many of these seemingly unaffected infants have evidence of hearing loss or central nervous system or other defeCts.6,13,14.1 l2,131,132,330,331.333-336 Gestational age at the time of maternal infection is the most important determinant of intrauterine transmission and fetal darnage.2-4,6,284.299,317 The risk of fetal infection and congenital anomalies decreases with increasing gestational age. Fetal damage is rare much beyond the first trimester of pregnancy. Availability of more sensitive antibody assays has led to refinement of our understanding of the risk of fetal infection and subsequent congenital defects throughout all stages of p r e g n a ~ ~ c y . ’Although ~ ~ ~ ” ~ the risk of defects does decrease with increasing gestational age, fetal infection can occur at any time during pregnancy. Data on the risk of fetal infection are inconsistent when maternal rubella occurs before conception.1,12,108,110,338-341If some risk exists, the risk is small.

Risk of Fetal Infection

Early attempts to define the risk of fetal infection relied on isolation of virus from products of c o n ~ e p t i o n . ~ ~ ~ - ~ ~ ~ Between 40% and 90% of products of conception obtained from women with clinical rubella during the first trimester were found to be infected. The higher rates were observed in serologically confirmed cases of maternal rubella and when improved isolation techniques were employed.319p320 Attempts were made to refme the risk estimates by evaluating placental and fetal tissue separately. In some of these studies, equal rates of persistent placental and fetal infection were observed, ranging from 80% to 90%.3193320 In others, persistent placental infection was found to be twice as frequent as fetal infection: 50% to 70% versus 20% to 30%.314*317 However, high rates of fetal infection accompanied placental infection when specimens obtained during the first 8 weeks of gestation were examined. For example, of 14 cases in which virus was cultured from placental tissue, six of seven fetuses were culture positive when maternal rubella occurred during the first 8 weeks of pregnancy. In contrast, only one of seven fetal specimens was positive when infection occurred between 9 and 14 weeks of gestation.314In another similar study, fetal infection rates decreased sharply after the eighth week of ‘See references 5,6,41,42,45,47,51-53,55, 111, 116,321-359.

Chapter 28

Table 28-1

899

Risk of Serologically Confirmed Congenital Rubella Infection and Associated Defects in Children Exposed to Symptomatic Maternal Rubella Infection, by Weeks of Gestation Infection

Weeks of Gestation

Rubella

No.

Tested

Defects'

Rate (%)

No.

Followed

Rate (%)

Overall Risk of Defects (%)b

~

10

36

6 18 36 33 59 32 31 25

Total

258d

a

90 (9)' 67 (4) 67 (12) 47 (17) 39 (13) 34 (20) 25 (8) 35 (11) 60 (15) 100 (8) 45 (1 17)

9 4 12 14 10

100 50 17 50

90 33 11 24

53 102

20

aDefects in seropositive patients only. bOverall risk of defects = rate of infection x rate of defects. CNumbersin parentheses are number of children infected. dNone of 11 infants whose mothers had subclinical rubella were infected. Adapted from Miller E, Cradock-Watson JE, Pollock TM. Consequences of confirmed maternal rubella at successive stages of pregnancy. Lancet 2:781, 1982, with permission.

gestation, whereas placental infection rates decreased but less After the eighth week, placental infection occurred in 36% (8 of 22) and fetal infection occurred in 10% (2 of 20) of cases. Although fetal infection was not documented beyond the 10th week of gestation, placental infections were identified up to the 16th week. Further data on the risk of fetal infection have been obtained from studies using sensitive laboratory tests to detect congenital infection in children born to mothers with serologically confirmed r ~ b e l l a . ' ~ Because ~ ~ " ~ congenital rubella is often subclinical in infants and young children, use of such tests is necessary to assess accurately the risk of congenital infection.6-103-108*331,333-336 In investigations in which this approach was used, with detection of rubellaspecific IgM antibody in sera to document congenital infection, the discrepancy between rates of placental and fetal infection seen in viral isolation studies is less apparent. These studies have provided new information on the events after maternal infection in the second and third trimesters. In a study involving a total of 273 children (269 of whom had IgM antibody assessment), Miller and colleague^'^^ reported that fetal infection after serologically documented symptomatic maternal rubella in the first trimester was, as expected, quite high: 81% (13 of 16), with rates of 90% and 67% for those exposed before 11weeks and at 11 to 12 weeks, respectively (Table 28-1). Of greater interest is that the infection rate was 39% (70 of 178) after exposure in the second trimester (decreasing steadily from 67% at 13 to 14 weeks to 25% at 23 to 26 weeks) but rose to 53% (34 of 64) with thirdtrimester infection (with infection rates of 35%, 60%, and 100% during the last 3 months of pregnancy, respectively). In another investigation of fetal infection after firsttrimester maternal rubella infection based on IgM determination, Cradock-Watson and associate^'^^ found that 32% of 166 children were infected after second-trimester exposure and that a comparable proportion (24% of 100) were infected after infection in the third trimester. The rate of infection increased during the latter stages of gestation

after initially decreasing to a low of 12% by the 28th week and was 58% (11 of 19) when maternal infection occurred near term. Even higher rates were observed when persistence of IgG antibody was used as the criterion for congenital infection. The true fetal infection rate probably lies between the rates calculated by using the IgM and persistent IgG data. In both studies, the fetal infection rate declined between 12 and 28 weeks, suggesting that the placenta may prevent transfer of virus, although not ~ompletely.'~~ Some of the infections recorded during the last weeks of pregnancy could have been perinatally or postnatally acquired (e.g., by means of exposure to virus in the birth canal or from breast milk), but the available evidence indicates that the placental barrier to infection may be relatively ineffective during the last month, perhaps to the same degree as that seen during the first trimester, and that the fetus is susceptible to infection throughout pregnancy, albeit to various

Risk of Congenital Defects Estimates of the risk of congenital anomalies in live-born children after fetal infection have been affected by a number of factors. Early retrospective and hospital-based studies led to overestimates of the risk of congenital defects after firsttrimester infection (up to 90%).6*'07~291 The risk of abnormalities as determined by prospective studies relying on a clinical diagnosis of maternal rubella varied considerably (10% to 54% overall, with a 10% to 20% risk for major defects recognizable in children up to 3 years old) and tended to underestimate the risk because serologic evaluation of infants was not performed.'07p3383345"49 The proportion of pregnancies electively terminated can affect observed malformation rates. The fact that fetal infection can occur during all stages of pregnancy also influences assessments of the risk of congenital defects. Because most infants born with congenital rubella who were exposed after the 12th week of gestation do not have grossly apparent defects, long-term follow-up is necessary to

900

Section I11

Viral Infections

detect subtle, late-appearing abnormalities, such as deafness and mental impairment~6.13,14,112.131.132.330,331,333-336 This is especially true for infants infected beyond the 16th to 29th week of gestation, who appear to be at little, if any, risk of con enital a n o m a l i e ~ . ’ ~Studies ’ ~ ~ ~ by ~ Peckham and associatef07335 demonstrate that estimates of the risk of defects are affected by the serologic status and age at evaluation of the child. The overall incidence of defects in 2 18 children studied when they were about 2 years old was 23%; it was 52% if maternal infection occurred before 8 weeks’ gestation, 36% at 9 to 12 weeks, and 10% at 13 to 20 weeks. No defects were observed when maternal infection occurred after 20 weeks. When considering only seropositive children, the overall risk of defects increased to 38%, with increased risks of 75%, 52%,and 1896, respectively, for the three gcstational periods previously cited. At follow-up when the children were 6 to 8 years old, the overall risk of abnormalities in infected children who were seropositive when 2 years old increased from 38% to 59%; the risk after first-trimester infection increased from 58% to 82%. Miller and c o - w ~ r k e r s observed ’~~ higher rates of defects in infected children observed for only 2 years (see Table 28- 1). Defects were seen in 9 of 9 seropositive children exposed during the first 1 1 weeks, 2 of 4 exposed at 1 1 to 12 weeks, 2 of 12 exposed at 13 to 14 weeks, and 7 of 14 exposed at 15 to 16 weeks. Congenital heart disease and deafness were observed after infection before the 1 lth week; deafness was the sole defect identified after infection at 1 1 to 16 weeks’ gestation. No defects were observed in 63 children infected after 16 weeks. However, some children infected in the third trimester had growth retardation. Although the number of subjects is small, results of the study of Miller and c o - w ~ r k e r s indicate ’~~ that the risk of damage in seropositive infants is 85% if fetal infection occurs in the first trimester and 35% after infection during weeks 13 to 16. These rates of defects are higher than previously reported, but they may be an accurate reflection of intrauterine events because all maternal cases were serologically confirmed and sensitive antibody assays were used to detect congenital infection. With further follow-up, higher rates of defects may be observed. These rates pertain to offspring known to be infected and are useful in evaluating the risk of defects given fetal infection. For counseling purposes, it is essential to know the risk of congenital defects after confirmed maternal infection. This can be derived by multiplying the rates of defects in infected fetuses by the rates of fetal infection. Based on the reported experience of Miller and colleagues,Io5the risks are 90% for maternal infection before the 1 Ith week, 33% for infection during weeks 1 1 to 12,11% for weeks 13 to 14, and 24% for weeks 15 to 16 (see Table 28-1). The risk after maternal infection in the first trimester is 69%.

NATURAL HISTORY

Postnatal Infection Virologic Findings The pertinent virologic findings of postnatal infection are depicted in Figure 28-2. The portal of entry for rubella virus is believed to be the upper respiratory tract. Virus then spreads

UNESS IMMUNITY-

+INCUBATION+-PERIOD

+-NODILL

ENLARGEMENT-

I- MALAISE-

FEVER

H

Figure 28-2 Relation of viral excretion and clinical findings in postnatally acquired rubella (Data from Alford CA Chronic congenital and perinatal infections In Avery GB [edl Neonatology Philadelphia, JB Lippincott, 1987 )

through the lymphatic system, or by a transient viremia to regional lymph nodes, where replication first occurs. Between 7 and 9 days after exposure, virus is released into the blood and may seed multiple tissues, including the placenta. By the 9th to 1 1 th day, viral excretion begins from the nasopharynx, as well as from the kidneys, cervix, gastrointestinal tract, and various other SiteS.9~278~294,301,342-3~.350 The viremia peaks at 10 to 17 days, just before rash onset, which usually occurs 16 to 18 days after exposure. Virus disappears from the serum in the next few days, as antibody becomes detectable.278.294*30i2350 However, infection may persist in peripheral blood lymphocytes and monocytes for 1 to 4 ~ e e k ~ Virus . ~ is ~ excreted , ~ , in~ high ~ titers ~ ~ from ~ ~naso~ pharyngeal secretions. Nasopharyngeal shedding rarely may be detected for up to 3 to 5 weeks. Although virus can usually be cultured from the nasopharynx from 7 days before to 14 days after rash onset, the highest risk of virus transmission is believed to be from 5 days before to 6 days after the appearance of rash. Viral shedding from other sites is not as consistent, intense, or prolonged.2y43350 Rubella virus has been cultured from skin at sites where rash was present and where it was absent.353’354

Humoral Immune Response In challenge studies conducted in the early 1960s, Green and c o - ~ o r k e r demonstrated s~~~ that neutralizing antibody was first detected in serum 14 to 18 days after exposure (usually 2 to 3 days after rash onset), peaked within a month, and persisted for the duration of the follow-up period of 6 to 12 months. The HI test soon became the standard method for detecting rubella antibodies after acute postnatal rubella infection because of its reliability and ease compared with the neutralization test. Several other methods for measuring rubella antibody responses have supplanted the HI test in popularity (see “The The kinetics of the immune response to acute infection detected by these various serologic assays, which have been exhaustively compared with the HI technique, is depicted in ~i~~~~~~_3.88-Y2,191,1Y5-205,207,2l4-224.226.229 In general, there are three distinct patterns of antibody kinetics. Antibodies of the IgG class measured by HI, latex agglutination, neutralization, immunofluorescence, single radial hemolysis (or hemolysis in gel) (not shown in Fig. 28-3), radioimmunoassay, and enzyme-linked immunoassay theta

Chapter 28

VIRUS

Figure 28-3 Schematic diagram of the immune response in acute rubella infection. CF, complement fixation; EIA, enzyme irnmunoassay; FINFIAX and IFA, imrnunofluorescence assays; HI, hemagglutination inhibition; IgM, immunoglobulin M; LA, latex agglutination; Nt, neutralization; PHA, passive agglutination; RIA, radioimrnunoassay. (Data from Herrmann KL. Rubella virus. In Lennette EH, Schmidt NJ. [eds]. Diagnostic Procedures for Viral, Rickettsia1 and Chlamydia1 Infections. Washington, DC, American Public Health Association, 1979, p 725, and from Herrmann KL. Available rubella serologic tests. Rev Infect Dis 7[Suppl 115108, 1985.)

precipitation (not shown) follow the first pattern. Such antibodies usually become detectable 5 to 15 days after rash onset, although they may appear earlier and may even be detected 1 or 2 days before the rash appears. The antibody titers rapidly increase to reach peak values at 15 to 30 days and then gradually decline over a period of years to a constant titer that varies from person to person. In some patients with low levels of residual antibody, a second exposure to rubella virus may lead to low-grade reinfection of the pharynx. A booster antibody response can then be detected with any of the assays. This rapidly terminates the new infection, which is most often subclinical, and little or no viremia occurs~38,44,47,50,54,56,260,305,329

A second pattern of immune response to rubella infection is seen when IgG antibodies are measured by passive hemagglutination. The peak titer of these antibodies is similar to that measured by HI, but the passive hemagglutination antibodies are relatively delayed in appearance, and levels rise only slowly to their maximal titers. They first become detectable 15 to 50 days after the onset of the rash and often take 200 days to reach peak titers. The antibodies probably persist for life. Booster responses may be seen with reinfections. Studies indicate that the predominant IgG subclass detected by all these various assays is probably IgG1.95,97 Failure to detect IgG3 may be indicative of reinfe~tion.~’ A third distinct pattern of antibody production is represented in Figure 28-3 by the IgM antibody class immune response. Rubella-specificIgM antibody can be measured by HI, immunofluorescence, radioimmunoassay, or enzyme immunoassay.99~l 57,206-210,213,215,224,225,230-228IgM antibodies are most consistently detectable 5 to 10 days after the onset of the rash, rise rapidly to peak values at around 20 days, and then decline so rapidly that they usually disappear by 50 to 70 days. In a few atients, however, low levels may persist for up to 1 year.355-35The booster IgG antibody response to re-

P

Rubella

901

infection described earlier does not usually involve the IgM class of antibody, and the presence of high-titer IgM antibodies usually indicates recent primary infection with rubella. However, more sensitive techniques, such as radioimmunoassay or enzyme immunoassay, may occasionally detect low levels of specific IgM antibodies in some patients with reinfections, which may cause some difficulty in differentiating subclinical reinfection, which is almost always of no consequence, from acute primary subclinical i n f e ~ t i o n . ~ ~ ’ ~ ’ ’ ~ ~ ~ Determination of avidity of rubella-specific IgG may help resolve this p r ~ b l e m . ~Primary ~ ~ ” ~ infection ~ appears to be associated with low-avidity IgG, and reinfection seems to be associated with high-avidity IgG. The kinetics of the immune response to rubella infection detected by other serologic assays is not as distinct as the three patterns just described, and marked variability between patients has been observed. Complement fixation antibodies or iota precipitins (not shown in Fig. 28-3) are lacking in the first 10 days after the rash and rise slowly to peak at 30 to 90 days.’” These antibodies persist for several years in one third of patients and may reappear during reinfections. Iota precipitins do not persist for more than a few months and do not usually reappear with reinfections. Antibodies of the IgA class appear within 10 days but may disappear within another 20 days or persist for several years.96,99,206,231 IgD and IgE antibodies appear rapidly (6 to 9 days) after infection, remain high for at least 2 months, and then decline slightly at 6 monthsY6 IgE antibodies reach an early peak similar to that seen for IgM and IgA. In contrast, the IgD response is somewhat delayed, like that of IgG. The antibody response after infection is generally considered to confer complete and permanent immunity. Clinical reinfection is rare, and reinfections usually pose little risk to the fetus because placental exposure to the virus is minimal.38,41,44,47,50,51,53-56,329 Some of the rare instances of fetal infection after maternal reinfection may be caused by an incomplete immune response to the various antigenic domains on each structural protein of the virus (see “The virus”).74-76,111,115,321,326-330 For example, three cases after natural infection have been reported involving women who had positive HI results but who had no detectable levels of neutralizing antibody.32183263328 The sensitivity of the neutralizing assay itself is an important determinant in interpreting these results. l11~196This phenomenon also may account for the four reported cases of congenital infection that followed reinfection of women who had presumably been immunized p r e v i o ~ s l yl6~Some ~ ~ ~of~ the ~ ~ reported ~~’ instances of maternal reinfection probably, and in at least one case definitely, represent cases of primary acute infection.536s1 13,323-325

Cellular Immune Response Cellular immunity to rubella virus has been measured by lymphocyte transformation response, secretion of interferon, secretion of macrophage migration-inhibitory factor, induction of delayed hypersensitivity to skin testing, and release of lymphokines by cultured lymphocyte^.^^^‘^^^ Peripheral blood lymphocytes from seropositive individuals respond better in each of these tests than do lymphocytes from uninfected persons, suggesting that these assays measure parameters of the cellular immune response to rubella virus. The results from other studies in which chromium 51 microcyto-

902


toxicity assays have been used are difficult to interpret because syngeneic cell lines have not been used to control for HLA-restricted response^.^^'*^^^ In the first weeks after natural rubella infection, some degree of transient lymphocyte suppression may Generally, cell-mediated immune responses precede the appearance of humoral immunity by 1 week, reach a peak value at the same time as the antibody response, and subsequently persist for many years, probably for life.”’ Acute infection may suppress skin reactivity to tuberculin testing for approximately 30 days.373

J 3

70

Local Immune Response The local antibody response at the portal of entry in the nasopharynx is essentiallyIgA in character; low levels of shortlived IgG antibody are rarely detectable in nasopharyngeal MONTHS YEARS secretions. The nasopharyngeal IgA antibody persists at detectAGE OF INFANTS AND CHILDREN able levels for at least 1 year after infection. Its persistence apparently minimizes the tendency for reinfection after Figure 2 8 4 Rate of virus excretion by age in infants and children with congenital rubella infection. (Data from Cooper LZ, Krugrnan S. natural rubella infection. The lack of local IgA nasopharyngeal Clinical manifestations of postnatal and congenital rubella. Arch response after parenteral administration of live rubella Ophthalrnol 77:434, 1967.) vaccines (less so with the RA 27/3 strain than with other strains) probably plays a key role in the increased incidence of subclinical reinfection after vaccination.38’40*44”54956*374~377 Local antibody levels tend to be higher in individuals resistant system.384-387 Virus has been isolated from the brain of a to challenge with live virus, but no specific titer of antibody 12-year-old boy with later-appearing subacute panencephalitis has been associated with complete protection. occurring after congenital rubella i n f e c t i ~ n . ~ ~ ~ ’ ~ ~ ~ A cell-mediated immune response in tonsillar cells has Humoral Immune Response been detected by lymphocyte transformation and secretion of migration-inhibitory factor after natural rubella and after Studies have shown that placental infection does not prevent intranasal challenge with live RA 2713 vaccine.378In guinea passive transfer of maternal antibody and that the infected pigs, the response first becomes detectable 1 to 2 weeks after fetus can mount an immune response.284~314-3’o~390-39’ Although intranasal vaccination, peaks at 4 weeks, and then disappears the development and function of the other components of the immune response of the fetus may be important, critical at about 6 weeks.379 factors that allow fetal infection to occur in the presence of antibody may be the timing when antibody is present in the Congenital Infection fetal circulation or the quality of the antibody that the fetus Virologic findings produces, or both. An important feature that distinguishes congenital Although placental transfer of antibody occurs despite persistent infection, levels of antibody in fetal blood during infection from postnatal infection is that the former is the first half of gestation are only 5% to 10% of those in C~rOn~C~~,13,284,310,317,380,381 Dwing the period of maternal viremia, the placenta may become infected and transmit virus maternal s e i - ~ r n . ~As ~ ’the - ~ placental ~~ transfer mechanisms to the fetus (see “Transmission In Utero”).2~6,284*’99.3’4-320 mature by mid-gestation (16 to 20 weeks), increasing levels of maternal IgG antibody are transferred to the fetus Although virus may persist for months in the placenta, recovery of virus from the placenta at birth occurs infre(Fig. 28-5).3y5 quently?” In contrast, after the fetus is infected, the virus The development of the fetal humoral immune system persists typically throughout gestation and for months postappears to be too late to limit the effects of the virus. Cells natally. It can infect many fetal organs or only a few?17In with membrane-bound immunoglobulins of all three major classes-IgM, IgG, and IgA-appear in the fetus as early as 9 infected infants, virus can be recovered from multiple sites (e.g., pharyngeal secretions, urine, conjunctival fluid, feces) to 1 1 weeks’ gestation.396However, circulating fetal antibody and is detectable in cerebrospinal fluid, bone marrow, and levels remain low until mid-gestation, despite the presence circulating white blood cells.+Pharyngeal shedding of virus of high titers of virus and the development of antigen receptors is more common, prolonged, and intense during the early on the cell surface (see Fig. 28-5). At this time, levels of fetal months after delivery (Fig. 28-4). By 1 year of age, only 2% antibody increase, with IgM antibody pred~minating.~~’~~~~-~’~ to 20%of infants shed ~irus.’~’-’~~ In rare instances, shedding Fetal IgA, IgD, and IgG also are made, although in lesser may continue beyond the age of 2 years.’80-28’Virus can be a m ~ ~ n tAs~in. the ~ case ~ ~with ~ ~other ~ chronic , ~ ~ intra~ isolated from the eye and cerebrospinal fluid, particularly uterine infections, congenital rubella infection may lead to when disease is evident in the corresponding organs and can an increase in total IgM antibody levels.3909392~3939401 Total IgA persist for more than a year in the eye and central nervous levels are also occasionally raised, but IgG levels seldom exceed those of uninfected infant^.^^'"^'^^^'*^^' At the time of delivery of infected infants, levels of IgG rubella antibodies in cord sera are equal to or greater than those in maternal +See references 2, 13, 161,277-282,284,314,315,317,319, 380-384.

Chapter 28

rn

4

c .-o

c 0

a,

Is1

2nd

3rd

4

6

MONTHS

TRIMESTER

12

YEARS

i

r

C

Figure 28-5 Schematic diagram of the immune response in the mother, fetus, and infant after maternal and fetal rubella infections in the first trimester of pregnancy. (Data from Alford CA. Immunology of rubella. In Friedman H, Prier JE [eds]. Rubella. Springfield, 111, Charles C Thomas, 1972.)

sera, even if the infant is born premat~rely.~~’ IgG is the dominant antibody present at delivery in rubella-infected infants and is mainly maternal in origin. In contrast, the IgM levels are lower but are totally fetus derived. In the first 3 to 5 months after birth, the levels of maternally derived IgG decrease as maternal antibody is catabolized (see Fig. 28-5).392In contrast, IgM antibodies increase in titer and can predominate. Later, as viral excretion wanes and disappears, the IgM antibody levels diminish, and IgG becomes the dominant and persistent antibody type. CradockWatson and colleague^^'^ found that total IgM was elevated in nearly all sera obtained from infected infants during the first 3 months of life and in one half of sera from infected infants 3 to 6 months old. Rubella-specific IgM has been shown consistently to persist for 6 months, frequently for a year, and rarely longer when assayed by sensitive serologic procedures, such as radioimmunoassay and immunofluorescence.Z12B401 For example, Cradock-Watson and colleagues4” also reported that IgM was detectable in 48 (96%) of 50 sera during the first 6 months of life and in 11 (29%) of 38 sera from children between 6.5 months and 2 years old. The total level of antibody, as measured by a variety of serologic tests, remains virtually unchanged throughout the first year of life, despite the fluctuations in immunoglobulin composition.392~401 High levels of IgG antibody are usually maintained for several years after detectable virus excretion ends, suggesting that there may be continued antigenic stimulation. During the first few years of life, some patients have a relative hypergammaglobulinemia, particularly of the IgM and IgG classes of antibody, which results from the increased antigenic stimulus accompanying the chronic i n f e ~ t i o n ~With ’ ~ ’ ~in-~ creasing time, however, antibody levels may decrease and even become undetectable in 10% to 20% of patient^.^^^*^"-^^ Cooper and c o - ~ o r k e r s ~found ’ ~ that the geometric mean HI titer decreased by a factor of 16 by age 5 years in 223 children

Rubella

903

with congenital rubella syndrome. No HI antibodies were detected in 8 of 29 5-year-old children. In a study from Japan, only 3% of 381 children with congenital infection observed for more than 17 years had undetectable HI titers.407There was an initial rapid decline from a geometric mean titer of 1:416 (28.7)to 1:84 (26.4)over the first 2 years of follow-up. After this, there was a modest continuing decline, and the final geometric mean titer was 1:42 (25.4). Cooper and co-worker~~’~ reported that congenitally infected children who have lost detectable rubella-specific antibody did not develop a boost in antibody titer after rubella vaccination. This finding may reflect some sort of immunologic tolerance that follows intrauterine exposure to rubella virus. None of the children with congenital rubella in Japan had evidence of significant boosts in antibody or a history of clinical disease when exposed during recent outbreaks of Hypogammaglobulinemia with low levels of all three major classes of immunoglobulins has been reported in a few instances of congenital rubella.133.161~409~410 Usually, only IgA is affected. There may also be instances when IgG levels are low, whereas levels of IgM are two or three times the upper limit of normal for adults. These IgG and IgM abnormalities may occur with or without IgA abn0rmalities.4’~ Over time, immunoglobulin development may become normal, and this can occur despite continued viral excretion but is more likely if viral titers are decreasing.”’ In addition to defects in the immune globulin levels, defects in specific antibody production have been observed. One such defect is a complete lack of antibody response to any antigen, including the rubella virus itself. Response only to the virus, in the absence of a response to most other antigens, has also been reported.”’ This state of immunologic unresponsiveness resolves in many patients. Antibody production becomes normal as the patient’s general condition improves and as immune globulin levels normalize. Immunoprecipitation studies of sera from patients with congenital rubella syndrome provide further information on defective antibody production. They indicate that the antibody profile to the three structural proteins of the rubella virus is qualitatively different from that observed in sera from persons with postnatally acquired infection (see “The V i r ~ s ” ) . ~Little ~ , ~ or ~ ,no ~ ~antibody to the core structural protein (C) is found, and the absolute and relative amounts of antibody to structural proteins E l and E2 appear to vary with These findings further suggest that the immune response of the infected fetus may be incomplete and may explain why detectable antibodies are not present in some sera.87,335,404-407 If a serum contains relatively little antibody to structural protein E l (i.e., hemagglutinin), assays that detect antibody to the whole virion will be more likely to be positive than those that detect antibody only to E l (e.g., the HI assay). It is not clear whether these abnormal antibody patterns persist for life. Cellular Immune Response Like the cells responsible for the humoral immune response (i.e., B cells), the cells involved in cellular immunity (i.e., T cells and macrophages) develop some of their functions early in However, little is known about their response in utero because appropriate specimens have not been obtainable for study. The cellular immune response of

904

Section I11

Viral Infections

difficulties have hampered direct studies of humans. Howthe infected fetus has been inferred from studies of infected ever, interferon that appeared to be specificallystimulated by infants and children. Available evidence indicates that some the presence of rubella virus in rubella-infected human infants with congenital rubella have impaired cellular embryos has been demonstrated!26 The interferon was found immune responses. as early as 7 weeks’ gestation and persisted as long as 12 weeks Retarded development of the thymus and lymphocyte after symptoms ceased in the mothers. Direct study of fetal depletion have been reported, but these abnormalities may blood and amniotic fluid has also shown that the fetus can result from the stress of infection rather than the virus produce interferon in response to the vir~s.4’~ it~elf.4’~ Abnormal delayed hypersensitivity skin reactions to Children with congenital infection do have the capacity a number of antigens (e.g., diphtheria toxoid, Candidu, to make interferon on challenge. For example, Desmyter and dinitrofluorobenzene) have also been This c o - ~ o r k e r s ~reported ~’ that interferon could not be detected defect has been associated with abnormalities in the from the serum or urine of nine such children 11to 18 months humoral system and resolves as antibody production returns old who were excreting virus. However, after vaccination with to normal. live measles vaccine (i.e., Edmonton B or Schwarz strains), Results of studies of in vitro lymphocyte blastogenesis in all the children seroconverted and produced detectable levels congenitally infected infants and children have been of interferon. confusing. Early studies demonstrated a poor response to phytohemagglutinin, vaccinia, and diphtheria t o ~ o i d . ~ ’ ~ . ~ ‘ ~ However, because rubella virus can depress the lymphocyte blastogenic response and the virus can be isolated from PATHOGENESIS lymphocytes of chronically infected infants, the abnormality may be a result of viral infection of the circulating blood cells Postnatal Infection rather than an inherent defect in cell-mediated imm~nity.~’~-~’~ This diminished cellular response may normalize over time The events leading to acute postnatal infection are relatively because elevated lymphocyte responses have been detected well known and have been detailed in “Natural History.” in some older infected Available information indicates that viral replication and Buimovici-Klein and colleagues372942’ showed that lymphopostinfection immune phenomena are involved in the clinical cytes from older children and adolescents with congenital manifestations of the illness. rubella had no or very poor lymphocyte proliferative responses Viremia may lead to seeding of multiple organs, but few to rubella virus antigens and had markedly reduced interferon are clinically affected.6 Speculation that the rash may be an and migration-inhibition factor production. These studies immune phenomenon caused by circulating immune indicated that these defects were greater in children exposed complexes has not been documented. Few persons with unearly in gestation than those exposed later, with the greatest complicated illness have immune complexes containing degree of abnormality in those whose mothers had been rubella virus, and virus has been isolated from involved and uninvolved s~n.123,128,353s354 Virus has been isolated from infected during the first 8 weeks of pregnancy. They also pointed out that these defects could persist long after viral lymph nodes and conjunctiva, accounting for the lymph excretion had ceased. It remains unclear if these cellular node enlargement and conjunctivitis observed in many immune defects are responsible for viral persistence or are patients.3503429 Virus has been isolated from synovial fluid, yet another manifestation of intrauterine infection.421 but immune mechanisms may play a role in some cases of Other investigators have confirmed that patients arthralgia and arthritis, particularly if symptoms are with congenital rubella have defects in cell-mediated p e r s i ~ t e n t . ’ ~Encephalitis ~ * ~ ~ ~ - ~is~probably ~ a manifestation i m m ~ n i t y . ’ ~ ~Verder ~ ’ ~ ~ *and ’ ~ ~colleague^'^^ reported a of the immune response, but direct viral invasion may be decreased proportion of suppressor or cytotoxic (CD8’) involved, particularly in the rare case of progressive panenT cells in an infant with congenital rubella. Rabinowe and cephalitis that has been reported to follow postnatal inc o - ~ o r k e r s ’documented ~~ persistent T cell abnormalities in It has been suggested that pregnant women patients with congenital infection who were 9 to 21 years are at increased risk of serious complications because of the old. Compared with normal subjects, the congenitally infected impaired immune response associated with pregnancy, but patients had depressed ratios of T4 cells (helper or inducer) there are few data to support this ~ l a i m . 4There ~ ~ - has ~ ~also ~ to T8 cells (from a decreased proportion of T4 and an inbeen interest, especially in Japan, in the influence of HLA creased percentage of T8 cells). Such findings persist for only type and other genetic factors on the incidence and severity 1 month after acute postnatal rubella infection.422 of postnatal infection.l18.119,122,124.127,439 No consistent pattern Lymphocytes of infected children were unable to kill has been reported. rubella-infected cells in a cytotoxicity assay.423These results were questioned because syngeneic target cells were not used, Congenital Infection and these responses are known to be HLA restricted. However, similar results have been found by Verder and associates,IM The outcome of maternal rubella infection follows a logical sequence of events, beginning with maternal infection, who observed abnormal killer and natural killer cell activities. followed by viremia, placental seeding, and dissemination of Interferon Response infection to the fetus (see “Transmission In Utero” and “Natural History”).2,6,284,299,314-320 The fetus may escape It has long been suggested that the fetus has a deficient infection entirely, succumb in utero, be born with multiple interferon response to viral infections, including rubella, but obvious defects, or appear to be normal at birth, only to this evidence has been derived from indirect studies with in develop abnormalities later in life.6,’33’07,278,330-337 The varivitro cell systems or animal models.173’L74,3’9,424.425 Technical

Chapter 28 ability in outcome is highlighted by the observation that one identical twin may be infected and the other pa red.^,^^',^^' The most important determinant of fetal outcome is gestational age at the time of infection.2’3’6 103,110,284,299,314,317 The disease is more severe and has a greater tendency to involve multiple organs when acquired during the first 8 weeks’ gestation. However, the factors that govern the influence of gestation are unknown. It is possible that immature cells are more easily infected and support the growth of virus better than older, more differentiated cells. It is also possible that the placenta becomes increasingly resistant to infection (or at least more able to limit infection) as it rapidly matures during the first trimester. A third possibility is that maturing fetal defense mechanisms become capable of confining and clearing the infection. This last explanation is probably important after 18 or 20 weeks’ gestation but seems unlikely in the latter half of the first trimester, when attenuation of fetal infection begins. It is likely that a combination of these and other factors are responsible for the decrease in virulence of fetal infection with increasing gestational age. The hallmark of fetal infection is its chronicity, with the tendency for virus to persist throughout fetal life and after birth.2,~3,~61,277-282,284,299.314-320,372-389 The factthat virus can be isolated long after birth also raises the possibility of reactivation, at least in brain t i s s ~ e . ~ It” ,is~not ~ ~clear why the virus has these properties, because the fetus is not truly immunologically tolerant and appears to be able to produce interferon.212,284,331.39 l,392,40 1,424-428 In any case, chronic or reactivated infection can lead to ongoing pathologic

Rubella

905

because of slow growth rates and limited doubling potential during the period of embryogenesis, when cell division and turnover are normally very rapid. Naeye and B l a n found ~~~~ histopathologic evidence for mitotic arrest and reduced cell numbers in infants who died of congenital rubella syndrome. These observations have been offered to explain the increased incidence of intrauterine growth retardation seen in infants with congenital rubella, but this explanation probably represents an oversimplification of the actual mechanisms involved. Immunologic responses also have been proposed as causes of cellular damage. Although cellular immune defects may be a result of chronic infection, it is possible that these defects contribute to ongoing tissue damage.372,421*459 Excessive serum immunoglobulin development, persistent antibody production in the face of viral replication for prolonged periods, and production of rheumatoid factor, all indicative of overstimulation of the immune system, also may have a role in the pathogenesis of congenital rubella The presence of immune complexes and autoantibodies and the influence of certain HLA types may contribute to the delayed expression of some signs of congenital rubella, such as pneumonitis, diabetes mellitus, thyroid dysfunction, and progressive rubella panencephalitis (see “Clinical Manifestations”).*Some of these immunologic events may be directly involved in tissue damage (e.g., immune complexes, autoantibodies), whereas others may allow the virus to persist or reactivate.

processes~6,13,14,107,131,132,330,331,333-336

The causes of cellular and tissue damage from congenital PATHOLOGY rubella infection are poorly defined.4243425 Only a variable, small number of cells are infected (1 per 1000 to 250,000).320 Postnatal Infection In tissue culture, infection with rubella virus has diverse effects, ranging from no obvious effect to cell destruction Little is known about the pathology of postnatally acquired (see “The Virus”); this is also likely to be the case in v ~ v o , ~rubella ~ ~ because patients seldom die of this mild disease. As but cytolysis is uncommon (see observed by Cherry? the histologic findings of tissues that Inflammation is minimal and consists mainly of infiltration have been examined (i.e., lymph nodes and autopsy of small lymphocytes. Polymorphonuclear leukocytes and specimens from patients dying with encephalitis) are plasma cells are lacking, particularly compared with other unremarkable. Changes in lymphoreticular tissue have been viral infections of the human fetus, in which inflammation limited to mild edema, nonspecific follicular hyperplasia, and general necrosis are quite extensive. In contrast, vascular and some loss of normal follicular morphology. Examination insufficiency appears to be more important than cell of brain tissue has revealed diffuse swelling, nonspecific destruction or secondary inflammatory damage in the genesis degeneration, and little meningeal and perivascular infiltrate. This suggestion is supported of congenital by the observation that rubella virus has low destructive Congenital Infection potential for cells growing in vitro, including those of human In contrast to the situation with postnatal rubella, much origin. A number of investigators have maintained multiple is known about the pathology of congenital rubella intypes of rubella-infected human fetal cells in culture for years fection.2’3’639’442-446’462 In general, small foci of infected cells without loss of viability or evidence of cytopathic e f f e ~ t . ~ ~ - @ ~ are seen in apparently normal tissue. Cellular necrosis and Other defects have been reported in chronically insecondary inflammation are seldom obvious, although a fected cells that might help explain the mechanism of generalized vasculitis predominates (see “Pathogenesis”). congenital defects. These include chromosomal breaks, The pathologic findings of the placenta include hypoplasia, reduced cellular multiplication time, and increased production inflammatory foci in chorionic villi, granulomatous changes, of a protein inhibitor that causes mitotic arrest of certain cell types.380,447,450-455 mild edema, focal hyalinization, and necrosis.442,443,462v463 Disease usually causes extensive damage to the endothelium A report by Bowden and associates456indicates that of the capillaries and smaller blood vessels of the chorion. rubella virus may interfere with mitosis by having an adverse The vessel lesions consist mainly of endothelial necrosis, effect on actin microfilaments. Observations of Yoneda and c o - ~ o r k e r show s ~ ~ ~that rubella virus may alter cell receptors to specific growth factors. All of these abnormalities, if ?See references 13, 14, 117, 120, 121, 123, 125, 126, 129-134.388, 389. occurring in vivo, may result in decreased cell multiplication

906

Section I11

Viral Infections

with fragmentation of intraluminal blood cells. Tondury and SmithM2postulated that emboli of infected endothelial cells originating from the chorion might seed target organs in the fetus. These emboli may also contribute to organ damage by obstructing the fetal blood supply. Petechiae and the presence of hemosiderin-laden phagocytes in surrounding tissue are evidence of functional vascular damage.443 Although not nearly as common as vascular lesions, specific cytolysis, presumably caused by direct viral effect on the cell, is also present in the placenta. This is characterized by cytoplasmic eosinophilia, nuclear pyknosis or karyorrhexis, and cellular necrosis. Specific cellular inclusion bodies, both nuclear and cytoplasmic, are rare but have been observed.463 Whereas placentitis would be expected to be present in all affected placentas, regardless of when fetal infection occurred, Garcia and colleaguesM3found that placental lesions appeared to be more intense when infection occurred in the last trimester of pregnancy. This finding is consistent with the observation that the placenta is not a barrier to fetal infection in the latter stages of pregnancy.1033109*333*335 Autopsies show that virtually every organ may be involved, with hypoplasia being a common finding. The necrotizing angiopathy of small blood vessels seen in the placenta is the most characteristic lesion in fetal organs. Cytolysis with tissue necrosis and accompanying inflammatory changes are also far less common but have been found in the myocardium, brain, spinal cord, skeletal muscle, viscera, and epithelial cells of the developing lens, inner ear (organ of Corti), and teeth. The overall pathologic process of congenital rubella, in keeping with its chronic nature, is progressive. Both healing and new lesions can be found in specimens obtained in the later stages of The pathologic changes vary among embryos in quantity and in organ distribution, and the location and nature of organ lesions depend somewhat on the gestational age at the time of infection.442The pathologic findings parallel the enormous variability of the clinical disease seen in infected newborns.

fever, headache, malaise, anorexia, mild conjunctivitis, coryza, sore throat, cough, and lymphadenopathy usually involving suboccipital, postauricular, and cervical nodes. The constitutional symptoms often subside rapidly with the appearance of the rash. The rash can last 1 to 5 days or longer and can be pruritic in adults. Infection without a rash is quite common. The ratio of subclinical to clinical infections has varied from 1:9 to 7:1.2609296 Subclinical infection can lead to fetal infection, although it is not clear whether the risk is as great as that associated with clinically apparent ~fection~2,3,6,105,108,335,341

Arthralgia and frank arthritis with recrudescence of lowgrade fever and other constitutional symptoms may appear after the rash fades. Joint involvement typically lasts 5 to 10 days but may be more persistent. The frequency of these symptoms is variable, but it is more common in adults, particularly women.g In some studies of adult patients, the frequency has been as high as 70%.* Thrombocytopenia (occurring in approximately 1 of 3000 patients) and acute postinfection encephalitis (occurring in 1 of 5000 to 6000 patients) are rare complications that usually occur 2 to 4 days after rash onset.’ Rare complications associated with postnatal rubella include myocarditis, Guillain-Barre syndrome, relapsing encephalitis, optic neuritis, and bone marrow a p l a ~ i a . ~ Tw . ~ o~ cases ” ~ ~ ~of a progressive panencephalitis, similar to measles-associated subacute sclerosing panencephalitis, have been r e p ~ r t e d ! ~ ~This , ~ ~ ~central nervous system disturbance is more likely to manifest in patients with congenital rubella syndrome, although it still occurs infreq ~ e n t l y . ~Testalgia ~ ~ - ~has ~ also ~ % been ~ ~ reported ~ in patients with rubella, but this may have been a coincidental finding.474,475

Congenital Infection

Gregg’s original report12in 1941 defined the rubella syndrome as a constellation of defects, usually involving some combination of congenital heart, eye, and hearing abnormalities, with or without mental retardation and microcephaly. After the extensive studies in the mid- 196Os, in which virologic and serologic methods of assessment were used, the pathologic CLINICAL MANIFESTATIONS potential associated with intrauterine rubella had to be greatly e ~ p a n d e d . The ~ . ~ recognition of various new defects Postnatal Infection associated with congenital rubella infection led to speculation that they had not existed before the 1962 to 1964 Rubella is usually a mild disease with few complications. the abnormalities in infants Clinical illness may be more severe in a d ~ l t s . ~ * ~ * pandemic. ~ ~ ~ . ~However, ~ ~ , ~a ~review ~ * of ~ ~ born during previous non-epidemic periods indicated Measles, varicella, and some enteroviruses acquired close to that they were not new but had not been appreciated delivery may be associated with serious illness in the newpreviously because of the small number of affected infants born, probably because of fetal exposure to transplacental st~died.4~~ viremia in the absence of protective levels of maternal antiThe virus can infect one or virtually all fetal organs and, body. One case report suggests that the same may be true in once established, can persist for long periods (see “Transrubella. Sheinis and associates465reported the death of a neomission In Utero,” “Natural History,” “Pathogenesis,” and nate with rash onset when 12 days old; the mother developed “Pathology”).5 Congenital rubella, a chronic infection, may rash on the day of delivery. This single observation needs to kill the fetus in utero, causing miscarriage or stillbirth. At the be confirmed. There are no conclusive data to indicate that other extreme, the infection may have no apparent effect infection in the immunocompromised host is associated clinically detectable at the delivery of normal-appearing with an increased risk of complications. infants. Alternatively, severe multiple birth defects may be The first symptoms of rubella occur after an incubation period of 16 to 18 days, with a range of 14 to 21 days. In the child, rash is often the first sign detected. In adolescents and adults, however, the eruption is commonly preceded by a ’See references 6, 13, 14,107, 131, 132, 161,277-282,284,299,314-320, 330-337,380-389, 1- to 5-day prodromal period characterized by low-grade

Chapter 28

Rubella

907

obvious in the newborn period. The wide spectrum of Permanent Manifestations disease is summarized later in the chapter (see Tables 28-3 Permanent manifestations include heart and other blood and 28-4). vessel defects, eye lesions, central nervous system abnormalities, Silent infections in the infant are much more common deafness, and a variety of other congenital anomalies. These than symptomatic ones. Schiff and colleagues334prospectively structural defects result from defective organogenesis (i.e., examined 4005 infants born after the 1964 rubella epidemic. some cardiac, eye, and other organ defects) and from tissue Based on virologic and serologic techniques to detect indestruction and scarring (i.e., hearing loss, brain damage, fection in the newborns, the overall rate of congenital rubella cataracts, chorioretinopathy,and vascular stenosis). Relatively was in excess of 2%, compared with only approximately 0.1% few defects result from gross anatomic abnormalities. It is in endemic years.3349341 Sixty-eight percent of the infected not certain that all of the malformations given in Table 28-2 newborns had subclinical infection during the neonatal are associated with congenital rubella.13’315,381,454,476-504 Because period. Among those who were followed, 71% developed many of them occur in the absence of intrauterine rubella manifestations of infection at various times in the first infection, their presence in affected infants may be coin5 years of life. Many important rubella defects can be cidental? undetectable or overlooked in the early months of life. Congenital heart disease is present in more than one half Existing manifestations of infection can progress, and new of children infected during the first 2 months of gestation. manifestations may appear throughout life~,13,14,107,131,132,330-337 The most common lesions, in descending order, are patent Some abnormalities of congenital rubella syndrome usually ductus arteriosus, pulmonary artery stenosis, and pulmonary are not detected until the second year of life or later (see valvular stenosis. Aortic valvular stenosis and tetralogy of Table 28-3). The silent and progressive nature of congenital Fallot have also been recorded. A patent ductus arteriosus rubella infection has important implications for accurate, occurs alone in approximately one third of cases; otherwise, timely diagnosis and appropriate short-term and long-term management. it is frequentl associated with pulmonary artery or valvular It is useful to group the clinical features of congenital s t e n ~ s i s . ~ ~ , ~Stenosis ~ ~ ~ ’ ’ of other vessels plays an important role in the spectrum of congenital rubella syndrome.44594989499 rubella into three categories: transient manifestations in These lesions may be related to coronary, cerebral, renal, and newborns and infants; permanent manifestations, which peripheral vascular disease seen in adults.131s2’ may be present at birth or become apparent during the first year of life; and developmental and late-onset maniA “salt and pepper” retinopathy caused by disturbed growth of the pigmentary layer of the retina is the most festations, which usually appear and progress during childhood, adolescence, and early adult life.133441s477 These common of all ocular finding^.^,'^,^^,^^^ Cataracts, often accompanied by microphthalmia, occur in approximately groupings overlap. one third of all cases of congenital rubella. Bilateral cataracts Transient Manifestations are found in one half of affected children. Primary glaucoma is relatively uncommon; it does not affect a cataractous eye. Transient manifestations appear to reflect ongoing heavy Cataracts and infantile glaucoma may not be present or viral infection, perhaps abetted by the newborn’s emerging, detectable at birth but usually become apparent during the often abnormal immune f u n ~ t i o n . ~ Examples ” ~ ~ ” ~ ~of these early weeks of life. Other ocular abnormalities occur later in manifestations include hepatosplenomegaly, hepatitis, life (see “Developmental and Late-Onset Manifestations”). jaundice, thrombocytopenia with petechiae and purpura, Children with congenital rubella syndrome exhibit a discrete bluish red (“blueberry muffin”) lesions of dermal number of central nervous system abnormalities that follow erythropoiesis, hemolytic anemia, chronic rash, adenopathy, widespread insult to the brain. Microcephaly can be a feature meningoencephatitis (in some cases), large anterior fontanelle, of this syndrome. Mental retardation and motor retardation interstitial pneumonia, myositis, myocarditis,diarrhea, cloudy are common and are directly related to the acute meningocornea, and disturbances in bone growth that appear as encephalitis in 10% to 20% of affected children at birth.’ striated radiolucencies in the long bones. More than 50% of infants with these transient findings usually have evidence of Behavioral and psychiatric disorders have been confirmed in intrauterine growth retardation and may continue to fail to many patients.L33441 Of particular interest is autism, which has thrive during infancy.278These transient abnormalities were been reported to occur with a frequency of approximately referred to as the expanded rubella syndrome when widely 6Y0.~lChronic encephalitis has been reported in young reported after the pandemic of 1962 to 1964. Careful review children? A late-onset progressive panencephalitis may occur of the early observations during the 1940s and 1950s revealed in the second decade of life.389*472p473 This is discussed later with other developmental manifestations. that these were not new manifestations of congenital rubella. The incidence of deafness has been underestimated These conditions usually are self-limiting and clear sponbecause many cases had been missed in infancy and early taneously over days or weeks? These lesions are important childhood. However, follow-up studies showed that deafness from a diagnostic and prognostic standpoint. They may be was the most common manifestation of congenital rubella, associated with other, more severe defects. This applies occurring in 80% or more of those infected.* In contrast to especially to thrombocytopenia and bone lesion^.'^*^'^ The mortality rate was approximately 35% in one group of infants other serious defects, hearing impairment often is the only significant consequence of congenital rubella. Rubellawho presented with neonatal thrombocytopenia. Extreme related defects of organogenesis (i.e., cataracts and some prematurity, gross cardiac lesions or myocarditis with early heart failure, rapidly progressive hepatitis, extensive meningoencephalitis, and fulminant interstitial pneumonitis con‘See references 6,9, 13, 14, 107, 131, 132, 330,331,333-336. tributed to the mortality during infancy:41

908


Table 28-2

Clinical Findings and Their Estimated Frequency of Occurrence in Young Symptomatic Infants with Congenitally Acquired Rubella ~

Clinical Findings Adenopathies Anemia Bone Micrognathia Extremities Bony radiolucencies Brain Encephalitis (active) Microcephaly Brain calcification Bulging fontanelle Cardiovascular system Pulmonary arterial hypoplasia Patent ductus arteriosus Coarctation of aortic isthmus lnterventricular septal defect lnterauricular septal defect Others Chromosomal abnormalities Dermal erythropoiesis (blueberry muffin syndrome) Dermatoglyphic abnormalities Ear Hearing defects (severe) Peripheral Central Eye Retinopathy Cataracts Cloudy cornea Glaucoma Microphthalmos Genitourinary tract Undescended testicle Polycystic kidneyb Bilobed kidney with reduplicated ureterb Hypospadias Unilateral agenesisb Renal artery stenosis with hypertensionb Hydroureter and hydronephrosisb Growth retardation Intrauterine Extrauterine Hepatitis HeDatosplenomeqalV lmmunoiogic dyscraiias Interstitial pneumonitis (acute, subacute, chronic) Jaundice (regurgitative) Leukopenia Myocardial necrosis Neurologic deficit Prematurity Thrombocytopenia withlwithout purpura Othersb Esophageal atresia Tracheoesophageal fistula Anencephaly Encephalocele Meningomyelocele Cleft palate Inguinal hernia Asp Ienia Nephritis (vascular) Clubfoot High palate Talipes equinovarus Depressed sternum Pes cavus Clinodactyly Brachydactyly Syndactyly Elfin facies

FrequencV

++ + + + ++ ++ + Rare + ++ ++ +

Rare Rare Rare ?

+ + +++ +++ + ++ +++ ++

Rare Rare

+ + +

Rare Rare Rare Rare Rare Rare

+++ ++ Rare +++ Rare ++ + + Rare ++ + ++

References

470,471 471.472 469 469 470,473-476 477,478 308.478.479 47a.mo. 481 374,470 482 482 482

13 447 483,484 485.486 470 470 470,487489 13 308, 374,469-471.477,487,490 470 471,477,487 470,487 470, 491 -493 470,494 492 492 14,493 492 493 478 308. 374. 469-471, 477, 490 308: 494. 496 . 121,470,477,497 477,490 472 477,478,488,495 13,479

3oa,374,469-471.477,490,495 308. 374,469-471,477, 490

Rare

308 490 490 469,490 479 308,490 478 490 494 494 494 494 494 494 494 494

aFrequencyof occurrence is classified as follows: +, less than 20%; ++. 20% to 50%;+++, 50% to 75%. bRarely associated with rubella syndrome (whether caused by infection is unknown). Incidence is seemingly increased in infants with congenital rubella.

Chapter 28

Table 28-3

Abnormalities of Congenital Rubella Usually Not Detected until Second Year or Later

Defects Hearing Peripheral Central Language Developmental Motor Intellectual Behavioral Psychiatric Autism Endocrine Diabetes Precocious puberty Hypothyroidism Thyroiditis Hyperthyroidism Growth hormone deficiency Addison's disease Visual Glaucoma (later onset) Subretinal neovascularization Keratic precipitates Keratoconus Corneal hydrops Lens absorption Dental Progressive panencephalitis Educational difficulties Hypertension

References 13, 323, 328, 498-501 13, 492, 501, 502 13, 503, 504 13,479,503 13,503 13, 503 13,434 13, 112, 120, 125, 126, 128, 505 13,14 506-510 507-509 112, 511 512-514 14 51 5 516, 517 515 518 518 519 494, 520 382,466,467 13 52 1

heart lesions) are uncommon after infection beyond 8 weeks' gestation. However, the organ of Corti is vulnerable to the effects of the virus up to the first 16 weeks and perhaps up to the first 18 to 20 weeks. The deafness, ranging from mild to profound and from unilateral or bilateral, is usually peripheral (sensorineural) and is more commonly bilateral. Central auditory impairment and langua e delay may lead to a misdiagnosis of mental r e t a r d a t i ~ n . ' ~ ~ ' ~ - ~ ' ~ Developmental and Late-Onset Manifestations Developmental and late-onset manifestations have been reviewed by Sever and Shaver and their colleague^.'^^"^^ They include endocrinopathies, deafness, ocular damage, vascular effects, and progression of central nervous system disease (Table 28-3).' A number of mechanisms may be responsible for the continuing disease process that leads to these abnormalities: persistent viral infection, viral reactivation, vascular insufficiency, and immunologic insult. The last problem may be mediated by circulating immune complexes and autoantibodies. Abnormalities in cellular immunity and genetic factors have also been studied. Insulin-dependent diabetes mellitus is the most frequent of all these manifestations, occurring in approximately 20% of patients by adulthood.'3~''7~'25~'30~132~512 This reported prevalence is 100 to 200 times that observed for the general

'See references 13, 14, 117, 125, 130, 131, 133, 330,335,389,441,473,474, 486,499,505-519,522-529.

Rubella

909

population. Studies of HLA type indicate that congenital rubella syndrome patients with diabetes have the same frequencies of selected HLA haplotypes as diabetic patients without the syndrome (e.g., increased HLA-DR3 and decreased HLA-DR2). The presence of pancreatic islet cell and cytotoxic surface antibodies in children with congenital rubella syndrome does not appear to be related to any specific HLA type. It has been postulated that congenital infection increases the penetrance of a preexisting susceptibility to diabetes in these patients.13' Rabinowe and associates'33also reported an elevation in the number of Ia-positive ("activated") T cells in patients with congenital rubella syndrome. They suggested that this T cell abnormality may be related in these patients to the increased incidence of diabetes mellitus and other diseases associated with autoantibodies. Thyroid dysfunction affects about 5% of patients and manifests as hyperthyroidism, hypothyroidism, and thyroiditis.1l7,129,5 13-518 Autoimmune mechanisms appear to be responsible for these abnormalities. For example, Clarke and colleagues129reported that 23% of 201 deaf teenagers with congenital infection had autoantibodies to the microsoma1 or globulin fraction, or both fractions, of the thyroid and that 20% of those with autoantibodies had thyroid gland dysfunction. Coexistence of diabetes and thyroid dysfunction has been reported, but the significance of the association is ~nknown."~J~~ Two cases of growth hormone deficiency have been reported.519The defect appears to be hypothalamic in origin. However, among eight growth-retarded older children with congenital rubella syndrome, Oberfield520found no evidence of functional abnormality in the hypothalamic-pituitary axis and normal or elevated levels of somatomedin C. Growth patterns in a group of 105 late adolescents revealed three patterns: growth consistently below the fifth percentile; growth in the normal range but early cessation of growth, usually with a final height below the fifth percentile; and normal growth. The magnitude of the cognitive deficits was closely correlated with growth failure.521Ziring14 has commented on a case with Addison's disease, and precocious puberty has been ob~erved.'~*'~ The delayed diagnosis of preexisting deafness has already been referred to. However, the hearing deficit can increase over time, and sudden onset of sensorineural deafness may occur after years of normal auditory acuity.346,510,530 As reported by Sever and co-worker~,'~~ the latter has been observed in a child 10 years old. A number of late-onset ocular defects can occur. Glaucoma has been reported in patients between 3 and 22 years old who did not previously have the congenital or infantile variety of glaucoma associated with congenital rubella syndrome.522 Other reported manifestations are keratic precipitates, keratoconus, corneal hydrops, and spontaneous lens a b ~ o r p t i o n . ~ ~ ~ , ~ ~ ~ The retinopathy of congenital rubella, which was previously believed to be completely benign, has more recently been associated with the delayed occurrence of visual difficulties caused by subretinal neo~ascularization.~~~~~~~~~~~ Another delayed manifestation associated with vascular changes is hypertension resulting from renal artery and aortic steno~is.~~~ Mental retardation, autism, and other behavioral problems may be delayed in appearance and can be progres~ive.'~~~' However, the most interesting and serious delayed central

910


nervous system manifestation is the occurrence of a progressive and fatal panencephalitis resembling subacute sclerosing panencephalitis that manifests during the second decade of life. The first cases were reported by Weil and Townsend and their c o - w ~ r k e r s . ~ At~ the ~ , ~time ~ ~ of their review, Waxham and W ~ l i n s k y ~found ’ ~ that 10 cases of progressive rubella panencephalitis had been identified among patients with congenital rubella syndrome. Two cases have been reported after postnatally acquired Patients with this condition present with increasing loss of mental function, seizures, and ataxia. These symptoms continue to progress until the patient is in a vegetative state and ultimately dies. Rubella virus has been recovered from the brain of one congenitally infected patient.388,389 Elevated serum and cerebrospinal fluid antibodies and increased amounts of cerebrospinal fluid protein and gamma globulin have been detected. Virus has also been isolated from lymphocytes, and rubella-specific immune complexes have been Although rare, this syndrome focuses attention on the ability of the virus to persist and to become reactivated after years of latency. Long-Term Prognosis Fifty survivors of the congenital rubella epidemic of 1939 to 1943 in Australia were seen at age 25, and their status was reviewed again in 1991.579Seven subjects had died in the interval-three with malignancies, three with cardiovascular disease, and one with the acquired immunodeficiency syndrome. Among the 1991 survivors, 5 were diabetic, all 40 examined were deaf, 23 had eye defects, and 16 had cardiovascular defects. Despite these conditions, the group was characterized by remarkably good social adjustment. Most (29) were married, and they had 51 children-nly 1 with a congenital defect (deafness presumed to be hereditary from his deaf father, who did not have congenital rubella). Most were of normal stature, although 6 of the 40 were less than the third percentile for height. This group of survivors is quite different from the approximately 300 survivors followed in New York since the rubella epidemic of 1963 to 1965.580In their late 20s, approximately one third of these survivors were leading relatively normal lives in the community, one third live with their parents and may have “noncompetitive” employment, and one third reside in facilities with 24-hour care. Neither the Australian nor the New York group is a representative sample of all survivors of maternal rubella infection, but these groups do offer insight on longterm prognosis. The differences in outcome between the Australian group (survivors of Norman Gregg’s original patients) and the New York group probably reflect the different methods by which the groups were collected and the significant differences in the medical technology of the 1940s compared with the 1960s.

LABORATORY DIAGNOSIS Timely, accurate diagnosis of acute primary rubella infection in the pregnant woman and congenital rubella infection in the infant is imperative if appropriate management is to be undertaken (see “Management Issues”). The diagnosis must be confirmed serologically or virologically because clinical diagnosis of postnatal and congenital rubella is unreliable. In

any suspected exposure of a pregnant woman, every effort should be made to confirm rubella infection so that accurate counseling can be offered about the risks to the fetus. Laboratory proof of congenital infection facilitates proper treatment, follow-up, and long-term management.

Maternal Infection Because of inapparent infection, the variable clinical manifestations of rubella, and the mimicking of rubella by other viral exanthems, laboratory diagnosis is essential in managing potential rubella infection during pregnancy (see “Natural History” and “Clinical manifestation^").'^^.'^^^^^^,^^^^^^^ Although virus can be cultured from the nose and throat, isolation techniques are impractical. Although reverse transcriptase-polymerase chain reaction (RT-PCR) offers another reliable tool for confirming the diagnosis during acute rubella, laboratory confirmation usually is limited to serologic testing (see “The Virus”). Acute primary infection can usually be documented by demonstrating a significant rise in antibody level between acute and convalescent sera or the presence of rubella-specific IgM antibody. Appropriate timing of specimen collection with regard to rash onset (or exposure in the case of subclinical infection) is critical for accurate interpretation of results. Diagnosis is greatly facilitated if the immune status is known before disease onset or exposure.259Women with laboratory evidence of immunity are not at risk. From a practical point of view, women with a history of vaccination on or after the first birthday should also be considered However, because seroconversion is not 100% (see “Prevention of Congenital Rubella”),serologic testing may be indicated on an individual basis in vaccinated women who have a known exposure or a rash and illness consistent with rubella to rule out acute primary infection. Traditionally, a fourfold or greater rise in antibody titer (i.e., HI, complement fixation, or latex agglutination tests) has been considered a significant rise in antibody. However, with the advent of enzyme immunoassay, the diagnosis may be based on significant changes in optical density expressed as an index rather than a titer. The acute-phase specimen should be taken as soon as possible after onset of the rash, ideally within 7 days. If a positive titer is obtained for a specimen taken on the day of rash onset or 1 to 2 days later, the risk of acute infection is low but cannot be excluded. The convalescent-phase serum sample should be taken 10 to 14 days later. If the first serum sample is obtained more than 7 days after rash onset, some assays (e.g., HI) may not be able to detect a significant antibody rise because titers may have already peaked. In this situation, measurement of antibodies that appear later in the course of infection may be useful. A significant rise in complement fixation titer or, for example, a high HI, latex agglutination, or enzyme immunoassay titer and little or no antibody as measured by passive hemagglutination suggests recent infection. When multiple serum samples are obtained in the course of the diagnostic workup, all should be tested simultaneously in the same laboratory to avoid misinterpretation of laboratory-related variations in titer. Although a single high titer is consistent with recent infection, it is not specific enough to conclude that recent infection has occurred.259

Chapter 28

Rubella

911

situations can be minimized if prenatal rubella testing is Detection of rubella-specific IgM (RIgM) is a very useful carried out routinely. Laboratories performing prenatal method for confirming acute, recent infection. Although screening should store these specimens until delivery in case RIgM testing is valuable, a number of factors can affect test retesting is n e c e s ~ a r y . ~ ~ ~ , ~ ~ ~ results. Results must be interpreted with careful attention to the timing of the specimens. Samples taken within the first several days after onset of rash may have low or even unCongenital Infection detectable levels of RIgM, but a specimen taken 7 to 14 days A presumptive diagnosis of congenital rubella infection later invariably shows higher titers of antibody. The levels of should be entertained for any infant born to a mother who RIgM may decline promptly thereafter. Many of the methods had documented or suspected rubella infection at any time previously described for detecting IgM have some limitations during pregnancy (see “Transmission In U t e r ~ ” ) . ’ ~The ~”~~ (see “The Virus”). IgM antibody testing may involve prediagnosis should also be considered in any infant with treatment of the serum by a variety of techniques to separate evidence of intrauterine growth retardation and other IgM from IgG, such as column chromatography, sucrose stigmata consistent with congenital infection, regardless of gradient centrifugation, or adsorption of IgG with staphylomaternal history (see “Clinical Manifestations”). Although coccal protein A. The serum IgM fraction can then be such findings are sensitive for clinically apparent disease, assayed by HI, immunofluorescence, radioimmunoassay, or enzyme ~mmunoassay~~57,206-210,213,215,224-228,230-238 A falsethey are nonspecific because many of them can be associated with other intrauterine infections, such as cytomegalovirus positive result may occur if the serum was pretreated with infection, syphilis, and toxoplasmosis. Many affected infants protein A, because about 5% of IgG is not removed. The are asymptomatic. As with maternal rubella, congenital inradioimmunoassay and enzyme immunoassay techniques fection must be confirmed by laboratory tests. can directly detect specific IgM antibodies in unfractionated In contrast to maternal rubella, attempting to isolate sera, but false-positiveresults may be produced by the presence rubella virus in tissue culture is a valuable tool for diagnosing of rheumatoid factor.157~207,209A solid-phase, immunosorbent congenital rubella in newborns. The virus is most readily (i.e., capture) technique appears to be unaffected by rheumatoid factor.993210,225,236 A warning is necessary. Whereas isolated from the posterior pharynx and less consistently so high or moderate titers provide very good evidence of recent from the conjunctivae, cerebrospinal fluid, or urine.** Virus infection, low rubella-specific IgM titers detected by isolation should be attempted as soon as congenital rubella sensitive assays must be interpreted cautiously. Low titers is suspected clinically because viral excretion wanes during have been shown to persist for many months in a few patients infancy (see Fig. 28-2). In older children in whom virus after natural infection and can be detected in some immune shedding has ceased from other sites, virus may be isolated patients with subclinical reinfection.41’51’53’55’355-360 Diagnosis from cataractous lens In children with encephalitis, of subclinical infection is relatively straightforward if the virus may persist in the cerebrospinal fluid for several years.360-362,361,362,486 woman is known to be susceptible,the exposure is recognized, There are two approaches for serologic diagnosis. First, and a serum sample is obtained approximately 28 days after exposure. The diagnosis is more difficult if the immune cord serum can be assayed for the presence of rubellastatus of the woman is unknown. However, it can be facilitated specific IgM antibody.390s392,393’401 Detectable IgM antibody is if the acute-phase serum specimen is obtained as soon as a reliable indicator of congenital infection because IgM is possibIe after a recognized exposure that did not occur more fetally derived. However, false-positive results may occur than 5 weeks earlier.259The convalescent serum sample, if because of rheumatoid factor or incomplete removal of IgG necessary, should then be obtained approximately 3 weeks (largely maternal), depending on the techniques used. A minority of newborns with stigmata of congenital rubella later. If the first specimen lacks detectable antibody, continued close clinical observance and serologic follow-up are may not have detectable levels of RIgM in sera taken during the first days of life, and some infections may go undiagnecessary. If the first specimen has detectable antibody and nosed if infection occurred late in pregnancy because it is was obtained within 7 to 10 days of exposure, there is no risk of infection, and further evaluation is unnecessary. A positive theoretically possible that there was inadequate time for the titer in a specimen obtained after this period indicates a need fetus to produce detectable levels of specific IgM antibodies for further serologic investigation. If test results of paired by the time of d e l i ~ e r y . ’ ~ * ’ ~ ~ * ’ ~ ~ serum specimens are inconclusive, RIgM testing may be A second approach is to monitor IgG levels in the infant over time to see if they persist. Maternally derived antibodies helpful, but a negative test result may be difficult to interpret. More significant diagnostic difficulties arise when women have a half-life of approximately 30 days?9ov3923393 As measured of unknown immune status are exposed at an unknown by the HI test, they usually decline at a rate of one twofold dilution per month and would be expected to disappear by 6 time, were exposed more than 5 weeks earlier, or had rash onset more than 3 weeks earlier.259In these situations, expert to 12 months of age (see Fig. 28-3). Persistence of IgG antibody at this age, especially in high titer, is presumptive consultation may be necessary if positive titers are obtained. evidence of intrauterine infection with rubella virus. Sera Where available, avidity testing of rubella IgG may be used should be drawn when the child is 3 and 5 to 6 months old, to help clarify the timing of infection. Recent rubella with a repeat specimen at 12 months if necessary. All serum infection is characterized by antibody of low avidity. When samples should be tested in parallel. such low-avidity antibody is found in the presence of rubella IgM, it supports a diagnosis of recent rubella i n f e c t i ~ n . ~ ~ ~ -Important ~~ limitations of this method are the delay in diagnosis and the fact that rubella infections occurring after Unfortunately, conclusive information about the timing of past infection and risk to the fetus is often not available, “See references 2, 13, 161,277-282,284,314,315,317,319,383, 384. even when a combination of antibody assays is used. These

912


birth may be mistaken for congenital infection^.'^^,^^^ The latter is usually more of a problem when attempting to diagnose congenital infection retrospectively in patients beyond infancy, especially if the incidence of rubella in childhood is high or vaccine has already been administered. A third limitation is that some infants and children with congenital rubella syndrome (particularly older children) may lack antibody as measured by HI.335,404-406 If the diagnosis is still suspected and the HI, IgM, and culture results are negative, retesting with an assay that detects antibody to all components of the virion, such as some enzyme immunoassays, is ad~ised.8~ Some cases with undetectable HI antibody may be from an incomplete immune response to all the structural proteins of the virus, including the hemagglutinin (see “The V i r u ~ ” ) . Other ~ * ~ ~ diagnostic ~ methods, such as measurement of cellular immunity and response to vaccine (i.e., a failure to boost antibody titer), may also be helpful in this situation, but a definitive retrospective diagnosis often cannot be made.372942’,535.536 Cerebrospinal fluid may also be examined for the presence of rubella-specific IgM.537As in the case for acquired infection, determination of avidity of IgG may be ~ s e f u l . ~ ~ ~ ~ ~ ” * ~ ~ ~ The availability of sensitive and specific tests for prenatal diagnosis of fetal infection after suspected or documented maternal rubella can greatly facilitate counseling. Although positive diagnoses were reported from examination of amniotic fluid, fetal blood, and chorionic villus sampling for virus isolation, rubella-specific IgM and antigens, interferon, and RNA,9934273539-545 the low sensitivity of these assays added little to the counseling process. Reverse transcription-nested polymerase chain reaction has been reported to offer a far more reliable and rapid tool and, where available, a valuable aid to c o u n ~ e l i n gTiming . ~ ~ ~ ~of~the ~ ~specimen collection related to the timing of maternal infection may influence sensitivity, which reached 100% (eight of eight specimens) for amniotic 5uid in one study and 83% (five of six specimens) for chorionic villus sampling in another study. Repeat testing may increase the yield of positive specimens.539s548

MANAGEMENT ISSUES

extensive viral replication is demonstrable a week or more before symptoms appear, with initial replication probably beginning even earlier. The amount of antirubella antibody in commercial immune globulin preparations is variable and unpredictable; specific hyperimmune globulin preparations are not available.5527553 Theoretically, the role of circulating antibodies in rubella is mainly to limit the viremia and possibly to prevent replication at the portal of entry; antibody is less valuable after infection has begun. Fetal infection occurred when immune globulin was administered to the mother in what appeared to be adequate amounts soon after exposure. Another disadvantage of immune globulin is that it may eliminate or reduce clinical findings without affecting viral replication. Clinical clues of maternal infection would be masked without adequate protection of the fetus, resulting in a false sense of security. It is recommended that use of immune globulin be confined to those rubella-susceptible women known to have been exposed who do not wish to interrupt their pregnancy under any circumstance^.^^^'^^^ In this situation, large doses (20 mL in adults) should be administered. The patient should be advised that protection from fetal infection cannot be guaranteed.

Termination of Pregnancy A discussion of the complex issues involved in the decision about termination of pregnancy for maternal rubella is beyond the scope of this chapter. The decision must be carefully weighed by the physician and the prospective parents. The physician must have a thorough understanding of the known facts about the pathogenesis and diagnosis of congenital rubella and the risks to the fetus depending on the timing of maternal infection. Where available, analysis of amniotic fluid, fetal blood, or chorionic villus sampling by reverse transcription-nested polymerase chain reaction may assist in antenatal diagnosis of i n f e ~ t i o n . 5 Expert ~ ~ ‘ ~ ~con~ sultation is desirable to ensure that the most current information is used in the decision-making process.

Clinical Management

Acute rubella infection usually requires little clinical management. However, the patient with congenital infection may require medical, surgical, educational, and rehabilitative management. Many lesions are not apparent at birth because they have not yet appeared or cannot be detected. In keeping with its chronicity, congenital rubella must be managed as a dynamic rather than a static disease state. A continuing effort on the part of the physician must be made to define initially the extent of the problem and to detect evidence of progressive disease or emergence of new problems over time. Because of the broad range of problems, a multidisciplinary team approach to care is essential. Complete pediatric, neurologic, cardiac, ophthalmologic, Use of Immune Globulin and audiologic examinations should be complemented by complete blood cell count, by radiologic bone surveys, and The role of passive immunization with immune globulin after exposure to rubella is controversial.2~6~9~2g4~3~~33z~335~549~55z often by evaluation of cerebrospinal fluid for all newborns in Brody and c o - w o r k e r ~reported ~ ~ ~ that large doses of immune whom the diagnosis is suspected, whether the infant is symptomatic or not. Some defects, such as interstitial globulin may have some efficacy, but in general, it proved to be more useful when given prophylactically than when pneumonitis, can be slowly progressive and apparently cause administered after exposure. This is not surprising because their major functional difficulties months after birth.

The major management issues associated with postnatal infection arise when a pregnant woman is at risk of acquiring infection. Confirming the diagnosis, counseling about the risks of infection of and damage to the fetus, and discussing courses of action, including the use of immune globulin and consideration of termination of pregnancy, require a thorough understanding of the natural history and consequences of rubella in pregnancy. In the case of congenital infection, the emphasis is on diagnosis and acute and long-term management. Isolation may be important to reduce spread of infection.

Chapter 28 Infected infants require scrutiny during the first 6 months of life. Serial assessment for immunologic dyscrasias is necessary during this period because the humoral defects may be masked by the presence of maternal immunoglobulin. Hearing defects and psychomotor difficulties are by far the most important problems because of their high incidence. Both often occur in infants who are initially asymptomatic. The new techniques for detection of hearing impairment in newborns and the state-mandated universal newborn hearing screening testing requirements have been initiated too recently to determine their utility in detection of unsuspected congenital rubella. Delay in diagnosis and therapeutic intervention has a profound impact on language development and skills acquisition and can mag* psychosocial adjustment problems within the entire family constellation. Because many children with congenital rubella are multihandicapped, early interdisciplinary treatment is warranted. Appropriate hearing aids; visual aids, including contact lenses; speech, language, occupational, and physical therapy; and special educational programs are frequently required for such children. Serial psychologic and perceptual testing may be very helpful for ongoing management, particularly when performed by individuals experienced in assessing multihandicapped, sensorially deprived children. In many cases, repeated testing is important because the problems appear to be progressive and require continuing assessment of the therapeutic approach. In the United States, most infants suspected of congenital rubella are eligible for early intervention and habilitation services authorized by the Federal Individuals with Disabilities Education Act. These programs offer such services to affected children beginning in infancy, a critical time for children who may be hearing impaired. The impact of universal newborn hearing screening programs as another tool for early detection of congenital rubella and of cochlear implants for children with severe rubella deafness remains to be seen.

Chemotherapy Because postnatal rubella is usually mild, there has been little need to pursue chemotherapeutic regimens, and the literature on this subject is sparse. Interferon has been used to treat chronic arthritis, and isoprinosine has been administered to a patient with postnatally acquired progressive rubella panen~ephalitis?~~~~~’~~~~ Chance temporal association between interferon administration and reported improvement in joint symptoms cannot be differentiated from potential therapeutic benefits of the interferon. In the trial of isoprinosine, no improvement was observed. The number of reports regarding treatment of infants with congenital rubella is somewhat limited. The course of congenital infection does not appear to be altered by any available chemotherapeutic agent. Because amantadine reduces the replication of rubella virus in vitro, it has theoretical possibilities as a chemotherapeutic agent.15*-16’Its use, however, has been confined to a 5-month-old infant with congenital infection.’61Neither virus excretion nor clinical status was affected. Interferon has also been administered to a few infants with congenital rubella syndrome. Arvin and associates555reported that nasopharyngeal excretion in three infants (3 to 5 months old) persisted throughout interferon administration, although at reduced titers compared with

Rubella

913

baseline. There was, however, no clinical effect. Larsson and c o - ~ o r k e r sadministered ~~~ interferon to a 14-month-old child and reported regression of a cutaneous eruption resulting from vasculitis and disappearance of viremia. However, viruria and other signs of viral persistence (e.g., rubellaspecific IgM in the cerebrospinal fluid) were unaffected. It is also not certain whether improvement in the rash was from interferon administration or was coincidental. A 10-monthold infant treated by Verder and c o - ~ o r k e r s ’may ~ ~ have benefited from interferon, but it is noteworthy that improvement was also seen after exchange transfusions that preceded the interferon treatment. Isoprinosine has been administered to some patients with progressive rubella p a n e n c e p h a l i t i ~ . ~ ~ ~ . ~ ~ ~ As for postnatally acquired disease, the results in this case have been disappointing.

Isolation Patients with rubella are considered infectious from the fifth day before to the seventh day after the onset of the rash and should he placed in contact isolation.558Exposed rubellasusceptible patients confined to hospital should be placed in contact isolation from the 7th through 21st day after exposure and tested appropriately to rule out asymptomatic infection.559 Infectious patients with congenital rubella should also be in contact isolation.558Isolation precautions should be instituted as soon as rubella or congenital rubella is suspected. Only persons known to be immune (i.e., those with serologic evidence of immunity or documentation of vaccination on or after the first birthday) should care for infectious or potentially infectious patient^.*^^,^^^ Children with congenital rubella syndrome should be considered infectious for the first year of life unless repeated pharyngeal and urine culture results are negative.2573558 Culture results are unlikely to become negative until the child is 3 to 6 months old (see Fig. 28-2). From a practical point of view, children older than 1 year are unlikely to be a significant source of infection. In the home situation, susceptible pregnant visitors should be informed of the potential risk of exposure.

PREVENTION OF CONGENITAL RUBELLA

Rubella Vaccine and Immunization Strategies Active immunization is the only practical means to prevent congenital rubella because passive immunization provides unreliable, transient protection (see “Management Issues”). However, there has been considerable debate about the best way to use the vaccine.3’5-7,30,35,560 Because rubella vaccination is not aimed primarily at protecting the individual, but rather the unborn fetus, two basic strategies have been proposed: universal childhood immunization and selective vaccination of susceptible girls and women of childbearing age. The former approach is designed to interrupt transmission of virus by vaccinating the reservoir of infection, reduce the overall risk of infection in the general population, and provide indirect protection of unvaccinated, postpubertal women. The latter approach directly protects those at risk of being infected when pregnant, limits overall vaccine use, and allows virus to circulate and boost vaccine-induced immunity in

914


the population. Experience gained during the past 30 years old recipients in 1994, and added a preschool MMR booster indicates that integration of both is necessary to achieve in 1996 (P Tookey, National Congenital Rubella Surveillance maximum control in the shortest possible time.5,30,33935 Program, personal communication, June 1999).33*35 At the time of licensure in 1969, available information Update on Vaccine Characteristics indicated that the live-attenuated rubella vaccines were safe, noncommunicable, and highly e f f e ~ t i v e . ~ ’ ~Although ’~~-~’ Approximately 200 million doses of vaccine have been information on the duration of vaccine-induced immunity administered in the United States since rubella vaccines were was limited, public health policy makers in the United States licensed in 1969. The RA 2713 strain of vaccine was licensed believed that vaccination of all children would provide profor use in the United States in 1979 and is now the only tection into the childbearing years. The duration and quality vaccine available. Although it has been used intranasally, it is of the immunity would have to be monitored continually. licensed only for subcutaneous administration. The RA 2713 Because vaccine virus could cross the placenta and infect the vaccine elicits an immune response that more closely fetus, cautious recommendations for vaccination of susceptible resembles that occurring after natural infection than the women of childbearing age were also p r ~ p o s e d . ~Vaccine ~ ’ - ~ ~ ~ Cendehill or HPV-77 strains of vaccines do.192,376,377,565 Howwas to be administered in this population only after ever, there are no data to indicate the need for revaccination susceptibility had been documented by serologic testing. of persons who had not previously received the RA 2713 Vaccinated women were also advised to avoid conception for vaccine. Although comparative data are not available, at least 2 months after vaccination. After Fleet and colleagues564 one study has shown that the RA 2713 vaccine induces antiisolated virus from the fetus of a woman who had conceived body formation to the three major rubella virus structural 7 weeks before vaccination, this time interval was increased proteins.” to 3 months as an extra p r e c a u t i ~ n . ~ ~ ~ , ~ ~ ~ Appropriate administration of vaccine induces an In England and other areas of the world, mass vaccination antibody response in 95% or more of persons 12 months old was considered undesirable because of concerns about the or older when vaccinated. Vaccine efficacy and challenge ~ ~ . ’ ~ ~studies indicate that more than 90% to 95% of vaccinated duration of vaccine-induced i m m ~ n i t y . ~ - ~In-stead, vaccine was targeted for all schoolgirls 1 1 to 14 years of age persons are protected against clinical illness or asymptomatic and postpubertal females known to be seronegative.As with viremia. Whereas vaccine-induced titers are lower than those the U.S. program, pregnancy was to be avoided for up to after natural infection and are more likely to increase after 3 months after immunization. The goal was to immunize at reexposure, protection after a single dose of vaccine is, for the most part, solid and lasts for at least 18 years, if not least 90% of the women immediately at risk and simultaneously provide a higher level of immunity throughout the for life.* childbearing-aged group. It was recognized that this approach Detectable HI antibodies persist in almost all vaccinated subjects who initially ~ e r ~ c ~ n ~ e Long-term r t . ~ ~ ~ ~ ~ ~ would take many years to have a significant effect on the incidence of congenital infection. studies of vaccinated persons who initially seroconverted and then lost detectable HI antibodies indicate that most of these The U.S. strategy prevented epidemic disease but initially individuals are also immune because they have detectable had little effect on the occurrence of infection in young antibodies as measured by other, more sensitive assays or adults, particularly women of childbearing age (see have a booster immune response (i.e., absence of IgM anti“Epidemiology”).5*24*31736,2583292 Although vaccine was recombody and a rapid rise and decline in IgG antibody) after remended for susceptible women, concerns about the effect of the vaccine on the fetus led to low immunization coverage in v a c c i n a t i ~ n Viremia . ~ ~ ~ ~and ~ ~reinfection ~~~ have been docuthis population. There was no evidence that infection was mented in some vaccinated persons and some naturally occurring in individuals who had been vaccinated years immune individuals who had very low titers of antibody.38,40,44,50~56 It is unknown how often this phenomenon earlier (see “Update on Vaccine Characteristics”). Childhood occurs or places the fetus at risk, but the incidence of both vaccination decreased the overall risk of infection, but virus events is believed to be 10w.~There are rare case reports of could still circulate in the community, especially wherever unvaccinated adolescents and adults c ~ n g r e g a t e d . ~ ~ congenital ~ ~ ~ ~ ~ infection ~ ~ ” ~ ~after ~ ~ reinfection of mothers who had been previously infected or vaccinated (see “The Virus” and Although congenital rubella syndrome could eventually be eliminated as vaccinated cohorts of children entered the “Natural History~~).43,45,52,1~~,~16,321,326-328 The lack of an international standard level of antibody considered to be childbearing years, this process would take many years, and protective frequently complicates the interpretation of seropotentially preventable cases of congenital infection would logic data when antibodies are detected only by tests more continue to occur.268Accordingly, specific recommendations sensitive than the HI test. Cutoff levels ranging from 5 to were made to increase vaccination levels in older individuals, particularly women of childbearing age (see “Vaccine 15 IU have been ~ ~ e dAvailable . information ~ ~ ~ ~ Recommendations”).255,257 indicates that any appropriately measured level of detectable Selective vaccination programs have not been successful antibody should be considered presumptive evidence of past because of the inability to immunize a sufficient proportion infection and This applies to naturally of the female population.7s33934 With this immunization acquired and vaccine-induced immunity. approach, large-scale epidemics continue to occur, and the Rubella vaccine is remarkably safe. Rash, low-grade fever, incidence of congenital rubella has not declined significantly and lymphadenopathy are occasionally observed. The polysince the introduction of vaccines. Because of these problems, neuropathies, myositis, and vasculitis associated with the in 1988, Great Britain implemented a program of MMR vaccination for all children in the second year of life, began a mass measles-rubella vaccine program for 5- to 16-year‘See references 38-40,43,44,46,48-50,54,56,57,260,305,566-569.

Chapter 28 HPV-77 strain of vaccine have not been reported after administration of the RA 2713 strain?’571 Vaccine-related arthralgia and arthritis remain a concern, particularly for susceptible adult women.538759,61,62,M Although arthralgia has been reported in up to 3% of susceptible children, arthritis has been reported rarely in these vaccinated subjects. In contrast, joint pain occurs in up to 40% of susceptible vaccinated females, with arthritis-like signs ~” and and symptoms reported in 10% to ~ O Y O . ~Persistent recurring joint complaints have been reported, but most studies indicate that they occur infrequently. The high frequency (5%) of persistent joint symptoms reported by one group of investigators has not been confirmed.83M However, this rate is stdl far less than that (30%) after natural infection, as reported by the same group of researchers.MPermanent disability and joint destruction have also been reported, but only rare1y:l~~~ Most published data indicate that these and other adverse events associated with rubella vaccine occur only in susceptible vaccinated persons.538There is no conclusive evidence that there is an increased risk of reactions in persons who are already immune at the time of v a c c i n a t i ~ n . ~Vaccination ~~”~~ programs of adults have not led to significant rates of absenteeism or disruption in every&y, work-related activities.8’271,273-276

Although some vaccinated persons intermittently shed virus in low titers from the pharynx 7 to 28 days after vaccination, there is no evidence that vaccine virus is spread to susceptible contacts.53565 Vaccine virus can, however, be recovered from breast milk and may be transmitted to the breast-fed neonate.61s3433572’573 The vaccine virus may elicit an immune response in some exposed neonates. There is no evidence of a significant alteration in the immune response or increased risk of reactions after vaccination at a later date.62364 Although a mild clinical infection from transmitted vaccine virus has been reported, infection with wild-type virus might have occurred.574 The fetotropic and teratogenic potential of rubella vaccine virus has greatly influenced vaccination practices, not only in the United States but also worldwide. With the increased emphasis on vaccinating susceptible,postpubertal females in the United States, especially recent immigrants, the need to have accurate information on the risks of the vaccine virus on the fetus became even more important. From 1971 through 1988, the Centers for Disease Control followed to term prospectively 321 pregnant women known to be susceptible to rubella by serologic testing who were Table 28-4

Rubella

915

vaccinated in the period from 3 months before to 3 months after conception (Table 28-4).65,255 Approximately one third received vaccine during the highest risk period for viremia and fetal defects (1 week before to 4 weeks after con~ e p t i o n ) . ~ Ninety-four *.~~ received HPV-77 or Cendehill vaccines, 1 received a vaccine of unknown strain, and 226 received RA 27/3vaccine. None of the 229 offspring (three mothers who received RA 2713 vaccine had twins) had malformations consistent with congenital rubella infection. Although the observed risk of congenital defects is zero, the maximal estimated theoretical risk of serious malformations attributable to any rubella vaccine is 1.2%, based on the 95% confidence limits of the binomial distribution. If only the infants exposed to the RA 27/3 vaccine are considered, the maximal theoretical risk is 1.7%. The overall maximal theoretical risk remains far less than that for congenital rubella syndrome after maternal infection with wild-type virus during the first trimester of pregnancy (up to 70%) and is no greater than the 2% to 3% rate of major birth defects in the absence of exposure to rubella Four children were born with various congenital malformations consistent with congenital rubella, and their mothers were later found to have received rubella vaccine within 3 months of con~eption.~*~~’ Clinical, epidemiologic, and laboratory data indicate that all the mothers had natural rubella infection. These favorable data are consistent with the experience reported with Cendehill and RA 2713 vaccines in the Federal Republic of Germany and the United Kingd0rn.6~~~~ None of 98 infants in the Federal Republic of Germany and none of 21 infants in Great Britain whose mothers were known to be susceptible when vaccinated were born with congenital anomalies consistent with congenital rubella syndrome. The most reassuring information comes from a rubella vaccine mass campaign involving 16 million women in Brazil during 2001 and 2002, among whom were 2327 susceptible,pregnant women. Follow-up studies on 76% of these women revealed an infection rate of 3.6% among their newborns but no evidence of increased abortion, stillbirth, preterm birth, or congenital rubella syndrome (R Soares, provisional data presented at the PAHO Conference, Washington, DC, March 3, 2004). Although fetal infection occurs, if rubella vaccine has any teratogenic potential, it must be rare.

Vaccination Recommendations The control of rubella and congenital rubella in the United States has been predicated on universal immunization of

Maximal Theoretical Risks of Congenital Rubella Syndrome after Rubella Vaccination by Vaccine Strain, United States, 1971 to 1988’ Risk of CRS

Vaccine Strain RA 27B Cendehill or HPV-77 Unknown Total

Susceptible Vaccinated Subjects

Normal Livebirths

Observed

Theoretical

226

22gb 94 1 324

0

0-1.8 0-3.8

94 1 321

aNowomen entered in the register after 1980 were vaccinated with Cendehill or HPV-77 vaccine. blncludes three twin births. CRS, congenital rubella syndrome.

0 0

0-1.2

916

Section I11

Viral Infections

children, with a single dose of vaccine given after the first birthday, and selective immunization of postpubertal and susceptible postpartum women. This approach remains the basis for current recommendations of the Advisory Committee on Immunization Practices (ACIP) of the Public Health Service and the American Academy of Pediatrics (AAP).255%257 However, part of this success has come from the recommended use of rubella vaccine as a component of the combined MMR vaccine, which in the United States is given routinely to 15-month-old children. As concerns arose about measles in adolescents and adults, attributed to the existence of a cohort of young adults representing the 2% to 10% failure rate for a single dose of measles vaccine and the theoretical possibility of waning immunityafter successful immunization in early childhood, the ACIP and AAP added a second dose to the measles immunization schedule in 1989. The specific recommendation was that the second dose be given just before school entry or in the prepubertal period and that the vaccine be given as the MMR ~ a c c i n e . ’ ~ ~ , ~ ~ ~ Rubella immunization (as MMR vaccine) should be offered to all women of childbearing age who do not have acceptable evidence of rubella immunity. Given the current data,routine screening of postpuberal women for susceptibility before rubella vaccination is no longer recommended. However, women should understand the theoretical risk of fetal infection and be advised not to become pregnant for at least 28 days after va~cination.’~~ Known pregnancy is still considered a contraindication. Missed opportunities should not be confused with bona fide contraindications for rubella immunization. These include the following: 1. Severe febrile illness 2. Altered immunity from congenital immunodeficiency; from acquired diseases such as leukemia, lymphoma, and generalized malignancy; and from therapy with radiation, corticosteroids, alkylating drugs, and antimetabolites 3. History of an anaphylactic reaction to neomycin (the vaccine does not contain penicillin) 4. Pregnancy, albeit because of theoretical concerns

Because vaccine virus is not transmitted through the nasopharynx, the presence of a susceptible pregnant woman in a household is not a contraindication for vaccination of other household members. Vaccine virus is present in breast milk and can infect the neonate, but breast-feeding also is not a contraindication to vaccination. Although vaccination is usually deferred for 8 to 12 weeks after receipt of immune globulin, receipt of anti-Rho (D) immune globulin (human) or blood products does not generally interfere with seroconversion and is not a contraindication to postpartum v a c c i n a t i ~ n . However, ~ ~ ~ - ~ ~in ~ this situation, 6- to 8-week postvaccination serologic testing should be performed to ensure that seroconversion has taken place.577This is the only situation in which postvaccination testing is recommended as routine.

Outbreak Control Although outbreak control is an after-the-fact method of prevention, rapid, aggressive responses to outbreaks are necessary to limit the spread of infection and can serve as a

catalyst to increase immunization levels. Although there is no conclusive evidence that vaccination after exposure prevents rubella, there are also no data to suggest that vaccinating an individual incubating rubella is harmful. Vaccination programs initiated in the middle of an outbreak serve to protect persons not adequately exposed in the current outbreak from future exposures. Although laboratory confirmation of cases is important, control measures-including isolation of suspected cases or susceptible exposed persons, vaccination or exclusion of susceptible persons, and confirmation of the immune status of exposed pregnant women-should be implemented as soon as a suspected case has been identified (see “Management Issues”). Ideally, mandatory exclusion and vaccination of susceptible individuals should be practiced to ensure high rates of vaccination in the shortest possible period, particularly in the medical setting. Vaccination during an outbreak has not been associated with significant absenteeism in the workp l a ~ e . ~However, ~ ~ ~ vaccination ’ ~ ~ ~ ~before - ~ ~the~ occurrence of an outbreak is preferable, because vaccination causes far less disruption of routine work activities and schedules than rubella infection.

Surveillance Surveillance of rubella and congenital rubella is necessary for rubella prevention because the information can be used to evaluate the progress of the immunization program, to identify high-risk groups that would benefit from specific interventions, and to monitor the safety, efficacy, and durability of the vaccine. Surveillance can also draw attention to small numbers of cases before they develop into sizable outbreaks. Because rubella and congenital rubella are reportable diseases, all suspected cases should be reported to local health officials.

Prospects for the Future Full implementation of the two-dose MMR vaccine recommendation should eliminate indigenous congenital rubella from the United States, and the PAHO goal of eliminating rubella in the Western Hemisphere by 2010 is realistic. However, given the frequency of international travel, all countries will remain at risk of imported disease during the foreseeable future. Clearly, there is more pressure on the world health community to eliminate measles globally. Including rubella vaccine in a combined vaccine with measles for global use remains the best hope of preventing what remains a significant disease burden in many other countries.581 Although 58% of countries have vaccine available, most have not implemented effective rubella immunization programs. A recent report from Morocco has demonstrated annual rates of congenital rubella syndrome in the range of 8.1 to 12.7 cases per 1000 live births.581aMaintaining high levels of immunization, ongoing surveillance (recognizing that the sporadic nature of new cases likely will add to delay in diagnosis), and prompt outbreak control measures remain critical for ultimate elimination of rubella. The efforts underway in the Western Hemisphere can be a global model that eventually will make rubella and congenital rubella syndrome matters of historic intere~t.~”

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208. Meurman OH, Vijanen MK, Granfors K. Solid-phase radioimmunoassay of rubella virus immunoglobulin M antibodies: comparison with sucrose density gradient centrifugation test. J Clin Microbiol 5:257, 1977. 209. Meurman OH, Ziola BR. IgM-class rheumatoid factor interference in the solid-phase radioimmunoassay of rubella-specific IgM antibodies. J Clin Pathol31:483, 1978. 210. Mortimer PP, Tedder RS, Hambling MH, et al. Antibody capture radioimmunoassay for anti-rubella IgM. J Hyg (Lond) 86:139, 1981. 211. Brown GC, Maassab HF, Veronelli JA, et al. Rubella antibodies in human serum: detection by the indirect fluorescent-antibody technic. Science 145:943, 1964. 212. Cradock-Watson JE, Ridehalgh MKS, Pattison JR, et al. Comparison of immunofluorescence and radioimmunoassay for detecting IgM antibody in infants with the congenital rubella syndrome. J Hyg (Lond) 83:413, 1979. 213. Leinikki PO, Shekarchi I, Dorsett P, et al. Determination of virusspecific IgM antibodies by using ELISA elimination of false-positive results with protein A-Sepharose absorption and subsequent IgM antibody assay. J Lab Clin Med 92849,1978. 214. Vejtorp M. Enzyme-linked immunosorbent assay for determination of rubella IgG antibodies. Acta Pathol Microbiol Scand 86387, 1978. 215. Vejtorp M, Fanoe E, Leerhoy J. Diagnosis of postnatal rubella by the enzyme-linked immunosorbent assay for rubella IgM and IgG antibodies. Acta Pathol Microbiol Scand 87:155,1979. 216. Bidwell D, Chantler SM, Morgan-Capner P, et al. Further investigation of the specificity and sensitivity of ELISA for rubella antibody screening. J Clin Pathol33:200, 1980. 217. Skendzel LP, Edson DC. Evaluation of enzyme immunosorbent rubella assays. Arch Pathol Lab Med 109391,1985. 218. Morgan-Capner P, Pullen HJM, Pattison JR, et al. A comparison of three tests for rubella antibody screening. J Clin Pathol32:542,1979. 219. Champsaur H, Dussaix E, Tournier P. Hemagglutination inhibition, single radial hemolysis, and ELISA tests for the detection of IgG and IgM to rubella virus. J Med Virol5273,1980. 220. Deibel R, D’Areangelis D, Ducharme CP, et al. Assay of rubella antibody by passive hemagglutination and by a modified indirect immunofluorescence test. Infection 8(Suppl3):S255,1980. 221. Zartarian MV, Friedly G, Peterson EM, et al. Detection of rubella antibodies by hemagglutination inhibition, indirect fluorescent-antibody test, and enzyme-linked immunosorbent assay. J Clin Microbiol 14640,1981. 222. Weissfeld AS, Gehle WD, Sonnenworth AC. Comparison of several test systems used for the determination of rubella immune status. J Clin Microbiol 1682, 1982. 223. Truant AL, Barksdale BL, Huber TW, et al. Comparison of an enzyme-linked immunosorbent assay with indirect hemagglutination inhibition for determination of rubella virus antibody: evaluation of immune status with commercial reagents in a clinical laboratory. J Clin Microbiol 17106, 1983. 224. Field PR, Gong CM. Diagnosis of postnatally acquired rubella by use of three enzyme-linked immunosorbent assays for specific immunoglobulins G and M and single radial hemolysis for specific immunoglobulin G. J Clin Microbiol20:951, 1984. 225. Cubie H, Edmond E. Comparison of five different methods of rubella IgM antibody testing. J Clin Pathol 38:203, 1985. 226. Enders G. Serologic test combinations for safe detection of rubella infections. Rev Infect Dis 7(Suppl l):S113,1985. 227. Forsgren M. Standardization of techniques and reagents for the study of rubella antibody. Rev Infect Dis 7(Suppl 1):S129, 1985. 228. Grillner L, Forsgren M, Nordenfelt E. Comparison between a commercial ELISA, Rubazyme, and hemolysis-in-gel test for determination of rubella antibodies. J Virol Methods 10:111, 1985. 229. Chernesky MA, Smaill F, Mahony JB, et al. Combined testing for antibodies to rubella non-structural and envelope proteins sentinels infections in two outbreaks. Diagn Microbiol Infect Dis 8:173, 1987. 230. Ankerst J, Christensen P, Kjellen L, et al. A routine diagnostic test for IgA and IgM antibodies to rubella virus: absorption of IgG with Staphylococcus aureus. J Infect Dis 130:268, 1974. 231. Pattison JR, Mace JE. Elution patterns of rubella IgM, IgA, and IgG antibodies from a dextran and an agarose gel. J Clin Pathol 28:670, 1975. 232. Pattison JR, Mace JE,Dane DS. The detection and avoidance of falsepositive reactions in tests for rubella-specific IgM. J Med Microbiol 9:355, 1975.

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293. Buescher EL. Behavior of rubella virus in adult populations. Arch Gesamte Viusforsch 16:470,1965. 294. Green RH, Balsame MR, Giles JP, et al. Studies of the natural history and prevention of rubella. Am J Dis Chdd 110:348,1965. 295. Horstmann DM, Riordan JT, Ohtawara M, et al. A natural epidemic of rubella in a closed population. Arch Gesamte Virusforsch 16483, 1965. 296. Brody JA. The infectiousness of rubella and the possibility of reinfection. Am J Public Health 561082,1966. 297. Bisno AL, Spence LP, Stewart JA, et al. Rubella in Trinidad: seroepidemiologic studies of an institutional outbreak. Am J Epidemiol 8974,1969. 298. Gale JL, Detels R, Kim KSW, et al. The epidemiology of rubella on Taiwan. 111. Family studies in cities of high and low attack rates. Int J Epidemiol 1:261,1972. 299. Neva FA, Alford CA Jr, Weller TH. Emerging perspective of rubella. Bacteriol Rev 28:444,1964. 300. Brody JA, Sever JL, McAlister R, et al. Rubella epidemic on St. Paul Island in the Pribilofs, 1963.I. Epidemiologic, clinical, and serologic findings. JAMA 191:619,1965. 301. Sever JL, Brody JA, Schiff GM, et al. Rubella epidemic on St. Paul Island in the Pribilofs, 1963.11. Clinical and laboratory findings for the intensive study population. JAMA 191:624,1965. 302. Halstead SB, Diwan AR, Oda AI. Susceptibility to rubella among adolescents and adults in Hawaii. JAMA 210:1881,1969. 303. Hinman AR, Irons B, Lewis M, Kandola K. Economic analyses of rubella and rubella vaccines: a global review. Bull World Health Organ 80264,2003. 304. Wilkins J, Leedom JM, Portnoy B, et al. Reinfection with rubella virus despite live vaccine-induced immunity. Am J Dis Child 118:275, 1969. 305. Chang TW,DesRosiers S, Weinstein, L. Clinical and serologic studies of an outbreak of rubella in a vaccinated population. N Engl J Med 283246,1970. 306. Gross PA, Portnoy B, Mathies AW, et al. A rubella outbreak among adolescent boys. Am J Dis Child 119:326,1970. 307. Shlian DM. Screening and immunization of rubella-susceptible women: experience in a large, prepaid medical group. JAMA 240662, 1978. 308. Preblud SR, Gross F, Halsey NA, et al. Assessment of susceptibility to measles and rubella. JAMA 247:1134,1982. 309. Miller KA. Rubella susceptibility in an adolescent female population. Mayo Clin Proc 59:31,1984. 310. M e n S. Rubella susceptibility in young adults. J Fam Pract 21:271, 1985. 311. &hen ZB, Rice LI, Felice ME. Rubella seronegativity in a low socioeconomic adolescent female population. Clin Pediatr (Phila) 24387, 1985. 312. Dorfman SF, Bowers CH Jr. Rubella susceptibility among prenatal and family planning clinic populations. Mt Sinai J Med 52:248, 1985. 313. Serdula MK, Marks JS, Ibara CM, et al. Premarital rubella screening program: from identification to vaccination of susceptible women in the state of Hawaii. Public Health Rep 101:329,1986. 3 14. Alford CA, Neva FA, Weller TH. Virologic and serologic studies on human products of conception after maternal rubella. N Engl J Med 271:1275,1964. 315. Horstmann DJ, Banatvala JE, Riordan JT,et al. Maternal rubella and the rubella syndrome in infants. Am J Dis Child 110408,1965. 316. Monif GRG, Sever JL, Schiff GM, et al. Isolation of rubella virus from products of conception. Am J Obstet Gynecol91:1143,1965. 317. Alford CA Jr. Congenital rubella: a review of the virologic and serologic phenomena occurring after maternal rubella in the first trimester. South Med J 59745,1966. 318. Heggie AD. Intrauterine infection in maternal rubella. J Pediatr 71: 777,1967. 319. Rawls WE, Desmyter J, Melnick JL. Serologic diagnosis and fetal involvement in maternal rubella. JAMA 203:627,1968. 320. Thompson Kh4, Tobin JO. Isolation of rubella virus from abortion material. BMJ 2:264,1970. 321. Strannegard 0, Holm SE, Hermodsson S, et al. Case of apparent reinfection with rubella. Lancet 1:240,1970. 322. Boue A, Nicholas A, Montagnon B. Reinfection with rubella in pregnant women. Lancet 2:1251,1971. 323. Haukenes G, Haram KO. Clinical rubella after reinfection. N Engl J Med 2871204,1972.

324. Northrop RL, Gardner WM, Geittman WF. Rubella reinfection during early pregnancy. Obstet Gynecol39524,1972. 325. Northrop RI, Gardner WM, Geittmann WF. Low-level immunity to rubella. N Engl J Med 287615,1972. 326. Eilard T, Strannegard 0. Rubella reinfection in pregnancy followed by transmission to the fetus. J Infect Dis 129594,1974. 327. Snijder JAM, Schroder FP, Hoekstra JH. Importance of IgM determination in cord blood in cases of suspected rubella infection. BMJ 1:23,1977. 328. Forsgren M, Carlstrom G, Strangert K. Congenital rubella after maternal reinfection. Scand J Infect Dis 11:81, 1979. 329. Fogel A, Handsher R, Barnea B. Subclinical rubella in pregnancyoccurrence and outcome. Isr J Med Sci 21:133,1985. 330. Sheridan MD. Final report of a prospective study of children whose mothers had rubella in early pregnancy. BMJ 2536,1964. 331. Butler NR, Dudgeon JA, Hayes K, et al. Persistence of rubella antibody with and without embryopathy: a follow-up study of children exposed to maternal rubella. BMJ 2:1027,1965. 332. Phillips GA, Melnick JL,Yow MD, et al. Persistence of virus in infants with congenital rubella and in normal infants with a history of maternal rubella. JAMA 193:1027,1965. 333. Hardy JB, McCracken GH Jr, Gilkeson MR, et al. Adverse fetal outcome following maternal rubella after the first trimester of pregnancy. JAMA 207:2414, 1969. 334. Schiff GM, Sutherland J, Light I. Congenital rubella. In Thalhammer 0 (ed). Prenatal Infections. International Symposium of Vienna, September 2-3,1970.Stuttgart, Georg Thieme Verlag, 1971,p 31. 335. Peckham GS. Clinical and laboratory study of children exposed in utero to maternal rubella. Arch Dis Child 47:571,1972. 336. Menser MA, Forrest JM. Rubella-high incidence of defects in children considered normal at birth. Med J Aust 1:123,1974. 337. Dudgeon JA. Infective causes of human malformations. Br Med Bull 32:77,1976. 338. Lundstrom R. Rubella during pregnancy: a follow-up study of children born after an epidemic of rubella in Sweden, 1951,with additional investigations on prophylaxis and treatment of maternal rubella. Acta Paediatr Sl(Supp1 133):1,1962. 339. Whitehouse WL. Rubella before conception as a cause of foetal abnormality. Lancet 1:139,1963. 340. Monif GRG, Hardy JB, Sever JL. Studies in congenital rubella, Baltimore 1964-65. I. Epidemiologic and virologic. Bull Johns Hopkins Hosp 118:85,1966. 341. Sever JL, Hardy JB, Nelson KB, et al. Rubella in the Collaborative Perinatal Research Study. 11. Clinical and laboratory findings in children through 3 years of age. Am J Dis Child 118123,1969. 342. Seppala M, Vaheri A. Natural rubella infection of the female genital tract. Lancet 1 :46,1974. 343. Buimovici-Klein E, Hite RL, Byrne T, et al. Isolation of rubella virus in milk after postpartum immunization. J Pediatr 91:939,1977. 344. Klein EB, Bryne T, Cooper LZ. Neonatal rubella in a breast-fed infant after postpartum maternal infection. J Pediatr 97:774,1980. 345. Manson MM, Logan WPD, Loy RM. Rubella and other virus infections during pregnancy. In Reports o n Public Health and Medical Subjects, No. 101.London, Her Majesty’s Stationery Office, 1960. 346. Siege1 M, Greenberg M. Fetal death, malformation and prematurity after maternal rubella: results of prospective study, 1949-1958. N Engl J Med 262389,1960. 347. Liggins GC, Phillips LI. Rubella embryopathy: an interim report on a New Zealand epidemic. BMJ 1:711, 1963. 348. Pitt D, Keir EH. Results of rubella in pregnancy, 111. Med J Aust 2737, 1965. 349. Sallomi SJ. Rubella in pregnancy: a review of prospective studies from the literature. Obstet Gynecol 27252,1966. 350. Heggie AD, Robbins FC. Natural rubella acquired after birth clinical features and complications. Am J Dis Child 118:12,1969. 351. Chantler JK, Tingle AJ. Isolation of rubella virus from human lymphocytes after acute infection. J Infect Dis 145:673,1982. 352. OShea S, Mutton D, Best JM. In vivo expression of rubella antigens on human leucocytes: detection by flow cytometry. J Med Virol 25:297,1988. 353. Heggie AD. Pathogenesis of the rubella exanthem: isolation of rubella virus from the skin. N Engl J Med 285:664,1971. 354. Heggie AD. Pathogenesis of the rubella exanthem: distribution of rubella virus in the skin during rubella with and without rash. J Infect Dis 137:74, 1978.

Chapter 28 355. Al-Nakib W, Best JM, Banatvala JE. Rubella-specific serum and nasopharyngeal immunoglobulin responses following naturally acquired and vaccine-induced infection: prolonged persistence of virusspecific IgM. Lancet 1:182,1975. 356. Pattison JR, Dane DS, Mace Jfi. The persistence of specific IgM after natural infection with rubella virus. Lancet 1:185,1975. 357. Meurman OH. Persistence of immunoglobulin G and immunoglobulin M antibodies after postnatal rubella infection determined by solid-phase radioimmunoassay. J Clin Microbiol7:34,1978. 358. Rousseau S, Hedman K. Rubella infection and reinfection distinguished by avidity of IgG. Letter to the editor. Lancet 1:1108, 1988. 359. Hedman K, Seppala I. Recent rubella virus infection indicated by a low avidity of specific IgG. J Clin Immuno~8214,1988. 360. Morgan-Capner P, Thomas HIJ. Serological distinction between primary rubella and reinfection. Letter to the editor. Lancet 1:1397, 1988. 361. Smith KA, Chess L, Mardiney MR Jr. The relationship between rubella hemagglutination inhibition antibody (HIA) and rubella induced in vitro lymphocyte tritiated thymidine incorporation. Cell lmmunol8: 321,1973. 362. Steele RW, Hensen SA, Vincent MM, et al. A 52Crmicroassay technique for cell-mediated immunity to viruses. J Immunol 1101502, 1973. 363. Honeyman MC, Forrest JM, Dorman DC. Cell-mediated immune response following natural rubella and rubella vaccination. Clin Exp Immunol 17:665, 1974. 364. McMorrow L, Vesikari T, Wolman SR, et al. Suppression of the response of lymphocytes to phytohemagglutinin in rubella. J Infect Dis 130464,1974. 365. Steele RW, Hensen SA, Vincent MM, et al. Development of specific cellular and humoral immune responses in children immunized with liver rubella virus vaccine. J Infect Dis 130449,1974. 366. Kanra GY, Vesikari T. Cytotoxic activity against rubella-infected cells in the supernatants of human lymphocyte cultures stimulated by rubella virus. Clin Exp Immunol 1917,1975. 367. Vesikari T, Kanra GY, Buimovici-Hein E, et al. Cell-mediated immunity in rubella assayed by cytotoxicity of supernatants from rubella virus-stimulated human lymphocyte cultures. Clin Exp Immunol 19:33, 1975. 368. Ganguly R, Cusumano CL, Waldman RH. Suppression of cellmediated immunity after infection with attenuated rubella virus. Infect Immun 13:464,1976. 369. Buimovici-Klein E, Weiss ICE, Cooper LZ. Interferon production in lymphocyte cultures after rubella infection in humans. J Infect Dis 135380,1977. 370. Rossier E, Phipps PH, Polley JR,et al. Absence of cell-mediated immunity to rubella virus 5 years after rubella vaccination. Can Med Assoc J 116:481, 1977. 371. Rossier E, Phipps PH, Weber JM, et al. Persistence of humoral and cell-mediated immunity to rubella virus in cloistered nuns and in schoolteachers. J Infect Dis 144137, 1981. 372. Buimovici-Klein E, Cooper LZ. Cell-mediated immune response to rubella infections. Rev Infect Dis 7(Suppl1):S123,1985. 373. Mori T, Shiozawa K. Suppression of tuberculin hypersensitivity caused by rubella infection. Am Rev Respir Dis 131:886, 1985. 374. Ogra PL, Kerr-Grant D, Umana G, et al. Antibody response in serum and nasopharynx after naturally acquired and vaccine-induced infection with rubella virus. N Engl J Med 2851333,1971. 375. Al-Nakib W, Best JM, Banatvala JE. Detection of rubella-specificserum IgG and IgA and nasopharyngeal IgA responses using a radioactive single radial immunodiffusion technique. Clin Exp Immunol22:293, 1975. 376. Plotkin SA, Farquhar JD. Immunity to rubella: comparison between naturally and artificially induced resistance. Postgrad Med J 48(Suppl):47, 1972. 377. Plotkin SA, Farquhar JD, Ogra PL. Immunologic properties of RA 27/3 rubella virus vaccine: a comparison with strains presently licensed in the United States. JAh4A 225:585, 1973. 378. Morag A, Beutner KR, Morag B, et al. Development and characteristics of in vitro correlates of cellular immunity to rubella virus in the systemic and mucosal sites in guinea pigs. J Immunol 113:1703, 1974. 379. Morag A, Morag B, Bernstein JM, et al. In vitro correlates of cellmediated immunity in human tonsils after natural or induced rubella virus infection. J Infect Dis 131:409,1975. 380. Selzer G. Virus isolation, inclusion bodies, and chromosomes in a rubella-infected human embryo. Lancet 2:336, 1963.

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381. Rudolph AJ, YOW MD, Phillips A, et al. Transplacental rubella infection in newly born infants. JAMA 1912343, 1965. 382. Catalan0 LW Jr, Fuccillo DA, Traub RG, et al. Isolation of rubella virus from placentas and throat cultures of infants: a prospective study after the 1964-65 epidemic. Obstet Gynecol38:6, 1971. 383. Schiff GM, Dine MS. Transmission of rubella from newborns: a controlled study among young adult women and report of an unusual case. Am J Dis Child 110447, 1965. 384. Plotkin SA, Cochran W, Lindquist JM, et al. Congenital rubella syndrome in late infancy. JAMA 200435, 1967. 385. Monif GRG, Sever JL. Chronic infection of the central nervous system with rubella virus. Neurology 16111,1966. 386. Desmond MM, Wilson GS, Melnick JL, et al. Congenital rubella encephalitis. J Pediatr 71:311, 1967. 387. Menser MA, Harley JD, Herzberg R, et al. Persistence of virus in lens for three years after prenatal rubella. Lancet 2:387, 1967. 388. Cremer NE, Oshiro LS, Weil ML, et al. Isolation of rubella virus from brain in chronic progressive panencephalitis. J Gen Virol 2%143, 1975. 389. Weil ML, Itabashi HH, Cremer NE, et al. Chronic progressive panencephalitis due to rubella virus simulating subacute sclerosing panencephalitis. N Engl J Med 292:994, 1975. 390. Alford CA Jr. Immunoglobulin determinations in the diagnosis of fetal infection. Pediatr Clin North Am 18:99, 1971. 391. Weller TH, Alford CA, Neva FA. Retrospective diagnosis by serologic means of congenitally acquired rubella infections. N Engl J Med 270:1039, 1964. 392. Alford CA Jr. Studies on antibody in congenital rubella infections. I. Physicochemical and immunologic investigations of rubellaneutralizing antibody. Am J Dis Child 110:455,1965. 393. Alford CA Jr, Blankenship WJ, Straumfjord JV,et al. The diagnostic significance of IgM-globulin elevations in newborn infants with chronic intrauterine infections. In Bergsma D (ed). Birth Defects. Original Articles Series, vol. 4, no. 5. New York, National Foundation-March of Dimes, 1968. 394. Gitlin D. The differentiation and maturation of specific immune mechanisms. Acta Paediatr Scand Suppl 17260,1967. 395. Gitlin D, Biasucci A. Development of gamma G, gamma A, beta IC-beta IA, CI esterase inhibitor, ceruloplasmin,transferrin, hemopexin, haptoglobin, fibrinogen, plasminogen, alpha 1-antitrypsin, orosomucoid, beta-lipoprotein, alpha 2-macroglobulin, and prealbumin in the human conceptus. J Clin Invest 48:1433,1969. 396. Lawton AR, Self KS, Royal SA, et al. Ontogeny of lymphocytes in the human fetus. Clin Immunol Immunopathol 1:104, 1972. 397. Bellanti JA, Artenstein MS, Olson LC, et al. Congenital rubella: clinicopathologic, virologic, and immunologic studies. Am J Dis Child 110 464,1965. Brown GC. Specific response of the immunoglobulins to 398. Baublis JV, rubella infection. Proc SOCExp Biol Med 128:206, 1968. 399. Cohen SM, Ducharme CP, Carpenter CA, et al. Rubella antibody in IgG and IgM immunoglobulins detected by immunofluorescence. J Lab Clin Med 72:760,1968. 400. Vesikari T, Vaheri A, Pettay 0, et al. Congenital rubella: immune response of the neonate and diagnosis by demonstration of specific IgM antibodies. J Pediatr 75:658, 1969. 401. Cradock-Watson JE, Ridehalgh MKS, Chantler S. Specific immunoglobulins in infants with the congenital rubella syndrome. J Hyg (Lond) 76109,1976. 402. McCracken GH Jr, Hardy JB, Chen TC, et al. Serum immunoglobulin levels in newborn infants. 11. Survey of cord and follow-up sera from 123 infants with congenital rubella. J Pediatr 74:383, 1969. 403. Alford CA Jr. Fetal antibody in the diagnosis of chronic intra-uterine infections. In Thalhammer 0 (ed). Prenatal Infections. International Symposium ofVienna, September 2-3,1970. Stuttgart, Georg Thieme, 1971: p 53. 404. Kenrick KG, Slinn RF, Dorman DC, et al. Immunoglobulins and rubella-virus antibodies in adults with congenital rubella. Lancet 1:548, 1968. 405. Hardy JB, Sever JL, Gilkeson MR.Declining antibody titers in children with congenital rubella. J Pediatr 75:213, 1969. 406. Cooper LZ, Florman AL, Ziring PR, et al. Loss of rubella hemagglutination-inhibition antibody in congenital rubella. Am J Dis Child 122:397, 1971. 407. Ueda K, Tokugawa K, Fukushige J, et al. Hemagglutination inhibition antibodies in congenital rubella: a 17-year follow-up in the Ryukyu 1slands.Am J Dis Child 141:211, 1987.

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408. Ueda K, Tokugawa K, Fukushige J, et al. Continuing problem in congenital rubella syndrome in southern Japan: its outbreak in Fukuoka and the surrounding areas after the 1965-1969 and 1975-1977 rubella epidemics. Fukuoka Acta Med 77:309, 1986. 409. Soothill JF, Hayes K, Dudgeon JA. The immunoglobulins in congenital rubella. Lancet 1:1385,1966. 410. Hancock MP, Huntley CC, Sever JL. Congenital rubella syndrome with immunoglobulin disorder. J Pediatr 72:636, 1968. 41 1. Hayward AR, E m G. Development of lymphocyte populations in the human foetal thymus and spleen. Clin Exp Immunol 17169, 1974. 412. Cooper MD, Dayton DH. In Cooper MD, Dayton DH (eds). Development of Host Defenses. New York, Raven Press, 1977. 413. Miller ME. In Miller ME (ed). Host Defenses in the Human Neonate. Monographs in Neonatology. New York, Grune & Stratton, 1978. 414. Berry CL, Thompson EN. Clinicopathological study of thymic dysplasia. Arch Dis Child 43:579, 1968. 415. White LR, Leiin S, Viavicencio 0, et al. Immune competence in congenital rubella: lymphocyte transformation, delayed hypersensitivity and response to vaccination. J Pediatr 73:229, 1968. 416. Montgomery JR, South MA, Rawls WE, et al. Viral inhibition of lymphocyte response to phytohemagglutinin. Science 157:1068,1967. 417. Olson GB, South MA, Good RA. Phytohemagglutinin unresponsiveness of lymphocytes from babies with congenital rubella. Nature 214695,1967. 418. Olson GB, Dent PB, Rawls WE, et al. Abnormalities of in vitro lymphocyte responses during rubella virus infections. J Exp Med 128:47, 1968. 419. Simmons JJ, Fitzgerald MG. Rubella virus and human lymphocytes in culture. Lancet 2937, 1968. 420. Marshall WC, Cope WA, Soothill JF, et al. In vitro lymphocyte response in some immunity deficiency diseases and in intrauterine virus infections. Proc R Soc Med 63:351, 1970. 421. Buimovici-Klein E, Lang PB, Ziring PR, et al. Impaired cell-mediated immune response in patients with congenital rubella: correlation with gestational age at time of infection. Pediatrics 61:620, 1979. 422. Hyypia T,Eskola J, Laine M, et al. B-cell function in vitro during rubella infection. Infect Immun 43:589,1984. 423. Fuccillo DA, Steele RW, Hensen SA, et al. Impaired cellular immunity to rubella virus in congenital rubella. Infect Immun 9231,1974. 424. Mims CA. Pathogenesis of viral infections in the fetus. Prog Med V i o l 10194, 1968. 425. Rawls WE. Congenital rubella: the significance of virus persistence. Prog Med Viol 10238,1968. 426. Alford CA Jr. Production of interferon-like substance by the rubellainfected human conceptus. Program and abstracts of the American Pediatric Society and Society of Pediatric Research Meeting, Atlantic City, April 29-May 2,1970, p 203. 427. Lebon P, Daffos F, Checoury A, et al. Presence of an acid-labile alphainterferon in sera from fetuses and children with congenital rubella. J Clin Microbiol21:755, 1985. 428. Desmyter J, Rawls WE, Melnick JL, et al. Interferon in congenital rubella: response to live attenuated measles vaccine. J l m m u n o l 9 9 771,1967. 429. McCarthy K, Taylor-Robinson CH, Pillinger SE. Isolation of rubella virus from cases in Britain. Lancet 2:593, 1963. 430. Hildebrandt HM, Maassab HF. Rubella synovitis in a I-year-old patient. N Engl J Med 2741428,1966. 431. Yanez JE,Thompson GR, Middelsen WM, et al. Rubella arthritis. Ann Intern Med 64:772,1966. 432. McCormick JN, Duthie JJR, Gerber H, et al. Rheumatoid polyarthritis after rubella. Ann Rheum Dis 37:266, 1978. 433. Graham R, Armstrong R, Simmons NA, et al. Isolation of rubella virus from synovial fluid in five cases of seronegative arthritis. Lancet 2649,1981. 434. Lebon P, Lyon G. Noncongenital rubella encephalitis. Lancet 2:468, 1974. 435. Wolinsky JS, Berg BO, Maitland CJ.Progressive rubella panencephalitis. Arch Neurol33:722,1976. 436. Squadrini F, Taparelli F, De Rienzo B, et al. Rubella virus isolation from cerebrospinal fluid in postnatal rubella encephalitis. BMJ 2:1329, 1977. 437. Thong YH, Steele RW, Vincent MM, et al. Impaired in vitro cellmediated immunity to rubella virus during pregnancy. N Engl J Med 289:604, 1973. 438. Weinberg ED. Pregnancy-associated depression of cell-mediated immunity. Rev Infect Dis 6814,1984.

439. Honeyman MC, Dorman DC, Menser MA, et al. HL-A antigens in congenital rubella and the role of antigens 1 and 8 in the epidemiology of natural rubella. Tissue Antigens 512,1975. 440. Forrester RM, Lees VT, Watson GH. Rubella syndrome: escape of a twin. BMJ 1:1403, 1966. 441. Cooper LZ. The history and medical consequences of rubella. Rev Infect Dis 7(Suppl l):Sl, 1985. 442. Tondury G, Smith DW. Fetal rubella pathology. J Pediatr 685467, 1966. 443. Driscoll SG. Histopathology of gestational rubella. Am J Dis Child 118:49, 1969. 444. Dudgeon JA. Teratogenic effect of rubella virus. Proc R SOCMed 63: 1254, 1970. 445. Menser MA, Reye RDK. The pathology of congenital rubella: a review written by request. Pathology 6215, 1974. 446. Esterly JR, Oppenheimer EH. Intrauterine rubella infection. In Rosenberg HS, Bolande RP (eds). Perspectives in Pediatric Pathology, vol. 1. Chicago,Year Book Medical Publishers, 1973, p 313. 447. Bout? A, Boue JG. Effects of rubella virus infection o n the division of human cells. Am J Dis Child 118:45, 1969. 448. Smith JL, Early EM, London WT, et al. Persistent rubella virus production in embryonic rabbit chondrocyte cell cultures (37465). Proc SOCExp Biol Med 143:1037,1973. 449. Heggie AD. Growth inhibition of human embryonic and fetal rat bones in organ culture by rubella virus. Teratology 15:47, 1977. 450. Rawls WE, Melnick JL, Rosenberg HA, et al. Spontaneous virus carrier cultures and postmortem isolation of virus from infants with congenital rubella. Proc Soc Exp Biol Med 120:623, 1965. 451. Boue A, Plotkin SA, Boue JG. Action du virus de la rubeole sur differents systemes de cultures de cellules embryonnaires humaines. Arch Gesamte Virusforsch 16443,1965. 452. Plotkin SA, Boue A, Boue JG. The in vitro growth of rubella virus in human embryo cells. Am J Epidemiol81:71,1965. 453. Chang TH, Moorhead PS, Boue JG, et al. Chromosome studies of human cells infected in utero and in vitro with rubella virus. Proc SOC Exp Biol Med 122:236, 1966. 454. Nusbacher J, Hirschhorn K, Cooper LZ. Chromosomal studies on congenital rubella. N Engl J Med 276:1409,1967. 455. Plotkin SA, Vaheri A. Human fibroblasts infected with rubella virus produce a growth inhibitor. Science 156659, 1967. 456. Bowden DS, Pedersen JS, Toh BH, et al. Distribution by immunofluorescence of viral products and actin-containing cytoskeleton filaments in rubella virus-infected cells. Arch Virol 92:211, 1987. 457. Yoneda T, Urade M, Sakuda M, et al. Altered growth, differentiation, and responsiveness to epidermal growth factor of human embryonic mesenchymal cells of palate by persistent rubella virus infection. J Clin Invest 77:1613, 1986. 458. Naeye RL, Blanc W. Pathogenesis of congenital rubella. JAMA 194: 1277,1965. 459. Dent PB, Olson GB, Good RA, et al. Rubella-virus/leukocyte interaction and its role in the pathogenesis of the congenital rubella syndrome. Lancet 1:291, 1968. 460. Reimer CB, Black CM, Phillips DJ, et al. The specificity of fetal IgM: antibody or anti-antibody? Ann N Y Acad Sci 25477,1975. 461. Robertson PW, Kertesz V, Cloonan MJ. Elimination of false-positive cytomegalovirus immunoglobulin M-fluorescent-antibody reactions with immunoglobulin M serum fractions. J Clin Microbiol 6174, 1977. 462. Altshuler G. Placentitis with a new light on an old TORCH. Obstet Gynecol Ann 6:197, 1977. 463. Garcia AGP, Marques RLS,Lobato YY, et al. Placental pathology in congenital rubella. Placenta 6281,1985. 464. Krugman S, Katz SL, Gershon AA, et al (eds). Rubella. In Infectious Diseases of Children, 8th ed. St. Louis, CV Mosby, 1985, p 307. 465. Sheinis M, Sarov I, Maor E, et al. Severe neonatal rubella following maternal infection. Pediatr Infect Dis 4:202, 1985. 466. Judelsohn RG, Wyll SA. Rubella in Bermuda: termination of an epidemic by mass vaccination. JAMA 223:401, 1973. 467. Fujimoto T, Katoh C, Hayakawa H, et al. Two cases of rubella infection with cardiac involvement. Jpn Heart J 20:227, 1979. 468. Saeed AA, Lange LS.GuUain-Barre syndrome after rubella. Postgrad Med J 54:333, 1978. 469. Callaghan N, Feely M, Walsh B. Relapsing neurological disorder associated with rubella virus infection in two sisters. J Neurol Neurosure Psvchiatrv 4 0 1 117. 1977. "

I

Chapter 28 470. Connolly JH, Hutchinson Wh4, Allen IV, et al. Carotid artery thrombosis, encephalitis, myelitis and optic neuritis associated with rubella virus infections. Brain 98:583, 1975. 471. Choutet P, Binet CH, Goudeau A, et al. Bone-marrow aplasia and primary rubella infection. Lancet 2966, 1979. 472. Townsend JJ, Baringer JR, Wolinsky JS, et al. Progressive rubella panencephalitis: late onset after congenital rubella. N Engl J Med 292990,1975. 473. Waxham MN, Wolinsky JS. Rubella virus and its effect on the nervous system. Neurol Clin 2:267,1984. 474. Schlossberg D, Topolosky MR. Military rubella. JAMA 2381273,1974. 475. Preblud SR, Dobbs HI, Sedmak GV, et al. Testalgia associated with rubella infection. South Med J 73:594,1980. 476. White LR, Sever JL,Alepa FP. Maternal and congenital rubella before 1964: frequency, clinical features, and search for isoimmune phenomena. Pediatrics 74198, 1969. 477. Cooper LZ. Rubella: a preventable cause of birth defects. I n Bergsma D (ed). Birth Defects. Original Article Series, vol. 4, no. 23. New York, National Foundation-March of Dimes, 1968. 478. Cooper LZ, Green RH, Krugman S, et al. Neonatal thrombocytopenic purpura and other manifestations of rubella contracted in utero. Am J Dis Child 110:416,1965. 479. Zinkham WH, Medearis DN, Osborn JE. Blood and bone marrow findings in congenital rubella. J Pediatr 71:512,1967. 480. Rudolph AJ, Singleton EB, Rosenberg HS, et al. Osseous manifestations of the congenital rubella syndrome. Am J Dis Child 110428,1965. 481. Rabinowitz JG, Wolf BS, Greenberg EI, et al. Osseous changes in rubella embryopathy. Radiology 85:494, 1965. 482. Wall WL, AItman DH, Gair DR, et al. Roentgenological findings in congenital rubella. Clin Pediatr 4704, 1965. 483. Reed GB Jr. Rubella bone lesions. J Pediatr 74:208, 1969. 484. Korones SB, Ainger LE, Monif GRG, et al. Congenital rubella syndrome: study of 22 infants. Am J Dis Child 110:434,1965. 485. Rorke LB, Spiro AJ. Cerebral lesions in congenital rubella syndrome. J Pediatr 70:243,1967. 486. Streissguth AP,Vanderveer BB, Shepard TH. Mental development of children with congenital rubella syndrome: a preliminary report. Am J Obstet Gynecol 108:391,1970. 487. Rowen M, Singer MI, Moran ET. Intracranial calcification in the congenital rubella syndrome. Am J Roentgen01 115236,1972. 488. Peters ER, Davis E L Congenital rubella syndrome: cerebral mineralizations and subperiosteal new bone formation as expressions of this disorder. Clin Pediatr (Phila) 5743,1966. 489. Hastreiter AR, Joorabchi B, Pujatti G, et al. Cardiovascular lesions associated with congenital rubella. J Pediatr 71:59, 1967. 490. Klein HZ, Markarian M. Dermal erythropoiesis in congenital rubella: description of an infected newborn who had purpura associated with marked extramedullary erythropoieses in the skin and elsewhere. Clin Pediatr (Phila) 8604,1969. 491. Brough AJ, Jones D, Page RH, et al. Dermal erythropoieses in neonatal infants. Pediatrics 40627,1967. 492. Achs R, Harper KG, Siegal M. Unusual dermatoglyphic findings associated with the rubella embryopathy. N Engl J Med 274148,1966. 493. Purvis-Smith SG, Howard PR, Menser MA. Dermatoglyphic defects and rubella teratogenesis. JAMA 209:1865,1969. 494. Murphy AM, Reid RR, Pollard I, et al. Rubella cataracts: further clinical and virologic observations. Am J Ophthalmol641109, 1967. 495. Collis WJ, Cohen DN. Rubella retinopathy: a progressive disorder. Arch Ophthalmol8433,1970. 496. Kresky B, Nauheim JS. Rubella retinitis. Am J Dis Child 113:305,1967. 497. Schiff GM, Sutherland JM, Light IJ, et al. Studies on congenital rubella. Am J Dis Child 110441,1965. 498. Menser MA, Dorman DC, Reye RDK, et al. Renal artery stenosis in the rubella syndrome. Lancet 1:790,1966. 499. Menser MA, Robertson SEJ, Dorman DC, et al. Renal lesions in congenital rubella. Pediatrics 40901, 1967. 500. Kaplan GW, McLaughlin AP 111.Urogenital anomalies and congenital rubella syndrome. Urology 2:148,1973. 501. Forrest JM, Menser MA. Congenital rubella in schoolchildren and adolescents. Arch Dis Child 4563,1970. 502. Korones SB, Ainger LE, Monif GR, et al. Congenital rubella syndrome: new clinical aspects with recovery of virus from affected infants. J Pediatr 67166, 1965. 503. South MA, Alford CA Jr. The immunology of chronic intrauterine infections. In Stiehm ER, Fulginiti VA (eds). Immunologic Disorders in Infants and Children. Philadelphia, WB Saunders, 1973, p 565.

Rubella

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504. Phelan P, Campbell F! Pulmonary complications of rubella embryopathy. J Pediatr 75202, 1969. 505. Karmody GS. Subclinical maternal rubella and congenital deafness. N Engl J Med 278:809,1968. 506. Ames MD, Plotkin SA, Winchester RA, et al. Central auditory imperception: a significant factor in congenital rubella deafness. JAMA 213:419, 1970. 507. Peckham CS, Martin JAM, Marshall WC, et al. Congenital rubella deafness: a preventable disease. Lancet 1:258, 1979. 508. Rossi M, Ferlito A, Polidoro F. Maternal rubella and hearing impairment in children. J Laryngol Otol94281, 1980. 509. Weinberger MM, Maslund MW, Asbed R, et al. Congenital rubella presenting as retarded language development. Am J Dis Child 120 125,1970. 510. Desmond MM, Fisher ES, Vorderman AL, et al. The longitudinal course of congenital rubella encephalitis in nonretarded children. J Pediatr 93:584, 1978. 511. Zausmer E. Congenital rubella: pathogenesis of motor deficits. Pediatrics 4716, 1971. 512. Menser MA, Forrest JM, Bransby RD. Rubella infection and diabetes mellitus. Lancet 1:57,1978. 513. Hanid TK. Hypothyroidism in congenital rubella. Lancet 2:854,1976. 514. Nieberg PI, Gardner LI. Thyroiditis and congenital rubella syndrome. J Pediatr 89156,1976. 515. Perez Comas A. Congenital rubella and acquired hypothyroidism secondary to Hashimoto thyroiditis. J Pediatr 88:1065,1976. 516. Ziring PR, Gallo G, Finegold M, et al. Chronic lymphocytic thyroiditis: identification of rubella virus antigen in the thyroid of a child with congenital rubella. J Pediatr 90:419,1977. 517. AvRuskin TW, Brakin M, Juan C. Congenital rubella and myxedema. Pediatrics 69:495, 1982. 518. Ziring PR, Fedun BA, Cooper LZ. Thyrotoxicosis in congenital rubella. J Pediatr 871002,1975. 519. Preece MA, Kearney PJ, Marshall WC. Growth hormone deficiency in congenital rubella. Lancet 22342,1977. 520. Oberiield SE, Cassulo AM, Chiriboga-Klein S, et al. Growth hormone dynamics in congenital rubella syndrome. Brain Dysfunct 1:303, 1988. 521. Chiriboga-Klein S, Oberfield SE, Cassulo AM, et al. Growth in congenital rubella syndrome and correlation with clinical manifestations. J Pediatr 115:251, 1989. 522. Boger WP 111. Late ocular complications in congenital rubella syndrome. Ophthalmology 821244,1980. 523. Deutman AF, Grizzard WS. Rubella retinopathy and subretinal neovascularization. Am J Ophthalmol85:82, 1978. 524. Frank KE, Purnell EW. Subretinal neovascularization following rubella retinopathy. Am J Ophthalmol86462,1978. 525. Boger WP 111, Petersen RA, Robb RM. Keratoconus and acute hydrops in mentally retarded patients with congenital rubella syndrome. Am J Ophthalmol91:231,1981. 526. Boger WP 111,Petersen RA, Robb RM. Spontaneous absorption of the lens in the congenital rubella syndrome.Arch OphthalmoI99:433,1981. 527. Gullikson JS. Tooth morphology in rubella syndrome children. J Dent Child 42:479, 1979. 528. No reference cited. 529. Fortuin NJ, Morrow AG, Roberts WC. Late vascular manifestations of the rubella syndrome: a roentgenographic-pathologic study. Am J Med 51:134, 1971. 530. Anderson H, Barr B, Wedenberg E. Genetic disposition-a prerequisite for maternal rubella deafness. Arch Otolaryngol91:141,1970. 531. Orth DH, Fishman GA, Segall M, et al. Rubella maculopathy. BMJ 64:201, 1980. 532. Wolinsky JS, Dau PC, Buimovici-Klein E, et al. Progressive rubella panencephalitis:immunovirological studies and results of isoprinosine therapy. Clin Exp Immunol35:397, 1979. 533. Preblud SR, Kushubar R, Friedman HM. Rubella hemagglutination inhibition titers. JAMA 247:1181, 1982. 534. Munro ND, Wild HJ, Sheppard S, et al. Fall and rise of immunity to rubella. BMJ 294481,1987. 535. Hoskins CS, w a n C, Wilkins B. The nerve deaf child-intrauterine rubella or not? Arch Dis Child 58:327,1983. 536. Iurio JL, Hosking CS, Pyman C. Retrospective diagnosis of congenital rubella. BMJ 2891566,1984. 537. Vesikari T, Meurman OH, Maki R. Persistent rubella-specific IgMantibody in the cerebrospinal fluid of a child with congenital rubella. Arch Dis Child 55:46, 1980.

926

Section I11

Viral Infections

538. Fitzgerald MG, M e n GR, Hosking CS. Low affinity antibody to 539. 540. 541. 542. 543.

544. 545.

546. 547.

548.

549. 550.

551.

552. 553. 554. 555.

556.

557.

558. 559.

rubella antigen in patients after rubella infection in utero. Pediatrics 81:812, 1988. Alestig K, Bartsch FK, Nilsson LA, et al. Studies of amniotic fluid in women infected with rubella. J Infect Dis 129:79,1974. Levine MJ, O m a n MN, Moore MG, et al. Diagnosis of congenital rubella in utero. N Engl J Med 2901187, 1974. Cederqvist LL, Zervoudakis IA, Ewool LC, et al. Prenatal diagnosis of congenital rubella. BMJ 276615,1977. Daffos F, Forestier F, Grangeot-Keros L, et al. Prenatal diagnosis of congenital rubella. Lancet 2:1, 1984. Terry GM, Ho-Terry L, Warren RC, et al. First trimester prenatal diagnosis of congenital rubella: a laboratory investigation. BMJ 292:930, 1986. Enders G, Jonatha W. Prenatal diagnosis of intrauterine rubella. Infection 15:162,1987. Ho-Terry L, Terry GM, Londesborough P, et al. Diagnosis of fetal rubella infection by nucleic acid hybridization. J Med Virol 24175, 1988. Bosma TJ, Corbett SO, Banatvala JE, Best JM. PCR for detection of rubella virus RNA in clinical samples. J Clin Microbiol33: 1075, 1995. Tanemura M, Suzumori K, Yagami Y, Katow S. Diagnosis of fetal rubella infection with reverse transcription and nested polymerase chain reaction: a study of 34 cases diagnosed in fetuses. Am J Obstet Gynecol 174578,1996. Revello MG, Baldanti F, Sarasini A, et al. Prenatal diagnosis of rubella virus infection by direct detection and semiquantitation of viral RNA in clinical samples by reverse transcription-PCR. J Clin Microbiol 35:708, 1997. McDonald JC. Gamma-globulin for prevention of rubella in pregnancy. BMJ 2:416,1963. Brody ]A, Sever JL, Schiff GM. Prevention of rubella by gamma globulin during an epidemic in Barrow, Alaska, in 1964. N Engl J Med 272:127, 1965. McCallin PF, Fuccillo DA, Ley AC, et al. Gammaglobulin as prophylaxis against rubella-induced congenital anomalies. Obstet Gynecol 39:185, 1972. Urquhart GED, Crawford RJ, Wallace J. Trial of high-titre human rubella immunoglobulin. BMJ 2:1331,1978. Schiff GM, Sever JL, Huebner RJ. Rubella virus: neutralizing antibody in commercial gamma globulin. Science 142:58, 1963. Armstrong RD, Siclair A, O’Keefe G, et al. Interferon treatment of chronic rubella associated arthritis. Clin Exp Rheumatol3:93, 1985. b i n AM, Schmidt NJ, Cantell K, et al. Alpha interferon administration to infants with congenital rubella. Antimicrob Agents Chemother 21:259, 1982. Larsson A, Forsgren M, Hardaf-Segerstad S, et al. Administration of interferon to an infant with congenital rubella syndrome involving persistent viremia and cutaneous vasculitis. Acta Paediatr Scand 65:105, 1976. Jan JE,Tingle A], Donald G, et al. Progressive rubella panencephalitis: clinical course and response to “Isoprinosine.” Dev Med Child Neurol 21548, 1979. Garner JS, Simmons BP. CDC guidelines for isolation precautions in hospitals. Infect Control 4:245, 1983. Williams WW. CDC guidelines for infection control in hospital personnel. Infect Control 4326, 1983.

560. Schoenbaum SC, Hyde JN, Bartoshesky L, et al. Benefit-cost analysis of rubella vaccination policy. N Engl J Med 294306,1976. 561. Furukawa T, Miyata T, Kondo K, et al. Clinical trials of RA 27/3 (Wistar) rubella vaccine in Japan. Am J Dis Child 118:262,1969. 562. Vaheri A, Vesikari T, Oker-Blom N, et al. Transmission of attenuated rubella vaccines to the human fetus: a preliminary report. Am J Dis Child 118:243,1969. 563. Recommendations of the Public Health Service Advisory Committee on Immunization Practices. Rubella vaccine. Am J Dis Child 118:397, 1969. 564. Fleet WF Jr, Benz EW Jr, Karzon DT, et al. Fetal consequences of maternal rubella immunization. JAMA 222621,1974. 565. Plotkin SA. Rubella vaccine. In Plotkin SA, Mortimer EA Jr (eds). Vaccines. Philadelphia, WB Saunders, 1988, p 235. 566. Brunell PA, Weigle K, Murphy MD. Antibody response following

measles-mumps-rubella vaccine under conditions of customary use. JAMA 250:1409,1983. 567. Mortimer PP, Edwards JMB, Porter AD, et al. Are many women immunized against rubella unnecessarily? J Hyg (Lond) 87:131,1981. 568. Greaves WL, Orenstein WA, Hinman AR, et al. Clinical efficacy of rubella vaccine. Pediatr Infect Dis 2284,1982. 569. Balfour HH Jr, Amren DP. Rubella, measles and mumps antibodies following vaccination of children. Am J Dis Child 132:573,1978. 570. Orenstein WA, Herrmann KL, Holmgreen P, et al. Prevalence of rubella antibodies in Massachusetts schoolchildren. Am J Epidemiol 124:290, 1986. 571. Rutledge SL, Snead OC 111. Neurologic complications of immunizations. J Pediatr 109:917, 1986. 572. Losonsky GA, Fishaut JM, Strussenberg J, et al. Effect of immunization against rubella o n lactation products. I. Development and characterization of specific immunologic reactivity in breast milk. J Infect Dis 145:654, 1982. 573. Losonsky GA, Fishaut JM, Strussenberg J, et al. Effect of immunization against rubella on lactation products. 11. Maternal-neonatal interactions. J Infect Dis 145:661, 1982. Millunchick EW, et al. Neonatal rubella 574. Landes RD, Bass JW, following maternal immunization. J Pediatr 97:465, 1980. 575. Centers for Disease Control. Immunization practices in collegesUnited States. MMWR Morb Mortal Wkly Rep 36:209, 1987. 576. Edgar WM, Hambling MH. Rubella vaccination and anti-D immunoglobulin administration in the puerperium. Br J Obstet Gynaecol 84:754, 1977. 577. Watt RW, McGucken RB. Failure of rubella immunization after blood transfusion: birth of congenitally infected infant. BMJ 281:977, 1980. 578. Black NA, Parsons A, Kurtz JB, et al. Post-pubertal rubella immunisation: a controlled trial of two vaccines. Lancet 2:990, 1983. 579. McIntosh ED, Menser MA. A fifty-year follow-up of congenital rubella. Lancet 340:414, 1992. 580. Noticeboard. Congenital rubella-50 years on. Lancet 337668,1991. 581. Schluter WW, Reef SE, Redd C, et al. Changing epidemiology of congenital rubella syndrome in the United States. J Infect Dis 178:636. 1998. 581a. Bloom S, Rguig A, Berraho A, et al. Congenital rubella syndrome burden in Morocco: a rapid retrospective assessment. Lancet 365~135-141,2005. 582. Plotkin SA, Katz M, Cordero IF. The eradication of rubella. JAMA 281:561, 1999.

Chapter 29 SMALLPOX AND VACCINIA Julia A. McMillan

Epidemiology and Transmission 927

mother and fetus have again become a matter of potential concern.

Variola Vaccinia

Microbiology 928 Pathogenesis, Pathology, and Prognosis 928 Variola Vaccinia

Clinical Manifestations 929 Variola Vaccinia

Diagnosis 930 Differential Diagnosis 931 Treatment 931 Variola Vaccinia

Prevention 932

In 1971, the US. Public Health Service accepted the recommendation of its Advisory Committee on Immunization Practices that routine smallpox vaccination in the United States be discontinued. This recommendation was based on two considerations. The risk of contracting smallpox in the United States was small, and the risk of complications from vaccinia outweighed the potential benefits.' Smallpox is the clinical disease caused by variola virus. Variola is a member of the genus Orthopoxvirus in the Poxviridae family, a genus that also includes monkeypox, cowpox, and rabbitpox, as well as vaccinia. Variola infection occurs only in humans, a fact that allowed eradication of this infection in the latter part of the 20th century in a global eradication program using preventive vaccine derived from the relatively benign vaccinia virus. The last case of smallpox identified in the United States occurred in 1949. In 1980, the world was declared free of smallpox by the World Health Organization; the last endemic case had been diagnosed in Somalia in 1977. Routine vaccination of children and the general public had been discontinued in the United States in 1972, and vaccination of health care workers was discontinued in 1976. In 1986, international agreement led to destruction of all variola isolates except stocks to be maintained in World Health Organizationdesignated laboratories in the United States and the Soviet Union. Concern that variola might be used as an agent of bioterrorism was raised during the 1990s, when it was learned that variola stored in the former Soviet Union had been sold to countries thought to be developing biological weapons. It is in this context that discussion of smallpox and vaccinia virus and their potential effects on the

EPIDEMIOLOGY AND TRANSMISSION Variola Variola was spread primarily through respiratory secretions in aerosolized droplets, and spread required prolonged (6 to 7 hours) face-to-face contact. Infection through direct contact with infected lesions, bedding, or clothing was thought to occur infrequently. The incubation period was 7 to 17 days (mean, 12 days). Infected individuals were not generally contagious until the rash appeared after a 3- to 4-day prodrome of fever, malaise, backache, vomiting, and prostration. Because of the severity of the prodromal illness, infected individuals were usually confined to home or hospital by the time they presented a risk to others, and it was therefore household contacts and health care professionals who were the most frequent secondary cases. Infectivity persisted until all scabs had separated from the skin of the affected individual. The likelihood of spread to a susceptible individual was considered to be lower than that for measles and similar to the rate for varicella. Low temperature and dry conditions prolong survival for the virus, and outbreaks in the past were more common during dry, winter months. Past recorded experience regarding the frequency of transmission of variola from mother to fetus must be considered against the backdrop of near-universal childhood vaccination. Infection during the first half of gestation resulted in an increased likelihood of fetal death or prematurity. Overall, the rate of fetal loss or death after premature delivery ranged from 57% to 81Y0.',~There are some documented cases of live-born infants infected in utero near term. In those instances, the likelihood of congenital or neonatal infection was greatest when the mother became ill during the period 4 days before delivery through the 9 days after deli~ery?~

Vaccinia Vaccinia virus transmission to the fetus after vaccination of pregnant women has also been documented:-' although the frequency with which it occurs and the severity of resulting disease are difficult to determine from available The latest surveys attempting to determine the rate of adverse effects of smallpox vaccination in the United States identified only one case of fetal vaccinia. In a retrospective study in Scotland that depended on maternal recollection of timing of vaccination, MacArthur6 found that fetal death occurred in 47% of pregnancies involving women vaccinated during the second or third trimesters and 24% of

928


those vaccinated during the first trimester. Other studies have failed to find an increased risk of fetal death, miscarriage, or fetal malformations.1’*12 Primary vaccination during pregnancy in the years in which these studies were conducted was unusual, however, and the potential impact on the fetus after vaccination of nonimmune pregnant women cannot be extrapolated accurately. For almost 30 years (1976 to 2002), vaccination against smallpox was available in the United States only for scientists who worked with vaccinia and related viruses in the laboratory setting. In 2002, the Department of Defense initiated a pre-event vaccination program to protect its personnel, and in 2003, the U.S. Public Health Service began vaccinating health care and public health workers who might be involved in caring for patients with smallpox or investigating circumstances surrounding the use of smallpox as an agent of bioterrorism. Criteria for exclusion of individuals at risk for adverse events (including pregnant women) were developed. Despite careful screening, by April 2003,103 women had been inadvertently vaccinated while pregnant or within 4 weeks of conception. Sixty-nineof the 103were primary vaccinees. No cases of fetal vaccinia have been reported. Two vaccinated pregnant health care workers experienced miscarriages early in their pregnancies, but no causal relationship between the vaccination and the miscarriage was determined.

MICROBIOLOGY The poxviruses, including variola and vaccinia, are large, complex, double-stranded DNA viruses with a diameter of approximately 200 nm. The nucleotides of the two viruses are 96% homologous, as are 93% of the amino acids of the glycoproteins that make up the envelope of the two viruses. These envelope glycoproteins are important in antibody recognition. Under electron microscopy the virions have a characteristic brick shape. Viral aggregates in infected host cells form intracytoplasmic inclusion bodies of approximately 10 pm. Both viruses can be grown on tissue culture derived from a variety of mammalian cells, and cytopathic changes can be detected within 1 to 6 days.

PATHOGENESIS, PATHOLOGY, AND PROGNOSIS

Variola Introduction of variola onto respiratory mucosa is followed by local multiplication and spread to lymph nodes. An asymptomatic viremia occurs on about the third or fourth day, distributing the virus to the spleen, bone marrow, and lymph nodes. Secondary viremia, occurring on about day 8, is followed on day 12 to 14 by systemic symptoms, including fever, malaise, headache, and prostration. During this secondary viremia, virus is carried by leukocytes to the dermis and oropharyngeal mucosa. Prodromal febrile illness is followed after about 3 days by development of enanthem and a maculopapular rash distributed at first primarily on the face, arms, and legs and then spreading to the trunk. Mortality rates after smallpox varied depending on age, prior vaccination, and availability of supportive care. To some

degree, mortality can be predicted by the characteristics of the rash (see “Clinical Manifestations”).Overall, the mortality rate was about 30%. The mortality rate due to smallpox among pregnant women was high. The more lethal hemorrhagic form of smallpox was more likely to occur in pregnant women. R ~ followed 225 pregnant women in India between 1959 and 1962 and found a 75% mortality rate among previously unvaccinated pregnant women who developed smallpox, compared with 24% to 25% among unvaccinated nonpregnant women and men. For vaccinated women, the mortality rate was 20.7%, compared with 3% to 4% for men and nonpregnant women. Dixon13reported an overall mortality rate of 40% among pregnant women in a smallpox outbreak in North Africa in 1946. Even when maternal infection is mild, transmission to the fetus can lead to increased rates of fetal death and premature delivery. Among 46 pregnancies followed by Lynch? 81% resulted in fetal death or early death after premature delivery. Others reported much less frequent adverse effects on the fetus.4The sequence of events that lead to infection of the placenta and fetus in relation to maternal viremia has not been conclusively established. Development of symptomatic infection at 2 to 3 weeks of life in infants born to mothers whose illness began just before delivery suggests that placental infection and transmission to the fetus developed during the secondary viremic phase.4711 The consequences of fetal infection have been documented to involve widely disseminated foci of necrosis (i.e., skin, thymus, lungs, liver, kidneys, intestines, and adrenals) and characteristic intracytoplasmic inclusion bodies (i.e., Guarnieri bodies) in the decidual cells of the ~ 1 a c e n t a . l ~ ” ~ It is thought that transplacental transmission of variola can occur at any time during gestation, and autopsy studies corroborate infection acquired during the second and third trimesters. Pathologic studies of fetuses lost during the first trimester are lacking; however, the increased frequency of miscarriage associated with maternal infection at that stage suggests a direct effect on the products of conception.

Vaccinia Vaccinia infection after maternal vaccination is thought to result from transient viremia. The frequency with which inoculation of vaccinia virus through vaccination leads to viremia probably is related to the invasiveness of the vaccinia strain and the vaccine status (i.e., primary versus revaccination) of the individual being vaccinated. A report involving persons vaccinated between 1930 and 1953 described isolation of vaccinia 3 to 10 days after vaccination with a strain that is thought to be more invasive than the current New York City Board of Health (NYCBOH) strain,16 the only vaccine now available in the United States. Viremia has been reported after NYCBOH strain va~cination,’~”’but the frequency with which it occurs is unknown. A study involving 28 healthy adults vaccinated using the NYCBOH vaccine failed to detect viremia after successful vaccination. Mihailescu and Petrovici” were able to isolate vaccinia from products of conception of 12 (3.2%) of 366 women who had been revaccinated during pregnancy and had undergone therapeutic abortion during the first to second month of gestation.

O

~

Chapter 29

Smallpox and Vaccinia

929

Figure 29-1 Generalized fetal vaccinia in an infant whose mother was immunized at 24 weeks' gestation. The infant was born at 30 weeks and survived. (From Hanshaw JC, Dudgeon JA. Viral Diseases of the Fetus and Newborn. Philadelphia, WB Saunders, 1978, p 216.)

Figure 29-2 The same patient as in Figure 29-1 at 18 months of age. Scarring persists, but the lesions have healed. Smallpox vaccination was attempted without success. (From Hanshaw JC, Dudgeon JA. Viral Diseases of the Fetus and Newborn. Philadelphia, WB Saunders, 1978, p 217.)

In the past, pregnancy was not considered a contraindication to vaccination during periods of increased smallpox risk, but despite widespread use of vaccine over the past century, only 50 cases of fetal infection (3 in the United States) have been reported.*' Levine and co-workers2' summarized 20 cases of fetal vaccinia infection reported between 1932 and 1972. At least 13 of the 20 women involved had received their first smallpox vaccination during the pregnancy. The time of vaccination ranged from 3 to 24 weeks of pregnancy, and delivery occurred an average of 8 weeks later. Ten infected

infants were born alive, and three survived (Figs. 29-1 and 29-2).

CLINICAL MANIFESTATIONS Va rioIa Variola major is the form of smallpox that is of the greatest historical significance because of its high overall mortality rate (30%). Onset of rash was preceded by approximately

930


3 days of fever, myalgia, headache, and backache. Vomiting, diarrhea, abdominal pain, and seizures sometimes accompanied this prodromal period. The fever often was reduced as the rash appeared, only to recur and persist until skin lesions had scabbed. The appearance of the rash in patients with variola major was predictive of the severity of illness and of the associated mortality. The most common rash (90% of patients) was called ordinary smallpox and consisted of papules that progressed first to fluid-filled vesicles and then to firm, tense pustules that scabbed after 10 days to 2 weeks before separating from the underlying skin. The “pox” were distributed over the entire body but predominated on the face and extremities, including the palms and soles. Unlike the lesions of varicella, which appear in various stages (e.g., papules, vesicles, scabs) at one time, smallpox lesions all develop at the same rate. An enanthem involving painful lesions of the mouth and throat preceded the development of the rash by a day or less. When the rash involved discrete lesions, it was referred to as ordinary-discrete smallpox. The case-fatality rate associated with this form was less than 10%. When lesions were more numerous and less discrete (i.e., ordinary-semiconfluent and ordinary-confluent smallpox), the mortality rate was higher, approximating 50% to 75% for ordinary-confluent cases. Flat smallpox, in which lesions evolved more slowly and finally coalesced, accounted for about 7% of cases, but the mortality rate was more than 90%. Hemorrhagic smallpox, or purpura variolosa, which was seen most commonly in pregnant women, was associated with an almost 100% mortality rate.” In the series of 255 pregnant women reported by Rao? smallpox was least likely to take the hemorrhagic form during the first trimester of pregnancy, and the highest likelihood of the hemorrhagic form was during the sixth month. Modified smallpox,affecting previously vaccinated individuals, was a milder disease with fewer and smaller skin lesions. Death with this form was rare. Alastrim, or variola minor, is virologically distinct from variola major. It was first recognized in the early 20th century in South Africa, spreading to the Americas and to Europe. As the name suggests, this form of smallpox was less severe, with a case-fatality rate of about 1%. The increased likelihood of fetal death associated with maternal infection during pregnancy was described previously. When pathologic examination of the fetus and placenta in such cases has been reported, the fetus has exhibited wellcircumscribed cutaneous and scalp lesions with maceration of internal organs, including the brain. Foci of necrosis and calcification have been seen in the thymus, lungs, liver, kidneys, intestines, and adrenals. Similar foci are seen in the placenta. 14,’ Marsden and Greenfield4 described 34 infants whose mothers developed smallpox late in pregnancy or during the 2 weeks after delivery. Some newborns escaped symptomatic illness, although failed attempts at subsequent vaccination suggest that they were infected in utero. Based on the timing of illness in the newborns that developed smallpox compared with the appearance of rash in the mother, these investigators conclude that transmission of virus from mother to fetus occurs during the expected time of secondary maternal viremia. Other reports substantiate their conclusions. These and other researchers2313 describe great variability in severity of neonatal illness, including instances in which one twin escaped clinical disease but the other developed smal1p0x.I~

The severity of fetal or neonatal involvement does not necessarily reflect the severity of maternal infection, nor her vaccination status. In his report of 47 cases of maternal-tofetal transmission of variola, Lynch2 described five infected infants born at term whose mothers had been exposed to smallpox during pregnancy but had escaped clinical disease, presumably because of prior vaccination. Vaccination of newborns whose mothers developed clinical smallpox before or shortly after their birth did not always protect them from disease. Details regarding the clinical findings and course associated with congenital variola are not available. Disease was acute and not associated with congenital anomalies. Some reports describe cutaneous lesions that are larger than those usually associated with smallpox. Among the 22 infants with congenital and neonatal smallpox described by Marsden and Greenfield? 3 died, 1 of whom was born prematurely.

Vaccinia Congenital vaccinia was rare, even during widespread vaccination programs. However, reported mortality rate associated with congenital vaccinia was high. Of the 16 cases reviewed by Green and co-workers,8 six infants were born alive, but only one ultimately survived. For at least 12 of the 16 women, vaccination during pregnancy had been their primary smallpox vaccination. Congenital vaccinia has been reported after vaccination between the 3rd and 24th weeks of pregnancy, but for most affected pregnancies, vaccination was in the second trimester. As is the case with congenital variola, large, discrete, circular necrotic lesions were seen on the skin of infected fetuses and newborns. Foci of necrosis studded multiple internal organs and the placenta. In utero vaccinia infection has not been associated with serious birth defects or with other long-term adverse events in surviving infants. Infants of mothers vaccinated during pregnancy that escaped fetal infection were not at risk for sequelae.

DIAGNOSIS Diagnosis of smallpox, whether in the pregnant woman, fetus, or newborn was usually based on clinical findings along with a history of exposure to disease or vaccination. Today, suspicion that a patient may have smallpox would imply introduction of the disease through bioterrorism, and great care should be taken to prevent spread of the infection and to confirm the diagnosis in the laboratory. If skin lesions are scabbed, one or more scabs should be removed and included. Local and state health authorities should be contacted immediately. State authorities should contact the Centers for Disease Control and Prevention (CDC). Patient samples should be collected only by an individual wearing protective gown, mask, and gloves, and that individual should be someone who has been vaccinated, if possible. Throat swabs and swabs of vesicular fluid should be obtained. Blood samples and the swabs should be placed into a container sealed with adhesive tape and then placed into a second, watertight container. All samples should be sent directly to a Biological Safety Level 4 laboratory, where they can be processed safely. Laboratory confirmation can be performed

Chapter 29 by electron microscopy, nucleic acid identification, immunohistochemical studies, and tissue culture using cell culture or chorioallantoic egg membrane. Similar technique should be employed to confirm infection in the neonate. There is no known reliable intrauterine test for diagnosing congenital infection.

DIFFERENTIAL DIAGNOSIS During the prodromal period, before the eruption of rash, maternal smallpox may be indistinguishable from other acute febrile illnesses. Once the rash appears, the pattern of eruption and the characteristics of individual pox lesions should help distinguish it from other conditions, such as rubella, measles, meningococcemia, rickettsial diseases, ratbite fever, and enteroviral infections. The widespread distribution of the lesions of variola major should distinguish it from localized papulovesicular rashes such as impetigo, shingles, and insect bites. Varicella is the viral infection most likely to be confused with smallpox. Recommended routine vaccination of children against varicella leaves many younger clinicians without experience in recognizing this formerly common infection of childhood. Table 29- 1 compares clinical characteristics of the two infections. In the past, smallpox sometimes was mistaken for drug eruptions and erythema multiforme, and hemorrhagic smallpox could be difficult to distinguish from meningococcemia, severe acute leukemia, or hemorrhagic varicella. Congenital variola or vaccinia would be expected only in the context of a history of maternal smallpox or smallpox vaccination. In addition to careful consideration of prenatal maternal history, review of maternal postpartum course is important, because historical reports suggest that neonatal smallpox may occur in association with maternal disease that manifests in the days after deli~ery.~ In the absence of a maternal history of smallpox or vaccination, fetal or neonatal variola or vaccinia could be mistaken for congenital herpes simplex infection, congenital syphilis, or congenital dermatologic disease such as epidermolysis bullosa.

TREATMENT Variola If maternal smallpox is suspected, contact and airborne isolation precautions, in addition to universal precautions, should be instituted immediately, and if possible, the patient should be cared for in a negative-pressure room. Local and

Table 29-1

Smallpox and Vaccinia

state health authorities should be notified. Family and community contacts, emergency medical personnel, and health care workers who might have been exposed to the patient should be identified and immunized as soon as possible. Immunization within 4 days can ameliorate illness and, in some cases, prevent infection completely. Patient management includes careful attention to fluid and electrolyte requirements and nutritional support. Antibiotic therapy, including an agent effective in treating infection caused by Staphylococcus uureus should be provided if secondary infection is suspected. Cidofovir, a nucleoside analogue that inhibits DNA polymerase, has activity against variola. When used early in the course of infection, it has been effective in treating poxvirus infections in animals. Cidofovir is approved for use in treating cytomegalovirus infection, but it has not been used to treat smallpox. Adverse effects of cidofovir, primarily renal toxicity, would limit its use in treating suspected congenital variola.

Vaccinia Adverse effects associated with administration of smallpox vaccine include inadvertent inoculation, including ocular inoculation, generalized vaccinia, eczema vaccinatum, progressive vaccinia (i.e., vaccinia necrosum) , postvaccinal encephalitis, and fetal vaccinia. Vaccination programs have developed careful screening tools to prevent vaccination of individuals thought to be particularly susceptible to these adverse effects, including exclusion of women who are pregnant or intend to become pregnant within 4 weeks of vaccination. Congenital vaccinia among live-born infants is rare, and inadvertent vaccination during pregnancy should not be a reason to recommend termination of pregnancy. Vaccinia immune globulin (VIG) has been used to treat some complications associated with smallpox vaccination, including eczema vaccinatum and progressive vaccinia. It may be used for those same reasons during pregnancy, but VIG is not recommended as prophylaxis against congenital vaccinia. No data are available regarding appropriate dose or efficacy of VIG for treatment of congenital vaccinia. Treatment may be considered, however, for a viable infant born with lesions after a history of maternal vaccination. For information concerning availability, indications, and administration of VIG, physicians should contact the CDC Clinical Consultation Team (phone: 877-554-4625). Cidofovir is available for treatment of complications of smallpox vaccination only under the investigational new drug (IND) protocol administered by the CDC. It will be released only as secondary treatment for complications that do not respond to treatment with VIG.

Clinical Features Distinguishing Chickenpox from Smallpox

Clinical Features

Chickenpox

Smallpox

Fever onset Rash characteristics

At the time of the rash Pock in different stages Develops rapidly More pocks on the body Spares palms and soles Rare

2-4 days before the rash

Mortality

931

Pocks in the same stages Develops slowly More pocks on face, arms, and legs Affects palms and soles 10%-30%, historically

932

Section I11

Viral Infections

PREVENTION After a remarkable, worldwide public health effort, smallpox was eradicated in nature during the latter part of the 20th century. Until concerns were raised regarding the potential use of smallpox as an agent of bioterrorism, protection from smallpox was thought to be unnecessary, and vaccination to protect against variola was discontinued. In the 21st century, inadvertent vaccination of pregnant military personnel, health care workers, and public health workers, many of whom are being vaccinated for the first time, poses the greatest risk for maternal and fetal infection. Careful screening of such individuals has been shown generally to be effective,but some vaccination during pregnancy has occurred despite screening. The National Smallpox Vaccine in Pregnancy Registry has been established to investigate instances of inadvertent smallpox vaccination during pregnancy. Civilian cases should be reported to state health departments or to the CDC (phone: 404-639-8253 or 877-554-4625). Military cases should be reported to the Department of Defense (phone: 619-553-9255; DSN: 619-553-9255; fax: 619-553-7601; e-mail: code25 @nhrc.navy.mil). Health care providers are encouraged to save and forward products of conception from pregnancy losses associated with vaccination during pregnancy to the CDC or the U.S. Department of Defense. Specimens should be frozen at -7OoC, preferably in viral transport media before and during transport. REFERENCES 1. Krugman S, Katz SL. Smallpox and vaccinia. In Infectious Diseases of Children, 7th ed. St. Louis, Mosby, 1981. 2. Lynch FW. Dermatologic conditions of the fetus with particular reference to variola and vaccinia. Arch Dermatol Syphilis Chic 26:997, 1932. 3. Rao AR, Prahlad I, Swaminathan M, et al. Pregnancy and smallpox. J Indian Med Assoc 40353,1963. 4. Marsden JP, Greenfield CRM. Inherited smallpox. Arch Dis Child 9309,1934.

5. Sharma R. Sharma R, Jagdev DK. Congenital smallpox. Scand J Infect Dis 3:245, 1971. 6. MacArthur P. Congenital vaccinia and vaccinia gravidarum. Lancet 2:1104, 1952. 7. Bourke GJ,Whitty RJ. Smallpox vaccination in pregnancy: a prospective study. BMJ 1:1544,1964. 8. Green DM, Reid SM, Rhaney K. Generalized vaccinia in the human foetus. Lancet 1:1296, 1966. 9. Lane JM, Ruben FL, Neff JM, et al. Complications of smallpox vaccination, 1968: results of ten statewide surveys. J Infect Dis 122:303,1970. 10. Lane JM, Ruben FL, Neff JM, et al. Complications of smallpox vaccination, 1968: national surveillance in the United States. N Engl J Med 281:1201, 1969. 11. Greenberg M, Yankauer A, Krugman S, et al. The effect of smallpox vaccination during pregnancy on the incidence of congenital malformations. Pediatrics 3:456, 1949. 12. Bellows MT, Hyman ME, Meritt KK. Effect of smallpox vaccination o n the outcome of pregnancy. Public Health Rep 64319,1949. 13. Dkon CW. Smallpox in Tripolitania, 1946 an epidemiological and clinical study of 500 cases, including trials of penicillin treatment. J Hyg 46351, 1948. 14. Garcia AGP. Fetal infection in chickenpox and alastrim, with histopathologic study of the placenta. Pediatrics 32895, 1963. 15. Marsden JP. Metastatic calcification. Notes on twins born shortly after an attack of smallpox in the mother. Br J Child Dis 28:193,1930. 16. Fenner F, Henderson DA, Arita I, et al. The pathogenesis, pathology and immunology of smallpox and vaccinia. In Smallpox and Its Eradication. Geneva, World Health Organization, 1988. 17. Blamer RJ, Norman JO, Heys FM, et al. Antibody response to cutaneous inoculation with vaccinia virus: viremia and viruria in vaccinated children. J Pediatr 26:176, 1964. 18. Cummings JF, Polhemus ME, Hawkes C, et al. Lack of vaccinia viremia after smallpox vaccination. Clin Infect Dis 38:456,2004. 19. Mihailescu R, Petrovici M. Effect of smallpox vaccination on the product of conception. Arch Roum Path Exp Microbiol3467-74,1975. 20. Centers for Disease Control and Prevention. Women with smallpox vaccine exposure during pregnancy reported to the National Smallpox Vaccine in Pregnancy Registry-United States, 2003. MMWR Morb Mortal Wkly Rep 52:386,2003. 21. Levine MM, Edsall G, Bruce-Chwatt LJ. Live-virus vaccines in pregnancy: risks and recommendations. Lancet 234,1974. 22. Paranjothy D, Samuel I. Pregnancy associated with haemorrhagic smallpox. J Obstet Gynaecol Br Emp 67:309,1960.

Chapter 30 LESS COMMON VIRAL INFECTIONS Yvonne A. Maldonado

Human Papillomavirus 933 Epstein-Barr Virus

934

Human Herpesvirus 6

935

Human Herpesvirus 7

936

Influenza A and B 936 Respiratory Syncytial Virus 937 Lymphocytic Choriomeningitis Virus

939

Molluscum Contagiosum 940 Rabies Virus 940 West Nile Virus

940

HUMAN PAPILLOMAVIRUS Human papillomavirus (HPV) is the cause of condyloma acuminatum (i.e., genital warts) and cervical condylomata.'" The risk to the infant born to a mother with HPV infection is the development of juvenile laryngeal papillomatosis and possible development of anogenital warts: Hajek' associated the presence of condyloma acuminatum in a mother at the time of deliverywith the subsequent development of laryngeal papilloma in her infant (Table 30-1). Cook and colleagues6 described a similar association in five of nine children with laryngeal papilloma. All five of the children who developed laryngeal papilloma when younger than 6 months old were born to mothers who had condylomata acuminata at the time of delivery. The mothers of two of four other children with laryngeal papilloma had genital warts but did not have them at the time of delivery. Seven (78%) of the nine children with laryngeal papilloma had mothers with condylomata acuminata. The expected incidence of condylomata acuminata in women in the population studied by Cook and colleagues6 was 1.5%. Six of the nine children also had skin warts. Quick and co-workers' described a strong association between laryngeal papilloma in young children and maternal condylomata. Twenty-one (68%) of the 31 patients with laryngeal papilloma they studied had been born to mothers who had had condylomata. The basis for this epidemiologic relationship is evident from the detection of HPV DNA sequences in genital and laryngeal papilloma t i s s ~ e s .A~ number of studies have reported rates of newborn infection that ranged from 4% to 72% among infants born to HPV-infected mothers and 0.6% to 20% among those born to mothers without detectable HPV DNA.8-'4However, Smith and colleague^'^ investigated the risk of perinatal transmission based on concordance and sequence match to HPV types of both parents. Only 9 ( 1.6%) of 574 of oral or genital specimens from newborns were

positive for HPV DNA, and of those, only one maternalinfant HPV match was detected, suggesting that perinatal transmission is rare.I5 Rare associations have been made between maternal genital HPV infections and neonatal giant cell hepatitisI6 and vulvar genital papillomas among stillborns." Both associationswere documented in small numbers of gestations but were confirmed by HPV DNA polymerase chain reaction (PCR) or by electron microscopy. HPV cannot be isolated by means of tissue culture, but HPV DNA sequences can be detected in cervical cells. Cervical infection is caused by several types of HPV, including types 6, 11, 16, 18, and 31, and it is very common in the United States and Europe. HPV can be detected in epithelial cells that have a normal histologic appearance and from tissue samples of patients whose papillomatous lesions are in remission." Clinically, most genital HPV infection is asymptomatic. The frequency of HPV detection has ranged from 5% to 15% in studies of women of childbearing age, with the highest incidence occurring among younger w ~ m e n . ' ~ - ~ ~ Pregnancy was not associated with a higher rate of infection. Although the incidence of cervical infection was 20% in women with a history of condyloma, most pregnant women with HPV infection do not have a history of genital warts. Infection of the infant probably occurs by exposure to the virus at delivery, although papillomatosis has been described in infants delivered by cesarean section. Tang and associates23 described an infant who was born with condylomata acuminata around the anal orifice. The mother also had condylomata acuminata. Whether this case reflects transplacental hematogenous spread or direct extension across intact membranes is not known. Despite the prevalence of genital HPV infection, juvenile laryngeal papillomatosis remains a rare disease. The incidence of recurrent respiratory papillomatosis is approximately 3.96 per 100,000 in the pediatric population, with an incidence of 7 of every 1000 children born to mothers with vaginal condyloma. The risk of subclinical transmission of HPV from mothers to infants is not known. HPV-6 and HPV-16 DNA sequences were detected in the cells from foreskin tissue of 3 of 70 infants.24These HPV types are also found in genital warts. Because of the prevalence of asymptomatic HPV infection, the feasibility of preventing the rare cases of laryngeal papillomatosis by considering maternal condyloma acuminatum as an indication for cesarean delivery is uncertain. Treatment of anogenital warts is not optimal, but podophyllum resin or podofilox is often used in older children and adults. Neither has been tested for safety or efficacy in children, and both are contraindicated for use in pregnancy. Laryngeal papillomas recur even after repeated surgical removal. Interferon has been used with some success for treatment of laryngeal papilloma^.^' Although the mainstay of surgical management has traditionally been the CO, laser,

934


Table 30-1

Effects of Other Viral Infections of the Fetus and Newborn

Infectious Agent

Increased Incidence of Abortion

Increased Risk of Prematurity

Human papillomavirus Epstein-Barr virus Human herpesvirus 6 Influenza viruses Respiratory syncytial virus Lymphocytic choriomeningitis virus

No Possibly No No No Yes

No Possibly No No No No

Molluxum contagiosum virus Rabies

No No

No No

newer surgical techniques have demonstrated efficacy in the management of pediatric patients, including powered instrumentation and the pulse-dye laser. The traditional adjuvant medical therapies used for pediatric recurrent respiratory papillomatosis continue to be commonly used, including topical interferon alfa-2a, retinoic acid, and indol-3-carbinoV diindolylmethane (13C/DIM).Topical cidofovir has demonstrated efficacy in selected patients. Research trials suggest that HPV vaccines may in the future be useful for therapy and for Two approaches have been pursued for HPV vaccines: preventive vaccines to evoke a neutralizing antibody response and prevent infection and therapeutic vaccines to generate cytotoxic T lymphocytes and destroy HPV-infected neoplastic cells.28

EPSTEIN-BARR VIRUS Epstein-Barr virus (EBV) is a human herpesvirus that is most familiar as the cause of infectious mononucleosis. However, most women of childbearingage have been infected asymptomatically in childhood. Because EBV cannot be isolated directly in tissue culture, serologic tests are used to detect recent primary or past infection. Persons infected with EBV form IgG and IgM antibodies to viral capsid antigens (VCAs)soon after infection.” About 80% form antibodies to early antigens (EAs), which usually fall to undetectablelevels 6 months after infection.The presence of antibodies to EAs at later times after acute infection may indicate viral rea~tivation.~’Antibodies to EBV-associated nuclear antigen (EBNA) develop 3 to 4 weeks after primary infection and probably persist for life, as do IgG antibodies to VCAs. Prospective studies using antibodies to EAs as a marker of recent maternal EBV infection have yielded conflicting results. In a group of 719 women evaluated by kart and Didier,3’ pregnancies associated with early fetal death, birth of infants with a congenital abnormality, prematurity or intrauterine growth retardation, and deaths or illnesses during the first week of life were more common in women who were EA antibody positive during the first 3 months of pregnancy than in those who were not. Whether these women had a recent primary EBV infection or reactivation of an infection cannot be determined because EBV EA antibodies persist in some otherwise healthy adults and are associated with the reactivation of past EBV infection. In contrast, Fleisher and

Major Clinical Manifestations in Infants Laryngeal papilloma, condyloma acuminatum ? Febrile illness in postnatal period Probably none Pneumonia, bronchiolitis, in postnatal period Hydrocephalus, chorioretinitis,viral meningitis, jaundice, ? thrombocytopenia Rash None known

Bolognese3’ found that the frequency of antibodies to EA in pregnant women was 55%, compared with 22% to 32% among nonpregnant adults, but the incidence of low birth weight, neonatal jaundice, or congenital anomalies was not increased among infants of women with anti-EA antibodies. Primary EBV infection during pregnancy is unusual33 because only 3.0% to 3.4% of pregnant women are s ~ s c e p t i b l e Recent . ~ ~ ~ ~primary ~ EBV infection is diagnosed by the presence of VCA IgG and IgM antibodies in the absence of antibodies to EBV-associated nuclear antigen?6Six women were studied who had primary EBV infections during pregnancy as established by the presence of IgM antibody to VCA and the absence of antibody to EBNA in their sera.34Of these, only one had symptoms compatible with mononucleosis during pregnancy; she gave birth to a normal infant. Four of the remaining five pregnancies terminated abnormally. One woman had a spontaneous abortion, and the other three were delivered of premature infants. All three of the premature infants were abnormal. One was stillborn, one had multiple congenital anomalies, and one was small for gestational age. The products of abortion and the premature infants were not studied for evidence of an EBV infection. The abnormal infants in this study did not have a characteristic syndrome but instead had a variety of abnormalities. Fleisher and Bolognese3’ identified three infants born to women who had had silent EBV seroconversion during the first trimester. Two infants were normal; one infant had tricuspid atresia. EBV IgM was not detected in cord blood serum, and EBV was not recovered from the cord blood lymphocytes. Three infants of mothers with a primary EBV infection and infectious mononucleosiswere normal at birth and had no serologic or virologic evidence of intrauterine infe~tion.~~ Early reports implicated EBV as a cause of congenital anomalies, particularly congenital heart disease; however, Tallqvist and colleagues39were unable to show an increase in incidence of antibodies to EBV in 6- to 23-month-old children with congenital heart disease compared with normal, agematched controls. EBV may cause congenital heart disease in an individual case, but this study suggests that it is not a common cause of cardiac defects. Brown and Stenchever4’ described an infant with multiple congenital anomalies who was born to a mother who had a positive monospot test result 4 weeks before conception and at 16 and 36 weeks‘ gestation. In addition to the anomalies, which involved many organs, the infant was small for gestational age. Normal

Chapter 30 chromosomal complements were found on standard and G-banded karyotypes. The total IgM level in the cord blood was not elevated. Studies were not performed for IgM VCA antibody or antibody to EA, and no attempts were made to isolate EBV. Although the evidence that the mother had mononucleosis near the time of conception is convincing, there is no virologic evidence that EBV was the cause of the anomalies. Goldberg and associates41described an infant born with hypotonia, micrognathia, bilateral cataracts, metaphyseal lucencies, and thrombocytopenia. Immunologic evidence suggesting possible EBV infection included an elevated total IgM level, the presence of IgM anti-VCA antibody at 22 days of age, and a delay in development of anti-EBNA antibody until 42 days of age. Weaver and co-workers described an infant with extrahepatic bile duct atresia and evidence of intrauterine EBV infection; EBV IgM was identified in serum obtained when the infant was 3 and 6 weeks old, and persistent EBV IgG was seen at 1 year.42 Although EBV cannot be recovered by standard tissue culture methods, the virus can be detected by its capacity to transform B lymphocytes into persistent lymphoblastoid cell lines. In studies conducted to identify cases of intrauterine EBV infection, Visintine and colleagues43and Chang and B l a n k e n ~ h i pobserved ~~ spontaneous transformation of lymphocytes obtained from cord blood, but it was not associated with EBV. EBV-transformed cells were not found in any samples of cord blood from 2000 newborns studied by Chang and set^^^ or from the 25 newborns tested by Joncas and associate^?^'^^ One study used nested PCR methods for amplifymg EBV DNA regions in circulating lymphocytes from 67 mother-infant pairs within 1week of birth?' Approximately 50% of the women and two of the neonates were EBV PCR positive. Visintine and colleagues43studied 82 normal term infants, 28 infants with congenital anomalies, and 29 infants suspected of having congenital infections; they were unable to isolate EBV from any of these infants. Two infants have been described in whom there was evidence of infection with EBV at birth.47,49 A congenital cytomegalovirus (CMV) infection coexisted in both. Most of the clinical findings in the infants were compatible with those usually found in congenital CMV infections and included microcephaly, periventricular calcifications, hepatosplenomegaly,and inclusions characteristic of CMV in sections of tissues or cells in urinary sediments. One infant had deformities of the hands similar to those seen in arthrogryposis. Neither CMV nor EBV was isolated from the saliva or secretions of these infants. In the first infant, IgM antibody to EBV was present at birth and EBNA-positive permanent lymphoblastoid cell lines were established on five occasions between 3 and 30 months of age. In the second infant, permanent lymphoblastoid cell lines were established from the peripheral blood at birth and from heart blood at 3 days of age. EBNA and EBV RNA were identified in these cells, and CMV DNA was identified in the cells from the liver of the same infant. Attempts to isolate EBV from secretions obtained from the maternal cervix have been unsuccessful~3~45 but the virus can be detected at this site by DNA hybridizati~n.~' There is little evidence suggesting that natal transmission of EBV occurs. However, EBV was recovered from genital ulcers in a young woman with infectious mononucleosis.5' Fatal EBV infection was diagnosed by DNA hybridization of lymph node tissue from one infant who presented with failure to

Less Common Viral Infections

935

thrive, emesis, diarrhea, and a macular rash at 14 days of age, but this infection might have been acquired in ~ t e r o . ~ * EBV can be transmitted to newborns in the perinatal period by blood t r a n ~ f u s i o n .Permanent ~ ~ ' ~ ~ lymphoblastoid lines that contained EBV antigens were established by Joncas and co-workersMfrom the blood of two infants who had been transfused. One of these infants did not develop permanent antibodies to EBV. There is no evidence at present that EBV causes congenital anomalies. Because the early and the late serologic responses of young infants to a primary EBV infection differ from those found when a primary infection occurs at an older age,3°,46,53 it will be difficult to screen large numbers of newborns for serologic evidence of an EBV infection sustained in utero.

HUMAN HERPESVIRUS 6 Human herpesvirus 6 (HHV-6) is a member of the herpesvirus family that has been identified as a cause of exanthema subitum (i.e., r ~ s e o l a ) . The ~ ~ ' ~virus ~ exhibits tropism for T lymphocytes and is most closely related to human CMV by genetic analysis.57 Seroepidemiologic studies have shown that HHV-6 is ubiquitous in the human population, regardless of geographic area, and that it infects more than 90% of infants during the first year of life.58-60 IgG antibodies to HHV-6 are detected in almost all infants at birth, with a subsequent decline in seropositivity rates by 4 to 6 months of age as transplacentally acquired antibody is lost. The highest rate of acquisition of HHV-6 infection appears to occur during the first 6 months to 1 year of life as maternal antibodies wane. The seroepidemiologic evidence and restriction enzyme analysis of paired virus isolates from mothers and their infants suggest that the usual route of transmission is perinatal or postnatal.61No cases of symptomatic intrauterine HHV-6 infection have been confirmed since the agent was identified in 1986.A case of intrauterine infection was documented by PCR in a fetus whose mother had human immunodeficiency virus infection and HHV-6 in peripheral blood mononuclear cells,62and 1 (0.28%) of 799 cord blood serum samples had IgM antibodies to HHV-6.63Another study, using HHV-6 DNA PCR applied to cord blood specimens from 305 infants, demonstrated a 1.6% (5 of 305) PCR positivity rate, suggesting in utero transmission.64Evidence of reinfection after presumed congenital HHV-6 infection also has been dem~nstrated.~~ As diagnostic assays become more widely available,congenital infections may be recognized. However, primary HHV-6 infection, with its anticipated higher risk of transmission to the fetus, should be rare during pregnancy, because almost all adult women have been infected in childhood. Analogous to human CMV infection, the reactivation of maternal HHV-6, although it may be common during pregnancy, is not expected to cause symptomatic intrauterine infection. In addition to the roseola syndrome, HHV-6 has been detected by PCR in peripheral blood lymphocytes obtained from infants younger than 3 months who had acute, nonspecific, febrile Two neonates who had fulminant hepatitis associated with HHV-6 infection have been de~cribed.6'~~~ Other associations found among infants include a mononucleosis-like syndrome?' pne~monitis,~' and one case report of possible immunodeficiency and pneumonitis

936

Section I11

Viral Infections

associated with HHV-6 infection.72 However, all clinical associations between disease in infants and HHV-6 infection must be evaluated with care because of the evidence that most infants become infected with this virus within a few months after birth and that the virus persists after primary infection, as is characteristic of herpesviruses.62Clinicians also must be aware of the potential for false-positive results in serologic assays and in attempts to detect the virus by PCR.56

HUMAN HERPESVIRUS 7 Human herpesvirus 7 (HHV-7) was discovered in the peripheral blood lymphocytes of a healthy adult in 1990.73HHV-7 belongs to the Roseolovirus genus within the Betaherpesvirinae subfamily, along with HHV-6 and CMV. Like HHV-6, it causes primary infection in most individuals during childhood. However, clinically symptomatic infection with HHV-7 appears to be significantly less common and occurs later than with HHV-6. Based on seroepidemiologic st~dies,’~.~~ HHV-7 infection is ubiquitous in childhood and generally occurs at a later age than HHV-6 infection. The average age at infection is about 2 years, and 75% of children are seropositive by 5 years of age. The primary mechanism of transmission is from contact with saliva of infected individuals. Because HHV-7 DNA has been detected in breast m a , breast-feeding may be another source of infection.77However, antibodies to HHV-7 in breast milk may protect against infection, and in one study, breastfeeding was associated with a lower risk of early acquisition of HHV-7 i n f e ~ t i o n . HHV-7 ~ ~ ’ ~ ~DNA has been detected in 2.7% of cervical swabs obtained from women in their third trimester of pregnancy but from none of the swabs of control women, suggesting that pregnancy may be associated with reactivation of HHV-7.79However, perinatal transmission from contact with infected maternal secretions is unknown, and neonatal infections with HHV-7 have not been reported.80 Clinical symptoms are rarely associated with HHV-7 infection but include nonspecific fever, with or without rash, which resembles exanthema subitum. Clinically apparent HHV-7 infections appear to have a high rate of central nervous system (CNS) i n v o l ~ e m e n t . ~ ” ~ ~

INFLUENZA A AND B Early investigations of the teratogenic potential of influenza virus were epidemiologic studies in which the diagnosis of influenza was not confirmed ser0logically.8~In 1959, Coffey and Jessupa5reported an incidence of 3.6% of congenital defects in 664 Irish women who had histories of having had influenza during pregnancy, compared with 1.5% of 663 women who did not have symptoms compatible with influenza. CNS anomalies were the most common type of defect, and of these, anencephaly was the most frequent. These investigators presented some evidence that women who had a history of having had influenza in the first trimester were more likely to give birth to children who had congenital anomalies than those who had influenza later in the pregnancy. This evidence provided credence to the report.

In a similar study conducted in Scotland, Doll and Hilla6 were unable to confirm that congenital anomalies occurred with a higher frequency in infants of women who had histories of influenza during pregnancy than in infants of women who did not. However, after reviewing the reported incidence of stillbirth related to anencephaly recorded by the Registrar General for Scotland, they concluded that there was a small increase in risk of anencephaly if the mother had had influenza during the first 2 months of pregnancy. In performing this analysis, certain assumptions were made because of the lack of precise data. Recorda7and Leckaaanalyzed the same data and were unable to find an association between influenza and malformations of the CNS. An increase in congenital defects in infants of mothers who had influenza-like symptoms at 5 to 11 weeks‘ gestation was reported by Hakosalo and Sa~en.’~ Most of these anomalies involved the CNS, but there was no increase in incidence of anencephaly in infants of women who had symptoms compatible with influenza compared with those who remained asymptomatic. All of these studies were undertaken during influenza epidemics. It was assumed that, under these circumstances, there would be a high correlation between a history of influenza as elicited from the patient and infection with influenza virus. However, during the 1957 outbreak, Wilson and Steingodemonstrated that 60% of pregnant women who denied symptoms of influenza had serologic evidence of having been recently infected. Conversely, 35% of those who stated that they had had influenza lacked serologic evidence of having been infected. Likewise, Hardy and co-workers9’ found that 24% of those who stated that they had had influenza lacked serologic evidence of past infection with the epidemic strain and 39% of those with titers suggesting recent infection denied symptoms of influenza. MacKenzie and Houghton9*summarized the reports implicating influenza virus as a cause of maternal morbidity and congenital anomalies and came to the conclusion that probably no association exists between maternal influenza infection and subsequent congenital malformations or neoplasms in childhood. Several studies have been performed in which infection by influenza virus has been serologically confirmed. Hardy and co-workers9*reported that the incidence of stillbirths was higher in 332 symptomatic pregnant women with serologically confirmed influenza infections than in 206 women with serologically confirmed infections who had remained asymptomatic or in 73 uninfected women. The control group of uninfected women was smaller than expected because the attack rate during the period of the study was very high. Major congenital anomalies occurred in 5.3% of women whose infections occurred during the first trimester, compared with 2.1% of 183 women infected during the second trimester and 1.1% of 275 women infected during the third trimester. Supernumerary digits, syndactyly, and skin anomalies were excluded from these figures. Among infants of mothers infected during the first trimester, cardiac anomalies were the most common type of abnormality; none of these infants had anencephaly. Griffiths and associates93observed a slight increase in congenital anomalies in infants born to women who had had serologically confirmed influenza during pregnancy compared with infants of women who had not; however, all of the infants with congenital anomalies were born to women who had had influenza in the second or third

Chapter 30 trimester. Monif and colleagues9*did not document infection in any of eight infants born to mothers who had influenza NHong Kong infections in the second and third trimesters. Wilson and Stein" found no increase in congenital anomalies in women with serologic evidence of having been recently infected with influenza virus who had conceived during the 3-month period when influenza was epidemic. Population-based epidemiologic studies have not demonstrated that influenza infections during pregnancy are significantly associated with adverse perinatal outcomes. However, influenza infections during pregnancy are more likely to result in hospitalization for respiratory symptoms in the pregnant woman than for nonpregnant Hartert and associatesg5conducted a matched cohort study of pregnant women to determine pregnancy outcomes associated with respiratory hospitalizations during influenza seasons from 1985to 1993. During those influenza seasons, 293 pregnant women were hospitalized for respiratory symptoms, at a rate of 5.1 per 1000 pregnant women. The prevalence of prematurity and low birth weight was not higher than a matched cohort of pregnant women hospitalized with nonrespiratory diagnoses. However, pregnant women with asthma had higher rates of respiratory hospitalizations than those without asthma, and all of three fetal deaths in this cohort were singleton, latethird-trimester intrauterine fetal deaths in mothers who had asthma and were current smokers.95 It can be said with certainty that intrauterine exposure to influenza virus does not cause a consistent syndrome. If there is a cause-and-effect association between influenza virus infections during pregnancy and congenital anomalies, the latter occur with low frequency. Hakosalo and have documented an increase in the use of nonprescription drugs during influenza outbreaks and have suggested that drugs rather than infection with influenza virus may exert an erratic teratogenic influence. A number of studies have investigated the possible association between influenza infection in pregnant women and subsequent development of bipolar affective disorders or schizophrenia among their offspring, with mixed re~ults.9~-~~ Viremia is rare during influenza infections, but it does occur. Few attempts have been made to demonstrate transplacental passage of the virus to the fetus. Ruben and colleagues"' tested the cord sera of infants born to 22 mothers who had been pregnant during an influenza NEngland/42/72 outbreak and who had had influenza hemagglutination inhibition titers to this virus of 1:16 or higher while pregnant. Forty-two cord serum samples were randomly collected from infants who had been born on the same day as the selected infants. Of the 64 cord serum samples tested, a fall in titer of fourfold or more was seen in four samples after treatment with 2-mercaptoethanol; this suggests that IgM antibody to influenza might have been present. Three of 16 cord blood samples tested gave positive lymphocyte transformation responses to influenza virus. All seven of the infants with evidence of antigenic recognition of influenza virus at birth had uncomplicated deliveries and remained healthy. Influenza NBangkok was isolated from the amniotic fluid of a mother with amnionitis and acute influenza infection at 36 weeks' gestation; the infant who was born at 39 weeks had serologic evidence of infection but was asymptomatic."' Yawn and associates"* studied a woman who developed influenza in the third trimester and died of pulmonary edema.


937

A virus similar to the prototype strain A,/Hong Kong/8/68 was isolated from the lung, hilar nodes, heart, spleen, liver, kidney, brain, and spinal cord of the mother and from the amniotic fluid and myocardium of the fetus. Ramphal and colleagues103studied another woman who died of complications of an influenza infection at term. A virus similar to strain NTexas/77 was isolated from maternal tissues, but influenza virus was not isolated from any of the fetal tissues tested. In contrast to intrauterine infections with influenza virus, which are rare, infections acquired by infants in the neonatal period are common. Passively transferred antibody to influenza virus may prevent symptomatic infections during the first few months of life if it is present in sufficient q~antity.''~"'~ Two cases of influenza NHong Kong/68 infection in infants who were younger than 1 month were described by Bauer and associates.lMThe first infant developed high fever, irritability, and nasal discharge when 10 days old; the second infant, who was premature, developed fever and nasal congestion when 14 days old. Symptoms were restricted to the upper respiratory system, and both infants recovered within 4 days of onset of the illness. Influenza virus infection may, however, be fatal in the neonatal peri~d."~ Several outbreaks of influenza virus infection have occurred in neonatal intensive care units. In general, illness has been mild.'06*'08Most of the eight infected neonates described by Meibalane and co-workers'08 had nonspecific symptoms, including apnea, lethargy, and poor feeding. Only two had cough or nasal congestion. None had tachypnea or respiratory distress, but three of five for whom chest radiographs were obtained had interstitial pneumonia. Infants younger than 6 months cannot be protected by influenza vaccine. All health care professionals who care for high-risk newborns should receive the influenza Ninfluenza B vaccine annually in the fall. Pregnancy is not a contraindication for the administration of influenza va~cine."~~"~

RESPIRATORY SYNCYTIAL VIRUS Although respiratory syncytial virus (RSV) is a common cause of upper respiratory tract infection in adults, there is no evidence that the virus causes intrauterine infection. Maternal infection has no known adverse effect on the fetus. RSV infections are frequently acquired by infants during the first few weeks of life and are associated with a high mortality rate. Two thirds of all infants become infected with RSV in the first year of life, and one third of them will develop lower respiratory tract symptoms, 2.5% will be hospitalized, and 1 in 1000 infants will die as a result of RSV infection."' It was originally thought that passively transferred maternal antibody to RSV contributed to the severity of the infection in young infants by causing an immunopathologic reaction in the lung.'I2 Later studies of the age-corrected incidence of symptomatic RSV infections showed a relative sparing of infants who were younger than 3 week~.''~,"~ This is the period during which maternal antibody is the highest. In subsequent studies, no evidence was found that the presence of maternal antibody adversely influenced the course of infection in the infant.'I5 Lamprecht and colleagues116found an inverse relationship between the level of maternal neutralizing antibody and the severity of the RSV infection in the infant.

938


Infants who are younger than 1 month have a higher Glezen and co-~orkers"~ found that the quantity of neutralmean maximal titer of virus in their secretions than those izing antibody to RSV in cord sera was lower in infants with who are 01der.I~~ Ninety-six percent of the infected infants proven RSV infections than in randomly selected infants. studied by Hall and co-worker~'~~ shed virus for 9 days. None of the infected infants who had antibody titers of 1:16 Objects contaminated with secretions from infected infants or higher developed serious infections. Some have suggested may be important sources of infection in nursery personnel. that breast-feeding decreases the possibility that an infant RSV in infected secretions is viable for up to 6 hours on will have a serious RSV infection early in life"'; however, this countertops, for up to 45 minutes on cloth gowns and paper has not been a consistent finding in every study. Because tissues, and for up to 20 minutes on skin.'36 Evidence suggests breast-feeding and crowded living conditions affect the incithat personnel are at least as important in spreading the dence of RSV infection in infants, it has been difficult to infection to infants as are other infected infants housed in define effects attributable solely to breast-feeding. Infection the same area and that infection control measures can reduce with RSV in infants who are younger than 4 weeks may be the risk of transmi~sion.'~~-'~' asymptomatic, consist of an afebrile upper respiratory Any infant with rhinorrhea, nasal congestion, or unexsyndrome, or be accompanied by fever, bronchiolitis or plained apnea should be segregated and investigated for RSV pneumonia, and apnea."' infection. Personnel should be made aware that this agent, RSV accounted for 55% of cases of viral pneumonia in which causes only mild colds in adults, can cause fatal illinfants younger than 1 month in one study that evaluated nesses in infants. The specific diagnosis of RSV infection hospitalized infants over a 5-year period.'20Most infants who should be sought for infection control purposes and because died had underlying medical conditions that involved the aerosolized ribavirin treatment has some effectiveness in heart or lungs.'2's'22Premature infants who have recovered infants with lower respiratory infection caused by this from hyaline membrane disease and who have bronchopulv i r ~ s . ' ~Methods - ' ~ ~ have been described for administering monary dysplasia are especially likely to develop severe ribavirin safely to infants receiving mechanical ~ e n t i l a t i o n . ' ~ " ~ ~ infections. The A subtype of RSV may have the potential to Questions concerning the benefits of ribavirin therapy for cause more severe disease than the B subtype.'23 RSV pneumonia and the indications for its use remain.'46*'47 The nosocomial outbreaks that have occurred in nurseries There is still a lack of consensus regarding appropriate caring for premature and ill term infants have varied in management of the infant with RSV infection specifically severity. Neligan and colleagues'24described an outbreak in with respect to the use of aerosolized r i b a ~ i r i n . l ~ *Despite *'~~ which eight infants were infected. The first symptom in all a number of studies in the United States and Canada regarding infants was the development of a clear nasal discharge when the use of aerosolized ribavirin, no clear improvement in 10 to 52 days old. Cough developed 2 to 7 days later. Three clinical outcomes is consistent across all studies of ventilated infants developed wheezing, and only one infant was seriously ill. In the outbreak described by Berkovich and T a r a n k ~ , ' ~ ~and nonventilated infants with RSV infection. However, infants who should be considered candidates for ribavirin 14 infants in a premature nursery became ill when 11 to 184 therapy include those who are at increased risk for complidays old. Of the 14 infants, 93% had coryza, 86% had dyspnea, cations of RSV because of congenital heart disease, chronic 64% had pneumonia, and 36% had fever. Upper respiratory lung disease, or immunodeficiency; infants with severe tract symptoms began 1 to 8 days before the first dyspnea in illness and signs of respiratory failure based on arterial 11 infants. Changes compatiblewith pneumonia were demonoxygen concentrations of less than 6 5 m m Hg and rising strable on chest roentgenograms 3 to 5 days before clinical Paco, concentrations; and infants who may be comevidence of lower respiratory tract involvement developed. promised by a prolonged illness because of an underlying The degree of illness in the nine infants studied by Mintz medical ~ondition.'~' and associatesIz6was mild in four, moderate in two, and Although the benefit of treatment with ribavirin is severe in two. One infant was asymptomatic. The infants controversial, there is clear evidence for the benefit of prowho were the most seriously ill had fever, cyanosis, pulphylaxis against RSV infection in infants at high risk for monary infiltrates, and respiratory deterioration. Infants with complications. Several studies demonstrated the benefits of RSV infections have developed respiratory arrest as a result RSV intravenous immune globulin (RSV IGIV) among of apnea.'27"28Most infants infected during nosocomial outselected infants at high risk for moderate to severe complibreaks of RSV in nurseries were born prematurely but had cations due to RSV infection."' Such high-risk patients include attained 4 weeks or more in chronologic age at the time they infants and children younger than 2 years with chronic lung developed the infection^.'^^"'^ Two nursery outbreaks were disease who have required medical therapy for lung disease associated with dual infections caused by RSV and rhinowithin 6 months of the RSV season and premature infants virus or parainfluenza virus 3.'29,'30 A diffuse viral pneumonia, who were 32 to 35 weeks' gestation at birth. RSV IGIV is which is indistinguishable from severe RSV pneumonia, can contraindicated for those with cyanotic congenital heart be caused in rare instances by parainfluenza viruses alone or, disease because of possible safety concerns. Subsequently, a rarely, by adenovirus."' Hall and c o - w o r k e r ~have ' ~ ~ shown humanized anti-RSV monoclonal antibody preparation, that infants who are younger than 3 weeks when they become palivizumab, was developed for intramuscular administration infected with RSV have a higher incidence of nonspecific and shown to reduce by 55% hospitalizations resulting from signs and a lower incidence of lower respiratory tract infection RSV infection in these high-risk infant~.'~' Moreover, initial than infants who are older than 3 weeks at the time of inconcerns regarding the safety of palivizumab among infants fection. RSV has been recovered from the oropharynx of with cyanotic congenital heart disease have been allayed based infants who were younger than 48 hours.'33It may be difficult on clinical trials. Because of its greater uniformity and ease to recognize the index case when RSV is introduced into the of administration and its efficacy in infants with cyanotic nursery.'34

Chapter 30

Table 30-2


939

Sources of Maternal or Neonatal Infection ~

Infectious Agent

Other People with Same Infection

Human papillomavirus Epstein-Barr virus Human herpesvirus 6 Influenza viruses Respiratory syncytial virus Lymphocytic choriomeningitis virus

Yes Yes Yes Yes Yes No

Molluscum contagiosum virus Rabies

-

Yes

congenital heart disease, palivizumab is now the preferred method of RSV prophylaxis. Improved survival of infants with RSV infection and underlying cardiopulmonary disease has been reported with advances in intensive care management.’52*’53 Nevertheless, families of infants with medical conditions that predispose to severe RSV disease should be advised to avoid the higher risk of exposure associated with group d a y ~ a r e . ‘ ~ ~

LYMPHOCYTIC CHORlOMENlNGlTlS VIRUS Lymphocytic choriomeningitis virus (LCV) is spread from animals, primarily rodents, to humans. Person-to-person spread has not been described (Table 30-2).’55 Mice and hamsters have most often been implicated as the source of human infections. When mice acquire LCV transplacentally or as newborns, they remain asymptomatic but shed the virus in their urine for month^.'^^*'^^ This phenomenon of “tolerance” has been extensively studied in laboratory-bred strains of mice. Domestic household mice also have been implicated as a source of human cases of infection with LCV.15*Several outbreaks in animal handlers and in families have been traced to pet Syrian (or golden) hamsters (Mesocricetus Adult and newborn hamsters remain asymptomatic after infection with LCV and shed the virus in feces and urine for months.’56In outbreaks in which human cases have been associated with contact with infected hamsters, the location of the hamster’s cage correlated with attack rate. When the hamster’s cage was in a common living area, 52% of 42 family members in contact with the hamster became infected.’59In contrast, no one became infected when the cage was located in a more remote area, such as a basement or landing. LCV can be shed also by asymptomatic guinea pigs and rat^.'^^,'^^,'^' The illness caused by LCV is accompanied by fever, headache, nausea, and myalgia lasting 5 to 15 day^.'^^*'^^,'^' In the outbreak of LCV described by Biggar and colleague^,'^^ fever occurred in 90% and headache in 85% of patients. Myalgia occurred in 80% and was described as severe. The neck, shoulders, back, and legs were most often involved. Pain on eye movement occurred in 59%, nausea in 53%, and vomiting in 35%. About one fourth of the patients had a sore throat or photophobia. The illness was biphasic in 24% and was accompanied by swollen glands in 16%. Six percent of the patients had a mononucleosis-like illness characterized by intermittent fever, adenopathy,pharyngitis, extreme fatigue, and rash. Twelve percent of those with serologic evidence of

Animal No No No No No House mice, pet Syrian hamsters, laboratory rats, rabbits

No Yes

having had an infection remained asymptomatic. Arthritis, encephalitis, and meningitis occurred in a few cases. The diagnosis of infection with LCV can be made by isolation of the virus or by serology. The indirect fluorescent antibody titer may be positive as early as the first day of symptom^.'^^,'^' The complement fixation titer generally does not rise until 10 days or longer after illness onset.’55’I6O The neutralization titer rises late, usually after the fourth week, but persists the l ~ n g e s t . ’ ~A~positive , ’ ~ ~ indirect fluorescent antibody titer, a falling indirect fluorescent antibody or complement fixation titer, or a rising neutralization titer suggests recent infection with LCV. LCV infections during pregnancy may be underdiagnosed as causes of congenital infections and are associated with abortion, intrauterine infection, and perinatal infection. Ackermann and associates‘62described a 23-year-old woman who developed a febrile illness beginning 4 weeks after she assumed the care of a Syrian hamster. She was 7 months pregnant at the time of the illness and sustained a spontaneous abortion 4 weeks after onset of the fever. LCV was isolated from curettage material. Complement fixation antibodies to LCV were present initially, and neutralizing antibodies appeared later-a pattern compatible with recent infection. Diebel and co-worker~’~~ studied a pregnant woman who acquired LCV from a hamster and developed meningitis. One month after the onset of illness, a spontaneous abortion occurred. Biggar and co-worker~’~~ described a woman who acquired LCV during the first trimester of pregnancy. She had a spontaneous abortion 1month after onset of the illness. U.S. cases of 26 serologicallyconfirmed congenital LCV infections identified between 1955 and 1996 were reviewed.’63Eightyfive percent (22 of 26) were term infants with a median birth weight of 3520 g. The most common congenital abnormalities identified were chorioretinopathy (88%), macrocephaly (43%), and microcephaly (3%). There was a 35% (9 infants) mortality rate, with a 63% (10 of 16) rate of severe neurologic sequelae among reported survivors. One fourth of mothers had gestational exposure to rodents, and 50% of all women reported symptoms consistent with LCV infection. Intrauterine infection of the fetus results in congenital hydrocephalus and chorioretinitis. In 1974, Ackermann and associate^'^^ reported that two children who were born to mothers who had been in contact with hamsters during the second half of pregnancy had hydrocephalus and chorioretinitis. Other problems included severe hyperbilirubinemia and myopia. The serologic pattern typical of recent infection was found in the mothers and infants and included a falling complement fixation titer and a rising neutralization titer to

940


LCV. Sheinbergas16' found a statistically significant relationship between the presence of antibody to LCV and the occurrence of hydrocephalus in infants younger than 1 year. Thirty percent of 40 infants with hydrocephalus had indirect fluorescent antibody to LCV, whereas only 2.7% of 110 infants with other nervous system diseases had antibody to LCV. Fourteen (87.5%) of 16 children who had serologically confirmed prenatal infection with LCV had hydrocephalus. Of these, six (37.5%) had been born with hydrocephalus, and the remainder developed it when 1 to 9 weeks old. Chorioretinal degeneration was found in 81%, and optic disk subaperformed trophy was found in 56%. Mets and colleag~es'~~ ophthalmologic surveys among residents of a home for the severely mentally retarded, and sera from the 4 residents with chorioretinal scars and 14 residents with chorioretinitis were tested for Toxoplasma gondii, rubella virus, CMV, herpes simplex virus, and lymphocytic choriomeningitis virus. Two of the 4 residents with chorioretinal scars and 3 of the 14 with chorioretinitishad elevated antibody titers only to LCV.'65 Komrower and colleague^'^^ described a mother who acquired LCV about a week before delivery. Despite segregation of the infant, LCV was acquired transplacentally or natally, and the infant subsequently became ill. The mother's initial symptoms included malaise, headache, fever, and cough. About 20 days after onset of symptoms and 12 days after delivery, increased numbers of cells and increased protein concentration occurred in the cerebrospinal fluid. The diagnosis of infection caused by LCV was confirmed by a rise in the mother's complement fixation titer from 1:2 to 1:64. The infant, who was probably premature, remained relatively stable until 1 1 days old, at which time seizures, stiff neck, and mild pleocytosis developed. The infant developed petechiae and died of a subarachnoid and intracerebral hemorrhage. LCV was isolated from the infant's cerebrospinal fluid and from mice caught in the home of the mother. Because apparently healthy mice and hamsters may shed LCV chronically, pregnant women should avoid direct contact with these animals and with aerosolized excreta. Unless appropriate measures have been taken to ensure that laboratory animals are free of LCV, these precautions should apply to laboratory as well as domestic rodents. LCV causes spontaneous abortions. Hydrocephalus and chorioretinitis are common in infants who have survived intrauterine infe&on.161,164-166 women who acquire an LCV infection during the weeks immediately before delivery may transmit the virus to their infants. Although the total number of intrauterine and perinatal infections from LCV is not large, the incidence of serious sequelae in the infant appears to be high.

MOLLUSCUM CONTAGIOSUM Molluscum contagiosum is a papular rash consisting of multiple discrete lesions that are acanthomas by histologic examination. The skin lesions are caused by a poxlike virus that has been difficult to study because it cannot be propagated in tissue culture. Epidemiologically, molluscum contagiosum is a disease of children and young adults. The virus may be transmitted by sexual conduct, given that the incidence increases among adolescents and young adults. Whether it is transmitted as a perinatal infection is not known.

Five women who delivered infants at a time when they had the lesions of molluscum contagiosum in the genital area have been described by Wilkin.16' None of the infants developed molluscum contagiosum. Mandel and Lewis168 reported an infant who developed two papules on the thigh when 1 week old. These enlarged and were excised when the child was 1 year old. The results of histologic examination and the findings on electron microscopy were compatible with molluscum contagiosum. In 1926, Young'69 reported an infant with molluscum contagiosum of the scalp. The lesions appeared when the infant was 1.5 months old. No histologic studies were performed.

RABIES VIRUS Transplacental transmission of rabies virus to the human fetus has not yet been described, although it is known that transplacental transmission occurs in experimental infections in many species.170-175 Spence and associate^"^ described an infant who was born 2 days before the onset of the mother's first symptom of encephalitis. The mother died of rabies on the fourth postpartum day. Rabies virus antigens were demonstrated in the cornea, lacrimal gland, and various parts of the brain by fluorescent antibody stain. The child survived despite the fact that the mother and infant lacked neutralizing antibodies to rabies at the time of the birth. Two reports describe the successful administration of horse antirabies hyperimmune serum and duck embryo vaccine to pregnant women.17o3176 Unusual untoward effects did not occur, and the infants were delivered at term and were healthy. The mothers did not develop serum sickness, anaphylaxis, or neurologic complications, but if they had, the viability of the fetus might have been threatened. Horse antiserum to rabies virus has been replaced by human rabies immune globulin. The chance of an adverse reaction to administration of human immune globulin is very small. The vaccine that was previously grown in duck embryos has been replaced with an inactivated vaccine derived from virus grown in human diploid fibroblast cells.177No serious reactions have been reported after administration of this vaccine, and it is possible to achieve titers that are about 10-fold higher than those found after administration of the duck embryo vaccine. Because of the high likelihood of fatal disease after the bite of a rabid animal, postexposure prophylaxis should always be given. Pregnancy is not a contraindication. When it is necessary to administer prophylaxis to a pregnant woman, human rabies immune globulin and human diploid cell vaccine should be used to minimize potential adverse effects on the pregnancy. After reviewing the available data, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention (CDC) has recommended human diploid cell vaccine to rabies virus as a pre-exposure immunization that is safe for use in pregnant women who will likely be exposed to wild rabies virus before completion of pregnancy.'78

WEST NILE VIRUS West Nile virus (WNV) is a mosquito-borne flavivirus that has caused epidemic infections in the United States since its

Chapter 30 introduction in 1999.'79 Since then, three cases of intrauterine and breast-feeding transmission have been reported in the literature.'60-'82In 2002, a previously healthy woman at 27 weeks' gestation developed a febrile illness, followed by lower extremity paresis and meningoencephalitis. At 38 weeks' gestation, she delivered an infant with bilateral chorioretinitis and severe, bilateral white matter loss in the temporal and occipital lobes. Maternal, cord, and infant blood samples at birth were positive for WNV-specific IgM and neutralizing antibodies; cerebrospinal fluid from the infant was W IgM positive; and the placenta was WNV PCR positive.'80 A second reported case of intrauterine WNV infection occurring in the second trimester resulted in congenital chorioretinal scarring and severe CNS malformations of the newborn.'" One case of probable breast-feeding transmission is reported in a woman who required red blood cell transfusions shortly after delivery. She began breast-feeding on the day of delivery and through the second day of hospitalization. The woman had developed symptoms consistent with meningoencephalitis 6 days before delivery; subsequent evaluation of the units of transfused blood revealed one unit that was WNV positive by PCR. Serum from the infant was positive for WNV-specific IgM at day 25 of life. The infant remained healthy at last report.'82 Although spontaneous abortions and stillbirths have been associated with flavivirus infections, these viruses have not previously been reported to be teratogenic. During 2002, the CDC investigated three other cases of maternal WNV infection in which the infants were all born at full term with no evidence of WNV infection or congenital sequelae; however, cranial imaging and ophthalmologic examinations were not performed on these infant^."^ No specific therapy is available for WNV infection, and the CDC does not recommend WNV screening of asymptomatic pregnant women. Pregnant women who have meningitis, encephalitis, acute flaccid paralysis, or unexplained fever in an area of ongoing WNV transmission should have serum and cerebrospinal fluid, if clinically indicated, tested for antibody to W.If WNV illness is diagnosed in the pregnant woman, ultrasound examination of the fetus should be considered no sooner than 2 to 4 weeks after maternal onset of illness, and fetal or amniotic testing can be considered. Infants born to women with known or suspected WNV infection during pregnancy should be evaluated for congenital WNV infection. Prevention of WNV infection should include application of insect repellant to skin and clothes when exposed to mosquitoes and avoidance of peak mosquito-feeding times at dawn and

REFERENCES Human Papillomavirus 1. Ono S, Saito H, Igarash M. The etiology of papilloma of the larynx. Ann Otol661119,1957. 2. Almeida JD, Oriel JD. Wart virus. Br J Derrnatol83:698, 1970. 3. Gissman L, Wolnik L, Ikenberg H, et al. Human papillomavirus types 6 and 11: DNA sequences in genital and laryngeal papillomas and in some cervical cancers. Proc Natl Acad Sci U S A 80:560, 1983. 4. Allen AL,Seigfried EC. The natural history of condyloma in children. J Am Acad Dermatol39951,1998. 5. Hajek EF. Contribution to the etiology of laryngeal papilloma in children. J Laryngol70166,1956. 6. Cook TA, Brunschwig JP, Butel JS, et al. Laryngeal papilloma: etiologic and therapeutic considerations. Ann Otol82:649, 1973.


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Epstein-Barr Virus 29. Henle W, Henle G, Horwitz CA. Epstein-Barr virus-specific diagnostic tests in infectious mononucleosis. Hum Patholk551, 1974. 30. Fleisher G, Henle W, Henle G, et al. Primary Epstein-Barr virus infection in American infants: clinical and serological observations. J Infect Dis 139553,1979. 31. Icart J, Didier J. Infections due to Epstein-Barr virus during pregnancy. J Infect Dis 143:499, 1981. 32. Fleisher G, Bolognese R. Persistent Epstein-Barr virus infection and pregnancy. J Infect Dis 142982,1983. 33. Le CT, Chang S, Lipson MH. Epstein-Barr virus infections during pregnancy. Am J Dis Child 137:466, 1983. 34. Icart J, Didier J, Dalens M, et al. Etude prospective de l'infection a virus Epstein-Barr (EBV) au cours de la grossesse. Biomedicine 34160,1981.

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35. Gervais F, J o n a s JH. Seroepidemiology in various population groups of the greater Montreal area. Comp Immunol Microbiol Infect Dis 2:207, 1979. 36. Horowitz CA, Henle W, Henle G, et al. Long-term serologic follow-up of patients for Epstein-Barr virus after recovery from infectious mononucleosis. J Infect Dis 151:1150,1985. 37. Fleisher G, Bolognese R. Epstein-Barr virus infections in pregnancy: a prospective study. J Pediatr 104374, 1984. 38. Fleisher G, Bolognese R. Infectious mononucleosis during gestation: report of three women and their infants studied prospectively. Pediatr Infect Dis 3:308, 1984. 39. Tdqvist H, Henle W, Klemola E, et al. Antibodies to Epstein-Barr virus at the ages of 6 to 23 months in children with congenital heart disease. Scand J Infect Dis 5:159,1973. 40. Brown ZA, Stenchever MA. Infectious mononucleosis and congenital an0maIies.h J Obstet Gynecol 131:108, 1978. 41. Goldberg GN, Fulginiti VA, Ray CG, et al. In utero Epstein-Barr virus (infectious mononucleosis) infection. JAMA 2461579, 1981. 42. Weaver LT, Nelson R, Bell TM. The association of extrahepatic bile duct atresia and neonatal Epstein-Barr virus infection. Acta Paediatr Scand 73:155, 1984. 43. Visintine AJ, Gerber P, Nahmias AJ. Leukocyte transforming agent (Epstein-Barr virus) in newborn infants and older individuals. J Pediatr 89571,1976. 44. Chang RS, Blankenship W. Spontaneous in vitro transformation of leukocytes from a neonate. Proc SOCExp Biol Med 144:337,1973. 45. Chang RS, Seto DY. Perinatal infection by Epstein-Barr virus. Lancet 2201,1979. 46. J o n a s J, Boucher J. Granger-Julien M, et al. Epstein-Barr virus in the neonatal period and in childhood. Can Med Assoc J 11033,1974. 47. J o n a s JH, Wills A, McLaughlin B. Congenital infection with cytomegalovirus and Epstein-Barr virus. Can Med Assoc J 117:1417,1977. 48. Meyohas MC, Marechal V, Sedire N, et al. Study of mother-to-child Epstein-Barr virus transmission by means of nested PCRs. J Viol 706816,1996. 49. Joncas J, Alfieri C, Leyritz M, et al. Dual congenital infection with the Epstein-Barr virus (EBV) and the cytomegalovirus (CMV). N Engl J Med 3041399, 1981. Lemon SM, Pagano JS. A second site for Epstein-Barr virus 50. Sibey JW, shedding: the uterine cervix Lancet 2:1122, 1986. 51. Portnoy J, Ahronheim GA, Ghibu F, et al. Recovery of Epstein-Barr virus from genital ulcers. N Engl J Med 31 1:966,1984. 52. Horwitz CA, McClain K, Henle W, et al. Fatal illness in a 2 week old infant: diagnosis by detection of Epstein-Barr virus genomes from a lymph node biopsy. J Pediatr 1033752, 1983. 53. Gervais F, Joncas JH. Correspondence-an unusual antibody response to Epstein-Barr virus during infancy. J Infect Dis 140:273, 1979.

Human Herpesvirus 6 54. Salahuddin SZ, Ablashi DV, Markham PD, et al. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science 234596,1986. 55. Lopez C, Pellett P, Stewart J, et al. Characteristics of human herpesvirus-6. J Infect Dis 157:1271, 1988. 56. Leach CT, Sumaya CV, Brown NA. Human herpesvirus-6 clinical implications of a recently discovered, ubiquitous agent. J Pediatr 1231: 173,1992. 57. Lawrence GL, Chee M, Craxton MA, et al. Human herpes virus 6 is closely related to human cytomegalovirus. J Virol64:287, 1989. 58. Baillargeon J, Piper J, Leach CT. Epidemiology of human herpesvirus 6 (HHV-6) infection in pregnant and non-pregnant women. J Clin Virol 16149,2000. 59. Dahl H, Fjaertoft G, Norsted T, et al. Reactivation of human herpesvirus 6 during pregnancy. J Infect Dis 1802035,1999. 60. A d a m 0, Krempe C, Kogler G, et al. Congenital infections with human herpesvirus 6. J Infect Dis 178544,1998. 61. Yamaniski K, Okada K, Ueda K, et al. Exanthem subitum and human herpes virus 6. Pediatr Infect Dis J 12:204, 1993. 62. Aubi 1-T, Poirel L, Agut H, et al. Intrauterine transmission of human herpes virus 6. Lancet 340482, 1992. 63. Dunne WM, Demmler GJ. Serologic evidence for congenital transmission of human herpesvirus 6. Lancet 340121,1992. 64. Adams 0, Krempe C, Kogler G, et al. Congenital infections with human herpesvirus 6. J Infect Dis 178:544, 1998. 65. van Loon NM, Gummuluru S. Sherwood DJ, et al. Direct sequence analysis of human herpesvirus 6 (HHV-6) sequences from infants and

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Human Herpesvirus 7 73. Black JB, Pellett PE. Human herpesvirus 7. Rev MedVirol3:217,1993. 74. Frenkel N, Schirmer EC, Wyatt LS, et al. Isolation of a new herpesvirus from human CD4+ T cells. Prof Natl Acad Sci U S A 87:748,1990. 75. Krueger GR, Koch B, Leyssens N, et al. Comparison of seroprevalences of human herpesvirus-6 and -7 in healthy blood donors from nine countries. Vox Sang 75193, 1998. 76. Clark DA, Freeland JML, Mackie PLK, et al. Prevalence of antibody to human herpesvirus 7 by age. J Infect Dis 168:251,1993. 77. Fujisaki H, Tanaka-Taya K, Tanabe H, et al. Detection of human herpesvirus 7 (HHV-7) DNA in breast milk by polymerase chain reaction and prevalence of HHV-7 antibody in breast-fed and bottlefed children. J Med Virol56275, 1998. 78. Lanphear BP, Hall CB, Black J, et al. Risk factors for the early acquisition of human herpesvirus 6 and human herpesvirus 7 infections in children. Pediatr Infect Dis J 17:792,1998. 79. Okuno T, Oishi H, Hayashi K, et al. Human herpesviruses 6 and 7 in cervixes of pregnant women. J Clin Microbiol 133:1968,1995. 80. Boutolleau D, Cointe D, Gautheret-Dejean A, et al. No evidence for a major risk of roseolovirus vertical transmission during pregnancy. Clin Infect Dis 361634,2003. 81. Torigoe S, Kumamoto T, Koide W, et al. Clinical manifestations associated with human herpesvirus 7 infection. Arch Dis Child 72518, 1995. 82. Torigoe S, Koide W, Yamada M, et al. Human herpesvirus 7 infection associated with central nervous system manifestations. J Pediatr 129:301, 1996. 83. Clark DA, Kidd IM, Collingham KE, et al. Diagnosis of primary human herpesvirus 6 and 7 infections in febrile infants by polymerase chain reaction. Arch Dis Child 7242, 1997. 84. Portolani M, Cermelli C, Mirandola P, et al. Isolation of human herpesvirus 7 from an infant with febrile syndrome. J Med Virol45: 282, 1995. Influenza A and B 85. Coffey VP, Jessup WJE. Maternal influenza and congenital deformities. Lancet 2:935, 1959. 86. Doll R, Hill AB. Asian influenza in pregnancy and congenital defects. Br J Prev SOC Med 14:167, 1960. 87. Record RG. Anencephalus in Scotland. Br J Prev SOCMed 15:93, 1961. 88. Leck I. Incidence of malformations following influenza epidemics. Br J Prev SOCMed 17:70, 1963. 89. Hakosalo J, Saxen L. Influenza epidemic and congenital defects. Lancet 2:1346, 1971. 90. Wilson MG, Stein AM. Teratogenic effects of Asian influenza. JAMA 210336,1969. 91. Hardy JMB, Azarowicz EN, Mannini A, et al. The effect of Asian influenza on the outcome of pregnancy. Baltimore 1957-1958. Am J Public Health 51:1182,1961. 92. MacKenzie JS, Houghton M. Influenza infections during pregnancy: association with congenital malformations and with subsequent neoplasms in children, and potential hazards of live virus vaccines. Bacteriol Rev 38:356, 1974. 93. Griffiths PD, Ronalds CJ, Heath RB. A prospective study of influenza infections during pregnancy. J Epidemiol Commun Health 34:124, 1980.

Chapter 30 94. Monif GRG, Soward DL, Eitzman DV. Serologic and immunologic

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virus in early hospitalizations for respiratory distress of young infants with cystic fibrosis. J Pediatr 1132326. 1988. 123. McConnochie KM, Hall CB, Walsh EE, et al. Variation in severity of respiratory syncytial virus infections with subtype. J Pediatr 11752, 1990. 124. Neligan GA, Steiner H, Gardner PS, et al. Respiratory syncytial virus infection of the newborn. BMJ 3:146,1970. 125. Berkovich S, Taranko L. Acute respiratory illness in the premature nursery associated with respiratory syncytial virus infection. Pediatrics 34753, 1964. 126. Mintz L, Ballard RA, Sniderman SH, et al. Nosocomial respiratory syncytial virus infections in an intensive care nursery: rapid diagnosis by direct immunofluorescence. Pediatrics 64:149, 1979. Welling MA, et al. A respiratory syncytial 127. Goldson EJ, McCarthy JT, virus outbreak in a transitional care nursery. Am J Dis Child 133:1280, 1979. 128. Church NR, Anas NG, Hall CB. Respiratory syncytial virus-related apnea in infants: demographics and outcome. Am J Dis Child 138247, 1984. 129. Valenti WM, Clarke TA, Hall CB, et al. Concurrent outbreaks of rhinovirus and respiratory syncytial virus in an intensive care nursery: epidemiology and associated risk factors. J Pediatr 100:722, 1982. 130. Meissner HC, Murray SA, Kiernan MA, et al. A simultaneous outbreak of respiratory syncytial virus and parainfluenza virus type 3 in a newborn nursery. J Pediatr 104:680, 1984. 131. Wensley DF, Baldwin VJ. Respiratory distress in the second week of life. J Pediatr 106326, 1985. 132. Hall CB, Kopelman AE, Douglas RG, et al. Neonatal respiratory syncytid virus infection. N Engl J Med 300393,1979. 133. Wilson CW, Stevenson DK, Arvin AM. A concurrent epidemic of respiratory syncytial virus and echovirus 7 infections in an intensive care nursery. Pediatr Infect Dis J 8:24, 1989. 134. Unger A, Tapia L, Minnich LL, et al. Atypical neonatal respiratory syncytial virus infection. J Pediatr 100:762, 1982. 135. Hall CB, Douglas RG Jr, Geiman JM. Respiratory syncytial virus infections in infants: quantitation and duration of shedding. J Pediatr 8911,1976. 136. Hall CB, Douglas RG Jr, Geiman JM. Possible transmission by fomites or respiratory syncytial virus. J Infect Dis 141:98,1980. 137. Snydman DR, Greer C, Meissner HC, et al. Prevention of nosocomial transmission of rewiratorv svncvtial virus in a newborn nurserv. Infect Control Hosp'Epidemidl9:iO5, 1988. 138. Ledair JM, Freeman J, Sullivan BF, et al. Prevention of nosocomial respiratory syncytial virus infections through compliance with glove and gown isolation urecautions. N End 1 Med 317329. 1987. 139. Ag& R, Cherry JD; Garakian AJ, et% Respiratory syncytial virus (RSV) infection rate in personnel caring for children with RSV infections. Routine isolation procedure vs routine procedure supplemented by use of masks and goggles. Am J Dis Child 141:695,1987. 140. Hall CB, McBride JT, Walsh EE, et al. Aerosolized ribavirin treatment of infants with respiratory syncytial viral infection: a randomized double-blind study. N Engl J Med 3081443,1983. 141. Hall CB, McBride JT, Gala CL, et al. Ribavirin treatment of respiratory syncytial viral infection in infants with underlying cardiopulmonary disease. JAMA 2543047, 1985. 142. Rodriguez WJ, Kim HW,Brandt CD, et al. Aerosolized ribavirin in the treatment of patients with respiratory syncytial virus disease. Pediatr Infect Dis J 6159, 1987. 143. Conrad DA, Christenson JC, Waner JL, et al. Aerosolized ribavirin treatment of respiratory syncytial virus infection in infants hospitalized during an epidemic. Pediatr Infect Dis J 6152, 1987. 144. Outwater KM, Meissner HC, Peterson MB. Ribavirin administration to infants receiving mechanical ventilation. Am J Dis Child 142:512, 1988. 145. Frankel LR, Wilson CW, Demers RR, et al. A technique for the administration of ribavirin to mechanically ventilated infants with severe respiratory syncytial virus infection. Crit Care Med 15:1051, 1987. 146. American Academy of Pediatrics Committee on Infectious Diseases. Ribavirin therapy of respiratory syncytial virus. Pediatrics 79475, 1987. 147. Wald ER, Dashefsky B, Green M. In re ribavirin: a case of premature adjudication?J Pediatr 112:154, 1988.

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148. Prober CG, Wang EEL. Reducing the morbidity of lower respiratory

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tract infections caused by respiratory syncytial virus: still no answer. Pediatrics 99472,1997. American Academy of Pediatrics. Committee on Infectious Diseases. Reassessment of the indications for ribavirin therapy in respiratory syncytial virus infections. Pediatrics 92137, 1996. Ribavirin therapy of respiratory syncytial virus. In Lepow PG, McCrachen ML, Phillips CF (eds). Report of the Committee on Infectious Diseases. Elk Grove Village, Ifl, American Academy of Pediatrics, 1991, pp 581-586. Meissner HC, Long SS; American Academy of Pediatrics Committee on Infectious Diseases and Committee on Fetus and Newborn. Revised indications for the use of palivizumab and respiratory syncytial virus immune globulin intravenous for the prevention of respiratory syncytial virus infections. Pediatrics 112:1447,2003. Moler FW,Khan AS, Meliones JN, et al. Respiratory syncytial virus morbidity and mortality estimates in congenital heart disease patients: a recent experience. Crit Care Med 201406, 1992. Navas L,Wang E, de Carvaho V, et al. Improved outcome of respiratory syncytial virus infection in a high-risk hospitalized population of Canadian children. J Pediatr 121:348,1992. Anderson LJ, Parker RA, Strikas RA, et al. Day-care center attendance and hospitalization for lower respiratory tract illness. Pediatrics 82: 300,1988.

meningitis virus: an underdiagnosed cause of congenital chorioretinitis. Am J Ophthalmoll30209,2000. 166. Chaste1 C, Bosshard S, LeGoff F, et al. Infection transplacentaire par le virus de la choriomeningite lymphocytaire. Nouv Presse Med 7:1089, 1978.

149.

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Molluscum Contagiosum 167. Wilkin IK. Molluscum contagiosum venereurn in a women’s outpatient clinic: a venereally transmitted disease. Am J Obstet Gynecol 128531, 1977. 168. Mandel MJ, Lewis RJ. Molluscum contagiosum of the newborn. Br J Dermatol 84:370, 1970. 169. Young WJ. Molluscum contagiosum with unusual distribution. Ky Med J 24467,1926.

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de mere atteinte de rage et soumis du traitement prophylactique par le serum et le vaccome amtorabiques. Bull SOCPathol Exp 59764, 1966. Relova RN. The hydrophobia boy. J Philipp Med Assoc 39:765,1963. Spence MR, Davidson DE, Dill GS, et al. Rabies exposure during pregnancy. Am J Obstet Gynecol 123:655, 1975. Meyer HM. FDA rabies vaccine. J Infect Dis 142:287,1980. Public Health Service Advisory Committee on Immunization Practices. Human Rabies Prevention-United States, 1999 Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 48:1,1999.

West Nile Virus 179. Nash D, Mostashari F, Fine A, et al. The outbreak of West Nile infection in the New York City area in 1999. N Engl J Med 344:1807,2001. 180. Centers for Disease Control and Prevention. Intrauterine West Nile virus infection-New York, 2002. MMWR Morb Mortal Wkly Rep 51:1135,2002. 181. Alpert SG,Fergerson J, Noel LP. Intrauterine West Nile virus: ocular and systemic findings. Am J Ophthalmol 136733,2003. 182. Centers for Disease Control and Prevention. Possible West Nile virus transmission to an infant through breast-feeding-Michigan, 2002. MMWR Morb Mortal Wkly Rep 51:877,2002. 183. Centers for Disease Control and Prevention. Interim guidelines for the

evaluation of infants born to mothers infected with West Nile virus during pregnancy. MMWR Morb Mortal Wkly Rep 53:154,2004.

Chapter 31 TOXOPLASMOSIS Jack S. Remington George Desmonts

Rima McLeod

The Organism 948 Oocyst Tachyzoite cyst

Transmission 951 Congenital Transmission Transmission by Ingestion Other Means of Transmission

Epidemiology 965 General Considerations Prevalence of Toxoplasma gondii Antibodies among Women of Childbearing Age Incidence of Acquired Infection during Pregnancy Prevalence of Congenital Toxoplasma gondii Infection Effects of Systematic Screening of Pregnant Women at Risk on the Prevalence of Congenital Toxoplasma gondii Infection and of Congenital Toxoplasmosis

Pathogenesis 974 Factors Operative during Initial Infection Factors Operative during Latent Infection

Pathology 979 Placenta Central Nervous System Eye Ear Lungs Heart Spleen Liver, Ascites Kidney Adrenals, Pituitary, Pancreas, and Thyroid Testes and Ovaries Skeletal Muscle Thymus

Skin Bone Immunoglobulin Abnormalities Toxoplasrna gondii-cytomegalovirus Infection

Clinical Manifestations 986 Infection in the Pregnant Woman Infection in the Infant

Diagnosis 1008 Diagnostic Methods Guidelines for Evaluation of the Newborn with Suspected Congenital Toxoplasmosis Serologic Diagnosis of Acquired Toxoplasma Infection in the Pregnant Woman Prenatal Diagnosis of Fetal Toxoplasma Infection Serologic Diagnosis in the Newborn

Differential Diagnosis 1034 Therapy

1035

General Comments Specific Therapy

Philippe Thulliez

Duration of Therapy Treatment of the Fetus through Treatment of the Pregnant Woman Sequelae of Congenital Toxoplasmosis in Children Who Received No Treatment

Prevention 1060 Food Oocysts and Cats Serologic Screening Prevention of Congenital Toxoplasmosis through Treatment of the Pregnant Woman Resources 1069

Among the most tragic infectious diseases of humans are those that pass from the pregnant woman to her unborn child. Toxoplasma gondii is a protozoal parasite that can cause devastating disease in the fetus and newborn yet remain unrecognized in women who acquire the infection during gestation. In addition, in most countries, congenital infection and congenital toxoplasmosis in the newborn go undiagnosed, thereby predisposing to the occurrence of untoward sequelae of the infection, including decreased vision or blindness, decreased hearing or deafness, and mental and psychomotor retardation. The cost estimates for special care of children with congenital toxoplasmosis born each year in the United States alone is in the hundreds of millions of dollars. An early estimate of the lifetime cost for special services for the infected children born each year was $221.9 million.' In 1990, Roberts and Frenkel estimated preventable medical costs to be $369 million as a low estimate for the number of congenital cases born each year and many hundreds of millions as a high estimate? Only relatively recently have most physicians, veterinarians, research scientists, and economists recognized the important position of T gondii among the significant pathogens of humans and animals. The organism is ubiquitous in nature and is the cause of a variety of illnesses that previously were thought to be due to other agents or to be of unknown cause. Toxoplasmic encephalitis has now proved to be a significant cause of morbidity and mortality in immunodeficient patients, including infants, children, and adults with acquired immunodeficiency syndrome (AIDS). Toxoplasmosis in domestic animals is of economic importance in countries such as England and New Zealand, where it causes abortion in sheep, and in Japan, where it has caused abortion in swine. It has been estimated that as many as 4100 of the 4.1 million infants born annually in recent years in the United States have the congenital infection. In a majority of infected infants, clinical signs

948

Section IV

Protozoan, Helminth, and Fungal Infections

are not present at birth, but sequelae of the congenital infection are recognized or develop later in life. In this chapter, the term congenital toxoplasrnosis refers to cases in which signs of disease related to congenital infection are present. The history of ‘I:gondii began in 1908, when Nicolle and Manceaux observed a parasite in mononuclear cells of the spleen and liver of a North African rodent, the gondi (Ctenodactylus gondi); this organism so closely resembled Leishmania that they tentatively named it Leishmania g ~ n d i i The . ~ next year they decided, on the basis of morphologic criteria, that it was not a Leishmania organism and proposed the name Toxoplasma (from the Greek toxon, “arc”) gondii? It might just as well have been called Toxoplasma cuniculi,because at the same time, and independently, Splendore found it in a rabbit that had died with paralysis in Brazil? The organism soon attracted attention as a cause of disease in animals, and in 1923, Janku, an ophthalmologist in Prague, described the first recognized case in humans! He found parasitic cysts in the retina of an 11-month-old child with congenital hydrocephalus and microphthalmia with coloboma in the macular region. The parasite noted by Janku was later (in 1928) recognized to be ‘I: gondii by Levaditi, who suggested a possible connection between congenital hydrocephalus and toxoplasmosis.7 It was not until 1937, however, that recognition of toxoplasmosis as a disease entity in humans had a real impact on medicine. In that year, Wolf and Cowen in the United States reported a fatal case of infantile granulomatous encephalitis that they believed to be caused by an encephalitozoon.’ Sabin and Olitski, who had previously encountered ‘I:gondii in guinea pigs? were able to make the correct diagnosis. Wolf and associates later recognized and reclassified the cases described by Torres in 1926 and by Richter in 1936 as earlier reports of congenital Wolf and Cowen and collaborators then performed numerous studies and established T. gondii as a cause of prenatally transmitted human disease.”*’4(Case 4 in the report by Paige and co-workers’2 is of special interest because it established beyond question that the infantile form of the infection was prenatal in origin.) The discovery of ‘I:gondii as a cause of disease acquired later in life has been credited to Pinkerton and Weinman. In 1940, they described a generalized fatal illness in a young man that was caused by this 0rgani~m.l~ In 1941, Pinkerton and Henderson provided a clinical description of two fatal cases of an acute febrile exanthematous disease in adults,I6 and in the same year, Sabin described cases of toxoplasmic encephalitis in children.17 In 1948, Sabin and Feldman originated a serologic test, the dye test, that allowed numerous investigators to study epidemiologic and clinical aspects of toxoplasmosis, to demonstrate that ‘I:gondii is the cause of a highly prevalent and widespread (most often asymptomatic) infection in humans, and to define the spectrum of disease in humans.” It was not until 1969, some 60 years after the lscovery of the parasite, that T. gondii was found to be a coccidian and that the definitive host was found to be the cat. Our understanding of T. gondii infection in pregnancy and in the neonate stems from studies performed over many decades. This problem can best be appreciated by reference to these earlier studies, published earlier in the 20th century. These studies are therefore reviewed in this chapter.

THE ORGANISM 1 gondii is a coccidian and exists in three forms outside the cat intestine: an oocyst, in which sporozoites are a proliferative form, formerly referred to as a “trophozoite” and more recently as an endozoite or tachyzoite; and a tissue cyst, which has an intracystic form termed a cystozoite or bradyzoite. (Because a single nomenclature has not been agreed on, the terms for each form are used as synonyms in this chapter.) For a more thorough discussion of the organism itself, including its cell biology, molecular biology, genetics, antigenic structure, and immunobiolo y the reader is referred to recent reviews on these subjects.fly32 The genome of T. gondii is available at http://toxodb.org. The parasite is a member of the apicomplexa (as are malarial parasites and cryptosporidia). It is a mosaic of an ancient eukaryotic ancestor that endocytosed an alga (which became a plastid-like organelle and transferred most of its genome to the eukaryote’s nucleus) and a mitochondrion that originated from an alpha pr~teobacter.~~-~’ Apicomplexan parasites also have unique secretory organelles important in attachment to the host cell, invasion, and establishment of the parasitophorous vacuole in which the parasitic organism resides as an obligate intracellular parasite. All of these organelles and the metabolic pathways and unique proteins they contain are unique in this parasite and not present in animals. Thus, they present a plethora of unique and novel, some plant-like, antimicrobial agent targets.33

oocyst The enteroepithelial cycle occurs in the intestines of members of the cat family (see “Transmission” section) and results in oocyst formation (Figs. 31-1 and 31-2). Schizogony and gametogony appear to take place throughout the small intestine but especially in the tips of the villi in the ileum. In cats, the prepatent period from the ingestion of cysts to oocyst production varies, ranging from 3 to 10 days after ingestion of tissue cysts, from 19 to 48 days after ingestion of ta~hyzoites,~~ and from 21 to 40 days after ingestion of oocysts.3’ Gametocytes appear throughout the small intestine from 3 to 15 days after infection. Fertilization is effected by a mature microgamete emerging from an epithelial cell into the lumen of the gut and then swimming to and penetrating a mature macrogamete, which probably resides in the epithelium, to form a zygote. After zygote and oocyst formation, no further development occurs within the gut of the cat. Oocysts pass out of the gut with the feces; peak oocyst production occurs between days 5 and 8. Oocysts are shed in the feces for periods that range from 7 to 20 days. As many as 10 million oocysts may be shed in the feces in a single day. The zygote divides into two sporoblasts. Each sporoblast develops a wall, the sporocyst, within which two further divisions take place to produce four sporozoites within each sporocyst and eight altogether within the oocyst. The M y sporulated oocyst is infective when ingested, giving rise to the extraintestinal forms. Within the cat, it also can give rise to the enteroepithelial cycle. Oocysts are spherical at first, but after sporulation they become more oval, measuring 11 to 14 pm by 9 to 11 pm (mean, 12.5 by 11 pm). The two sporocysts are approximately

Chapter 3 1

Toxoplasmosis

949

Figure 31-1 The three forms of Toxoplasma. A, Tachyzoites from peritoneal fluid of a 3-day infected mouse. B, Tachyzoite in cytoplasm of chick embryo fibroblast. C, Cyst in brain stained with periodic acid-Schiff. D, Cyst in myocardium of fatal human case. E, Microisolated cyst from brain in mouse. F, Unsporulated (left) and sporulated (right) oocysts. (From Remington JS. Toxoplasmosis. In Kelly V [ed]. Brennemann's Practice of Pediatrics, vol. 2. New York, Harper & Row, 1970.)

8.5 by 6 pm, and the sporozoites are about 8 by 2 pm. Depending on the temperature and availability of oxygen, sporulation occurs in 1 to 21 days.38,39Sporulation takes place in 2 to 3 days at 24" C, 5 to 8 days at 15" C, and 14 to 21 days at 11" C.40Oocysts do not sporulate below 4" C or above 37" C.38

Tachyzoite Tachyzoites are crescentic or oval, with one end attenuated (pointed) and the other end rounded (see Fig. 31-1A and B); they are 2 to 4 pm wide and 4 to 8 pm long. The organisms stain well with either Wright or Giemsa stain. This form of the organism is employed in serologic tests (e.g., Sabin-Feldman dye test, fluorescent antibody methods, agglutination test). Locomotion is by gliding or by body fle~ion.4'*~'

The tachyzoite form requires an intracellular habitat to survive and multiply. It cannot survive desiccation, freezing and thawing, or action of the digestive juices of the human st0mach.4~This form of the parasite is destroyed within a few minutes in gastric juice, but a relatively small proportion of parasites can survive in tryptic digestive fluid for at least 3 hours but not as long as 6 hours. The organism is propagated in the laboratory in the peritoneum of in tissue cultures of mammalian and in embryonated hens' eggs.44Variations in strain virulence correlate positively with invasiveness and with the rate of multiplication of this form in tissue culture.& The tachyzoites occur within vacuoles4' in their host cells (see Fig. 31-1B), and a definite space and an intravacuolar network are present between the parasite and the vacuole wall.48Host cell mitochondria and endoplasmic reticulum

950

Section IV


Figure 31-2 The life cycle of Toxoplasma gondii. The cat appears to be the definitive host. (From Rernington JS, McLeod R. Toxoplasrnosis. In Braude Al [ed]. International Textbook of Medicine, vol. 11, Medical Microbiology and Infectious Disease. Philadelphia, WB Saunders, 1981, p 1818.)

are concentrated in the host cell at the edge of the vacuole.49 Reproduction in the tissues is by end~dyogeny.~’ This is a process of internal budding in which two daughter cells are formed within the parent cell and are released with disruption of the parent cell. When additional nuclear divisions occur before the daughter organisms are completely separated, rosettes are formed; repeated endodyogeny results in a large collection of parasites within a cell. The tachyzoite form is seen in the acute stage of the infection, during which it invades every kind of mammalian cell (see “Pathology” section). After host cell invasion, the organisms multiply within their vacuoles approximately

every 4 to 6 hours and form rosettes. The cytoplasm becomes so filled with tachyzoites that ultimately the cell is disrupted, releasing organisms that then invade contiguous ~ e l l s ~or’ . ~ ~ are phag~ cytosed.Colonies ~~ of pseudocysts containing tachyzoites produced by endodyogeny may persist within host cells for prolonged periods without forming a true cyst. The duration of this type of infection in vivo is not known.

Cyst The tissue cyst (see Fig. 31-1C and D) is formed within the host cell and may vary in size, ranging from cysts that

Chapter 31 contain only a few organisms to large cysts, 200 pm in size, that contain approximately 3000 organisms.55This form of T. gondii stains well with periodic acid-Schiff (PAS) stain, which causes it to stand out from the background tissue. The cyst wall is argyrophilic and weakly positive for PAS staining. Such cysts are demonstrable as early as the first week of infection in animalss6and probably persist containing their viable parasites throughout the life of the host.36Although they may exist in virtually every organ, the brain and skeletal and heart muscles (see Fig. 31-1C and D) appear to be the most common sites of latent infection.57Cysts are spherical in the brain and conform to the shape of muscle fibers in heart and skeletal muscles (see Fig. 31-1D). Because of this persistence in tissues, the demonstration of cysts in histologic sections does not necessarily mean that the infection was recently acquired. The cyst wall is disrupted by peptic or tryptic digestion, and the liberated parasites remain viable for at least 2 hours in pepsin-hydrochloric acid and for as long as 6 hours in tryp~in;~thereby allowing them to survive the normal digestive period in the stomach and even longer in the duodenum. In the presence of tissue, the liberated organisms remain viable for 3 hours in peptic digestive fluid and for at least 6 hours in tryptic digestive fluid. Freezing and thawing, heating above 66" C, and desiccation destroy this tissue cyst form; however, the organisms can survive as long as 2 months at 4" C.43Tissue cysts are rendered nonviable when internal temperatures have reached 66" C or -12" C.58 Until more data are available, it appears that freezing at -20" C for 18 to 24 hours, followed by thawing, should be considered adequate for cyst d e s t r ~ c t i o n . 4 ~ * ~ ~ * ~ ~ Like the tachyzoite, the cyst develops within a host cell vacuole.61,62Cysts may attain a relatively enormous size while still within the host cell. It has been suggested that tissue cysts in the brain are preferentially located within neurons and are retained within viable host cells irrespective of size or age.63This would explain the long-term survival of latent infection because the intracellular location could provide the minimal metabolic requirements of the resting stage (bradyz~ite).~~ A number of factors lead to bradyzoite differentiation and cyst formation, including arginine starvation, alkaline or acidic pH, and interferon-? (IFN-y) stimulation of inducible nitric oxide synthase (iNOS) and nitric ~ x i d e . ~Cysts , ~ ~can , ~form ~ in tissue culture systems devoid of antibody and ~ o m p l e r n e n t . ~Immunity ~ - ~ ~ is of prime importance in regard to the presence of the different forms of the parasite during the extraintestinal cycle in the infected host. During the acute, initial state of the infection, parasites are present mainly as tachyzoites, which are responsible for parasitemia and systemic infection. When the host has developed an immune response, the infection usually reaches a latent or chronic stage, during which cysts are present in many tissues, and in the immunocompetent host, parasitemia and systemic infection with tachyzoites have subsided. These schematic definitions of the stages of the infection are important to the later discussion on congenital transmission. These two stages were defined by Frenkel and Friedlander in 195270as the first and third stages of T. gondii infection. They also described a second, subacute stage as a hypothesis to explain the pathogenesis of lesions observed in congenital toxoplasmosis. The existence of an intermediate stage of uncertain duration also seems likely in cases with

Toxoplasmosis

951

subclinical infection, during which both encysted parasites and low-grade systemic infection with tachyzoites are present in the immune host. Whether "dormant" tachyzoites are present during chronic infection in addition to tissue cysts is not known.

TRANSMISSION Congenital transmission of T. gondii from an infected mother to her fetus was the first form of transmission to be re~0gnized.l~ Investigators in the reported cases raised two hypotheses in an attempt to explain congenital transmission. They considered that transmission might occur as a consequence of the acute, initial stage of the infection in a pregnant woman or as a consequence of a recrudescence (either local or systemic with recurrent parasitemia) of a chronic (latent) maternal infection during pregnancy. Experimental studies of congenital infections in different animal species were helpful for understanding this form of transmission, but definitive data were not obtained until prospective studies were performed in humans in nations such as Austria, where screening for the diagnosis of T. gondii infection among pregnant women is routinely performed, and France, where screening is compulsory.

Congenital Transmission Experimental Studies Laboratory Animals. Experiments performed to study congenital transmission during the acute stage of the infection in mice and rats revealed that the rate of transmission depends on a number of variables, including time during gestation at which the pregnant animal is infected, the site of infection, and the strain of the parasite and of the mice or rats.71-75 In studies with acutely infected pregnant rats, Hellbrugge noted that parasitemia persisted for 18 days, corresponding to the length of gestation (21 days).76T. gondii did not infect the fetuses until day 16; hence, despite the duration of parasitemia, transmission to the fetus occurred only in the last third of pregnancy. The organisms could be found in the placentas earlier but not in the fetuses. By days 17 and 18 of gestation, all placentas and all fetuses were infected. Congenital transmission of T gondii from chronically infected animals to their offspring has been reported in rats,77-82guinea pigs,83rabbits,84and mice.78385 The strain of the parasite appears to be important in determining whether transmission occurs. In some young animals born to chronically infected mothers, development to maturity proceeds without signs of toxoplasmosis, and infected females in those litters have in turn given birth to infected pr~geny.~~.~~ In a study of persistent parasitemia in mice used for transmission studies, 50% of the mice with chronic infection (with a strain of T. gondii that frequently was transmitted to the offspring) showed p a r a ~ i t e m i a .A~ ~similar , ~ ~ percentage of such mice produced T. gondii-infected offspring. Mice chronically infected with another strain of IT: gondii and rats with chronic infection produced far fewer infected fetuses, and such animals did not have demonstrable parasitemia.

952

Section IV


During the course of the chronic infection in rats, Hellbrugge was able to produce a 100% rate of infection in the fetuses, but this depended on the size of the original ino~ulum.’~ Thus, in rodents, congenital transmission can occur during both acute and chronic maternal infections. These experimental results suggest a close relationship between maternal parasitemia and transmission to the fetus. They also highlight the importance of the placental barrier in delaying fetal infection. T. gondii is found earlier in the placenta than in the fetus. Minipigs*’ and subhuman primates” also have served as useful experimental models for studying congenital toxoplasmosis. In interpretation of these studies, it is important to recognize that placentas of rodents, subhuman primates, and humans

Domestic Animals. Congenital infection with T. gondii has been observed during both natural and experimental infections in most domestic animal species, including cats, dogs, pigs, goats, and Congenitalinfection is frequent in sheep and goats, is less frequent in pigs, and has not been documented in cattle. Toxoplasmosis occurs as an epizootic infection in pregnant ewes and causes early embryonic death, mummification of the fetus, abortion, stillbirth, or birth of weakened lambs with congenital infection. Embryonic death and stillbirth may result from fetal infection but occur most often as a result of the focal necrotic lesions present in the placental cotyledons. In sheep as well, the placenta is invaded first and the fetus only some days later. In a series of studies on experimental congenital transmission of ovine toxoplasmosis, Jacobs and Hartley found that transmission occurred only in ewes infected during pregnancy, not before pregnancy.98If seronegative ewes were infected at 30 days of gestation, early death or mummification of congenitally infected fetuses frequently followed. In ewes infected at 90 days of pregnancy, congenital transmission occurred frequently, but only a small proportion of these ewes aborted. In many cases they gave birth to live lambs, of which about 20% died. In studies of ewes with naturally acquired infection and antibodies before experimental challenge, Hartley noted substantial immunity, but he also observed congenital transmission and some abortions among these ewes.99 Beverley and colleagues reported similar results.Iw These investigatorsfound that experimental infection of ewes before mating generally prevented abortion related to T gondii infection acquired in mid-pregnancy.’w In a trial with a killed vaccine, only ewes developing relatively high antibody titers manifested any protection against fetal death after challenge.Lo131o1 The protection was only partial in that the pregnancy was often normal, but the fetus and placenta were both infected. In a trial with live, attenuated parasite vaccine, protection of sheep was manifested as increased live births of healthy lambs.lo2 Studies in Humans The excellent correlation between isolation of T. gondii from placental tissue and infection of the neonate, along with results obtained at autopsy of neonates with congenital toxoplasmosis suggesting that the infection is acquired by the fetus in utero through the bloodstream, has led to the concept that infection of the placenta is an obligatory step between maternal and fetal infection. A likely scenario is that

organisms reach the placenta during parasitemia in the mother. They then invade and multiply within cells of the placenta, and eventually some gain access to the fetal circulation. MATERNAL PARASITEMIA

Acute Infection. From pathology studies in patients with toxoplasmosis, as well as from experiments in animals, it can be concluded that parasitemia occurs during the acute, initial stage of both subclinical and symptomatic infections. In an attempt to define the magnitude and duration of the parasitemia during subclinical infection, inoculation of mice was performed with clots of blood taken from women with recent subclinical infections (G Desmonts, unpublished data); these were the first seropositive blood samples obtained from pregnant women who were previously seronegative and who had been tested repeatedly during pregnancy. Approximately 50 patients were examined, and none of the samples were found to be seropositive.Because this method has proved to be valuable for isolation of T. gondii from patients with congenital toxoplasmosis (Table 3 1- 1) and from newborns with subclinical infections, the absence of demonstrable organisms in these women suggests that parasitemia during the acute stage of acquired subclinical infection is no longer present, at least by the method employed, once serum antibodies are detectable. Attempts at isolation of T. gondii from blood of more than 30 patients with toxoplasmic lymphadenopathy were unsuccessful (JS Remington, unpublished data). If it is accepted that transmission of T. gondii from a mother to her fetus reflects that parasitemia occurred in the mother, evidence indicates that parasitemia occurs at an early stage of the mother’s infection before the appearance of serum antibodiesio3and clinical signs (if signs occur). We have observed this in several cases of acquired toxoplasmosis in pregnant women in whom lymphadenopathy appeared during the first month after they had been delivered of newborns with congenital 1: gondii infection. Precise data are not available on the timing of events that occur after initial infection in humans. The delay between initial infection and occurrence of parasitemia is not known. Important considerations include the duration of parasitemia during the initial stage of the infection and the actual time between the initial infection and the earliest appearance of demonstrable specific antibodies.

Table 31-1

Parasitemia in Clinical Forms of Congenital Toxoplasmosis’

Clinical Form GeneraIized Neurologic or ocular Subclinical Total

No. of infants

No. with Parasitemia (%)

21 29 19 69

15 (71) 5 (17) 10 (52) 30 (43)

alnfantswere studied during the first 2 months of life, but no infants had detectable parasiternia after 4 weeks of age. Adapted from Desrnonts G, Couvreur J. Toxoplasrnosis: epidemiologic and serologic aspects of perinatal infection. In Krugrnan 5, Gershon AA (eds). Infections of the Fetus and the Newborn Infant. Progress in Clinical and Biological Research, vol. 3. New York, Alan R Liss, 1975, pp 115-132, with permission.

Chapter 3 1 Table 31-2

September 25‘ November 19

953

Serologic Results Associated with Recurrent Parasitemia in a Patient with Acquired Immunodeficiency Syndrome

Date of Sample in 1985

March 5 May 3 May 20

Toxoplasmosis

IFAa(IU/mL)

IgG Agglutination Ted’ (IUlmL)

40 40 40 400 400

25 25 25 1600 800

IgM ISAGA’

’Performed at St. Louis Hospital (F. Derouin). bPerformedat Institute de Puericulture (G. Desmonts). ‘Parasitemia was demonstrated in this sample, drawn during an episode of fever, without clinical evidence of neurologic involvement FA, immunofluorescent antibody test; IgG, IgM, Immunoglobulins G, M; ISAGA, immunosorbent agglutination assay.

Chronic Infection (Persistentor Recurrent Parasitemia). A systematic search for persistent parasitemia in humans, especially during pregnancy (as has been performed in animals), has not been reported. Nevertheless, one case report bearing on this subject is pertinent here. Persistent parasitemia was evident in a clinically asymptomatic, otherwise healthy, 19-year-old primigravid woman during 14 months after she gave birth to a congenitally infected infant who died during de1i~ery.I’~ This parasitemia persisted despite treatment with pyrimethamine and sulfadiazine. During the period of parasitemia, the patient again became pregnant; the result of this second pregnancy was a healthy baby with no evidence of congenital toxoplasmosis.This case of persistent parasitemia is unique in our experience. Huldt (G Huldt, personal communication to JSRemington, 1987) isolated T. gondii from the blood of an elderly but otherwise healthy woman 1 year after clinical lymphadenopathy. In another case, a woman 60 years of age with a suspected lymphoma had detectable parasitemia on several occasions during a period of 2 years. As has been observed in normal laboratory animals, parasitemia may be observed during chronic infection in the immunodeficient patient despite the presence of neutralizing antibodies in the serum.’o5 Recurrent parasitemia may be associated with an increase in the immunoglobulin G (IgG) T. gondii antibody titer. An example is given in Table 31-2, in which data from one of the AIDS cases reported by Derouin and colleagues are shown.’“ This case demonstrates that, in the presence of a low antibody titer, recurrent parasitemia may induce an anamnestic response with an increase in IgG titer but with no evidence of stimulation of formation of IgM antibody. Thus, the possibility of recurrent parasitemia should be considered when a significant increase in IgG antibody titer occurs in a patient known to have had a low stable preexisting titer. lo’ Although uncommon, such increases are sometimes observed even in immunologically competent patients, suggesting that a low-grade systemic infection with possible recurrence of parasitemia can persist for several months so long as cellmediated immunity is not fully established. DEMONSTRATION OF TOXOPLASMA GONDll IN PLACENTAS

Histologic Demonstration. T gondii organisms have been demonstrated histologically in human (See also “Placenta” section under “Pathology.”)

In 1967, Sarrut reported histologic findings in the placentas of eight patients with congenital toxoplasmosis, with microscopic demonstration of the organism in four of them.”’ She noted a correlation between the clinical pattern of neonatal disease and the presence of histologically demonstrable parasites. Both cysts and tachyzoites were numerous and easily demonstrated in three patients with severe systemic fetal disease, whereas parasites were microscopically demonstrable in only one of five patients (see also under “Pathology”) with milder disease. Parasites were not noted in cases in which clinical signs of the infection were delayed until weeks after birth. On the contrary, results following injection of placental tissue into mice were positive in patients with congenital toxoplasmosis, as well as in those with subclinical infe~tion.”~ Isolation Studies Toxoplasma gondii in Placentas during Acute Infection. From the original studies performed in France in the 1960s, it was concluded that T. gondii frequently could be isolated from the placenta when acute infection occurred during pregnancy, but that such isolation was rarely if ever possible when infection occurred before c~nception.”~ This was true even for women with high antibody titers at the beginning of pregnancy, which suggested that infection might have been acquired shortly before conception. Similar results were obtained by Aspock and colleag~es.”~These authors examined 2451 women who had decided on termination of their pregnancy. Of these women, 1139 (46%) were seropositive and 77 (3%) had a T. gondii indirect fluorescent antibody test titer of 1:256 or higher. The researchers injected the products of conception of 51 of these 77 women into mice. None of the results were positive. Because the researchers had used the whole product of conception after induced abortion, this negative result suggests that this conclusionthat placental infection is seldom if ever present at the time of delivery in women with high antibody titers at the beginning of pregnancy-might also be true for decidua, embryos, and placental tissues obtained early in pregnancy from such women. When infection is acquired during pregnancy, the frequency of isolation of T, gondii from placentas obtained at the time of delivery is dependent on when seroconversion occurred during pregnancy. Table 31-3 shows the results obtained in 321 such cases. The frequency of positive isolation

954

Section IV

Table 31-3


Attempts to Isolate Toxoplasma’ from Placenta at Delivery in Women Who Acquired Toxoplasma Infection during Pregnancy infection Acquired during First Trimester

Maternal Treatment During Pregnancy

Infection Acquired during Second Trimester

infection Acquired during Third Trimester

No.

No.

No.

Positive

No.

Examined

(%)

Examined

Positive (%)

No. Examined

Total

No.

No. Positive

No.

(%)

Examined

Positive (%)

~

None 5 piramycin Total

16 89 105

4 (25) 7 (8) 11 (10)

13 144 157

7 (54) 28 (19) 35 (22)

23 36 59

15 (65) 16 (44) 31 (53)

52 269 321

26 (50) 51 (19) 77 (24)

aBy mouse inoculation. Adapted from Desmonts G, Couvreur J. Congenital toxoplasrnosis: a prospective study of the offspring of 542 women who acquired toxoplasmosis during pregnancy: pathophysiology of congenital disease. In Thalharnrner 0, Baumgarten K, Pollak A (eds).Perinatal Medicine, Sixth European Congress, Vienna. Stuttgart, Georg Thieme, 1979, pp 51-60, with permission.

depended on the trimester of pregnancy in which maternal infection was acquired the later it was acquired, the more frequently were parasites isolated. The frequency of isolation also depended on whether the women received pharmacologic treatment. Organisms were isolated less often if spiramycin was administered before delivery. These data were collected in the 1960s and 1970s during surveys carried out by Desmonts and Couvreur,116which were feasibility studies of measures for prevention of congenital toxoplasmosis. The measures became compulsory in France in 1978. For many years (in the laboratory of one of us [GD]), placental tissue of women considered to be at risk of giving birth to a child with congenital 1: gondii infection was routinely injected into mice for attempts at isolation of the parasite. (The number of placental inoculations performed in the Laboratoire de Serologie Neonatale et de Recherche sur la Toxoplasmose, Institut de Puericulture de Paris, averaged 800 per year.) The results support the conclusions of the initial surveys: T. gondii organisms frequently were present in the placenta on delivery when the acute infection occurred during pregnancy; the later the infection was acquired, the more frequently the placenta was involved. When infection occurred during the last few weeks of pregnancy, placental infection was demonstrable in more than 80% of cases. A virtually perfect correlation was observed between neonatal and placental infection (see “Diagnosis” section) when the mother did not receive treatment during gestation or duration of the treatment was too brief or an inadequate dose of spiramycin (less than 3 g) was used.’17 Among 85 pregnancies ending in delivery of a child with congenital T gondii infection, isolation of T. gondii from placental tissue was successful in 76 of 85 cases (89%). If the fact that only a relatively small portion of the placenta was digested for the inoculation into mice is taken into account, the high proportion of positive results supports the concept that placental infection is an obligatory occurrence between maternal and fetal infection. It also demonstrates that if the mother receives no or inadequate treatment, placental infection persists until delivery. Nevertheless, placental infection may not be demonstrable by mouse inoculation on delivery of a child with congenital Toxoplasma infection when the mother received treatment during pregnancy. In the series of cases reported by Couvreur and colleague^,"^ the proportion of

placentas from which T. gondii was isolated was 89 of 118 (75%) if the mothers had received treatment for more than 15 days with 3 g per day of spiramycin. This proportion was 10 of 20 (50%) if pyrimethamine plus sulfonamides was added to treatment during the last months of pregnancy. Toxoplasmagondii in Placentas during Chronic Infection. A study was performed by Remington and colleagues (in collaboration with Beverly Koops) in Palo Alto, California, to determine whether T. gondii can be isolated from placentas of women with stable dye test titers. Of the 499 placentas obtained consecutively, 112 (22%) were from women with positive dye test results. The digestion procedure (see “Isolation Procedures” later under “Diagnosis”) was performed on 101 of these placentas. T. gonclii organisms were not isolated from any of them. Thus, in the population studied, chronic (latent) infection with T gondii does not appear to involve the placenta significantly. By contrast, T gondii has been isolated with relative ease from the adult human brain5’ skeletal and uterus.”’ Another study in which an attempt was made to isolate the organism from placental tissue is that of Ruiz and associates in Costa Rica.”’ Much smaller amounts of tissue were injected into mice, but isolation was successful in 1 of 100 placentas. The dye test titer in the mother from whose placenta the organism was isolated was 1:1024. Adequate clinical and serologic data for the offspring were not provided. The researchers stated that T. gondii organisms were not demonstrable in the placental tissue by microscopic examination. This finding is not surprising in view of the findings of Sarrut.”’ The high dye test titer in this case might have been due to an infection acquired during pregnancy. Ruoss and Bourne failed to isolate 2: gondii from 677 placentas of mothers who were delivered of viable infants and who had low T. gondii antibody titers.’” It can be concluded from these studies that placental infection is extremely rare in pregnant women with chronic T gondii infection. FETAL TOXOPLASMA GONDIl INFECTION AND CONGENITAL TOXOPLASMOSIS

Acute Infectionin the Mother. Direct data that demonstrate the frequency with which T gondii is transmitted to the fetus during the period of acute infection in the mother come from prospective studies such as those performed by

Chapter 31 Desmonts and Couvreur,"* Kraubig,121 Kimball and colleagues,'22 and Stray-Peder~en.'~~ Fetal infection, the consequence of placental infection, depends on the time during gestation when maternal infection was acquired. Table 31-4 (which summarizes findings from the same group of cases as in Table 31-3, although the number of cases in both tables is not the same because placentas were available in only 32 1 of the 542 pregnancies) shows data collected in the 1960s and 1970s by Couvreur and Desmonts. In Table 31-4, children are classified into five groups: those with no congenital infection, subclinical congenital infection, mild congenital toxoplasmosis, severe congenital toxoplasmosis, and stillbirth or early death (shortly after birth). Children were considered

Table 31-4

Outcome of 542 Pregnancies in Which Maternal Toxoplasma Infection Was Acquired during Gestation: Incidence of Congenital Toxoplasmosis and Effect of Spiramycin Treatment in Mother during Pregnancy No. of Affected lnfanb (%) No matment

Outcome in Offspring

No congenital Toxoplasma infection Congenital toxoplasmosis Subclinical Mild Severe Stillbirth or perinatal deatha Total

Treatment

60 (39)

297 (77)

64 (41)

65 (17) 13 (3) 10 (2) 3 (1) 388 (100)

14 (9) 7 (5) 9 (6) 154 (100)

aSee text. Adapted from Desmonts G, Couvreur J. Congenital toxoplasrnosis: a prospective study of the offspring of 542 women who acquired toxoplasmosis during pregnancy: pathophysiology of congenital disease. In Thalhammer 0, Baumgarten K, Pollak A (eds). Perinatal Medicine, Sixth European Congress, Vienna. Stuttgart, Georg Thieme, 1979, pp 51 -60, with permission.

Table 31-5

Toxoplasmosis

955

to be free of congenital infection if they had no clinical manifestations suggesting congenital toxoplasmosis and if their results on T. gondii serologic testing became negative after disappearance of passively transmitted maternal antibodies. Congenital infection was classified as subclinical if no clinical signs of disease related to toxoplasmosis occurred during infancy. Clinical disease was considered to be mild if the infant was apparently normal, with normal development on follow-up evaluation. An example of mild disease is that of a child with no mental retardation or neurologic disorder on later examination but with isolated retinal scars discovered during a prospective eye examination (or, in one case, isolated intracranial calcifications on radiographic examination) performed because the child was at risk of having congenital T. gondii infection, having been born to a mother who acquired the infection during gestation. Cases were considered to be severe if both chorioretinitis and intracranial calcifications were present or if mental retardation or neurologic disorders were present. From the results shown in Table 3 1-4, the subclinical form is by far the most frequent presentation of congenital T gondii infection. Severe cases with survival of the fetus are scarce. In 500 pregnancies, it was possible to ascertain the trimester during which T. gondii infection had been acquired (Table 31-5). T. gondii infection occurred in the fetus or was present in the newborn in 14%, 29%, and 59% of cases of maternal infection acquired during the first, second, and third trimesters, respectively. The proportion of cases of congenital toxoplasmosis was higher in the first- and second-trimester groups than in the third-trimester group. This was especially true for severe congenital toxoplasmosis (including cases with stillbirths, perinatal deaths, or severe neonatal disease). No case of severe toxoplasmosis was observed among the 76 offspring of mothers who had acquired T gondii infection during their third trimester. Approach to detection and management of infection acquired during gestation determines and can modify severity of infection detected in infants and their later o ~ t c o m e s . ' ~Of~ -interest, ~ ~ ~ after systemic serologic screening and treatment for T. gondii infection acquired in gestation was introduced in France in 1978, the frequency of severe toxoplasmosis diagnosed in

Frequency of Stillbirth, Clinical Congenital Toxoplasmosis, and Subclinical Infection among Offspring of 500 Women Who Acquired Toxoplasma Infection during Pregnanw No. of Affected Infants (96)

Outcome in Offspring No congenital Toxoplasma infection Congenital toxoplasmosis Subclinical

Mild Severe Stillbirth or perinatal deathb Total

Infection Acquired during First Trimester

Infection Acquired during Second Trimester

Infection Acquired during Third Trimester

109 (86)

173 (71)

52 (41)

3 (2) 1 (1) 7 (6) 6 (5) 126 (100)

49 (20) 13 (5) 6 (2) 5 (2) 246 (1 00)

68 (53) 8 (6) 0 (0) 0 (0) 128 (100)

aForty-two pregnancies are not included from Table 31-3 because it was not possible to ascertain the trimester during which infection occurred in the mother. bSee text. Adapted from Desmonts G, Couvreur J. Congenital toxoplasmosis: a prospective study of the offspring of 542 women who acquired toxoplasmosis during pregnancy: pathophysiology of congenital disease. In Thalhammer 0, Baumgarten K, Pollak A (eds). Perinatal Medicine, Sixth European Congress, Vienna. Stuttgart, Georg Thierne, 1979, pp 51-60, with permission.

956

Section IV

Table 31-6


Severity of Manifestations of Congenital Toxoplasmosis in Paris before (1949-1960) and after (1984-1992) Introduction of Serologic Screening and Treatment programs No. of Affected Infants ( O h )

Period 1949 to 1960 1984 to 1992

No. of Newborns

CNS Disease

147 234

93 (63%) 8 (3%)”

Hydrocephalus

Retinitidscar

Subclinical

62 (67% of 93)

54 (33%) 60 (26%)

0 166 (71 %)

-a

asevereocular or neurologic disease occurred only when infants were born to mothers from foreign countries where there was no screening during pregnancy (e.g., Morocco, Algeria, United Kingdom), they were not screened, or mothers were immunodeficient or erroneously considered immune. It also is noteworthy that in one hospital in France, in 1957, among 1085 premature infants, 7 had toxoplasmosis, whereas in this same hospital between 1980 and 1990, among approximately 10,000 premature infants, 2 had toxoplasmosis. CNS, central nervous system.

Table 31-7

Fetal Toxoplasma Infection as a Function of Duration of PregnanM

Time of Maternal Infection Periconception 6-16 wk 17-20 Wk 21-35 wk Close to term

No. of Women

% Infected

182 503 116 88 41

1.2 4.5 17.3 28.9 75

Women were treated during gestation as soon as feasible after diagnosis of the acute acquired infection was established or strongly suspected. If prenatal diagnosis was made in the fetus, treatment was with pyrimethamine-sulfadiazine; otherwise it was spiramycin. Adapted from Forestier F. Fetal diseases, prenatal diagnosis and practical measures. Presse Med 20:1448-1454, 1991, with permission.

newborns diminished remarkably (Table 31-6). This is discussed in more detail under “Effects of Systematic Screening of Pregnant Women at Risk on the Prevalence of Congenital T i p l a s m a gondii Infection and of Congenital Toxoplasmosis.” Experience acquired since 1 978128-13’ has confirmed these earlier findings: Transmission of the parasite to the fetus was dependent on the time of acquisition of maternal infection during pregnancy. The proportion of cases that resulted in congenital T. gondii infection was very low if maternal infection was acquired during the first few weeks after conception. The later maternal infection was acquired, the more frequent was transmission to the fetus. The frequency of congenital infection was 80% or higher if maternal infection was acquired during the last few weeks before delivery and if it was not treated. Table 31-7 shows the frequency of transmission by gestational age observed in a group of 930 women with acute Toxoplasma infection acquired during pregnancy who were referred to the Institut de Pukriculture in Paris for prenatal diagnosis. The incidence of transmission rose from 1.2% when maternal infection occurred around the time of conception to 75% when it occurred close to term. These data were updated by Hohlfeld and c o - ~ o r k e r s , ’whose ~~ report includes the 2632 pregnant women for whom a prenatal diagnosis was performed between 1983 and 1992 (Table 31-8). The observed incidence of transmission rose from 0% when maternal infection was acquired before week

Table 31-8

Incidence of Congenital Toxoplasma gondii Infection by Gestational Age at Time of Maternal Infectiona

Week of Gestation

Infected Fetuses1 Total No. Fetuses

Incidence

0-2 3-6 7-10 11-14 15-18 19-22 23-26 27-30 3 1-34 Unknown Total

01100 6B84 91503 3715 11 491392 441237 3011 16 7132 46 W351 1942632

0

(%I

1.6 1.8 7.2 13 19 26 22 67 7.4

’Maternal infection was treated with spiramycin in a dose of 9 million IU (3 g) daily. Adapted from Hohlfeld P, et al. Prenatal diagnosis of congenital toxoplasmosis with polymerase-chain-reaction test on amniotic fluid. N Engl J Med 331595-699, 1994.

2 of pregnancy to 67% when it was acquired between weeks 3 1 and 34. The incidence of transmission remained very low, less than 2%, when maternal infection was acquired during the first 10 weeks of gestation. It rose sharply when maternal infection was acquired during weeks 15 to 34. To appropriately interpret the data provided by Hohlfeld and co-workers, a number of points deserve discussion. Their patients were referred to the Institut de Pukriculture for prenatal diagnosis. Thus, cases with fetal death in utero before the time of amniocentesis were not included. The consequence is that the incidence of congenital infection when maternal infection occurred during the first few weeks of pregnancy is slightly underestimated. For example, when Daffos and collea ues reported the first 746 cases from this same series, they’ estimated the incidence of transmission to be 0.6% among 159 women with “periconceptional infection” and 3.7% among 487 women whose infection was acquired between weeks 6 and 16 of gestation. The observed incidence rates were 1.8% and 4.7%, respectively, if those fetuses that died in utero because of congenital toxoplasmosis before the time of blood sampling were included in the

Q’

Chapter 31 report. Another consequence of the recruitment of the cases reported by Hohlfeld and co-workers is that the number of cases with acquired maternal infection after week 26 of gestation is small, because maternal infection acquired late during pregnancy was not discovered early enough to allow for performance of a prenatal diagnosis. The incidence of congenital infection was reported to be 194 of 2632 (7.4%). If, however, one excludes 100 cases of maternal infection acquired before week 2, and 351 in which gestational age at the time of maternal infection was unknown, the distribution of cases would be as follows: maternal infection acquired at gestational age 3 to 14 weeks, 1398 cases; 15 to 26 weeks, 745 cases; and 27 to 34 weeks, 38 cases. Most of the cases studied by Hohlfeld and co-workers occurred in women who acquired infection early in pregnancy. If cases of maternal acquired infection had been equally distributed through each of the weeks of gestation, from weeks 3 to 34, the adjusted mean transmission rate would have been 19.5%. The transmission rate observed by Jenum and associates in Norway’32was 1 1 of 47 (23%). A higher transmission rate, 65 of 190 (34%),was observed in a series of 190 consecutive cases of maternal acute Toxoplasma infection, each of whose sera was examined in a single laboratory in Paris (P Thulliez, personal communication to G Desmonts, 1999). These cases were more equally distributed in regard to gestational age at time of infection. The incidence rates of congenital infection in this series of 190 women were as follows: 4 to 16 weeks, 5 of 44 ( 1 1%); 17 to 28 weeks, 15 of 71 (21%); and 29 to 40 weeks, 45 of 75 (60%). In another series, reported by Dunn and associate^,'^' the mean rate of transmission was 29% in 603 cases studied in Lyon between 1987 and 1995. A critical point to remember in reviewing the data obtained in the European countries where screening for Toxoplasma infection during pregnancy is routinely performed is that most patients are treated during pregnancy-which probably reduces the incidence of transmission of the parasite. The frequency of congenital toxoplasmosis (i.e., of fetal lesions or of clinical manifestations in the infant with congenital infection) also is highly dependent on the time of acquisition of maternal infection during pregnancy. The earlier maternal infection was acquired, the higher was the prevalence of fetal or neonatal disease among infants with congenital T. gondii infection. A number of observations suggest that T. gondii may be present in the placenta but is transmitted to the previously uninfected fetus only after a delay. This delay has been termed the prenatal incubation period by Thalhammer.’33”34 Placental infection is a potential source of infection of the infant even long after maternal parasitemia has subsided. This has been documented in studies in which, after induced abortions, samples of fetal tissues and placentas were injected into mice in an attempt to isolate T. gondii. Table 31-9 shows the results obtained in 177 such cases in which no attempt at prenatal diagnosis of fetal infection had been made. Isolation attempts were successful from placentas in 10 cases (6%). In 8 of the 10 cases, placental and fetal tissues were injected separately and T. gondii organisms were isolated solely from the placentas and not from the fetus in 4 of those 8 cases. The fetuses were not infected at the time the pregnancies were terminated. In one of these cases, pregnancy was terminated at week 21 in a woman who had

Table 31-9

Toxoplasmosis

957

Isolation of Toxop/dsmd from Placental and Fetal Tissue after Termination of Pregnancy in 177 Women Who Acquired Infection Just before or during Gestation

Maternal infection category la No. of cases No. of positive isolations Maternal infection category ila No. of cases No. of positive isolations

115 10 (9%)b 62 0

aCategoryI: Toxoplasma infection was proved to have been acquired during pregnancy; category (I: Toxoplasma infection was noted to have been recently acquired; it occurred either before or soon after conception as judged by serologic test results obtained at the time of first examination, when patients were in their fourth to eighth week of gestation. No attempt at prenatal diagnosis was made in any of the cases. bToxoplasmawas isolated in two cases from mixed placental and fetal tissues after curettage, in four cases from both placenta and fetal tissues injected separately, and in four cases solely from the placenta. Adapted from Desmonts G, Forestier F, Thulliez P, et al. Prenatal diagnosis of congenital toxoplasmosis. Lancet 1 :500-504, 1985, with permission.

Table 31-10

Frequency of Findings in the Fetus Correlated with Gestational Age When Infection Was Acquired

Fetal Gestational Age (wk) when infected

Frequency of Ultrasound Evidence’ of infection

4 6 17-23 >24

31 (60%) of 52 16 (25%) of 63 1 (3%) of 33

Frequency (%) of Cerebral Ventricular Dilatation 48 12 0 ~

~~~~~

aAscites,pericarditis, necrotic foci in brain. Data from Daffos F, et al. Letter to the editor. Lancet 344: 541, 1994.

acquired her infection shortly before the fourth week of gestation. This case demonstrates that delay between maternal and fetal infection may be longer than 16 weeks. In other cases, the delay may be much shorter. Among 22 pregnancies terminated because congenital I: gondii infection had been demonstrated in the fetus by prenatal diagnosis (see “Prenatal Diagnosis of Fetal Toxoplasma gondii Infection” in “Diagnosis”secti0n) (data not included in Table 31-9), the time that elapsed between maternal and fetal infection evidently was less than 8 weeks in 2 cases, less than 6 weeks in 2 cases, and less than 4 weeks in 1 case. The case histories also suggested that the later during gestation maternal infection occurred, the shorter was the delay between maternal and fetal ?: gondii infection (Table 31-10). The data of Daffos demonstrate that it is almost always first- and secondtrimester infections that are associated with substantial brain necrosis and hydrocephal~s.’~~ Recent data reveal that the magnitude of fetal involvement correlates with amount

958

Section IV


of parasite DNA in amniotic fluid (see under “Polymerase Chain Reaction Assay” [“Diagnosis”] and “Pre~ention”).’~~ The severity of the disease depends on the age of the fetus at the time of transmission (see Table 31-10). This is determined both by the time during pregnancy when maternal infection occurs and by the duration of the delay between maternal infection and transmission to the fetus (prenatal incubation period). The earlier the fetus is infected, the more severe the disease in the newborn. The likelihood that transmission will occur early in fetal life is greater when the mother acquires her infection during the first or second trimester of pregnancy. Results of examination of fetuses after induced abortion agree with these conclusions. Among the 177 cases in which pregnancies were terminated without any prior attempt at prenatal diagnosis (see Table 31-9), results of inoculation tests of fetal tissues were positive in 4 cases. In each of these 4, macroscopic lesions were evident on gross examination of the aborted fetus at autopsy. The same was true for 22 fetuses of women in whom the decision to terminate the pregnancy was made after fetal infection was demonstrated by isolation of I: gondii from amniotic fluid or from cord blood samples obtained in an attempt at prenatal diagnosis.”’ Each of these 22 fetuses had multiple necrotic foci in the brain, even when appearance on a previous ultrasound examination (performed before the pregnancy was terminated) was normal. Transmission during the third trimester almost always results in either subclinical infection or mild congenital toxoplasmosis. Exceptions have been noted: In two cases (G Desmonts, unpublished observations) in which maternal infection was acquired after 30 weeks of gestation, the offspring had severe systemic disease and died in the newborn period. By collecting data from pregnancies that resulted in birth of severely damaged infants, it was possible to define more precisely the weeks of pregnancy during which infection produces the greatest risk of severe congenital toxoplasmosis in the newborn infant. The period of highest risk was weeks 10 to 24.12’ Although the incidence of transmission to the fetus is highest during weeks 26 to 40, it results in milder infection in the newborn. Weeks 1 to 10 constituted a lowrisk period because transmission to the fetus was infrequent. Although infrequent, cases have been observed in which infection was acquired before week 7, or even shortly before conception, which resulted in the birth of severely damaged infants. The attempt at prenatal diagnosis by Daffos and ass~ciates’~’in 159 cases of periconceptional maternal infection (i.e., infections that, as judged by serologic test results, had been acquired at the time of conception or within a few weeks after conception) revealed fetal infection in only 1.8% of cases (see earlier). Thus, in these circumstances, transmission of parasites is infrequent. A question that is frequently asked when toxoplasmic lymphadenopathy is diagnosed in women of childbearing age or when serologic test results in a sample of serum drawn for routine testing very early in pregnancy suggest recently acquired I: gondii infection is as follows: How long before pregnancy is acquisition of T. gondii infection to be considered a risk factor for transmission of the parasite to the fetus in a future pregnancy?The answer is that if toxoplasmic lymphadenopathy was already present at the time of conception, and/or if two samples of serum, the first drawn

before the eighth week of .gestation and the second 3 weeks later, are examined in parallel and have identical IgG titers, the initial stage of the infection probably occurred before conception. The avidity test also is helpful in this setting, because high-avidity IgG antibodies develop at least 12 to 16 weeks (depending on the test kit used) after acquisition of infection. Thus, the presence of high-avidity antibodies indicates that infection was acquired more than 12 to 16 weeks earlier (see also later discussions of serodiagnosis and avidity a s ~ a y s ) . ’ ~ ~In“ ~these ’ conditions, the risk for congenital T. gondii infection is extremely low. Unfortunately, accumulated data do not allow for a more definitive answer. Cases that demonstrate that the exception does occur have been reported. Of special interest are cases in which the diagnosis of toxoplasmic lymphadenopathy was well established before pregnancy occurred, because they provide reliable information in regard to the timing of events (clinical signs in the mother, beginning of pregnancy, and the development of signs, if any, in the infant). A summary of the history of the first reported appeared in the third and fourth editions of this Another case was reported by Marty and co-workers in 1991,14’ and a third was reported by Vogel and associates in 1996.’43The time elapsed between the occurrence of lymphadenopathy and conception was 2 months for the first case and 3 and 2 months, respectively, for the next two cases. The patient described by Marty and co-workers received spiramycin for 6 weeks at the time of lymphadenopathy; however, she did not receive treatment during pregnancy. Neither the first (studied by Desmonts)14’ nor the third (Vogel) mother received any treatment. In the three cases, no specific sign of congenital toxoplasmosis was recognized in the newborn (except possibly in the case reported by Marty and coworkers, in which slight splenomegaly was noted in the neonate). Strabismus was noted at the age of 3 months in the first case. None of the infants was given treatment before the diagnosis of congenital toxoplasmosis infection was established. Definitive diagnosis was made in two infants when obstructive hydrocephalus developed, at the ages of 4 months and 9 months, respectively. In the case described by Marty and co-workers, infection was still subclinical when the diagnosis was made at the age of 8 months because of an increase in the antibody load (see “Diagnosis” section). The clinical patterns and the delayed antibody response observed in the infants are highly suggestive that transmission of the parasite to the fetuses occurred after maternal IgG had reached a significant level in the fetal blood (i.e., after 17 to 20 weeks of gestation), and probably later in the patient (described by Marty and co-workers) whose infection remained subclinical, despite absence of treatment before the eighth month of life. These three cases demonstrate that infection in the 3 months before conception does not always confer effective immunity against congenital transmission. Transmission rarely occurs in these conditions,however. In our experience,128 no other example of congenital infection has arisen among several hundred cases in which toxoplasmic lymphadenopathy occurred before pregnancy. Advice given (G Desmonts) was that patients should receive spiramycin treatment if lymphadenopathy had occurred during the 6 months preceding pregnancy. This intervention possibly reduced the incidence of congenital infection among the offspring of these patients.

Chapter 31 That fetal infection is rare when maternal acquisition of 7: gondii infection has occurred even a short time before pregnancy is in agreement with the observation first made by Feldman and Miller,144and amply confirmed since, that congenital infection does not occur in siblings (except twins) of a child with congenital toxoplasmosis. Several exceptions have been reported. In one instance described by Garcia, congenital T. gondii infection affected offspring of two successive pregnancies.”’ The first infant, delivered by cesarean section for fetal distress at the seventh month of gestation, died at 24 hours with multiple organ involvement with T. gondii. About 5 months after delivery of this infant, the mother again became pregnant. This pregnancy ended in spontaneous abortion of a macerated fetus at about the sixth month of gestation. Microscopic examination revealed T. gondii infection in both cases, in fetal as well as placental tissue. Although the proof rests solely on histologic findings, the data presented in these cases appear incontrovertible. Silveira and colleagues’45also reported that ?: gondii had been transmitted from a Brazilian mother infected 20 years earlier. The mother had a chorioretinal macular scar and positive result on serologic tests for T. gondii infection over a 20-year period. She was without known immunocompromise and transmitted T. gondii to her fetus. Details of the evaluation for immunocompromise and clonal type of parasite were not available (Silveira, personal communication to J Remington, 2003). Manifestations in the infant included IgG and IgM specific for ?: gondii, a macular scar, and a cerebral calcification. Two cases of transmission to the fetuses of women with subclinical infection acquired before pregnancy also have been published in France. Time of infection was well established in both cases, because sera drawn before conception were available for comparison with the mandatory sample taken at the beginning of pregnancy.’46,’47In both cases, sera were negative for ?: gondii antibodies 7 months before pregnancy and found to be positive, with a high but stable titer of IgG antibodies at 3 and 4 weeks of gestation, respectively. Thus, infection had occurred about 1 to 2 months before conception in both cases. In both, prenatal diagnostic testing proved positive, and severe fetal lesions were demonstrated after termination of the pregnancies. Therefore, it is well established that the acute subclinical infection in a pregnant woman can result in fetal infection and congenital toxoplasmosis, even when acquired by the mother before conception. Serologic screening tests for acute 1: gondii infection during pregnancy usually are performed at weeks 8 to 12 of gestation. If the results suggest a recently acquired infection, it formerly was difficult, even with the help of a second sampling of serum 3 weeks later, to decide whether infection occurred before or after the time of conception (see “Diagnosis” section). These cases were classified as “periconceptional,” and in our practice (G D e s m ~ n t s ) , ’ ~these ~’’~~ women were managed as if they had been infected during gestation (spiramycin treatment and prenatal diagnosis). The transmission rate observed after “periconceptional” infection was 3 of 161 (1.8%).I3O With the availability of the avidity assay, acquisition can be more readily dated regarding whether it occurred before conception if the test is performed during the first 12 to 16 weeks of gestation.

Toxoplasmosis

959

It is apparent that the rate of transmission of the parasite from a woman to her fetus after the acute infection rises from virtually zero, when T. gondii infection was acquired several months (the exact number is unclear) before pregnancy, to about 2% (or slightly less), when acquired at about the time of conception. An important point is that the transmission rate remains low for several weeks (approximately 10) after the beginning of pregnancy. After the tenth week of gestation, a shift occurs from this low transmission rate toward a steeply increasing incidence of congenital infection in relation to the gestational age. This shift was observed in the 11- to 14- week gestational age group in the series reported by Hohlfeld and co-worker~’~~ and after week 13 in the series reported by Dunn and associate^.'^' Several hypotheses might explain this shift from a low toward a steeply rising risk of transmission. One relies on a truism: Congenital toxoplasmosis is a fetopathy, resulting from a placental infection. Thus, a placenta and a fetus are necessary for the disease to develop. Hence, congenital T. gondii infection, when resulting from an infection acquired by the mother before the formation of the placenta, is the consequence of a recurrent parasitemia. The incidence of transmission in this situation depends on the frequency of recurrent parasitemia in a woman whose cell-mediated immunity developed (see the with regard to Toxoplasmahas not yet “Pathogenesis”section). When maternal infection is acquired later during pregnancy, the parasite can reach the placenta during the initial parasitemia, which occurs in the mother before the development of any immune response. This mode of transmission is more effective for colonization of the placenta by the parasite. The later the infection occurs in the fetus, however, the less severe the disease, because immunologic maturation has had time to develop. A summary of the data just presented is shown in Figure 31-3, in which percentages of risk are given, to suggest a range in magnitude and not necessarily exact data. It also should be noted that the data used in this figure were obtained from women almost all of whom received spiramycin treatment during pregnancy. Hence, the outcome in the fetuses would have been more severe, both for transmission rates and for severity of infection, if results from untreated pregnancies only had been used.

Chronic Maternal Toxoplasma Infection. Data obtained in prospective studies have established that chronic (or latent) maternal infection, per se, is not a risk for congenital infection.I4 Also, as a rule, evidence of previous chronic (latent) infection signifies that the future mother is not at risk of giving birth to a child with congenital T gondii infection. These observations constitute the basis for the preventive measures that have been adopted by and have proved effective in countries such as Austria and F r a n ~ e . ’ ~Immunity ~-’~~ associated with chronic (latent) infection is relative only in laboratory animals (see “Pathogenesis” section) and in Five cases have been published that suggest that this statement might be true for humans as well.’393151-’53 Four of the cases were reported from France. This is not surprising because such cases usually are observed only in countries where screening for Toxoplasma infection during pregnancy is performed routinely. A summary of the histories of the four cases follows: The women were known from previous pregnancies to have low

960

Section IV


Weeks of gestation when maternal infection occurred

ransmission rate’ incidence of congenita ifection

6 months (?) before pregnancy

lirtually

Conception

’revalence* of congenital oxoplasmosis (mild, moderate, )r severe) among fetuses or ifants with congenital ifection

280%

3isk for the mother of jiving birth to a child with ievere congenital nfection Low risk (low transmission rate)

2%

iigh irevalence

280%

10th week Highest risk

24th week

280%

I

ncreasing 3

20%

30th week

Low risk (congenital infection is frequent but mainly mild)

Delivery

280%

6%

*Percentages are given as a range according to what has been observed among women, most of whom were treated with spiramycin during pregnancy.

Figure 31-3 Transmission rate and prevalence of congenital Toxoplasma infection or congenital toxoplasmosis among offspring of women with acute Toxoplasma infection in relation to gestational age at time of maternal infection.

and stable titers of IgG antibodies, characteristic of past infection and immunity. The same low titer of IgG was present at the beginning of the new pregnancy. Thus, these women were considered to be immune, so that their fetus was judged not to be at risk. Treatment was therefore not given during gestation. Congenital T. gondii infection was demonstrated in each case: A subclinical infection was noted when the child was 12 months of age in one case (the histo of which was published in previous editions of this book)12L41;spontaneous abortion occurred at 12 weeks of gestation, with demonstration of the parasite in fetal tissues in another case”’; and congenital toxoplasmosis (chorioretinitis) was diagnosed at birth in the third case1” and at 9 months of age in the fourth case.153In each of the four cases, a serologic relapse occurred during pregnancy, as evidenced by a significant increase in IgG antibodies that reached high titers in each woman. In three of the women, samples of sera drawn during pregnancy were available for retrospective examination. Of interest is that in these three cases, IgA antibodies were present at the beginning of the serologic relapse. An IgM response was noted in only one woman. Serologic relapse had occurred between weeks 8 and 11 of gestation in the

case ending in abortion and after weeks 10, 16, and 19, respectively, in the other three cases. Silveira and colleague^'^^ also reported that T. gondii had been transmitted from a Brazilian mother infected 20 years earlier, as described. Even if some cases have gone unpublished (Dr. Jacques Couvreur has data on two additional cases, as described in a personal communication to G Desmonts, 1999), the examples of offspring with congenital T. gondii infection born to mothers who, at the beginning of pregnancy, had serologic test results that established the presence of a chronic (latent) infection are exceptional.When this does occur, immunologic dysfunction must be suspected as having been the cause. The first case we was that of a woman who had a low CD4+/CD8+ ratio associated with Hodgkin’s disease, from which she had recovered 2 years before becoming pregnant. She also previously underwent a splenectomy. No immunologic dysfunction was demonstrated in the other three women. Reinfection with oocysts of another T. gondii strain was suggested as an explanation for the cases observed by both Fortier and Gavinet and their ~ o - w o r k e r sEach .~~~~~~~ woman had contact with kittens at the beginning of or during week 20 of gestation, respectively.

Chapter 31 Transmission of T. gondii from mother to fetus has been observed in immunodeficient women owing to reactivation of the chronic infection, primarily in patients with AIDS (see "Congenital Toxoplasma gondii Infection and Acquired Immunodeficiency Syndrome" later, under "Clinical Manifestations"). It also has occurred as a consequence of other immunocompromised states that appear to have resulted in an active but subclinical infection in the chronically infected pregnant woman. One case was reported in the third and fourth editions of this b ~ o k . ' ~ , ' Two ~ ~ , additional '~~ cases were published in 1990,'39and a fourth in 1995 by d'Ercole and colleague^.'^^ The immunologic dysfunction was associated with lupus erythematosus in three of the four patients and with pancytopenia in one. This last patient, as well as one of those with lupus, also previously had a splenectomy. Each of the four patients was given corticosteroids during gestation. Three'39did not receive treatment for their T. gondii infection. The serologic evidence for (chronic) active infection was the unusually high IgG titers that had been present since childhood in two of the cases (titers of greater than 4000 IU for more than 5 and 10 years, respectively). One of these women gave birth to an infant with severe congenital toxoplasmosis that resulted in the death of the child at the age of 3 months. Congenital toxoplasmosis was diagnosed in the other case when chorioretinitis occurred in the infant at the age of 4 months. In one of the four mothers, the IgG titer rose from a relatively low titer at the beginning of pregnancy to 800 IU, and a weakly positive IgM test titer developed. One of her twin infants, a boy, died at the age of 9 days from toxoplasmic encephalomyelitis. His twin sister had subclinical congenital T. gondii infection. The case report published by d'Ercole and colleagues'55is of special interest because the affected woman was known to have both lupus erythematosus and high T. gondii IgG antibody titers, together with a strongly positive IgA test result, before becoming pregnant. For this reason she was monitored with 'I:gondii serologic tests for two consecutive pregnancies. During both pregnancies, recurrence of serologic signs of activity of 'I: gondii infection was observed. She had an increase in IgG titers and an IgM test result that became temporarily positive. Despite treatment with spiramycin,prenatal diagnosis revealed that the infection was transmitted to the fetus in both of these pregnancies. During the first pregnancy, the fetus died in utero at a gestational age of 23 weeks. In the second pregnancy, the mother received pyrimethamine and sulfonamide after the polymerase chain reaction (PCR) assay result was observed to be positive in amniotic fluid at 23 weeks of gestation. This pregnancy ended in delivery of a child who was considered to have 'I:gondii infection as indicated by the presence of IgA serum antibodies in the newborn. The infant was given pharmacologic treatment and at 1 year of age exhibited no signs of congenital toxoplasmosis and had no T. gondii antibodies. The cases just described demonstrate conclusively that the presence of a chronic, yet active T. gondii infection in an immunocompromised pregnant woman results in a significant risk of congenital infection for the fetus and newborn. In addition to women with AIDS, this is especially true for women who must receive long-term treatment with corticosteroids during gestation. In this context, it is important to note that HIV-infected women older than 50

Toxoplasmosis

961

years of age and who were born outside the United States had the highest seroprevalence of T. gondii a n t i b ~ d i e s . ' ~ ~ Treatment of HIV infection in the woman chronically infected with T. gondii15' also would be expected to substantially reduce or eliminate congenital T. gondii infection, although no data rigorously demonstrating this effect have been provided. In the past, chronic Toxoplasma infection in the mother was considered to be responsible for repeated abortions, stillbirths, or perinatal fetal mortality. In an attempt to determine whether 'I: gondii is indeed a contributing cause of stillbirth and perinatal infant mortality in women with chronic (latent) infection, Remington and colleagues performed a study in El Salvador, where the incidence of the infection in the childbearing age group was approximately 65% and the perinatal infant mortality rate was very high.'58,'59In the Maternity Hospital in San Salvador, a dye test was performed on serum obtained from 103 mothers on the day of the death of their newborn infants or, in the case of death in utero, at the time of delivery. The dye test was repeated 1 month later to determine whether the titers were stable, and a skin test was performed at the same time. A high percentage of the mothers had dye test titers of 1:lOOO or higher,159in marked contrast with the test results in the pregnant population in the United States. Sixty-five percent of the 103 women in this study had a positive dye test result. One hundred ten infants were examined. The diagnostic categories, with number of affected fetuses in each category, were as follows: cranial deformities, 5; premature births, 45; stillbirths, 40; and miscellaneous, 70. Fifty-eight of the mothers had had previous abortions; 26 had had one abortion, 12 had had two or more abortions, and more than 7 had given birth to dead infants. At least 20 g of each infant's brain and a similar amount of liver were injected into 10 to 20 mice. 'I:gondii was not isolated from any of the infants, which suggested that in this population, T. gondii was not an important cause of perinatal fetal mortality. Ferraris and Avitto, in Rome, obtained similar results for their population.I6' Several prospective surveys have been performed to determine whether chronic T. gondii infection is a cause of abortion. In a study in Palo Alto, California, and its immediate surroundings, tissue specimens were obtained from aborted fetuses in 272 women. (For the initial portion of this study, see the work of Remington and co-workers.16') Seventy-nine (29%) of these women had positive dye test titers. Of these 79 women, at least 18 had had one abortion, and at least 8 had had two or more abortions. T. gondii was isolated from two specimens obtained from two chronically infected women-one specimen came from decidual tissue obtained at curettage after spontaneous abortion and the other from the aborted fetus and decidual tissues. Chronic T. gondii infection in the first case was evident from the stable dye and hemagglutination test titers, at levels lower than those usually associated with acute T. gondii infection, and a positive skin test result. Subsequent attempts to isolate the organism from endometrial tissue and from menstrual blood were unsuccessful. The second case was that of a 27-year-old white woman whose first two pregnancies (in 1960 and 1962) had resulted in the births of normal offspring. In February 1963, she aborted at approximately 5 weeks of gestation. A dye test performed at that time showed a titer of

962

Section N


1:512, and an attempt to isolate T. gondii from the abortion tissues was unsuccessful. She aborted again in March 1964, and her serum again showed a titer of 1512. T. gondii was isolated from the aborted fetus and decidual tissues. The presence in this case of identical dye test titers in serum samples collected 1 year apart is proof of chronic infection with T gondii and appears to establish the fact that T. gondii can be associated with abortion during the chronic stage of infection in women in the United States. A similar case, in which 'I:gondii was isolated from products of abortion, has been described by Meylan in Switzerland.162 Ruoss and Bourne, in England, failed to isolate T. gondii from products of conception in 104 cases of abortion (25 occurred in patients with low titers of T gondii antibodies).I2' Janssen and colleagues attempted to isolate T. gondii from 218 samples of maternal or fetal tissue obtained in 172 cases of abortion and followingcurettage in 10 nonpregnant women who had had ab0rti0ns.l~~ Of these women, 70% had positive dye test titers, and 29% showed positive results on the complement fixation (CF) test. Janssen and colleagues were successful in isolating T. gondii in only one case-from curettage material taken after a second abortion in a woman who had a proven chronic (latent) infection. An attempt to isolate the parasite from products of a previous abortion in this woman 5 months earlier had been unsuccessful; at that time, her dye test titer was 1:256 and her CF test titer was 1:5. A third abortion occurred 7 months later, and the products of abortion were thoroughly studied; however, attempts to isolate the parasite from placenta, fetus, and tissue obtained at curettage all were unsuccessful. Like Remington and cow o r k e r ~ , ' ~ Janssen ~ . ' ~ and colleagues concluded that they could not state unequivocally that T gondii was responsible for the abortion in their cases. They believed that isolation of T. gondii from abortion tissues of women with latent infection is possible, but only in rare cases. Kimball and colleagues from the United States performed a serologic study in a population of 5033 pregnant women in New York City and found no evidence to suggest an association of T. gondii infection with habitual ab~rtion.'~' By contrast, their evidence suggesting an association between chronic T. gondii infection and sporadic abortion was substantial. This association was particularly significant in white patients, especially those with positive results on CF tests. It is unclear whether this was an association caused by other factors or a cause and effect relationship. It is not known whether these sporadic abortions are related to recurrent parasitemia or to persistence of encysted T gondii in uterine tissue."' The significanceof T.gondii infection as a cause of abortion has been a subject of considerable conjecture among workers in this field throughout the world. A detailed review of this subject was presented in the first two editions of this b o ~ k ' ~ ,it' is ~ omitted ~; from the present edition because no new data are available.

Transmission by Ingestion Whether the mode of transmission consists of infective oocysts or meat that contains cysts, it appears that the natural route of transmission usually proceeds from animals (and contaminated soil) to humans by way of ingestion.

Meat

Because the results of feeding tissues from chronically infected mice or rats to other mice were much more successful than the results of similar feedings of tissues from acutely it was hypothesized that the cyst infected animals,43,44,87,'68.'69 form, found in the chronic infection, was better able to withstand the digestive process. Microscopically, the cyst wall was seen to be destroyed immediately on contact with pepsin hydrochloride; however, the liberated parasites were infective for mice as long as after 2 hours of exposure to peptic digestive fluid but not after 3 h0urs.4~When trypsin was used, liberated parasites were infective for up to 6 hours of digestion, the longest period te~ted.4~ These data, combined with those on the seroepidemiology of T. gondii infection in domestic animals used for human consumption, led a number of workers to suggest that meat may serve as a source of human ?: gondii infection.43 In 1956, Weinman and Chandler published a classic article suggesting a meat-to-human route to explain the spread of T. gondii.17' Their investigations stemmed from a study in which they noted that humans are more likely to have antibody titers to T. gondii if they eat undercooked pork. This observation led Jacobs and co-workers to explore the occurrence of T gondii cysts in the edible flesh of meat animals. Samples of mutton, pork, and beef from abattoirs in Baltimore were digested in artificial gastric juice; infection was demonstrated in 12 of 50 samples (24%) of pork, 8 of 86 samples (9.3%) of mutton, and only 1 of 60 samples ( 1.7%) of beef.43(The single isolation from beef was questionable, according to the authors.) Similar results have been found in samples of meat from butcher shops in Palo Alto, California, and from other areas of the ~ o r l d . " ~ ~ ' D~ubey ~ , ' and ~~~'~~ colleagues have reported on the distribution of T. gondii tissue cysts in commercial cuts of pork.'s3 In a genotypic analysis of 43 isolates of T gondii from pigs in Iowa, 87% were type 11. Type 111 genotype was identified in only 16.3% of the isolates. These prevalence rates are similar to the frequencies with which they occur in cases of the disease in humans. Type I strains were not identified, although these strains have previously been shown to account for 10% to 25% of cases of toxoplasmosis in humans.'84 Isolation of T. gondii from beef was reported by Catar and colleagues in Czech~slovakia.'~~ The cyst form was found in 8 of 85 cattle (9.4%). T. gondii has not been isolated from cattle slaughtered in the United state^.^^,'^^,''^ It should be recognized, however, that only relatively small specimens have been evaluated. Other workers have shown that persons who handle raw meat, even without consuming it, have a higher prevalence of antibodies to T. gondii. A listing of studies of isolation of T. gondii from muscle of domestic animals from around the world is presented in Table 3 1- 1 1.187-204 In 1965, Desmonts and colleagues in Paris published what appears to be definitive evidence in favor of the meatto-human hyp~thesis.~'~ They found that among children in a French hospital, antibodies to ?: gondii developed at a rate five times that in the general population. Because it was the custom in this hospital to serve undercooked meat (mainly beef or horsemeat) as a therapeutic measure, these workers reasoned that this practice explained the higher incidence of infection among this hospitalized population. To test this hypothesis, they added undercooked mutton to the diet and

Chapter 31 Table 31-1 1

Isolation of Toxoplasma gondii from Muscle of Domestic Animals

Toxoplasmosis

963

handling and preparation of meat products are an important factor in the spread of t o x ~ p l a s m o s i s . ~ ~ ~ ~ ~ ~ ~ OOCJJS~

Species

Country

Proportion Positive for T: gondii (%)

Sheep

Australia New Zealand United States Germany Denmark Norway Iran Japan Czechoslovakia New Zealand United States United States Germany Germany Germany Denmark Czechoslovakia United States United States Germany Italy Denmark Norway Japan Japan Japan

8/32 (25) 315 (60) 8/86 (9.3) 6150 (12) 7131 (23) 691174 (39.6) 5166 (7.5) 3/26 (11.5) 8/85 (9.4) of80 (0) 1I6Ob(1.7) 01350‘ 01500 OD4 011260 0130 14 (432) (3.2) 12/50 (24) 17011000 (17) 54500 (10.8) 18/60 (30) 10129 (35) 20163 (31.7) 3161 (5) 251130 (19) 4190 (2.1)

Cattle

Swine

Reference No. Munday“ 187 188 189 190 191 192 193 194 187 188 186 195 189 196 190 197 188 198 199 200 190 201 202 203 204

aUnpublisheddata. bResultwas considered to be equivocal, suggesting that there were actually no isolates. Tissues fed to cats; the rest were inoculated into mice. Adapted from Munday EL. The epidemiology of toxoplasmosis with particular reference to the Tasmanian environment. Thesis, University of Melbourne, Melbourne, Australia, 1971, 95 pp.

observed that the yearly rate of acquisition of antibody to T. gondii doubled. Clinical signs of infection, mainly lymphadenopathy, developed in some of the children. Severe illness was not observed in any of them. Four years later, Kean and colleagues in New York reported a miniepidemic of toxoplasmosis in five medical students.’06 Epidemiologic evidence strongly implicated the ingestion of undercooked hamburgers, which the authors recognized might have been contaminated with mutton or pork, as the source of infection in these A number of isolated cases and recent miniepidemics of acute acquired T. gondii infection have been reported. Included were at least one case of congenital toxoplasmosis associated with consumption of undercooked venison or preparation of venison (R McLeod, personal observation), another that resulted in significant illness in adults who in ested undercooked lamb (J Remington, unpublished data)?’one in which undercooked kangaroo meat resulted in acute infection in 12 adults and a case of congenital toxoplasmosis?1° and another linked to undercooked pork.’” In regard to venison, a high prevalence of T. gondii antibodies has been reported in white-tailed deer in the United state^."^"^^ The prevalence rates in various countries indicate that the habits and customs of various populations in regard to the

Although ingestion of undercooked meat (especiallymutton or pork) explained one mode of transmission, such a hypothesis did not explain how herbivorous animals and vegetarian humans became infected. In humans, the prevalence of T gondii antibodies was the same among vegetarian populations (e.g., Hindus) as among meat-eating populations in the same geographic area (e.g., Christians A possible explanation was and Muslims in India).218,219 forthcoming when Hutchison and associates,220as well as several others working independently,2213222 described a new form of the parasite, the oocyst. Oocyst formation has been found to occur only in members of the cat family (e.g., domestic cat, bobcat, mountain lion). Cats may excrete up to 10 million oocysts in a single day, and excretion may continue for 2 weeks. Immunity to the intestinal stages in cats is apparently not absolute, because renewed oocyst production may occur when a cat becomes reinfe~ted’’~or infected with the related coccidian Isospora. Once shed, the oocyst sporulates in 1 to 5 days and becomes infectious; it may remain so for more than 1 year under appropriate conditions (e.g., in warm, moist s0il).2*~*”~ This form of the parasite may be inactivated by freezing, heating to a temperature of 45OC to 55OC, drying, or treating with formalin, ammonia, or tincture of iodine. (For further information on the biology of the oocyst, the reader is referred to the works of Frenkel and D~bey.’’*~’~) Its buoyancy allows it to float to the top layers of soil after rain, a location more conducive to transmission than the deeper soil where cats usually bury their feces. Transport of the oocyst from the site of deposit may occur by a number of vectors. Coprophagous invertebrates such as cockroaches and flies may mechanically carry oocysts to food.227~229 Earthworms also may play a role by carrying oocysts to the soil ~ u r f a c e . ~ ~ * ’ ~ O * ~ ~ ~ A number of attempts have been made to demonstrate oocysts in the feces of cats in their natural surroundings. Whereas Dubey was unable to demonstrate oocysts of ?: gondii in the feces of 510 domiciled seropositive and seronegative cats in Kansas City,232Wallace detected them in the feces of 12 of 1604 stray or unwanted cats (0.7%) on the island of Oahu, Hawaii.233In his studies in the South Pacific, Wallace had previously noted that T. gondii antibodies were far more common in humans, rats, and pigs on Pacific atolls on which cats were present than on atolls without ~ a t s . ~ ~ ~ - ~ Munday made similar epidemiologic observations for sheep on the Tasmanian islands.237 In a study performed in Germany, Janitschke and Kuhn found oocysts in the feces of approximately 1% of privately owned cats238or cats from animal care facilitiesz3’; Werner and Walton found a similar ratio in the house cats of U.S. Armed Forces families in the Kanto Plain (Tokyo) area of Japan.240These low prevalence rates contrast markedly with results of a series of epidemiologic studies in Costa Rica. Ruiz and Frenkel noted that 23% of 237 cats were excreting oocysts. Of interest is the fact that 64% of the excreters were kitten^."^ A report from Beirut, Lebanon, described the incidence of “T. gondii-like oocysts” in the feces of 9.9% of 313 cats.241In a similar study from Brno, Czechoslovakia, oocysts of T gondii were demonstrated

964

Section IV

Table 31-12

Protozoan, Helminth, and Fungal Infections raspberries and that they also can adhere to raspberries and blueberries. Consumption of fresh produce with T. gondii oocysts could thus be a source of transmission to humans. Ooocysts excreted by cats can directly contaminate produce and water used for agriculture.

Prevalence of Toxoplasma Oocysts in Feces of Naturally Infected Cats

Country

Examined

No. Positive

Positive

Australia

74 185 237 91 161

1 1 55 4 3

1.3 0.5 23.2 4.4 1.9

502 308 694 200 250 90

5 4 4 2 1 1 4 2 14 1 2 0 12 7

0.9 1.3 0.5 1.o 0.4 1.1 0.8 0.4 7.0 0.9 2.0 0.0 0.7 0.7

No.

Brazil

Costa Rica Czechoslovakia Germany Berlin Hannover Munich

Hungary Italy Japan

446

Netherlands Nigeria Spain United Kingdom United States

567 200 104 100 510 1604 1000

%

Adapted from Dubey JP. Toxoplasmosis in cats. Feline Praa 16:12-26, 1986, with permission.

in feces of 1.9% of 620 cats.242The prevalence of T. gondii oocysts in the feces of naturally infected cats in which their presence was proved by mouse inoculation is shown in Table 31-12. The relative importance of the oocyst versus undercooked or raw meat in transmission of T. gondii to humans remains to be defined. Whereas meat appears to be of primary importance in most areas of the United States, as shown by Etheredge and Frenkel,243this is not true for other geographic areas. Epidemics of toxoplasmosis associated with presumptive exposure to infected cats support the importance of this mode of t r a n s m i s s i ~ n . ~ ~ - ~ ~ '

Waterborne Epidemics (Oocysts). A cluster of cases of T. gondii in Panama246and another in a suburb of SHo Paulo, appear to have been associated with oocystcontaminated drinking water. An epidemic in Victoria, Canada, also was considered to be associated with oocysts from wild cats in reservoir water. This reservoir was thought to be contaminated with ?: gondii oocysts excreted by cougars.249

Incidence of Infection in Animals That Feed on the Ground. Approximately 80% of black bears and about 60% of raccoons in the United States have antibodies to 1: gondii. The authors suggest that infection in these animals is a good indicator of the prevalence of T. gondii in the environment, because raccoons and bears scavenge for their Dubey and his colleagues suggested that these observations may be linked to the ingestion of oocysts from an environment heavily contaminated with this form of 'I: gondii. In certain areas of Brazil, a high prevalence of infection in chickens and young children has been noted.249

Milk T gondii has been transmitted successfully through milk directly to suckling young in experimental mouse models.'8*254 The organism also has been found in the milk during acute experimental infection in cats, dogs, guinea pigs, rabbits, and sheep (see Fig. 3 1-2).256It has been isolated from the colostrum of a cow and from the milk of naturally infected asymptomatic pig^.^^,^" Langer reported isolation of 'I:gondii from the milk of 3 of 18 women.258Remarkably, in two of the three women, results of the dye tests and CF tests were negative. This is the first such report of isolation from human milk. Interpretation of Langer's results, however, is complicated by the fact that pollen grains contaminated his preparations, which were being examined microscopically for the presence of cysts, and he was unable to decide retrospectively which of his preparations showed pollen grains or 'I: gondii cysts.259 Transmission during breast-feeding in humans has not been demonstrated. It is conceivable that such might be the case if a mother were to acquire her infection during the last weeks of pregnancy. In these circumstances, the risk of transplacental transmission is so high (approaching 100%) that the possible additional risk of breast-feeding would be insignificant.260 Unpasteurized milk (goat milk has been especially implicated) has been implicated as a vehicle for transmission of T. g ~ n d i i , * ~ 'but - ' ~the ~ process of pasteurization would kill all forms of the organism.

Chicken and Eggs

Latent infection was found in chickens obtained from a poultry-processing plant by Jacobs and Melton (see Mussels and Oysters. The illness and deaths of sea otters on Fig. 31-2).264Because chicken usually is well cooked before the central coast of California (especially around Moro Bay) eating, it is unlikely that it plays a significant role in transhave drawn attention to the presence of T. gondii in r n u s ~ e l s . Mussels ~ ~ ~ , ~ appear ~ ~ to concentrate o o c y ~ t that s ~ ~ ~ mission. These investigators also were able to isolate T. gondii from 1 of 327 eggs laid by 16 chickens with experimentally then can be consumed by the otters. Infections in aquatic induced chronic infections. The epidemiologic significance mammals indicate contamination and survival of oocysts in of this finding may be assessed in relation to the number of seawater.250Lindsay and a s ~ o c i a t e s ~demonstrated ~ ~ ~ ' ~ ~ that raw eggs consumed by different population groups. The oocysts can persist in seawater for many months, sporulate, report by Pande and co-workers of isolation from chicken and remain infectious. eggs265was fraudulently and thus their data are open to question. Prevalence of the infection in chickens Oocysts on Fruits. Kniel and c o-worke r~'~ found ~ that reflects T. gondii strains in their environment because they oocysts can persist and remain infective for up to 8 weeks on

Chapter 3 1 feed from the ground.267Prevalence of T. gondii was determined in 118 free-range chickens from 14 counties in Ohio and in 1 1 chickens from a pig farm in Massachusetts. T. gondii antibodies were demonstrated in 20 of 118 chickens (17%) from Ohio and isolated from 11 of 20 seropositive chickens (55%). Parasites were not isolated from tissues of 63 seronegative chickens. Nineteen isolates were genotyped; five were type I1 and 14 were type 111.

Other Means of Transmission Blood Transfusion Net0 and associates recovered T. gondii from blood donated by an asymptomatic person for transfusion.z68T. gondii was shown to survive in whole citrated blood stored at 4” C for up to 50 Kimball and co-workers inferred that the risk of transmission of ?: gondii through blood to children who had received numerous transfusions was not great because the prevalence of positive serologic tests for T. gondii antibodies in these children was no different from that in children in the normal population.laa A majority of their patients, however, had received transfusions of packed red blood cells; if T. gondii remains viable in leukocyte^,'^^ transfusion of whole blood may be a mode of transmission of the parasite. Because prolonged parasitemia has been observed during latent toxoplasmosis in experimental animalsa6 and in humans with asymptomatic acquired toxoplasmosis,’04”90transfused blood must be considered a potential vehicle for transmission of the infection. Siegal and colleagues described four patients with acute leukemia in whom overt toxoplasmosis developed after they were given leukocytes from donors with chronic myelogenous 1e~kernia.l~~ Three of the four patients died. Retrospective serologic analyses suggested that the transfused donor white cells were the source of the parasite. If a pregnant woman is to receive a whole blood transfusion, selection of a donor without antibodies to T. gondii is advisable whenever possible. Patients with chronic myelogenous leukemia and high titers of antibody to T. gondii should not be used as blood or blood cell donor^.'^^,^^^

Laboratory-Acquired Infections (Including infections Acquired at Autopsy) A number of cases of toxoplasmosis have been acquired by laboratory personnel who handle infected animals or We are contaminated needles and glassware.2023203~z7’~273 aware of numerous cases of laboratory-acquired infection with T. gondii that have occurred in recent years. At the Palo Alto Medical Foundation laboratory and Stanford University, more than a dozen such instances have been identified. Some cases were in pregnant women (JS Remington, unpublished data). Certainly, this experience indicates that pregnancy is a contraindication to working with ?: gondii for women who have no demonstrable T. gondii antibodies. One instance has been reported of toxoplasmosis acquired during performance of an

Arthropods The data derived from studies of multiple potential insect vectors are negative and inconclusive.l 9 Flies and cockroaches may serve as carriers of oocysts (see Fig. 31-2).227,228,255

Toxoplasmosis

965

Miscellaneous Free organisms have been identified within the alveoli of infants with congenital toxoplasmosis (see “Lungs” in “Pathology” section) and have been isolated from saliva275 and ll gondii has been reported to survive for 4 to 6 days in saliva, tears, and milk?77The demonstrated presence of organisms in the glomeruli and tubules of the kidneys and in the mucosa of the bladder and intestine suggests that contamination through mucosa or breaks in skin by tachyzoites in urine and feces might be a remotely possible (but unlikely) source of infection in persons caring for such infants. Transmission from such sources has never been proved. ?: gondii has been transmitted by organ transplantation, most often through organs from a seropositive donor transplanted into a seronegative r e ~ i p i e n t . ~ ~ ~ . ~ ~ ~

EPIDEMIOLOGY General Considerations Toxoplasmosis is a zoonosis; the definitive host is the cat, and all other hosts are incidental. The organism occurs in nature in herbivorous, omnivorous, and carnivorous animals, including all orders of mammals, some birds, and probably some reptiles, although in reptiles this suggestion rests solely on interpretation of histologic preparations.28’In regard to T.gondii in cold-blooded hosts, data suggest that natural infection might occur under suitable environmental condition^.^^^*^^^ The organism is ubiquitous in nature, and toxoplasmosis is one of the most common infections of humans throughout the world. In humans, the prevalence of positive serologic test titers increases with age, indicating past exposure, and no significant difference in prevalence between men and women exists in reports from the United States. Considerable geographic differences exist in prevalence rates. Differences in the epidemiology of the infection in various geographic locales and between population groups within the same locale may be explained by differences in exposure to the two main sources of the infection: the tissue cyst (in flesh of animals) and the oocyst (in soil contaminated by cat feces).The high prevalence of infection in France has been attributed to a preference for consumption of undercooked meat.205A similarly high prevalence in Central America has been related to the frequency of stray cats in a climate favoring survival of oocysts and to the type of Examples of factors affecting the frequency of the infection are shown in Table 31-13. Of special note are reports of outbreaks of T. gondii infections among family members.2a4-288 In 1993, the European Network on Congenital Toxoplasmosis, which includes approximately 50 institutions in Europe with investigators interested in different aspects of congenital toxoplasmosis, was organized and has been funded by the Biomedicine Research Program of the Commission of the European Union. The Network has been overseen by Dr. Eskild Petersen of Copenhagen and Dr. Ruth Gilbert of London. Its initial focus has been on diagnosis, including quality control, education and prevention, and identification of risk factors for infection during gestation. In 1995, the European Multicenter Study on Congenital Toxoplasmosis

966

Section IV

Table 31-13


Factors Affecting the Incidence of Toxoplasma Infection among Different Populations

Factor

Considerations

Cat population (mainly feral and stray cats)

If present, the size of the population of cats within the locale inhabited by the specific human population in question. Certain temperatures and humidity levels favor maturation and survival of oocysts in soil. Very cold and hot, dry climates are adverse

Climatic conditions

Method of farming of food animals Hygienic habits in regard to food for human consumption Cultural habits in

regard to cooking of food

conditions. Access of cats to food of these animals varies according to whether the animals are in the fields, in pens, or in stables. Whether food is exposed to coprophagous insects (flies and cockroaches) and whether meat has been previously frozen influence the incidence. Principally, meat is importantthe size of portions and whether served raw, rare, or well cooked.

Hygienic conditions and occupational situations favoring acquisition of infection from contaminated soil

(EMSCOT) was organized to gain further knowledge of the epidemiology and natural history of congenital toxoplasmosis and to perform prospective, controlled trials of new treatments and treatment regimens (E Petersen, personal communication to JS Remington, 1998). Among studies designed to identify the risk factors for T. gondii infection during pregnancy, results from France, Italy, Norway, and Yugoslavia were reported.2’5’217*289v290 Three of these studies reported a comparison between pregnant women who had recently seroconverted or who had evidence of recently acquired infection with seronegative matched controls. The study from Yugoslavia compared seronegative with seropositive persons who had past infection. The conclusions of these four studies-for example, that ingestion of raw or undercooked meat, use of kitchen knives that have not been sufficiently washed, and ingestion of unwashed raw vegetables or fruits are factors associated with an increased risk-are not unexpected. In a recent case-control study from Europe examining risk factors that predispose pregnant women to infection with T. g ~ n d i i the ~ ~ authors l concluded that exposure to inadequately cooked or cured meat accounted for approximately 30% to 63% of infections; thus, exposure to meat was interpreted to be the main risk factor for pregnant women in Europe. Other risk factors included contact with soil, which apparently accounted for approximately 6% to 17% of infections; travel outside Europe or the United States and Canada also apparently accounted for some infections. Although contact with soil would presumably reflect risk from cat excrement, the authors concluded that

direct “contact with cats” was not a risk factor. They also concluded that mode of acquisition for a large proportion of infections (14% to 49%) remained unexplained. In a recent s t u d y exploring risk factors recognized by mothers of infants with congenital toxoplasmosis in the United States between 1981 and 1998, undercooked meat and possible cat excrement exposure, either one or both, were recognized by approximately 50% of the mothers, but the remainder of the mothers could not identify risk factors. Consumption of meat that had been frozen was associated with a lower risk. Surprisingly, in Naples, Italy, Buffolano and colleagues*” observed an increased risk associated with consumption of cured pork; this might be related to the fact that in southern Italy, cured pork usually contains only 1% salt to fresh weight, is stored at less than 12’ C, and may be eaten within 10 days of slaughter. A pet cat at home was not associated with an increased risk in any of these studies, but cleaning the cat litter box was a significant risk factor among women in the study from N0rway.2’~Health education was associated with a lower risk when it was provided using printed educational materials in a book or magazine.289This improved efficacy of print (versus oral) information was observed in the past in Saint Antoine Hospital in Paris (Table 31-14); the yearly seroconversion rate decreased from 37 per 1000 to 11 per 1000 when explanatory drawings were given to every seronegative pregnant woman.

Prevalence of Toxoplasma gondii Antibodies among Women of Childbearing Age Knowledge of the prevalence of antibodies in women in the childbearing age group is important because of its relevance to the strategic approach for prevention of congenital toxoplasmosis. In evaluating results obtained in any serologic survey, the factors noted earlier under “General Considerations” (in epidemiology) must be examined, in addition to two potential causes of differences that may not be real: the serologic method used (and its accuracy) for collection of the data and the dates of collection of the sera. Data from studies of pregnant women in New York City, London, and Paris are shown in Table 31-14. These data were obtained in surveys performed during the years 1960 to 1970 and were largely from results of the dye test. They are shown here for comparison with more recent data. Data on the prevalence of antibodies in pregnant women or women in the childbearing age group for the United States and for other areas of the world are shown in Tables 3 1- 15, 3 1-16, and 3 1-17. 214,293-376,1170-1174 The prevalence rate among pregnant women in Palo Alto, California, has decreased remarkably, from 27% in 1964 and 24% in 1974 to 10% in 1987 and 1998. The prevalence among pregnant women in Malmo, Sweden, has diminished since 1983. Relevant to the variability in prevalence of infection among populations within a given geographic area are the observations of Ades and associates.377They studied the prevalence of maternal antibody in an anonymous neonatal serosurvey in London in 1991. Among women born in the United Kingdom, the seroprevalence was estimated to be 12.7% in inner-city London, 7.5% in suburban London, and 5.5% in nonmetropolitan areas. The prevalence in women from India was 7.6%; Africa, 15% to 41%; Pakistan and Bangladesh, 21%; Ireland, 31%; and the Caribbean, 33%.

Chapter 3 1

Table 31-14

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Effect of Attempts at Health Education on Incidence of Toxoplasma Infection in Selected Populations of Pregnant Women in the Paris Area

Hospital’

Period

Pinard and Baudelocque‘ Centres Medico-Sociaux CPCAMd Hospital Xe Saint Antoine‘

Pre-1960

1961-1970 1973-1975 1973 1974 1974-1981

Longjumeaug

Seroconversion Rateb

Yearly Seroconversion Rate (per 1000)

111356 73/2496 1w10 71463 31658 2011938

60 64 59 37 11 22

”Patients from several obstetric departments. Sera were examined in one laboratory (G Desmonts) with the same level of sensitivity of the serologic methods. bNumber of seroconversions observedlnumber of seronegative women screened in the dye test and/or agglutination test. ‘Serum samples, taken during pregnancy, were examined only after delivery. dNo information was given on how to avoid becoming infected. The mode of transmission of Toxoplasma was not known a t that time. eLittleor no information was given on how to avoid becoming infected. ’There was an intensive attempt at health education of seronegative women on how to avoid becoming infected. In 1973,only verbal instructions were given. In 1974,patients were given drawings illustrating the cycle and transmission of the parasite, with explanations in the language of the patient. g0nly oral instructions were given. Modified from Roux C, Desmonts G, Mulliez N, et al. Toxoplasmose et grossesse: bilan de deux ans de prophylaxie de la toxoplasmose J Gynecol Obstet Biol Reprod 5:249-264,1976,with permission. congenitale B la rnaternite de I‘hbpital Saint-Antoine (1973-1974).

Table 31-1 5

Prevalence of Toxoplasma Dye Test Antibodies in Three Populationsof Pregnant Women % Positive

Paris Age Group (yr)

15-19 20-24 25-29 30-34 235 Total

New York

London

French

Other9

16 27 33

15 27 33 34 36 22

80 81 86 95 96 87

56 53 78 77 80 70

40 50 32

”Spaniards, North African Muslims, and Portuguese. Adapted from Desmonts G, Couvreur J. Toxoplasmosis in pregnancy and its transmission to the fetus. Bull NY Acad Med 50:146-159, 1974,with permission.

Thus, much of the variation between districts might be explained by ethnic group or country-of-birth composition. Recent data from France are available from a national survey performed in 1995 for the Direction Genkrale de la Santk.378 The seroprevalencewas 54.3%, with considerable geographic differences. Lower prevalence rates were noted in the northeast of the country (30% to 40%) than in the southwest or northwest (55% to 65%). Differences also were noted depending on the country of origin: France, 55%; other European countries, 46%; North Africa, 51%; and south Saharan Africa, 40%. A high prevalence (64%) was observed among women practicing, or whose husbands practiced, a “learned profession.” In the Paris area, the seroprevalence had decreased from more than 80% in the 1960s to 72% in the 1970s. It was still higher than 65% in 1995. In Liege,

Belgium, T h o u m ~ i n ~reported ’~ that the seroprevalence decreased from 70% between 1966 and 1975, to 62% between 1976 and 1981, and to 47% between 1982 and 1987. In Norway, Jenum and colleagues345reported a prevalence of 10.9%, ranging from 13% in the southeastern part of the country and in Oslo to 6.7% in the north. These rates observed from 1992 to 1994 are similar to those reported in the mid- 1970s. Cultural habits with regard to food probably are the major cause of the differences in frequency of i? gondii infection from one country to another, from one region to another in the same country, and from one ethnic group to another in the same region. The data just described all reveal a decrease in the prevalence rate of T. gondii antibodies in the United States and in Europe during the past 3 decades. This decrease is more striking in countries that had a high prevalence than in those in which it was low. Because meat probably is the main vector of infection in most developed countries, it seems logical to relate this decrease to a less frequent presence of T. gondii in meat, which probably results from improved methods in the way the animals are raised and in the processing of meat.380’38’ Data from one city or single population within that city may not accurately reflect the true prevalence or incidence of infection either in that city or elsewhere. The prevalence of the infection has decreased dramatically in the past 20 years or so but not necessarily in subpopulations, such as Los Angeles Hispanics, Floridians (Haitians), and Salvadorians. What are the prevalence and incidence of congenital toxoplasmosis (and T. gondii infection) in the United States? We have no objective data to answer this question. It should be emphasized that the lack of systematic serologic screening of pregnant women in the United States for acute acquired i? gondii infections severely limits our ability to accurately assess the incidence of ‘ I gondii infection among pregnant women in different populations and of congenital T. gondii infection.

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Table 31-16

Protozoan, Helminth, and FungalInfections

Prevalence of Toxoplasma Antibodies among Pregnant Women of Childbearing Age from Various Geographic Locales, Worldwide

Locale Central African Republic Gabon, Africa Senegal, Africa Tanzania, Africa Togo, tropical Africa Tunis, Africa Zambia, Africa Buenos Aires, Argentina Buenos Aires Province, Argentina Melbourne, Australia Western Australia Vienna, Austria Bangladesh Brussels, Belgium Belgium Cotonou, Republic of Benin Yadunde. Cameroon Santiago, Chile Chengdu, China Lanzhou, China Taiwan, China Quindio, Colombia Pointe-Noire, Congo Copenhagen, Denmark Denmark Egypt (rural area) Eastern England Ethiopia Southern Finland Strasbourg, France Franceville (Gabon) La Guadeloupe, French West lndies Lower Saxony, Germany Berlin, Germany Greifswald, Germany (northeast) Wiirzburg, Germany Germany Athens, Greece Patras, Greece Crete, Greece Guatemala Szeged, Hungary India Jakarta, Indonesia Central Italy Urmia, Iran Hyogo Prefecture, Japan Kuwait Kuwait (urban) Islamic Republic of Mauritania Casablanca, Morocco Nepal Tilburg, The Netherlands Papua New Guinea Benue River Basin Area, Nigeria Ib adan, Nigeria Niger Delta, Nigeria Nigeria Norway Panama City, Panama Zakopane, Poland Lisbon, Portugal Santo Doming0 Riyadh, Saudi Arabia Western Scotland Central Scotland and Midland England Ljubljana, Slovenia Barcelona, Spain

Reference No. 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 31 1 312 313 314 315 1170 317 318 319 214 320 1171 322 323 324 325 326 327 328 368 329 371 330 33 1 332 333 334 375 335 1172 372 337 338 339 340 34 1 342 343 344 342 345 346 347 348 349 3 50 351 352 353 354

% Positive

81 60 4.2 48.5 -50 46.5 23 58.9 53.4 4 35 36.7 38.5 56 46 53.6 77 59 39 7.3 9 60 43 28.7 27 43 7.7 >75 20 36 71.2 -60 46 54 68 41.6 36 24 52 29.5 -45 69 45 14 49 32.8 6 58 45.7 -22 51 54.8 -40 18 43.7 78 -60 43.7 10.9 -63 36 64 47 30 13 15 34 50

Chapter 3 1

Toxoplasmosis

969

Table 31-1 6 Prevalence of Toxoplasma Antibodies among Pregnant Women of Childbearing Age from Various Geoaraphic Locales, Worldwidront‘d Locale Barcelona, Spain Malmo, Sweden South Sweden Stockholm, Sweden Basal, Switzerland Geneva, Switzerland Switzerland Dar Es Salaam, Tanzania Chiang Mai, Thailand Bangkok, Thailand Bangkok, Thailand Turkey United Arab Emirates United States Eastern Tennessee Timok Region, eastern Yugoslavia Slovenia, Yugoslavia Slovenia, Yugoslavia

Table 31-17

Prevalence of Toxoplasma Antibodies among Pregnant Women and Nonpregnant Women of Childbearing Age from Various Geographic Locales in the United States

Locale Palo Alto, California Birmingham, Alabama Chicago, Illinois Massachusetts Denver, Colorado Los Angeles, California Houston, Texas New Hampshire

% Positive

1oa 30b 12( 14d 3.3e 30’ 129 13h

aJS Remington, unpublished data, 2004. bFrom Hunter, 1983.39’ CPersonalcommunication from Dr. Rima McLeod, 1987. dPersonal communication from Dr. Roger Eaton, 1998. ePersonalcommunication from Dr. Douglas Hershey, 1986 ‘Personal communication from Dr. Andrea Kovacs, 1993. gPersonal communication from Dr. Fred Bakht, 1993. hPersonal communication from Dr. Roger Eaton, 1998.

Numerous variables influence whether congenital transmission will occur. Many of these factors are recognized but poorly understood. They include the strain and virulence of 2: gondii, inoculum size, route of infection, time during gestation, and immunocompetence of the pregnant woman. All of these also pertain to infection of the fetus and its outcome in the newborn thereafter.

Incidence of Acquired Infection during Pregnancy Estimates from Prevalence Rates: Mathematical Epidemiologic Models Once seroconversion occurs, IgG antibodies essentially persist for the life of the affected person. Thus, the prevalence

Reference No.

% Positive

376 355 1173 1173 356 357 3 58 3 59 360 361 362 354a. 363 364 1174 369 365 366,367 374

25.3 40 25.7 14 53 42 46.9 35 3 13 14 65 22.9 15 11 46 -50 34

of antibodies increases with increasing age and the proportion of uninfected persons decreases. If the hypothesis is accepted that the risk of acquiring 7: gondii infection from the environment is the same at any age, and if this yearly seroconversion rate is known, the prevalence of antibodies in relation to age and the proportion of seronegative persons in this population at a given age can be computed easily.387 Consider as an example a population of infants 1 year of age who are not infected and thus are seronegative: If their risk of acquiring i? gondii infection is 10% per year, that is, for a yearly seroconversion rate of lo%, the probability that these infants will still be free of infection (seronegative) is 0.9 at 2 years of age, 0.81 at 3 years of age, 0.729 at 4 years of age, and so on. At age 20, the prevalence of antibodies will be 86.5%, and the proportion of seronegative persons will be 13.5%. The curves shown in Figure 31-4 depict the theoretical antibody prevalence rates, in relation to age, for a fixed yearly seroconversion rate ranging from 0.1% to 20% (representative of possible rates in various locations). The frequency of acquisition of i? gondii infection at a given age (the incidence of T. gondii infection at that age) is dependent on both the proportion of the population that is seronegative at that age and on the rate of seroconversion. In the example just given, in a population with a 10% yearly seroconversion rate from the age of 1year, the incidence of acquired infection between 20 and 21 years of age will be 10% of 135.%h -tat is, 13.5 per 1000. The balance between the prevalence of immunity due to past infection and the risk of acquiring infection can result in apparently paradoxical findings when one examines the incidence of infection in the young adult. For example, in a population with a yearly seroconversion rate of 5% from the age of 1 year, the prevalence of antibodies will be 62% at age 20 and the incidence of infection between ages 20 and 2 1 will be 18.9 per 1000. Thus, owing to the higher number of seronegatives,a lower constant risk of infection-5Yo instead of 10% per year-results in a higher frequency of infection acquired by the young adult. Taking into account the number of pregnancies by age group, and the age distribution of pregnant women in France, Papoz and c o - ~ o r k e r sset ~ ~up * a mathematical epidemiologic

970

Section IV

Protozoan, Helminth, and Fungal Infections 20%

100

71%

10%

at least temporarily more than outweigh the influence of the falling infection rates, resulting in a higher number of infected pregnant women. This important conclusion is used in the following discussion.

90

Estimates from Prospective Studies of Acquired Infection during Pregnancy and Consequences of Health Education

80

Lo w

TOXOPLASMOSIS INCIDENCE RATES AND RISK TO FETUS

$ if60

i5

50

Y40

5

3 3 30 V 20 10

10

20

30 40 &E IN YEARS

50

60

70

Figure 3 1 4 Incidence rates in mother and risk to fetus. (Data from Frenkel JK. Toxoplasma in and around us. BioScience 23:343-352,1973.)

model to determine the expected frequency of acquired infection in France. This model was applied to a survey of the prevalence of T gondii antibodies that they performed during 1982 and 1983; 7605 women from ages 14 to 44 years were tested. The prevalence of antibodies rose from 52% before the age of 20 to 83% after the age of 40 years and averaged 63.5%. The yearly seroconversion rate calculated for each of the 1-year age groups ranged from 2.7% to 5.1%; the average rate was 3.69%. The authors calculated that in the absence of intervention during pregnancy, the incidence of infection during pregnancy should be 10.6 per 1000 pregnancies. This rate is close to the highest possible rate during pregnancy in those epidemiologic conditions. These estimations of the frequency of acquired toxoplasmosis during pregnancy calculated from the increase in prevalence of antibodies with increasing age are based on the hypothesis that the risk of infection has been constant over time. As discussed earlier, however, clear evidence indicates that the prevalence of antibodies among pregnant women has decreased over the past decades in France, as well as in other countries. This finding suggests a decrease in the risk of acquiring infection and, thus, in seroconversion rates. Larsen and L e b e ~ h published ~'~ a modified mathematical epidemiologic model for prediction of the frequency of 'I: gondii infection during pregnancy in situations of changing infection rates. They concluded that in countries in transition from high to low infection rates, it is likely that the influence of decreasing immunity of the population will

During the early 1950s, congenital toxoplasmosis was recognized as a frequent cause of severe neonatal disease in France, 113,384 and the feasibility of screening pregnant women for acquired infection during pregnancy was investigated. During the first survey performed in Paris at Pinard and Baudelocque Hospitals, sera obtained from pregnant women at first prenatal visit (i.e., at the end of the second month of gestation) were stored frozen. After delivery, these sera were examined in parallel with cord sera. Of the 2228 pregnant women studied, 1872 had a positive dye test result at the beginning of pregnancy, for a prevalence of 84%; 356 (16%) were seronegative at first prenatal examination. Seroconversion from a negative to a positive dye test result was observed in 1 1 women, for an incidence of 11 of 356 (3%) among seronegative women. Because the mean time elapsed between the first prenatal examination and delivery was 6 months, the yearly seroconversion rate was estimated to be 60 per 1000. With reference to the entire group of 2228 pregnant women, both seronegative and seropositive, the incidence of seroconversion was 11 of 2228 (0.49%). Because these women were observed for a period of 6 months and because the duration of pregnancy is 9 months, this corresponds to an incidence rate of 7.3 per 1000 pregnancies. (These different means of expressing the frequency of ?: gondii infection during pregnancy frequently result in misunderstandings in comparing data reported by different investigators.) The high prevalence of antibodies in the population of women of childbearing age in the Paris area suggested that a simple program for screening 'I: gondii infection during pregnancy was possible. From 1961 to 1970,women in their second month of gestation who attended the Centres Prenataw of the Caisse &Assurance Maladie were tested for ?: gondii antibodies. Those with a negative dye test result were examined again at month 7 and again at the time of delivery. The examinations were timed to allow identification of women who seroconverted so that appropriate treatment could be given and to permit evaluation of their newborns specifically for the presence of 7: gondii infection at birth. In the 2493 seronegative women who were repeatedly tested during pregnancy, 73 seroconversions were observed. Because the mean time elapsed between the first and last serum sampling was 5Y' months, the yearly seroconversion rate was 64 per 1000. During the years of the study, the prevalence of dye test antibodies was observed to be decreasing among the study population of women: The prevalence was 83.5% in 1961 and 72% in 1970 (M.E Seror and J.J. Hazemann, personal communication to G Desmonts). Thus, according to the mathematical epidemiologic model set up by Larsen and L e b e ~ h , ~the ' ~ incidence of 7: gondii infection acquired during pregnancy probably was rising. Serologic screening for ?:gondii infection during pregnancy became common practice in France and in several European countries during those years. It also should be noted that the life cycle of the parasite was elucidated in the years 1970 to

Chapter 3 1 1971, so that it became possible to instruct women about the mode of transmission of T. gondii and how they could avoid becoming infected. Whereas this health education was carefully attempted in some obstetric centers, no attempt at education was made in others. Table 31-14 shows the yearly conversion rates observed before 1970 and those observed after 1970 in three obstetric centers located in the Paris area. The sera all were tested in a single laboratory (G Desmonts). In one center (Hospital X), little or no information was provided on how seronegative women might avoid infection. The observed seroconversion rate was 59 per 1000, a rate that was essentially identical to the values observed before 1970 (60 or 64 per 1000). The seroconversion rate was significantlylower when health education was attempted, especially when explanatory drawings were provided to seronegative women. Thoumsin and colleagues reported a summary of 22 years of screening for T. gondii infection during pregnancy in Liege, Belgium.379 From 1966 to 1987, 20,901 pregnant women attending the Department of Obstetrics of the C.H.R. of Liege were screened. The numbers of seroconversions observed were 129 (6.4%) among 2027 seronegative women from 1966 to 1975 and 74 (2.8%) among 2601 women from 1976 to 1981. After 1981, prophylactic counseling was provided by a specially trained nurse to all seronegative pregnant women. From 1982 to 1987, the number of seroconversionsobserved was 48 of 3859 (1.2%). The authors do not state the mean time during which their patients were examined for possible seroconversion. If it was approximately 6 months, these data would suggest that the yearly seroconversion rate was greater than 120 per 1000 before 1975, 56 per 1000 from 1976 to 1981, and 24 per 1000 from 1982 to 1987. These values demonstrate a decrease in the risk of infection quite similar to that shown in Table 31-14. Since 1978, it has been obligatory under French law to test pregnant women for T. gondii infection acquired during gestation. The common practice is to perform a test for T. gondii antibodies at the first prenatal visit (usually at weeks 10 to 15). The result is reported to the patient; if it is negative, the laboratory that performed the test must send a letter to the woman describing hygienic measures she can practice to avoid infection with T. gondii. Serologic testing of seronegative women is repeated monthly until delivery to identify those who seroconvert. If the test performed at the first prenatal visit is suggestive of a recently acquired infection, an avidity assay should be performed. In some instances, a second sample of serum is obtained to attempt to determine whether the infection was acquired during the first few weeks of pregnancy or earlier. One consequence of this procedure is that the surveillance for acquired T. gondii infection now encompasses the entire pregnancy, including the first 10 weeks and not solely the last 30 weeks of gestation, as was the case during the first surveys performed in France (discussed earlier). Jeannel and associates385reported the results of a survey performed in the Paris area between 1981 and 1983. The prevalence of T. gondii antibodies was estimated to be 67.3%. Among 2216 pregnant women at risk, the rate of seroconversion was 1.6% per 9 months of pregnancy, which corresponds to a yearly seroconversion rate equal to 21 per 1000. A national inquiry regarding the present status of T. gondii infection during pregnancy in France was set up by

Toxoplasmosis

971

the Reseau National de la Sante Publique in 1995.378The medical data for each of the 13,459 women whose delivery occurred in France during the first week of February 1995 were analyzed. The overall prevalence of T. gondii antibodies was 54.3%. T gondii infection was acquired during pregnancy by 89 women, representing an incidence of 6.6 per 1000 pregnancies. If the incidence was reported in only those women who were seronegativeat the beginning of pregnancy, the percentage was 1.48%. This corresponds approximately to a yearly seroconversion rate of 19 per 1000, essentially the same as it was 20 years earlier among patients who received health education (see Table 31-14) and the same as the rate observed by Jeannel and associates between 1981 and 1983. The incidence among primiparous women was twice that of multiparous women. This finding suggests that women who knew they were seronegative because they had been repeatedly tested for infection with T. gondii during a previous pregnancy tried to avoid acquiring this infection when they again became pregnant. Jenum and c o - w ~ r k e r s ’reported ~~ the results of a screening program that was conducted in Norway from 1992 to 1994. The prevalence of T. gondii infection in Norway is very low when compared with that in France, where it is still high. All 35,940 women examined received an information folder that contained health care advice with specific precautions to be taken to prevent T gondii infection. The first sample of serum was collected at approximately the tenth gestational week and examined for T. gondii antibodies. Retesting was requested for seronegative women at approximately weeks 22 and 38 of gestation. Tests for evidence of acute infection also were performed on the serum sample obtained during the tenth week to identify infections that had occurred during the first 10 weeks of pregnancy. Hence, the model of the survey was planned to encompass the first 38 weeks of gestation. The average time during which women remained under observation for the study was, in fact, 34 weeks. The prevalence of antibodies due to infection acquired before pregnancy was 10.9%. Among 32,033 seronegative women, 47 (0.147%) fulfilled the criteria for acquired infection during pregnancy. The seroconversion rate calculated for 40 weeks of pregnancy was 0.173%. This percentage corresponds to a yearly seroconversion rate of 2.3 per 1000. Jenum and co-workers observed a higher number of seroconversions during the first trimester of pregnancy (0.287% per 40 weeks, which is a yearly seroconversion rate equal to 3.8 per 1000) than during the second and third trimesters. They suggest that this difference might be related to the health education advice given at the first prenatal visit. The differences in the frequency of T. gondii infection from one country to another can be illustrated by the differences in the incidence rates as well as in the prevalence rates. As an example, the yearly seroconversion rates calculated from the data from Norway’32are nearly eight times lower than those calculated from the data obtained in 1995 in France,378and the antibody prevalence rate at the age of pregnancy is five times lower in Norway than it is in France. In the Paris area, the yearly seroconversion rate observed during pregnancy was approximately 60 per 1000 during the late 1950s and early 1960s, and it was about 19 per 1000 in 1995. This lower seroconversion rate was observed as early as 1974, however, when instruction became available

972

Section IV


to pregnant women on how they could avoid becoming infected (see Table 3 1-14)?86As judged by the results of more recent s t ~ d i e s ~ ’ *no~ ’significant ~~ decrease in seroconversion rates occurred between 1974 and 1995. The decrease from approximately 60 per 1000 to approximately 20 per 1000 occurred during the early 1970s. In considering the incidence rates, that is, the frequency of seroconversions in the total population of pregnant women (seropositive as well as seronegative), no significant difference is found between the incidence rates observed in the late 1950s and in 1995; the incidence rate during the first prospective study performed in Paris before 1960 was 7.3 per 1000 pre nancies. The incidence reported by Ancelle and in 1996 was 6.6 (k 1.4) per 1000 pregnancies. In this epidemiologic situation, that is, in a country in transition from a very high to a lower infection rate, the influence of decreasing immunity in the population should have outweighed the influence of the falling infection rate, resulting in a higher number of women who acquired the infection during gestation (despite the decreasing risk of acquiring the infection in the general p~pulation).’~~ This effect was not observed, and the most likely reason is that health care education of pregnant women reduced the risk of acquiring T. gondii infection during pregnancy. The seroconversion rates observed during these relatively recent surveys from France and from Norway can be used to calculate an expected prevalence rate according to the methods discussed earlier?82,3833387 This calculated “expected” prevalence rate is lower than the observed prevalence rates in both surveys. This finding suggests that the risk of becoming infected with T. gondii is lower among pregnant women than in nonpregnant women, perhaps also the result of health care education provided at the first prenatal visit. Thus, the timing of providing pregnant women with the appropriate information on prevention of infection with ‘I:gondii at the first prenatal visit probably skews results of prospective studies of acquired T. gondii infection during pregnancy by selectively reducing the frequency of infection acquired during the second half of pregnancy.

Prevalence of Congenital Toxoplasrna gondii Infection lndirect Estimates from lncidence Rates of Maternal Toxoplasmagondii Infection The prevalence of congenital ‘I: gondi? infection can be estimated from the incidence rate of T. gondii infection acquired during pregnancy by multiplying the figure for the number of mothers who acquire infection during pregnancy by the transmission rate of the parasite to the fetus. For example, according to Frenkel (see Fig. 31-4), if the yearly seroconversion rate in a population is 30 per 1000, the rate of neonatal T. gondii infection will be 4.6 per 1000 births. From the epidemiologic model derived from a survey performed in France in 1982 to 1983, Papoz and colleagues382 calculated that the risk of neonatal T. gondii infection to be 6.4 per 1000 births. A more recent study of the age-specific prevalence of T. gondii antibodies in the United States used data and sera from the third National Health and Nutrition Examination and Survey (NHANES 111,1989 to 1994,N = 17,658).388The

investigators modeled the incidence of acute infection in pregnant women using the declining prevalence from the study in military recruits and the age-specific prevalence from the NHANES I11 study. They estimate that the incidence among seronegative women is 0.27% during pregnancy in the United States. With a birth cohort of 4 million and an estimated overall transmission rate of 33%, approximately 3500 children are expected to be born with congenital toxoplasmosis each year in the United States. This rate should vary by geographic region and may be declining if the trend demonstrated in the military recruit study is continuing (J McAuley, personal communication to JS Remington, 1998). Unfortunately, at present, objective data are lacking on the prevalence of congenital T. gondii infection or congenital toxoplasmosis for the United States. Because screening of pregnant women in the United States is not systematic, our ability to accurately assess the incidence of T. gondii infection among pregnant women in different populations and of congenital T. gondii infection is limited. Data from one city or single population within that city may not accurately reflect the true prevalence or incidence of infection either in that city or elsewhere. Although the prevalence of the infection has decreased in some areas of the United States during the past 20 years or so, this is not necessarily the case in subpopulations even in those same areas.

Direct Estimates from Studies at Birth or during lnfancy Estimates from Clinical Informationor from Findings at Autopsy. Estimates from clinical observations and from autopsy findings are based on data derived mainly from older s t ~ d i e s , ~which ’ ~ ~ ’ underestimated ~~ the actual prevalence, because congenital infection uncommonly results in stillbirth or neonatal death and frequently is not diagnosed during infancy because of subclinical infection in the infant and delayed occurrence of signs of infection.389s390 Estimates from Serologic Screening of Neonates or Infants.One of the first studies that relied on determination of total IgM levels in cord blood, followed by serologic testing of infants who had elevated levels, was performed at the University of Alabama.391As stressed by the investigators, such studies result in an underestimate of the true incidence of the infection and the disease, because infants with congenital infection may not have an increase in total IgM in their cord blood or demonstrable IgM T. gondii antibodies. This survey revealed what has proved to be a historical trend toward a decrease in prevalence of congenital T. gondii infection in Alabama; the observed rate was 2 per 1000 during the first year of the study and 0.6 per 1000 during the last year. Although different methods were used in a later study by this same group, the observed rate for the later study was approximately 0.1 per 1000 births.391 The Commonwealth of Massachusetts began screening newborn sera in January 1986 to determine the incidence of congenital ?: gondii infection. Blood specimens are collected on filter paper and utilized to test for IgM antibodies by the sensitive IgM enzyme-linked immunosorbent assay (ELISA). From 1986 to 1998, 99 infants were detected who had IgM T. gondii antibodies, reflecting an incidence of approximately 1 in 10,000 births (R Eaton, personal communication to JS Remington, 1998).Although a careful follow-up evaluation

Chapter 3 1 was not performed for all seronegative infants, it is known that the diagnosis was missed in at least six infants in whom IgM antibodies were not detected but who were referred by local physicians. In one of these later-diagnosed children, 1: gondii was isolated from cerebrospinal fluid; the infection was suspected on clinical grounds in this child, who was born prematurely with hydrocephalus, cerebral calcifications, and bilateral chorioretinitis. Thus, this reported incidence is lower than the actual incidence despite the sensitivity of the method used to detect IgM antibodies of ?: gondii. Nevertheless, if as many as 50% of cases were missed (which is unlikely) with the methodology used by the New England Regional Screening Program, an incidence of 1 per 10,000 births is strikingly different from the incidence of 1.3 per 1000 reported by Kimball and co-workers in 1971 from a prospective screening study of pregnant women in New York City.’” With the discovery of the importance of detecting IgA and IgE antibodies (see “Diagnosis”section) in the newborn, serologic studies of newborns such as those being performed in Massachusetts should detect a higher percentage of infected infants. The Danish Congenital Toxoplasmosis Study Group has published results of their feasibility study of neonatal screening for T. gondii infection in the absence of prenatal treatment.392The focus of their study was different from that of the Massachusetts group in that they sought to determine the prevalence of the infection among live neonates and the maternofetal transmission rate in infected mothers who had received no treatment. Secondarily,they assessed the feasibility and acceptability of neonatal screening using T. gondii IgM antibody testing on samples from phenylketonuria (PKU) cards. They reported a surprisingly low transmission rate of 19.4%. The researchers state that a neonatal screeningprogram based on detection of IgM T. gondii antibodies alone identifies between 70% and 80% of cases of congenital toxoplasmosis, but not all pregnancies and infants in their study were thoroughly evaluated, thus making the data difficult to evaluate. Although this detection rate is certainly preferable to no screening, the possible occurrence of significant numbers of false-negative reactions is disturbing. Yet Lebech and his colleagues stated that their IgM method with PKU cards could be used in large-scale newborn screening for congenital T. gondii infection. It is hoped that improved technology will be developed to reduce the numbers of infected infants who will go undetected with use of presently available methods.393The group in Massachusetts uses a special IgM method that is designed to be highly sensitive, attempting to thereby lessen the likelihood of false-negative results. No data are provided in the publication of the Danish group on sensitivity or specificity, or of the Boston Group on sensitivity, of their IgM antibody method in newborns. Denmark began screening of all newborns rather than pregnant women beginning in 1999 (E Petersen, personal communication to JS R e m i r ~ g t o n ) . ~ ~ ’ ~ ~ ~ ~ Even if the prevalence of congenital infection is underestimated, however, the present data (at least from Alabama and Massachusetts) strongly suggest that the rate has significantly decreased during the last 2 decades in the United States. This decrease in the prevalence rate of congenital T. gondii infection parallels the historical decrease in antibody prevalence rate observed in the adult. This would be expected from the epidemiologic models discussed earlier; in a popu-

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lation in which the seroprevalence rate was rather low (well below 50% in the adult, as it is in the United States), a decrease in the risk of acquiring infection immediately results in a decrease in the incidence of acquired infection in women in the childbearing age group. An attempt to define the prevalence of congenital 7: gondii infection in infants in the Paris area was made in a cooperative study with the Centre de Bilans de Santk de la Caisse Primaire &Assurance Maladie de Paris.395 An opportunity arose to perform serologic tests because infants at 10 months of age underwent a general health examination. From 1970 to 1980,26,402 infants were examined. T. gondii antibodies were present in the serum of 295 (l.l%), and all had high titers in the dye test. Of the mothers, 51 had high dye test titers, suggesting that the infection present in the infant was congenital in origin. Two-hundred ten mothers had either a negative or a low dye test titer, suggesting that their infection had been acquired long before the recent pregnancy. In their infants, congenital infection was considered as excluded or unlikely; their infection was postnatally acquired. In 34 cases, it was not possible to decide between congenital or postnatally acquired infection. Thus, the incidence of acquired infection during the first 10 months of life was between 7.9 and 9.2 per 1000. The prevalence of congenital infection was between 1.9 and 3.2 per 1000. None of the infants had severe toxoplasmosis. The fact that congenital infection was asymptomatic would be expected because this cohort was recruited through general health examination of 10-month-old infants. On yearly follow-up of these children, however, chorioretinitis was present or was discovered in 12 of 54 (22%). This prevalence rate of congenital infection of approximately 2 per 1000, observed between 1970 and 1980, is three times lower than the risk (6.4 per 1000) calculated by Papoz and associates382from their epidemiologic model and the antibody prevalence survey among pregnant women that they performed in 1982 and 1983. During this decade (1970 to 1980), screening for T. gondii infection during pregnancy was becoming a common practice in France, and information on how to avoid acquiring the infection was provided to seronegative women. We believe that health education might have been responsible for this difference between the expected risk calculated by Papoz and associates and the lower prevalence rate that was observed.

Effects of Systematic Screening of Pregnant Women at Risk on the Prevalence of Congenital Toxoplasma gondii Infection and of Congenital Toxoplasmosis The purpose of the first attempts at systematic serologic screening was to identify pregnant women at risk, to try to prevent congenital toxoplasmosis or, if such infection was present, to allow for early instigation of treatment. Once the life cycle of the parasite was elucidated, primary preventive measures were possible through education of seronegative women (see “Prevention” section and Table 31-62). This is now currently done in several European countries and has proved moderately effective, as judged by the data discussed earlier; acquired T. gondii infection during pregnancy apparently is three times less frequent in France than it would be were no information provided to seronegative

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pregnant women in regard to the sources of infection and how they may reduce their risk of acquiring the infection. This estimation is very close to the conclusions of Foulon and who calculated that in Brussels, Belgium, primary preventive measures reduced the seroconversion rates during pregnancy by 63%. Even better results are possible, however. One critical point is the time at which this education is provided. In most cases, this intervention occurs during the first prenatal visit, at approximately the tenth week of pregnancy. This timing does not reduce the number of infections acquired during the first 10 weeks of gestation or the number of seroconversions that occur within 2 weeks after the first prenatal visit, because women whose seroconversion occurs at this time probably were in the initial stage of the infection (during which parasitemia occurs before antibodies become detectable in the serum) at the time they received the instruction. Thus, the results of such an education program can only be a reduction in the number of infections that occur later during pregnancy. Because late acquired infections are those for which the rate of congenital transmission is the highest (resulting primarily in subclinical cases), it is understandable that in addition to a lower number of infections acquired during gestation, health education, if provided at first prenatal visit at about the tenth week of pregnancy, should result in a lower rate of transmission than observed in the previous surveys performed before the means by which ?: gondii is horizontally transmitted to humans was known. In addition, the proportion of infected fetuses with the more severe form of congenital toxoplasmosis might be higher unless treatment during gestation is effective in the infected fetus. Screening for T. gondii infection during pregnancy is now a common practice in several European countries. After surveys performed in Austria in the 1950s and 1960s, a national program was introduced in 1975 that required serologic examination of every pregnant woman for T. gondii infection. In cases with suspected primary infection acquired during pregnancy, the woman receives immediate treatment. From 1975 through 1998, no cases of congenital toxoplasmosis were registered in women who had been tested and (in instances of recent infection) given treatment in accordance with the regulations. Moreover, no recommendations for induced abortion had to be given, and no serious side effects of treatment were observed. The incidence of congenital T gondii infection in Austria is now 1 to 2 cases per 10,000 newborns, compared with the incidence of 20 to 35 per 10,000 that would be expected without the screening and its consequences ( H Aspock, personal communication to JS Remington, 1998).304s396 In France, congenital toxoplasmosis was the most frequent fetopathy in the years 1950 to 1960. For example, in this period, several cases of congenital toxoplasmosis were diagnosed each year among approximately 1000 premature infants admitted annually to l’H8pital de 1’Institut de PuCriculture de Paris. In 1957, for instance, 7 cases were diagnosed among 1085 newborns. In the same hospital, however, only two cases have been observed between 1980 and 1990. Within 40 years the pediatrician has been witness to a dramatic change in the presenting signs of the disease ( J Couvreur, written communication to JS Remington, 1998). In the past, patients were referred to the specialized toxoplasmosis clinic in Paris because they had clinical symptoms or often severe

signs that suggested congenital toxoplasmosis. For instance, in a group of 147 neonates or infants with congenital T gondii infection studied between 1949 and 1960,62.5% had signs of central nervous system (CNS) involvement (with hydrocephalus in two thirds of the patients), and 32.5% had retinochoroiditis without clinical evidence of CNS involvement. Despite their being asymptomatic, most patients now attend the specialized clinic because they are suspected of having, or are diagnosed as having, congenital T gondii infection. Congenital T gondii infection is subclinical and remains subclinical in a majority of them. For example, congenital infection remained subclinical in 166 of 234 infants (71%) observed between 1984 and 1992. In this group, 60 of 234 (26%) had a retinal scar but no CNS involvement; CNS involvement with or without hydrocephaluswas present in 8 of 234 (3%) of these infants. At present, severe neurologic or ocular involvement, or both, is observed only among infants born to women in the following patient groups: patients referred from foreign countries where screening is not performed during pregnancy (e.g., Morocco, Algeria, United Kingdom), mothers who for any reason were not screened during pregnancy, mothers who were immunodeficient, and mothers who were erroneously considered to be immune. With these exceptions, in which the clinical status may be considered abnormal (see “Chronic Maternal Toxoplasrna Infection”), prenatal screening for maternal ‘I:gondii infection during pregnancy has proved effective as a preventive measure for congenital toxoplasmosis in France (see Table 31-6). Testing for anti-T. gondii antibodies in Italy is free. Testing takes place before conception and in the first trimester and is repeated monthly for pregnant women who so desire. This program was initiated in 1998. In a study of this screening program by Mombro and c o - ~ o r k e r s 60 , ~ ~mothers ~ seroconverted or had probable acute acquired infection during gestation. No congenitally infected infants were born to women identified with seroconversion or probable acute acquired infection in their first trimester. Thirteen (21%) infected infants were born to mothers who seroconverted, and 2 (40/0) infected infants were born to mothers with probable infections acquired during gestation. Transmission rates were 5 of 29 seroconverters (17%) and 2 of 12 (17%) with probable infection in the second trimester; 8 of 23 pregnant women (35%) acquired their infection in the third trimester.397

PATHOGENESIS

Factors Operative during Initial Infection Virulence of Toxoplasma gondii An isoenzyme analysis of T gondii isolates demonstrated

that certain patterns correlated with virulence of tachyzoites for mice.398Similar results have been obtained by restriction fragment length polymorphism (RFLP) analysis.399Population genetic analysis revealed three predominant lineages designated strain types I, 11, and III.400v401 A majority of human cases of toxoplasmosis (both postnatally acquired and congenital) are due to type I1401s402; 10% to 25% are due to type I. It is likely that virulence, as well as inoculum size and the genetic background of the infected person, influences transmission and severity of congenital toxoplasmosis.

Chapter 3 1 In a study by Ajzenberg and associates403of clonal type of isolates of T. gondii in France between 1987 and 2001, almost all (85% in the whole series, and 96% in 57 consecutive isolates from a laboratory in Limoges and a laboratory in Paris) of 86 congenitally infected children had clonal type I1 parasites. Type I and atypical isolates were not found in cases of asymptomatic or mild congenital toxoplasmosis. Three isolates with atypical genotypes, which were virulent in mice, were associated with severe congenital infection. In four cases, T. gondii was isolated only from placenta, the infant was not infected, and all four were of clonal type I. Type I1 isolates occurred in persons with different levels of severity of their signs and symptoms. The main factor influencing severity was reported to be time of acquisition of the infection during gestation. This finding contrasts with that in a small series from Spain (where serologic screening during gestation is not the standard of care, as it is in France) in which all isolates were of clonal type I.404 reported In a preliminary study, Grigg and that very severe eye disease in adults was associated with infection with type I or recombinant clonal types of parasites. These results are reminiscent of the findings reported by Ajzenberg and colleag~es,4~~ who noted severe disease in congenitally infected children with parasites with atypical genotypes. By contrast, in a guinea pig model studied by Flori and associate^,^^ the highest levels of parasitemia and highest rates of transmission, neonatal death, and pathology (e.g., hepatitis) were associated with clonal type I1 infecti0ns.8~ In the future, data concerning relationship of clonal type to frequency of transmission of congenital ?: gondii infection or severity of illness in those infected will be of interest. In a separate study by Romand, clonal type of parasites was not included in their analysis. Nonetheless, the highest amounts of parasite DNA detected in amniotic fluid by PCR assay were associated with the most severe disease in the newborn and most often were related to time in gestation when the infection was acquired (as discussed in “Polymerase Chain Reaction Assay” under “Diagnosis”). It is unclear at present whether any relationship exists between a specific clonal type(s) and either transmission or severity of the infection in the newborn or progression of disease in the congenitally infected infant. suggest A recent report and accompanying that the amount of genetic variability in the three predominant clonal types (I, 11, and 111) indicates that they are derived from a single recombination (cross) of two ancestral strains.4023407 The authors of this report estimated that the recombination occurred at the time during which humans began to use domesticated livestock for and was associated with the acquisition of direct oral infectivity (i.e., ability of bradyzoite to be infectious when ingested). The three strains, which are clonal and show little genetic variation, have only one of two possible alleles for genes at many different loci. From the alleles present in the three strains, the genotype of the diploid ancestor can be inferred. In Brazil, clonal type ID11 recombinant parasites have been identified that appear to have different biologic behavior in mice and cause far more prominent eye infections in older children and ad~lts.4’~ Sixty percent of Brazilian children younger than 10 years of age in Minas Gerais state have serologic evidence of Eighty percent of adults are seropositive, and 20% of these

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have recurrent eye di~ease.~” Fifty percent of adults older than 60 years have eye disease. Whether the manifestations of congenital toxoplasmosis within these populations will differ remains to be determined. The incidence of overt congenital toxoplasmosis in Siio Paulo appears to be relatively high; for example, between 2001 and 2004, one physician in a children’s hospital cared for 31 newborn infants (24 symptomatic) with congenital toxoplasmosis diagnosed by serologic testing or PCR assay (E Diniz, personal communication to R McLeod, 2004). In Guyana, ancient clonal types of T. gondii have been lethal,403but whether differences in congenital infections exist with such unusual clonal types of the parasite is not known. Role of Cells and Antibody After local invasion (usually in the intestines), the organisms invade cells directly or are phagocytosed. They multiply intracellularly, causing host cell disruption, and then invade contiguous cells. Whereas human monocytes and neutrophils kill the vast majority of ingested T. gondii organisms, tachyzoites survive within macrophages derived in vitro from peripheral blood m o n o c y t e ~ . Data ~ ~ ~have - ~ ~ shown ~ that human peritoneal and alveolar macrophages kill T. g ~ n d i i . ~Cytotoxic ’~ T lymphocyte-mediated lysis of T. gondii-infected target cells did not lead to death of the intracellular parasites, however, indicating that intracellular T. gondii remains alive after lysis of host cells by cytolytic T cell^:'^,^'^ The presence of persistent parasitemia observed in humans’” and animal^'^,^'^ can best be explained by the existence of intracellular parasites in the circulation. T. gondii invades every organ and tissue of the human host except non-nucleated red blood cells, although evidence indicates that invasion of these cells may occur as Termination of continued tissue destruction by T. gondii depends both on the development of cell-mediated immunity and on antibodies. Continued destruction may occur in those sites where ready access to circulating antibody is impeded (e.g., CNS, eye). Despite the ability of antibody in the presence of complement to kill extracellular T. gondii effectively in vitro, the intracellular habitat of this protozoon protects it from the effects of circulating antibody. Cyst formation can be demonstrated as early as the eighth day of experimental infection.56 Cysts persist in multiple organs and tissues after immunity is acquired, probably for the life of the host. The barrier to passive diffusion of antibodies into brain and eye has been given as an explanation of the continued proliferation of the parasite in these sites at the same time at which it is disappearing from extraneural This barrier also has been employed as an explanation of what has been interpreted as a greater latent infection of the CNS than of extraneural tissues. Nevertheless, cysts may persist and may be abundant in tissues where antibody is not opposed by such a barrier (e.g., cardiac and skeletal muscle).420 The ability of the pregnant woman to control multiplication and spread of T. gondii depends not only on specific antibody synthesis but also on the time of appearance of cell-mediated immunity. In addition to the immunosuppression associated with pregnancy itself, cell-mediated immunity, at least as measured by antigen-specific lymphocyte transformation, may not be demonstrable for weeks or even

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months after acute infection with T. gondii in human^.^^'.^^^ Although the importance of cellular immunity in the control of the initial acute infection in humans has not been defined, it is likely, from what is known about the immunology of toxoplasmosis in animal models29-30and studies with human immune cells,423-426 that cell-mediated immunity plays a major role. The helper T cell type 2 (T,2) bias (toward humoral immunity and away from cellular immunity) established during normal gestation may compromise successful immunity against T gondii, which requires a strong TH1response. In addition, it has been proposed that a strong T,1 response against T. gondii may overcome the protective TH2cytokines at the maternal-fetal interface and result in fetal l 0 s s . 4 ~ ’For ~ ~ ~a~discussion of the immunoregulation of T. gondii infection and toxoplasmosis, the reader is referred to other sources.28-30~429-436 Age Evidence for the supposition that maturity is an important factor in host resistance to T gondii comes not only from experiments that have revealed remarkable resistance to T. gondii in adult rats437and chickens438when compared with newborns of those species but from observations in humans as well. The infection in the mother frequently goes unrecognized, whereas the newborn may be severely damaged, even when infection of the fetus occurs after the fifth month of gestation (when maternal antibody first becomes available to the fetus and immunoglobulin and complement synthesis can Deckert-Schliiter and co-workers established a model of congenital T. gondii encephalitis in mice following prenatal infection with the parasite.&’ Disease in the newborn mice during the first 2 weeks of life exhibited the key histopathologic features of human congenital toxoplasmic encephalitis, including foci of necrosis, intracerebral calcifications, and ventriculitis. Of importance, the findings differed significantly from the histopathologic features found in adult mice with toxoplasmic encephalitis. The immune response in the prenatally infected mice was mediated predominantly by the innate immune system, with preferential recruitment of macrophages and granulocytes to the brain. Gender That the lymphadenopathic form of toxoplasmosis is more commonly observed in females has been recognized for many ~ears.4~’ In studies in laboratory animals, Kittas and colleagues demonstrated that female mice are more likely than male mice to die from T. gondii infection and that mortality rates were increased in gonadectomized male and female mice given estrogens.4439444 Results of Alexander and his group29conclusively demonstrated that gender differences in susceptibility to T. gondii operate at the level of the innate immune response, as measured by interleukin- 12 (IL-12) and IFN-y production. Pathologic changes were more severe and the mortality rate was higher in female mice than in their male counterparts; production of the cytokines at high levels was significantly earlier in the male mice. Role of Human leukocyte Antigen Class II Genes The frequency of the human leukocyte antigen (HLA) class I1 gene DQ3 was found to be increased in infants with congenital toxoplasmosis and hydrocephalus relative to the

frequency of this gene in the U.S. population or in infants with congenital toxoplasmosis who did not have hydroc e p h a l u ~Of .~~ interest is that this unique frequency of DQ3 also was noted to be a genetic marker of susceptibility to development of toxoplasmic encephalitis in patients with AIDS.* HLA class I1 DQ genes function in transgenic mice to protect against brain parasite burden. DQ1 protects better than DQ3. This observation is consonant with the observation that the DQ3 gene is more frequent in infants with congenital toxoplasmosis with hydrocephalus than in those without hydrocephalus, and than in the U.S.p o p ~ l a t i o n . ~ ~ Reinfection Although survival from the acute stages of the initial T. gondii infection usually results in resistance to reinfection, the immunity associated with the chronic (latent) infection is only relative. Immunity to T. gondii in mice protects against but does not necessarily prevent reinfe~tion.&~-~~’ Mice immunized with one strain of T. gondii and subsequently challenged with another strain have both strains encysted in their tissues. This undoubtedly occurs in humans also, but its significance is unknown (see “Transmission”section).

Factors Operative during Latent Infection Cyst Rupture

Factors that influence tachyzoite and bradyzoite interconversion are critical to understanding the pathogenesis of recrudescent infection. Histologic evidence suggesting that cyst rupture concurs in humans has been reported.4532454 Indirect evidence in favor of cyst rupture in the normal host is suggested by the frequent development of new retinal lesions contiguous to the border of older scars and is reported in the studies by L a i n ~ o nand ~ ~van der Waaij.455In the brains of chronically infected mice, it is not unusual to find large and small cysts close together, suggesting the possibility that cyst rupture or “leakage” of bradyzoites has caused the satellite cysts. It is not clear whether the satellite cysts are the result of cyst rupture or whether they simply developed at the same time as did the larger cysts in the same area. Huldt has demonstrated fluorescence around T. gondii cysts by using the immunofluorescent antibody (IFA) meth0d.4~~ Her results suggest that antigen may “leak” from cysts. That this antigen does not excite an inflammatory response is suggested by the lack of any cellular reaction around almost all cysts observed in histologic sections of tissue from chronically infected animals. Under certain circumstances, leakage may excite an inflammatory response in which previously committed lymphocytes participate, perhaps releasing a cytokine that disrupts the cyst wall. Release of enzymes from intact or degenerating neutrophils or macrophages might also result in destruction of the cyst wall with liberation of parasites. Organisms that are intracellular and located within cysts are protected from the action of antibody and cell-mediated immunity. Changes in the host cell membrane that may occur at the time of infection might predispose the infected cell to disruption by lymphokine-activated killer or lymphocyte^.^^,^^^^^^^ Cyst rupture would lead to release of viable organisms that, if released into areas deficient in

Chapter 3 1

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of resistance against ‘I:g0ndii.4~’Hara and associates noted that V62+ y6 T cells were anergic with or without clonal expansion during the newborn period in two infants with Persistence of “Active Infection the congenital infection. Clonal expansion of V62 was not observed to be associated with T cell response downreguFrenkel has suggested that cyst rupture is responsible for lation, and no deletion of V62’ yS T cells was observed. T cell underlying persistent immunity and antibody and that the anergy was noted in the infants at the age of 1 month, and encysted form of the organism causes localized or generalized 1: gondii-specific anergy was noted at 5 months. relapse.” Another possibility is that organisms that have Cord blood of infants with congenital toxoplasmosis has resided intracellularly as terminal colonies or pseudocysts been reported to have increased numbers of CD45RO’ for months or years are released after cell destruction from T cells.471In the study by Hara and associates, most of the other causes. Such intracellular persistence, which can lead CD45RO+ T cells were y6 T cells, and these T cell levels were to recrudescence of the tachyzoite form of the parasite in not always elevated, especially in an infant with severe humans and animals, appears probable. Indirect evidence disease in the newborn period.469In their study, despite for this persistence comes from experimental observations persistent ap T cell unresponsiveness in two infants with in a number of mammalian species. Persistent parasitemia has been demonstrated not only in laboratory animals86’418’458congenital toxoplasmosis, y6 T cells became reactive to live T. gondii-infected cells and produced IFN-y after the infants but also in humans. 104~194,459In addition, a constant antigenic reached 1 year of age. The investigators postulated that stimulus has been suggested to account for the persistence of because treatment of congenital toxoplasmosis usually is T. gondii antibodies, which may remain at high titers for discontinued after 1 year without evidence of clinical years after the acute infection and at lower titers for the life relapse, the reversal of peripheral tolerance of y6 T cells may of the infected host. Antigen-specific lymphocyte proliferation contribute to the spread of ‘I: gondii after 1 year of age in has been demonstrated in persons who had acquired the congenitally infected infants in whom toxoplasmosis is infection as long ago as 19 years previously.421Another severe and in whom T cell unresponsiveness to T. gondii observation pointing to the persistence of active infection (lysate antigen) persists. during chronicity is that despite having high levels of neutralizing antibody titers, hypergammagl0bulinernia,460.~~~ McLeod and co-workers demonstrated absence of lymphocyte response to T. gondii antigens in some infants and resistance to challenge with an ordinarily lethal dose of (usually those with the most severe manifestations) with T. gondii, laboratory rats and mice chronically infected with congenital toxoplasmosis.472For almost all infants, response I: gondii can transmit the organism to their offspring transto T. gondii antigens was present by 1 year of age, when placentally (see “Transmission”~ e c t i o n ) . ~ ~ ” ~ medications had been discontinued. Their lymphocyte “ImmunologicUnresponsiveness” to Toxoplasma response often was of lesser magnitude than that of their gondii Antigens mothers or other infected adults. The mechanism or mechanisms of this absence of response and its restoration Results of studies in laboratory animals suggest that maternal by 1 year of age remain to be determined. IgG antibody may inhibit formation of antibody to T. gondii Vallochi and colleagues41oalso found diminished magnitude in the The studies revealed that significantsuppression of lymphocyte blastogenesis in patients with eye disease of the antibody response to living tachyzoites of T. gondii whom they believed to be congenitally infected, in contrast occurs when passive antibody is present even in very low with those they believed to have acute acquired infection concentrations, and that passive administration of IgG T.gondii antibody to newborn rabbits infected with ‘I:gondii with chorioretinal lesions. In an interesting study, Fatoohi and colleagues473from may significantly delay IgM T. gondii antibody formation.463 Lyon, France, determined the percentage of T cells that Although previous reports on the in vitro response of became activated on exposure to T. gondii antigen. The human T cells to ‘I:gondii did not demonstrate proliferation purpose of their investigation was to determine whether this of T cells from seronegative McLeod and cotest could be used to diagnose congenital infection. They workers described blastogenic response of lymphocytes reported that on day 7 following exposure of T cells to from uninfected persons to relatively high concentrations of soluble ‘I:gondii antigen, the percentage of T cells expressing T. gondii antigensa6 Subauste and colleagues425also have CD25, which is a marker for the IL2 receptor, increased to clearly demonstrated in vitro reactivity to ‘I:gondii of premore than 7% in 38 congenitally infected infants younger sumablyunprimed CD4’aP T cells fiom ‘I:gondii-seronegative than 1 year of age. This same increase also was observed in adults and newborns. In addition, they demonstrated that cell cultures from 48 congenitally infected children between ap T cells produce IFN-y in response to ‘I:gondii, an effector 1 and 6 years of age, 9 children older than 5 years, and 24 function that may be critical to the early immune response pregnant women. Nine of 89 uninfected infants when they to the parasite. This rapid and remarkable ap T cell response were tested initially had values of 7% or greater, but such in previously unexposed persons, the explanation for which values were not observed when these infants were re-tested. remains to be defined, may play an important role in the Information was not provided about the time during the early events of the immune response to ‘I:gondii. first year of life when cells were obtained or severity of illness The observation that T. gondii induces expansion of the or manifestations of infection in these infants. These particular V region, V62, of the y6 T cell response in acquired findings contrast with the lack of lymphocyte blastogenic i n f e ~ t i o n ~led ~ ’ ,Hara ~ ~ ~and associates to examine V62+ y6 T cell tolerance in infantswith congenital ‘I:gondii infection.469 response to ‘I: gondii lysate antigen preparations of a substantial number of the infants enrolled in the National Important in this regard is the observation by Subauste and (Chicago) Collaborative Treatment Trial (NCCTS).472 Some colleagues424that y6 T cells produce IFN-y, a major mediator antibody (e.g., brain and retina), could result in significant tissue damage. I’

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suggeststhat parasite replication and the resulting destruction of retinal tissue causes the eye disease. Support for the role of the parasite per se also comes from studies in which results of PCR assay in samples of vitreous from adults with the acute acquired infection were p o ~ i t i v e . ~ ~Studies ~ . ~ " with PCR analysis also demonstrated that parasite DNA may be detected in aqueous In one mouse model, ablation of the inflammatory mediator iNOS led to increased retinal necrosis.504In another mouse model, CD4' T cells also contributed to retinal necrosis; CD4' and CD8' T cells and antibody all reduced parasite burden. Cell-mediated immunity controls infection in the eye, but when the response is too robust, CD4' T cells also contribute to retinal d e s t r u c t i ~ n . " ~ ~ ~ ~ ~ ~ Data are not available in humans that clarify whether the pathogenesis of eye disease related to T gondii in young children is the same as or different from that in adults. It is difficult to extrapolate data directly from animal models to lmmunodepression humans. The immunologic parameters that may or may not operate in each situation constitute a major factor in deterThe immunodepression observed in mice infected with mining the severity and outcome of eye infection and disease. T gondii constitutes further evidence of the persistence of Recurrent parasitemia may provide at least one clue to active infection and the persistent immunologic effect of the the means whereby toxoplasmic chorioretinitis occurs withorganism. Strickland and c o - w o r k e r ~and ~ ~ ~Hibbs and out concurrent systemic infection. Uveitis usually develops associates475have noted that mice infected with T. gondii in persons with relatively low and stable antibody levels. have significantly depressed levels of hemagglutinins and Because spontaneous parasitemia can occur during the hemolysins after immunization with sheep red blood cells. chronic (latent) infection in humans, wandering cells conHuldt and co-workers found that neonatal infection in the taining T gondii could distribute these organisms into mouse affects both the anatomy and the function of the tissues with very low antibody levels, thereby allowing for Additional studies by Hibbs and associates invasion of susceptible cells. By contrast, the contiguity of revealed an impaired responsiveness to tetanus toxoid and old and new lesions497and the presence of parasites in areas remarkable prolongation of allograft rejection time in of retina without lesions506in eyes of congenitally infected T. gondii-infected Pregnant mice have a markedly fetuses also suggest that pathogenesis of new lesions may be decreased resistance to T gondii infecti0n.4~~ Whether similar due to cysts and factors that lead to cyst rupture. immunodepression occurs in humans in the acute congenital A substantial degree of antibody-induced tolerance or acquired infection remains to be determined. As mentioned to T. gondii has been demonstrated in experimental earlier, failure of lymphocyte recognition of T. gondii antigens animals,4623463,507 and it is probable that such tolerance also and significant functional and quantitative alterations in occurs in humans, although to what degree is unknown. It T lymphocyte subpopulations have been reported in the may be that maternal antibody-induced tolerance in the acute acquired infections in humans,42'v422,47y~48' but the newborn contributes to continued multiplication of T. gondii, mechanisms underlying these effects have not been identified. resulting in numerous cysts in the retina and other tissues. Special Problems Concerning Pathogenesis in When, in later life, cysts are for some reason recognized and the Eye destroyed or simply rupture, with release of parasites that invade and destroy new host cells, perhaps when the cytokine The plethora of data and the controversy that exists regarding milieu is altered as a result of stress or other factors, so that immunity and hypersensitivity as they pertain to toxoplasmic the immune response is less effective, clinically apparent chorioretinitis related to congenital toxoplasmosis preclude chorioretinitis occurs. The occurrence of cyst destruction in complete coverage of the subject here. The reader is referred other tissues (e.g., skeletal muscle) would not usually lead to to reviews of the relevant literature by O'Connor and colleague^^^^-^^^ and to related work in the mouse model of clinical illness. A small inflammatory focus in a large muscle mass probably would go unnoticed, whereas its occurrence congenital ocular t o ~ o p l a s r n o s i s . 4Whereas ~ ~ ~ ~ ~Frenkel ~ has in the retina could cause impaired vision, especially if macular been a proponent of the theory that toxoplasmic chorioin location. retinitis in older children and adults is a hypersensitivity Although the peak incidence of chorioretinitis related to O'Connor and colleagues concluded that congenital T. gondii infection usually is between the ages of both the acute and the recurrent forms of necrotizing 15 and 20 years, chorioretinitis may not occur until late in I gondii chorioretinitis are due to multiplication of ' adult life. Crawford described a patient in whom the first eye tachyzoites in the retina and that release of antigen into the symptoms occurred at the age of 61 years?" For the next retina of previously sensitized persons does not result in 9 years, the inflammatory activity in the posterior segment recurrence of the inflammatory response. T. gondii antigen of one eye continued relentlessly, causing pain and ultimately and antibody have been detected in ocular fluids in experiblindness. The severity of the pain necessitated enucleation. mental ocular tox~plasmosis.~~~ The rapid resolution of inflammation that occurs with antimicrobial treatment in Masses of cysts were found in the retina. In such cases, it is infants, children, and adults with congenital t o x ~ p l a s m o s i s ~ ~impossible ~ to determine whether the primary infection was

possible explanations include differences in antigen preparation, time in culture, and test method and the much greater proportion of children with severe disease in the Chicago study (NCCTS).Another difference was in the time of assay relative to time of birth, because almost all of the Chicago (NCCTS) children's lymphocytes underwent blastogenesis after 1 year of age. The authors also postulate that the French infant patients may have differed in having a lower parasite burden as a result of maternal treatment, which might have lessened immune unresponsiveness. In terms of mechanisms responsible for more severe illness in the fetus and infant, the finding that essentially all of the infants these French investigators studied responded to T. gondii antigens is important. Other aspects of immunologic unresponsiveness are discussed under "Special Problems Concerning Pathogenesis in the Eye" and in the "Diagnosis" section.

Chapter 3 1

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979

mouse model of Deckert-Schliiter and ass0ciates,4~~ it is of congenital or acquired. In approximately 10% of 240 cases of interest that congenitally infected mice have similar probable ocular toxoplasmosis studied by Hogan and periventricular lesions, unlike in adult mice. It remains to be associates, the onset of eye disease occurred after the age of determined whether this difference is due to immaturity of 50 years.509 the fetal immune system, unique interaction of T. gondii A prolonged recurrent course involving only one eye is antigens with the fetal immune system, or development of not unusual. For example, Jacobs and co-workers isolated the fetal brain at the time infection is initiated, or to some T. gondii from the eye of a man who had had unilateral combination of these. chorioretinitis for 8.5 years, which illustrates the ability of the parasite (and reactions to it) to persist in tissues for years.510In a similar case, Hogan and associates made a PATHOLOGY retrospective diagnosis of congenital toxoplasmosis from a history of neonatal pneumonia and chorioretinitis in a patient In reviewing the literature on the pathology of congenital at age 1.5 years and of cerebral calcifications at the age of toxoplasmosis, it is immediately apparent that the genesis of 14 years.511The patient experienced recurrent attacks of the natural infection in the fetus is entirely comparable with chorioretinitis, which resulted in a loss of vision by the age that observed in experimental toxoplasmosis in animals. The of 12 years and, finally, in enucleation of the left eye at the position of necrotic foci and lesions in general suggests that age of 20 years; 'I:gondii was isolated from the enucleated eye. the organisms reach the brain and all other organs through Recent reports of significant numbers of cases of the bloodstream. Noteworthy is the remarkable variability in toxoplasmic chorioretinitis that occurred during the acute distribution of lesions and parasites among the different acquired infection in adults highlight the difficulties in reported cases (Table 31-18).513-516 Age at the time of autopsy attributing all of the cases of toxoplasmic chorioretinitis occurring later in life to the congenital i n f e c t i ~ n . ~ ~ ~ ' ~ ~ *is a major modifymg factor, but others include the virulence of the strain of T. gondii, the number of organisms actually The unique predilection of T. gondii for maculae, brain transmitted from the mother to the fetus, the time during periaqueductal and periventricular areas, and basal ganglia pregnancy when the infection occurred, the developmental in congenital toxoplasmosis remains unexplained. In the

Table 31-18

Organ Involvement in 10 Cases of Congenital Toxoplasmosis M

OrganlSystem Central nervous system Eyes Heart Lungs Spleen Liver Pancreas Adrenal gland Kidney Testes Ovary Uterus Bladder Gastrointestinal organs Thyroid Thymus Pituitary Striated muscle Skin, subcutaneous tissue Umbilicus Blood vessels Lymph nodes Diaphragm Bone marrow

11-16 mo

F 2 days

F 120 days

F 26 days

F 42 days

M Stillborn

F

ABC

ABC

ABC

ABC AB 0 B? 0 0 0 0

ABC AB

F 30 days

0 0

0 0 0

0 0 0

0 0

0

M 31 days

F 63 days

0

0 0 0 AB 0 0

-

-

3.5 days

AB AB B 0 0

AB 0 ABC -

-

-

A -

AB -

A A

0 0 -

A AC -

-

-

-

0

aNot described. bC = typical inflammatory picture-parasites. (B = typical inflammatory picture-no parasites. dA = parasites found-no inflammatory infiltrate. eO = no lesions of toxoplasmosis found on examination. F, female; M, male. Adapted from Rodney MB, Mitchell H, Redner B, et al. Infantile toxoplasmosis: report of a case with autopsy. Pediatrics 5:649-663, 1950, with permission.

980

Section IV


maturity of the infant's immune system, and the number of organs and tissues carefully examined. After the appearance of early reports of cases of congenital toxoplasmosis, the prevailing impression was that the infection manifested itself in infants mainly as an encephalomyelitis and that visceral lesions were uncommon and insignificant. This view reflected the observation of a marked degree of damage to the CNS without a comparable degree of extraneural involvement in these infants. In some cases, however, extraneural lesions are severe and may even predominate. 12,5163517Thus, at autopsy, in some cases only the CNS and eyes may be involved, whereas in others wide dissemination of lesions and parasites may be noted. Between these two extremes are wide variations in the degree of organ and tissue involvement, but the CNS is never spared. The clinical importance of lesions in the CNS and eye is magnified by the lack of ability of these tissues to regenerate, compared with the remarkable regenerative capacity of other tissues in the body. Active regeneration of extraneural tissues may be observed even in the most acute stages of infection in the infant.518 Thus, in extraneural organs, residual lesions may be so slight and insignificant that they are easily overlooked. In the CNS and eye, on the other hand, the relative lesser ability of nerve cells to regenerate leads to more severe permanent The presence of I: gondii in the cells lining alveoli and in the endothelium of pulmonary vessels led Callahan and coworkers to suggest that aspiration of infected amniotic fluid in the lungs may be a route of entry of the organism into the That infection by this route may occur cannot be disputed. The diffuse character of the lung changes contrasts with the more focal lesions found in other organs and tissues. Zuelzer pointed out that this difference may be due to the position of the lungs in the route of circulation: Before dissemination to other tissues of the body all blood with parasites entering the venous circulation must first pass through the alveolar capillaries. Thus, the lungs are exposed to more parasites than any other single organ.518

Placenta The first description of 'I:gondii in placental tissues was by Neghme and co-workers."' Subsequently, a number of similar observations have been made."0~1'2~519~522 Evidence for the likelihood of the hematogenous route of spread of T. gondii to the placenta is supplied by the fact that groups of tachyzoites can be found widely dispersed in the chorionic plate, decidua, and amnion, and organisms have been observed in the placental villi and umbilical cord without associated significant lesions (Fig. 3 1-5).'09-"'3523-525 The first description of the histopathologic features of a 'I: gondiiinfected placenta of a woman with AIDS was by Piche and colleagues in 1997.526The woman experienced a spontaneous abortion associated with fever and 'I:gondii pneumonia. In five cases studied by Benirschke and Driscoll, the most consistent findings in the placentas were chronic inflammatory reactions in the decidua capsularis and focal reactions in the villi.52' The lesions appeared to be more severe in infants who died soon after birth. Villous lesions develop at random throughout the placenta. Single or multiple neighboring villi with low-grade chronic inflammation, activation of Hofbauer cells, necrobiosis of component cells, and proliferative fibrosis may be seen. Although villous

Figure 31-5 (arrow).

Toxoplasma cyst in the placenta of an infected fetus

lesions frequently are observed in placental toxoplasmosis, histologic examination of these foci does not reveal parasites; they occur in free villi and in villi attached to the decidua. Lymphocytes and other mononuclear cells, rarely plasma cells, make up the intravillous and perivillous infiltrates. The decidual infiltrate consists primarily of lymphocytes. Inflammation of the umbilical cord is uncommon. When fetal hydrops is present, the placenta also is hydropic. The organism is seen mainly in the tissue cyst form and may be present in the connective tissues of the amnionic and chorionic membranes and Wharton's jelly and in the decidua. Benirschke and Driscoll observed one specimen from which the parasite was isolated in which contiguous decidua capsularis, chorion, and amnion contained organisms.521In a retrospective histologic examination of 13 placentas of newborns with serologic test results suggestive of congenital 'I: gondii infection, Garcia and associates observed organisms that had the morphology of 'I: gondii tachyzoites in 4 cases.527Of interest is that in 10 of their cases, on gross examination, the placenta was found to be abnormal, suggesting the diagnosis of prolonged fetal distress, hematogenous infection, or both. In some cases, the diagnosis was made initially from examination of the p l a ~ e n t a . 'Altshuler ~ ~ ~ ~ ~made ~ a premortem diagnosis by noting cysts in connective tissue beneath the amnion in a very hydropic pla~enta.~" The fetal villi showed hydrops, an abundance of Hofbauer cells, and vascular proliferation. Numerous erythroblasts were present within the vessels of the terminal villi. Elliott described lesions in a placenta following a thirdmonth spontaneous abortion of a macerated fetus.520The placenta showed nodular accumulations of histiocytes beneath the syncytial layer. In villi that had pronounced histiocytic infiltrates, the syncytial layer was raised away from the villous stroma, and the infiltrate had spilled into the intervillous space. Disruption of the syncytium was associated with coagulation necrosis of the villous stroma and fibrinous exudate. Both encysted and free forms of 'I:gondii were present in the areas of histiocytic inflammation,

Chapter 31

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981

Figure 31-6 A, Large cyst (arrow)in glomerular space. 6, Toxoplasma cyst (arrow)in the retina. Note incomplete pigmentation of the choroid. C, T ~ x ~ p l a s mcyst a (arrow)in the fetal cortex of the adrenal gland. D, Section of brain showing abscess (to the left), normal brain (on right), and area of gliosis (between). Encysted parasites were abundant a t the periphety of these areas. (From Miller MJ, Seaman E, Remington JS. The clinical spectrum of congenital toxoplasmosis: problems in recognition. J Pediatr 70:714-723, 1967.)

in the zones of coagulation necrosis, and in the villi without either necrotizing inflammation or syncytial loss. The location of the organisms varied, but they seemed to be concentrated at the interface between the stroma and the trophoblast. This aggregation of histiocytes and organisms at the stroma-trophoblast interface suggested to Elliott that this is a favored site of growth for the parasite.

Central Nervous System In infants who die in the newborn period, the severity of the cellular reaction in the leptomeninges of both brain and spinal cord reflects the amount of damage done to underlying tissue. The pia-arachnoid overlying destructive cortical or spinal cord lesions shows congestion of the vessels and infiltration of large numbers of lymphocytes, plasma cells, macrophages, and eosinophils. This type of change is particularly noticeable around small arterioles, venules, and capillaries. Complete obliteration of the gyri and sulci may be noted; the line of demarcation between the pia-arachnoid and brain substance is obscured. Parasites frequently are found within intimal cells of the arterioles, venules, and capillaries.513 In the cerebral hemispheres, brain stem, and cerebellum, extensive diffuse and focal alterations of the parenchymal architecture are seen (Figs. 31-6 and 31-7).70,513*518,529,530 The most characteristic change is the extensive necrosis of the brain parenchyma due to vascular involvement by lesions. The lesions are most intense in the cortex and basal ganglia and at times in the periventricular areas; they are marked by the formation of glial nodules,” which Wolf and co-workers

referred to as characteristic miliary granulomas.530Necrosis may progress to actual formation of cysts, which have a homogeneous eosinophilic material at the center of the cyst cavity. At the periphery of these cystic areas, focal calcification of necrotic, individual nerve cells may be evident. Calcification within zones of necrosis may be extensive, with the formation of broad bands of calcific material involving most of the cortical layers, or it may be scattered diffusely throughout the foci of necrosis. The calcium salts are deposited in coarse granules or in finely divided particles, which give the appearance of “calcium dust.” Many cells become completely calcified, whereas others contain only a few particles of finely divided calcium. Some pathologists have suggested that the T gondii organisms themselves become encrusted with calcium salts.’135’8 (Cells containing fine particles of calcium also are observed in cytomegalovirus infection of the fetus or newborn and may be mistakenly construed as evidence of T. gondii.) The extent of calcification appears to depend on the severity of the reaction and the duration of the infe~tion.~‘~ T. gondii tachyzoites and cysts are seen in and adjacent to the necrotic foci, near or in the glial nodules, in perivascular regions, and in cerebral tissue uninvolved by inflammatory change (see Figs. 31-6D and 31-7D).529

Hervas and colleagues described an infant who developed progressive drowsiness, a weak cry, and grunting in the newborn period.53’ Computed tomography (CT) revealed cerebral calcifications, multiple ring-enhancing lesions mimicking a brain abscess, and moderate ventricular enlargement. At autopsy, T. gondii organisms were seen in the ventricular cerebrospinal fluid. Widespread necrosis and

982

Section IV


Figure 31-7 A, Toxop/asma cyst (arrow)within a glomerulus. Similar cysts were identified in endothelial cells of the glomeruli as well as free in the glomerular spaces. B, Encysted parasites (arrow)in a renal tubule cell. Other cysts were present within lumina of several tubules. C, Toxoplasma cyst (arrow) in immature testicular tissue. D, Toxoplasma cyst in cerebral cortex. Note lack of inflammatory response. (From Miller MJ, Seaman E, Remington JS. The clinical spectrum of congenital toxoplasmosis: problems in recognition. J Pediatr 70:714-723,1967.)

granulomatous lesions with mononuclear infiltrates also were noted. The degree of change in the spinal cord is extremely variable. It may consist of local infiltration of lymphocytes and plasma cells or, on the other hand, almost complete disruption of the normal architecture, caused by the transformation of the gray and white matter into a mass of necrotic granulation tissue, may be seen. T. gondii cysts, which can be identified in the white matter, usually are unassociated with inflammatory reaction. Periaqueductal and periventricular vasculitis with necrosis is a lesion that occurs only in tox~plasmosis.~~ The large areas of necrosis have been attributed to vascular thrombosis. The necrotic brain tissue autolyzes and gradually sloughs into the ventricles. The protein content of such ventricular fluid may be in the range of grams per deciliter, and the fluid has been shown to contain significant amounts of T. gondii antige11s.5~~ If the cerebral aqueduct of Sylvius becomes obstructed by the ependymitis, the lateral and third ventricles begin to resemble an abscess cavity containing accumulations of T. gondii and inflammatory Hydrocephalus develops in such children, and the necrotic brain tissue may calcify and become visible on radiographs. The fourth ventricle may show ulcers and ependymal nodules but is free from periventricular vasculitis and necrosis, apparently as a consequence of adequate drainage of its fluid through the foramina of Luschka and Magendie. The cerebrospinal fluid that communicates with the fourth ventricle often contains several hundred milligrams per deciliter of protein and fewer inflammatory cells than are

seen in the lateral ventricle Frequently, inflammation and necrosis are seen to involve the hypothalamus surrounding the third ventricle. Wolf and co-workers suggested that such lesions in the floor of the third ventricle probably cause the temperature lability observed in infants with congenital t o x ~ p l a s m o s i s Destruction . ~ ~ ~ ~ ~ ~ ~of brain tissue, especially intense periventricular necrosis, rather than obstruction of ventricular passages, appears to account for the development of hydrocephalus in some cases.518*530

The histopathologic features of the ocular lesions depend on their stage of development at the time of the examination; a number of studies describing lesions in the earliestrecognized cases have been published,'2316,535-540 and were reviewed by Hogan in his classic thesis.540The description that follows is based on Hogan's summary of his and other cases. The primary and principal lesions are found in the retina and choroid; secondary changes, such as iridocyclitis and cataracts,536that occur in other portions of the eye are considered to represent complications of the chorioretinitis. Intraocular inflammation may cause microphthalmia, owing to arrest in development of the eye, or a secondary atrophy may result in shrinkage of the globe. The frequently reported failure of regression of the fetal pupillary vessels may indicate that an arrest in development occurred. The inflammation commences in the retina (see Fig. 3 1 -6B), and a copious exudate in the vitreous produces

Chapter 3 1 a marked haze. Secondary involvement of the choroid causes marked elevation; small satellite foci are common. After healing, the lesions are atrophic and pale, with a variable amount of pigmentation at the margins. The organisms first lodge in the capillaries of the inner layers of the retina, invade the endothelium, and extend into adjacent tissues. An intense focal inflammatory reaction results, with edema and infiltration of polymorphonuclear leukocytes, lymphocytes, plasma cells, mononuclear cells, and, in some cases, eosinophils. The reaction results in disruption and disorganization of the retinal layers. Cells are dislocated from the nuclear layers into the adjacent fiber layers. The external limiting membrane may be ruptured, displacing retinal cells into the subretinal space. The inner limiting membrane may also be interrupted, and cells from the inner nuclear layers are then displaced into the adjacent vitreous. Glial tissue, vascular connective tissue, and inflammatory exudate also extend through the interruptions in the inner and outer limiting membranes. In the zones of most acute inflammation, all retinal supporting and neural tissues are completely destroyed. The pigmentary epithelium shows extensive destruction. The retina may detach.506 In the healing process, proliferation of the pigment bordering the inflammatory foci occurs. Large lesions cause considerable necrosis and destruction, resulting in marked central atrophy of the retina and choroid. Disorganization of retinal cells has occurred.506 Inflammation in the choroid is most acute beneath the retinal foci and is rather well demarcated. Bruch's membrane frequently is destroyed, and proliferation of connective tissue into the subretinal space may be seen. Retina and choroid thereby become fixed to each other by a scar. The choroidal vessels usually are engorged and show perivascular infiltration of lymphocytes, plasma cells, mononuclear cells, and eosinophils. Lymphocytes predominate, and both CD4' and CD8' lymphocytes are Organisms are present in the retinal lesions and, in general, are most numerous where the lesions are most severe (see Fig. 31-6B). Occasional parasites without an accompanying reaction are observed in relatively normal portions of the retina near the margins of inflammatory foci. The organisms may occur singly or in clusters, free or intracellularly, or in cysts (see Fig. 31-1C and D). They are rarely seen in the choroid. They also have been found in the tissues of the optic papilla and in optic nerve associated with inflammatory cells in congenital cases.506,515 Serofibrinous exudate and inflammatory cells extend into the vitreous through dehiscences in the inner limiting membrane of the retina. The exudate may be accompanied by masses of budding capillaries, and the vitreous becomes infiltrated with granulation tissue. The optic disk may show papillitis, sometimes associated with optic neuritis506and sometimes secondary to inflammation in the adjacent retina or a papilledema caused by the hydrocephalus. Leptomeningeal inflammation may be present around the optic nerve.

Ear The presence of the parasite in the mastoid and inner ear and the accompanying inflammatory and pathologic changes have been considered to be causes of deafness in congenital

Toxoplasmosis

983

toxoplasmosis.513~541 Also, brain-stem involvement affecting auditory nuclei can lead to inability to process auditory input.

Lungs The alveolar septa may be widened, edematous, and infiltrated with mononuclear cells, occasional plasma cells, and rare eosinophils. The walls of small blood vessels may be infiltrated with lymphocytes and mononuclear cells, and parasites may be found in endothelial cells.513In many cases, some degree of bronchopneumonia, often caused by suprainfection with other agents, is present. ?: gondii has been identified in the epithelial cells lining alveoli and within the endothelium of small blood vessels in such cases; in some affected patients, the pneumonic process was considered to be a prominent part of the general disease.513Single organisms have been found free in alveoli in the cases described by Zuelzer518 and Paige and co-workers.l 2 Of interest, their pathologic findings are identical to those described for adults in whom the lungs were particularly involved.I6For a review of this subject in congenital and acquired cases, the reader is referred to the ublished articles by C o ~ v r e u r ~ ~ * and Pomeroy and Filice. 54Y

Heart ?: gondii is almost always found in the heart in the form of cysts in myocardial fibers, accompanied by pathologic changes in the heart muscle. A focal infiltration with lymphocytes, plasma cells, mononuclear cells, and occasional eosinophils is seen. These foci usually do not contain organisms. In the focal areas of infiltration, the myocardial cells may undergo hyaline necrosis and fragmentation. Parasites are found in myocardial fibers in large aggregates and in cysts without any accompanying inflammatory reaction (see Fig. 5-1D). Single parasites often may be present in areas of beginning necrosis and peripherally in larger areas of necrosis.513.518,529 Extensive calcification of the heart, involving primarily the right ventricle and intraventricular septum, was observed in a 3-hour-old infant and was attributed to congenital toxoplasmosis.544Of interest in this regard is the consistent finding of marked calcification in hearts of mice experimentally infected with less virulent strains. As is the case with other tissues, the organisms can invade the myocardial fibers without destroying them or producing inflammatory reactions in the surrounding tissue. Myocarditis probably is produced by the rupture of parasitized cells, which liberates the organisms that then cause an inflammatory reaction in the surrounding tissue?" Involvement of the heart has been demonstrated in a congenitally infected infant with AIDS who died of Pneumocystis pneumonia and toxoplasmosis. Autopsy was limited to cardiac biopsy and revealed marked autolytic changes without evidence of inflammatory reaction or fibrosis. 1 ' : gondii organisms were identified in the muscle fibers.544

Spleen Marked engorgement of the splenic pulp may be noted, along with erythropoiesis.In general, no significant pathologic

984

Section IV


Inasmuch as Huldt had previously demonstrated antigenantibody complexes in glomeruli of mice infected with an avirulent strain of T. g0ndii,4~~ experimental evidence was available to support these authors' hypothesis that their case represented immune complex nephritis induced by T. gondii; no renal biopsy was made to support this suggestion. In Liver, Ascites 1974, a case of what appears to have been acute acquired toxoplasmosis was reported in a 10-year-old girl; light In most cases, parasites are not identified in the liver, and microscopy showed interstitial nephritis without glomerular neither necrosis nor inflammatory cell infiltrations are lesions. Eleven months after treatment with pyrimethamine, present. In some instances, areas of marked hepatocellular sullisomidine, and spiramycin, a second renal biopsy revealed degenerative changes do occur but without associated slight granular segmental deposits of IgM and PIC in the cellular i n f i l t r a t i ~ n . ~ The ~ ' ~ ~periportal ~ ' ~ ~ ~ spaces may glomeruli. No immune deposits were found in the glomeruli be infiltrated with mononuclear cells, neutrophils, and of a renal biopsy specimen obtained 4 months after eosinophils. Enlargement of the liver frequently is protreatment.552 nounced and is accompanied by erythropoiesis, as occurs In that same year, Shahin and associates reported a case of also in the spleen. In a few cases, hepatic cirrhosis has been nephrotic syndrome in a 4-month-old infant with congenital observed as a sequel to congenital toxoplasmosis.545Caldera toxoplasmosis.553 Granular and pseudolinear glomerular and co-workers have described calcification in the liver seen deposits of IgM, fibrinogen, and T gondii antigen and antiboth radiologically and at body were demonstrated in the glomeruli of the initial Congenital toxoplasmosis was diagnosed by exfoliative biopsy of renal tissue. After approximately 7 months of cytologic examination of ascitic fluid in a 7-week-old infant treatment, a second renal biopsy showed no evidence of the born at 38 weeks of gestation. Hepatomegaly and anemia T gondii antigen-antibody complexes previously noted, but developed shortly after birth, and liver failure and ascites IgM, fibrinogen, and the fourth component of complement during the first week of life. Because an extensive workup (C4) were present. IgG and C3 were not demonstrable in the failed to reveal a cause, a paracentesis was performed that glomeruli in either biopsy specimen. Light microscopy of revealed tachyzoites both in Wright-stained smear prepthe first renal biopsy revealed glomeruli with a diffuse mild arations and in electron microscopy sections. This case is increase in mesangial cells and matrix. One glomerulus reminiscent of that of an adult patient with AIDS in whom contained a segmented area of sclerosis that adhered to the diagnosis of toxoplasmosis was first established on Bowman's capsule. Other findings included rare foci of examination of Wright-Giemsa-stained smears of ascitic fluid obtained because of suspected bacterial ~ e r i t 0 n i t i . s . ~ ~ ~tubular atrophy and associated interstitial fibrosis, occasional hyaline casts, focal tubular and interstitial calcification, and prominent tubular hyaline droplets. The second renal biopsy Kidney specimen, obtained after treatment with prednisone for 7 months and with pyrimethamine and sulfadiazine for Numerous foci of hematopoiesis may be seen in the kidney. 3 weeks, revealed glomeruli with varying degrees of damage, Focal glomerulitis often has been observed; in such cases, a ranging from total hyalinization to partial collapse and majority of glomeruIi remain i n t a ~ t . ~ In ' ~ fully ' ~ ' ~developed segmental sclerosis. The tubulointerstitial changes were not lesions, glomerular tufts undergo massive necrosis, and significantly different from those observed in the first biopsy necrosis of adjacent tubules may be seen. In the earlier stages specimen. The results of electron microscopy also were of the glomerular lesion, some capillary loops are still intact; reported. in others, necrotic areas are observed in the basement Couvreur and associates have reported two cases of membrane and epithelium, and the lumina are occluded by nephrotic syndrome associated with congenital toxofibrin thrombi. In some of these partly preserved glomeruli, p l a ~ m o s i s Outcome .~~~ was fatal in one case, and T. gondii single parasites have been found in cells of the exudate within cysts were demonstrated in glomeruli. the capsular space or embedded in the necrotic remains of the capillary T. gondii cysts have been found in glomeruli and renal tubules of kidneys in which there were Adrenals, Pituitary, Pancreas, and Thyroid no other associated lesions (see Figs. 31-6A and 31-7A and Parasites and numerous foci of necrosis have been identified B).548,549In severely affected kidneys, focal areas of necrosis in the adrenal cortex (see Fig. 3 1-6C). Similar areas of necrosis also are found in the collecting tubules in the medulla. The have been found in the p a n ~ r e a s . ' * * ~Parasites, ' ~ ~ ~ ~usually ~~~'~ inflammatory infiltrations are predominantly mononuclear, without associated inflammation, have been found in the although in some cases, numerous eosinophils also are seen p i t ~ i t a r y . ~ ' ~Large . ~ ~ ' clusters of organisms, without acscattered throughout. In 1966, Fediushina and Sherstennikova companying inflammation or necrosis, have been found in reported the pathologic findings in the kidneys in nine cases the acini of the thyroid gland.'* of congenital toxoplasmosis.550In three of these cases, distinct changes in the glomeruli were noted, and as described by these investigators, many of the changes appear to resemble Testes and Ovaries those observed in glomerulonephritis from other causes, There is frequently an acute interstitial inflammation with including streptococcal infection. focal areas of necrosis.'2~70~513~517~51s Necrosis of the seminifIn 1972, Wickbom and Winberg reported a case of a erous tubules with preservation of adjacent units is 10-week-old boy with congenital toxoplasmosis who developed severe nephritis with the nephrotic syndrome.551 common, with infiltration with plasma cells, lymphocytes,

changes that could be attributed to direct destruction by the parasite have been noted in the spleen. In some cases, an eosinophilic leukocytic infiltration has been Organisms are rarely seen in the spleen.

Chapter 3 1 mononuclear cells, and eosinophils. Parasites often are observed in the spermatogonia of intact tubules (see Fig. 317C). Focal hematopoiesis has been observed in the interstitia of these organs.

Skeletal Muscle Involvement varies, ranging in degree from parasitized fibers without pathologic changes to focal areas of infiltration or widespread myositis with necrosis. The organisms in parasitized fibers are found beneath the sarcolemmalsheaths. Hundreds of organisms may be present in a single long tubular space in a fiber, and T. gondii cysts frequently are seen in muscle fibers. The affected fibers are swollen and lose their striations, but as a rule, no inflammatory reactions are noted. By contrast, focal areas of inflammation and necrosis may be present in areas where only a few parasites or none can be identified. The cellular infiltrate consists mainly of mononuclear cells, but lymphocytes, plasma cells, and eosinophils also are present. In rare instances, focal inflammatory lesions may be found adjacent to heavily parasitized but unbroken muscle fibers.518Noteworthy is the description of severe involvement of the extraocular muscles in the case described by Rodney and c o - ~ o r k e r s . ~ ~ ~

Thymus Sarrut observed a hypoplastic thymus in an infant who died of congenital toxoplasmosis at the age of 1 month (personal communication to G Desmonts, 1980). The disease was not diagnosed before autopsy. 1: gondii organisms were isolated from the brain and heart. The histologic picture in this case was quite different from that described in experimental infection in newborn mice476in that in the former, hypoplasia involved both lymphocytes and Hassall’s corpuscles.

Skin Torres found T. gondii tachyzoites without formation of lesions in the subcutaneous tissue of one infant.555In a case (“case 5”) reported by Paige and associates, T. gondii organisms were present in the subcutaneous tissue, again with no associated inflammatory lesion or necrosis.” No rash was noted in the infant.

Bone Milgram described osseous changes in a fatal case of congenital toxoplasmosis.517The infant died on day 17, and at autopsy widespread active infection was discovered. The parasite was found in almost all tissues of the body. Large numbers of inflammatory cells were found in the bone marrow, with deficient osteogenesis and remodeling in the primary spongiosa. Intracellular aggregates of T. gondii were present in macrophages in the bone marrow.

Immunoglobulin Abnormalities Subtle abnormalities have been noted in the development of immunoglobulins in infants with subclinical congenital toxoplasmosis.556In several infants, retarded development of IgA for the first 3 years of life and excessive development of

Toxoplasmosis

985

IgG and IgM were noted. The latter abnormality also is seen in congenital rubella, cytomegalic inclusion disease, and syphilis. In the T. gondii-infected children, the degree of increase in IgG and IgM appeared to be directly related to the severity of the infection. Macroglobulinemia in infants with congenital infections apparently was first described in infants with congenital The first such report involving a case of congenital toxoplasmosis appeared in 1959; the affected newborn had hydrocephalus and died at approximately 2 months of age.560 A serum protein abnormality was suspected when blood taken for routine laboratory work became clotted in the syringe in the absence of cryoglobulins in the blood. Oxelius described monoclonal (M) immunoglobulins in the serum and cerebrospinal fluid of three newborns with severe clinical signs of congenital toxoplasmosis.561The M components were of the IgG class and included both kappa and lambda types. Because the M proteins were found in the sera of newborns but not in the sera of their mothers, Oxelius concluded that the M immunoglobulins were either selectively transferred or synthesized by the newborn. There appeared to be either local production or a selective local accumulation of the M immunoglobulins in the cerebrospinal fluid. The M components disappeared and the IgM level in serum and cerebrospinal fluid decreased after therapy. Dye test antibodies were localized to the site of the M components in the electrophoretic patterns of both serum and cerebrospinal fluid. Rheumatoid factors also were found in the serum and cerebrospinal fluid of newborns with congenital toxoplasmosis; of interest, however, they were not present in the sera of these infants’ mothers. These findings are especially interesting because long-standing bacterial and parasitic infections usually are associated with hypergammaglobulinemia of the diffuse polyclonal type. Also of interest is that the M components have been described in congenital syphilis as well.562 Reports by Van Camp and associates563and Griscelli and colleague^^^,^^^ suggest that the observation by Oxelius may not be uncommon. Griscelli and colleagues performed a survey of 27 newborns and older infants who had the severe form of congenital toxoplasmosis. In 11 of the infants, M IgG components were noted. These authors concluded that these components were synthesized by the fetus, because they could be detected up to 75 days post partum and were absent in maternal serum. They were unable to define any anti-T. gondii antibody in isolated M IgG. Four of the clonal M components in their 11 cases could be assigned to the kappa light chain and five to the lambda type. In the other two cases, it was not possible to assign the M component to either light chain type. Separation of the serum into IgM and IgG fractions by gel filtration confirmed that the M component was IgG. They noted that whereas early treatment induced a shift of IgG concentration toward physiologic ranges, the levels of IgA and IgD remained elevated in most infants with congenital toxoplasmosis. Absorption of the hypergammaglobulinemic sera with antigens of T. gondii resulted in almost complete loss of the dye test antibodies but did not affect the presence of the M component or significantly reduce the immunoglobulin levels. Similar results have been reported in T. gondii-infected mice; hypergammaglobulinemia and a condition that appeared to be a

986

Section IV


monoclonal spike was observed.&l The underlying mechanism or the cause of the appearance of M components in infants with congenital toxoplasmosis is unknown.

Toxoplasma gondii-C ytomegaIovirus Infection A number of reports of dual infection with IT: gondiicytomegalovirus have a ~ p e a r e d . ~ ~In~ systematically -~~' searching for cytomegalovirus infection among nine autopsies in cases of congenital toxoplasmosis, Vinh and co-workers found these two diseases coexisting in two instance^.^^ Sotelo-Avila and associates described a case of coexisting congenital toxoplasmosis and cytomegalovirus infection in a microcephalic infant who died at the age of 15 days.567 Microscopically, numerous areas of calcification and necrosis and large cells with the characteristic nuclear inclusions of cytomegalovirus were seen. Aggregates of T. gondii were found in the cytoplasm of many of the cytomegalic inclusion cells in the CNS, lungs, retina, kidneys, and liver. Maszkiewicz and colleagues described a case of cytomegalic inclusion disease with toxoplasmosis in a premature infant.56s


Infection in the Pregnant Woman Because acute acquired ?: gondii infection in the pregnant woman usually is unrecognized, the infection in such cases has been said to be asymptomatic. A diagnosis of asymptomatic infection is based largely on retrospective questioning of mothers who gave birth to infected infants and requires prospective clinical studies for documentation. Even if signs and symptoms are more frequently associated with the acute infection, they often are so slight as to escape the memory in the vast majority of women. The most commonly recognized clinical manifestations of acquired toxoplasmosis are lymphadenopathy and fatigue without fever.271,571*576 The groups of nodes most commonly involved are the ceMcal, suboccipital, supraclavicular,axillary, and inguinal. The adenopathy may be localized (e.g., most commonly a single posterior cervical node is enlarged), or it may involve multiple areas, including retroperitoneal and mesenteric nodes.577Palpable nodes usually are discrete, vary in firmness, and may or may not be tender; there is no tendency toward suppuration. The lymphadenopathy may occasionally have a febrile course accompanied by malaise, headache, fatigue, sore throat, and myalgia-features that closely simulate those of infectious mononucleosis. The spleen578and liver579also may be involved.244~5s0~583 Atypical lymphocytes indistinguishable from those seen in infectious mononucleosis may be present in smears of peripheral blood. In some patients, lymphadenopathy may persist for as long as 1 year, and malaise also may be persistent, although this finding is more difficult to relate directly to the infection.573An exanthem may be present-it has been described in a pregnant patient.'15 An association of T. gondii infection and the clinical syndromes of polymyositis and dermatomyositis has been r e p ~ r t e d . ~ ~ Cho - ~rioretinitis ~' occurs in the acute acquired infection, and many such cases have been d ~ c u m e n t e d . ~ ~In~ .Sio ~ ~ ' Paulo and Minais Gerais, Brazil, retinal disease has been reported to be common in the acute acquired infection.4099410

Infection in the Infant General Considerations A diagnosis of congenital T gondii infection usually is considered in infants who show signs of hydrocephalus, chorioretinitis, and intracranial calcifications. These signs, often described as the classic triad,596were present in the first proven case of congenital toxoplasmosis described by Wolf and colleagues in 1939." Since this original observation was made, however, they, as well as other investigators, have seen and described congenitally infected infants who presented with a variety of clinical signs; the clinical spectrum may range from normal appearance at birth to a picture of erythroblastosis, hydrops fetalis, the classic triad of toxoplasmosis, or a variety of other Thus, such wide variation in clinical signs precludes a diagnosis according to strict adherence to a set of specific clinical criteria. Such adherence may lead to misdiagnoses, especially in cases of congenital toxoplasmosis in which the signs mimic those of other disease states. Until the variability in the clinical picture of congenital T. gondii infection is appreciated by pediatricians and until the diagnosis is considered more often in infants with mild nonspecific illness, the blindness, mental retardation, and even death related to T. gondii infection will continue to go unrecognized. Congenital T. gondii infection may occur in one of four forms: (1) a neonatal disease; (2) a disease (severe or mild) occurring in the first months of life; (3) sequelae or relapse of a previously undiagnosed infection during infancy, childhood, or adolescence; or (4) a subclinical infection. When clinically recognized in the neonate, the infection usually is severe. Symptoms and signs of generalized infection may be prominent, and signs referable to the CNS are always present. The neurologic signs frequently are more extensive than might be suspected at first. In other neonates, neurologic signs (e.g., convulsions, bulging fontanelle, nystagmus, abnormal increase in circumference of the skull) are the major indications of the diagnosis. Such manifestations are not always associated with gross cerebral damage; instead, they may be related to an active encephalitis not yet associated with irreversible cerebral necrosis or to obstruction of the cerebral aqueduct of Sylvius caused by edema or inflammatory cells, or both, rather than to permanent obstruction. In these latter infants who receive treatment, signs and symptoms may disappear and development may be normal thereafter. Mild cases in the neonate usually are not recognized. Identification of the disease has been possible in prospective studies, however, when infants born to mothers known to have acquired 'I: gondii infection during pregnancy are examined. The most frequent signs include isolated chorioretinal scars. Such cases prove that the infection was active during fetal life without causing detectable systemic damage. Most children with congenital T. gondii infection are said to have been normal at birth, as signs or symptoms become manifest weeks, months, or years later. Obviously, in many cases this clinical picture is not one of delayed onset of disease but one of late recognition of disease. Nevertheless, it has been possible to verify delayed onset of disease weeks or months or years after birth in children who at birth had no abnormalities that could be related to toxo~lasmosis.'09~''4~3s4556

Chapter 31 Disease with delayed onset may be severe and is most frequently seen in premature infants, in whom severe CNS and eye lesions appear during the first 3 months after birth. In the full-term infant with delayed onset of disease, manifestations arise mainly during the first 2 months of life. Clinical signs may be related to generalized infection (e.g., hepatosplenomegaly, delayed onset of icterus, lymphadenopathy); CNS involvement (e.g., encephalitis or hydrocephalus), which may occur after a more protracted period; or eye lesions, which may develop months or years after birth in infants and children whose fundi are checked repeatedly. Sequelae most often are ocular (e.g., chorioretinitis occurring at school age or adolescence), but in some cases they are neurologic-for instance, convulsions may lead to the discovery of cerebral calcifications or retinal scars. Ocular lesions may recur during childhood, adolescence, or adulthood. In some instances, neurologic relapses (e.g., late obstruction of the aqueduct) have been observed. Congenital T. gondii infection in the newborn in the series from France, as well as in a study performed in the United States,384*598 most frequently was a subclinical or inapparent infection, not, as had previously been thought, an obvious and fulminant one. In those infants who were clinically normal at birth, the infection was diagnosed by demonstration of persistent serologic test titers. Such asymptomatic infants may suffer no untoward sequelae of the infection, or abnormalities such as chorioretinitis, strabismus, blindness, hydrocephaly or microcephaly, psychomotor and mental retardation, epilepsy, or deafness may develop or become apparent only months or even years later.599-601 Such patients-asymptomatic at birth but demonstrating untoward sequelae later-were noted by Callahan and co-workers in the early 1940s (their cases 3 and 4).5’3 Frequently, neurologic signs or hydrocephalus appears between 3 and 12 months of life?’* In patients with encephalitic lesions, CNS abnormalities that produce clinical signs rarely develop after the first year (see “Follow-up Studies” later At present, no parameters are available to use in predicting the outcome in a newborn with asymptomatic T. gondii infection. Hundreds of reports, however, attest to the crippling effects of infection when severe disease is apparent at birth.

Clinically Apparent Disease. One of the most complete studies was that of Eichenwald, who in 1947 initiated a study to discover the clinical forms of congenital toxoplasmosis and to determine the natural history of the infection and its effect on the infant.596The cases were referred by a group of cooperating hospitals in a systematic and prearranged manner. Sera were obtained from three groups of infants and their mothers. The first two groups consisted of 5492 infants examined because they had either undiagnosed CNS disease in the first year of life (neurologic disease group) or undiagnosed non-neurologic diseases during the first 2 months of life (generalizeddisease group). The third group consisted of 5761 normal infants. The incidence rates of serologically proven cases in the three groups were 4.9%, 1.3%, and 0.07%, respectively. Of the 11,253 infants studied, 156 had serologically proven congenital toxoplasmosis; 69% were in the neurologic disease group, and 28% were in the

Table 31-19

Toxoplasmosis

987

Signs and Symptoms Occurring before Diagnosis or during the Course of Acute Congenital Toxoplasmosis Frequency of Occurrence (%) in Infants with

Signs and Symptoms Chorioretinitis Abnormal spinal fluid Anemia Convulsions lntracranial calcification Jaundice HydrocephaIus Fever Splenomegaly Lymphadenopathy Hepatomegaly Vomiting Microcephaly Diarrhea Cataracts Eosinophilia Abnormal bleeding Hypothermia Glaucoma Optic atrophy Microphthalmia Rash Pneumonitis

Neurologic Disease’ (108 Cases)

Generalized Diseasg (44 Cases)

94 55

66 84

51 50 50

77 18 4

29 28 25 21 17 17 16 13 6 5 4

80 0 77 90 68 77 48 0 25 0 18 18 20 0 0 0 25 41

3 2 2 2 2 1

0

%fants with otherwise undiagnosed central nervous system diseases in the first year of life. blnfantswith otherwise undiagnosed non-neurologic disease during the first 2 months of life. Adapted from Eichenwald HF. A study of congenital toxoplasmosis. In Siim JC (ed). Human Toxoplasmosis. Copenhagen, Munksgaard, 1960, pp 41-49, with permission. Study performed in 1947.

generalized disease group. The signs and symptoms in the infants in these two groups are shown in Table 31-19. Approximately one third showed signs and symptoms of an acute infectious process, with splenomegaly, hepatomegaly, jaundice, anemia, chorioretinitis,and abnormal cerebrospinal fluid as the most common findings. The so-called classic triad of toxoplasmosis was demonstrated in only a small proportion of the patients. The fact that 98% of the infants had clinical evidence of infection can be explained by the manner in which the case material was collected for the study. Despite the fact that Eichenwald clearly defined this, his data for years have been misinterpreted to show that all infants with congenital T. gondii infection have signs and symptoms of infection, as set forth in Table 31-19. Most of the patients were evaluated over a period from birth to the age of 5 years or beyond. The overall mortality rate was 12% (no significant differences in mortality rate existed between the clinical groups), and approximately 85% of the survivors were mentally retarded. Convulsions, spasticity, and palsies developed in almost 75%, and about 50% had severely

988

Section IV

Table 31-20


Major Sequelae of Congenital Toxoplasmosis among 105 Patients Followed 4 Years or More

Condition Mental retardation Convulsions Spasticity and palsies Severely impaired vision Hydrocephalus or microcephaly Deafness Normal

No. (%) with Neurologic Disease” (70 patients)

No. (%)with Generalized Diseaseb (31 patients)

69 (98) 58 (83) 53 (76) 48 (69) 31 (44) 12 (17) 6 (9)

25 (81) 24 (77) 18 (58) 13 (42) 2 (6) 3 (10) 5 (16)

No. (%)with Subclinical Disease (4 patients)

~~~~~

Tnfants with otherwise undiagnosed central netvous system diseases in the first year of life. blnfants with otherwise undiagnosed non-neurologic diseases during the first 2 months of life. Adapted from Eichenwald HF. A study of congenital toxoplasmosis. In Siim JC (ed). Human Toxoplasmosis. Copenhagen, Munksgaard, 1960, pp 41-49, with permission. Study performed in 1947.

impaired vision (Table 31-20). It is noteworthy that deafness, usually attributed to congenital viral infections (e.g., cytomegalovirus infection, rubella), also occurs as a sequel to congenital T gondii infection. The signs and symptoms in this series of patients differ in many respects from those recorded in reports published earlier, owing undoubtedly to the fact that the cases studied by Eichenwald were drawn from a relatively unselected group rather than from a limited survey based on infants tested solely because they showed most of the so-called classic signs of congenital toxoplasmosis.

Subdinid Infection. Studies of subclinical infection have been performed in an attempt to determine the following: how often congenital T. gondii infection is subclinical; whether it is really subclinical or whether, in fact, initial signs have gone unrecognized; and what the prognosis is for subclinical infection. For information on prognosis, see “Follow-up Studies,” later on in this section. Alford and colleagues performed a series of studies to determine the medical significance of the subclinical form of congenital ?: gondii infection.556Their serologic screening program (see “Diagnosis” section) was performed in a moderately low-socioeconomic-status urban population in the southern United States, and 10 infants with congenital T gondii infection were detected among 7500 newborns screened (1 proven case per 750 deliveries over a study period of 2.5 years). The findings in the 10 newborns are shown in Table 31-21. Only 1 infant had signs that suggested T gondii infection (hepatosplenomegaly, chorioretinitis, cerebral calcification). Thus, 9 of the infected infants would have escaped detection were it not for the laboratory screening program. The investigators pointed out that, nevertheless, significant abnormalities were found in this group of newborns with so-called subclinical infection. Half were premature, and the average birth weight of the infected infants, 2664g, was 349g less than that of control infants (3013 g). Although no signs or symptoms referable to the nervous system were present in the 9 infants, abnormalities in the cerebrospinal fluid were noted in each of the 8 infants in whom this examination was performed. Cerebrospinal fluid lymphocytosis (10 to 110 cells per pL) and elevated

Table 31-21

Data in 10 Newborns with Congenita I Toxoplasma Infection Identified by the Presence of IgM Toxoplasma Antibodies

Finding Maternal illness (“flu”) Diagnosis suspected (neonate) Gestational prematuritp Intrauterine growth retardationb Hepatosplenomegaly Jaundice Thrombocytopenia Anemia Chorioretinitis Abnormal head size Hydrocephalus M icrocephaly Abnormal cerebrospinal fluid Abnormalities on neurologic examination Serum IgM elevated Serum IgM Toxoplasma antibody

No. of Infants 2 1 5 2 1 1 1 1 2 0 1 0 8‘ 1 9 10

a:.:.:.:........ : ...........R !ORE TIff/T(S............. ...... ............... ......

.....

-

ANEMIA - A B S M

HEPA TOSPLENOMEGALY

...G.?....

too0 190

989

- AfORMAL > HYSICA) AND MFNTA/ D N n OPMENT-NOR&AL CHORIORE77NITIS ABSENT > THUOM8OCYTOR3“A - A B S W

-7 days

>7 days

>7 days

Disseminated candidiasis

Renal candidiasis

CNS candidiasis

~~

Blood culture by catheter grows Candida spp but peripheral blood cultures sterile Only blood cultures grow Candida spp Blood and urine, CSF or other sites grow Candida spp Clinical and/or radiographic evidence for multiorgan involvement Urine culture grows Candida spp Ultrasound evidence of renal fungal lesions CSF culture grows Candida spp CSF culture grows Candida spp i signs of inflammation; lesions by cranial imaging

Physical examination Biopsy and culture of lesions

Physical examination Culture of lesions for Candida spp

Physical examination

Physical examination

~~

Diagnosis

Systemic antifungal therapy




Catheter removal and systemic antifungal therapy


Topical antifungal therapy Systemic antifungal therapy for pneumonia

Topical or oral antifungal therapy Topical antifungal therapy

Treatment

'Factors, in addition t o those listed in Table 33-2, pertaining t o the specific clinical syndrome listed. CNS, central nervous system; CSF, cerebrospinal fluid; ROP. retinopathy of prematurity; UTI, urinary tract infection; VLBW, very low birth weight.

Sepsis None to focal neurologic signs

Sepsis Urinary tract obstruction

Sepsis

>7 days

Sepsis

*

Widespread erythematous maculopapular rash vesicles Pneumonia in preterm infants Erosive, crusting lesions in dependent areas

Intense erythema of perineal area with satellite lesions

Candidemia

lntravascular catheters

7 days

2500 g

Birth Weight (9) 11000

NICU, neonatal intensive care unit. Data from Centers for Disease Control and Prevention, Division of Health Care Quality Promotion. National Nosocomial Infections Surveillance ("IS) system report, data summary from January 1992 to June 2003, issued August 2003. Am J Infect Control 301481-498, 2003.

resulting from therapeutic or diagnostic interventions.'86Risk stratification techniques that attempt to control for distribution of risk have included severity of illness score, intensity of care required, and birth weight.74 Because the risk for developing nosocomial infection is greater for lower-birthweight infants:' the NNIS system breaks down data collection and analysis into birth weight categories (Tables 35-5 and 35-6).'912'94 The use of invasive devices, however, also is an important factor to consider. The appropriate denominator for an infection related to the use of a medical device, such as a CVC-related primary bloodstream infection, according to NNIS, would be total device days for the population during the surveillance period. The formula generally used for calculating nosocomial infection rates is (x/y)k, where x equals the number of events (infections) over a specific time period, y equals the population at risk for development of the outcome, and k is a constant and a multiple of 10. Rates can be expressed as a percentage (k = loo), although device-related infections usually are expressed as events per 1000 device days (k = 1000). A value should be selected for k that results in a rate greater than Because use of invasive devices is such a significant risk factor both for bloodstream infection and ventilatorassociated pneumonia, assessing NICU practices with device use may be warranted. "IS provides a benchmark for NICU device utilization broken down into birth weight categories. An NICU device utilization ratio can be calculated using the following formula: Number of device days Number of patient days In those units with device utilization ratios above the NNIS 90th percentile, investigation into the practices surrounding use of invasive devices may be ~ a r r a n t e d . 'Calculating ~~ monthly and annual rates to employ as benchmarks can assist in identification of a potential problem in device-related procedures. Surveillance data must be arranged and presented in a way that facilitates interpretation, comparison both directed internally and with comparable external benchmarks, and dissemination within the organization. Quality improvement tools (e.g., control and run charts) can be useful for these purposes. Statistical tools should be used to determine the significance of findings, although statistical significance should always be balanced with the evaluation of clinical

1001-1500 1501-2500 >2500

Umbilical and CR-BSlb 10.6 6.4 4.1 3.7

VAPC 3.3 2.5 2.1 1.4

aNICU component of reported data, January 1995 to June 2003 (VAP data are for January 2002 through June 2003 only). bNumber of umbilical and central line-related (CR) bloodstream infections (BSls) x 1000/number of umbilical and central line days. 'Number of VAP cases x 1000/number of ventilator days. NICU, neonatal intensive care unit; VAP, ventilator-associated pneumonia. Data from Centers for Disease Control and Prevention, Division of Health Care Quality Promotion. National Nosocomial Infections Surveillance (NNIS) system report, data summary from January 1992 to June 2003, issued August 2003. Am J Infect Control 301481-498, 2003.

~ignificance."~ External benchmarking through interhospital comparison is a valuable tool for improving quality of are'^,'^^ but should be performed only when surveillance methodologies (e.g., case definitions, case finding, data collection methods, intensity of ~urveillance)'~~ can reasonably be assumed to be consistent between facilities. Few overall infection rates in NICUs are available, but a small study done in 17 children's hospitals performing NICU nosocomial infection surveillance reported a median nosocomial infection rate of 8.9 infections per 1000 patient days (range, 4.6 to 18.1).19' NNIS does not provide a benchmark for overall infection rates within NICUs. Instead, NNIS provides birth weight-stratified device-associated infection rates for umbilical and central intravascular line-associated bloodstream infections. The most recent rates for catheterrelated bloodstream infections (137 to 143 NICUs reporting) and ventilator-associated pneumonias (78 to 96 NICUs reporting) are summarized in Table 3 E ~ 6 . l ~ ~ Once arranged and interpreted, nosocomial infection data must be shared with personnel who can effect change and implement infection control interventions. Written reports summarizing the data and appropriate control charts should be provided to the facility's infection control committee, unit leaders, and members of the hospital administration on an ongoing basis. The interval between reports is determined by the needs of the institution. In addition to formal written reports, face-to-face reports are appropriate in the event of identification of a serious problem or an outbreak. ICPs can serve as consultants to assist NICU or neonatology service leaders in addressing infection rate increases or outbreak management.

Outbreak (Epidemic) Investigation Surveillance activities typically identify endemic nosocomial infections (i.e., those infections that represent the usual level of disease within the nursery or NlCU).'99Although the rate can fluctuate over time, in the absence of interventions that

1190

Section V

Table 35-7

Diagnosis and Management

Reported Nursery Outbreaks of Infection

Causative Organism

Source

Staphylococcusaureus (pyoderma) Staphylococcusaureus MRSA Enterococcus faecium (VRE) Clostridium species Serratia marcescens 5. marcescens Enterobacter sakazakii Klebsiella pneumoniae, antibiotic-resistant

Hospital staff Skin barrier paste (Stomahesive) Horizontal transmission'? Unknown Horizontal transmission? Horizontal transmission Milk bottles Powdered milk formula Environment, breast milk, horizontal transmission Air conditioners Unknown Sink taps Horizontal transmission Hospital staff? Horizontal transmission? Horizontal transmission? Unknown Unknown Environment

Acinetobacter species Pseudomonas aeruginosa Chryselbacteriummeningosepticum Salmonella enterica Tuberculosis, multidrug-resistant Adenovirus type 8 Parainfluenza virus type 3 Influenza A virus Respiratory syncytial virus Rotavirus

Reference

Year

Location

212 206 207 79 210 204 115 201 106

2002 2000 200 1 2001 2002 1998 2002 1998 2001

Taipei, Taiwan Leeds, UK Washington, DC Omaha Manitoba, Canada Leipzig, Germany Zurich Brussels London

202 203 211 209 136 205 161 162 208 157

1996 1999 1996 1999 1998 1998 1996 1999 2002 2002

Bahamas Maryland London Rio de Janeiro New York Heidelberg, Germany Winnipeg, Canada Barcelona, Spain Riyadh, Saudi Arabia Holland

aHorizontaltransmission refers to indirect contact transmission by contaminated equipment or health care workers' hands. MRSA, methicillin-resistant5taphylococcusaureus; VRE, vancornycin-resistant enterococci.

successfully reduce risk of infection, the difference rarely is statistically significant. Establishing an NICU's endemic infection rate and expected variation around that rate allows the ICP to rapidly identify unusual increases in rates that may indicate on outbreak (epidemic) of a particular infection. Using baseline surveillance data along with aggregate data from sources such as the "IS system allows the ICP to develop meaningful threshold rates for initiating outbreak investigation.Is8Alternatively,HCWs can be the first to sense an increase in infections, which then can be confirmed or refuted by surveillance data?00Even a single case of infection due to an unusual and potentially dangerous pathogen (e.g., Salmonella) can constitute the index case for a subsequent outbreak and thus merits rapid and comprehensive investigation. Outbreaks may need to be reported to health authorities, depending on local and state requirements as well as the organism involved. Numerous studies have described nursery and NICU epidemics caused by a variety of pathogens (Table 35-7), and most such epidemics have required the coordinated efforts of ICPs, NICU leadership, staff, and hospital administration for resolution.79, 106,115,136,I 57J6 I, 162,ZO 1-2 12 Outbreak investigation and intervention should be approached systematically, applying sound epidemiologic principles. In general, the process should include the f o l l o ~ i n g ' ~ ~ ~ ~ ' ' " : Confirming that an outbreak exists, by comparing the outbreak infection rate with baseline data (or with rates reported in the literature if baseline data are not available),and communicating concerns to stakeholders within the institution (and to those in other agencies if notification of health authorities is necessary) Assembling the appropriate personnel to assist in developing a case definition and in planning immediate measures to prevent new cases

Performing active surveillance using the case definition to search for additional infections and collecting critical data and specimens Characterizing cases of infection by person, place, and time, including plotting of an epidemic curve (to facilitate identification of shared risk factors among involved patients, such as invasive devices, proximity to other infected patients or temporal association with infection in such patients, common underlying diagnoses, shared medical or nursing staff, surgery, and medications, including antimicrobial agents) Formulating a working hypothesis and testing this hypothesis (if the severity of the problem warrants this level of study, and provided that the institution has and can commit the necessary resources), with use of analytic approaches, including case-control and cohort studies, as appropriate to determine the likely cause of the outbreak Instituting and evaluating control measures, which can be implemented anywhere in the foregoing process (more directed measures become possible as more is learned about the outbreak, and efficacy of control measures can be judged on whether the outbreak resolves, as indicated by return of number of cases to endemic levels or by cessation of occurrence of infections) Reporting findings to appropriate personnel, including unit staff, hospital administration, and public health authorities (if involved in management of the outbreak), in comprehensive written reports, including summaries of how the outbreak was first recognized, study and analysis methods used, interventions implemented to resolve the epidemic, results, and a discussion of any other important outcomes or surveillance and control measures identified

Chapter 35

Infections Acquired in the Nursery: Epidemiology and Control

1191

Interventions used to control and limit outbreaks usually nosocomial or health cart+associated infections. Hand hygiene have consisted of isolation and cohorting of infected or should be performed before and after all patient contacts; colonized infants to prevent transmission of organisms. before donning sterile gloves to perform an invasive proTransmission-based precautions, a system developed by the cedure; after contact with blood, body fluids or excretions, CDC, can be used to determine the most effective barrier mucous membranes, nonintact skin, and wound dressings; precautions to use with affected patients. Cohorting, or placing in moving from a contaminated body site to a clean body site infants infected or colonized with the outbreak organism during patient care (ie., from changing a diaper to pertogether in geographically segregated areas and assigning forming mouth care); after contact with inanimate objects in dedicated staff and equipment to their care, also has been the immediate vicinity of the patient; after removing gloves; and before eating and after using the r e ~ t r o o m . ’When ~~ used successfully to halt outbreaks in nurseries and NICUs. hands are visibly soiled or contaminated with proteinaceous In extreme cases, closure of an NICU to admissions has been blood, or body fluids, and after using the restnecessary to bring an outbreak under ~ o n t r o l . ~ ~ ~ ’ ~ ~ , ’materials, ~~ Every attempt should be made to identify the source of a room, hands should be washed with antimicrobial soap and nursery outbreak, although this is not always possible. Sources water. Soaps containing 2% to 4% chlorhexidine gluconate implicated in NICU outbreaks have included medications, or 0.3% t r i ~ l o s a n ’are ~ ~recommended for hand washing in equipment, and enteral feeding solutions; person-to-person n~rseries.’~~ When hands are not visibly soiled, alcohol-based transmission and environmental reservoirs also have been hand rubs, foams, or gels are an important tool for hand reported. 102,106,157,201,202,213 Efforts to identify the source may hygiene. Compared with washing with soap and water, use of include culturing of specimens from HCWs, equipment, and the alcohol-based products is at least as effective against a the environment, although careful consideration should be variety of pathogens and requires less time, and these agents given to the potential benefits before initiating these measures. are less damaging to skin. The CDC “Guideline for Hand Culture of samples from the environment and equipment, in Hygiene in the Health Care Setting” calls for use of alcohol view of the vast number of objects that could be contamihand rubs, foams, or gels as the primary method to clean nated, usually is not helpful in identifying the source of an hands, except when hands are visibly soiled.I3l Programs outbreak unless specific case characteristics or microbiologic that have been successful in improving hand hygiene and data strongly suggest the location. Culture of specimens decreasing nosocomial infection have used multidisciplinary obtained from HCWs when person-to-person transmission teams to develop interventions focusing on use of the is suspected may be more likely to identify the source of an alcohol rubs in the settin of institutional commitment and outbreak, but it must be remembered that an HCW whose support for the initiativetJ7~15 culture specimen yields the outbreak organism may have HCWs should wash hands and forearms to the elbows on been transiently colonized while working with an affected arrival in the nursery. A 3-minute scrub has been suggested?l6 infant, rather than constituting the source of the infection. but consensus on optimal duration of initial hand hygiene is Management of culture-positive HCWs (possible furlough, lacking. At a minimum, the initial wash should be long treatment, and return to work criteria) should be planned in enough to ensure thorough washing and rinsing of all parts advance of widespread culture surveillance and should involve of the hands and forearms. Routine hand washing throughsupervisors of affected employees and occupational health out care delivery should consist of wetting the hands, applying services.’” product, rubbing all surfaces of the hands and fingers vigorously for at least 15 seconds, rinsing, and patting dry with disposable t0we1s.l~~ Wearing hand jewelry has been Standard and Transmission-Based Precautions associated with increased microbial load on hands. Whether in the Nursery this results in increased transmission of pathogens is not The most widely accepted guideline for preventing the known. Many experts, however, recommend that hand and transmission of infections in hospitals was developed by the wrist jewelry not be worn in the In addition, CDC. Most recently revised in 1996, the system contains two the CDC guideline states that staff who have direct contact tiers of precautions. The first and most important, standard with infants in NICUs should not wear artificial fingernails precautions, was designed for the management of all or nail extenders.”’ Only natural nails kept less than Y..inch hospitalized patients regardless of their diagnosis or presumed long should be allowed. infection status. The second, transmission-based precautions, Clean, nonsterile gloves are to be worn whenever contact with blood, body fluids, secretions, excretions, and contamiis intended for patients documented or suspected to be infected or colonized with highly transmissible or epidemiologically nated items is anticipated. The HCW should change gloves when moving from dirty to clean tasks performed on the important pathogens for which additional precautions to same patient, such as after changing a diaper and before interrupt transmission are needed.25 Standard precautions are designed to reduce the risk of suctioning a patient, and whenever they become soiled. Because hands can become contaminated during removal of transmission of microorganisms from both recognized and gloves, and because gloves may have tiny, unnoticeable defects, unrecognized sources and are to be followed for the care of all patients, including neonates. They apply to blood; all wearing gloves is not a substitute for hand hygiene. Hand body fluids, secretions, and excretions except sweat; nonintact hygiene must be performed immediately after glove removal.25 skin; and mucous membranes. Components of standard Personnel in nurseries including the NICU historically have worn cover gowns for all routine patient contact. The precautions include hand hygiene and wearing gloves, gowns, practice has not been found to reduce infection or colonizand masks and other forms of eye protection. ation in neonates and is u n n e c e ~ s a r y ? Instead, ’ ~ ~ ~ ~ CDC ~ guideHand hygiene plays a key role for caregivers in the reduction lines recommend nonsterile, fluid-resistant gowns to be worn of nosocomial infection for patient^'^.^'^ and in prevention of

1192

Section V


as barrier protection when soiling of clothing is anticipated and in performing procedures likely to result in splashing or spraying of body substance^.^^ Possible examples of such procedures in the NICU are placing an arterial line and irrigating a wound. The Perinatal Guidelines of the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists recommend that a longsleeved gown be worn over clothing when a neonate is held outside the bassinette by nursery personnel.’” Nonsterile masks, face shields, goggles, and other eye protectors are worn in various combinations to provide barrier protection and should be used during procedures and patient care activities that are likely to generate splashes or sprays of body substances and fl~ids.’~ Standard precautions also require that reusable patient care equipment be cleaned and appropriately reprocessed between patients; that soiled linen be handled carefully to prevent contamination of skin, clothing, or the environment; that sharps (i.e., needles, scalpels) be handled carefully to prevent exposure to blood-borne pathogens; and that mouthpieces and other resuscitation devices be used, rather than mouth-to-mouth methods of re~uscitation.’~ In addition to standard precautions, which must be used for every patient, the CDC recommends transmission-based precautions when the patient is known or suspected to be infected or colonized with epidemiologically important or highly transmissible organisms. Always used in addition to standard precautions, transmission-based precautions comprise three categories: contact precautions, droplet precautions, and airborne precautions. Contact precautions involve the use of barriers to prevent transmission of organisms by direct or indirect contact with the patient or contaminated objects in the patient’s immediate e n ~ i r o n m e n t Sources .~~ of indirect contact transmission in nurseries can include patient care equipment such as monitor leads, thermometers, isolettes, breast pumps,lE6 toys, and instruments and contaminated hands.222 The patient requiring contact precautions should be placed in a private room whenever possible but, after consultation with an infection control practitioner, can be cohorted with a patient infected with the same microorganism but no other infection.25Many nurseries, however, have few if any isolation rooms. The American Academy of Pediatrics states that infected neonates requiring contact precautions can be safely cared for without an isolation room if staffing is adequate to allow appropriate hand hygiene, a 4-to 6-footwide space can be provided between care stations, adequate hand hygiene facilities are available, and staff members are well trained regarding infection transmission modes.’” HCWs should wear clean, nonsterile gloves when entering the room or space of a patient requiring contact precautions and should wear a cover gown when their clothing will have contact with the infant, environmental surfaces, or items in the infant’s area. A cover gown also should be worn when the infant has excretions or secretions that are not well contained, such as diarrhea or wound drainage, which may escape the diaper or dressing. Infant care equipment should be dedicated to the patient if possible so that it is not shared with 0thers.2~ Examples of conditions in the neonate that require contact precautions include neonatal mucocutaneous herpes simplex virus infection, respiratory syncytial virus infection, varicella

(also see airborne precautions), infection or colonization with a resistant organism such as MRSA or a multiple drug-resistant gram-negative bacillus, and congenital rubella syndrome. Droplet precautions are intended to reduce the risk of transmission of infectious agents in large-particle droplets from an infected person. Such transmission usually occurs when the infected person generates droplets during coughmg, sneezing, or talking, or during procedures such as suctioning. These relatively large droplets travel only short distances and do not remain suspended in the air, but can be deposited on the conjunctiva, nasal mucosa, andfor mouth of persons working within 3 feet of the infected patient.25 Patients requiring droplet precautions should be placed in private rooms (see earlier discussion of isolation rooms in nurseries in the paragraph on contact precautions), and staff should wear masks when working within 3 feet of the patient.25 Examples of conditions in the neonate that necessitate droplet precautions are pertussis and invasive N. meningitidis infection. Airborne precautions are designed to reduce the risk of airborne transmission of infectious agents.25 Because of their small size, airborne droplet nuclei and dust particles containing infectious agents or spores can be widely spread on air currents or through ventilation systems and inhaled by or deposited on susceptible hosts. Special air-handling systems and ventilation are required to prevent transmission. Patients requiring airborne precautions should be placed in private rooms in negative air-pressure ventilation with 6 to 12 air changes per hour. Air should be externally exhausted or subjected to high-efficiency particulate air (HEPA) filtration if it is recirculated.222 Examples of conditions in the neonate for which airborne precautions are required are varicella-zoster virus infections and measles. Susceptible HCWs should not enter the rooms of patients with these viral infections. If assignment cannot be avoided, susceptible staff members should wear masks to deliver care. If immunity has been documented, staff members need not wear masks.222Airborne precautions also are required for active pulmonary tuberculosis, and although neonates are rarely contagious, the CDC recommends isolating patients while they are being e~ aluated.~’~ A more important consideration is the need to isolate the family of a suspected tuberculosis patient until an evaluation for pulmonary tuberculosis has been completed, because the source of infection frequently is a member of the child’s family.223,Z24

Physical Environment Before the 1990s, well-baby nurseries and many NICUs were constructed as large, brightly lit open wards with rows of incubators surrounded by equipment. Sinks could be provided in such rooms only around the periphery, limiting access to hand hygiene facilities for staff and families. In these NICUs, parents’ time with their infant was severely restricted, and the units were designed for the convenience and function of the HCW.225More recently, perinatal care professionals have come to understand that neonates (and especially preterm infants) can benefit from a quiet, soothing atmosphere and protection from unnecessary light, noise, handling, uncomfortable positioning, and sleep disruptions?26 If infants are kept in a central nursery rather than roomingin with mothers, at least 30 square feet of floor space should

Chapter 35


be provided per neonate, and bassinets should be at least 3 feet apart.216Teams designing units delivering higher levels of perinatal care, including NICUs, should plan individual bed areas large enough for families to stay at the bedside for extended periods of time without interfering with the staffs ability to care for the child. If individual rooms cannot be provided, at least 150 square feet of floor space should be allowed for each neonate in an NICU, incubators or overhead warmers should be separated by at least 6 to 8 feet, and aisles should be at least 8 feet A scrub sink with foot, knee, or touchless (electronic sensor) controls should be provided at the entrance to every nursery and should be large and deep enough to control splashing. Sinks in patient care areas should be provided at a minimum ratio of 1 sink for at least every 6 to 8 stations in the well-baby nursery and 1 sink for every 3 or 4 stations in higher-level nurseries, including the NICU.’I6 Every bed position should be within 20 feet of a hand-washing sink and accessible for children and persons in wheelchairs.227For NICUs composed of individual rooms, a hand-washing sink should be located in each room near the door to facilitate hand hygiene on entering and leaving the room. Environmental surfaces should be designed so that they are easy to clean and do not harbor microorganisms. Sink taps and drains, for instance, have been implicated in outbreaks of infection.2283z29 Installing sinks with seamless construction may minimize this risk by decreasing areas where water can pool and microorganisms proliferate. Faucet aerators have been implicated in outbreaks of infection and should be avoided in the intensive care unit.230Although carpeting can reduce noise levels in a busy NICU, the CDC “Guidelines for Environmental Infection Control in HealthCare Facilities” recommend against use of carpeting in areas where spills are likely, including intensive care units. The guidelines further recommend against upholstered furniture in NICUS.~~’ If, for reasons of noise reduction and developmentally appropriate care, porous surfaces such as carpeting and cloth upholstery are selected for the NICU, cleaning must be performed carefully. Carpet should be vacuumed regularly with equipment fitted with HEPA filters, and upholstered furniture should be removed from inpatient areas to be cleaned. Attention also should be paid to air-handling systems. According to the Perinatal Guidelines, minimal standards for inpatient perinatal care areas include six air changes per hour, and a minimum of two changes should consist entirely of outside air. Air delivered to the NICU should be filtered with at least 90% efficiency. In addition, nurseries should include at least one isolation room capable of providing negative pressure vented to the outside, observation windows with blinds for privacy, and the capability for remote m~nitoring.~~~’~~~

General Housekeeping Floors and other horizontal surfaces should be cleaned daily by trained personnel using Environmental Protection Agency (EPA)-registered hospital disinfectantddetergents. These products (including phenolics and other chemical surface disinfectants) must be prepared in accordance with manufacturers’ recommendations and used carefully to avoid exposing neonates to these products. Phenolics should not be used on surfaces that come in direct contact with neo-

1193

nates’ skin.231High-touch areas, such as counter tops, work surfaces,doorknobs, and light switches,may need to be cleaned more frequently because they can be heavily contaminated during the process of delivering care. Hard, nonporous surfaces should be “wet dusted” rather than dry dusted, to avoid dispersing particulates into the air, and then disinfected using standard hospital disinfectant^.'^^ Sinks should be scrubbed daily with a disinfectant detergent. Walls, windows, and curtains should be cleaned regularly to prevent dust accumulation, but daily cleaning is not necessary unless they are visibly soiled. Bassinets and incubators should be cleaned and disinfected between infants, but care must be taken to rinse cleaning products from surfaces with water before use. Care units should not be cleaned with phenolics or other chemical germicides during an infant’s stay. Instead, infants who remain in the nursery for long periods of time should periodically be moved to freshly cleaned and disinfected units.23’ Patient care equipment must be cleaned, disinfected, and, when appropriate, sterilized between patients. Sterilization (required for devices that enter the vascular system, tissue, or sterile body cavities)and higher levels of disinfection (required for equipment that comes in contact with mucous membranes or that has prolonged or intimate contact with the newborn’s skin) must be performed under controlled conditions in the central processing department of the hospital. Examples of patient care equipment that require these levels of processing are endotracheal tubes, resuscitation bags, and face masks.216,232,233Low-level disinfection is required for less critical equipment, such as stethoscopes or blood pressure cuffs, and usually can be performed at point of use (e.g., the bedside), although this type of equipment should be dedicated to individual patients whenever possible.

Linens Requirements for linen handling and management for neonates do not vary appreciably from those for other hospitalized patients. Although soiled linen can contain large numbers of organisms capable of causing infections, transmission to patients appears to be rare. Studies suggesting linen as a source of infection often have failed to confirm it as the source of infection.234At least one report, however, has implicated linen in the transmission of group A streptoco~ci.~~ Investigation of this outbreak revealed that clothing worn by the neonates was being washed in the local hospital “mini laundry,” rather than being processed under the usual laundry contract. Investigation of the dryers revealed extensive contamination with the outbreak organism. This case illustrates the importance of having standard hospital laundry protocols and ensuring that appropriate water and dryer temperatures are maintained. When such protocols are followed, the mechanical actions of washing and rinsing, combined with hot water and/or the addition of chemicals such as chlorine bleach, and a final commercial dryer and/or ironing step significantly reduce bacterial Few hospitals in the United States use cloth diapers, but regardless of type used, soiled diapers should be carefully bagged in plastic and removed from the unit every 8 hours.216

Health Care Workers HCWs caring for neonates have the potential both to transmit infections to infants and to acquire infections from

1194

Section V

Table 35-8


Immunizing Agents Strongly Recommended for Health Care Workers

Vaccine

Recommendation

Hepatitis B recombinant vaccine Influenza vaccine Measles live-virus vaccine

Vaccinate all HCWs at risk of exposure t o blood and body fluids. Vaccinate HCWs annually. Vaccine should be considered for all HCWs, including those born before 1957, who have no proof of immunity (receipt of 2 doses of live vaccine on or after first birthday, physician-diagnosed measles, or serologic evidence of immunity). HCWs believed t o be susceptible can be vaccinated; adults born before 1957 can be considered immune. HCWs, both male and female, who lack documentation of receipt of vaccine on or after first birthday or serologic evidence of immunity should be vaccinated; adults born before 1957 can be considered immune, except women of childbearing age. HCWs without a reliable history of varicella or serologic evidence of varicella immunity should be vaccinated.

Mumps live-virus vaccine Rubella live-virus vaccine Varicella-zoster live-virus vaccine

HCW, health care worker. Data from Bolyard EA, Tablan OC, Williams WW, et al. Guideline for infection control in health care personnel, 1998. Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol 19:407-463, 1998.

patients. Educating HCWs about infection control principles is crucial to preventing such transmission. Hospitals should provide education about infection control policies, procedures, and guidelines to staff in all job categories during new employee orientation and on a regular basis throughout employment. The content of this education should include hand hygiene, principles of infection control, the importance of individual responsibility for infection control, and the importance of collaborating with the infection control department in monitoring and investigating potentially harmful infectious exposures and outbreaks. Transmission of infectious organisms between patients and HCWs has been well documented. Several studies have indicated that a high proportion of HCWs acquire RSV (34% to 56%) when working with infected children, and these workers appear to be important in the spread of the illness within hospital^.^^'.^^^ Although 82% of the infected HCWs in one of these RSV studies were asymptomatic, staff should be aware of the importance of self-screeningfor communicable disease. They should be encouraged to report personal infectious illnesses to supervisors, who in turn should report them to occupational health services and infection control. In general, HCWs with respiratory, cutaneous, mucocutaneous, or gastrointestinal infections should not deliver direct patient care to neonates.2I6 In addition, seronegative staff members exposed to illnesses, such as varicella and measles, should not work during the contagious portion of the incubation period.232 Staff members with HSV infection rarely have been implicated in transmission of the virus to infants and thus do not need to be routinely excluded from direct patient care. Those with herpes labialis or cold sores should be instructed to cover the lesions and not to touch their lesions, and to comply with hand hygiene policies. Persons with genital lesions also are unlikely t o transmit HSV so long as hand hygiene policies are followed. However, HCWs who are unlikely or unable to comply with the infection control measures and those with herpetic whitlow should not deliver direct patient care to neonates until lesions have healed.240 Acquisition of CMV often is a concern of pregnant HCWs because of the potential effect on the fetus. Approximately 1% of newborn infants in most nurseries and a higher percentage of older children (up to 70% of children 1 to

3 years of age in child-care centers) excrete CMV without

clinical manifestation^.'^^ The risk of acquiring CMV infection has not been shown to be higher for HCWs than for the general For this reason, pregnant caregivers need not be excluded from the care of neonates suspected to be shedding CMV. They should be advised of the importance of standard precautions. HCWs in well-baby nurseries and NICUs should be as free from transmissible infectious diseases as possible?16 and ensuring that they are immune to vaccine-preventablediseases is an essential part of a personnel health program. The CDC recommends several immunizations for health care personnel (Table 35-8). Staffing levels in a patient care setting also can affect patient outcomes. A number of studies suggest that as patient-tonurse ratios in intensive care units increase, so do nosocomial infections and mortality rate^.^^,'^^,'^ Although optimal staffing ratios have not been established for NICUs and will vary according to characteristics of individual units, one study demonstrated that the incidence of clustered S. aureus infections was 16 times higher after periods when the infantto-nurse ratio exceeded 7: 1. Decreased compliance with hand hygiene during a period of understaffing frequently is cited as contributing to nosocomial infection rate increases.” Further study is necessary to determine best practice surrounding staffing levels in NICUs.

Family-Centered Care: Parents and Visitors to the Newborn Infant The first NICUs in the late 1960s grouped infants together in large, brightly lit rooms with incubators placed in rows. Parents were allowed very little time with their babies and even less physical contact. In the decades since, it has been recognized that “the parent is the most important caregiver and constant influence in an infant’s life”225and that HCWs working in NICUs should encourage parents to become involved in the nonmedical aspects of their child’s care. Principles of family-centered care also include liberal NICU visitation for relatives, siblings, and family friends and the involvement of parents in the development of nursery policies and programs that promote parenting skills.226

Chapter 35


1195

Although contraindications to breast-feeding are few, mothers who have active untreated tuberculosis, human immunodeficiency virus (HIV) infection, breast abscesses (as opposed to simple mastitis that is being treated with antimicrobial therapy), or HSV lesions around the nipples should not breast-feed. Mothers who are hepatitis B surface antigen positive may breast-feed, because ingestion of an infected mother's milk has not been shown to increase the risk of transmission to her child, but the infant must receive 0 They feel well enough. hepatitis B virus immune globulin (HBIG) and vaccine They wash their hands well under supervision. immediately after birth.248 Because systemic disease may A clean gown is worn. develop in preterm infants with low concentrations of transContact of the neonate with contaminated dressings, placentally acquired antibodies to CMV following ingestion linen, clothing, or pads is avoided.245 of milk of CMV-seropositive mothers, decisions regarding breast-feeding should consider the benefits of human milk A mother with a transmissible illness not requiring versus the risk of CMV transmission. Freezing breast milk separation from her infant should be carefully educated has been shown to decrease viral titers but does not eliminate about the mode of transmission and precautions necessary CMV; pasteurization of human milk can inactivate CMV. to protect her infant. Personal protective equipment, such as Either method may be considered in attempts to decrease cover gowns, gloves, and masks, and hand hygiene facilities risk of transmission for breast-feeding NICU neonates.249 should be readily available to her, and she should perform Neonates in the NICU frequently are incapable of breasthand hygiene and don a long-sleeved cover gown before feeding because of maternal separation, unstable respiratory handling her infant. If wounds or abscesses are present, status, and immaturity of the sucking reflex. For these reasons, drainage should be contained within a dressing. If drainage mothers of such infants must use a breast pump to coUect cannot be completely contained, separation from the infant milk for administration through a feeding tube. Pumping, may be necessary. Care should be taken to prevent the infant collection, and storage of breast milk create opportunities from coming in contact with soiled linens, clothing, dressings, for contamination of the milk, and for cross-infection if or other potentially contaminated items. The mother with equipment is shared between mothers. Several studies have active genital HSV lesions need not be separated from her demonstrated contamination of breast pumps, contamination infant if the foregoing precautions are taken. Those with of expressed milk that had been frozen and thawed, and herpes labialis should not kiss or nuzzle their infants until higher levels of stool colonization with aerobic bacteria in lesions have cleared; lesions should be covered and a surgical infants fed precollected breast milk. 16,250*251 mask may be worn until the lesions are crusted and dry, and Consensus is lacking on the safe level of microbiologic careful hand hygiene should be stressed. contamination of breast milk, and most expressed breast Mothers with viral respiratory infections should be made milk contains normal skin flora. Although breast milk conaware that many of these illnesses are transmitted by contact taining greater than 100 CFU/mL of gram-negative bacteria with infected secretions as well as by droplet spread, that has been reported to cause feeding intolerance and to be soiled tissues should be disposed of carefully, and that hand associated with suspected sepsis, routine bacterial culturing hygiene is critical to transmission prevention. Masks can be Instead, worn to reduce the risk of droplet t r a n s m i s s i ~ n . ~ ~ ~ ' ~ ~ of ~ expressed breast milk is not recommended.249v250 efforts to ensure safety of expressed milk should focus on As previously mentioned, although very few infections optimal collection, storage, and administration techniques. require separation of mother and infant, women with unCleaning and disinfection of breast pumps should be included treated active pulmonary tuberculosis should be separated in educational material provided to nursing mothers (Table from their infants until they no longer are contagious. 35-9). In addition, mothers should be instructed to perform Mothers with group A streptococcal infections, especially hand hygiene and cleanse nipples with cotton and plain when involving draining wounds, also should be isolated water before expressing milk in sterile containers. 1923249 from their infants until they no longer are contagious. Less Expressed breast milk can be refrigerated for up to certain is the necessity of separating mothers with peripartum 48 hours and can be safely frozen (-20" C f 2°C [-4"F varicella (onset of infection within 5 days before or 2 days f 3.6" F]) for up to 6 months.192It can be thawed quickly after delivery) from their uninfected infants. The Perinatal under warm running water (avoiding contamination with Guidelines recommend that such infants remain with their tap water) or gradually in a refrigerator. Exposure to high mothers after receiving varicella-zoster immune globulin temperatures, as may be experienced in a microwave, can (VZIG) but caution that infant and mother must be carefully destroy valuable components of the milk. Thawed breast managed in airborne and contact precautions245to prevent milk can be stored in the refrigerator for up to 24 hours transmission within the nursery. Some experts recommend before it must be discarded. To avoid proliferation of microseparating these mothers from their infants until all lesions organisms, milk administered through a feeding tube by are dried and crusted.246 continuous infusion should hang no longer than 4 to 6 hours Breast-feeding before replacement of the milk, container, and For mothers who choose not to breast-feed, commercial Numerous studies support the value of human milk for ininfant formula is available. Most hospitals now use sterile, fants (see Chapter 5). Besides providing optimal nutritional ready-to-feed formulas provided by the manufacturer in content for infants, it has been shown to be associated with bottles, with sterile nipples to attach just before use. Nipples a lower incidence of infections and sepsis in the first year of Care must be taken, however, to minimize risk of infection for the neonate. Mothers can transmit infections to neonates both during delivery and post partum, although separation of mother and newborn rarely is indicated. In the absence of certain specific infections, mothers, including those with postpartum fever not attributed to a specific infection, should be allowed to handle their infants if the following conditions are met:

1196

Section V

Table 35-9


Collection and Storage of Expressed Breast Milk

Each mother is supplied with a personal pumping kit. Nursing staff instruct mothers in techniques of milk expression and appropriate procedures for cleaning breast pump parts: Wipe all horizontal surfaces at the pumping station with hospital disinfectant before and after pumping. Wash hands with soapy water before and after pumping. Wash all parts of the breast pump kit that have been in contact with milk in hot water and dish detergent or in a dishwasher. Expressed milk is collected in sterile, single-use plastic (polycarbonateor polypropylene)containers. Breast milk containers are labeled with infant’s name and the date and time of collection. Administration containers (bottle or syringe) are similarly labeled when breast milk is transferred from collection containers. All HCWs wear gloves when handling and administering breast milk. Two persons check t h e labeled administration container against the infant’s hospital identification band before administering breast milk (may be two HCWs or one HCW and a family member). HCW. health

care worker. From Infection Control Policy, Children’s Hospital and Regional Medical Center, Seattle, 2003

are best attached at the bedside just before feeding, and the unit should be used immediately and discarded within 4 hours after the bottle is ~ncapped.’~’ Specialty and less commonly used formulas may not be available as a ready-to-feed product, and breast milk supplements do not come in liquid form. After a recent report of a case of fatal Enterobacter sakazakii meningitis in a neonate fed contaminated powdered infant formula:7 concerns have risen about the safety of these products. Although powdered formulas are not sterile, preparation and storage practices can decrease the possibility of proliferation of microorganisms after preparation. The CDC, the Food and Drug Administration, and the American Dietetic Association offered updated recommendations on the safe preparation and administration of commercial formula after the recall of the product linked to the E. sakazakii case. These recommendations instruct the care provider as follows: Use alternatives (ready-to-feedor concentrated formulas) to powdered infant formula whenever possible. Prepare formula using aseptic technique in a designated formula preparation room. Refrigerate prepared formula so that a temperature of 2” to 3” C is reached by 4 hours after preparation, and discard any reconstituted formula stored longer than 24 hours. Limit ambient-temperature hang time of continuously infused formula to no longer than 4 hours. Use hygienic handling techniques at feeding time, and avoid open delivery systems. Have written guidelines for managing a manufacturer’s recall of contaminated formula.252 The FDA also recommended that boiling water be used to prepare powdered formulas, but concerns about this recommendation include potential damage to formula components from the high temperature of the water, a lack of evidence that using this method would lull potential pathogens in the formula, and risk of injury to persons preparing the f0rmula.2~’

Co-bedding The concept of co-bedding, or the bunlung of twin infants (or other multiples) in a single isolette or crib, is being explored in NICUs for the potential benefits offered to the babies. Co-bedding as a component of developmentally

supportive care is based on the premise that extrauterine adaptation of twin neonates is enhanced by continued physical contact with the other twin.253Potential benefits need further study but may include increased bonding, decreased need for temperature support, and easier transition to home. It is certainly possible, however, for one of a set of multiples to be infected while the others are not, and for parents to be implicated as vectors in infection transmission. It also is possible for invasive devices and intravascular catheters to be dislodged by close contact with an active sibling. Therefore, exclusion criteria for co-bedding infants should include clinical findings suggesting infection that could be transmitted to a sibling (e.g., draining wound) and the need for drains and central venous or arterial line^.*^^-'^^

Visitors The principles of family-centered care encourage liberal visitation policies, both in the well-baby nursery (or roomingin scenario) and in the NICU. Parents, including fathers, should be allowed unlimited visitation to their newborns, and siblings also should be allowed liberal visitation. Expanding the number of visitors to neonates may, however, increase the risk of disease exposure if education and screening for symptoms of infection are not implemented. Written policies should be in place to guide sibling visits, and parents should be encouraged to share the responsibility of protecting their newborn from contagious illnesses. The Perinatal Guidelines regarding persons who visit newborns are listed in Table 35-10. Adult visitors to neonates, including parents, have been implicated in outbreaks of infections including P aeruginosa infection, pertussis, and Salmonella i n f e c t i ~ n . ’ Ac ~ ’cord~~~~~~~~ ingly, the principles for sibling visitation should be applied to adult visitors as well. They should be screened for symptoms of contagious illness, instructed to perform hand hygiene before entering the NICU and before and after touching the neonate, and should interact only with the family member they came to the hospital to visit. Families of neonates who have lengthy NICU stays may come to know each other well and serve as sources of emotional support to one another. Nevertheless, they should be educated about the potential of transmitting microorganisms and infections between families if standard precautions and physical separation are not maintained, even though they may be sharing an inpatient space.

Chapter 35

Table 35-1 0


1197

Guidelines for Sibling Visits to Well-Baby and High-Risk Nurseries

Sibling visits should be encouraged for healthy and ill newborns. Parents should be interviewed at a site outside the nursery to establish that the siblings are not i l l before allowing them to visit. Children with fever or other symptoms of an acute illness such as upper respiratory infection or gastroenteritis, or those recently exposed to a known communicable disease such as chickenpox, should not be allowed to visit. Visiting children should visit only their sibling. Children should be prepared in advance for their visit. Visitors should be adequately observed and monitored by hospital staff. Children should carefully wash their hands before patient contact. Throughout t h e visit, siblings should be supervised by parents or another responsible adult.

Data from American Academy of Pediatrics and American College of Obstetricians and Gynecologists. Care of the neonate. In Gilstrap LC, Oh W (eds).Guidelines for Perinatal Care, 5th ed. Elk Grove Village, 111, American Academy of Pediatrics, and Washington DC, American College of Obstetricians and Gynecologists, 2002, pp 331 -353.

Skin and Cord Care

Ocular Prophylaxis

Bathing the newborn is standard practice in nurseries, but Although blindness resulting from neonatal conjunctivitis is very little standardization in frequency or cleansing product rare in the United States, with a reported incidence of 1.6% exists. If not performed carefully, bathing actually can be or less, the rate among the 80 million infants born annually detrimental to the infant, resulting in hypothermia, increased throughout the world is as high as 23%.259 Chlamydia crying with resulting increases in oxygen consumption, trachornatis has been the most common etiologic agent in respiratory distress, and instability of vital signs.257Although the United States, but other organisms such as Neisseria the initial bath or cleansing should be delayed until the gonorrhoeae, S. aureus, and E. coli also can cause ophthalmia neonate’s temperature has been stable for several hours, neonatorum.260Use of 1% silver nitrate drops, at one time removing blood and drying the skin immediately after the agent of choice, is no longer recommended because of delivery may remove potentially infectious microorganisms concerns about associated chemical irritation. Agents thought such as hepatitis B virus, HSV, and HIV, minimizing risk to to be equally efficacious and now recommended include 1% the neonate from maternal infection.249When the newborn tetracycline and 0.5% erythromycin ophthalmic ointments, requires an intramuscular injection in the delivery room, administered from sterile single-use tubes or vials. 156~245 infection sites should be cleansed with alcohol to prevent Povidone-iodine (2.5%) ophthalmic solution also can be transmission of organisms that may be present in maternal used and in one study was shown to be more effective than silver nitrate or erythromycin in the prevention of ophthalmia blood and body For routine bathing in the first few weeks of life, plain warm water should be used. This is neonatorum. Bacterial resistance has not been seen with especially important for preterm infants, as well as full-term this agent, it causes less toxicity than either silver nitrate or infants with barrier compromise such as abrasions or erythromycin,and it is less expensivea definite consideration dermatitis. If a soap is necessary for heavily soiled areas, a in developing countries.259Whatever the agent selected, it mild pH-neutral product without additives should be used, should reach all parts of the conjunctival sac, and the eyes and duration of soaping should be restricted to less than should not be irrigated after application. 5 minutes no more than three times per week.257 Ophthalmic agents will not necessarily prevent ocular or disseminated gonorrhea in infants born to mothers with Few randomized studies comparing cord care regimens active infection at time of delivery. These infants should be and infection rates have been performed, and consensus has given parenteral antimicrobial therapy as well as ocular not been reached on best practice regarding care of the p r o p h y l a ~ i s . ’ ~Some ~ , ~ ~experts ~ also advise giving infants umbilical cord stump. A review published in 2003 described born to mothers with untreated genital chlamydia1infections care regimens used for more than 2 decades, including a course of oral erythromycin beginning on the second or combinations of triple dye, chlorhexidine, 70% alcohol, bacitracin, hexachlorophene, povidone-iodine, and “dry care” third day of life.261 (soap and water cleansing of soiled periumbilical skin) and found variable impact on colonization of the stump.258The Device-Related Infections study authors suggested that dry cord care alone may be Primary Bloodstream Infections insufficient and that chlorhexidine seemed to be a favorable antiseptic choice for cord care because of its activity against Primary bloodstream infections (defined by the CDC NNIS gram-positive and gram-negative bacteria. They went on to System as being due to a pathogen cultured from one or more blood specimens not related to an infection at another stress, however, that large, well-designed studies were required site) account for a large proportion of infections in NICU before firm conclusions could be drawn. The current Periinfants:’ and most are related to the use of an intravascular natal Guidelines do not recommend a specific regimen but catheter.36Peripheral intravenous catheters (PIVs) are the warn that use of alcohol alone is not an effective method of preventing umbilical cord colonization and ~mphalitis.’~~ most frequently used devices for the neonate for intravenous therapy of short duration. When longer access is necessary, The Perinatal Guidelines further recommend that diapers be nontunneled CVCs such as umbilical catheters and PICCs folded away from and below the stump and that emollients most commonly are The most recent data available not be applied to the

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Section V

Table 35-1 1


Strategies for Prevention of Catheter-Related Bloodstream Infections in Adult and Pediatric Patients

Conduct surveillance in NlCUs to determine catheter-related bloodstream infection rates, monitor trends, and identify infection

control lapses. Investigate events leading to unexpected life-threatening or fatal outcomes. Select the catheter, insertion technique, and insertion site with the lowest risk for complications for the anticipated type and duration of intravenous therapy. Use a CVC with t h e minimal number of ports essential f o r management of t h e patient. Designate one port for hyperalimentation if a multilumen catheter is used. Educate HCWs who insert and maintain catheters, and assess their knowledge and competence periodically. Use aseptic technique and maximal sterile barriers during insertion of CVCs (cap, mask, sterile gown, sterile gloves, and a large sterile barrier). Do not routinely replace CVCs, PICCs, or pulmonary artery catheters to prevent catheter-related infections. Do not remove on the basis of fever alone. In pediatric patients, leave peripheral venous catheters in place until intravenous therapy is completed unless a complication (e.g., phlebitis, infiltration) occurs. Remove intravascular catheters promptly when no longer essential. Observe proper hand hygiene procedures either by washing with antiseptic-containing soap and water or use of waterless alcohol-based products before and after working with intravascular lines. Disinfect skin with an appropriate antiseptic before catheter insertion and during dressing changes. A 2% chlorhexidine-based preparation is preferred. Do not use topical antibiotic ointment or creams on insertion sites, except when using dialysis catheters. Use either sterile gauze or sterile, transparent, semipermeable dressing to cover t h e catheter site. Replace gauze dressings on short-term CVC sites every 2 days and transparent dressings at least weekly, except in pediatric patients, in whom the risk of dislodging the catheter outweighs the benefit of changing the dressing. Change if damp, loosened, or visibly soiled. Replace dressings on tunneled or implanted CVC sites no more t h a n once per week until the insertion site has healed. Chlorhexidine sponge dressings are contraindicated in neonates younger than 7 days or those born at a gestational age of less than 26 weeks. Clean injection ports with 70% alcohol or an iodophor before accessing the system. Use disposable transducer assemblies with peripheral arterial catheters and pressure monitoring devices. Keep all components of such systems sterile, and do not administer dextrose-containing solutions or parenteral nutrition fluids through them. CVC, central venous catheter; HCW, health care worker; NICU, neonatal intensive care unit; PICC, peripherally inserted central catheter. Data from Centers for Disease Control and Prevention. Guidelines for prevention of intravascular catheter-related infections. MMWR Morb Mortal Wkly Rep 51(No. RR-10):32, 2002.

from NNIS (August 2003) revealed that the mean umbilical catheter- and CVC-associated bloodstream infection rates for NICUs ranged from 10.6 per 1000 catheter days for infants whose birth weight was less than 1000 g to 3.7 per 1000 catheter days in infants whose birth weight was 2500 g or more.’94The CDC recommends implementing strategies to reduce the incidence of such infections that strike a balance between patient safety and cost-effectiveness. Few large studies of risks related to intravascular devices have been performed in NICU patients. As a result, intravascular device recommendations for neonates are based on those developed for adults and older pediatric patients (Table 35-11).Several differences in their management should be considered. Although the CDC recommends, in certain circumstances,using antimicrobial- or antiseptic-impregnated CVCs in adults whose catheters are expected to remain in place more than 5 days,36these catheters are not available in sizes small enough for neonates. Of more importance, studies to evaluate their safety in neonates, especially premature neonates of very low birth weight, have not been performed. In addition, although the CDC recommends changing the insertion site of PIVs at least every 72 to 96 hours in adults, data suggest that leaving PIVs in place in pediatric patients does not increase the risk of complications.262The 2002 CDC guidelines recommend that PIVs be left in place in children until therapy is completed, unless complications occur. Careful skin antisepsis before insertion of an intravascular catheter is critical to prevention of intravascular devicerelated bacteremia, although care in the selection of a

product for use on neonatal skin is required. Chlorhexidine preparations are recommended by the CDC because these products have been found to be superior to povidone-iodine in reducing the risk for peripheral catheter colonization in neonates. Residues left on the skin by chlorhexidine prolong its half-life, providing improved protection for catheters in neonates that must be left in place for longer periods of timeF5’ Umbilical veins and arteries are available for CVC insertion only in neonates and are typically used for several days; thereafter, the CVC is replaced with another, nontunneled CVC or PICC if continued central venous access is required. The umbilicus provides a site that can be cannulated easily, allowing for collection of blood specimens and hernodynamic measurements, but after birth, the umbilicus quickly becomes heavily colonized with skin flora and other microorganisms. Colonization and catheter-related bloodstream infection rates for umbilical vein and umbilical artery catheters are similar. Colonization rates for umbilical artery catheters are estimated to be 40% to 55%; the estimated rate for umbilical artery catheter-related bloodstream infection is 5%?6 Colonization rates are from 22% to 59% for umbilical vein catheters; rates for umbilical vein catheter-related bloodstream infections are 3% to 8?40.~~ A summary of the CDC recommendations for management of umbilical catheters36is presented in Table 35-12.

Ventilator-Associated Pneumonia As mentioned earlier, NNIS data indicate that nosocomial pneumonia is the second most common infection type in

Chapter 35

Table 35-1 2


1199

Summary of CDC Recommendations for Management of Umbilical Catheters

Cleanse umbilical insertion site with an antiseptic before catheter insertion. Avoid tincture of iodine; povidone-iodine can be used. Add low doses of heparin to fluid infused through umbilical artery catheters. Remove and do not replace umbilical catheters if signs of catheter-related bloodstream infection, vascular insufficiency, or thrombosis are present. Remove umbilical catheters as soon as possible when no longer needed or if any sign of vascular insufficiency to the lower extremities is observed. Umbilical artery catheters should not be left in place for longer than 5 days. Umbilical venous catheters should be removed as soon as possible when no longer needed but can be used for up to 14 days if managed aseptically. CDC, Centers for Disease Control and Prevention.

Data from Centers for Disease Control and Prevention. Guidelines for prevention of intravascular catheter-related infections. MMWR Morb Mortal Wkly Rep 51(No RR-10):32, 2002.

removing endotracheal tubes as soon as indication for their use ceases are key infection control strategies. As an alternative to endotracheal intubation, noninvasive nasal continuous positive airway pressure (CPAP) ventilation avoids some of the common risk factors for ventilator-associated Removal of nasogastric or endotracheal tube as soon as pneumonia and has been used successfullyfor neonate^?^^"^^ clinically feasible Adequate hand hygiene between patients Respiratory care equipment that comes in contact with Semirecumbent positioning of the patient mucous membranes of ventilated patients or that is part of Avoidance of unnecessary reintubation the ventilator circuit should be single use (discarded after Provision of adequate nutritional support one-time use with a single patient) or be subjected to steriliAvoidance of gastric overdistention zation or high-level disinfection between patients. Wet heat Scheduled drainage of condensate from ventilator circuits pasteurization (processing at 76OC for 30 minutes) or Data from Kollef MH. Current concepts: the prevention of chemical disinfectants can be used to achieve high-level ventilator-associated pneumonia. N Engl J Med 340:627-634, 1999. disinfection of reusable respiratory equipment.263Ventilator circuits should be changed no more frequently than every 48 hours, and evidence suggests that extending the length of time between changes to 7 days does not increase the risk of NICU patients. Risk factors for ventilator-associated ventilator-associated pneumonia.z70s271 Circuits should be pneumonia can be grouped as host-related (prematurity, monitored for accumulation of condensate and drained low birth weight, sedation or use of paralytic agents), deviceperiodically, with care taken to avoid allowing the conrelated (endotracheal intubation, mechanical ventilation, densate, a potential reservoir for pathogens, to drain toward orogastric or nasogastric tube placement) and factors that the Sterile fluids should be used for nebulization, increase bacterial colonization of the stomach or nasoand sterile water should be used to rinse reusable semipharynx (broad-spectrum antimicrobial agents, antacids, or critical equipment and devices such as in-line medication H, b l o c k e r ~ ) . 5 ~Ventilator-associated ,~"~~~ pneumonia generally nebulizers.263 refers to bacterial pneumonia that develops in patients who Basic infection control measures, such as hand hygiene are receiving mechanical ventilation. Aspiration and direct and wearing gloves during suctioning and respiratory maniinoculation of bacteria are the primary routes of entry into pulation, also can reduce the risk of nosocomial pneumonia. the lower respiratory tract; the source of these organisms Both open, single-use and closed, multiuse suction systems may be the patient's endogenous flora or transmission from other patients, staff members, or the e n ~ i r o n m e n t .Few ~ ~ ' ~ ~ are ~ available. If an open system is used, a sterile single-use catheter should be used each time the patient is suctioned. studies have been performed to assess the effectiveness of Closed systems, which do not need to be changed daily and prevention strategies in pediatric patients. Strategies to prevent can be used for up to 7 have the advantage of lower ventilator-associated pneumonia in the NICU patient are costs and decreased environmental cross-contamination258 therefore based primarily on studies performed in adults but have not been shown to decrease the incidence of noso(Table 35-13). Hand hygiene remains critical to the precomial pneumonia when compared with open systems.273v274 vention of ventilator-associatedpneumonia, and HCWs should Although not well studied in pediatric patients, aspiration consistently apply the principles of standard precautions to of oropharyngeal secretions is believed to contribute to the care of the ventilated patient, wearing gloves to handle development of ventilator-associated pneumonia in adults.275 respiratory secretions or objects contaminated by them, and Placing the mechanically ventilated patient in a semichanging gloves and performing hand hygiene between recumbent position or elevating the head of the bed in an contacts with a contaminated body site and the respiratory attempt to minimize aspiration is recommended unless tract or a respiratory tract device. medically contraindicated. Also, placement of enteral feeding Because mechanical ventilation is a significant risk factor tubes should be verified before their To prevent for the development of nosocomial infection or ventilatorregurgitation and potential aspiration of stomach contents associated pneumonia, weaning from ventilation and

Table 35-1 3

Effective Strategies for Prevention of Ventilator-AssociatedPneumonia

1200

Section V


by the sedated patient, overdistention of the stomach should be avoided by regular monitoring of the patient’s intestinal motility, serial measurement of residual gastric volume or abdominal girth, reducing the use of narcotics and anticholinergic agents, and adjusting the rate and volume of enteral fee ding^.^^^,^^^ Oral decontamination, with the intent of decreasing oropharyngeal colonization, has been studied in adults and seems to lower the incidence of ventilatorassociated pneumonia (although not duration of ventilation or mortality but further work is needed to determine whether this is an effective strategy in neonates. In addition, medications such as sucralfate, as opposed to histamine H, receptor antagonists and antacids, which raise gastric pH and can potentially result in increased bacterial colonization of the stomach, have been used to prevent development of stress ulcers and have been associated with lower incidence of ventilator-associated pneumonia in adults.277Two studies suggest, however, that this approach is of no benefit in pediatric patients, but the authors stress that additional studies with larger sample sizes are needed to confirm these

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213. Ng W, Rajadurai VS, Pradeepkumar VK, et al. Parainfluenza w e 3 viral outbreak in a neonatal nursery. Ann Acad Med Singapore 28: 471-475,1999. 214. Larson EL, Early E, Cloonan P, et al. An organizational climate intervention associated with increased handwashing and decreased nosocomial infections. Behav Med 26:14-22,2000. 215. Pittet D. Improving adherence to hand hygiene practice: a multidisciplinary approach. Emerg Infect Dis 2234-240,2001. 216. American Academy of Pediatrics and American College of Obstetricians and Gynecologists. Inpatient perinatal care services. In Gilstrap LC, Oh W (eds). Guidelines for Perinatal Care, 5th ed. Elk Grove Viage, Ill, American Academy of Pediatrics, and Washington, DC, American College of Obstetricians and Gynecologists, 2002, pp 17-55. 217. Salisbury DM, Hutfilz P, Treen LM, et al. The effect of rings on microbial load of health care workers’ hands. Am J Infect Control 25:24-27,1997. 218. Trick WE, Vernon MO, Hayes RA, et al. Impact of ring wearing on hand contamination and comparison of hand hygiene agents in a hospital. Clin Infect Dis 36:1383-1390,2003. 219. Peke S, Ching D, Easa D, Melish ME. Gowning does not affect colonization or infection rates in a neonatal intensive care unit. Arch Pediatr Adolesc Med 148:1016-1020,1994. 220. Birenbaum HJ, Glorioso L, Rosenberger C, et al. Gowning on a postpartum ward fails to decrease colonization in the newborn infant. Am J Dis Child 144:1031-1033,1990, 221. American Academy of Pediatrics and American College of Obstetricians and Gynecologists. Infection control. In Gilstrap LC, Oh W (eds). Guidelines for Perinatal Care, 5th ed. Elk Grove Village, Ill, American Academy of Pediatrics, and Washington, DC, American College of Obstetricians and Gynecologists, 2002, pp 331-353. 222. American Academy of Pediatrics. Infection control for hospitalized children. In Pickering LK (ed). Red Book 2003 Report of the Committee o n Infectious Diseases, 26th ed. Elk Grove Village, Ill, American Academy of Pediatrics, 2003, pp 146-155. 223. Bozzi D, Burwen D, Dooley S, et al. Guideline for preventing the transmission of Mycobacterium tuberculosis in health care fac MMWR Mortal Morb Wkly Rep 43:l-132,1994. 224. Munoz FM, Ong LT, Seavy D, et al. Tuberculosis among adult visitors of children with suspected tuberculosis and employees at a children’s hospital. Infect Control Hosp Epidemiol23:568-572,2002. 225. Bowie BH, Hall RB, Faulkner J, Anderson B. Single-room infant care: future trends in special care nursery planning and design. Neonatal Netw 22:27-34,2003. 226. Harrison H. The principles for family-centered neonatal care. Pediatrics 92:643-650, 1993. 227. White RD, Brown 1, Cicco R, et al. Recommended standards for newborn ICU design: report of the Fifth Consensus Conference on newborn ICU design. Consensus Committee to Establish Recommended Standards for Newborn ICU Design, Clearwater Beach, Fla, 2002. Available at http://www.nd.edu/-kkolberg/DesignStandards.htm 228. Brown DG, Baublis J. Reservoirs of Pseudomonas in an intensive care unit for newborn infants: mechanisms of control. J Pediatr 90453-457, 1977. 229. Bert F, Maubec E, Bruneau B, et al. Multi-resistant Pseudomonas aeruginosa outbreak associated with contaminated tap water in a neurosurgery intensive care unit. J Hosp Infect 39:53-62, 1998. 230. Kappstein I, Grundmann H, Hauer T, Niemeyer C. Aerators as a reservoir of Acinetobacter junii: an outbreak of bacteraemia in paediatric oncology patients. J Hosp Infect 44:27-30,2000. 23 1. Sehulster L, Chinn RY. Guidelines for environmental infection control in health-care facilities. Recommendations of CDC and the Health Care lnfection Control Practices Advisory Committee (HICPAC). MMWR Recomm Rep 52:l-42,2003. 232. Moore D. Newborn nursery and neonatal intensive care unit. I n Carrico R (ed). APIC Text of Infection Control and Epidemiology. Washington, DC, Association for Professionals in Infection Control and Epidemiology, 2002, pp 48-55. 233. Rutala WA. APIC guideline for selection and use of disinfectants. 1994, 1995, and 1996 APIC Guidelines Committee. Association for Professionals in Infection Control and Epidemiology, Inc. Am J Infect Control 24313-342,1996. 234. Pugliese G, Hubbard C. Central services, linens, and laundry. In Bennett W,Brachman P (eds). Hospital Infections, 4th ed. Philadelphia, Lippincott-Raven, 1998, pp 725-739. Brachman P 235. Rhame FS. The inanimate environment. In Bennett JV, (eds). Hospital Infections, 4th ed. Philadelphia, Lippincott-Raven, 1998, pp 299-324.

Chapter 35


236. Centers for Disease Control and Prevention, Health Care Infections Control Practices Advisory Committee (HICPAC). Guidelines for environmental infection control in health-care facilities. Chicago, Ill, American Society for Health Care Engineering and the American Hospital Association, 2004. 237. Hall CB, Douglas RG Jr, Geiman JM, Messner MK. Nosocomial respiratory syncytial virus infections. N Engl J Med 293:1343-1346, 1975. 238. Hall CB, Kopelman AE, Douglas RG Jr, et al. Neonatal respiratory syncytial virus infection. N Engl J Med 300:393-396,1979. 239. Hall CB, Geiman JM, Douglas RG Jr, Meagher MP. Control of nosocomial respiratory syncytial viral infections. Pediatrics 62:728-732, 1978. 240. American Academy of Pediatrics. Herpes simplex. In Pickering LK (ed). Red Book 2003 Report of the Committee on Infectious Diseases, 26th ed. Elk Grove Village, Ill, American Academy of Pediatrics, 2003, pp 344-353. 241. American Academy of Pediatrics. Cytomegalovirus infection. In Pickering LK (ed). Red Book 2003 Report of the Committee on Infectious Diseases, 26th ed. Elk Grove Village, Ill, American Academy of Pediatrics, 2003, pp 259-262. 242. Ahlfors K, Ivarsson SA, Johnsson T, Renmarker K. Risk of cytomegalovirus infection in nurses and congenital infection in their offspring. Acta Paediatr Scand 70819-823,1981. 243. Balcarek KB, Bagley R, Cloud GA, Pass RF. Cytomegalovirus infection among employees of a children’s hospital. No evidence for increased risk associated with patient care. JAMA 263:840-844, 1990. 244. Fridkin SK, Pear SM, Williamson TH, et al. The role of understaffing in central venous catheter-associated bloodstream infections. Infect Control Hosp Epidemiol 17150-158, 1996. 245. American Academy of Pediatrics and American College of Obstetricians and Gynecologists. Perinatal infections. In Gilstrap LC, Oh W (eds). Guidelines for Perinatal Care, 5th ed. Elk Grove Village, Ill, American Academy of Pediatrics, and Washington, DC, American College of Obstetricians and Gynecologists, 2002, pp 285-329. 246. Brunell PA. Fetal and neonatal varicella-zoster infections. Semin Perinatol 747-56,1983. 247. Fallot ME, Boyd JL 3rd, Oski FA. Breast-feeding reduces incidence of hospital admissions for infection in infants. Pediatrics 65:1121-1124, 1980. 248. American Academy of Pediatrics. Human milk. In Pickering LK (ed). Red Book 2003 Report of the Committee on Infectious Diseases, 26th ed. Elk Grove Village, Ill, American Academy of Pediatrics, 2003, pp 117-123. 249. American Academy of Pediatrics and American College of Obstetricians and Gynecologists. Care of the neonate. In Gilstrap LC, Oh W (eds). Guidelines for Perinatal Care, 5th ed. Elk Grove Village, Ill, American Academy of Pediatrics, and Washington, DC, American College of Obstetricians and Gynecologists, 2002, pp 187-235. 250. el-Mohandes AE, Schatz V, Keiser JF, Jackson BJ. Bacterial contaminants of collected and frozen human milk used in an intensive care nursery. Am J Infect Control 21:226-230,1993. 251. DAmico CJ, DiNardo CA, Krystofiak S. Preventing contamination of breast pump kit attachments in the NICU. J Perinat Neonatal Nurs 17:150-157,2003. 252. Baker RD. Infant formula safety. Pediatrics 110833-835,2002. 253. Nyqvist KH, Lutes LM. Co-bedding twins: a developmentallysupportive care strategy. J Obstet Gynecol Neonatal Nurs 27:450-456, 1998. 254. DellaPorta K, Aforismo D, Butler-OHara M. Co-bedding of twins in the neonatal intensive care unit. Pediatr Nurs 24529-531,1998. 255. Wittrock B, Lavin MA, Pierry D, et al. Parents as a vector for nosocomial infection in the neonatal intensive care unit. Infect Control Hosp Epidemiol22:472,2001. 256. Cartolano GL, Moulies ME, Seguier JC, Boisivon A. A parent as a vector of Salmonella brandenburg nosocomial infection in a neonatal intensive care unit. Clin Microbiol Infect 9560-562,2003. 257. Darmstadt GL, Dinulos JG. Neonatal skin care. Pediatr Clin North Am 47757-782,2000. 258. Mullany LC, Darmstadt GL, Tielsch JM. Role of antimicrobial applications to the umbilical cord in neonates to prevent bacterial

259.

260. 261. 262. 263. 264. 265.

266. 267. 268.

269. 270. 271. 272. 273. 274.

275.

276.

277. 278.

279.

1205

colonization and infection: review of the evidence. Pediatr Infect Dis J 22~996-1002,2003. Isenberg SJ, Apt L, Wood M. A controlled trial of povidone-iodine as prophylaxis against ophthalmia neonatorum. N Engl J Med 332: 562-566,1995. Isenberg SJ, Apt L, Campeas D. Ocular applications of povidoneiodine. Dermatology 204(Suppl 1):92-95,2002, Smith J, Finn A. Antimicrobial prophylaxis. Arch Dis Child 80:388392,1999. Garland JS, Dunne WM Jr, Havens P, et al. Peripheral intravenous catheter complications in critically ill children: A prospective study. Pediatrics 891 145-1150, 1992. Centers for Disease Control and Prevention. Guidelines for prevention of nosocomial pneumonia. MMWR Morb Mortal Wkly Rep 46(No. RR- 1):l-79, 1997. Kawagoe JY, Segre CA, Pereira CR, et al. Risk factors for nosocomial infections in critically ill newborns: a 5-year prospective cohort study. Am J Infect Control 29:109-114,2001. Pepe R. Nosocomial pneumonia. In Carrico R (ed). APIC Text of Infection Control and Epidemiology. Washington, DC, Association for Professionals in Infection Control and Epidemiology, 2002, pp 88-1-88-3. Craven DE, Steger KA. Hospital-acquired pneumonia: perspectives for the health care epidemiologist. Infect Control Hosp Epidemiol 18: 783-795,1997. Kollef MH. The prevention of ventilator-associated pneumonia. N Engl J Med 340627-634, 1999. Lesiuk W, Lesiuk L, Maliczowska M, Puzniak G. Non-invasive mandatory ventilation in extremely low birth weight and very low birth weight newborns with failed respiration. Przegl Lek 59(Suppl 1): 57-59,2002, Fernandez-Jurado MI, Fernandez-Baena M. Use of laryngeal mask airway for prolonged ventilatory support in a preterm newborn. Paediatr Anaesth 12:369-370,2002. Lien TC, Lin MY, Chu CC, et aI. Ventilator-associated pneumonia with circuit changes every 2 days versus every week. Zhonghua Yi Xue Za Zhi (Taipei) 64:161-167,2001. Kotilainen HR, Keroack MA. Cost analysis and clinical impact of weekly ventilator circuit changes in patients in intensive care unit. Am J Infect Control 25:117-120, 1997. Stoller JK, Orens DK, Fatica C, et al. Weekly versus daily changes of inline suction catheters: impact on rates of ventilator-associated pneumonia and associated costs. Respir Care 48:494-499,2003, Zeitoun SS, de Barros AL, Diccini S. A prospective, randomized study of ventilator-associated pneumonia in patients using a closed vs. open suction system. J Clin Nurs 12:484-489,2003. Deppe SA, Kelly JW, Thoi LL, et al. Incidence of colonization, nosocomial pneumonia, and mortality in critically ill patients using a Trach Care closed-suction system versus an open-suction system: prospective, randomized study. Crit Care Med 18:1389-1393, 1990. Bergmans DC, Bonten MJ, Gaillard CA, et al. Prevention of ventilatorassociated pneumonia by oral decontamination: a prospective, randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med 164382-388,2001. Pugin J, Auckenthaler R, Lew DP, Suter PM. Oropharyngeal decontamination decreases incidence of ventilator-associated pneumonia. A randomized, placebo-controlled, double-blind clinical trial. JAMA 265:2704-27 10,1991. Cook DJ, Reeve BK, Guyatt GH, et al. Stress ulcer prophylaxis in critically ill patients. Resolving discordant meta-analyses. JAMA 275:308-314, 1996. Ildizdas K,Yapicioglu H, Ydmaz H. Occurrence of ventilator-associated pneumonia in mechanically ventilated pediatric intensive care patients during stress ulcer prophylaxis with sucralfate, ranitidine, and omeprazole. J Crit Care 17240-245,2002. Lopriore E, Markhorst DG, Gemke RJ. Ventilator-associated pneumonia and upper airway colonisation with gram negative bacilli: the role of stress ulcer prophylaxis in children. Intensive Care Med 28:763-767, 2002.

Chapter 36 LABORATORY AIDS FOR DIAGNOSIS OF NEONATAL SEPSIS Carl T. D‘Angio

Geoffrey A. Weinberg

Diagnostic Utility of Laboratory Tests

1207

Complete Blood Counts and White Blood Cell Ratios 1208 Total Leukocyte Count, Differential Leukocyte Count, and Morphology Total Neutrophil Count Total Nonsegniented Neutrophil Count Neutrophil Ratios Platelet Count

Acute-Phase Reactants 1211 C-Reactive Protein Erythrocyte Sedimentation Rate Other Acute-Phase Reactants

Additional Laboratory Studies 1214 Cytokine Concentrations Lymphocyte and Neutrophil Marker Analysis Miscellaneous Analytes Microscopic Examination of Placenta, Umbilical Cord, Gastric Aspirates, and External Ear Canal Fluid Screening Panels

Perspectivesand Conclusions 1217

For years, investigators have sought a test or panel of tests able to diagnose neonatal sepsis accurately and more rapidly than is possible with the isolation of microorganisms from specimens of sterile body fluids or tissues. Although results of some studies have been encouraging, the isolation of microorganisms from sources such as the blood, cerebrospinal fluid (CSF), urine, other body fluids (peritoneal, pleural, joint, middle ear), or tissues (bone marrow, liver, spleen) remains the most valid method of diagnosing bacterial sepsis. Many advances in nonculture methods, which may nevertheless remain microorganism specific, such as tests employing polymerase chain reaction (PCR) amplification technology, hold the promise of more rapid diagnosis of infection. In this chapter, nonspecific laboratory aids for the diagnosis of invasive bacterial infections are discussed. Specific microbiologic techniques are discussed in Chapter 6 and in chapters dealing with specific pathogens.

DIAGNOSTIC UTILITY OF LABORATORY TESTS In establishing the usefulness of any laboratory determination, a balance must be reached between sensitivity and specificity.’ For the clinician faced with a decision to institute or withhold therapy on the basis of a test result, the predictive

values (and perhaps likelihood ratios’) of that test also are of importance. In relation to neonatal infection, these terms can be defined as follows (Fig. 36-1): Sensitivity: If infection is present, how often is the test result abnormal? Specijicity: If infection is absent, how often is the test result normal? Positive predictive value: If the test result is abnormal, how often is infection present? Negative predictive value: If the test result is normal, how often is infection absent? Likelihood ratio, positive test result: If the result is abnormal, how much does that result raise the pretest probability of disease? Likelihood ratio, negative test result: If the result is normal, how much does that result lower the pretest probability of disease?

In attempting to discover the presence of a serious illness such as neonatal bacteremia, which is life-threatening yet treatable, diagnostic tests with maximal (100%) sensitivity and negative predictive value are desirable. In other words, if infection is present, the result would always be abnormal; if the result is normal, infection would always be absent. The reduced specificity and positive predictive value that this combination may engender usually are acceptable, because overtreatment with antibiotics on the basis of a false-positive result is likely to be of limited harm compared with withholding therapy on the basis of a false-negative result. Some authorities prefer the use of likelihood ratios, because predictive values vary with the prevalence of a disease but likelihood ratios relate only to the test performance (sensitivity, specificity).3*4 Large likelihood ratios (greater than 10) imply that a test result will conclusively raise the probability of the disease’s being present, whereas small likelihood ratios (less than 0.1) minimize the probability of the disease’s being present. In reviewing a report of a new laboratory aid for the diagnosis of neonatal sepsis, the first consideration is to determine what reference standard was used to evaluate the new test (i.e., what was the “gold standard” used). In one study, for example, among infants who died with unequivocal evidence of infection at autopsy, bacteria were grown from 32 of 39 antemortem blood cultures (sensitivity of only 82Y0).~Among 50 infants without pathologic findings of infection at autopsy, 48 had negative blood culture results (specificity of 96%). A positive blood or CSF culture result had a 94% chance of being associated with serious neonatal infection (positive predictive value of 94%), whereas a negative blood culture result indicated absence of serious

1208

Section V

Diagnosis and Management Bacterial Infection Present

Laboratory Test Result

Positive

Negative

YrS

No

TRUE POSITIVES

FALSE POSITIVES

POSITIVE PREDICTIVE VALUE

(a)

(b)

(a)/(a+b)

FALSE NEGATIVE3

TRUE NEGATIVES

NEGATIVE PREDICTIVE VALUE

(C)

(4

(d)/(c+d)

SENSITIVITY

SPECIFICITY

PREVALENCE

(a)/(a+c)

(W(b+d)

(a+c)/(a+b+c+d)

LIKELIHOOD RATIO,

LIKELIHOOD RATIO,

POSITIVE

NEGATIVE

sensitivity/( 1 -specificity)

( 1-sensitivity )/specificity

Figure 36-1 Diagnostic test characteristics. Sensitivity, specificity, postive predictive value, and negative predictive value are commonly expressed as percentages; likelihood ratios represent -fold increases or -fold decreases in pr~bability.’.~

infection only 87% of the time (negative predictive value of 87%). In fact, it is likely that the predictive values cited in this study already are different from those that may be observed in practice, because of the high prevalence (44%) of positive bacterial culture results in the autopsy cases re~iewed.~ (High prevalence inflates the positive predictive value and depresses the negative predictive value; low prevalence depresses the positive predictive value and inflates the negative predictive value.) Thus, the lack of perfection of the generally accepted “gold standard” of bacterial culture complicates the search for new laboratory aids in the diagnosis of neonatal sepsis, because it may be unclear whether a new test is truly functioning better than culture, which itself may not be “perfect.” Interpretation of bacterial culture results may become even more complicated as intrapartum antibiotic prophylaxis to prevent early-onset group B streptococcal sepsis becomes more c0mmon.6.~Of course, it may not be clinically necessary to require detection of only bacterial sepsis. Tests that yield results considered “falsely positive” in the absence of bacterial disease may still be clinically useful in assigning normal versus abnormal status if the results register positive because of serious viral disease that may require antiviral therapy (e.g., neonatal enterovirus or herpes simplex infections). Two additional points merit consideration in this context. First, unless the report is generated from an unselected cohort or prospective study, the predictive values given in the report may be misleading. Prevalence of sepsis may vary greatly if certain groups of newborns are pre-selected, which will in turn alter the predictive values of the test being studied. The most useful test in one population of infants of very low birth weight may function quite differently in another population of older, larger-birth-weight“growers.” Second, because the body’s response to an infection necessarily begins after the invasion of a pathogen, it may never be possible to diagnose an infection immediately-there may always be a lag in the physiologic response on which the diagnostic test is based. Each report of a new test claiming superiority to

bacterial culture must be critically evaluated in the field, and standardization both within clinical laboratories and between institutions is required.

COMPLETE BLOOD COUNTS AND WHITE BLOOD CELL RATIOS

Total Leukocyte Count, Differential Leukocyte Count, and Morphology It has been known for many years that total leukocyte counts are of limited value in the diagnosis of septicemia of the newborn.”-’“ Normal at the time of initial evaluation in more than one third of infants with proven b a ~ t e r e m i a , ~ . ’ ~ - ~ ~ total leukocyte counts are particularly unreliable indicators of infection during the first several hours of early-onset (within 48 hours of birth) sepsis. Conversely,among neonates evaluated for suspected sepsis, far less than half of those with reduced (fewer than 5000 cells per mm3) or elevated (greater than 20,000 cells per mm3)cell counts ultimately are identified as being i n f e ~ t e d . ~ ~ ’ ~ ~ ~ ~ * ~ ’ Differential leukocyte counts have not functioned well as markers for infectious disease in the newborn period. Increased percentages of lymphocytes have been described in association with pertussis and congenital syphilis,whereas minor changes of little diagnostic value have been noted in infants with ABO incompatibility, in sepsis, and in maternal hypertensi~n.’~*’~ Monocyte counts, normally higher in neonates than in older children or adults, may be further elevated in some cases of congenital syphilis, perinatal listeriosis, ABO incompatibility, and recovery from Eosinophilia, a common finding in premature infants, has been related to a number of factors, including low birth weight, immaturity, establishment of positive nitrogen balance, improved nutritional status, and use of total parenteral nutrition or blood transfusion^.^^"^ A dramatic fall in the absolute number of eosinophils, detectable only if serial counts have been per-

Chapter 36

Laboratory Aids for Diagnosis of Neonatal Sepsis

1209

VERY LOW BIRTH WEIGHT INFANTS

-

1

- \\

-

0

6 12 18 24 30 36 42 48 54 60

Time (h)

-'.------

\

"

I

o

I

I

12 24

1

\

I

36

I

48

I

60

I

72

I

96 Hours

I

I

120

144

formed, frequently accompanies sepsis or serious inf e c t i ~ n . ~ Basophil ~ ' ~ ~ ' ~ counts " tend to follow the fluctuations in eosinophil numbers in ill or healthy newborns.4' Conflicting data have been reported for the utility of differential leukocyte counts for identifymg neonates with bacterial meningiti~.~~,~' Several investigators have shown that, in association with serious bacterial infection, significant changes in neutrophil morphology occur, with the appearance of toxic granules, Dohle bodies, and v a ~ u o l i z a t i o n . ~These ~ , ~ ' ~features ~~ are of limited value in establishing a diagnosis; their presence has, at best, a positive predictive value for sepsis of only slightly more than 50%5,23v43-45 and, at worst, 33% to 37%.46347 Identical morphologic features can occur as artifacts in citrateanticoagulated blood samples stored for longer than 1 hour before smears are made.4s

Total Neutrophil Count Recognizing the low predictive value of total leukocyte counts in serious neonatal bacterial disease, several investigators have studied the dynamics of neutrophil counts during the first month of life.33340,43s49-54 These researchers and others uncovered patterns of change sufficiently constant to establish limits of normal variation (Fig. 36-2) and defined noninfectious conditions involving the mother or the infant that might have significant effects on neutrophil values (Tables 36-1 and 36-2). It was suggested that, largely on the basis of these data, calculation of the absolute number of circulating neutrophis (polymorphonudear plus immature forms) might provide a useful index of neonatal infection. Clinical experience has only partly supported this premise.

I

C

C

168 14 21-28 days days

Figure 36-2 Total neutrophil counts in normal term infants and in very low birth weight infants (inset). The limits for term infants are close to those defined by X a n t h o ~ Marks , ~ ~ and ~olleagues,~' and Schelonka and associates53but are significantly higher during the first 18 hours of life than the reference values of Manroe and c o - ~ o r k e r s(Data .~~ from Gregory J, Hey E. Blood neutrophil response to bacterial infection in the first month of life. Arch Dis Child 47:747-753, 1972; inset, data from Mouzinho A, Rosenfeld CR, Sanchez PJ, Risser R. Revised reference ranges for circulating neutrophils in very-lowbirth-weight neonates. Pediatrics 94~76-82,1999.)

Most series of consecutive cases of neonatal sepsis have shown abnormal neutrophil counts at the time of onset of symptoms in only about two thirds of infant^.^*^^-'^^^^^^^^*^^^-^^ In some series, however, up to 80% to 90% of infected infants have had abnormal values,21*46,49,69 whereas in other series, initial neutrophil counts were reduced or elevated in only one fourth to one third of infants with bacteremia, particularly when counts were determined early in the course of i l l n e ~ s . ~ ~ Thus, , ~ ~ , " the neutrophil count, although slightly more sensitive than the total leukocyte count, is too often normal in the face of serious infection to be used as a guide for treatment. Baley and associates investigated the causes of neutropenia among consecutive admissions to a neonatal intensive care unit.50 Low neutrophil counts were found in 6% of these infants, most of whom were premature and of low birth weight. Less than one half of the episodes of neutropenia could be attributed to infection (bacterial, viral, necrotizing enterocolitis);a majority were of unknown cause or occurred in infants with perinatal complications. Similar findings have been described by Rodwell and co-workers among 1000 infants evaluated for sepsis in the first 24 hours of life?7 In specific clinical situations, however, the neutrophil count can be of value. Although the association among neutropenia, respiratory distress, and early-onset (less than 48 hours) sepsis caused by group B streptococci is well documerited, 1621,62,71-74 the recognition that a similar association exists for early sepsis caused by other microorganisms has not been adequately emphasized. Several authors have described infants with septicemia related to Haemophilus i n f l ~ e n z a e ,p~n~e,u~m~ o c ~ c c i ? ~Escherichia -~~ ~ o l ior , ~non~ enterococcal group D streptococci" whose clinical course

1210

Section V

Table 36-1


Clinical Factors Affecting Neutrophil Counts in Newborn Infants Neutrophil Counts’ Decrease

Factor Maternal h y p e r t e n ~ i o n ~ ~ - ~ ’ Maternal fever, neonate healthy 26 hours intrapartum oxytocin administration Asphyxia (5-minute Apgar score 2000 g 7 days 8-14 days 7 days” 8-14 days

Mean Peak Serum Concentration (WmU

Mean Serum Half-life (hr)

Plasma Clearance (rnUmin/1.73 mz)

24 23.6

4.9 2.6

30 48

22.3 21 8.9 6.2

2.6 2.1 6.1 5.4

52 75 50 93 ~

aAverageweight at time of study, 3100 g.

1229

~~

1230

Section V


term infants.2 No accumulation of penicillin in serum is observed after 7 to 10 days of daily doses of procaine penicillin G, and the drug is well tolerated without evidence of local reaction at the site of injection. The concentrations of penicillin in urine and the urinary excretion after equivalent doses are similar for both procaine penicillin G and aqueous penicillin G.

BenzathinePenicillin G. Penicillin can be detected in serum and urine for up to 12 days after a single dose of 50,000 units/kg of benzathine penicillin G given intramuscularly to newborns. Peak serum concentrations of 0.4 to 2.5 pg/mL (mean, 1.2 pg/mL) are observed 12 to 24 hours after administration, and levels of 0.07 to 0.09 pg/mL are present at 12 day^."^>'^' Urinary concentrations range from 4 to 170 pg/mL for 7 days and from 0.3 to 25 pg/mL for 8 to 12 days after a dose of 50,000 units/kg of benzathine penicillin. This preparation is well tolerated by infants. Muscle damage from intramuscular injection as judged from creatinine values does not appear to be appreciably different from that after intramuscular administration of the other penicillins.

Cerebrospinal Fluid Penetration Penicillin does not penetrate CSF well, even when meninges are inflamed. Peak concentrations of 1 to 2 pg/mL are measured 30 minutes to 1 hour after an intravenous dose of 40,000 unitdkg of penicillin G is given to infants and children with bacterial meningitis.15*These values are 2% to 5% of concomitant serum concentrations and exceed the MIC values for streptococci and susceptible pneumococci by 50to 100-fold. CSF concentrations of penicillin, however, are not optimal to treat neonatal meningitis caused by penicillinresistant pneumococci. When meningeal inflammation is decreased, the concentrations of penicillin are reduced substantially. Concentrations of penicillin in CSF during the first several days of therapy are maintained in the range of 0.5 to 1 pg/mL; thereafter, the values are 0.1 pg/mL or less by 4 hours after the dose. Most newborns with uninflamed meninges have undetectable concentrations of penicillin in the CSF after a dose of 50,000 units/kg of intramuscular benzathine penicillin G.'56 With a dose of 100,000 units/kg, the mean peak concentration obtained 12 to 24 hours later is 0.06 pg/mL but falls to very low values by 48 to 72 hours.lS9For this reason, we do not recommend this long-acting penicillin for therapy for infants with congenital neurosyphilis. By contrast, mean CSF concentrations range from 0.12 to 0.7pg/mL between 4 and 24 hours after a dose of 50,OOo unitskg of procaine penicillin G is administered by inramuscular injection to These CSF values are at least severalfold greater than the required minimum spirocheticidal concentration.l6*

Oral Administration Potassium penicillin G has been administered orally to premature and term Mean peak serum concentrations at 2 and 6 hours after a dose of 22,000 units/kg were 1.4 and 0.7 pg/mL, respectively, in premature infants. The corresponding values in term neonates were 1.7 and 0.2 pg/mL.

Elimination Most of the penicillin dose is excreted in the urine in unchanged form. Tubular secretion accounts for approximately

90% of urinary penicillin, whereas glomerular filtration contributes the remaining 10%. Biliary excretion also occurs, and this may be an important route of elimination in newborns with renal failure.

Clinical Implications Penicillin remains effective for therapy for infections caused by group B streptococci, susceptible pneumococci and staphylococci, meningococci, susceptible gonococci, and T. pallidum. The dosage recommended for neonatal sepsis or pneumonia is 50,000 to 100,000 units/kg per day administered in two to four divided doses, whereas that for meningitis is 150,000 to 200,000 unitslkg per day in two to four divided doses, depending on birth weight and postnatal age.'63Neonatal meningitis caused by penicillin-resistant pneumococci must be treated with cefotaxime with or without vancomycin, depending on the MIC values. Oral penicillin therapy has no place in the management of neonates with acute systemic infections. Because central nervous system involvement in congenital syphilis is difficult to exclude with certainty, benzathine penicillin G should not be used for therapy for this disease unless new diagnostic modalities to rule out neurosyphilis are developed.'64 Its use for asymptomatic infants with normal findings on CSF examination and roentgenologic studies but who have positive results on treponemal serologic studies, presumably from maternal origin, is acceptable if follow-up can be ensured. For symptomatic infants and for asymptomatic infants with laboratory or radiologic evidence suggestive of congenital syphilis, the recommended regimen is either aqueous penicillin G, 50,000 units/kg daily for 10 to 14 days administered intramuscularly or intravenously in two divided doses, or procaine penicillin G, 50,000 unitslkg daily for 10 to 14 days administered once daily intramuscularly. All forms of penicillin are well tolerated in newborns. Cutaneous allergic manifestations to penicillin are rare in the newborn and young infant, and evidence for sensitization to the drug in infants who receive penicillin in the neonatal period, thus increasing the risk of an allergic response on reexposure, is lacking.

AMPICILLIN

Antimicrobial Activity Ampicillin commonly is used alone or in combination with aminoglycosides for treatment of suspected or proven neonatal bacterial infections. Compared with penicillin G, ampicillin has increased in vitro efficacy against most strains of enterococci and L. monocytogenes as well as against some gram-negative pathogens, such as typeable and nontypeable Haemophilus, Escherichia coli, Proteus mirabilis, and Salmonella species. It is not as active, however, against group A and group B streptococci and susceptible strains of staphylococci and pneumococci. Approximately 90% of group B streptococci and Listeria organisms are inhibited by 0.06 pg/mL or less of ampicillin. Almost two thirds of the gram-negative enteric bacilli isolated from CSF cultures of infants enrolled in the Second Neonatal Meningitis Cooperative Study (1976 to 1978) were inhibited by 10 pg/mL

Chapter 37

Table 37-4

1231

Pharmacokinetics of Ampicillin in Newborns Birth Weight/ Age Group

Dosage (Route) 50 mg/kg

Clinical Pharmacology of Antibacterial Agents

(IM)

100 mg/kg (IM)

Mean Peak Serum Concentration (WmU


Mean Plasma Clearance (mt./min/1.73 m')

104 130

6.2 2

21 30

81 84

4.7 2.3

42 63

213 216

4.7 3.5

NA NA

180 187

3.1 1.8

NA NA

2500 g 7 days 8-14 days >2500 g 7 days 8-14 days 2500 g 7 days 8-14 days >2500 g 7 days 8-14 days

IM, intramuscular; NA, not available.

or less of ampi~illin.'~~ Recently, however, an increased rate of ampicillin-resistant gram-negative bacilli has been reported and possibly linked to the frequent use of intrapartum prophylaxis with ampicillin to prevent early-onset group B streptococcal neonatal infection.'66

after a 50-mglkg intravenous dose and exceed the MIC values for group B streptococci and Listeriu by 50- to 300-f0ld.~~ By contrast, against many E. coli strains, these peak concentrations equal or exceed the MIC values by only severalfold. The values in CSF are lower later than in the course of meningitis, when meningeal inflammation subsides.

Pharmacokinetic Data

Oral Administration

Serum ampicillin concentration-time curves after intramuscular doses of 5 to 25mg/kg have been determined in n e w b o r r ~ s . ' ~ ~The - ' ~ ~mean peak serum concentrations 30 minutes to 1 hour after 5,10,20, and 25 mglkg doses were 16, 25,54, and 57 pg/mL, respectively, whereas the values at 12 hours were from 1 to 15 pg/mL (mean, 5 pg/mL). After 50-mg/kg doses, the mean peak values were from 100 to 130pg/mL in low-birth-weight infants and from 80 to 85 pg/mL in larger term infants (Table 37-4). Peak serum concentrations as high as 300 pg/mL (mean values, 180 to 216 pg/mL) are observed 1 to 2 hours after the lOO-mg/kg dose.35These latter values exceed the MI& values of group B streptococci by at least 3000-fold. The elimination half-life of ampicillin is inversely correlated with birth weight and postnatal age. Half-life times of 3 to 6 hours are noted in the first week of life and are 2 to 3.5 hours thereafter. Similar correlations with birth weight and chronologic age are observed with the plasma clearance of ampicillin. A mean peak serum concentration of 135pg/mL for premature infants with gestational ages of 26 to 33 weeks was found after an intravenous 100-mglkg dose of ampicillin, whereas for those infants with gestational ages of 34 to 40 weeks, it was 153 pg/mL.I7' When the loading dose was followed by maintenance ampicillin doses of 50 mglkg intravenously at 12- to 18-hour intervals, the mean peak and trough serum concentrations in steady-state conditions were 113 and 30 pg/mL, respectively, for premature neonates and 140 and 37 pg/mL for full-term neonates. The steady-state serum half-life for ampicillin was about 9.5 hours for premature newborns and 7 hours for full-term newborns.

Oral administration of 20- to 30-mg/kg doses of ampicillin trihydrate to normal, fasting full-term infants during the first 4 days of life produced peak values of 20 to 30 pg/mL 4 hours after the doses.'67 Higher peak serum concentrations are achieved by oral administration of the anhydrous form of ampicillin rather than the trihydrate preparation."' In our e~perience,'~~ mean peak serum concentrations of 6.4 and 6.1 pg/mL occurred at 1 and 2 hours, respectively, after a 25-mg/kg dose of ampicillin trihydrate, and the drug was absorbed equally well in both fasting and concomitantly milk-fed infants. Because of better absorption, amoxicillin would be expected to achieve higher serum concentrations than those observed for ampicillin after equivalent doses.

Cerebrospinal Fluid Penetration

Clinical Implications

Concentrations of ampicillin in CSF vary greatly. The largest concentrations (3 to 18 pg/mL) occur approximately 2 hours

Vast clinical experience has demonstrated that ampicillin is a safe and effective drug for therapy for neonatal bacterial

Safety Ampicillin is a safe drug when administered parenterally to newborns. Nonspecific rashes and urticaria are rarely observed, and diarrhea is uncommon. Elevations of serum glutamic-oxaloacetic transaminase and creatinine values frequently are detected in neonates and probably represent local tissue destruction at the site of intramuscular injection. Mild eosinophilia may be noted in newborns and young infants. Alteration of the microbial flora of the bowel may occur after parented administration of ampicillin, but overgrowth of resistant gram-negative organisms and Cundida albicuns occurs more frequently after oral administ r a t i ~ n . Diarrhea '~~ usually subsides on discontinuation of therapy. Amoxicillin is better tolerated, with fewer gastrointestinal side effects, than is orally administered ampicillin.

1232

Section V

Table 37-5


Fharmacokinetics of Methicillin and Nafcillin in Newborns Birth Weight/ Age Group

Dwg (Dosage)

Methicillin (25 mglkg per

dose)

Mean Peak Serum Concentration WmL)

2000 g 0-7 days 15 days >2000 g

0-7 days

Nafcillin

(50 mgikg per

15 days 2000 g

dose)a

0-7 days 8-28 days

Peak Serum Half-life (hr)

Mean Plasma Clearance (rn~/min/1.73m3

58 39

2.8 1.8

32 79

49 41

2.2 1.1

62 128

*160

4 3.2

0.91b 1.2b

aData from reference 181.

"Total body clearance (mL/min/kg).

infections caused by susceptible organisms. Combined ampicillin and aminoglycoside therapy is appropriate initial empirical management of suspected bacterial infections of neonates because it provides broad antimicrobial activity and potential synergism against many strains of group B streptococci, Listeria, and e n t e r o c ~ c c i . ~ ' - ~ ~ ' ~ ~ For systemic bacterial infections other than meningitis, a dosage of 50 to 75 mg/kg per day in two to three divided doses in the first week of life and of 75 to 100 mg/kg per day in three to four divided doses thereafter is recommended. For therapy for bacterial meningitis, we recommend a dosage of 150 to 200 mg/kg per day given in three to four divided doses, although some consultants use dosages as high as 300 mg/kg per day. We are not in favor of oral administration of ampicillin to newborns. As a general rule, infants with suspected or proven bacterial infections caused by susceptible organisms should receive parented treatment in the hospital. Otitis media in infants younger than 6 weeks of age may be better treated with other antimicrobial agents, such as amoxicillin-clavulanate or a cephalosporin, because S. aureus and resistant gramnegative organisms are possible etiologic agents.'74

ANTISTAPHYLOCOCCAL PENICILLINS S. aureus infections occur in nurseries either as sporadic cases or in the form of disease outbreaks. In recent years, multiply-resistant strains, especially coagulase-negative staphylococcal species, have been responsible for an increasing number of nosocomially acquired staphylococcal infections in many neonatal care units. Familiarity with the antistaphylococcal penicillins is essential for physicians involved in the care of newborns with infections caused by susceptible staphylococci.

Antimicrobial Activity The antistaphylococcalpenicillins are resistant to hydrolysis by most staphylococcal P-lactamases by virtue of a substituted side chain that acts by steric hindrance at the site of enzyme attachment. Most penicillinase-producing staphylococci are inhibited by 2.5 to 5 pg/mL or less of methicillin Currently, and by 0.5 p g / d or less of nafcillin and o~acillin.'~'

methicillin-resistant S. aureus (MRSA) strains constitute a relatively common cause of infection outbreaks in some nurseries, and methicillin-resistant Staphylococcus epidermidis (MRSE) strains are an important cause of catheter-associated disease, particularly among low-birth-weight premature infants. These challenging isolates possess altered PBPs with low affinity for binding to antistaphylococcal penicillins and cephalo~porins.'~~ Glycopeptide antibiotics such as vancomycin or teicoplanin are the drugs of choice for infections caused by these resistant strains. The topical antimicrobial agent mupirocin has been used successfully to eradicate MRSA strains from sites of the newborn body colonized with these strains and to prevent their spread to other infant^."^ In addition, tolerant staphylococci (with an MBC greater than five times the MIC) have been de~cribed.'~' Infections caused by these uncommon staphylococcal isolates may require combined therapy with aminoglycosides or rifampin or the use of vancomycin alone.

Pharmacokinetic Data Methicillin. Peak serum concentrations of methicillin are higher in the first week of life than during the remainder of the newborn p e r i ~ d . ' ~ ' .For ' ~ ~example, after 25-mg/kg intramuscular doses, mean peak values of 58 and 49 pg/mL are observed in 0- to 7-day-old infants who weigh 2000 g or less and those who weigh more than 2000 g at birth, respectively, whereas for these same birth weights, values of 39 and 41 pg/mL are achieved in infants 15 days of age or older (Table 37-5).'79A 50-mg/kg intramuscular dose produces a mean peak serum concentration of 80 pg/mL 30 minutes to 1 hour later. The half-life values become smaller with increasing birth weight and postnatal age. This observation correlateswith the substantial increase in the plasma clearance of methicillin that occurs during the neonatal period. Urine concentrations of methican are from 275 to 880 pg/mL in the first 2 hours after a 20-mg/kg intramuscular dose and usually are greater than 120 pg/mL for up to 12 hours after the dose. Approximately 30% of the dose is excreted in urine in the first 6 hours after administration.I6' NafciUh. The administration of 5-, lo-, 15-, and 20-mg/kg intramuscular doses of nafcillin to full-term newborns in the first 4 days of life produces mean peak serum concentrations

Chapter 37

Clinical. Pharmacology of Antibacterial Agents

1233

1 hour later of 10, 25, 30, and 37 pg/mL, respecti~ely.'~'~'~~methicillin and for oxacillin (preferred) is 25 to 50mg/kg every 8 to 12 hours (50 to 150mg/kg per day) in the first These concentrations are significantly higher than those week of life and every 6 to 8 hours (75 to 200 mg/kg per day) obtained in older children receiving comparable amounts of thereafter. The larger dosage is indicated for infants with this drug.'" Hepatic clearance evidently is the principal route disseminated disease or meningitis. For nafcillin, we recomof nafcillin elimination, because only 8% to 25% of this drug mend 25mg/kg per dose given every 12 hours in the first is excreted in the urine in a 24-hour period.18' week of life and every 6 to 8 hours thereafter. Peak concentrations of nafcillin of 100 to 160 pg/mL were In the unlikely circumstance that the Staphylococcus obtained during steady-state conditions after 33- to 50-mg/kg species is susceptible to penicillin, this agent is preferred for intravenous doses were administered to premature infants therapy. If an infant does not respond to antimicrobial therapy weighing less than 2000 g at birth (see Table 37-5).'" The as anticipated, the physician should suspect an occult site of half-life ranged from 2.2 to 5.5 hours in these low-birthstaphylococcal disease ( e g , abscess, osteomyelitis, endoweight neonates. carditis), resistance of the pathogen to the drug given, or When nafcillin is given orally to newborns, mean peak tolerance of the organism to the antibiotic. Appropriate serum concentrations are 20% to 60% of those obtained drainage of purulent foci, addition of an aminoglycoside or after an identical dose is administered Oral doses of 5 to 20 mg/kg of nafcillin result in mean peak rifampin to the regimen, and use of vancomycin are among serum concentrations of 3 to 21 pg/mL 2 to 4 hours after several options to consider in management of unresponsive ingestion. infections. Oxacillin.The pharmacokinetics of oxacillin in neonates'is

similar to that of methicillin. Mean peak serum concenCARBENlClLLlN trations of approximately 50 and 100 pg/mL are produced by 20- and 50-mg/kg intramuscular doses, respe~tively.'~~"~~ Carbenicillin is an a-carboxybenzyl penicillin that possesses The serum half-life of oxacillin in premature infants is about activity against l? aeruginosa and some indole-positive Proteus 3 hours in the first week of life and 1.5 hours thereafter. strains. In addition, essentially all bacteria susceptible to Urinary concentrations are from 174 to 510 pg/mL in the ampicillin also are susceptible to carbenicillin. Although the first 2 hours after a 20-mg/kg dose; 17% of the dose is combination of carbenicillin and an aminoglycosideprovides excreted during 6 hours after administration in infants 8 to a broader antimicrobial activity, ampicillin plus an amino14 days of age, whereas 34% is excreted in infants 20 to glycoside is the combination preferred in most nurseries. 21 days of age.'68 Carbenicillin is no longer available in the United States, Cloxadlh. Oral administration of 5-, lo-, 20-, and 50-mg/kg having been replaced by newer, more active agents. single doses of cloxacillin to full-term neonates during the first 4 days of life results in mean peak serum concentrations Antimicrobial Activity of 15, 24, 32, and 92 pg/mL, respectively, 1 to 2 hours after ingestion of this d r ~ g . ' ~The ' mean concentrations at Like ampicillin, carbenicillin is effective in vitro against the 12 hours after these doses are given fall to 0, 3, 8, and two most common pathogens of neonatal septicemia and 19 pg/mL, respectively. meningitis, E. coli and group B streptococci. L. monocytogenes and enterococci are less susceptible in vitro to carbenicillin than to ampicillin. Klebsiella and many Pseudomonas species, Safety Most other than l? aeruginosa, are resistant to ~arbenicillin.~' The antistaphylococcalpenicillins are well tolerated and safe isolates in hospital-acquired staphylococcal infection also in newborn and young infants. Repeated intramuscular inare resistant to this agent.'89 Combinations of carbenicillin jections of methicillin frequently result in muscle damage and gentamicin are synergistic in vitro against l? aeruginosa, and elevation of creatinine concentrations. Formation of enterococci, and many Listeria isolate^.^' sterile muscle abscesses occasionally follows intramuscular administration. Nephrotoxicity (interstitial nephritis or Pharmacokinetic Data cystitis) is rare in newborns and occurs in 3% to 5% of children who receive large doses of methicillin and possibly The pharmacokinetic data for carbenicillin are similar to the other antistaphylococcal penicillins, with the exception those for ampicillin in newborns. Peak serum concentrations of nafcillin.184~185Reversible hematologic abnormalities such of 180 to 190 pg/mL are observed after lOO-mg/kg doses in as neutropenia or eosinophilia commonly are observed in all neonates except term infants older than 1 week of age, in children undergoing treatment with these drugs, but their whom peak values are from 140 to 150 pg/mL (Table 37-6).lW incidence in newborns is unknown. 185-188 Because nafcillin Although peak serum concentrations after intravenous doses has a predominant biliary excretion, accumulation of this drug are about twice those obtained after identical intramuscular in serum can occur in jaundiced neonates, and potential doses are given, the dose-response curves for both routes of adverse effects can develop. Extravasation of nafcillin at the administration are similar after the peak concentration is injection site can result in necrosis of local tissue. achieved.19' Serum half-life is inversely correlated with birth weight, chronologic age, and rate of creatinine c l e a r a n ~ e . ' ~ - ' ~ ~ During the first week of life, mean half-life values are from 3 Clinical Implications to 6 hours, whereas for neonates aged 1 to 4 weeks, values of Any of these antistaphylococcal drugs can be used for therapy 2 to 3 hours are ~bserved.'~'Plasma clearance of carbenicillin for staphylococcal infections in neonates. The dosage of increases appreciably during the first 30 days of life.

1234

Section V


Table 37-6 Pharmacokinetics of Carbenicillin, Ticarcillin, and Piperacillin in Neonates Drug (Dosage, Route)

Birth Weight/ Age Group

Carbenicillin (100mglkg; IM)

2000 g 7 days 8-14days >2000 g 7 days 8-14 days 2000 g Mean, 2.5 days >2000 g Mean, 3 days Mean, 34 days" 1000-1520g (mean, 1300 g) 7 days 1500-3580g (mean, 1930 g) 7 days 2265-3900g (mean, 3108 g) 7 days 850-1400g (mean, 1200 g) 8-14days 1500-2170 g (mean, 1725 g) 8-14days 2265-3900g (mean, 3108 g) 8-14days

Ticarcillin (75 mglkg; IM)

PiperaciIIin (75 mg/kg; IV)

Mean Peak Serum Concentration (W m L )


Mean Plasma Clearance (mUminll.73 m2)

180 186

5.7 3.6

25 35

185 143

4.2 2.1

45 77

189

5.6

31

159 125

4.9 2.2

54 118

137

4.3

1.7b

149

3.4

1Bb

129

2.5

2.5b

110

3.2

3.2b

100

2.5

3.4b

97

1.7

4.4b

aTicarcillin dosage of 100 mgkg. bTotal body clearance (muminlkg). IM,intramuscularly; IV, intravenously.

Because carbenicillin is eliminated by renal mechanisms, extremely large concentrations are present in urine. Concentrations of 800 to 5500 pg/mL (mean, 2689 pg/mL) are noted during the first 6 hours after administration of a lOO-mg/kg dose.'"

Clinical Implications Historically, carbenicillin given alone or preferably in combination with an aminoglycoside was used for therapy for neonatal infections caused by €? aeruginosa or indolepositive Proteus species. Newer antimicrobial agents are now preferred for these infections. Although synergism between carbenicillinand gentamicin has been observed in vitro against enterococci, L. monocytogenes, and I? aer~ginosa,~'the clinical significance of this phenomenon is uncertain. The dosage schedule for carbenicillin is the following: 100 mg/kg given every 12 hours for all infants younger than 1 week of age, every 8 hours for infants older than 7 days weighing less than 2000g at birth, and every 6 hours for neonates older than 7 days weighing more than 2000 g at birth. The drug should be administered intravenously over 20 to 30 minutes. The drug is well tolerated and safe in newborns. Platelet dysfunction, hypokalemia, and allergic manifestations observed in older patients have not been reported in neonates. Carbenicillin is a disodium salt that contains 4.7 mEq

of sodium per gram of drug, which should be a consideration in some newborns, such as those with heart failure.

TICARCILLIN Ticarcillin is a semisynthetic penicillin with pharmacologic and toxic properties virtually identical to those of carbenicillin. Its in vitro activity is similar to that of carbenicillin, with the exception that ticarcillin is more active against P. aer~ginosa.'~~ Mean peak serum concentrations of 189 pg/mL are seen 1 hour after administration of 75-mg/kg intramuscular doses to low-birth-weight infants younger than 7 days of age and of 125 to 160 pg/mL to older neonates (see Table 37-6).'93 The half-life and plasma clearance during the neonatal period are similar to those for ~ a r b e n i c i l l i n . ' ~ ~ , ' ~ ~ Comparative clinical studies of carbenicillin and ticarcillin have not been conducted to identify an advantage of one drug over the other. As noted previously, in the United States, carbenicillin is no longer available. Use of ticarcillin alone or combined with clavulanate (Timentin) is preferred in patients with P. aeruginosa infections because of its greater in vitro activity against this organism. Although the quantity of sodium per gram is larger for ticarcillin than for carbenicillin, the lower dosage schedule for ticarcillin that is recommended for neonates and young infants provides a



1235

important Characteristics of Extended-Spectrum Penicillins Extended-Spectrum Penicillin

Characteristic

Carbenicillin

licarcillin

Azlocillin

Mezlocillin

Piperacillin

++ ++

++ ++

++ ++

++

++

++ ++ ++

Antibacterial activity

Gram-positive cocci Streptococci Enterococci Staphylococcus aureu9 Gram-negative bacilli

Coliforms Klebsiella spp. Pseudomonas aeruginosa

Anaerobes Bacteroides fragilis

Body clearance

Renal Hepatic Sodium content (rnEq/g)

++

-

-

++

++

-

-

+ +

+

+ ++

t

+

+ ++

++ -

++ -

+ +

+ +

+

4.7

5.1

2.2

1.9

1.9

++

++

+

aPenicillin-resistantstrains. ++, good; +, moderate; -, poor.

smaller amount of sodium per dose of drug, which conceivably could be advantageous in infants with cardiac or renal disease. The dose is 75mg/kg administered every 12 hours to infants younger than 1 week of age, and every 8 and every 6 hours to older infants weighing 2000 g or less and more than 2000 g at birth, respectively. The co-administration of clavulanic acid with ticarcillin significantly enhances the antibacterial activity of the latter drug against several organisms, including some ticarcillinresistant strains of E. coli, Klebsiella pneumoniae, I? mirabilis, and s t a p h y l o c ~ c c i . ' ~Clavulanic ~ ~ ' ~ ~ acid is a p-lactam with weak antibacterial activity, but it has the property of being a potent irreversible inhibitor of several P-lactamases produced by gram-positive and gram-negative bacteria.lg7Information regarding the use of this compound in newborns is limited. Pharmacokinetic data obtained in three newborns with gramnegative infections treated with a ticarcillin-to-clavulanic acid weight ratio of 25:l included peak serum concentrations and half-life values similar to those observed after administration of ticarcillin a10ne.l~~This drug combination is potentially very useful in the treatment of neonatal infections. We have prescribed ticarcillin-clavulanate either alone or, more commonly, with an aminoglycoside for infants with nosocomial gram-negative enteric infections, with satisfactory safety and effectiveness.

Antimicrobial Activity

Mezlocillin, azlocillin, and piperacillin are active against a broad range of gram-positive and gram-negative bacteria (Table 37-7). In contrast with carbenicillin and ticarcillin, which show poor activity against K. pneumoniae, piperacillin is active against most isolates of this organism, whereas mezlocillin and azlocillin inhibit about 50%. They also are active against l? mirabilis and many strains of Enterobacter and .Serratia marcescens. Because these antibiotics are susceptible to hydrolysis by p-lactamases, they have very limited activity against p-lactamase-producing Enterobacteriaceae organisms.199200 Piperacillin is the most active of these agents against I! aeruginosa. Mezlocillin, the least active of the three, is at least as effective as ticarcillin against this organism. Ninety percent of l? aeruginosa isolates are inhibited by approximately 16,32, and 128 pg/mL of piperacillin, azlocillin, and mezlocillin, respectively."l These drugs have good activity against penicillinsusceptible strains of s. aureus, streptococci, Haemophilus injluenzae, Neisseria meningitidis, and L. monocytogenes. Penicillin- or ampicillin-resistant strains of these bacteria, however, also are resistant to these agents. In contrast with carbenicillin and ticarcillin, acylampicillins are active against enterococci. Activity against many anaerobes, such as Bacteroides fiagilis, Bacteroides melaninogenicus, and ClostriACY LAMPICILLINS dium perfringens, is good. When aminoglycosides are combined with any of these three agents, in vitro synergistic activity against r! aeruginosa, The acylampicillins, a group of semisynthetic penicillins, incoliforms, and susceptible S. aureus strains can be demonclude the ureidopenicillins-mezlocillin and azlocillin-and ~ , ~synergistic ~ and antagonistic interactions a piperazine derivative of ampicillin called p i p e r a ~ i l l i n . ' ~ ~ '~~t~r~a t e d . ' ~Both have been observed when these penicillins were combined These drugs have not been approved by the FDA for use in with various cephalosporins?"-202Antagonism may be related newborns. Many pathogens incriminated in neonatal into the ability of certain cephalosporins to induce j3-lactamase fections are susceptible in vitro to these antibiotics, but their production, which, in turn, inactivates the penicillins.200 most important feature is activity against I! aeruginosa.

1236

Section V


Pharmacokinetic Data M e z l o c i l h The pharmacokinetic behavior of mezlocillin has been studied in more than 150 premature and full-term infant^?'^-^^ Peak serum concentrations after 75-mg/kg intravenous doses occur at the end of drug infusion and range from a mean of about 260 pg/mL for newborns in the first week of life to 139 pg/mL for older neonates.206After intramuscular administration of an identical dose, peak concentrations were observed 30 minutes after the injection and ranged from a mean of 155 pg/mL for infants 1 week of age or younger to 121 pg/mL for those older than 7 days. No drug accumulation is observed after multiple doses of mezlocillin are a d m i n i ~ t e r e d ? Plasma ~ ~ , ~ ~clearance of this drug increases with advancing gestational and postnatal ages. The half-life of mezlocillin is inversely related to gestational age and postnatal age. It decreases from about 4.5 hours in premature infants aged 1 week or younger to about 1.6 hours in full-term neonates older than 7 days.206 Available information on the CSF penetration of mezlocillin in newborns is limited. In one study, concentrations of 20 to 90 pg/mL were measured at various intervals after 75-mg/kg intravenous doses.207In another study, however, values ranging from 0 to 13.7 pglmL (mean, 5.5 pg/mL) were found in nine neonates 1 to 3 hours after lOO-mg/kg mezlocillin doses were intravenously injected.208 The mechanisms of mezlocillin elimination have not been studied in newborns. Renal excretion is the principal route of elimination in adults. Up to 30% of a mezlocillin dose, however, may be excreted in bile.209

To improve antibacterial activity, a P-lactamase inhibitor, tazobactam, has been combined with piperacillin in an 8:l ratio. The mean half-life for piperacillin-tazobactam in neonates is approximately 1.5 hours. Addition of tazobactam provides coverage against P-lactamase-producing bacteria resistant to piperacillin alone. CSF penetration of this compound is

Safety Adverse reactions from parenteral administration of mezlocillin, azlocillin, or piperacillin are rare in newborns. Hypersensitivityreactions, diarrhea, neutropenia, eosinophilia, and elevated serum concentrations of hepatic enzymes are infrequent compared with transient complications encountered in older children and adults who received these drugs.lW Impaired hemostasis secondary to platelet dysfunction occurs less frequently with these antibiotics than with carbenicillin and ticarciIlir1.2’~ The sodium content of these drugs is less than half of that of carbenicillin or ticarcillin (see Table 37-7), which may be important in some newborns with cardiac or renal disease.

Clinical Implications

Mezlocillin and piperacillin, either alone or combined with aminoglycosides, have been used successfully for the treatment of bacteriologically proven neonatal infections. Experience is limited, however, with routine use of these agents for initial therapy in newborns with suspected sepsis. Accordingly, these agents should be reserved for situations in Azlocillin. After a 50-mg/kg intravenous dose of azlocillin, which a clear benefit can be derived from their use. Potential concentrations of about 200 pg/mL are obtained at the end recipients include newborns with I! aeruginosa sepsis, infants of drug infusion. Concentrations at 1 and 5 hours after the in whom sodium restriction is necessary, and neonates with ~ ’ ~ ~ ~ ’problems in whom it would be desirable to minimize dose are approximately 100 and 50 pg/mL, r e s p e c t i ~ e l y . ~ ~ ~ . bleeding The elimination half-life is about 2.5 hours. Most of the antibiotic-associated hemostatic impairment. azlocillin dose is excreted unchanged in the urine. Biliary The dosage schedule for mezlocillin is 75mg/kg given excretion accounts for only 5% of the dose. every 12 hours during the first week of life and every 8 hours thereafter. The proper dosage schedule for piperacillin for piperacillin.The mean peak serum concentration of piperanewborns has not been established. One study suggested cillin after an intravenous dose of 100mg/kg is about that piperacillin doses of 100 mg/kg every 12 hours may be 180 pg/mL, and it may be as high as 250 pg/mL in newborns appropriate and that a dose of 200mg/kg every 12 hours with impaired renal function?12 The half-life is prolonged should be used for meningitis.’” In a more complete and ranges from 3.5 to 14 hours (median, 6.5 hours). By pharmacokinetic a dosage schedule of 75 mg/kg contrast, the reported half-life of piperacillin for infants 1 to given every 12 and 8 hours for infants with gestational ages 6 months of age is about 47 minutes.213Repeated adminisof less than 36 weeks and postnatal ages of 0 to 7 days and tration of this drug does not result in its accumulation in older than 1 week of age, respectively, was recommended. serum.In one study;l4 a 75-mg/kg intravenous dose of piperaFor full-term infants (greater than 36 weeks of gestation), a d i n given to 28 neonates born at 29 to 40 weeks of gestational 75-mg/kg dose given every 8 hours during the first week age and at a weight of 860 to 3900g resulted in peak and of life and every 6 hours thereafter was recommended. trough serum concentrations ranging from 70 to 360 pg/mL Additional data are required before a dosage schedule can be and 5 to 34 WmL, respectively (see Table 37-6). The mean halfsuggested for azlocillin. life values ranged from 1.7 to 4.3 hours; half-life was inversely related to gestational age, postnatal age, and birth ~eight.2’~ CSF piperacillin concentrations of 2.6 to 6 pg/mL were CEPHALOSPORINS measured in three neonates without meningitis within 7 hours of the intravenous administration of a 100-mglkg dose.’I2 In All cephalosporins are semisynthetic derivatives of a one infant with Pseudomonas meningitis, piperacillin reached 7-aminocephalosporanic acid nucleus. The individual a concentration of 19 pg/mL in the CSF 2.5 hours after a derivatives differ chemically by the addition of various side 200-mg/kg intravenous dose was given?I2 chains. Cefoxitin and moxalactam are not technically The major route of piperacillin excretion is through the cephalosporins2’*but generally are included in discussions kidney. Up to 30% to 40% of the dose, however, may be eliminated by nonrenal mechanisms in ~ h i l d r e n . ~ ’ ~ , ~ ’ ~ of these antibiotics because of their close similarities to

Chapter 37 members of this group of drugs. Moxalactam is no longer available because of the potential for bleeding resulting from interference in prothrombin synthesis. It was ineffective against group B streptococci, limiting its usefulness in neonates. The cephalosporins exert their antibacterial action in a manner similar to that described earlier for penicillin. It has become customary, albeit confusing at times, to group cephalosporins into generations of agents on the basis of their antibacterial spectrum of activity (see subsequent discussion),rather than their time of introduction for clinical use.z19First-generation cephalosporins include cefazolin, cephalothin, cephalexin, and cefadroxil. Among the secondgeneration agents are cefaclor, cefprozil, cefamandole, cefuroxime, loracarbef, and cefoxitin. The most useful agents for the treatment of neonatal infections belong to the thirdgeneration cephalosporins, which include cefoperazone, cefotaxime, ceftizoxime, ceftriaxone, and ceftazidime. Oral third-generation compounds include cefixime, cefpodoxime, ceftibuten, cefdinir, and cefetamet. A fourth-generation cephalosporin, cefepime, is still undergoing clinical evaluation in infants and children, and very limited information is available for the neonatal age group. Cefepime has been shown to be effective for therapy for meningitis in children and should be useful for treatment of multiresistant gramnegative bacillary infections in pediatric patients. Cefpirome, another fourth-generation agent, has not been studied in infants. The characteristics of many of the just-mentioned cephalosporins, particularly the oral agents, are not discussed because of the lack of neonatal studies evaluating these agents.

AntimicrobiaI Activity The first-generation cephalosporinshave good activity against gram-positive organisms but limited activity against gramnegative bacteria. Susceptible pathogens include streptococci, penicillin-susceptible and penicillin-resistant staphylococci, and penicillin-susceptible pneumococci. Enterococci, methicillin-resistant staphylococci, and L. monocytogenes are resistant to these agents. Although typically the activity against coliforms is good, other antibiotics usually are preferred for treatment of infections caused by these organisms. Pseudomonas species, S. marcescens, Enterobacter species, indolepositive Proteus species, and B. fiagilis all are resistant to these antibacterial agents.”” Because of their improved stability to hydrolysis by p-lactamases, the second-generation cephalosporins have increased activity against many gram-negative bacteria compared with that of first-generation antibiotics. Cefamandole has in vitro activity against gram-positive cocci comparable with that of cephalothin and also is active against H. influenzae, Enterobacter cloacae, Klebsiella, E. coli, and Citrobacter. Cefuroxime is more active than cephalothin against group B streptococci, pneumococci, and gram-negative enteric bacilli and also is active against H. influenzae, meningococci, gonococci, and staphylococci.220Cefoxitin has considerably less activity against gram-positive cocci compared with the first-generation cephalosporins, but its spectrum of activity against gram-negative enteric bacilli is at least as good as that of cefamandole. In addition, cefoxitin has excellent in vitro activity against B. fiagilis and other anaerobe^.^'' Cefaclor, an oral cephalosporin, has a spectrum of activity similar to


1237

that of cefamandole.”” The second-generation agents have very poor activity against l? aeruginosa, enterococci, and L. monocytogenes. The third-generation cephalosporins have excellent in vitro activity against H. influenzae, gonococci, meningococci, and many gram-negative enteric bacilli.’I9 Ceftazidime and cefoperazone, however, are the only ones with adequate antiPseudomonas activity. Susceptibility of gram-positive organisms to these agents is variable but generally is lower than that to either first- or second- generation antibiotics. L. rnonocytogenes and enterococci are uniformly resistant to these agents. The fourth-generation cephalosporins demonstrate activity against gram-positive and gram-negative bacterial pathogens and circumvent the development of resistance to other broadspectrum cephalosporins that occurs with l? aeruginosa. Evidence also indicates that isolates of ceftazidime- and cefotaxime-resistant Enterobacter species are susceptible to cefepime.’’’ Resistant organisms include enterococci, L. monocytogenes, methicillin-resistant S. aureus and S. epidermidis, and anaerobes. Resistance to the cephalosporins develops through several mechanisms. Cephalothin and cefazolin can be inactivated through enzymatic hydrolysis by p-lactamases.222Exposure of some gram-negative bacteria, such as P aeruginosa or E. cloacae, to second- or third-generation agents can induce the production of chromosomally mediated potent p-lactamases by these bacteria, which can hydrolyze even the P-lactamase-stable cephalosporins.’’’ Several plasmidmediated p-lactamases have been shown to play a role in the resistance of certain gram-negative enteric bacilli to thirdgeneration cephalosporin~?~~ Other mechanisms of resistance include alterations in the permeability of the outer membranes of gram-negative bacteria to these drugs that limit their ability to reach the PBP target sites. Mutations leading to functional or quantitative changes in PBPs constitute an additional means by which bacteria can resist the antimicrobial action of these d r ~ g s . ~ ~ ~ * ~ ~ ~

Pharmacokinetic Data Cqhalothin.The intramuscular administration of a lO-mg/kg dose of cephalothin to full-term newborns in the first 4 days of life results in a 1-hour mean serum concentration of 12.4 ~ g / m L . A ’ ~20-mg/kg ~ dose given to a similar group of neonates produced mean concentrations of 47, 39, 10, and 2 pg/mL at 0.5, 1, 4, and 8 hours, respectively, after the i n j e ~ t i 0 n . lIn ~ ~another study, premature newborns given 12.5-mg/kg intramuscular doses achieved concentrations of 22, 12, 2.4, and 0.5 pg/mL at 0.5, 2, 6, and 12 hours, respectively, after the injection, and these values were noted to be slightly lower than those for full-term newborns receiving an identical dose.z24 After the intravenous infusion of 20 mg/kg of cephalothin to six newborns 3 to 21 days of age, serum concentrations of 61,35,7, and 2 pg/mL were detected 0.25, 1,4, and 8 hours, respectively, after the end of the infu~ion.”~ The mean halflife was about 1.5 hours. The continuous intravenous infusion of 40 mg/kg per day of cephalothin produces serum values of 24 to 35 pg/mL in premature infants and lower concentrations of 7 to 22 pg/mL in full-term neonates. Increasing the dose to 80mg/kg per day resulted in serum concen-

1238

Section V


trations of 50 to 120 pg/mL in the premature infants and 32 11 pg/mL at 0.5, 1,5, and 12 hours, re~pectively.’~~ The halflife values were from 2 to 11 hours (mean, 6 hours). to 50 pg/mL for those born at term.226 Cephalothin does not penetrate into the CSF to any CSF cefuroxime concentrations of 2.3 to 5.3 pg/mL were measured in three newborns with rneningiti~.~~’ These appreciable extent, even in the presence of meningeal inflammation. The drug is metabolized in the body to deacetylvalues represented 12% to 25% of the corresponding serum cephalothin, which is only 20% as active as ~ e p h a l o t h i n . ~ ~concentrations. ~ In three other neonates without meningeal inflammation, concentrations were lower and ranged from Both cephalothin and its metabolite are excreted in the 0.4 to 1.5 pg/mL. In a brief publication, a CSF cefuroxime urine, primarily by tubular secretion. Approximately 60% of concentration of 20 pg/mL was found after the third dose of the cephalothin dose can be recovered in the urine within the drug in one patient, and concentrations of 50 and 8 hours of drug administration.225 47 pg/mL were detected 2.5 and 3 hours, respectively, after Cefazolin. The intramuscular administration of 20 and an intravenous dose in a second infant with hydrocephalu~.~~~ 25 mg/kg doses of cefazolin produces serum concentrations of 30 to 35 pg/mL and 55 to 65 pg/mL, respectively, 1 hour Cefotaxime. Several investigators have evaluated the after the dose. The concentrations at 12 hours drop to 2 to pharmacokinetic properties of cefotaxime in newborn^.'^^-^^' 3 pg/mL and to 13 to 18 pg/mL, respectively. 228 Intravenous A 25-mg/kg intravenous dose produces concentrations of 60 doses of 25 mg/kg administered to six premature infants 2 to to 80pg/mL immediately after the end of drug infusion, 12 days of age resulted in mean serum concentrations of 92, which decreases to 35 to 50 pg/mL 30 minutes later.237’240 79,48, and 12 pg/mL at 0.5, 1,4, and 12 hours, respectively, Serum cefotaxime concentrations are higher in premature after the end of the infusion.225The serum half-life of cefazolin newborns and in those younger than 1 week of age. The decreases from 4.5 to 5 hours in the first week of life to administration of a 50-mg/kg intravenous dose during the approximately 3 hours by 3 to 4 weeks of age. first week of life results in peak serum concentrations of CSF penetration of cefazolin is poor. The drug is excreted 116 pg/mL (range, 46 to 186 pg/mL) in low-birth-weight in the urine in unchanged form.227About 45% of the dose infants, compared with 133 pg/mL (range, 76 to 208 pg/mL) can be recovered in the urine within 12 hours,225and 80% to in term neonates (Table 37-8).238Values decline thereafter to 100% is recovered within 24 hours of administration.227y228 approximately 34 to 38 pg/mL 6 hours after the dose. The mean half-life is 4.6 hours for low-birth-weight neonates Cephalexin. A 15-mg/kg oral dose of cephalexin given to and 3.4 hours for larger newborns.23sWhen cefotaxime was newborns on their first day of life produces a mean peak administered intramuscularly at a dose of 50 mg/kg, a mean serum concentration of about 10pg/mL 4 hours after peak value of 93 pg/mL was measured 30 minutes after the drug ingestion.229Increasing the dose to 50 mg/kg provides a injection.239The apparent discrepancy between the peak conmean peak serum value of about 29 pg/mL (range, 23 to centrations obtained after intravenous and intramuscular 44 pg/mL) 2 hours after the dose. From 18% to 66% (mean, identical doses of cefotaxime is related to differences in the 39%) of the total dose is excreted in the urine over a 24-hour antibiotic assays employed. The former s t u d y used a bioperi0d.2~~ assay technique that measures the total concentration of both Cefaclor. Data on the pharmacokinetics of cefaclor in newcefotaxime and its biologically active metabolite desacetyl borns are limited. After a single oral dose of 7.5 mg/kg given cefotaxime, whereas the latter used a high-pressure to 10 full-term neonates, peak serum concentrations of from liquid chromatography method that provides separate 0.7 to 19 pglmL (mean, 7.7pg/mL) were observed 1 hour measurements of both compounds. after drug ingestion.230The mean serum concentrations at Cefotaxime is rapidly metabolized in the body to desacetyl 6 hours dropped to 3.5 pg/mL. A study performed in infants cefotaxime through the action of esterases found in the liver, and children revealed that peak serum values of 3 to 22 pg/mL erythrocytes, and other tissues.242This metabolite is bio(mean, 11 pg/mL) are observed 30 minutes after 15-mg/kg logically active, but its antibacterial activity is generally lower doses and that bioavailability is not affected by cothan that of cefotaxime. Synergistic interactions against many administration of drug and milk.231 organisms can be demonstrated when these two compounds are combined in ~ i t r o . ’Desacetyl ~~ cefotaxime accounts for Cefuroxime. After the administration of lO-mg/kg intra15% to 45% of the peak and for 45% to 70% of the trough muscular doses, peak serum concentrations ranged between 15 and 25 pg/mL 30 minutes to 1 hour after the injection.232 concentrations of totd c e f ~ t a x i m e . ~ ~ ~ - ~ ~ ~ Both cefotaxime and its metabolite penetrate well into Serum concentration was inversely related to birth weight. the CSF of infants with meningitis.23772449245 Concentrations Half-life times were from 3.6 to 5.6 hours. Repeated adof 7.1 to 30 pg/mL were detected 1 to 2 hours after a 50-mglkg ministration of the drug did not result in serum accumulation. intravenous dose and represented 27% to 63%, respectively, About 70% of the daily cefuroxime dose could be recovered of simultaneouslymeasured serum values. CSF concentrations in the urine in a 24-hour period. Intramuscular doses of as high as 20 pg/mL in neonates with or without meningitis 25 mglkg given to neonates weighing less than 2.5 kg during have been reported.24 Some investigators2453246 have noted their first week of life produced mean serum concentrations that higher CSF concentrations and greater penetration are of 49,30, and 15 pg/mL 2,4, and 8 hours after the injection, achieved with desacetyl cefotaxime than with cefotaxime. re~pectively.2~~ For newborns weighing more than 2.5 kg, the This observation suggests that the metabolite either is more corresponding values were lower (34, 21, and 9 pg/mL, capable of crossing the meninges than the parent compound respectively). Median serum concentrations of cefuroxime or is cleared more slowly once it reaches the CSF. measured on the third or fourth day of therapy with 25-mg/kg About 80% of the cefotaxime dose is excreted in the intramuscular injections given every 12 hours to a group of urine. Only a third of the drug is eliminated in unchanged premature and full-term infants were 45, 42, 26, and

Chapter 37

Table 37-8

Antibiotic'

Cefotaxime Ceftriaxone

Cefoperazone Ceftazidime


1239

Pharmacokinetics of Selected Third-Generation Cephalosporins in Neonates Birth Weight or Gestational AgelAge Group

Mean Peak Serum Concentration (IrglmL)


c2000 910-7 days 2000 910-7 days c1500 9 / 1 4 days 2000 g 1-12 mo (average, 3 mo) (10 rng/kg per dose)

Mean Peak Serum Concentration ( W m L)


Mean Plasma Clearance (mUmin/l.732)

25 30 26

5.9 6.7 4.1

27 30 50

Chapter 37 and weighing between 1120 and 1780 g. In a second stud?’* of premature infants aged 2 months or younger, a shorter mean half-life of 3 to 5 hours was found. A significant correlation was found between vancomycin serum half-life and clearance and a patient’s body weight or postnatal age.313,314 Neonates undergoing ECMO have a larger volume of distribution, lower clearance, and longer half-life of vancomycin than are observed in other infants.315 The CSF concentrations of vancomycin are 10% to 15% of the concomitant serum concentrations in infants with minimal meningeal inflammation, as seen in ventriculoperitoneal shunt infections?1 The degree of penetration is similar to that for nafcillin. In premature infants, born at 26 to 31 weeks of gestational age, dosages of 20 mg/kg every 18 to 24 hours were associated with CSF vancomycin concentrations of 2.2 to 5.6 pg/mL, which were 26% to 68% of their corresponding serum values.316 In low-birth-weight premature infants, blood sampling to determine peak concentrations of vancomycin should be performed 15 to 30 minutes after a 60-minute infusion. This measurement usually is performed after the third dose of vancomycin is given. Once a therapeutic peak serum concentration is achieved, concentrations should be monitored weekly if there is a change in renal function or if potentially nephrotoxic drugs are concomitantly given. The peak serum concentration that is considered to be therapeutic is 20 to 30 pg/mL, although concentrations of 30 to 40 pg/mL are preferred in treating meningitis. The upper limit of activity that must not be exceeded is unknown, but it is prudent to maintain serum concentrations below 50 pg/mL. Trough (predose) vancomycin values should be approximately 10 pg/mL or lower.


1245

preparations of this drug should be used only for the treatment of pseudomembranous colitis caused by C. difficile. Because of the increasing isolation of vancomycin-resistant enterococci, however, vancomycin is not recommended for treatment of antibiotic-associated Metronidazole is the drug of choice for this condition. The dosage schedule for vancomycin in neonates is 10 to 15 mg/kg every 12 hours (20 to 30 mg/kg per day) in the first week of life and every 8 hours (30 to 45mg/kg per day) thereafter. For premature infants, a different dosage schedule has been proposed that takes into account body weight and postnatal age to modify both the total daily dose and the dosing intervals for van~omycin.~’~ Although this dosage schedule resulted in more consistent peak and trough serum concentrations within the desired therapeutic range, approximately 25% of trough and 33% of peak concentrations fell outside the recommended therapeutic values.314Accordingly, monitoring serum vancomycin concentrations is essential in low-birth-weight premature infants and other infants with altered renal function who are given this drug. Beyond the newborn period, daily administration of 40 to 60mg/kg (divided into three or four doses) is recommended. The larger dosage is used for treatment of central nervous system infection. The dramatic increase in worldwide prevalence of vancomycin-resistant enterococci and the serious threat posed by the spread of vancomycin resistant to other grampositive organisms such as staphylococci should discourage the use of this antibiotic for antimicrobial prophylaxis in infants of very low birth weight and for empirical therapy for neonatal sepsis of unknown etiology. Thus, each nursery needs to implement a policy to restrict the liberal use of vancomycin for these situations.

Safety Initial experience with vancomycin in the 1950s suggested a moderate incidence of ototoxicity and nephrotoxicity. These adverse effects were presumably related to the impurities found in early preparations of the Further studies have indicated that vancomycin is well tolerated and safe when administered intravenously, particularly in newborns and young infants?l If it is administered over a period of less than 30 minutes, some patients develop a histamine reaction characterized by an erythematous, pruritic rash on the upper part of the body and arms and on the neck and face. This reaction persists for several hours and tends to resolve with antihistamine medications. Use of a slower infusion rate (i.e., over 45 to 60 minutes) usually avoids this adverse event.

Clinical Implications The primary indication for vancomycin therapy in newborns is for infections caused by methicillin-resistant staphylococci and by ampicillin-resistant enterococci. Vancomycin is effective for therapy of infections due to MRSA strains, an increasing problem in many American nurseries. We believe that vancomycin is the initial drug of choice for documented infections caused by S. epidermidis, because most strains are resistant to penicillin, methicillin, cephalosporins, and aminoglycosides.Vancomycin usually is not absorbed from the gastrointestinal tract, and oral

AMINOGLYCOSIDES For more than 3 decades, the aminoglycosides have been relied on for therapy for neonatal sepsis and meningitis because of their broad-spectrum antibacterial activity against gram-negative bacilli. Many neonatal care units, however, have limited their use because of a low therapeutic index and the emergence of resistant strains among gram-negative enteric bacilli. For example, serum aminoglycoside concentrations are only one to five times the MBCw for many gram-negative enteric organisms, and CSF concentrations are, at most, only one to two times greater. Streptomycin is no longer used, owing to the prevalence of resistant strains and to ototoxicity.Use of kanamycin also has been abandoned because of its lack of activity against k? aeruginosu and development of resistant coliform strains in many neonatal units during the 197Os?l9Currently, gentamicin, tobramycin, and amikacin are the aminoglycosides of choice in most nurseries worldwide. Because amikacin is resistant to degradation by most of the plasmid-mediated bacterial enzymes that inactivate kanamycin, gentamicin, and tobramycin, some U.S. nurseries have held amikacin in reserve for treatment of nosocomially acquired infections due to multidrug-resistant gram-negative organisms. Gentamicin resistance occurs frequently enough in some European, Latin American, and U.S. centers to warrant use of amikacin as a first-line drug for therapy of life-threatening gram-negative infections, and

12%

Section V


its routine use has not resulted in emergence of resistant strains. The history of aminoglycoside usage in the late 1950s and 1960s is an excellent example of the inherent problems of adapting dosages derived from studies in adults to newborns. Irreversible ototoxicity in neonates was caused by excessive doses of streptomycin or kanamycin. By contrast, the pharmacokinetics of gentamicin, tobramycin, amikacin, and netilmicin were carefully defined in the neonate before routine use of these drugs; appropriate studies thus provided a scientific basis for safe and effective dosage regimens. The risk of aminoglycosidetoxicity has been proved to be minimal when these agents are administered to infants in the proper dosage and when serum concentrations are closely monitored and kept within the recommended therapeutic range. During recent years, accumulating evidence generated in adults and children indicates that aminoglycoside administration using extended dosing intervals is at least as safe and effective as giving these drugs in two or three divided doses. The rationale for this concept is based on the concentrationdependent bacterial killing and prolonged postantibiotic effect (PAE) (discussed later under "Use of Extended Dosing Intervals") of the aminoglyco~ides.~~",~~' Several studies suggest that sin e-daily-dose regimens also apply in the neonatal The relevance of these results is discussed later.

Antimicrobial Activity Aminoglycosides act on microbial ribosomes to irreversibly inhibit protein synthesis. Possible mechanisms of bacterial resistance to these drugs include alteration of the ribosomal binding site, changes in the cell surface proteins to prevent entrance of drug into the cell, and induction of aminoglycosideinactivating enzymes. Antibiotic resistance in clinical situations is most often a result of extrachromosomallycontrolled (R-factor) Phosphorylation, adenylation, and acetylation are the three most common enzymatic mechanisms encountered. In general, gentamicin, tobramycin, amikacin, and netilmicin have good antibacterial activity against most gramnegative strains isolated in many hospitals worldwide. On a weight-for-weight basis, tobramycin has the greatest antiPseudomonas activity,342and amikacin is the only drug of this class that reliably provides activity against Serratia species and nosocomially acquired resistant coliforms. Although staphylococciare the only gram-positive organisms susceptible in vitro to aminoglycosides, infections caused by these pathogens usually do not respond satisfactorily to aminoglycoside therapy alone. Synergisticbactericidal activity between aminoglycosides and the penicillins has been demonstrated in vitro and in animals against S. a ~ r e u sgroup , ~ ~ B streptoL. mon~cytogenes,~~ and e n t e r o c ~ c c iin~ ~spite of low-level resistance of the microorganism to the aminoglycoside alone.

General Pharmacologic Considerations Traditionally, the intramuscular route has been preferred for the administration of aminoglycosides to avoid potentially toxic peak serum concentrations. Pharmacokinetic studies of k a n a m y ~ i n ,g~e~n t a m i ~ i n , and ~ ~ ~netilmicin4" ,~~ have, however, demonstrated that the serum concentration-time

curves after an intramuscular injection and after a 20-minute intravenous infusion are nearly superimposable. Although peak serum concentrations immediately after the intravenous dose may at times be considerably higher than the desired peak value, this elevation is transient and not clinically significant. The 6-hour serum concentrations, half-lives, and AUC values for these drugs also are equivalent. These drugs cannot be administered orally for treatment of systemic infection because they are not absorbed from the intact gastrointestinal Absorption through an inflamed gastrointestinal mucosa has, however, been suggested by studies in infants with gastroenteritis or necrotizing enterocolitis who were given oral n e o m ~ c i nand ~ ~in, infants ~~~ with shigello~is~~* and necrotizing e n t e r o ~ o l i t i who s ~ ~ ~were given oral gentamicin. More than 10% of the administered dose of gentamicin was excreted in the urine during the acute phase of Shigella dysentery, compared with only 2% after the acute inflammation had subsided. Peak serum gentamicin values of more than 10 pg/mL were detected in four children with necrotizing enterocolitis who received 2.5 mglkg every 4 hours by nasogastric tube in addition to 7.5 mg/kg per day by the intramuscular route.349The mean peak gentamicin concentration was slightly higher than that detected in a control group of infants receiving the drug only intramuscularly. The mean trough gentamicin values, however, were similar. By contrast, the prophylactic use of oral gentamicin in neonates at high risk for the development of necrotizing enterocolitis results in mean serum gentamicin concentrations below 2 &mL, with therapeutic serum values achieved only rare1y.350,351 Pharmacokinetic studies have demonstrated a prolonged washout phase in neonates for netiLmicin4"and gentamicin?' Mean terminal half-life of 62 to 110 hours and detectable serum and urine drug activity for as long as 11 and 14 days, respectively, after discontinuation of these drugs have been recorded. Presumably, the prolonged washout reflects release of the drug that was bound to tissue, most likely renal, during the steady state. The practical significance of these findings is unknown. Persistent small serum concentrations could conceivably place the infant who requires a second course of therapy at increased risk for the development of aminoglycoside-associatedtoxicity. It also is possible that the subinhibitory concentrations of aminoglycosides persisting in the urine could exert selective pressure for the emergence of resistant gram-negative organisms in neonatal intensive care units. Finally, several studies have indicated that aminoglycoside pharmacokinetics in the very low birth weight premature infant is highly variable because of renal immaturity and unpredictable extracellular fluid vo1umes.40*352-358 Therefore, these infants may require frequent measurement of serum drug concentrations and individualizationof dosage regimens. The pharmacokinetic properties of several aminoglycosides are compared in Table 37-10. Peak serum concentrations should be maintained at 5 to 8 pg/mL for gentamicin, tobramycin, and netilmicin and at 15 to 25 &mL for kanamycin and amikacin. Trough values should be kept below 2 pg/mL for the former drugs and below 10pg/mL for the latter agents. To determine peak serum concentrations, a blood sample should be drawn 15 to 30 minutes after completion of the intravenous infusion (from another intravenous site) and 45 to 60 minutes after the intramuscular administration.

Chapter 37

Table 37-1 0

Drug (Dose) Arni kaci n (7.5 rnglkg)

Gentarnicin (1.5 rng/kg)a Tobrarnycin (2 rnglkg)

Netilrnicin (3 rnglkg)


1247

Comparative Pharmacokinetics of Aminoglycosides in Neonates Birth Weight/ Age Group

Peak Serum Concentration (WmL)

2000 g 7 days >7 days >2000 g 7 days >7 days 2000 g n days >2000g n days All infants 27 days 2500 g c7 days 7 days >2500 g c7 days 7 days 2000 g 2000 g ’* The idiosyncratic reaction of bone marrow aplasia occurs in 1 in 30,000 to 1 in 50,000 patients receiving chloramphenicol treatment and is not dose related; whether this effect also occurs in newborns is not known. Other rare adverse effects of chloramphenicol therapy include sensorineural hearing loss, anaphylaxis, and retrobulbar neuritis, but these complications have been described only in older patients?59s460

Clinical Implications No rationale exists for the routine use of chloramphenicol in newborns. The agent can be considered an alternative to aminoglycosides for therapy for neonatal meningitis caused by gram-negative enteric bacilli in areas of the developing world, where third-generation cephalosporins are prohibitively expensive. The main drawbacks of chloramphenicol therapy are the drug’s toxicity and its bacteriostatic rather than bactericidal activity against gram-negative enteric pathogens. Considerable interpatient variation is observed in serum chloramphenicol concentrations in the first weeks of life. Consequently, it is advisable to monitor serum values whenever possible to avoid either toxic or subtherapeutic concentrations. Peak serum concentrations should be within

SULFONAMIDES The sulfonamides are structural analogues ofp-aminobenzoic acid and differ from each other according to various substitutions on the sulfonamide group of the benzene ring. These drugs were commonly used in the prophylaxis and treatment of neonatal bacterial infections, but their usefulness in neonates has become greatly limited because of the availability of superior antimicrobial agents, the emergence of resistant bacteria, and the association of kernicterus with sulfonamide administration in some premature infants. At present, no indications exist for their use in premature infants.

Antimicrobial Activity The sulfonamides are bacteriostatic agents with a wide range of antimicrobial activity against both gram-positive and gram-negative organism^.^^' In addition, some sulfonamides are active against Toxoplasma gondii, the causative organism of congenital toxoplasmosis. Antimicrobial action is based on competition with the structurally similar p-aminobenzoic acid for the same enzyme, thus preventing normal utilization of p-aminobenzoic acid by microbes. Synthesis of folic acid is inhibited at the dihydropteroic acid step. Acquired bacterial resistance to sulfonamides plays a significant role in therapeutic failures with this class of drugs. The origin of sulfonamide resistance is disputed, but the evidence indicates that mutations occurring randomly give rise to resistant variants, which are then favored by selection in the presence of the drug.%* Resistance is more likely to develop if treatment is prolonged. Transfer of multiple drug resistance (R-factor-mediated) among strains of coliform bacilli has been responsible for the emergence of sulfonamideresistant Shigella strains worldwide.

Pharmacokinetic Data A number of sulfonamide derivatives are currently available. As a general rule, the short-acting sulfonamides, such as sulfadiazine, trisulfapyrimidine, and sulfisoxazole, are most commonly used for acute urinary tract infections. The first two agents also are employed, in combination with pyrimethamine, for the treatment of congenital toxoplasmosis (see Chapter 31). Sulfadiazine is absorbed slowly from the gastrointestinal tract, reaching peak values 8 hours after administration. Sulfisoxazole is absorbed more rapidly, attaining earlier peak values that are 50% higher than those of ~ u l f a d i a z i n eThe . ~ ~ ~serum concentration-time curves for sulfisoxazole and triple sulfonamides are similar. The pharmacokinetic properties for several of the sulfonamide derivatives have been studied in newborns. Sulfadiazine administered subcutaneously in an initial dose of 100 mg/kg, followed in 48 hours by 50 mg/kg given every

Chapter 37


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24 hours for 3 days, produces mean peak serum values of

administration of single daily intravenous doses of 5.25 mg/kg 170 pg/mL and trough values of 90 to 110 pg/mL. Although of trimethoprim and 26.25 mg/kg of sulfamethoxazoleto 12 these concentrations are within the desired therapeutic range neonates?” On the third day of therapy, peak serum values (50 to 150 pg/mL), the individual values vary c~nsiderably.~~were from 3 to 6.4pg/mL. The mean serum half-life was Serum concentrations of 110 to 180 pg/mL were found after 19 hours after one dose and about 25 hours after multiple an initial 1OO-mg/kg sulfadiazine dose given subcutaneously, doses. The peak serum concentrations for sulfamethoxazole followed in 48 hours by a 50-mg/kg dose of triple sulfonamide ranged from 72 to 135 pg/mL after one dose but increased to given orally every 12 hours. Sulfisoxazole administered subvalues of 120 to 200 pg/mL after multiple doses. The mean cutaneously in a dose of 75 mg/kg every 12 hours results in trough serum concentration for sulfamethoxazole 24 hours serum concentrations of 60 to 120 pg/mL.I5 after the first dose was 20 pg/mL. The mean serum half-life The sulfonamides are excreted primarily by renal for sulfamethoxazole was 16.5 hours after one dose and mechanism^.^^ Glomerular filtration is the major mechanism 23.3 hours after multiple doses. The half-life values for both of excretion for both the free and the acetylated forms. Tubular drugs are longer in neonates than in older children and reabsorption occurs to various degrees for most sulfonamides. adults. Diminished renal function in neonates explains in part why The paucity of information on trimethoprimthey are able to maintain serum concentrations in the therasulfamethoxazole in newborns precludes its use in this age peutic range for longer periods than those observed in group except under extraordinary circumstances, and even children or adults. then it should be used with great caution. Physicians should be aware of the adverse effects of this compound before its use in neonates and in pregnant or nursing women; high Safety concentrations are found in amniotic fluid, fetal serum, and As a general rule, the sulfonamides are well tolerated by breast mdk after administration to the mother.471 newborns; crystalluria and hematuria are uncommon in The drug combination is available only as a preparation neonates. Use of these drugs in newborns has been greatly with a fixed trimethoprim-to-sulfamethoxazole ratio of 1:s. reduced by the demonstration that sulfonamides displace One suggested dosage schedule is to give an initial loading bilirubin from albumin-binding sites, with the development dose consisting of 2 mg/kg of trimethoprim and 10 mg/kg of of kernicterus observed in some premature infants who sulfamethoxazole,450followed by maintenance doses of received prophylactic treatment.15 Sulfonamides also may 0.6 mg/kg of trimethoprim and 3 mg/kg of sulfamethoxazole cause hemolysis in neonates who have erythrocyte G6PD given every 12 hours. deficiency.’ Cutaneous hypersensitivity reactions are rare in young infants.

Clinical Implications Because of the availability of safer and more effective antimicrobial agents, the sulfonamides should not be used during the neonatal period for therapy for bacterial infections. Their principal usefulness is in dual-agent treatment (pyrimethamine and sulfadiazine) of congenital toxoplasmosis. Neonates with acute urinary tract infections should receive parenteral treatment with ampicillin and an aminoglycoside until bloodstream invasion has been ruled out by blood culture. Bacteremia is found in approximately 20% of young infants with urinary tract infections.

TRIMETHOPRIM-SULFAMETHOXAZOLE The combination agent trimethoprim-sulfamethoxazole provides sequential and synergistic inhibition of microbial folic acid synthesis.466 Trimethoprim-sulfamethoxazole currently is used in the United States for therapy for urinary tract infections, otitis media and sinusitis, shigellosis, and Pneurnocystisjiroveci infections. It is not approved for use in newborns because of insufficient pharmacokinetic, safety, and efficacy data in this age group. Nevertheless, this compound has been successfully used alone or in combination with an aminoglycoside for the treatment of neonatal meningitis caused by gram-negativeenteric bacilli, particularly Salmonella organism^.^^-^' Treatment failures also have been observed.468 Mean peak and trough serum concentrations of trimethoprim were 3.4 pg/mL and 0.8 pg/mL, respectively,after

MACROLIDES The macrolide antimicrobial agents that have been used in neonates include erythromycin and spiramycin. Although the lincomycins (e.g., clindamycin) are not macrolides, they are included in this section because of similarities in their antibacterial activities and clinical uses. These drugs were used to treat neonatal staphylococcalinfections in the 1950s, when penicillin-resistant staphylococcal strains were prevalent and the penicillinase-resistant penicillins were not yet available. Erythromycin is useful in the young infant for therapy for infections caused by Chlamydia trachornatis and Bordetella pertussis; spiramycin, for treatment of toxoplasmosis; and clindamycin, for its activity against anaerobes, including B. fiagilis. The role of the newer macrolides, such as clarithromycin and roxithromycin, and of the azalide azithromycin for treatment of neonatal infections has not yet been defined. Erythromycin. Erythromycin is primarily a bacteriostatic agent that acts by interfering with protein synthesis through binding to ribosomes of susceptible bacteria and inhibiting the translocation steps.472Resistance to the macrolide antibiotics is due to demethylation of adenine in 23s ribosomal RNA, which results in reduced affinity between the antibiotic and the ribosome. Erythromycin is active against most gram-positive bacteria, including many penicillin-resistant strains of staphylococci. In some areas, penicillin-resistant pneumococci also are resistant to the macrolides; the higher the MIC of penicillin for pneumococci, the greater the MIC wiU be for the macrolides. In addition, most strains of Neisseriu

Section V

1256


-

Erythromycin ethylsuccinate

2.0

. -

1.5

9)

5

‘0 .-

-

1.a

2

0.5

c

2 c a

8 C

I

I

I

1

2

3

I

1

4 5 Time (h)

I

6

1

I

7

8

Figure 37-2 Serum concentration-time curves after administration of erythromicin ethylsuccinate and estolate to infants younger than 4 months of age.

species, T. pallidum, Mycoplasma pneumoniae, Ureaplasma urealyticum, B. pertussis, and C. trachomatis are susceptible to this agent. Erythromycin is rarely administered parenterally, owing to the associated tissue damage. Oral administration of erythromycin estolate to premature infants produced serum concentrations of 1 to 2 pg/mL 3 to 4 hours after a lO-mg/kg dose, and values of 0.5 pg/mL or greater were detected for a minimum of 6 h o ~ r s . 4Serum ~~ concentration of erythromycin was independent of birth weight, postnatal age, and gastric acidity. Accumulation of drug in serum did not result from repeated doses every 6 hours for 8 days. Similar pharmacokinetic results have been observed in full-term newborns.474 In a comparative pharmacokinetic study of erythromycin estolate and erythromycin ethylsuccinate,28 infants younger than 4 months of age, 12 of whom were neonates, were evaluated.4” The mean peak serum concentrations in infants taking the estolate were slightly greater than those taking the ethylsuccinate: 1.8 pg/mL as opposed to 1.3 pg/mL. During the steady state, the peak serum concentration was achieved in 3.2 hours for the estolate preparation, compared with 0.8 hour for the ethylsuccinate form of erythromycin (Fig. 37-2). Following analysis by the two-compartment model of pharmacokinetics, a similar difference was found in the mean absorption and elimination half-life values: absorption half-life values of 0.72 and 0.3 hour and elimination half-life values of 6.58 and 2.2 hours for the estolate and the ethylsuccinate, respectively. Thus, 12-hour dosing intervals are appropriate for the estolate. Erythromycin is excreted in the urine and bile, but only a fraction of the total dose can be accounted for by these two excretory routes. Although erythromycin is uniformly distributed throughout most of the body, concentrations in CSF are low, even in the presence of meningeal inflammation. Drug concentrations in tears 1 hour after administration were greater than the highest serum concentration measured in 70% of infants, ranging from 2 to 5.4pg/mL for the ethylsuccinate and from 0.6 to 5 pg/mL for the est0late.4~~ Erythromycin estolate is well tolerated by newborns. Cholestatic jaundice resulting from hypersensitivity to this preparation occurs primarily in teenagers and adults and has

not been reported in infants younger than 6 weeks of age.476 Loose stools as a side effect of erythromycin therapy were noted in about 2.5% of greater than 10,000 children evaluated in one study, including 69 neonates.477The concomitant administration of erythromycin and theophylline can lead to reduced clearance of the latter drug, with resultant inSerum theophylline creased risk of theophylline concentrations should therefore be monitored in these patients, and the dosage reduced if necessary. A recent report of a cluster of cases of pyloric stenosis among infants given erythromycin for prophylaxis after exposure to pertussis has raised concern about usage of erythromycin in neonates and young infants.479 Clindamycin. Clindamycin differs from its parent compound

lincomycin in that it is more completely absorbed from the gut, has fewer adverse effects, and has greater antibacterial activity in ~ i t r o . ~Indeed, ~’ lincomycin is only of historical interest in the United States. The drug is primarily a bacteriostatic agent that acts by inhibiting protein synthesis through binding to bacterial ribosomes. Clindamycin is active against gram-positive cocci such as S. aureus, S. pneumoniae (including many multidrug-resistant strains), and S. pyogenes. Aerobic gram-negative bacteria usually are not susceptible to this antibiotic. This drug’s most notable feature is its activity against anaerobic bacteria, especially members of the Bacteroides Resistance to clindamycin appears to be related to alterations of its target site and not to reduced uptake or to breakdown of the drug by resistant bacteria.481 Clindamycin administered intravenously in a dosage schedule of 20 mg/kg per day administered in three or four divided doses to premature and term infants results in mean peak serum concentrations of 11 pg/mL, whereas trough values are from 2.8 to 5.5 pg/mL:’* The serum elimination half-life is inversely related to gestational age and birth weight. Premature neonates demonstrate a mean serum half-life of 8.7 hours, compared with 3.6 hours for term newborns.482In another a serum elimination half-life of 3.5 to 9.8 hours (mean, 6.3 hours) was noted in12 neonates who received intravenous doses of 3.2 to 11 mg/kg every 6 hours. Clindamycin penetration into the CSF was once considered poor, but data in experimental meningitis models indicate excellent CSF concentrations after parenteral administration, The drug is eliminated primarily by the liver, with only about 10% excreted in unchanged form in the urine. Adverse effects of clindamycin include diarrhea, rashes, elevated levels of hepatic enzymes, granulocytopenia, thrombocytopenia, and Stevens-Johnson syndrome. The most serious and potentially lethal complication is pseudomembranous colitis, but this condition is rare in newborns and young infants, even though as many as 50% to 60% of such infants have gastrointestinal colonization with C. dificile. This adverse effect also is observed with the use of p-lactam and other antimicrobials.

Clinical Implications With the availability of newer penicillin analogues and vancomycin for treatment of staphylococcal infections, macrolides are no longer recommended for therapy for these infections in neonates. Erythromycin is currently the drug of

Chapter 37 choice for chlamydia1 conjunctivitis and pneumonitis, as well as for pertussis. The dosage is lOmg/kg given orally every 12 hours during the first week of life and every 8 hours thereafter. Peak serum concentrations of erythromycin are at least two to three times greater than the MICs reported for C. trachomatis (0.5 ~ ( g / m Land ) ~ several ~~ times greater than the MICs for B. pertussis (0.04 to 0.78 ~ g / m L ) A ? ~possible ~ advantage of the estolate is the persistence for 8 hours or longer of serum drug concentrations that are greater than the MICs for these two organisms. Recent clinical information suggests that clindamycin can be effectively used to treat methicillin-resistant (MRSA) but clindamycin-susceptible S. aureus infections.@5B486 This type of MRSA strain is more frequently acquired in the community than in the hospital. Caution is advised, however, because resistance to clindamycin can be induced after selective antimicrobial pressure. Inducible resistance can be identified in the laboratory by a technique named the D-test. Use of clindamycin in selected MRSA-infected cases can obviate the need for vancomycin therapy. Use of clindamycin in newborns also should be restricted, because as many as 50% of asymptomatic neonates are colonized with C. difficile, the presumed etiologic agent of pseudomembranous Evidence for an association of C. dificile colonization with colitis in newborns is lacking, however. For treatment of the rare B. fiagilis infections in newborns, especially those involving the central nervous system, we prefer the use of either metronidazole or clindamycin, although the latter has been said to have poor penetration into the CSF:88 albeit good penetration into brain tissue?89Accordingly, clindamycin has been used successfullyfor therapy for Toxoplasrna encephalitis in adults with human immunodeficiency virus infections.490 Whether congenital toxoplasmosis can be effectively treated with this agent remains undefined. Spiramycin is a macrolide antibiotic commonly used for the treatment of toxoplasmosis worldwide; its use and pharmacokinetic properties are discussed in Chapter 31.

OTHER ANTIBACTERIAL AGENTS Mupirocin. Mupirocin, a topical antibiotic formerly called “pseudomonic acid” (derived from fermentation of Pseudomonas fluorescens), has been used extensively in recent years to eliminate MRSA carriage and prevent outbreaks of neonatal MRSA infection in several n u r ~ e r i e s . ~Mupirocin ~’.~~~ interferes with bacterial RNA and protein synthesis by binding to bacterial isoleucyl-transfer RNA synthetase and preventing incorporation of isoleucine into protein chains.493 Trace amounts absorbed into the systemic circulation are rapidly hydrolyzed, and the inactive metabolite has a plasma half-life of less than 30 minutes.494This antibiotic has little cross-resistance with other antimicrobial agents, probably because of its unique mechanism of action. Mupirocin inhibits the growth of staphylococci and streptococci (except enterococci) in low concentrations and is bactericidal in high concentrations readily achieved by topical appli~ation.4~~ The drug is not active against members of Enterobacteriaceae, l? aeruginosa, or fungi. Emergence of resistant staphylococci has been reported with long-term topical therapy.496It also is possible that prolonged use of the drug may result in overgrowth of nonsusceptible organisms, such as fungi.


1257

Only local adverse effects such as itching or rash have been reported with mupirocin. Because mupirocin is prepared with a polyethylene glycol vehicle, the possibility of absorption and serious renal toxicity should be kept in mind if the compound is applied to extensive open wounds or skin lesi0ns.4~~

Rifampin. Because of the lack of relevant pharmacokinetic studies in newborns, many potentially useful antimicrobial agents are not discussed in this chapter. For example, rifampin usually is used in other parts of the world for the treatment of congenital tuberculosis. It is possible that with the increasing number of tuberculosis cases seen worldwide among patients with acquired immunodeficiency syndrome, this antibiotic will be used more frequently in the future in newborns of tuberculosis-affected mothers. Rifampin also might provide a synergistic effect when given with antistaphylococcaldrugs for therapy for of systemicstaphylococcal infections in selected neonates.498Italian investigators found mean peak serum rifampin concentrations of 5.8 pg/mL 12 hours after a lO-mg/kg dose was given orally to 18 male term newborns during their first 3 days of life.499By contrast, peak values were detected earlier (at 4 hours) and were substantially lower in older infants and children given a similar dosage of rifampin. These investigators proposed not to exceed a dosage of 10 mg/kg per day when rifampin is given orally to term newborn infants. Metronidazole. Metronidazole is another example of a potentially useful antimicrobial agent that has been poorly evaluated in the neonatal period. This drug has been occasionally used for the treatment of anaerobic infections in newborns, such as necrotizing enterocolitis and B. fiagilis meningitis. In one study, metronidazole pharmacokinetics was examined in 11 infants ranging in gestational age from 28 to 40 weeks and in chronologic age from 0 to 3 days.5n0 Elimination half-life was inversely related to gestational age, ranging from 22.5 to 109 hours. To achieve drug concentrations above the MIC required for treatment of anaerobic infections (i.e., 4 to 8 pg/mL), the investigators proposed an initial single intravenous dose of 15 mg/kg, followed 24 hours later in term infants and 48 hours later in preterm neonates by a dose of 7.5 mg/kg every 12 hours.

Ciprofloxacin.Several case reports have described the use of the quinolone ciprofloxacin in nosocomial outbreaks of neonatal infection^.^^'-^^^ No pharmacokinetic studies on ciprofloxacin, however, have been conducted in newborns; therefore, neonatal dosages used have been extrapolated from data generated in older children and adults. Although quinolones have not been approved by the FDA for use in children younger than 18 years of age, clinical pharmacologic data are available for many children but very few infants. The potential neonatal indications for parenteral administration of ciprofloxacin include treatment of multidrug-resistant gram-negative infections (species of Klebsiella, Enterobacter, Acinetobacter, Salmonella, Steno trophomonas, or Pseudomonas resistant to all other antibiotics) and meningitis caused by Flavobacterium meningosepticum. In these selected clinical situations, doses of 10 to 40 mg/kg per day, divided every 12 hours, have been used. Ampicillin-Sulbactam.Combination of a p-lactamase inhibitor (i.e., sulbactam or clavulanic acid) with ampicillin or

1258

Section V


amoxicillin offers the theoretical advantage of expanding the activity of the aminopenicillin against p-lactamaseproducing bacteria, such as methicillin-susceptible S. aureus, coliform bacilli, and some anaerobes. Experience with the use of these agents in the neonatal period is very limited. Pharmacokinetic data are available only for ampicillinsulbactam. In the reported study, this latter combination was administered to 16 newborns, 15 preterm infants, and 1 term infant.M8A dose of 50 mgkg of each drug every 12 hours was associated with mean plasma concentrations of 110 pg/mL for sulbactam and 87 pg/mL for ampicillin at 3 hours after dosing. Mean elimination half-lives were 7.9 hours for sulbactam and 9.4 hours for ampicillin. Evidence for significant accumulation of either drug was lacking, and both were well tolerated. Carefully designed pharmacokinetic studies are needed before this attractive combination can be used in the neonatal period.

Teicoplanin. Teicoplanin is a glycopeptide antibiotic that is almost identical to vancomycin with regard to antibacterial spectrum of activity, and it is used frequently in Europe for similar indications. It may have some advantages over vancomycin in terms of tolerability, with a lower propensity to cause nephrotoxicity and histaminic-type reactions, and in terms of ease of administration and monitoring requirements. Despite these potential advantages, pharmacokinetic data adequate to formulate dosage regimens in neonates are lacking. In a French study, four neonates received a single dose of 6 mg/kg, and the mean peak serum teicoplanin concentration was 19.6 pg/mL, with a mean half-life of 30 ho~rs.5’~ In several noncomparative trials, the clinical and bacteriologic response rates ranged between 80% and 100% in 173 infected neonates given teicoplanin 8 to 10 mgkg intravenously once daily, after a loading dose of 10 to 20 mg/kg.”’

Linemlid. Linezolid is an oxazolidinone antibiotic recently approved for treatment of infections caused by glycopeptideresistant strains of Enterococcus faecium, S. aureus, and S. pneumoniue. Because these microorganisms are becoming more common in critically ill neonates, linezolid is likely to play an increasingly important therapeutic role in the neonatal period. Data generated in term neonates and young infants given linezolid suggest that intravenous or oral doses of lomglkg every 8 hours are safe and effective, and that linezolid in this regimen is comparable to vancomycin for therapy of resistant gram-positive infection^.^"-^^^ The suggested dose for preterm infants and for those younger than 7 days of chronologic age is 10 mg/kg every 12 hours. The potential emergence and spread of oxazolidinone resistance will depend on the prudence with which linezolid is used in neonatal intensive care units.

DOSAGE SCHEDULES FOR ANTIBIOTICS COMMONLY USED IN NEONATES Dosage schedules for antibacterial agents commonly prescribed for the treatment of neonatal bacterial infections are presented in Table 37-12. For some drugs, the appropriate dosage schedules following initial doses should be based on measurement of serum concentrations.

REFERENCES 1. Roberts RJ. Drug Therapy in Infants: Pharmacologic Principles and Clinical Experience. Philadelphia, WB Saunders, 1984,p 3. 2. Huang NN, High RH. Comparision of serum levels following the administration of oral and parented preparations of penicillin to infants and children of various age groups. J Pediatr 42:657,1953. 3. Weiss CF, Glazko A], Weston JK. Chloramphenicol in the newborn infant: a physiologic explanation of its toxicity when given in doses. N Engl J Med 262:787,1960. 4. Kauffman RE, Thirumoorthi MC, Buckley ]A, et al. Relative bioavailability of intravenous chloramphenicol succinate and oral chloramphenicol palmitate in infants and children. J Pediatr 99963, 1981. 5. Shankaran S, KauMnan RE. Use of chloramphenicol palmitate in neonates. J Pediatr 105:113,1984. 6. Boccazzi A, Rizzo M, Caccamo ML, et al. Comparison of the concentrations of ceftazidime in the serum of newborn infants after intravenous and intramuscular administration. Antimicrob Agents Chemother 24:955, 1983. 7. Mulhall A. Antibiotic treatment of neonates4oes route of administration matter? Dev Pharmacol Ther 8:1, 1985. 8. Ristuccia AM. Chloramphenicol: clinical pharmacology in pediatrics. Ther Drug Monit 7159,1985. 9. Beutler E. Drug-induced hemolytic anemia. Pharmacol Rev 21:73, 1969. 10. Friis-Hansen B. Body water compartments in children: changes during growth and related changes in body composition. Pediatrics 28:169, 1961. 11. McCracken GH Jr. Clinical pharmacology of gentamicin in infants 2 to 24 months of age. Am J Dis Child 124884,1972. 12. Wise R. The clinical relevances of protein binding and tissue concentrations in antimicrobial therapy. Clin Pharmacol 11:463, 1977. 13. K u a H,Mauser-Ganshorn A, Stickel HH. Differences in the binding of drugs to plasma proteins from newborn and adult man: I. Eur J Clin Pharmacol 11:463,1977. 14. Schaad UB, Hayton WL, Stoeckel K. Single-dose certriaxone kinetics in the newborn. Clin Pharmacol Ther 37:522,1985. 15. Silverman WA, Andersen DH, Blanc WA, et al. A difference in mortality rate and incidence of kernicterus among premature infants allotted to two prophylactic antibacterial regimens. Pediatrics 18:614,1956. 16. Brodersen R, Friis-Hansen B, Stern L. Drug-induced displacement of bilirubin from albumin in the newborn. Dev Pharmacol Ther 6217, 1983. 17. Cashore WJ, Oh W, Brodersen R. Bilirubin-displacing effect of furosemide and sulfisoxazole:an in vitro and in vivo study in neonatal serum. Dev Pharmacol Ther 6:230,1983. 18. Stutman HR, Parker KM, Marks MI. Potential of moxalactam and other new antimicrobial agents for bilirubin-albumin displacement in neonates. Pediatrics 75:294,1985. 19. Gulian JM, Gonard V, Dalmasso C, et al. Bilirubin displacement by ceftriaxone in neonates: evaluation by determination of “free”bilirubin and erythrocyte-bound bilirubin. J Antimicrob Chemother 19823,1987. 20. Brodersen R, Ebbesen F. Bilirubin-displacing effect of ampicillin, indomethacin, chlorpromazine, gentamicin, and parabens in vitro and in newborn infants. J Pharm Sci 72248,1983. 21. Sakamoto H, Murakawa T, Hirose T, et al. Effect of ceftizoxime, a new cephalosporin antibiotic, on binding of bilirubin to human serum albumin. Chemotherapy 29:244,1983. 22. Walker PC. Neonatal bilirubin toxicity: a review of kernicterus and the implications of drug-induced bilirubin displacement. CLin Pharmacokinet 13326,1987. 23. Robertson A, Fink S, Karp W. Effect of cephalosporins o n bilirubinalbumin binding. J Pediatr 112291,1988. 24. Guignard JP. Drugs and the neonatal kidney. Dev Pharmacol Ther 4(Suppl 1):19, 1982. 25. Myers MG, Roberts RJ, Mirhij NJ. Effects of gestational age, birth weight, and hypoxemia o n pharmacokinetics of amikacin in serum in infants. Antimicrob Agents Chemother 11:1027, 1977. 26. Handwerger S,Tomasz A. Antibiotic tolerance among clinical isolates of bacteria. Rev Infect Dis 7368,1985. 27. Moellering RC Jr. Rationale for use of antimicrobial combinations. Am J Med 75(Suppl2A):4,1983. 28. Giamarellou H. Aminoglycosides plus beta-lactams against gram negative organisms: evaluation of in vitro synergy and chemical interactions. Am J Med 8O(Suppl. 6B):126,1982.

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151. 152.

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157.

158. 159. 160. 161. 162. 163. 164. 165.

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169.

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171. 172.

173. 174. 175. 176.

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184. 185. 186. 187.

188. 189. 190.

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