Medical Management of Infectious Disease (Clinical Guides to Medical Management)

Medical Management of Infectious Disease edited by

Christopher Grace University of Vermont Burlington, Vermont, U.S.A.

MARCEL DEKKER, INC.

NEW YORK • BASEL

Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. ISBN: 0-8247-0850-4 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-260-6300; fax: 41-61-260-6333 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright 䉷 2003 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3

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PRINTED IN THE UNITED STATES OF AMERICA

To my wife, Dr. Julie Olin, for her support, encouragement, and meticulous review of each chapter.

Foreword

Perhaps no advances in medicine have reduced morbidity and mortality as effectively as those improving prevention, diagnosis, and treatment of infectious disease. The developed world takes for granted eradication of smallpox (until the potential recrudescence spawned by the specter of bioterrorism), control of malaria, and prevention of polio. We now have remarkably effective treatment for diverse, formerly uniformly life-threatening bacterial and some viral infections such as mastoiditis, endocarditis, and liver abscess to name but a few. Judicious use of diagnostic, prophylactic, and therapeutic tools by physicians in virtually all disciplines is needed to realize the benefits that are now so attainable. The medical management series, of which this volume is a key component, was developed in collaboration with the late Graham Garratt to bring eminently practical information to clinicians in a format fashioned to optimize its accessibility and utility. The series is designed to provide ‘‘consultation’’ simulating that provided in practice by specialists to generalists and those in other specialties as well as to medical students, house staff, and fellows. The information presented is linked to cardinal signs and symptoms to enhance its accessibility relevant to specific clinical entities encountered in ambulatory care, emergency, and in-patient settings. Dr. Grace and his colleagues have fulfilled the objectives of the medical management series admirably. The individual chapters provide detailed descriptions of manifestations and pathophysiology of infections, pragmatic presentation of pharmacologic principles and practice, characterization of clinical syndromes and their management, consideration of populations at increased risk, and articulation of lynchpins of health maintenance in a post9/11 world. The contributing authors are knowledgeable. They are consummate clinicians as well as scholars. Their guidance is predicated on practical experience and in-depth knowledge. Their insights are compelling, and their opinions are authoritative. Their material is presented clearly and cogently. Diagrams, tables, and other aids enhance assimilation and facilitate comprehension. All who care for patients can benefit from this volume. Dr. Grace and his colleagues have provided a firm foundation for enhancing quality of care by enabling clinicians to access and utilize comprehensive information pertinent to the prevention, diagnosis, and treatment of infectious disease. Dr. Grace has, indeed, edited a volume that can serve well as a clinician’s consultant. Burton E. Sobel v

Preface

The practice of medicine has been shifting to a greater and greater extent to the outpatient setting. This is true for the management of infectious diseases as it is for all other disciplines. This shift has occurred because of economic pressures, improved outpatient and home care, enhanced diagnostics, better understanding of antibiotic pharmacokinetics and dynamics, and a growing armamentarium of antibiotic agents. All of these advances have improved our ability to manage common infections such as pneumonia, bronchitis, cellulitis, and gastrointestinal and genitourinary infections in the community locale. More complex illnesses such as osteomyelitis, septic arthritis, endocarditis, and infections involving immunocompromised hosts and in those receiving renal dialysis or using injection drugs are often being managed in the outpatient setting. Confounding these advances are new and emerging infections, globalization with greater international travel, an increasing number and complexity of immunocompromised patients, and now the threat of bioterrorism. This text was written for those providing primary care to patients, including family physicians, internists, emergency department physicians, gynecologists, surgeons, nurse practitioners, physician assistants, and medical subspecialists who provide primary care to their specialty patients. It is directed toward the adult patient and deals with infections encountered in the outpatient setting. The text also supplies the provider with initial diagnostic and therapeutic options and suggestions for the office patient needing to be hospitalized because of infections. The book can be read as a general review or used as a quick and practical reference to help the provider manage a large array of infections. Liberal use of tables, charts, photographs, and flow diagrams has been made to help keep the book practical and user-friendly. Every chapter is summarized with ‘‘Key Points’’ boxes to help the busy clinician access needed information quickly. Part I includes reviews of the pathogenesis, interpretation, and treatment of fever, the evaluation of the patient with fever and rash, the febrile patient without an obvious fever source, and noninfectious etiologies of fever. The approach to treating the patient with various infectious disease emergencies or positive blood cultures is summarized. Reviews are provided of antibiotic pharmacokinetics and dynamics, appropriate use of the microbiology laboratory, and commonly used outpatient-based oral and intravenous antibiotics. vii

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Preface

Part II examines common infectious syndromes involving the oral, respiratory, genitourinary and gastrointestinal tracts, as well as infections involving intra-abdominal organs, heart, skin and soft tissues, joints, bones, and the eye. An approach to the testing and initial evaluation of the person with human immunodeficiency virus infection is presented. Patients with unique geographic exposure such as those with regionally acquired fungal, parasitic, and viral syndromes, and those with tick-borne infections are presented. Part III reviews infections in special hosts such as the immunocompromised or pregnant patient, those receiving renal dialysis or living in nursing homes, the international traveler, and patients with animal contact–related illnesses. The continued epidemic of injection drug use necessitated a chapter involving infections in these patients. Epstein Barr virus–related infections are reviewed, as is the poorly understood chronic fatigue syndrome. Part IV summarizes infectious disease–related health maintenance issues such as vaccination and postexposure prophylaxis. The anthrax attacks in the fall of 2001 necessitated the final chapter on bioterrorism. Increasing bacterial resistance and widespread drug toxicities have made it imperative that all providers prescribe antibiotics judiciously. The epidemics of vancomycinresistant enterococci, methicillin-resistant Staphylococcus aureus, resistant aerobic gramnegative bacilli, and Clostridium difficile colitis have made it very clear that the overuse of antibiotics is dangerous. Ballooning health care costs and insurance policies with inadequate prescription coverage highlight the importance of being cognizant of antibiotic costs. This is emphasized throughout the text by comparing the average wholesale costs of antibiotics that may be used to treat infections. The book begins and concludes with quotations from Sir William Osler to emphasize the importance of the primary care clinician’s role in the recognition, diagnosis, and appropriate management of infections in the office setting. It is my hope that this text assists the primary provider in achieving these goals. Christopher J. Grace

Contents

Foreword Burton E. Sobel Preface Contributors

I.

v vii xiii

INTRODUCTION 1.

Fever Christopher J. Grace

1

2.

Infectious Disease Emergencies: Recognition and Initial Management Robert E. Levitz

17

3.

Commonly Used Oral Antibiotics Thomas Lamarre, William Maher, and Robert Fass

41

4.

Pharmacokinetics and Dynamics John W. Ahern

77

5.

The Clinician and the Microbiology Laboratory Daniel J. Diekema

97

6.

Outpatient Parenteral Antibiotic Therapy Donald M. Poretz

115

7.

Fever and Rash Mary Beth Ramundo

129

8.

Noninfectious and Cryptic Fevers Brad E. Robinson and Christopher J. Grace

151

9.

Blood Cultures Cheryl A. Smith

169

ix

x

Contents

II.

CLINICAL SYNDROMES

A.

B.

C.

Respiratory Tract 10.

Upper Respiratory Tract Infections W. Kemper Alston and Kristen I. Fahrner

187

11.

Common Oral Infections H. Charles Hill II, Thomas W. Connolly, and Susan M. Hill

209

12.

Community-Acquired Pneumonia and Bronchitis John G. Bartlett and Christopher J. Grace

227

13.

Tuberculosis C. Fordham von Reyn

251

14.

Common Cold and Influenza Sherif B. Mossad

265

Genitourinary Tract 15.

Urinary Tract Infections Kevin D. Dieckhaus

279

16.

Gynecological Infections Rebecca A. Clark

301

17.

Male Urogenital Syndromes Craig S. Conover, Sheila M. Badri, and Mark Potter

319

Cardiac 18.

D.

E.

Endocarditis JoAnn Tufariello and Franklin D. Lowy

347

Skin and Soft Tissue 19.

Bacterial Infections of the Skin and Soft Tissues Jeffrey Parsonnet

373

20.

Nonbacterial Infections of the Skin Anita Licata

393

21.

Ocular Infections Martin Mayers, Essene Bell, and Michael H. Miller

409

Gastrointestinal Tract 22.

Infectious Diarrhea Beth D. Kirkpatrick

437

23.

Hepatitis Jayant A. Talwalkar and Michael R. Charlton

455

24.

Intra-Abdominal Infections Neil H. Hyman and Christopher J. Grace

473

Contents

F.

Human Immunodeficiency Virus 25.

26.

G.

H.

III.

xi

The Patient with Human Immunodeficiency Virus Infection: Recognition, Testing, and Initial Assessment Kenneth H. Mayer and Daniel E. Cohen

495

Evaluation of the Symptomatic Human Immunodeficiency Virus–Infected Patient Janine Maenza

513

Bone and Joint 27.

Septic Arthritis and Bursitis Ellis H. Tobin and Eric S. Brecher

535

28.

Osteomyelitis Keith Collins

557

29.

Diabetic Foot Infections Christopher J. Grace and Michael A. Ricci

581

Geographic Exposure 30.

Tick-Borne Infections Robert P. Smith

599

31.

Endemic Fungal and Viral Infections Harold Henderson

621

32.

Common Manifestations of Parasitic Infections Sampath Kumar and Gordon M. Trenholme

633

INFECTIONS IN SPECIAL HOSTS 33.

The Pregnant Patient Mary-Margaret Andrews

645

34.

The Immune-Compromised Patient Robert W. Lyons

661

35.

Infections in the Injection Drug User Audrey L. French

677

36.

Infections in the Dialysis Patient Michael Berkoben

695

37.

Infections in the Patient with Animal Contact Anthony L. Esposito and George Abraham

709

38.

The Patient with Fatigue Irving E. Salit

723

39.

Epstein-Barr Virus Infection and Infectious Mononucleosis–Like Illnesses Irving E. Salit

40.

Evaluation of the International Traveler Beth D. Kirkpatrick

735 749

xii

Contents

41.

IV.

The Patient Living in a Nursing Home Henry S. Sacks

771

HEALTH MAINTENANCE 42.

Postexposure Prophylaxis Judith L. Steinberg

787

43.

Adult Immunization W. Kemper Alston

807

44.

Bioterrorism Christopher J. Grace

821

Index

855

Contributors

George Abraham Department of Medicine, Saint Vincent Hospital at Worcester Medical Center, and University of Massachusetts, Worcester, Massachusetts, U.S.A. John W. Ahern Department of Pharmacotherapy, Fletcher Allen Health Care, Burlington, Vermont, U.S.A. W. Kemper Alston Infectious Diseases Unit, College of Medicine, University of Vermont, Burlington, Vermont, U.S.A. Mary-Margaret Andrews Infectious Disease Section, Dartmouth-Hitchcock Medical Center, and Department of Medicine, Dartmouth Medical School, Lebanon, New Hampshire, U.S.A. Sheila M. Badri Division of Infectious Diseases, Rush Medical College, and Cook County Hospital, Chicago, Illinois, U.S.A John G. Bartlett Infectious Diseases Division, School of Medicine, Johns Hopkins University, Baltimore, Maryland, U.S.A. Essene Bell Department of Ophthalmology, Bronx Lebanon Hospital Center, Bronx, New York, U.S.A. Michael Berkoben Duke University Medical Center, Durham, and Gambro Healthcare, Henderson, North Carolina, U.S.A. Eric S. Brecher

Pennsylvania Hospital, Philadelphia, Pennsylvania, U.S.A.

Michael R. Charlton Division of Hepatology and Liver Transplantation, Mayo Clinic and Foundation, Rochester, Minnesota, U.S.A. Rebecca A. Clark Department of Medicine, Louisiana State University Health Science Center, New Orleans, Louisiana, U.S.A. Daniel E. Cohen Department of Research and Evaluation, Fenway Community Health, Boston, Massachusetts, U.S.A. Keith Collins

Champlain Valley Physician’s Hospital, Plattsburgh, New York, U.S.A. xiii

xiv

Contributors

Thomas W. Connolly U.S.A.

College of Medicine, University of Vermont, Burlington, Vermont,

Craig S. Conover Division of Infectious Diseases, Rush Medical College, and Cook County Hospital, Chicago, Illinois, U.S.A. Kevin D. Dieckhaus Division of Infectious Disease, Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut, U.S.A. Daniel J. Diekema Department of Internal Medicine and Pathology, College of Medicine, University of Iowa, Iowa City, Iowa, U.S.A. Anthony L. Esposito Department of Medicine, Saint Vincent Hospital at Worcester Medical Center, and University of Massachusetts, Worcester, Massachusetts, U.S.A. Kristen I. Fahrner Department of Surgery, Fletcher Allen Health Care, University of Vermont, Burlington, Vermont, U.S.A. Robert Fass† Division of Infectious Diseases, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, U.S.A. Audrey L. French Division of Infectious Diseases, Cook County Hospital, and Rush Medical College, Chicago, Illinois, U.S.A. Christopher J. Grace Infectious Diseases Unit, Fletcher Allen Health Care, University of Vermont, Burlington, Vermont, U.S.A. Harold Henderson Division of Infectious Disease, University of Mississippi Medical Center, Jackson, Mississippi, U.S.A. H. Charles Hill II Vermont, U.S.A. Susan M. Hill mont, U.S.A.

Department of Dental Hygiene, University of Vermont, Burlington,

Department of Dental Hygiene, University of Vermont, Burlington, Ver-

Neil H. Hyman Division of General Surgery, Department of Surgery, College of Medicine, University of Vermont, Burlington, Vermont, U.S.A. Beth D. Kirkpatrick Infectious Diseases Unit, College of Medicine, University of Vermont, Burlington, Vermont, U.S.A. Sampath Kumar Rush College of Medicine, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois, U.S.A. Thomas Lamarre U.S.A.

Infectious Disease Consultants of Cincinnati, Cincinnati, Ohio,

Robert E. Levitz Department of Medicine, University of Connecticut, Farmington, and Division of Infectious Diseases, Hartford Hospital, Hartford, Connecticut, U.S.A. Anita Licata Dermatology Unit, Fletcher Allen Health Care, University of Vermont, Burlington, Vermont, U.S.A. Franklin D. Lowy Departments of Medicine and Pathology, College of Physicians and Surgeons, Columbia University, New York, New York, U.S.A. †

Deceased.

Contributors

xv

Robert W. Lyons Department of Medicine, University of Connecticut, Farmington; Department of Infectious Disease, Saint Francis Hospital, Hartford; and Department of Internal Medicine, Yale University, New Haven, Connecticut, U.S.A. Janine Maenza Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, U.S.A. William Maher Division of Infectious Diseases, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, U.S.A. Kenneth H. Mayer Division of Infectious Disease, Department of Medicine, Brown University, and The Miriam Hospital, Providence, Rhode Island, U.S.A. Martin Mayers Department of Ophthalmology, Bronx Lebanon Hospital Center, and Albert Einstein College of Medicine, Bronx, New York, U.S.A. Michael H. Miller Infectious Disease Section, Departments of Medicine and Ophthalmology, Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, U.S.A. Sherif B. Mossad Infectious Disease Department, Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A. Jeffrey Parsonnet Infectious Disease Section, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, U.S.A. Donald M. Poretz

Inova Fairfax Hospital, Falls Church, Virginia, U.S.A.

Mark Potter School of Medicine, Loyola Stritch University, and Provident Hospital of Cook County, Chicago, Illinois, U.S.A. Mary Beth Ramundo Infectious Diseases Unit, Fletcher Allen Health Care, University of Vermont, Burlington, Vermont, U.S.A. Michael A. Ricci Division of Vascular Surgery, Department of Surgery, College of Medicine, University of Vermont, Burlington, Vermont, U.S.A. Brad E. Robinson Infectious Diseases Unit, Fletcher Allen Health Care, University of Vermont, Burlington, Vermont, U.S.A. Henry S. Sacks Thomas C. Chalmers Clinical Trials Unit, Mount Sinai School of Medicine, New York, New York, U.S.A. Irving E. Salit Immunodeficiency Clinic, Department of Medicine and Infectious Diseases, Toronto General Hospital, and University of Toronto, Toronto, Ontario, Canada Cheryl A. Smith Division of Infectious Diseases, St. Francis Hospital and Medical Center, Hartford, Connecticut, U.S.A. Robert P. Smith Maine Medical Center, Portland, Maine, and Infectious Diseases Unit, College of Medicine, University of Vermont, Burlington, Vermont, U.S.A. Judith L. Steinberg School of Medicine, Boston University, Boston, and Neponset Health Center, Dorchester, Massachusetts, U.S.A. Jayant A. Talwalkar Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota, U.S.A.

xvi

Contributors

Ellis H. Tobin Upstate Infectious Disease Associates, and Department of Medicine, Albany Medical College, Albany, New York, U.S.A. Gordon M. Trenholme Department of Infectious Disease, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois, U.S.A. JoAnn Tufariello Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, U.S.A. C. Fordham von Reyn Infectious Disease Section, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, U.S.A.

1 Fever Christopher J. Grace University of Vermont, Burlington, Vermont, U.S.A.

1

INTRODUCTION

‘‘Humanity has but three great enemies: fever, famine and war; of these by far the greatest, by far the most terrible, is fever’’ (Osler 1896). This often quoted line from Sir William Osler’s address at the 47th annual meeting of the American Medical Association is as true today as it was in 1896. Fever is one of the most common and worrisome symptoms that primary care providers must assess. It may be a symptom of a self-limited viral infection, a life-threatening infection, or a cryptic noninfectious illness. ‘‘Fever is nature’s engine which she brings into the field to remove her enemy’’ (Paybe 1900). Thomas Sydenham’s analogy of fever as a therapeutic force is as true as Osler’s appraisal. It is now well recognized that fever is a part of a physiological response that helps the host combat both infectious and noninfectious illness. Therefore, an understanding of what defines an abnormal temperature, the pathophysiological characteristics of temperature regulation, the beneficial and harmful effects of fever, and its treatment is vital to the care of the febrile patient. This chapter reviews the history of fever and thermometry, the normal temperature and its measurement, thermoregulation, issues surrounding the controversies of treating a fever, and antipyretic therapy. 2

HISTORY

The ancients believed that illness was due to the interdiction of the gods. In Leviticus 26:12, the Lord said, ‘‘But break my covenants, then be sure this is what I will do. I will bring upon you sudden terror and recurrent fever.’’ Pre-Socratic Greek thought separated illness from religious and mythical entities and attempted to explain it with rational reasoning and observable phenomena as a part of nature. Anaximander (638–547 B.C.) and Pythagoras (580–489 B.C.) postulated that all substances were made up of fire, air, earth, and water. The four elements were paired with their opposites. Change and continuity occurred through interaction of these opposites. Empedocles (490–430 B.C.) hypothesized that disease was due to an imbalance of one of these elements. From here evolved the theory of the four humors (blood, yellow bile, black bile, and phlegm) as developed by Hippocrates (460–377 B.C.) and his followers (Figure 1). These humors were derived from the digestion of food. In the Corpus Hippocraticum, disease was discussed as an imbalance of these four humors. Each humor was associated 1

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Figure 1 Theory of humors. The inner dotted box represents the essential elements (air, fire, water, earth) that make up all matter, as developed in the fifth century B.C. These elements may be manifested as heat, dryness, coldness, and moisture (central diamond), as described by the third century B.C. The theory of humors as developed by Hippocrates and his students stated that digested food was transformed into one of four humors (outer box), blood, yellow bile, black bile, and phlegm. (Adapted from Mettler 1947.)

with a season, temperament, and personality. Blood was hot and moist and associated with a sanguine, cheerful, and warm personality. Phlegm (the white matter mixed with blood) was cold and moist and associated with a phlegmatic, sluggish, apathetic personality. Yellow bile was hot and dry and associated with a choleric, quick tempered personality. Black bile was cold and dry and associated with a melancholic, gloomy personality. Fever was due to an excess of yellow bile, which was associated with fire, which was hot and dry. Therapeutic intervention was based on rebalancing the humors by removing the offending excessive humor. Modalities included changes in diet and exercise, drugs such as hellebore that induced vomiting and diarrhea, venesection (bloodletting), and cauterization (burning) to release or consume excess humor or to cause suppuration of wounds that allowed the drainage of the humors. Galen (A.D. 129–200) perpetuated the humoral theory, which remained essentially intact for the next 1500 years. After the discovery of the circulation by William Harvey in 1628, fever was felt to be caused by either the friction of blood in the vessels or fermentation or putrefaction of liquids in the blood. Well into the 18th century, fever was still felt to be a disease in and of itself, and some medical authorities listed over 100 types of fever (putrid, essential, malign, ataxic, etc.) Francis Broussais (1772–1838) attempted to correlate febrile illness with pathological changes found at postmortem examination, thus suggesting that fever was a symptom of illness. Claude Bernard (1813–1878) introduced the concepts underlying homeostasis and recognized that metabolic processes generated heat. Carl von Liebermeister (1833–1901) proposed the theory of an internal set point that regulated the body’s temperature. William Welsh (1850–1934) hypothesized that the central nervous system controls heat regulation from a region near the thalamus. He further hypothesized that fever may be beneficial to the host immune system. He suggested that microbes cause temperature elevation indirectly by stimulating leukocytes to release substances he called ‘‘ferments.’’ In the 1940s, these ferments were isolated from monocytes and called endogenous pyrogen. During the 1970s and 1980s, Dinarello, Beutler, and Murphy defined

Fever

3

these pyrogens as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-␣), and interferon (INF). Galen may have been the first physician to devise a scale for measuring the qualities of heat and cold. For all intents and purposes, though, elevation of body temperature was guessed at by the use of the physician’s hand until the discovery of the air thermometer in the late 16th century by Galileo Galilei (1564–1642). Santorio Santorio (1561–1636) established the basic principles of medical thermometry by inventing a liquid based instrument with a temperature scale that showed that temperature changes were measurable and reproducible (see Figure 2). His thermometer was open at one end, thus exposing temperature recordings to barometric pressure. In 1654, Ferdinand II, grand duke of Tuscany, resolved this issue by sealing both ends of the instrument and is thus credited with the first liquid in glass thermometer. In 1665, Robert Hook, Robert Boyle, and Christian Huygens suggested that thermometers could be calibrated from a single fixed point. Gabriel Fahrenheit (1686–1736) was the

Figure 2 Oral thermometer of Santorio. The patient would place the end of the instrument (glass enclosed air) in his or her mouth. Wine within the glass column served as the marker. As the air became heated from the patient, the level of liquid in the tube dropped, showing the degrees of heat. Liquid not in the tube is held in an open reservoir at the bottom. The instrument had 110 divisions; the heat of the candle and cold of snow represented end points. (Adapted from McLaury 1983.)

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first to use mercury in a glass thermometer. He developed a scale for the thermometer marking the freezing point of water at 32⬚ and boiling water at 212⬚. Gradations of temperature were referred to as degrees of Fahrenheit (⬚F). Anders Celsius (1701–1744) developed a second scale of measurement with the freezing of water marked at 0⬚ and boiling at 100⬚. There were 100 gradations between these points measured as degrees Celsius (⬚C). Anton de Haen (1704–1776) of the Vienna Hospital noted in his voluminous Ratio Medendi that the temperatures of healthy and ill patients had diurnal variations. Antoine Cesar Becquerel and Gilbert Breschset established the mean ‘‘normal’’ body temperature as 98.6⬚F in 1835. Clinical thermometry did not become accepted practice until the publication of The Course of Temperature in Diseases: A Manual of Medical Thermometry by Carl Reinhold August Wunderlich (1815–1877) in 1868. Over an 18-year period he performed several million temperature recordings on 25,000 patients using an axillary thermometer. This feat of data collection is even more impressive when it is recognized that the patients had to hold the 22.5-cm-long instrument under an arm for 20 minutes for each reading. Although he reinforced the notion that the normal temperature was 98.6⬚F, Wunderlich emphasized that the normal temperature was better thought of as a range with the upper limit at 100.4⬚F. It was his work that helped demonstrate that fever was a sign of illness, not a disease in and of itself. A shortened, portable thermometer was introduced by T. Clifford Allbutt (1836–1925) in 1867. Edouard Sequin (1812–1880) helped introduce the thermometer to the United States in the 1860s and encouraged its use by the lay population to help reduce medical quackery. 3

NORMAL TEMPERATURE

The International Union Physiological Sciences Thermal Commission has defined fever as a ‘‘state of elevated core temperature, which is often, but not necessarily, part of the defensive responses of multicellular organisms to the invasion of microorganisms or inanimate matter recognized as pathogenic or alien by the host’’ (International Union Physiological Sciences Thermal Commission 1987). Although 37⬚C (98.6⬚F) is referred to as the ‘‘normal’’ human temperature, it is more accurate to think of the normal temperature as a range from 36⬚C (96.8⬚F) to 37.7⬚C (99.9⬚F). The mean temperature, derived from a study of 700 recordings from 148 persons was 36.8⬚C ⫾ 0.4⬚C. Other studies have shown that normal healthy adults can have oral temperatures as high as 38.2⬚C (100.8⬚F). Numerous studies, including those of Wunderlich, have shown that a person’s temperature is rarely 98.6⬚F. In addition, body temperature varies according to the site where it is measured. Rectal temperatures are, on average, 0.4⬚C (0.8⬚F) higher than oral readings and 0.8⬚C (1.6⬚F) greater than tympanic temperatures. Pulmonary artery (PA) temperatures are 0.4⬚C (0.7⬚F) higher than oral temperatures but 0.2⬚C (0.4⬚F) lower than rectal temperatures. Temperatures demonstrate a diurnal variation with maximal temperatures in the late afternoon to early evening and lowest temperatures in the early morning. This diurnal variation normally fluctuates by 1.0⬚C (1.8⬚F), and variation can be as high as 1.3⬚C (2.4⬚F) in some individuals. Recent studies have suggested that the late afternoon temperatures >37.7⬚C (99.9⬚F) and early morning temperatures >37.2⬚C (98.9⬚F) are above the normal range for young healthy adults. The normal diurnal variation is maintained during a febrile response but in an exaggerated manner. This drop in temperature (heat loss) during the night, mediated by the evaporation of sweat, is the cause of ‘‘night sweats’’ characteristic of most infections (see Figure 3).

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5

TEMPERATURE Normal temperature: Ranges from 36⬚C to 37.7⬚C (96.8⬚F–99.5⬚F), though healthy persons can have ‘‘normal’’ temperatures as high as 38.2⬚C (100.8⬚F). Rectal temperature is often higher than pulmonary artery temperature, which can be higher than simultaneous oral temperature. Diurnal variations are usually about 1⬚C (1.8⬚F) (see Figure 3). Febrile illness: Temperatures due to infection are rarely >41⬚C (106⬚F). Within this range temperatures do not cause thermal injury. Fever patterns or temperature height during illness rarely is helpful diagnostically. Hyperthermia: Excessive temperature is not mediated by the cytokine pathway. Heat stroke may result from excessive environmental temperature or physical exertion. Malignant hyperthermia may result from use of halothane, methoxyflurane, cyclopropane, or succinylcholine. Neuroleptic malignant syndrome may be due to haloperidol, thiothixene, or phenothiazine use. Thermometers: It is best to use electronic digital instruments rectally or orally. Ear thermometers have been inaccurate when compared to digital instruments and show significant variability from ear to ear.

Temperature differences have not been demonstrated between the young and old, Caucasian and non-Caucasian races, or smokers and nonsmokers. Women may show an increased temperature of 0.5⬚C during ovulation. Analysis of fever patterns as a diagnostic tool is a centuries old art. Temperatures have been described as sustained (elevated temperature throughout the entire 24 hours of a day with fluctuations of 1⬚C), hectic (a type of intermittent fever with wide swings >1.4⬚C), and remittent (temperature that is normal during some part of the day). Wunderlich, as part of his treatise on temperature over 130 years ago, stressed the variety of fever patterns but also the lack of specificity and the fact that rarely do the patterns of fever help in making a clinical diagnosis. More recently Musher and associates (1979) prospectively and retrospectively studied approximately 300 febrile patients. They were unable to find a correlation between a specific infection and the pattern of fever. Occasionally temperature patterns may be helpful diagnostically such as with the cyclic tertian (every 48 hours with Plasmodium vivax or P. ovale) or quartan (every 72 hours with P. malariae) fevers of malaria. Patients who have Hodgkin’s lymphoma may demonstrate a relapsing fever lasting 3–10 days alternating with afebrile periods of 3–10 days (Pel Epstein fever). As part of the physiological response of temperature, the heart rate increases by 4 beats/min for each 1⬚C rise in temperature. Exceptions to this rule are illnesses that are associated with a pulse–temperature deficit such as typhoid fever, Legionella sp. infections, and drug fevers, wherein the temperature rise is out of proportion to the observed heart rate. In the author’s experience, fever patterns or the height of the temperature rarely if ever helps define the cause.

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Figure 3 Fever curves during febrile and afebrile conditions. The broken line represents the normal diurnal variation of temperature: peaking in the late afternoon and reaching a nadir in the early morning. The solid line is the temperature curve during a febrile illness. The diurnal variation is maintained but at a higher set point during infection. Heat is generated by shivering, causing chills (C). The temperature rises as a result of an increase in the hypothalamic set point (rising vertical dotted arrow) to a new, higher set point (40⬚C). Heat is lost by sweating (S) when the set point is lowered (falling vertical arrow) toward the ‘‘normal’’ set point. The solid arrow represents administration of an antipyretic, which artificially lowers the set point to a greater extent than would be expected during the normal diurnal variation of an infection, causing a marked fall in temperature. The patient experiences a ‘‘drenching’’ night sweat.

4

HYPERTHERMIA

Fever is a normal physiological response mediated by cytokines that ‘‘reset’’ the hypothalamic set point (discussed later). It represents a homeostatic mechanism balancing heat loss and generation. In response to infections, temperatures rarely rise above 41⬚C (106⬚F). Temperatures within this limit do not cause thermal injury to body tissues. The lethal limits of body temperature are as low as 26⬚C (78.8⬚F) and as high as 43⬚C (109.4⬚F). Hyperthermia, in contrast to fever, is a rise in body temperature not mediated by cytokines that represents a failure of thermoregulatory control to maintain body temperature within the normal physiological range. This failure of homeostasis may result from excessive ambient temperature, physical exertion, or an adverse reaction to certain drugs. Heat stroke is due to excessive environmental temperature. This is characteristically seen in the elderly during a heat wave associated with high humidity. These patients generally have underlying illnesses and exhibit headache, confusion, and prostration. Temperatures are often >41⬚C (106⬚F) and have reached as high as 44.4⬚C (112⬚F). In young individuals heat stroke may develop in response to excessive and prolonged exertion such

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as marathon running. These patients manifest rhabdomyalysis, renal failure, and disseminated intravascular coagulation (DIC). For patients with heat stroke, antipyretic agents are ineffectual and cooling must be done with external measures. Malignant hyperthermia is a rapid rise in temperature in response to certain inhalational anesthetic agents in genetically predisposed persons. These agents include halothane, methoxyflurane, cyclopropane, and ethyl ether or muscle relaxants such as succinylcholine. In addition to fever, patients have lessened relaxation during anesthetic induction and elevated creatinine phosphokinase (CPK) level. The neuroleptic malignant syndrome is brought on by neuroleptic agents such as haloperidol, thiothixene, or piperazine phenothiazines. Patients may demonstrate tachycardia, labile blood pressure, diaphoresis, catatonia, and muscular rigidity. Temperatures may exceed 41⬚C. 5

TEMPERATURE MEASUREMENT

The goal of temperature measurement is to record the core (abdomen, thorax, and cranium) body temperature. The goal standard is measurement of the pulmonary artery (PA) temperature. Since this is not practical during routine medical care, estimates of the core temperature are usually derived from the oval and rectal temperatures. Peripheral temperature measurements (skin or axilla) are not representative of the core temperature. For 200 years the standard tool for the measurement of temperature has been the mercury in glass thermometer (MIGT). The instrument must be left in place (mouth or rectum) for 5–8 minutes and may be uncomfortable or inconvenient for the patient. Recently environmental and health concerns have been raised about the accidental release of the mercury. Electronic instruments that use a heat sensing thermister coupled with a digital readout have come into greater use. They must be left in place (mouth or rectum) for 20–40 seconds and may also be inconvenient. More recently infrared ear thermometers (IETs) have become popular because of their ease of use. It is believed that this measurement represents core temperature since the external carotid artery supplies the tympanic membrane. The device measures heat radiation from the tympanic membrane and surrounding ear canal during a 1⬚C and in a few persons >2.5⬚C. Irwin (1999) found oral temperatures were generally higher than tympanic measurements and that 58% of oral temperatures were 1⬚F higher than tympanic temperatures. In that study, 9/160 measurements were 2.2⬚F higher orally than by IET. Because of these concerns, many authorities (Jensen et al., 2000; Giuliano et al., 2000) continue to recommend the use of digital thermometers orally or preferably rectally. Others have gone so far as to characterize reliance on IET as potentially dangerous (Modell et al., 1998). 6

THERMOREGULATION

In warm-blooded animals, body temperature is controlled within a narrow range by balancing heat production and conservation with heat loss. This homeostatic control maintains the body at a ‘‘set point’’ by a coordinated effort involving autonomic, endocrinological,

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THERMOREGULATION AND ANTIPYRETICS Temperature is part of a complex physiological response to infection involving immunological, hormonal, and behavioral aspects (see Table 1 and Figure 4). The febrile response is believed to be beneficial (see Table 2). Endogenous pyrogens (IL-1, TNF, IL-6, and interferons) mediate temperature elevation by stimulating prostaglandin E2 production by COX. Aspirin and NSAIDs block COX-1 and COX-2 nonselectively, accounting for their antipyretic and anti-inflammatory actions. Acetaminophen may block a hypothesized third COX isoenzyme. The main concerns of antipyretics are their toxicities (see Table 3). Selective COX-2 inhibitors such as celecoxib and rofecoxib cause less gastrointestinal toxicity. Reducing a fever may make the patient more symptomatic by exacerbating the cyclic chills and sweats (see Figure 3). Temperatures should be lowered only to reduce the patient’s symptoms.

metabolic, and behavioral mechanisms. Heat is generated to maintain normal temperature or to raise it during a febrile illness. During normal afebrile times, heat arises from cellular metabolism, oxidation of nutrients, circulation of blood, and contraction of involuntary muscles. During febrile states, increased heat can be generated by skeletal muscle contraction (shivering). The heat generated in the core is distributed to the periphery by the circulation. In response to increased core temperature, cutaneous blood flow increases via the autonomic nervous system, causing heat loss by radiation and convection. Autonomic nerves also control sweating, causing heat loss by evaporation. Sweat loss of 1% of body weight can lower body temperature by 5⬚C. Decreased core temperature results in peripheral vasoconstriction, thus shunting blood centrally. A network of neurons extending from the hypothalamus to the spinal cord controls this heat distribution. The main component of this network is the preoptic region of the anterior hypothalamus. The neurons of this area are thermosensitive and receive input from receptors in the skin and core organs and via the mediators transported by the blood. When an invasive pathogen (the exogenous pyrogen) is phagocytized by white blood cells, endogenous pyrogens that mediate a complex inflammatory and immunological response to the infection are released (see Figure 4). In addition to microbial pathogens, endogenous pyrogen release can be stimulated by antigen–antibody complexes, complement, and bile acids. The endogenous pyrogens are cytokines, including IL-1, IL-6, TNF␣, and the interferons. These act locally and systemically, individually and in combinations, to trigger a large array of metabolic, physiological, and immunological responses. IL-1 (␣ and ␤) is a polypeptide secreted by mononuclear cells, pulmonary macrophages, keratinocytes, gingival and corneal epithelium, renal mesangial cells, cerebral astrocytes, and the reticuloendothelial system of the liver and spleen. It stimulates the bone marrow to increase neutrophils, polymorphonuclear (PMN) leukocytes to increase phagocytosis and bacterial killing, and fibroblasts to increase collagen synthesis. It induces IL2, cytotoxic T lymphocytes (CTLs), and acute phase reactant production. It increases secretion of IL-1, IL-6, and TNF. TNF-␣ is a polypeptide secreted by macrophages, monocytes, astrocytes, endothelial cells, kupffer cells, natural killer cells, and some tumors. It causes hemorrhagic necrosis

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Figure 4 Fever, immunity, and the inflammatory response. Exogenous pyrogen stimulates cytokine (endogenous pyrogen) release. IL-1, IL-6, TNF, and INF reset the hypothalamic set point via OVLT. The body temperature is raised. The inflammatory and immunological responses then control the exogenous pyrogen (dotted lines). WBC, white blood cell; IL-1, interleukin-1; IL-6, interleukin-6; TNF, tumor necrosis factor; ␦ INF, interferon; OVLT, organum vasculosum of the lamina terminalis.

of tumors in vitro, accounting for its primary name. It reduces lipoprotein lipase activity, resulting in decreased lipid uptake and clinical wasting, hence its other name, cachectic. It stimulates osteoclast, neutrophil, and CTL activity and B cell differentiation. It induces a procoagulant effect, leading to vascular thrombosis, and stimulates IL-1 release. It induces TNF-␣, IL-1, and IL-6. The interferons (␣, ␤, ␥) are glycoproteins produced by leukocytes that have been shown to have immune modulating, antitumor, antiviral, and antibacterial effects. Interferon-gamma (INF-␥) is secreted by T and natural killer (NK) cells. It stimulates B cell differentiation, antibody secretion, NK cell activity, and endothelium adhesion molecule expression. It increases secretion of TNF-␣ and IL-1. IL-6 is a potent cytokine secreted by monocytes, macrophages, fibroblasts, endothelial cells, keratinocytes, and bone marrow stromal cells. It induces acute phase proteins, CTL response, B cell proliferation, and antibody production and is a potent inducer of prostaglandin synthesis. Its secretion is under the control of TNF and IL-1, and therefore it has been described as a ‘‘downstream’’ mediator of fever, which is released after IL-1 and TNF-␣ are produced in response to infection. It decreases IL-1 and TNF-␣ secretion. Hormones affected by these cytokines include glucagon, growth hormone, cortisol, thyroid stimulating hormone, thyroxine, erythropoietin, and corticotrophin. These cause an increase in gluconeogenesis, muscle proteolysis, and increase in oxygen and caloric demand. There is increased synthesis of hepatic acute phase reactants such as C-reactive

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protein (CRP), haptoglobin, ceruloplasmin, fibrinogen, ferritin, complement, and serum amyloid A. There is a decrease in serum albumin, transferrin, hematocrit, zinc, and iron levels. Table 1 summarizes the effects of IL-1, the most potent of the endogenous pyrogens. In addition to immunological and hormonal changes, cytokines cause temperature elevation as part of the response to infection. These cytokines stimulate prostaglandin synthesis in the preoptic areas of the anterior hypothalamus. Endogenous pyrogens, however, are not able to reach the preoptic region of the anterior hypothalamus directly since they are unable to cross the blood–brain barrier (BBB). It is hypothesized that they mediate their effects via the organum vasculosum of the lamina terminalis (OVLT), a structure adjacent to the preoptic area with a ‘‘leaky’’ BBB that allows entry of the cytokines. Cytokines activate phospholipase A2, causing release of membrane bound arachidonic acid. They also increase synthesis of cylooxygenase (COX), which catalyzes arachidonic acid to prostaglandin G2 and H2, which are the intermediate precursors of prostaglandin E2 (PGE2) (see Figure 5). PGE2 decreases the firing rate of the preoptic ‘‘warm-sensitive’’ neurons in the preoptic region. The change in the firing rate of these neurons results in an upward resetting of the hypothalamic temperature set point. If the hypothalamic set point is raised (i.e., during an infection), the body is perceived to be cooler than the new set point. Physiological and behavioral changes are set in motion to raise the body temperature to match the higher set point. Shivering is initiated to generate heat, blood is shunted to the core to conserve heat, and sweating diminishes. The individual may seek warmth by covering up with blankets and raising the ambient temperature. The generated heat raises the body temperature to match the elevated set point. Anorexia, malaise, and somnolence are commonly experienced. When the hypothalamic set point is lowered, either as part of the normal diurnal fluctuations that occur during an infection or in response to antipyretic agents, the hypothalamus perceives the core temperature as higher than the set point and initiates heat loss by evaporation (sweating) and radiation (cutaneous vasodilation) (see Figure 3). The cyclic nature of the diurnal fluctuations is experienced by the patient as alternating chills and sweats. Recently (Boulant, 2000) it has been shown that these cytokines also stimulate the preoptic region via afferent vagal nerves that release norepinephrine, which in turn stimulates COX to produce PGE2. These two different mechanisms of cytokine activity (direct blood-borne and neural fiber–mediated) may account for the biphasic nature of the febrile response seen in experimental models.

Table 1 Direct and Indirect Effects of Interleukin 1 Metabolic • • • • • • • • •

↑ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↑

Corticosteroids Insulin Zinc Iron Albumin Cytochrome P 450 Lipoprotein lipase Weight Acute phase reactants

Physiological • • • • •

↑ ↑ ↓ ↓ ↑

Temperature Sleep Appetite Blood pressure Sodium excretion

Immunological • • • • • •

↑ ↑ ↑ ↑ ↑ ↑

White blood cells T cell activation B cell activation Natural killer cell activation Interferon Procoagulants

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Figure 5 Prostaglandin E2 production. Prostaglandin E2 is synthesized from membrane bound phospholipid by phospholipase A2 and COX. Corticosteroids inhibit phospholipase A2, whereas aspirin and nonsteroidal anti-inflammatory drugs inhibit COX. Acetaminophen may also inhibit a hypothesized third COX isoenzyme. IL-1, interleukin 1; TNF, tumor necrosis factor; IL-6, interleukin 6; IFN, interferon; ASA, acetylsalicylic acid; NSAIDs, nonsteroidal anti-inflammatory drugs; COX, cyclooxygenase.

As with all homeostatic processes, there are feedback mechanisms to control the rise in temperature. Endogenous antipyretics protect against the danger of unchecked temperature elevation. These substances include cortisone, cortisol, arginine vasopressin, adrenocorticotropin hormone (ACTH), ␣ melanocyte–stimulating hormone, ␦ melanocyte–stimulating hormone, IL-10, and perhaps TNF. When cytokines are released, there is also a release of soluble cytokine receptors that directly inhibit the cytokine effects. These mechanisms account for the potent antipyretic effect of corticosteroids when administered to patients who have fever.

7

IS FEVER GOOD OR BAD?

Fever is an adaptive mechanism that is part of the inflammatory and immunological response to microbial invasion. It should therefore be viewed as beneficial. The reasoning and data to support this idea fall into three categories (see Table 2).

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Table 2 Benefits of Fever Teleological • It is a phylogenetically old host response. • It evolved over 4 million years ago. • All vertebrates experience temperature elevation in response to infection. • Fever confirms a survival advantage in all vertebrates studied. • Fever is metabolically expensive. • If it were not beneficial, it should have been selected out. In vitro temperature elevation • ↑ Leukocyte mobility. • ↑ White blood cell bactericidal activity. • ↑ Immunoregulatory effects of IL-1. • ↑ Antibody production by B cells. In vivo studies in cold-blooded fish and lizards • Increasing the febrile state increased survival rate. • Antipyretics decreased survival rate.

7.1

Teleological

Fever has been documented in vertebrates, including mammals, birds, reptiles, amphibians, and fish, arthropods, including crabs, shrimps, and lobsters, and annelids, such as worms and leeches as a response to microbial infection. This suggests that fever as a host defense evolved over 4 million years ago. Fever is a metabolically expensive response. In mammals and birds, energy consumption must be increased by 20% to maintain a temperature 2⬚C– 3⬚C above the normal state. This energy expenditure also occurs in cold-blooded creatures that seek warmer environments when infected. If fever were not beneficial, this metabolically expensive response should have been eliminated by natural selection. 7.2

In Vitro Studies

Laboratory studies (Kluger, 1996) have shown that raising the temperature increases leukocyte motility and bactericidal activity, T lymphocyte transformation, and B cell antibody production. Human leukocytes heated to 38⬚C–40⬚C showed maximal phagocytic activity. Raising the temperature of the experimental environment increases the immunoregulatory effects of IL-1 and INF. The bacterial requirement for iron increases as the temperature is elevated. IL-1 causes PMN to release lactoferrin, which in turn decreases serum iron level, a vital nutrient for bacterial growth. Studies have shown that temperatures within the expected febrile range of a host interfere with microorganism growth and that antibiotics may work more effectively at higher temperatures. 7.3

In Vivo Studies

Studies in mammals and reptiles have demonstrated a survival benefit associated with elevation in body temperature. Similar studies have shown a survival disadvantage to artificially lowering temperature with antipyretics. The classic study was done in the 1970s by Kluger and colleagues (1975), who showed a relationship between the body temperature of an infected lizard, Dipsosaurus dorsalis, and survival. Lizards infected with Aeromonas hydrophilia were placed in incubators heated to different temperatures. All those lizards allowed to raise their body temperature in this manner survived. Those animals kept ar-

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tificially normothermic by blocking their movement into warmer areas had a 30% survival rate. An increasingly higher temperature correlated with increased survival rate. In a follow-up study, infected lizards treated with antipyretics had a poor survival rate if fever did not develop, a finding that suggests that artificially lowering body temperature with salicylates was harmful. Similar studies have been done in goldfish. Studies involving rabbits infected with Pasteurella multocida demonstrated better survival rates with increasing temperature within the normal range of the febrile response for these rabbits. Ferrets with influenza infection have less nasal viral shedding with increased temperatures than ferrets with lesser temperature elevations. Demonstration of a survival benefit from temperature elevation in humans has been more elusive. Hypothermia has been recognized as a poor prognostic marker during sepsis. In a retrospective study of patients with gram-negative bacteremia Bryant and associates (1971) found a positive correlation between the maximal temperature on the day of initial bacteremia and survival rate. Others (Weinstein et al., 1978) have noted a similar relationship between temperature elevation and survival rate in patients with spontaneous bacterial peritonitis. 8

ANTIPYRETIC THERAPY

Willow tree bark has been known for centuries for its fever reducing properties. Its use was first scientifically described in 1763 by the Reverend Edward Stone. In 1829 Henri Leroux isolated salicin from willow bark, and Raffaele Piria produced salicylic acid from the bark extract in 1838. By the late 19th century sodium salicylate was used as an antipyretic and anti-inflammatory drug, though poor taste and gastric irritation interfered with its use. In 1897 Felix Hoffman produced acetylsalicylic acid (subsequently named aspirin), which was effective and better tolerated. The Bayer Company also developed and produced phenacetin in 1887. Acetaminophen, the major metabolite of phenacetin, was shown to have fewer side effects and replaced it for use in the late 1940s. Indomethacin was produced in 1963. In 1971, John Vane showed that the antipyretic and anti-inflammatory activities of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) were due to blockade of COX involved in prostaglandin synthesis. Subsequently two isoenzymes, COX-1 and COX-2, have been identified. COX-2 plays the major role in the febrile and inflammatory response. Aspirin and older NSAIDs are nonselective COX inhibitors. Newer NSAIDs such as celecoxib (Celebrex, Searle) and rofecoxib (Vioxx, Merck) are selective COX-2 inhibitors. A third COX enzyme that may be blocked by acetaminophen, thus accounting for its antipyretic abilities, but negligible anti-inflammatory activity, has been hypothesized. Through most of recorded history, fever has been thought of as a disorder to be eradicated or an unpleasant or potentially dangerous symptom. In either case, most providers and patients feel that the febrile response should be suppressed. Although the studies discussed have demonstrated a survival disadvantage for those lizards, fish, and rabbits treated with antipyretics, extensive antipyretic use in humans during the last 30 years has not been shown to be obviously detrimental. Adding to the science and myth is a multibillion-dollar industry marketing antipyretic agents in hundreds of varied formulations to a worried and uncomfortable lay population. It needs to be reinforced that fever, even fever of 41⬚C, is not detrimental. Within the range of temperatures caused by most infections and noninfections alike, high temperatures do not cause thermal injury to the patient. Table 3 summarizes the pros and cons of antipyretic therapy. The major concerns related to antipyretic drug use involve toxicities. Gastrointestinal (GI) toxicities include

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Table 3 Advantages and Disadvantages of Antipyretic Therapy Advantagesa 1. ↓ Symptoms of fever 2. ↓ Metabolic demand in the elderly with cardiopulmonary disease 3. ↓ Metabolic demand in patients with central nervous system injury 4. ↓ Toxic encephalopathy in the elderly 5. ↓ Risk of febrile seizures in children Disadvantages 1. Fever potentially beneficial (see Table 2) 2. ↑ Chills and sweats 3. Toxicities of drugs • Gastrointestinalb • Renalb • Hepaticb,c • Antiplatelet activityb • Rashb • Reye’s syndromed a

Empirical only, no scientific proof of validity. Associated with aspirin and nonsteroidal anti-inflammatory drugs. c Associated with acetaminophen. d Aspirin use in children with influenza and varicella infection. b

dyspepsia (10%–20% of patients), ulcer formation, and bleeding. Those at most risk for GI adverse events include the elderly, those with preexisting peptic disease or bleeding, and those taking high doses of the drugs and taking concomitant steroids or anticoagulants. Acetaminophen can cause liver toxicity when used in cumulative doses of 4 g in a 24hour period. Nonselective COX inhibitors can cause fluid and electrolyte disorders, acute renal failure, and interstitial nephritis. Patients at increased risk for NSAID related acute renal failure include those with dehydration, congestive heart failure, and liver failure, all conditions associated with low intravascular volumes. Less commonly, hyperkalemia can be seen. Those at risk include insulin-dependent diabetics and those receiving ␤-blockers or potassium sparing diuretics. Long-term use of combinations of acetaminophen and NSAIDs can cause analgesia-induced nephropathy. NSAIDs are antiplatelet agents and thus may pose a bleeding risk to those undergoing surgery. Selective COX-2 inhibitors are reported to have reduced GI and renal toxicity; however, they are considerably more expensive (30 20-mg capsules for $70.00) than aspirin and acetaminophen. It has been suggested that fever should be treated to reduce the metabolic demand in patients with acute cardiopulmonary illness or with central nervous system injury. Although the reasoning behind this suggestion is sound, data supporting it are nonexistent. In addition, it should be noted that intravenous indomethacin has been shown to cause coronary vasoconstriction in patients with coronary artery disease. The use of antipyretics to reduce symptoms is a double-edged sword. Patients made uncomfortable by fever may feel transiently better after temperature reduction. For some patients, antipyretic therapy may exacerbate the cyclic chills and sweats that are part of a febrile illness and may in fact make them feel worse (see Figure 3). The decision, therefore, to use or not use an antipyretic agent is dependent on what makes the patient most com-

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fortable. Many patients are not particularly symptomatic or aware of their fever; treating the fever may only make them feel worse. If it is elected to treat a fever with an antipyretic drug, it should be given ‘‘around the clock’’ and not ‘‘as needed.’’ This continuous suppression of the hypothalamic set point may help alleviate the sharp peaks and valleys of the daily fever elevations and reductions, thus diminishing the associated chills and sweats. Aspirin, NSAIDs, and acetaminophen are equally efficacious in reducing temperatures. Sponge bathing with tepid water may improve heat evaporation while preventing peripheral vasoconstriction. Cooling blankets should be avoided. They may be very uncomfortable to the patient and counterproductive since the cold surface may cause shivering, increase metabolic rate, and actually raise core temperature. 9

SUMMARY

Fever is part of a complex metabolic, immunological, and behavioral response to infection and to noninfectious illness. This response has evolved over millions of years and is most likely beneficial to the host. Treatment with antipyretic agents should be limited to uncomfortably symptomatic patients or those with specific risks posed by the elevated metabolic rate that accompanies the fever. Toxicities from antipyretics need to be kept in mind. Fever, as a representation of infectious disease, has been a great enemy to humanity. It is also part of nature’s engine to control infection. Osler and Sydenham were both correct. BIBLIOGRAPHY Atkins E. Fever: Its history, cause and function. Yale J Biol Med 55:283–289, 1982. Boulant JA. Role of the preoptic-anterior hypothalamus in thermoregulation and fever. Clin Infect Dis 31:S157–S161, 2000. Bryant RE, Hood AF, Hood CE, Koening MG. Factors affecting mortality of gram-negative rod bacteremia, Arch Intern Med 127:120–128, 1971. Giuliano KK, Giuliano AJ, Scott SS, MacLachlan E, Pysznik E, Elliot S, Woytowicz D. Temperature measurement in critically ill adults: A comparison of tympanic and oral methods. Am J Crit Care 9:254–261, 2000. Haller JS. Medical thermometry—a short history. West J Med 142:108–116, 1985. International Union Physiological Sciences Thermal Commission. Glossary of terms thermal physiology, 2nd ed. Pflugers Arch 78:567–587, 1987. Irwin S. Comparison of the oral thermometer versus the tympanic thermometer. Clin Nurse Spec 13:85–89, 1999. Jensen BN, Jensen FS, Madsen SN, Løssi K. Accuracy of digital tympants, oral, axillary and rectal thermometers compared with standard rectal mercury thermometers. Eur J Surg 166:848–851, 2000. Kluger MJ, Kozak W, Conn CA, Leon LR, Soszynski D. The adaptive value of fever. Infect Dis Clin North Am 10(1):1–20, 1996. Kluger MJ, Ringler DH, Anver MR. Fever and survival. Science 188:166–168, 1975. Mackowiak PA, Worden G. Carl Reinhold August Wunderlich and the evolution of clinical thermometry. Clin Infect Dis 18:458–467, 1994. McLaury RL. A history of clinical thermometry. Oklahoma State Med Assoc. 76:420–426, 1983. Mettler CC. History of Medicine. Toronto: Blakiston, 1947. Modell JG, Katholi CR, Kumaramangalam SM, Hudson EC, Graham BS. Unreliability of infrared tympanic thermometer in clinical practice: A comparative study with oral mercury and electronic thermometers. South Med J 91(7):649–654, 1998.

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Musher DM, Fainstein V, Young EJ, Pruett TL. Fever patterns: Lack of clinical significance. Arch Intern Med 139(11):1225–2228, 1979. Netea MG, Kullberg BJ, Van der Meer JWM. Circulating cytokines as mediators of fever. Clin Infect Dis 21:S178–S184, 2000. Osler W. The study of fevers of the south. JAMA XXVI:999–1004, 1896. Paybe HF. Thomas Sydenham. London: T Fisher Unwinn, 1900. Simmons DL, Wagner D, Westover K. Nonsteroidal anti-inflammatory drugs, acetaminophen, cyclooxygenase 2, and fever. Clin Infect Dis 31:S211–S218, 2000. Weinstein MR, Jannini PB, Stafon CW, Eichoff TC. Spontaneous bacterial peritonitis: A review of 28 cases with emphasis on improved survival and factors influencing prognosis. Am J Med 64:592–598, 1978.

2 Infectious Disease Emergencies Recognition and Initial Management Robert E. Levitz University of Connecticut, Farmington, and Hartford Hospital, Hartford, Connecticut, U.S.A.

1

INTRODUCTION

Almost any infectious disease, under certain circumstances, may be considered to be a true emergency. This chapter discusses diseases that are often life threatening emergencies on presentation. These infections include bacterial meningitis, herpes simplex type 1 (HSVI) encephalitis, necrotizing soft tissue infections, tick-borne diseases, neutropenic fever, malaria, and septic shock. The purpose of this chapter is to aid the clinician in recognition and diagnosis of these conditions and initiation of the appropriate therapy. Patients with acute or fulminant illness due to bacterial endocarditis (Chapter 18), arthropod-borne encephalitis (Chapter 31), or intra-abdominal infection (Chapter 24); the ill human immunodeficiency virus (HIV) patient (Chapter 26); and other immunocompromised patients (Chapter 34) are reviewed in other sections of this book. Consultation of infectious disease experts is recommended when managing any of these acute life-threatening infections.

2

ACUTE BACTERIAL MENINGITIS

With the introduction of modern antibiotic therapy, the mortality rates for patients diagnosed with acute bacterial meningitis have fallen rapidly. Currently, 70% of all deaths of bacterial meningitis occur within the first 2 days of hospitalization. It is possible that many of these deaths could be prevented by earlier diagnosis and prompt pharmacological therapy. Besides reducing mortality rate, early treatment probably can decrease subsequent neurological deficits such as deafness and learning disabilities. 2.1

Clinical Presentation

The onset of bacterial meningitis is generally acute, with headache, fever, and neck stiffness. Confusion progressing to coma may occur over the initial 24–48 hours. Seizures can occur in up to 30% of patients. Palsies of cranial nerve (typically cranial nerves III, IV, VI, and VII) and focal neurological deficits may also occur. 17

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BACTERIAL MENINGITIS Clinical presentation Sudden onset of headache, fever, meningismus Seizures, focal neurological deficits Altered mental status progressing to coma over 24–48 hours Diagnosis CT/MRI prior to LP only if papilledema, seizure, focal neurological deficit, head and neck infection present CSF interpretation (see Table 1) Bacteriology (see Table 2) S. pneumoniae Most common Associated with skull fracture Concern for penicillin/cephalosporin resistance N. meningitidis Most rapidly fatal Petechial rash Need for isolation for initial 24 hours of therapy H. influenzae Less common because of HIB vaccine Antibiotic therapy (see Table 3) Steroids Consider if there is evidence of increased intracranial pressure Begin prior to antibiotics Meningococcal prophylaxis Close family contacts Health care workers involved in airway intubation, oral suctioning, and cardiopulmonary resuscitation Rifampin 600 mg qd, minocycline 100 mg bid for 2 days, or ciprofloxacin 500 mg X1

On physical examination, the patient appears acutely ill and may be confused and combative. Photophobia may be present; the neck is stiff. Other signs of meningismus such as Kerning’s sign (tightness and pain in the hamstring muscles when extending the knees) or Brusinski’s sign (retraction of the legs when flexing the neck) are present in only 50% of patients. Rash (discussed later) can be seen with meningococcemia. It is important to examine the mouth, sinuses, and ears to look for contiguous foci of infection that would raise concern of a brain abscess. If otitis media, sinusitis, or an odontogenic focus of infection is found, the patient should have a computed axial tomographic (CT) scan to rule out a brain abscess. 2.2

Diagnosis

The rapid diagnosis of bacterial meningitis requires that a lumbar puncture (LP) be performed in all patients with symptoms or signs of meningitis. Unfortunately, many physicians delay LP while awaiting CT or magnetic resonance imaging (MRI) scan results. This wait causes a delay in making a proper diagnosis and institution of therapy. If the patient’s physical examination findings are nonfocal, head and neck examination does not reveal a

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pyogenic focus, or evidence of papilledema and no history of seizure or skull fracture is obtained, then the clinician can proceed directly with the LP without prior neurological imaging. The risk of herniation after LP has been greatly overestimated and is certainly less than the risk of delayed therapy for meningitis. The one exception would be the presence of gross papilledema. After insertion of the LP needle, the opening pressure should be measured. In a LP, the cerebrospinal fluid (CSF) is usually withdrawn into three sterile tubes containing approximately 2 ml of fluid per tube. The first tube is for Gram stain and culture since it is least likely to be contaminated. The second tube may be used for protein and glucose measurements. The third tube is usually used for cell count and differential (see Table 1). In addition two sets of blood cultures should be performed. Over 90% of patients with bacterial meningitis have a cell count greater than 100 white blood cells (WBCs) per microliter, with a predominance of polymorphonuclear (PMN) leukocytes. In 75% of patients CSF glucose level less than 55 mg% and usually less than 50% of a simultaneously obtained blood glucose level. CSF protein levels are elevated in the vast majority of patients and are often above 100 mg%. Prior outpatient antibiotic therapy has no significant effect on the CSF cell count, differential, glucose, or protein finding. However, prior therapy reduces the sensitivity of the CSF Gram stain and culture. Antigen detection assays, including coagglutination and latex agglutination, may be used to detect bacterial antigens in CSF when culture findings may be negative as a result of prior antibiotic use. Polymerase chain reaction (PCR) may be useful in the future to detect bacterial deoxyribonucleic acid (DNA). It must be noted that several viral infections of the central nervous system, such as herpes simplex type 1 or mumps, can mimic acute bacterial meningitis both in symptoms

Table 1 Cerebrospinal Fluid Analysis CSF Parameter Opening pressure WBC count WBC differential

Glucose

Protein Lactate Gram stain

Culture Antigen detection H. influenzae N. meningitidis S. pneumoniae

Bacterial Meningitis >180 mm H2O >1000 cells/mm3 Range 10,000 >80% PMN

100 mg% >35 mg% (⫹) in 60%–90%, though only 50% in L. monocytogenes (⫹) in 70%–85% 60%–100% sensitivity

Aseptic Meningitis 40 mg%

50 yearsf

Ceftriaxone Ceftriaxone and ampicillin

Cell-mediated immune defect

Ceftazidime and ampicillin and vancomycin

CSF shunt Neurosurgery Basilar skull fracturef

Ceftazidime and vancomycin Ceftriaxone

2 g q12h 2 g q12h 2 g q4h 2 g q8h 2 g q4h 15 mg/kg q12h 2 g q8h 15 mg/kg q12h 2 g q12h

a

GNR, gram-negative rod, CSF, cerebrospinal fluid. Assuming normal renal function. c Gram-positive cocci, presumed S. pneumoniae. d Gram-negative cocci, presumed N. meningitidis. e Gram-positive rod, presumed L. monocytogenes. f Consider adding vancomycin if penicillin is intermediately resistant or resistant S. pneumoniae is present in the community. b

evidence of cerebral edema on CT or MRI imaging. It must be emphasized that clinical trials have not proved this point and the use of steroids in the treatment of adult patients remains controversial. Theoretical concerns about use of corticosteriods are tightening of the blood–brain barrier caused by the steroids and reduced penetration of vancomycin into the CSF. They could prove detrimental to patients with penicillin- and cephalosporinresistant pneumococcal meningitis. 3

HERPES SIMPLEX TYPE 1 ENCEPHALITIS

Herpes simplex virus type 1 (HSV-1) encephalitis is the most common sporadic type in the United States. It is also the only viral encephalitis amenable to treatment. It carries a high mortality rate, and for those who survive, a significant morbidity rate. Therefore, early recognition and treatment are essential. HSV is a double-strained DNA virus of the Herpesviridae family. These viruses, including varicella zoster virus and Epstein-Barr virus, have in common the ability to cause chronic lifelong infections and to reactivate. HSV-1 commonly reactivates in the form of orolabial blisters. On rare occasions, reactivation may take place along the trigeminal or autonomic nerve roots with extension into the brain parenchyma. This involve-

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HSV-1 ENCEPHALITIS Most common sporadic viral encephalitis Treatable but associated with high mortality and mobidity rates Clinical presentation Fever, headache Confusion, altered personality, seizures Stiff neck present or not present Diagnosis MRI scan most sensitive and specific imaging modality LP with lymphotic pleocytosis (see Table 1) CSF PCR for HSV-1 DNA Therapy Acyclovir 10 mg/kg q8h for 21 days

ment classically occurs in the frontal, temporal, or parietal lobes. Occasionally in adults, HSV-1 encephalitis can be due to newly acquired infection and not reactivation. 3.1

Clinical Presentation and Diagnosis

In contrast to bacterial meningitis that involves infection of the membranes surrounding the brain, HSV-1 encephalitis is a direct infection of the brain tissue parenchyma. Patients therefore have symptoms of altered brain function more often than headache or meningismus. The onset may be acute over several days to subacute over a week or more. In addition to fever and headache, the patient experiences confusion, altered personality, focal neurological deficits, and/or seizures. Confusion may progress to coma. The patient may not have a stiff neck. The presence or absence of concomitant orolabial HSV infection does not help establish the diagnosis. If the patient has had a seizure or has focal neurological signs, a CT scan should be performed to rule out a mass lesion prior to LP. It must be emphasized that the CT scan is an insensitive tool for demonstrating CNS abnormalities due to HSV-1 infection. A negative CT scan finding should not be interpreted as ruling out the diagnosis. Characteristically the LP shows a high opening pressure, a lymphocytic pleocytosis, and a normal glucose level but an elevated protein level. The Gram stain and bacterial culture results are negative. CSF results seen in HSV-1 encephalitis appear similar to those seen in viral meningitis and other viral encephalitides. However, an elevated red blood cell count in the CSF should suggest a diagnosis of HSV-1 encephalitis. The yield of growing HSV-1 from the CSF is very low. The determination of herpes simplex DNA in spinal fluid by PCR is sensitive and very specific. In contrast to the CT scan, the MRI scan is very sensitive for delineating changes due to HSV-1 encephalitis. Electroencephalograms may reveal a characteristic spike and dome pattern of HSV-1. 3.2

Therapy

The only available and tested therapy is high-dose intravenous acyclovir. Standard dose is 10 mg/kg every 8 hours if renal function is normal. The duration of therapy is 21 days.

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25

NECROTIZING SOFT TISSUE INFECTIONS Bacterial infection as a consequence of tissue hypoxia, trauma, or bacteremia involving the subcutaneous fat, fascia, muscle, and possibly skin Increased risk in patients with diabetes, hepatic cirrhosis, and immunocomprimise Approach to the recognition, diagnosis, and therapy (see Figure 1) Need for rapid recognition and surgical de´bridement Clinical presentation Fever, localized pain (may not be proportionate to clinical exam results) Crepitus, bullae, anesthetic skin, areas of skin necrosis Syndromes and bacteriology (see Table 4) Diagnosis Clinical examination CT/MRI scan Surgical exploration Therapy Urgent de´bridement Antibiotic therapy (see Table 4)

Even with early acyclovir therapy, HSV-1 encephalitis has a mortality rate of more than 50%. In those surviving, the majority have permanent neurological sequelae. 4

NECROTIZING SOFT TISSUE INFECTIONS

Recognition and treatment of necrotizing or gangrenous soft tissue infection are true medical emergencies. These infections stem from a variety of different pathogens and often have different clinical manifestations. The nomenclature and taxonomy of necrotizing soft tissue infections are confusing. Bacteria such as Clostridium perfringens or Streptococcus pyogenes can cause necrotizing infections of the skin, subcutaneous tissue, and muscle. Often more than one tissue compartment (skin, subcutaneous tissue, fascia, or muscle) is involved simultaneously. Different bacteria can cause clinical syndromes that appear identical. Often these infections are polymicrobic. Types of soft-tissue necrotizing infections have historically been called clostridium cellulitis, nonclostridium crepitant cellulitis, necrotizing fasciitis, clostridial myonecrosis, anaerobic streptococcal myonecrosis, and synergistic nonclostridial anaerobic myonecrosis. More important than assigning a specific name to an infection are prompt recognition and urgent surgical exploration and de´bridement of involved tissue. 4.1

Pathophysiological Characteristics

Any condition that can cause tissue trauma or hypoxia can lead to the development of a necrotizing subcutaneous infection. Therefore, necrotizing soft tissue infections often originate in areas of trauma and crush injury, burns, and gastrointestinal malignancy. Rare cases of clostridial myositis (gas gangrene) have been reported after intramuscular injections. It should also be emphasized that, on occasion, severe clostridial infections may appear spontaneously. These cases seem to be associated with clinically silent malignancies, especially those in the large bowel. Patients with diabetes mellitus are predisposed to necrotizing soft tissue infections. This predisposition is most likely related to accelerated atherosclerosis and vascular insufficiency and diminished WBC function.

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Gas in infected tissue is produced by bacteria in an anaerobic environment as the end product of fermentation. Gases are primarily hydrogen and nitrogen. GNRs such as Escherichia coli and Klebsiella spp. and gram-positive cocci such as Staphylococcus aureus and S. pyogenes are facultative bacteria and may utilize anaerobic (and thus produce gas) or aerobic metabolism. The subcutaneous gas produced can increase tissue pressure and lead to hypoxic damage to the tissue. Tissue necrosis can also be caused by vascular thrombosis or bacterial toxin production. Thrombosis of vessels is common in anaerobic infections because of the production of heparinase. In the case of Clostridium perfringens, another toxin, called lecithinase, is produced by the organism and may be responsible for some of the extensive necrosis. Clostridium spp. also produce exotoxin, which destroys PMN. This explains the typical Gram stain finding of clostridial myonecrosis, which reveals many gram-positive rods but only few PMNs. 4.2

Clinical Syndromes

The approach to the patient with suspected necrotizing soft tissue infection is summarized in Figure 1. The presence of palpable crepitus or radiological evidence of gas in the soft tissue, the formation of blisters or bullae in an area of cellulitis, areas of anesthesia in the midst of cellulitis, and extreme pain disproportionate to the physical examination findings are hallmarks of necrotizing infections. When any of these signs is present, urgent surgical exploration is indicated to confirm the clinical suspicion, evaluate the extent and depth of tissue involvement, and begin surgical de´bridement. If there is doubt about the diagnosis prior to surgical exploration, imaging of the involved area with CT or MRI scan may help demonstrate gas in the soft tissue and delineate the extent of tissue necrosis. 4.2.1 Clostridial Cellulitis Clostridium spp. are gram-positive obligate anaerobes that normally inhabit the human gastrointestinal and genital tracts. Clostridial cellulitis is a necrotizing infection of devitalized subcutaneous tissue without involvement of the fascia or muscle. Gas formation is common and extensive; in fact, more gas is seen in this infection than in clostridial myositis. Infection is generally due to C. perfringens that has been introduced into inadequately de´brided traumatic wounds. Clostridial cellulitis can also arise from infections in the perineum, abdominal wall, or lower extremities contaminated with fecal flora. The incubation period is usually several days. There is little local pain or systemic toxicity. Surgical exploration is necessary to determine the extent of tissue involvement. The large amount of gas present, the lack of extreme pain, and the minimal systemic toxicity make clostridium cellulitis more likely than clostridium myositis. Occasionally S. aureus or anaerobic streptococci can also cause crepitant cellulitis, especially in the diabetic patient. 4.2.2

Necrotizing Fasciitis

Necrotizing fasciitis is an acute infection characterized by rapid progression and prominent systemic toxicity. Minor trauma or prior surgery is the usual predisposing factor. There is an increased risk in diabetes mellitus, alcoholism, and cirrhosis patients. When necrotizing fasciitis is caused by S. pyogenes, the syndrome is referred to as streptococcal gangrene or type II necrotizing fasciitis. Crepitus is rarely present. Anesthesia of the skin is common because of thrombosis of small blood vessels and destruction of the superficial nerves in the necrotic subcutaneous tissue. The skin appearance gradually changes from erythema to the formation of large cutaneous bullae. Aspiration of these bullae usually yields strep-

Infectious Disease Emergencies

27

Figure 1 Approach to the patient with suspected necrotizing skin or subcutaneous infection. High suspicion is required to diagnose and treat necrotizing soft tissue infections rapidly. Risk factors should be determined, and clinical examination should seek hallmarks of a necrotizing infection. CT or MRI imaging may be helpful. Differentiating types of subcutaneous necrotizing infections (horizontal arrows) can be difficult. All patients need urgent surgical exploration and de´bridement. If the microbiological characteristics are not clear, broad-spectrum antibiotics should be instituted until culture results are available.

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Levitz

tococci by Gram stain and S. pyogenes by culture. Later, patchy skin necrosis resembling that of a full-thickness burn develops. Laboratory evaluation reveals leukocytosis, thrombocytopenia, and renal insufficiency. Blood cultures in streptococcal gangrene often have positive results and metastatic infections may be seen. Type I necrotizing fasciitis is caused by a mixture of non–group A streptococcus, aerobic GNRs such as E. coli, Klebsiella spp. and occasionally Pseudomonas aeruginosa; and anaerobic bacilli such as Bacteroides spp. Aside from the difference in Gram stain morphological features, this mixed infection emits a foul smell at surgery, whereas a group A streptococcal infection has little odor. Mixed necrotizing fasciitis of the male genitalia is referred to as Fournier’s gangrene. Despite antibiotic therapy and surgical removal of necrotic soft tissue and fascia, the mortality rate in necrotizing fasciitis remains 30% to 35%. 4.2.3

Clostridium Myonecrosis

Classical gas gangrene secondary to C. perfringens generally originates in contaminated wounds. The incubation period may range from a few hours to several days. Severe pain at the initial site of injury is the earliest symptom. Gas in the tissue, on the other hand, is often a later sign of infection. The lack of tissue gas does not exclude clostridial gangrene. The patient’s condition appears toxic with tachycardia, fever (generally low-grade), and leukocytosis. Disseminated intravascular coagulopathy as well as renal insufficiency can be seen. Creatinine phosphokinase (CPK) level may be elevated. Symptoms of advanced clostridial myonecrosis are diffuse bronzing of the skin, formation of bullae containing hemorrhagic fluid, cutaneous gangrene, and finally crepitus. C. septicum can also cause myonecrosis, although this infection is classically seen in neutropenic patients. Muscle involvement usually begins spontaneously without antecedent trauma. As with C. perfringens infection, the onset is acute and progression rapid. Mortality rate approaches 67%–100%. 4.2.4

Nonclostridial Myonecrosis

Myonecrosis can be caused by bacteria other than Clostridium spp. Anaerobic streptococci such as Peptostreptococcus are most commonly implicated. There is more extensive cutaneous erythema in anaerobic streptococcal myositis than there is in clostridial disease. Early on, pain is less prominent than in clostridial gangrene. Gram stain is also helpful in differentiating the two syndromes as PMNs are present in the tissue fluid of anaerobic streptococcal gangrene. S. pyogenes can also cause acute myositis. It may occur spontaneously or after trauma. The onset is acute and progression rapid. The patient is toxic and the pain can be intense. The muscle is swollen and tense, and a compartment syndrome may develop. Eventually the skin may become involved with bullae formation and cutaneous necrosis. Synergistic nonclostridial anaerobic myonecrosis is another life-threatening soft-tissue infection involving muscle as well as fascia and soft tissue. Obese diabetic patients are at particularly high risk for this infection. Infection generally begins on the leg or the perineum especially if a perirectal abscess is present. The patient appears toxic and is in severe pain. The skin shows patchy necrosis, and ulcers draining foul-smelling pus are common. Gas is present in the tissue in approximately one-quarter of cases. A combination of anaerobic bacteria such as Bacteroides spp. or Peptostreptococcus spp. and aerobic GNRs are usually isolated. Thus, this syndrome may be considered an extension of a type I necrotizing fasciitis caused by similar pathogens.

Infectious Disease Emergencies

4.3

29

Initial Management

Extensive surgical de´bridement is the key to success. Antibiotics are also important but are not effective without concomitant surgical intervention. Because of the variety of bacteria involved in these infections, a Gram stain may be useful to guide the initial antibiotic therapy. Gram-positive cocci in pairs would suggest S. pyogenes; large grampositive bacilli are indicative of Clostridium spp; GNRs alone or a mixture of GNRs and gram-positive cocci would suggest a synergistic infection. If infection due to S. pyogenes is suspected, high-dose penicillin G (4 million U q4h) and clindamycin (900 mg intravenously [IV] q8h) should be started. If a mixed infection is suspected or Gram stain results are not available, a broad spectrum of antibiotics should be initiated to cover aerobic and anaerobic GNRs, streptococci, and staphylococci (see Table 4). The antibiotic regimen can be narrowed on the basis of culture results. Patients generally require repeated surgical exploration and de´bridement over the initial 48 hours of therapy. The use of hyperbaric oxygen has been advocated in the treatment of clostridial myositis as a means of limiting the amount of tissue excision required. There are a number of case reports documenting clinical improvement of patients treated with hyperbaric oxygen. However, no controlled studies have been performed, and the consensus of opinion is that immediate surgical de´bridement coupled with antibiotic therapy is still the initial treatment of choice. Hyperbaric oxygen may be useful as an adjuvant therapy after extensive surgery has been performed. 5

ARTHROPOD-BORNE DISEASES

Arthropod borne diseases (also see Chapter 30) often appear with nonspecific symptoms and may be difficult to differentiate from viral influenza or a typical bacterial infection. Failure to recognize and diagnose these diseases can lead to a severe or even fatal outcome. 5.1

Rocky Mountain Spotted Fever

Rocky Mountain spotted fever (RMSF) is a tick-borne disease caused by Rickettsia rickettsii. The two most important ticks transmitting this disease are Dermacentor andersoni, the wood tick, which is the principal vector in the western United States, and Dermacentor variabilis, the dog tick, the common vector in the eastern United States. In the South, the Lone Star Tick, Amblyomma americanum, is also implicated. Despite the name, 82% of recently reported cases occurred in the southern Atlantic coast and south central regions of the United States and less than 2% in the mountain states. Since untreated the disease has a case fatality rate of 25%, it is exceedingly important that this diagnosis not be overlooked. As might be expected in a tick-borne disease, most cases occur during the summer months, when tick activity is at its peak. People who are frequently outdoors and have high tick exposure are at highest risk for disease. After the bite of the infected tick the rickettsiae multiply in the vascular endothelium. Damage to the vessels appears to account for the most prominent clinical manifestations such as rash, headache, mental confusion, myocarditis, and renal disease. 5.1.1

Clinical Manifestations

Although many patients may recall a history of tick bites, a substantial minority does not. The disease should be considered for all patients with possible tick exposure. The onset

Mix of GNR, GPC

Necrotizing fasciitis Type I

GPR GPC GNR

C. perfringens Peptostreptococci, E. coli, Klebsiella spp., Pseudomonas spp., Bacteroides spp., streptococci

S. pyogenes

E. coli, Klebsiella spp., Pseudomonas spp., Bacteroides spp., streptococci

C. perfringens

Bacteriological characteristics

b

GPR, gram-positive rod; GNR, gram-negative rod; GPC, gram-positive coccus. Assuming normal renal function. c Or ciprofloxacin 400 mg q8h.

a

Myonecrosis Clostridial Nonclostridial, synergistic

GPC in chains

GPR

Clostridial cellulitis

Type II

Gram stain resulta

Clinical syndrome

Table 4 Necrotizing Soft Tissue Infections

Penicillin G Ceftazidimec Vancomycin Metronidazole

Ceftazidime Vancomycin Metronidazole Penicillin G and clindamycin

Penicillin G

Antibiotic(s)

4 million U q4h 2 g q8h 15 mg/kg q12h 500 mg q8h

2 g q8h 15 mg/kg q12h 500 mg q8h 4 million U q4h 900 mg q8h

4 million U q4h

Doseb

30 Levitz

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31

ARTHROPOD-BORNE INFECTIONS Rocky Mountain Spotted fever Mostly in south Atlantic and south central US Onset 2–7 days after tick bite Abrupt onset of headache, fever Rash after fever begins Periphery → central Possible palm and sole involvement Maculopapular, progressing to petechial/hemorrhagic Diagnosis Leukopenia, thrombocytopenia IFA of skin biopsy PCR of rickettsial DNA in blood Fourfold rise in IgG Therapy: doxycycline 100 mg bid Ehrlichiosis Transmitted by Ixodes scapularis, as are Lyme disease and babesiosis Onset ⬃7 days after tick bite Headache, fever, myalgia Rash in 10% (sparing of palms and soles) Diagnosis Morulae in WBC (see Chapter 30, Figure 6) Leukopenia, thrombocytopenia Fourfold rise in IgG Therapy: doxycycline 100 mg bid

of the disease is generally about 2 to 7 days after the bite of an infected tick. Although the onset may be gradual, in most patients it is abrupt, with fever up to 39⬚C–41⬚C. Most importantly patients complain of severe headache, which is often the chief complaint. The headache is excruciating and intense in the frontal area and is generally unresponsive to acetaminophen or nonsteroidal anti-inflammatory agents. There may be accompanying myalgias, and nausea and vomiting. The characteristic rash usually appears several days after the fever has begun. The lesions are generally pink and appear at first in the periphery on the wrists and ankles. The rash then spreads to the trunk. Importantly the rash is present on the palms and soles, quite a rare location for any other diseases of infectious cause outside secondary syphilis. The rash becomes maculopapular and then may become petechial or hemorrhagic. Only half of patients have the rash within the first 3 days of therapy. A not uncommon clinical scenario is that these undiagnosed patients are placed on an antibiotic empirically and when the rash appears it is ascribed to an allergic reaction. Most allergic reactions except true erythema multiforme do not affect the palms and soles. Also to be emphasized is that multiple studies of RMSF suggest that the characteristic rash may never appear in a substantial minority of patients, who thus have ‘‘spotless’’ fever. The mortality rate in this group is often higher as a result of delayed diagnosis. If it is untreated, organ failure is common and often associated with hypotension, circulatory failure, adult respiratory distress syndrome, and arrhythmia. Severe neurological disease including meningoencephalitis and coma may ensue. Fortunately, in recovered patients permanent neurological damage is uncommon.

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5.1.2

Diagnosis and Treatment

There is no existing rapid diagnostic test for RMSF. Currently the Centers for Disease Control and Prevention use an indirect immunofluorescence assay (IFA) to detect IgG antibodies to R. rickettsii. A confirmed case of RMSF generally shows a fourfold or greater rise in the IFA titers in two serum specimens. Acute laboratory data are not very helpful, although leukopenia and thrombocytopenia are present in most cases. The usual treatment of RMSF is doxycycline 100 mg twice a day orally or intravenously for 7 days. Parenteral chloramphenicol therapy is also quite effective. Even with antibiotic therapy the mortality rate of this disease remains around 5%–7%; generally it is related to diagnostic delays. 5.2

Ehrlichiosis

Human monocytotrophic ehrlichiosis caused by Ehrlichia chaffeensis and human granulocytic ehrlichiosis caused by E. phagocytophilia represent another class of tick-borne zoonoses that can have a clinically similar presentation to that of Rocky Mountain spotted fever. The peak incidence is in the summertime. Cases have been reported in over 30 states, particularly in the northeastern, south central, and southeastern United States. In the Northeast, the tick vectors are Ixodes scapularis (deer tick), which also spreads Borrelia burgdorferi, the agent of Lyme disease, and Babesia microti. Human monocytotrophic ehrlichiosis in the South is most likely spread by the Lone Star tick, Amblyomma americanum. After entry into the bloodstream via tick bite, the Ehrlichiae invade either monocytes or PMNs, depending on the species. 5.2.1

Clinical Manifestations

After an incubation period of about 1 week there is an acute onset of headache, fever, myalgias, and malaise. A maculopapular rash is present in about a third of patients with human monocytotrophic ehrlichiosis but only about 10% of patients with human granulocytic ehrlichiosis. The rash characteristically does not involve the palms and soles and therefore helps differentiate the disease from RMSF. Nausea, vomiting, and diarrhea are common. Severe manifestations include rhabdomyolysis, renal failure, hemolysis, and thrombocytopenia. The disease has been mistaken for thrombotic thrombocytopenic purpura. About 40% of patients with human monocytic ehrlichiosis require hospitalization. Numerous deaths have been reported for both types of ehrlichiosis. Laboratory features common to both types of ehrlichiosis include leukopenia, thrombocytopenia, anemia, and elevated hepatic transaminase level. 5.2.2.

Diagnosis and Treatment

Human granulocytic ehrlichiosis can often be diagnosed by the finding of morulae in the peripheral blood smear (see Figure 6, Chapter 30). Diagnosis is generally made by an IFA finding that demonstrates a fourfold or greater rise in antibody titers. Doxycycline 100 mg twice daily has been quite effective in rapidly relieving the symptoms of this disease and preventing severe morbidity and mortality. Chloramphenicol has not been shown to be effective in this disease and should generally not be used. The quinolones have excellent activity against Ehrlichia spp., but there are limited clinical data to support their use. Since Lyme disease, ehrlichiosis, and RMSF all respond to doxycycline therapy, this antibiotic should be strongly considered when a patient has a febrile illness after a tick bite.

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FALCIPARUM MALARIA Importance of taking a travel history in febrile patients Transmitted by Anopheles mosquito in Asia, Central Africa, South America Can have high parasite loads with rapid progression of hemolytic anemia, renal failure, circulatory collapse, and coma Presentation Fever, headache Altered consciousness Anemia and thrombocytopenia Leukopenia or leukocytosis Diagnosis: thick/thin Giemsa stained blood smear Therapy Hospitalization Quinine sulfate and doxycycline (see Chapter 39, Table 11)

6

MALARIA

Malaria (also see chapter 39) is caused by one of four protozoan species of the genus Plasmodia: P. falciparum, P. vivax, P. ovale, and P. malariae. The disease is transmitted by infection of the sporozoite form through the bite of the female Anopheles sp. mosquito. Whereas all species of malaria can cause significant disease, only P. falciparum is typically life-threatening. 6.1

Pathophysiological Characteristics

After transmission to blood by a mosquito bite, the sporozoite invades the liver parenchymal cells. After 2 weeks merozoites are released into the bloodstream, where they invade erythrocytes and develop into a trophozoite. The trophozoite then can produce more merozoites, thus continuing the cycle of erythrocyte parasitism, or produce gametocytes. The male and female gametocytes are then taken up by mosquitoes on a subsequent bite and continue the cycle of infection to other humans. The symptoms of malaria are related to the changes in the red blood cell rheological features caused by parasitic infections. The parasitized erythrocytes become lodged in the microvasculature, causing tissue ischemia and hypoxic damage. The lysis of infected red cells with the release of merozoites is often associated with a paroxysm of chills, fever, myalgias, headache, nausea, and vomiting. Parasitized red cells are also filtered and destroyed in the spleen, resulting in hemolytic anemia. Since P. falciparum can invade red cells at any point in their development, very high levels of parasitemia can be seen. Blockage of cerebral arteries secondary to parasitized red cells causes cerebral malaria with alteration of consciousness or coma. 6.2

Clinical Presentation

Symptoms begin with shaking chills and temperatures up to 40⬚C. Headache, myalgias, abdominal pain, vomiting, and diarrhea are all common. In severe falciparum malaria, altered consciousness can be followed by coma. The paroxysm usually ends with severe diaphoresis and resolution of fever until the next paroxysm begins. Renal failure can occur

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with P. falciparum as a result of hemolysis and hemoglobinuria. Such patients have jaundice and dark urine (blackwater fever). Surprisingly, sometimes the chief complaint of malaria patients is that they have the disease. This generally occurs in immigrants from countries where malaria is indigenous and common and they are able to recognize their symptoms. The malaria paroxysm of fevers is related to the lysis of red cells with release of the new infectious merozoites. This event occurs continuously or irregularly with P. falciparum, as opposed to the every48-hour, or tertian pattern, with P. vivax. Patients who are at risk for falciparum malaria are those who have traveled to endemic areas such as Asia, Central Africa, or South America. In the author’s experience, failure to ascertain a travel history is the leading cause of missed diagnosis and the resultant increased morbidity and mortality rates for malaria. 6.3

Diagnosis

The diagnosis is made from review of a thin or thick Giemsa stained blood smear. Typically all sizes of red blood cells are infected. Often 5% or more of the circulating erythrocytes are infected. Multiple ring forms can be seen in a single red blood cell. Multiple smears may be needed before the diagnosis is confirmed. Patients may be anemic and thrombocytopenic with either leukocytosis or leukopenia. Since the level of parasitemia and hemolysis can be extensive, the patient may rapidly become severely anemic and hemodynamically unstable. 6.4

Treatment

P. falciparum is assumed to be resistant to chloroquine. The most common recommended treatment is quinine sulfate plus doxycycline administered for 1 week (see Chapter 39, Table 11). If the patient has severe nausea and vomiting or cannot take oral medications, treatment is begun with intravenous quinadine in a setting with cardiac monitoring. Highdose mefloquine and halofantrine are second-line agents. Unfortunately high doses of mefloquine are associated with severe neurological and gastrointestinal side effects. Halofantrine can prolong the q-t interval and thus must be administered in a setting with cardiac monitoring. In severely ill patients when parasitemia is greater than 15%, exchange transfusion may be considered to decrease the parasite burden rapidly. Corticosteroids have not been shown to be helpful in severe malaria, including cerebral malaria. 7

NEUTROPENIC FEVER

Recognition and rapid institution of antibiotic therapy have reduced the mortality rate of neutropenic fever from >50% to 90 With food 18–45 (Varies on salt of drug used) 37 55 90

65–85 99 90 96 70–90

80

Antibiotic

Tetracycline Doxycycline Erythromycin

Azithromycin Clarithromycin Clindamycin

Ciprofloxacin Levofloxacin Moxifloxacin Gatifloxacin Co-trimoxazole

Metronidazole

No

No Slightly No No No

Yes No No

Slightly Slightly Yes

Absorption decreased by food

65–85 24–38 50 20 44 (Trimethoprim) 70 (Sulfamethoxazole) 95

Human immunodeficiency virus 1 Legionella pneumophila serogroup 1 Epstein-Barr virus (EBV)b

Anti-HIV-1 IgG

Throat swab Blood Nasopharyngeal wash/swab Serum

>99

>99

Serogroup 1 antigen

Urine

95

95

Heterophile IgM

Blood

85

>95

a

CLIA, Clinical Laboratory Improvement Act; IgG, immunogloblin G; HIV-1, human immunodeficiency virus 1. CLIA-waived test commercially available. c Compared to gastric biopsy as gold standard. d For nasal swab, 73%; for nasopharyngeal wash specimens, 81%. b

The Microbiology Laboratory

4.2

103

Rapid Influenza A and B Antigen Detection

A rapid (10-minute) point of care immunoassay for the detection of influenza A and B antigens has been released (QuickVue, Quidel, San Diego, CA), and other such tests may follow. Using either nasal swab or nasopharyngeal wash specimens, this test has demonstrated a sensitivity of 73% (for nasal swab) to 81% (for nasal wash or aspirate) and a specificity of >95% for the detection of influenza A and B antigens. The test does not differentiate between influenzas A and B. Although patients with influenza may be treated empirically in the proper clinical setting, the ability to diagnose the condition rapidly may aid treatment decisions in some clinical situations and may be important for epidemiological purposes. Negative results require confirmation by cell culture techniques. The rapid point of care test for influenza detection has recently become a CLIA-waived test. 4.3

Heterophile Antibody Screen for Epstein-Barr Virus (Monospot)

For patients with signs and symptoms of infectious mononucleosis, detection of heterophile antibodies is diagnostic of Epstein-Barr virus (EBV) infection. Several qualitative agglutination or enzyme-linked immunoassays are available for rapid detection of heterophile antibodies. The sensitivity of these tests is approximately 85%, but the specificity is excellent. Most cases of falsely negative heterophile antibody test results occur in the pediatric population (in whom the clinical course may be less severe) or early in the clinical illness (in which case the heterophile antibody may become detectable later in the clinical course). A persistently negative heterophile antibody finding in the proper clinical setting should prompt a more diligent search for other infectious causes of a mononucleosis syndrome (e.g., cytomegalovirus [CMV], toxoplasma, human immunodeficiency [HIV]). 4.4

Helicobacter pylori Antibody (Immunoglobulin G) Detection Immunoassay

Helicobacter pylori infects approximately two-thirds of the world’s population. In the United States, the overall prevalence of H. pylori is 30% but varies with age. Although most people who are infected with H. pylori are asymptomatic, the organism has been associated with peptic ulcer disease (PUD), gastritis, gastric cancer, and mucosal-associated-lymphoid-type lymphoma. Since PUD is a commonly diagnosed condition, and since antimicrobial treatment of H. pylori infection in the setting of PUD is recognized to prevent recurrences of disease, the clinician frequently needs to know whether a patient is infected with H. pylori. Several rapid (⬃10-minute) immunoassays are now available for the detection of immunoglobulin G (IgG) antibodies to H. pylori and are comparable in sensitivity and specificity to the traditional serological tests. These tests are useful as relatively inexpensive, noninvasive diagnostic tools to assist in deciding whether to treat a PUD patient with antimicrobials in addition to the usual antacid therapy. Because these tests detect antibody to H. pylori they are not useful for following response to therapy—some patients remain seropositive for an extended period after therapy. 5

OTHER RAPID DIAGNOSTIC TESTS PERFORMED IN THE LABORATORY

There are several other rapid tests available for the diagnosis of infectious diseases, and the list will certainly grow each year. As clinics and hospitals increasingly outsource

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microbiology services, there will be more demand for ‘‘point of care’’ tests that can quickly, easily, and accurately detect common infectious agents in clinical specimens. Two of these tests merit specific mention. 5.1

Rapid Human Immunodeficiency Virus Testing

A rapid (⬃30-minute) enzyme immunoassay for the detection of antibody to HIV-1 has been available for several years (HIV-1 SUDS, Murex), and other rapid tests will soon be available. This test has a sensitivity and specificity comparable to those of the traditional HIV-1 enzyme-linked immunosorbent assay (ELISA) (>99%). As does any HIV antibody detection test, the rapid HIV test requires prior confirmation by Western blot before the result is reported as positive—in a low-prevalence population, the positive predictive value of the rapid test alone is poor. However, because of the extremely high sensitivity and high negative predictive value, the rapid HIV test has been helpful in at least two important clinical settings. After exposure of a health care worker (HCW) to potentially HIV infected blood, a negative rapid HIV test on the source patient can provide important information to be used in deciding whether the exposed HCW should receive antiretroviral prophylaxis. Similarly, rapid HIV test results for a woman in labor with unknown HIV status can aid the obstetrician and pediatrician in deciding whether to administer antiretroviral therapy during labor and/or in the perinatal period to prevent HIV transmission from mother to child. Rapid HIV serological testing has the same limitations that all HIV serological testing has—namely, detectable HIV antibody may not appear until 3–6 months after HIV infection. If the patient practices risky behavior within that window, a false-negative test result can be seen. Conversely, false-positive results are common in low-prevalence populations—so confirmation of positive rapid HIV test results with Western blot analysis is required. 5.2

Legionella Urinary Antigen

Because Legionella spp. require special growth requirements, they are not detected in routine sputum culture samples; special media are required. For this reason, legionellosis is underdiagnosed—some have estimated that 1:8 (CF); ⱖ32 (EIA) Confirm ⫹ EIA with WB 4-Fold rise, ⱖ1:80 4-Fold rise 4-Fold rise, IgG ⱖ 512 4-Fold rise 4-Fold rise 4-Fold rise Any titer positive Specific band(s) diagnostic Confirm ⫹ IHA/IFA with WB 4-Fold rise 4-Fold rise or ⱖ1:160 4-Fold rise, IgG ⱖ32 ⱖ1:128 Positive ⱖ1:128 Positive 4-Fold rise 4-Fold rise 4-Fold rise ⱖ1:8 ⱖ1:32 To confirm positive RPR/VDRL ⱖ1:5 4-Fold rise

CF, complement fixation; IFA, immunofluorescence assay; IHA, indirect hemagglutination; EIA, enzyme immunoassay; WB, Western blot (Immunoblot); ASO titer, anti–streptolysin O titer; FTA-ABS, fluorescent treponemal antibody adsorption; MHA-TP, microhemagglutination test for Treponema pallidum; BF, bentonite flocculation; RPR, VDRL, Venereal Disease Research Laboratory.

As previously discussed, contamination of blood culture specimens can increase costs and cause diagnostic confusion. The best preventive measure against contamination is optimal site preparation. In addition, separate venipunctures should be performed to help interpret cultures containing common skin contaminants (coagulase-negative staphylococci, diphtheroids, etc.). Obtaining blood cultures through central venous lines should be discouraged, since increased isolation of contaminants and line colonizers results. If blood cultures are obtained through central venous catheters (CVCs), a simultaneous culture from a peripheral venipuncture site should be obtained to assist in interpreting the blood culture result. For example, the isolation of coagulase-negative staphylococcus from a single bottle obtained from a CVC is less likely to be clinically significant if results of peripheral cultures obtained simultaneously are negative. The most common manual blood culture system still in use is the Isolator (Wampole Laboratories, Cranbury, NJ). This is a lysis-centrifugation system in which the cellular components in the blood are lysed, the tube is centrifuged, and the sediment is cultured onto a variety of media for isolation of microorganisms. The Isolator is still used in many

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institutions to enhance detection of some (usually fungal) organisms. Although broth-based automated systems perform comparably in the detection of virtually all bacteria and Candida spp., the lysis centrifugation system may enhance detection of certain intracellular pathogens such as Histoplasma capsulatum, Mycobacterium spp., Bartonella spp., and Legionella spp. In addition, a lysis-centrifugation method provides the flexibility to culture a blood sample immediately to special media for detection of pathogens with particular growth requirements. Some organisms are difficult to isolate in blood cultures and require special consideration by the laboratory. Brucella spp. are slow growing, fastidious intracellular organisms. Their recovery may be enhanced either through the use of lysis-centrifugation blood cultures (plated to Brucella spp. blood agar) or with prolonged incubation of blood culture bottles (up to 3 weeks) with blind subculture each week to a Brucella spp. blood agar plate. Abiotrophia spp. (formerly known as nutritionally variant streptococci) require vitamin B6 for growth. The broth based automated systems support growth of these organisms, which may not grow on a standard sheep blood agar plate after subculture. A positive signal from a blood culture and lack of growth on subculture should raise suspicion of Abiotrophia spp.—subculture to a plate streaked with Staphylococcus aureus or containing a pyridoxal (B6) disk demonstrates growth of tiny satellite colonies. Other bacteria that may require special handling to optimize recovery include Mycobacterium spp., Bartonella spp., and certain organisms from the HACEK group of fastidious gram-negative organisms responsible for some cases of ‘‘culture-negative’’ endocarditis (Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae). If these organisms are suspected, the laboratory should be notified to improve the likelihood of successful recovery. 7.2

Respiratory Tract Specimens

Most outpatient respiratory tract infections are treated empirically, without obtaining a specimen for culture. In general this is appropriate. Respiratory tract cultures in outpatient practice should primarily consist of throat cultures obtained for the diagnosis of group A streptococcus (for which the properly obtained throat swab culture is the gold standard). Many have questioned the value of cultures of expectorated sputum—patients with bacteremic pneumonia often do not demonstrate the offending organism in sputum culture, and sputum is frequently contaminated with oropharygeal flora. If a sputum sample is obtained, a Gram stain assists in determining whether it is appropriate for culture; in addition, the Gram stain may provide all the information necessary for initiation of antimicrobial therapy. Many bacterial respiratory tract pathogens are not easily cultured in the laboratory, requiring special media or non-culture-based detection methods. A partial list of these organisms includes Legionella spp., Mycobacterium spp., Mycoplasma pneumoniae, Chlamydia spp., Nocardia spp., and Bordetella pertussis. Text and tables in other sections of this chapter address detection of many of these organisms. 7.3

Cerebrospinal Fluid Specimens

Obtaining cerebrospinal fluid (CSF) for bacterial culture is an emergency procedure, since untreated bacterial meningitis can be rapidly fatal. Empirical treatment for suspected bacterial meningitis should never be withheld because of a delay in obtaining CSF for culture. If a lumbar puncture (LP) is delayed by difficulty in performing the procedure or the need to obtain a computed tomography (CT) scan prior to the LP, antibiotics should be admin-

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istered as blood cultures are obtained. The most common causes of bacterial meningitis (e.g., Streptococcus pneumoniae, Neisseria meningitidis) are often detectable in blood cultures, and CSF parameters are not immediately altered by antibiotic therapy. When CSF is collected for bacterial culture, it should be sent immediately to the laboratory to enhance organism detection. Commercial bacterial antigen detection procedures (for H. influenza, N. meningitidis, S. agalactiae, and S. pneumoniae) do not add significantly to Gram stain of a centrifuged CSF specimen in the diagnosis of bacterial meningitis—sensitivities of Gram stain for the detection of specific organisms in CSF are outlined in Table 7. 7.4

Urinary Tract Specimens

Specimens from voided urine are commonly contaminated with periurethral and genital tract flora. To decrease the likelihood of contamination, careful preparation of the periurethral area and collection of a midstream specimen are recommended. Even in this setting, up to a third of voided urine specimens harbor contaminants. The reason quantitative urine culture techniques are important is that they can distinguish between contamination and true infection—contaminants are generally present in quantities of 104 CFU/ml. Most laboratories use a calibrated loop to obtain a specified standard volume of urine for culture (e.g., 0.001 ml), allowing for colony counts to provide quantitative results (e.g., 1 colony equals 1000 CFU/ml). Contaminants can sometimes be present in larger numbers (e.g., >104 CFU/ml), causing false-positive results—often as a result of a specimen’s sitting at room temperature for too long or contaminating bacteria’s growing to high levels in a urinary catheter collection bag or tube. Rapid transport of specimens to the lab (or refrigeration if a delay occurs) and careful attention to collection technique can minimize this problem. Conversely, some patients (particularly young women) can have urinary tract infection associated with 104 CFU/ml). As noted, however, patients may have urinary tract infection associated with lower colony counts (102 –104 CFU/ml). Nitrate reductase and leukocyte esterase screening tests have lower sensitivity in this case, so a negative test result in the proper clinical setting should be confirmed by a urine culture. 7.5

Genital Tract Specimens

Most genital tract specimens are submitted to the clinical microbiology laboratory for detection of two predominant pathogens, Neisseria gonorrhoeae and Chlamydia trachomatis. N. gonorrhoeae is a fastidious organism that does not grow well in the presence of other flora. For this reason, various chocolate-agar-based selective media (containing antibiotics to inhibit commensals) have been developed for isolation of N. gonorrhoeae. These media are available in transport systems (e.g., JEMBEC, Ames) that contain an individual agar plate with selective media and a CO2 generating tablet. These systems allow for immediate plating of the specimen, which improves yield (since N. gonorrhoeae is intolerant of drying and low-CO2 environments). Direct tests (nonculture) for N. gonorrhoeae are available (Table 5). Some that are based on nucleic acid amplification can be used to detect Chlamydia trachomatis simultaneously. These tests do not significantly enhance the sensitivity of a well-collected culture specimen, but they allow for detection of these pathogens in urine as well as cervical or urethral specimens. Because an organism’s DNA may persist for days to weeks after successful therapy, the nucleic acid detection tests cannot be used to test for cure. In addition, such tests are not admissible evidence in medicolegal cases (e.g., sexual abuse, sexual assault). Of the genital ulcer syndromes (herpes simplex, syphilis, chancroid, lymphogranuloma venereum, and granuloma inguinale), only one is due to a bacterial pathogen easily isolated in the laboratory—Haemophilus ducreyi, the cause of chancroid. If chancroid is considered (in contrast to syphilis, these ulcers are painful and do not have indurated margins), a swab specimen from the base of an ulcer should be collected and the laboratory notified that H. ducreyi is suspected. The diagnosis of syphilis is based on dark-field microscopy and serological evaluation, whereas herpes simplex is easily detected with direct techniques and/or viral culture. The evaluation of vaginitis is based on clinical and microscopic characteristics (Table 2). Cultures of vaginal discharge are not recommended. 7.6

Skin and Soft Tissue Specimens

Because skin and wound surfaces are colonized with bacteria that can be either pathogenic or commensal, cultures of skin, soft tissue, and wound surfaces rarely provide useful information. If an infected collection or abscess is present, careful disinfection of the wound surface prior to incision and drainage may provide good material for culture. The largest amount of material possible should be sent to the laboratory for culture—preferably in the syringe with which it was collected or in a collection tube. Rapid transport of such

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a specimen to the laboratory allows optimal detection of anaerobes or mixed aerobic– anaerobic infections. 7.7

Stool Specimens

Although most cases of acute diarrhea are self-limited, protracted or severe symptoms merit investigation, including stool cultures to identify common bacterial causes. Because stool contains so many bacteria (>1010 CFU/g), isolation of one of the few recognized enteropathogens in culture is challenging. Most laboratories routinely attempt to identify common pathogens such as Salmonella, Shigella, and Campylobacter spp. in all diarrheal stools submitted for enteropathogen detection. However, some laboratories do not routinely attempt to detect many other potential pathogens, including Aeromonas spp., Plesiomonas spp., Vibrio parahaemolyticus, Vibrio cholerae, Yersinia enterocolitica, or Escherichia coli 0157:H7. When you suspect these pathogens, you should call your laboratory to determine whether they use procedures to detect these organisms and specifically request them if they do not. A careful exposure history and attention to the epidemiological details can help to focus laboratory efforts. Toxin producing strains of Clostridium difficile commonly cause antibiotic-associated diarrhea. Since C. difficile can also be part of fecal flora without producing toxin, most laboratories do not attempt to culture the organism but offer a toxin assay. Many EIA tests are commercially available for the detection of C. difficile toxin A or B, with reported sensitivities ranging from 63% to 99% and specificities from 75% to 100%. Because of varying sensitivities, three negative toxin assay results should be obtained prior to excluding the diagnosis if the suspicion is high. Rare C. difficile strains may produce toxin B without producing toxin A, so EIA assays for toxin A only may produce some falsenegative results. In addition to having bacterial culture, patients with appropriate travel or exposure history should have stools sent for ova and parasite exam, Giardia spp. antigen, and Cryptosporidium spp. antigen detection. 8

CULTURE DETECTION OF COMMON FUNGAL PATHOGENS

Serious fungal infections have increased in frequency with an increase in numbers of immunocompromised patients (e.g., acquired immunodeficiency syndrome [AIDS], transplantation). For the clinician in the outpatient setting, few occasions call for culture identification of fungal pathogens. Mucocutaneous fungal infections are generally diagnosed clinically and treated empirically (e.g., yeast vaginitis, oropharyngeal candidiasis). An extremely wide variety of fungi can cause skin infection (dermatophytes); culture and species level identification of these organisms serve little purpose in most clinical settings. In some clinical situations it is important to know the identity of a fungal pathogen in outpatient practice. For example, refractory oropharyngeal candidiasis in an AIDS patient may require culture for susceptibility testing of the Candida spp. responsible. Table 8 gives recommendations for studies that should be available in the laboratory to assist in the management of fungal infections. 9

CULTURE DETECTION OF COMMON VIRAL PATHOGENS

Laboratory detection of viruses includes (1) culture techniques for viral isolation, (2) rapid assays that detect viral antigens (e.g., EIA, LA), (3) nucleic acid amplification techniques (e.g. PCR), and (4) serological tests that detect antibody response to viral infection.

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Table 8 Recommendations for Studies of Fungal Isolates from Clinical Specimens (Outpatient) Setting

Recommendation

Routine

Species level identification of all Candida spp. isolates from sterile sites Genus level identification of molds Routine antifungal susceptibility testing not recommended; some institutions may wish to batch test annually to establish local antibiogram

AIDSa and oropharygeal candidiasis

Routine antifungal susceptibility testing not required Susceptibility testing potentially useful in patients unresponsive to treatment Relevant drugs: fluconazole, itraconazole

a

AIDS, acquired immunodeficiency syndrome.

Viral culture involves growing viruses in cell lines and observing for cytopathic effect (CPE). Each virus grows best in particular cell lines. When CPE is detected, definitive identification of the virus can proceed by using antigen detection techniques (e.g., direct or indirect fluorescent antibody assays) or molecular methods. Shell vial assays are modifications of viral culture in which the inoculum is centrifuged onto a cell monolayer grown on a circular cover slip. The cover slips can be removed early in the incubation period (18–48 hours), at which time direct fluorescent antibody assay (DFA) or indirect fluorescent antibody assay (IFA) can be performed to detect viral antigens prior to the development of CPE. Shell vial techniques and rapid detection assays have greatly reduced the time needed for diagnosis of many viral infections. Serological evaluation remains a common method for diagnosis of viral infections. Serological data for viral pathogens must be interpreted in light of the usual time course of infection, the particular antibody detected, and the nature of the viral antigen to which the immune response is measured. For many common viral infections (e.g., Herpes simplex virus) serological analysis is of limited utility—except to document previous infection. Viral infections diagnosed by serological analysis include Epstein-Barr virus, parvovirus B19, rubella virus, hepatitis viruses (A, B, C, D, E, G), HIV, human T-cell lymphotropic viruses (HTLV-1 and HTLV-2), arboviruses (encephalitis viruses, dengue, Colorado tick fever virus), and hantaviruses. Rapid, direct detection of viral antigens or nucleic acids has revolutionized viral diagnostics. A partial listing of commonly used direct viral detection methods can be found in Table 5, but new tests are introduced regularly. Given the complexity and rapid evolution of viral diagnostics, it is best to call the laboratory prior to collecting and sending a specimen for virus detection. In addition, if you collect specimens for viral diagnostics, up-to-date viral transport media should be readily available in your office refrigerator to prevent undue delays in specimen collection. 10 10.1

ANTIMICROBIAL SUSCEPTIBILITY TESTING Bacteria

Increasing rates of resistance of common bacterial pathogens to antibiotics are a worldwide crisis. Several systems for antibiotic susceptibility testing (AST) are available to the clin-

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ical microbiology laboratory. Traditional reference methods include macro- or microtube dilution, which provides an exact measure of minimal inhibitory concentration (MIC), and disk diffusion, which provides a zone of inhibition that is converted to a categorical value of susceptible, intermediate, or resistant. In the United States, the breakpoint MICs and zone diameters that define these categories are set by the National Committee on Clinical Laboratory Standards (NCCLS). Conventional tube dilution or disk diffusion AST has been replaced in many laboratories by automated commercial systems, which are convenient, less-labor intensive, and more rapid for many organisms. The Etest (AB Biodisk, Solna, Sweden), a gradient diffusion system, is based on disk diffusion but allows for determination of MICs by using an agar-based method. Although AST results can be useful to help guide treatment, they are often not predictive of the success or failure of antimicrobial therapy. The susceptibility of an organism to an antibiotic should always be interpreted in light of the clinical setting, site of infection, and response to empirical therapy. For example, it is well recognized that penicillin resistance in S. pneumoniae is clinically relevant for closed space infections (e.g., meningitis and otitis media) but does not appear to correlate with clinical response in cases of pneumonia. This is because much higher penicillin concentrations reach lung tissue than may cross into middle ear fluid or CSF. Likewise, there is little correlation between susceptibility category and successful treatment of urinary tract infection for antibiotics that are concentrated to high levels in the urine. 10.2

Fungi

Antifungal susceptibility testing advanced considerably in the 1990s. A standardized testing method for yeast isolates to fluconazole and itraconazole is now available in many laboratories. The correlation between antifungal susceptibility testing and clinical outcome has been established mainly in the therapy of oropharyngeal candidiasis in AIDS patients. Table 8 gives current recommendations for susceptibility testing of fungal isolates in clinical laboratories. 10.3

Viruses

Antiviral susceptibility testing in the outpatient setting is limited primarily to genotypic and/or phenotypic testing of HIV for patients on antiretroviral therapy. Rarely, a patient with refractory herpes simplex virus (HSV) infection may harbor an acyclovir-resistant strain, and it is not uncommon for cytomegalovirus-causing retinitis to develop resistance to antiviral therapy. These resistances are usually suspected clinically and treated empirically, but they can be detected in referral or research laboratories.

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CONCLUSION

Diagnostic testing for infectious agents is advancing rapidly, as new methods for rapid or molecular detection of pathogens become available each year. In addition, as new emerging pathogens are described, new diagnostic tests soon follow. The future holds many exciting prospects, including rapid direct detection of bacterial pathogens in clinical specimens— and perhaps the rapid direct detection of resistance genes in the same samples. The astute clinician will keep abreast of the literature, in order to adopt those technologies most likely to have a direct, beneficial impact on patient management in the office setting.

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BIBLIOGRAPHY Cockerill FR. Conventional and genetic laboratory tests used to guide antimicrobial therapy. Mayo Clin Proc 73:1007–1021, 1998. Gill VJ, Fedorko DP, Witebsky FG. The clinician and the microbiology laboratory. In: Mandell GL, Bennett JE, Dolin R, ed. Principles and Practice of Infectious Diseases. 3rd ed. Philadelphia: Churchill Livingstone, 2000, pp 184–221. Hines J, Nachamkin I. Effective use of the clinical microbiology laboratory for diagnosing diarrheal diseases. Clin Infect Dis 23(S1):S97–S101, 1996. Isenberg HD. Essential Procedures for Clinical Microbiology. Washington, DC: American Society for Microbiology Press, 1998. Lewis RE, Klepser ME, Pfaller MA. Update on clinical antifungal susceptibility testing. Pharmacotherapy 18:509–515, 1998. Miller JM. A guide to specimen management in clinical microbiology. 2nd ed. Washington DC: American Society for Microbiology Press, 1999. Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH, eds. Manual of Clinical Microbiology. 7th ed. Washington, DC: American Society for Microbiology Press, 1999. Pezzlo M. Detection of urinary tract infections by rapid methods. Clin Microbiol Rev 1:268–280, 1988. Reimer LG, Carroll KC. Role of the microbiology laboratory in the diagnosis of lower respiratory tract infections. Clin Infect Dis 26:742–748, 1998. Reimer LG, Wilson ML, Weinstein ML. Update on the detection of bacteremia and fungemia. Clin Microbiol Rev 10:444–465, 1997.

6 Outpatient Parenteral Antibiotic Therapy Donald M. Poretz Inova Fairfax Hospital, Falls Church, Virginia, U.S.A.

1

INTRODUCTION

Traditionally, the treatment of certain infections such as osteomyelitis, infective endocarditis, and severe wound infections has required hospitalization for up to several weeks to administer parenteral antibiotics. Over the past several years, however, many of these infections have been shown to be treated effectively and safely on an outpatient basis with parenteral antibiotics. Extensive experience has documented clinical efficacy and cost saving for outpatient parenteral antibiotic therapy (OPAT), and in many instances this has become the standard of care for a variety of infectious processes. Most of the initial studies focused on bone and joint infections. Currently, though, a wide variety of other infectious diseases have been shown to be amenable to outpatient treatment, including soft tissue and wound infections, osteomyelitis, septic arthritis and prosthetic joint infections, pneumonia, sinusitis, otitis media and mastoiditis, endocarditis and vascular graft infections, visceral abscesses, complicated urinary tract infections, pelvic inflammatory disease, meningitis, neutropenic fevers, bacteremias, fungal infections, severe herpetic infections, and cytomegalovirus infections. The advent of new potent antimicrobics with prolonged half-lives that can be infused over 30 to 60 minutes without sacrificing antimicrobial activity together with miniaturized infusion devices that allow for ease of administration have made OPAT a reasonable alternative to hospitalization. Additionally, economic pressures from third-party payers and managed care providers have promoted less expensive alternatives to hospitalization. New drugs with excellent bioavailability have expanded the types of infections being treated orally. Agents such as the flouroquinalones (ciprofloxacin, levofloxacin, gatifloxacin), macrolides (azithromycin), clindamycin, metronidazole, trimethoprim-sulfamethoxazole, and doxycycline are very well absorbed orally and should be used parenterally only if the patient is unable to take them orally. An approach to the patient being considered for OPAT is outlined in Figure 1. Infectious disease consultation should be considered prior to the initiation of OPAT to assist with patient selection, antimicrobial use, and type of venous access and to help with drug and complication monitoring. 115

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OUTPATIENT PARENTERAL ANTIBIOTIC THERAPY Complex (Table 1) ID consultation suggested Adverse effects (Table 7) Need for close monitoring (Table 6) Amenable to a wide array of infections (Table 3) Varied venous access devices (Table 2 and Figure 2) Cost savings compared to hospitalization Antibiotics expensive (Table 5) More convenient for patient Team approach needed Physician Nurse Pharmacist Supply vendor Patient Attending physician ultimately responsible Approach to the patient when OPAT considered (Figure 1)

2

PATIENT SELECTION

The primary consideration in selection of candidates for OPAT is the clinical status of the patient. Experience has shown that certain criteria are necessary to evaluate a candidate for outpatient therapy (Table 1). The patient’s vital signs should be stable with body temperature either being normal or heading in that direction. If a wound is present, the drainage needs to be contained in a bandage that is easily manipulated by the patient, the patient’s family member, or a health care provider. In cases of infective endocarditis, there should be no recent evidence of embolic phenomena, conduction abnormalities, or congestive heart failure. Patients with respiratory infections should be able to handle their own secretions. Any concurrent disease such as diabetes mellitus obviously requires appropriate attention. The patient and his or her family must be educated about all aspects of OPAT and what their responsibilities will be, and consideration given to family responsibilities such as care of small children or elderly patients that could hinder compliance. Adequate venous access needs to be established. Consideration of the patient’s social circumstances and general psychological state is important. Patients need to understand that their medications have to be administered at regular specific intervals either by them, a family member, or a home care provider. Contraindications for OPAT include drug abuse, alcoholism, psychotic behavior, or a home environment that would prohibit proper treatment because of lack of electricity, running water, refrigeration, or adequate cleanliness. Financial considerations including reimbursement by third-party payers must be investigated before OPAT is instituted. An understanding of the cost of drugs, equipment, and other aspects of home and outpatient care is important. The attending physician is ultimately responsible for any potential adversities associated with OPAT.

Outpatient Parenteral Antibiotic Therapy

Figure 1 Approach to outpatient parenteral antibiotic therapy (OPAT).

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Table 1 Candidates and Contraindications to Outpatient Parenteral Antibiotic Therapy Candidates Inability to take oral medications Organism sensitive to parenteral antimicrobials only Infection amenable to OPAT (Table 3) Adequate insurance Ability to insert and maintain chronic venous access Stable and safe home environment Good patient compliance Contraindications Active drug and alcohol abuse Poor compliance Psychiatric and social instability

3 3.1

EQUIPMENT REQUIRED Catheters

Several intravenous access devices are commercially available to treat individuals on an outpatient basis (Table 2). For short courses of therapy lasting for a few days, a butterfly needle, also called a winged infusion needle, can be used. These devices are short, insert easily, and can usually accept 30- to 60-minute infusions without infiltrating. They infiltrate easily, though, and are difficult to stabilize. They are infrequently used for individuals who require prolonged courses of therapy. A heparin lock, also called an over-the-needle catheter or angiocatheter, is commonly used for short-term therapy lasting from a few days to a couple of weeks. These lines can be difficult to insert when patients have poor venous access and like the butterfly needle cannot be used by individuals who need prolonged courses of therapy. Several catheters that can be used for prolonged periods are illustrated in Figure 2. Midline catheters fill the void between short peripheral devices and longer central catheters. These catheters are typically 6 to 10 inches in length. They are inserted into the antecubital fossa but do not enter the thoracic cavity and are therefore not true central catheters. They are made of elastomeric hydrogel that softens and expands when in contact with the venous system. Heparin must be used to prevent clotting, and sterile dressing changes are recommended. Midline catheters can be kept in place for several weeks. There have been reports of anaphylactic-type reactions associated with some of these catheters. Peripherally inserted central venous catheters (PICCs) are commonly used for longterm therapy in individuals with poor venous access. They are inserted in the antecubital fossa and threaded into the superior vena cava. These lines are particularly useful when irritating solutions are being infused. Sterile dressing changes are required and maintenance with heparin is necessary. A chest radiograph must be taken after insertion to make sure that the tip of the catheter lies in the superior vena cava. Indwelling surgically introduced central venous catheters (CVCs) such as Groshong and Hickman catheters are good for long-term therapy (many months or even years). Hickman catheters require daily maintenance with heparin, whereas Groshong catheters require weekly maintenance with saline solution. They both require frequent dressing changes. Potential complications of insertion include pneumothorax, hemohydrothorax,

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Table 2 Intravenous Access Devicesa Device

Duration of use

Advantages

Butterfly

Day(s)

Heplock

Days

Midline

Weeks

PICC

Weeks to months

Long duration of use Safety of insertion

CVC Groshong Hickman

Weeks to months

Long duration of use Can draw blood from

Central port Port-A-Cath Mediport

Months to years

Long duration of use Can draw blood from Less maintenance than CVC Lower infection rates

a

Ease of insertion small infection risk Ease of insertion limited infection risk Ease of insertion limited infection risk

Disadvantages Short duration of use Short duration of use Not a true central catheter; requires heparin flush Need for professional insertion and maintenance Requires heparin flush Infection, thrombophlebitis Clotting Invasive procedure Need for professional insertion and maintenance Requires heparin or saline solution flush Invasive procedure Need for professional insertion and maintenance Access by Huber needle Requires heparin or saline solution flush

PICC, peripherally inserted central catheter; CVC, central venous catheter.

hemorrhage, air embolism, venous thrombosis, catheter thrombosis, catheter tip migration, and catheter sepsis. Blood can be drawn from these lines, eliminating the need for potential repeat venipunctures. Implanted catheters (Port-A-Cath and MediPort) are disklike devices with which the entire access system is placed under the skin. They are good for long-term therapy and infusion of irritating solutions. Less maintenance is required, but they require surgical placement and access for intravenous therapy with a special Huber needle. Some patients prefer these devices because they are cosmetically more acceptable. They have the same insertion complications as CVCs. 3.2

Infusion Devices

Antibiotics can be administered via several types of mechanical infusion devices. The simplest and least expensive method is the gravity drip bag. This is often used in conjunction with a lyophilized antibiotic that is mixed with sterile precautions into the bag before infusion. Fixed rate infusion pumps include elastomeric reservoirs or electronic syringe pumps. Elastomeric reservoirs have distended balloons that force the medication through a capillary tube, with a fixed resistance, allowing for a preset rate of drug infusion

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Figure 2 Torso showing positions of midline catheter in the right arm, peripherally inserted central catheter (PICC) in the left arm, tunneled central venous catheter (CVC) in the left chest, and implanted infusaport in the right chest. All catheters, except the midline, enter the chest cavity. The catheter tip generally resides in the superior vena cava.

wherever the device is placed in relation to the body. Programmable pumps allow drugs to be administered from a cassette or external reservoir at a determined rate and interval. These programmable pumps can infuse antibiotics intermittently and are useful for administration of antibiotics with short half-life and frequent dosing intervals such as benzyl penicillin (every 4 hours). The antibiotic cassettes can be replaced once daily. These devices, which offer accuracy and convenience, also add to the cost of infusions.

4

LOCATION

Patients who are receiving OPAT can be infused with medication at infusion centers, in the physician’s office, or at home. An ‘‘infusion center’’ often incorporates physicians’ offices, laboratory and treatment facilities, and nursing, pharmacy, and financial services under one roof. It essentially functions as a daytime hospital but with much easier access for patients. The main advantage of these centers is that physicians are on site to exercise maximal control over the infusions. Patients can be examined, laboratory studies can be obtained as necessary, the entire staff is on hand to handle any complications or emergencies as they arise, and communication among physicians, nurses, pharmacists, and

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administrators is instantaneous. The infusion center is an ideal location to care for higherrisk patients who cannot be treated effectively and safely at home. Office-based infusion is similar to the infusion center concept but without all of the ancillary personnel. Antibiotic administration in the office setting requires careful scheduling to ensure that office space needed for regular practice activities is not occupied by patients who require infusions. A third OPAT model is infusion of patients with antibiotics at home. This procedure is often contracted to a commercial home infusion company that supplies trained personnel, antibiotics, and all other necessary intravenous equipment, although some physicians are able to administer these programs through their own office. Home infusions are usually given by nurses who specialize in intravenous therapy or by the patients themselves. Nurses examine the patient at regular intervals, change the intravenous devices when indicated, maintain sterile technique, manage catheter dressings and flushing, and communicate with the attending physician. Each home infusion company has its own quality assurance guidelines, but it is important to emphasize that the attending physician is still ultimately responsible for the care of the patient regardless of who is administering the medication. 5

TREATABLE INFECTIONS

Experience from many centers has shown that a wide variety of infections requiring parenteral antibiotics can be treated on an outpatient basis (Table 3). Many of these patients may require therapy for up to 6 weeks, and some may need rehospitalization for de´bridement of wounds and other surgical procedures but can be quickly discharged to resume their care at home. These patients may also have diabetes mellitus, renal insufficiency, and other medical problems that also need to be closely monitored. Because these patients require prolonged therapy, long-line vascular access (PICC, CVC, or port) devices are commonly used. Osteomyelitis and skin and soft tissue infections are probably the most common entities treated outside the hospital. Patients with chronic urinary tract infections including those with neurogenic bladders, recurrent prostatic disease, congenital abnormalities of the urinary tract, and other chronic conditions often have infections caused by microorganisms that are susceptible to drugs that can only be given parenterally. These patients can often be treated as outpatients without ever being admitted to the hospital. Various pulmonary infections including acute exacerbations of chronic bronchitis, cystic fibrosis, and bron-

Table 3 Infections Amenable to Outpatient Parenteral Antibiotic Therapy Bone, joint, and soft tissue Genitourinary Ears, nose, and throat Pulmonary Intraabdominal Endovascular Prosthetic device Infections associated with immunodeficiency states Febrile neutropenia (nonseptic)

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chiectasis are amenable to outpatient therapy. Ear, nose, and throat infections including acute and chronic sinusitis recalcitrant to oral antibiotic therapy are additional conditions that can be safely treated on an outpatient basis. Endothelial surface infections such as infective endocarditis and infected vascular grafts often require prolonged intravenous therapy. Assuming patients are free of emboli and conduction abnormalities and are not in congestive heart failure, OPAT is an acceptable alternative to hospitalization as long as patients are monitored closely. More recently, opportunistic infections associated with the acquired immunodeficiency syndrome (AIDS) that require intravenous medications including acyclovir, ganciclovir, cidofovir, foscarnet, and amphotericin B have been effectively treated outside the hospital. Additionally, it has been shown that febrile neutropenic patients who are not septic can be begun on outpatient intravenous therapy after blood cultures are obtained without exposure to a potentially more pathogenic hospital environment. Regardless of the type of infection being treated, patients usually elect to be treated either at home, in a doctor’s office, or in an infusion center rather than a hospital. Figures 3–7 illustrate varied infections treated by OPAT.

6

ANTIBIOTICS USED IN THE OUTPATIENT SETTING

Almost any antibiotic can be administered in the outpatient arena. Those that have longer half-lives and are not irritating to veins have been particularly well accepted by patients and prescribing physicians (see Table 4). Ceftriaxone, for example, needs to be given only once daily, is non venoirritative, and has few side effects. Aminoglycosides are easily administered on an outpatient basis, both intravenously and intramuscularly, and are commonly given once daily. Monitoring of trough levels of aminoglycosides and vancomycin correlates well with potential nephrotoxicity (see Chapter 4, Tables 3 and 4). A knowledge of serum half-life, potential side effects, and drug interactions is necessary before a final decision is made as to which antimicrobic will be used. The cost of these antibiotics is often quite high (see Table 5).

Figure 3 Heel ulcer with contiguous osteomyelitis of the calcaneus (polymicrobic).

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Figure 4 Saphenectomy site infection secondary to Staphylococcus aureus and Streptococcus pyogenes.

7

MONITORING OF PATIENTS

Patients receiving OPAT need to be carefully monitored, wherever they are receiving their medications. Protocols and teaching guides that include explanations of parenteral antibiotic therapy, aseptic technique, and emergency procedures should be written and followed carefully by nurses, pharmacists, and physicians administering the medications. Patients need to be physically evaluated at regular intervals, and appropriate laboratory studies should be maintained on a flow sheet for rapid review (see Table 6). Complete blood counts and renal and hepatic function should be tested once or twice weekly.

Figure 5 Cytomegalovirus retinitis.

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Figure 6 Facial cellulitis and abscess secondary to Staphylococcus aureus infection.

The most common side effects seen with parenteral antibiotics include gastrointestinal complaints such as nausea, loose stools, and abdominal discomfort. Occasionally significant diarrhea, which may be related to Clostridium difficile toxin production, occurs. This may necessitate changing to a different antibiotic or adding oral metronidazole. Other common reactions related to antibiotics include a variety of rashes and renal and hepatic toxicities. A peculiar disulfiram-like reaction to cephalosporins with a methylthiotetrazole side chain (cefamandole, cefoperazone) can be seen when alcohol is taken concurrently with one of these drugs. Therefore, all patients should be told that they cannot consume alcohol while they are taking these medications. Vancomycin can be associated with ‘‘redman syndrome,’’ a flushing erythema of the upper torso that may occur during infusion.

Figure 7 Infected skull prosthesis secondary to coagulase-negative Staphylococcus spp. infection.

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Table 4 Half-Life of Selected Antibiotics Antibiotic Cefazolin Ceftriaxone Ceftazidime Ampicillin Nafcillin Meropenem Imipenem

Half-life, h 1.5 7.0 2.0 1.0 0.5 1.0 1.0

Table 5 Dosing and Cost of Commonly Used Parenteral Antibiotics Dose

Cost per dose in dollarsa

1–4 ⫻ 106 U 1–2 g 3g 1–2 g 3.1 g 4.5 g 1–2 g 1.5 g 1–2 g 1–2 g 1–2 g 500 mg 1g 1–2 g 700 mg (7 mg/kg/day for 100-kg person) 700 mg (7 mg/kg/day for 100-kg person 600 mg 500 mg 1g 50 mg (0.5 mg/kg for 100-kg person) 500 mg (5 mg/kg for 100-kg person) 300–500 mg (3–5 mg/kg for 100-kg person) 200–400 mg 500 mg 500 mg 400 mg 500 mg

0.89–3.56 1.55–3.10 15.50 3.15–6.30 15.40 21.93 2.60–5.20 13.80 14.70–29.40 45.60–91.2 17.06–34.12 31.00 52.56 16.98–33.96 12.64

Drug (trade name) Penicillin G Ampicillin Ampicillin-sulbactam (Unasyn) Nafcillin Ticarcillin-clavulanate (Timentin) Piperacillin-tazobactam (Zosyn) Cefazolin Cefuroxime (Zinacef) Ceftazidime (Fortaz) Ceftriaxone (Rocephin) Cefepime (Maxipime) Imipenem (Primaxin) Meropenem (Merem) Aztreonam (Azactam) Gentamicin Tobramycin Clindamycin Azithromycin (Zithromax) Vancomycin Amphotericin B (Fungizone) Amphotericin B lipid complex (Abelcet) Amphotericin B Liposone (Ambisome) Fluconazole (Diflucan) Acyclovir Ganciclovir (Cytovene) Ciprofloxacin (Cipro) Levofloxacin (Levaquin) a

Average wholesale price (2000 Drug Topics Red Book).

63.00 26.25 24.40 27.50 11.64 1000.00 1130.40–1884.00 87.60–175.20 40.00 35.67 30.00 39.60

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Table 6 Laboratory Parameters That Should Be Monitored during Outpatient Parenteral Antibiotic Therapy Times per week Antiinfective agent

␤-Lactams Aztreonam Cephalosporins Imipenem Meropenem Piperacillin Ticarcillin Aminoglycosides

Complete Creatinine Potassium Magnesium blood count level level level 1

1

1 1

1 2

Clindamycin Vancomycin Trimethoprimsulfamethoxazole Pentamidine

1 1 1

1 2 1

1

2

2

2

2

Amphotericin B Fluconazole Ganciclovir Acyclovir Foscarnet

1 1 2 1 1

2 1 1 1 2

2

2

1

1 1

Cidofovir

1

1

Other Nafcillin, oxacillin, ceftriaxone; monitor LFTs weekly

2 Peak and trougha levels, consider audiograms Trough levelsb

Daily glucose level; chemistry profile 2⫻/wk

Chemistry profile, calcium 1⫻/wk Urinalysis and chemistry profile 1⫻/wk

a

See Chapter 4, Tables 3 and 4. See Chapter 4, Table 5. Source: Williams et al. 1997.

b

This can often be controlled when the infusion is slowed to 1–2 hours or the patient is pretreated with an antihistamine. The first dose of any antibiotic should always be given in the presence of either medical or nursing personnel to make sure that an acute accelerated allergic reaction does not occur. The most common laboratory abnormality noted during infusions of ␤-lactam antibiotics, but also seen in patients who are receiving clindamycin and vancomycin, is leukopenia, which is usually dose-related and reverses within a few days after the drug is discontinued. Elevation of liver enzyme levels may be nonspecific or related to the antibiotic being used. Attention to drug levels is of particular importance when aminoglycosides (peak and trough) or vancomycin (trough only) is being administered. Infections are uncommon when heparin locks are used. Midline catheters, PICC lines, and CVCs can cause localized inflammation and infection at the insertion site, thrombophlebitis along the course of the catheter, venous thrombosis, and bacteremias. These longer catheters occasionally clot, requiring thrombolytic therapy or removal, or may break or leak, requiring replacement (see Table 7).

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Table 7 Adverse Effects of Outpatient Parenteral Antibiotic Therapy Catheter related Phlebitis and thrombosis Access site infections Bacteremia Drug toxicity–related Leukopenia Elevated liver enzyme levels Renal toxicity Clotting abnormalities Antabuse effect Diarrhea and C. difficile colitis Infusion-related Vasovagal reactions Red man syndrome Drug interactionsa a

See Chapter 4, Table 4.

8

FINANCIAL AND LEGAL CONSIDERATIONS

Several studies have documented a 50%–75% reduction in cost when comparing OPAT to in-hospital care. Many third-party payers have recognized these dramatic financial savings and have routinely included this type of coverage in their policies. As of this writing, Medicare has not covered OPAT, although several legislative bills have been awaiting congressional approval to make this a covered service. As hospitals and physicians become more involved in home health care programs, medicolegal liability will also become an important issue. There have been a few instances of litigation by patients who have experienced adverse events while being treated as outpatients, the most common of which is ototoxicity from aminoglycosides, but other adverse reactions will undoubtedly occur. When a patient is discharged from the hospital to receive parenteral antibiotics as an outpatient, the physician who signs the orders is ultimately responsible for any potential complication. Doctors who wish to participate in overseeing outpatient intravenous programs need to understand all aspects of this type of care and carefully monitor their patients. BIBLIOGRAPHY Francioli P, Etienne J, Hoigne R, Thys J-P, Gerber A. Treatment of streptococcal endocarditis with a single daily dose of ceftriaxone sodium for four weeks. JAMA 26:264–267, 1992. Gilbert DN, Dworkin RJ, Raber SR, Leggett JE. Outpatient parenteral antimicrobial-drug therapy. N Engl J Med 337(12):829–838, 1997. Outpatient parenteral antibiotic therapy. Infec Dis Clin North Am 12(4):1998. Outpatient parenteral antimicrobial therapy: Current status. Proceedings of an OPAT Advisory Board Meeting, May 16–18, 1996, Chicago. A special report from Scientific American Medicine, July 1997. Poretz DM. High tech comes home (editorial). Am J Med 91(5):453–454, 1991. Poretz DM. Home intravenous antibiotic therapy. Clin Geriatr Med 7:749–763, 1991. Poretz DM. Commentary: A decade’s experience. IDCP 4(3):217–218, 1995.

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Tice AD. Outpatient parenteral antibiotic therapy: Management of serious infections. Hosp Pract 28(suppl 1 and 2):6–10, 36–39, 1993. White MC, Ragland KE. Surveillance of intravenous catheter-related infections among home care clients. Am J Infect Control 22:231–235, 1994. Williams DN, Rehm SJ, Tice AD, Bradley JS, Kind AC, Craig WA. Practice guidelines for community-based parenteral anti-infective therapy. CID 25:787–801, 1997.

7 Fever and Rash Mary Beth Ramundo University of Vermont, Burlington, Vermont, U.S.A.

1

INTRODUCTION

The differential diagnosis of fever and rash in an adult is quite extensive and includes a variety of infectious and noninfectious causes. Some of these are infectious disease emergencies such as toxic shock syndrome and meningococcemia. Others such as measles are a public health risk. Making a timely and specific diagnosis in an adult with a fever and rash is extremely important. There are a limited number of ways the skin can react to an infection. Generally the diagnosis cannot be made through the characteristics of the rash alone; a characteristic rash can be suggestive of a specific etiology but is usually not diagnostic. A specific type of rash may not be unique to a particular pathogen. The skin manifestations associated with a specific infectious agent may be variable, and different types of skin lesions may be seen at different times in the course of one infection. Host factors such as neutropenia may also affect the way the skin reacts to infection. Skin lesions associated with infection can result from several different mechanisms. Organisms may replicate within the skin itself. They can produce toxins that can damage the skin or elicit an inflammatory response. Vascular involvement can result in skin lesions. Multiple mechanisms of skin damage may be involved simultaneously. A microorganism can have systemic effects not only on the skin (exanthem) but also on the mucous membranes (enanthem). This chapter concentrates on systemic infections that cause fever and rash. Chapter 8 reviews the more common noninfectious causes of fever and rash, and Chapters 19 and 20 review localized bacterial and nonbacterial infections of the skin, respectively.

2

APPROACH TO THE PATIENT

A thorough history is extremely important in limiting the differential diagnosis for the adult with fever and rash (see Table 1). Exposures to potential pathogens should be sought, including those related to occupation, contact with ill individuals or animals, ingestion of specific foods, sexual practices, and insect bites. Knowledge of known allergies may be useful. A thorough medication history including vaccines and the use of over-the-counter medications should be obtained. Past medical history is especially important in regard to 129

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APPROACH TO THE PATIENT WITH FEVER AND RASH Obtain a thorough history (Table 1) Characterize the rash (Table 2) Assess for life-threatening illnesses (Table 3) Compare risks and exposures with the type of rash to help determine the differential diagnosis (Table 4)

a patient’s immune status. History of a heart murmur or splenectomy may be especially important. Social history should include questions regarding injection drug use (IDU) and travel. The time of year may be a vital consideration in the differential diagnosis. The history should also include specifics about the rash such as when and where the lesions were first noticed, the nature of the lesions, the timing of the development of the skin findings with any associated symptoms, the pattern of spread or any change in the morphological features of the lesions, and painful or pruritic effects of the lesions. When examining the patient who has a fever and rash, it is important to examine the entire skin surface in good light, preferably natural light. As some skin lesions may

Table 1 Important Historical Information in Evaluation of the Adult with Fever and Rash Allergies Medications Past and present Immunosuppressives Vaccines Over-the-counter medications Corticosteroids Past medical history Valvular heart disease Renal failure Diabetes mellitus Liver disease

Rash Where and when it appeared Pattern of spread Type of lesion (Table 2) Timing of rash Associated symptoms Pain or pruritus Change in morphological features of lesions

Immune status Malignancy Transplantation Splenectomy Human immunodeficiency virus Social history Occupation Travel (domestic and foreign) Animal contact Injection drug use Contact with ill persons Insect exposure Sexual practices Alcohol use

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be contagious, it is advisable to wear gloves for the exam. The lesions should be palpated. In addition to accurate characterization of the skin lesions, attention to their distribution and arrangement is necessary. For example, are the lesions grouped or linear in their arrangement? Mucous membranes in both the oral and genital regions, in addition to the scalp, hair, nails, and intertriginous areas, should all be examined. Lymphadenopathy, hepatosplenomegaly, joint effusions, and heart murmurs should be looked for. The differential diagnosis of fever and rash in an adult can be approached by assessment of the predominant type of skin lesion. Thus, it is important that the skin findings be accurately characterized. Table 2 summarizes the types of common skin lesions. Several dermatological definitions and examples follow. A macule is a flat discoloration less than 1 centimeter in diameter and is exemplified by a freckle. A patch is a large macule; a cafe´ au lait spot is considered a patch. Papules are elevated and palpable but measure less than 1 centimeter in diameter; molluscum contagiosum is best described as an umbilicated papule. A plaque is a flat-topped raised lesion measuring more than 1.5 centimeters in diameter; the lesions of psoriasis can be described as plaques. Nodules are rounded raised lesions greater than 1 centimeter in diameter. Tumors are usually greater than 2 to 3 centimeters in diameter. Vesicles are well-circumscribed, fluid-filled lesions up to 1 centimeter in diameter. Vesicles that are greater than 1 centimeter in diameter are classified as bullae. Pustules are elevated lesions filled with pus. A wheal or hive is a well-demarcated, elevated lesion that is usually pink in color and present for less than 24 hours. Petechiae and purpura represent bleeding into the skin, may or may not be palpable, and do not blanch with pressure. Ecchymoses are large areas of bleeding into the skin. Certain infections can present a diffuse erythema that blanches with minimal pressure. Crusts, scales, ulcers, and excoriations are secondary lesions that can complicate any of the primary skin lesions. An assessment of the degree of illness of the patient is important. Unstable vital signs or an acutely ill appearance suggests a life-threatening illness, the need for hospitalization, and urgent empirical therapy (see Table 3). Rashes can be divided into six categories: macules/papules, diffuse erythema, vesicles/bullae, nodules, petechiae/purpura, and urticaria. Combining information from the history and the type of rash can help determine the causative agent (see Table 4).

Table 2 Types of Skin Lesions Macule = flat discoloration 1 cm in diameter Papule = solid elevated lesion 1.5 cm in diameter Nodule = rounded elevated lesion >1 cm in diameter Vesicle = fluid-filled elevated lesion up to 1 cm in diameter Bulla = vesicle >1 cm in diameter Pustule = elevated lesions filled with pus Wheal = well-demarcated raised lesion lasting > HSV-2 Acute primary gingivostomatitis Usually asymptomatic infection of children < 5 years of age Occasionally symptomatic infection in young adults Multiple painful ulcerations throughout oral cavity Oral acyclovir or valacyclovir (may shorten course) Peridex or ‘‘magic mouthwash’’ Recurrent herpes labialis ‘‘Cold sores’’ Recurrent ulcerations around lips Topical penciclovir (may shorten course) Recurrent intraoral stomatitis Less severe than primary infection Zoster Dermatomal distribution of pain and ulcerations Ulcers similar to those of HSV May accompany painful tooth Acyclovir, valacyclovir, famciclovir (may shorten course) Aphthous stomatitis (canker sores) Idiopathic recurrent painful ulcerations Noninfectious Large, chronic, and recurrent ulceration suggestive of underlying malignancy Kenalog in Orabase cream

causes include aggressive toothbrushing, biting oneself, impingement on a sharp tooth surface, and local pressure from an ill-fitting denture. Self-mutilation through intentional body piercing and oral sexual activities can also ulcerate the mucosa, including the ventral surface of the tongue and the floor of the mouth. Size and shape of the ulcer(s) vary considerably. Early lesions tend to be shallow with erythematous borders with superficial, gray or yellow fibrin exudates. More chronic ulcers show a rolled-up, indurated border that can mimic the appearance of oral malignancies. The diagnosis is established by history and examination. Removal of the source of injury along with rinsing and soaking with normal saline solution several times each day are recommended. Antibiotic use is rarely indicated. Lesions that do not significantly improve after a 2-week period should be biopsied. 7.2

Herpes Simplex Virus

Herpes simplex virus 1 (HSV-1) and HSV-2 cause three clinically distinct syndromes: acute herpetic gingivostomatitis (AHGS), recurrent herpes labialis (RHL), and recurrent intraoral herpes stomatitis (RIHS). Although HSV-1 is more common intraorally, HSV-2 causes up to 10%–15% of recurrent oral herpes labialis. The lesions in each disease progress in a predictable manner. They begin as small, discrete vesicles, which coalesce

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and then ulcerate. The ulcers are covered by a yellowish exudate. The duration, symptoms, and severity of the disease depend on the patient’s prior exposure to the virus as well as his or her immunocompetence. More than 90% of adults are seropositive for antibodies against HSV. Patients may shed HSV asymptomatically in their saliva (also see Chapter 20, Sec. 4.3). 7.2.1

Acute Herpetic Gingivostomatitis

AHGS is the primary HSV infection and occurs predominantly in children below 5 years of age. On occasion young adults may have primary oral infection. More than 90% of primary infections are asymptomatic, but when the disease is symptomatic, the patient can be very uncomfortable. The disease presents itself initially as numerous small vesicles on any or all of the soft tissue surfaces of the mouth, nose, tonsils, and pharynx. These shortlived vesicles coalesce, then rupture, leaving painful ulcers surrounded by erythema and edema. The patient’s discomfort is often sufficient to discourage food and fluid intake completely. Fever and malaise may be present during the first several days. Lesions usually resolve within 10–14 days. The disease is contagious. The sharing of eating utensils and toothbrushes should be prevented. Definitive diagnosis in questionable cases can be made with viral culture and Tzanck preparations. 7.2.2

Recurrent Herpes Labialis

RHL or ‘‘cold sores’’ is a cyclical cutaneous condition experienced by 40% of adults. There is often a prodrome of itching and burning. Short-lived vesicles develop immediately around the mouth, then ulcerate, leaving painful shallow ulcers. Recrudescences are less severe than the primary infection. The eruption is self-limited, lasting 7–10 days. 7.2.3

Recurrent Intraoral Herpes Stomatitis

Recurrent intraoral herpes stomatitis can manifest in one of two ways, depending on the immunological health of the patient. In the immunocompetent patient, the lesions are not preceded by prodromal symptoms typical of RHL. Most of the ulcerations are less than 5 mm in diameter and tend to occur on the keratinized soft tissues of the mouth, including the hard palate, gingiva, and dense mucosa covering edentulous ridges. The precipitating factor(s) for the outbreak is generally not obvious though minor trauma may be a risk. Pain is generally mild. In the immunocompromised patient, the ulcers may enlarge, extend along both mucosal and cutaneous surfaces, and cause considerable pain and local tissue destruction. In the debilitated patient, disseminated infection is possible. 7.2.4

Therapy

Treatment for AHGS with oral acyclovir (Zovirax 200 mg 5⫻/day) or valacyclovir (Valtrex 1000 mg bid) shortens the duration of symptoms and viral shedding (see Chapter 20, Table 8). Therapy should be continued for 10–14 days. Topical therapy with penciclovir cream (Denavir 10 mg/g) applied every 2 hours for 5 days may shorten the time to ulcer healing and provide analgesia for patients with RHL, especially if used during the prodromal phase. Pain may be lessened with mouthwashes such as 1 teaspoonful each of table salt and baking soda in a pint of water, Peridex, or a concoction commonly known as ‘‘magic mouthwash’’ (0.5% viscous lidocaine, diphenhydramine hydrochloride, and magnesium containing antacid in a 1:1:1 ratio). The degree of pain relief is correlated with the length of contact time between the ulcer and the agents. Patients should be carefully instructed

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and encouraged to retain the agent in the mouth for a full minute, if possible, before expectorating. 7.3

Zoster

Herpes zoster or shingles is caused by the reactivation of the varicella zoster virus (VZV), the etiological agent of chickenpox (see Chapter 20, Section 4.4.2). It generally effects middle-aged and older patients. Its appearance may suggest an occult immune deficiency such as HIV infection. Zoster presents a prodrome of malaise, fever, and tenderness along the skin in a dermatomal distribution. Within a few days, the characteristic unilateral vesicular eruption on the skin and/or mucous membrane appears. The intraoral ulcers are similar in appearance to HSV, though they tend to be smaller and less painful. Regional lymphadenopathy may accompany the lesions. The acute infection generally lasts a week. In addition to unilateral intraoral vesicles, patients may complain of severe tooth pain. Many patients have undergone serial extraction of otherwise healthy teeth before the diagnosis of shingles was established. VZV is treated with acyclovir (800 mg orally 5⫻/day), famciclovir (Famvir 500 mg tid), or valacyclovir (1000 mg tid) for 7–10 days. In the immune compromised patient, early recognition and aggressive treatment may affect outcome. Perhaps the most debilitating sequela of VZV infection is postherpetic neuralgia. There is some evidence to suggest that early aggressive treatment of the initial vesicles with antiviral therapy may decrease the incidence of postherpetic neuralgia. 7.4

Recurrent Aphthous Stomatitis (Canker Sores)

Recurrent aphthous stomatitis (RAS) occurs singly or in small groups, primarily on the ventral surface of the tongue, floor of the mouth, soft palate, and buccal mucosa. Sores appear as shallow craters that are covered by a whitish membrane surrounded by intense inflammation. These ulcers are very painful and tend to recur. Healing occurs within 7– 10 days without intervention. RAS is not an infection and is not transmissible, though these ulcers are often confused with those caused by HSV. The cause is unknown, though associations with stress, trauma, menstruation, and food allergy have been made. Some patients have associated them with dental procedures. RAS minor, which affects 80% of RAS patients, causes recurrent small (3 mm–1 cm) painful ulcers. There are usually one to five ulcers at a time. In the immunocompetent patient, the ulcers most often occur on the nonkeratinized mucous membranes (lateral and buccal mucosa, maxillary and mandibular sulci, soft palate, and ventral tongue), a feature that helps differentiate RAS from herpes. The lesions heal spontaneously, usually over 5– 10 days. Differentiation from herpes stomatitis can usually be made with viral culture. It must be kept in mind that, in 10% of cases of oral HSV the virus is shed asymptomatically, with a potential to cause a false-positive result for HSV when RAS is the current, active disease. Treatment is palliative: topical triamcinolone acetonide cream 0.1% (Kenalog in Orabase) two to three times daily, Aphthasol (amlexanox 5%) oral paste applied four times daily, chlorhexidine mouthwash, and topical anesthetics such as viscous lidocaine or overthe-counter agents containing benzocaine. In immunocompromised patients RAS major may develop with large (1–3 cm) and numerous (1–10) ulcers that are very debilitating and slow to heal. Nonhealing aphthous lesions may be a clinical sign of undiagnosed immunological disease. In severe cases with extensive ulceration, some trials have shown improved healing with the use of thalidomide

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(Thalomid) 200 mg once a day for 4 weeks. Men and women must use effective birth control during use and for 1 month after cessation of thalidomide. 8

MASSES

Intraoral masses include human papilloma virus (HPV), molluscum cantagiosum, papillary hyperplasia, epidermoid cysts, lymphoma, and squamous cell carcinoma. Intraoral masses and/or nonresolving ulcerations require biopsy to exclude malignancy. HPV is the causative agent of both benign and malignant warts (also see Chapter 16, Section 6; Chapter 17, Section 4; and Chapter 20, Section 4.1). On nonkeratinized surfaces, warts may be flat or verrucous and are generally asymptomatic. In the HIV infected population they may manifest as single, exophytic, cauliflower-like projections that can become quite large. Treatment is not always needed if the warts are asymptomatic. If necessary, warts can be removed with simple excision, electrosurgical excision, or CO2 laser ablation. 9

INFECTIONS OF THE HYPOPHARYNX AND PARAPHARANGEAL SPACES

Dental disease rarely leads to life-threatening infection because of the improvements in dental care and early antibiotic therapy. There are rare occasions when an odontogenic infection may progress rapidly, spread beyond the tooth and surrounding alveolar bone, and become life-threatening (see Figure 3). The fascial planes of the mouth cavity and neck are ‘‘open’’ and provide conduits that can facilitate the spread of infection, potentially leading to abscess formation and necrotizing fasciitis. Infections of the hypopharynx and parapharyngeal spaces are the most common lifethreatening odontogenic infections (see Chapter 10). They most often originate in an inINFECTIONS OF THE HYPOPHARYNX AND SALIVARY GLANDSa Mandibular and submandibular abscesses Originate in apical root abscess of mandibular molars Spread along open fascial planes to submandibular, sublingual, and retropharyngeal spaces May spread down neck to pleura and mediastinum Submandibular, submental, and/or sublingual pain, swelling, and erythema Fever, toxicity CT or MRI scan to help delineate infection and need for drainage Concern for airway obstruction; urgent dental and ENT consultation Treat with penicillin/metronidazole, ampicillin/sulbactam, ceftriaxone/clindamycin, piperacillin/tazobactam Salivary gland infections Parotid > submandibular Often associated with duct obstruction Pain, swelling at mandibular angle or submandible Fever, toxicity Most often due to S. aureus Treat with antibiotic (Keflex or cefazolin) and hydration Sialagogues (after obstruction relieved) a

CT, computed tomography; MRI, magnetic resonance imaging; ENT, ear, nose, and throat.

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fected mandibular molar. Through the roots of the offending tooth, the infection gains access to the mandibular bone, followed by the sublingual and submandibular spaces. From there the infection can spread posteriorly and inferiorly to the submandibular, peritonsillar, parapharyngeal, retropharyngeal, and prevertebral spaces. Occasionally the infection may spread down the neck to the pleural space and mediastinum. Of greatest concern is progression of infection to the sublingual or retropharyngeal ‘‘danger space,’’ which can cause airway obstruction. These infections are polymicrobic, representing the normal oral flora that invade the tissues of the mouth and neck. Anaerobic streptococci, Fusobacterium, Bacteroides, Peptostreptococcus, and Actinomyces species, are often present in addition to aerobic streptococci. Aerobic GNRs and S. aureus are uncommon pathogens in this setting. 9.1

Submandibular Abscess

The most serious extraoral swelling, a submandibular abscess, occurs at the lower border of the mandible, extending posteriorly and obliterating the contour of the mandibular angle. Patients appear acutely ill with jaw, neck, and mouth pain and facial swelling and fever. The swelling and erythema may spread down the neck subcutaneously or along deeper facial planes between the trachea and the anterior border of the sternocleidomastoid muscle. Trismus, interfering with jaw opening, may be present. Examination of the intraoral cavity may reveal a carious lower molar with surrounding erythema and edema, swelling of the peritonsillar tissues extending into the soft palate, and deviation of the uvula away from the side of the infection. The sublingual space may be swollen and tender, causing elevation and deviation of the tongue. The triad of trismus, deviation of the uvula, and elevation of the tongue indicates the need for urgent management, including hospitalization, rehydration, intravenous antibiotics (as suggested in Section 9.3), and airway protection, followed by early extraction and incision and drainage of the infected tooth. 9.2

Ludwig’s Angina

Ludwig’s angina, first described by Wilhelm Frederick von Ludwig in 1836, is a bilateral, rapidly progressing infection that causes swelling of the spaces below the angle of the mandible, inferior to the chin and floor of the mouth. It usually originates from an abscessed second or third mandibular molar. The bilateral submandibular, submental, and sublingual swelling is firm without frank abscess formation. The sublingual swelling may be extensive, pushing the tongue upward toward the roof of the mouth and threatening the airway. The patient may complain of dysphagia, odynophagia, difficulty in speaking with a characteristic ‘‘hot potato’’ voice, and difficulty in managing salivary secretions. Airway obstruction may be imminent. The patient may require rapid oral intubation or tracheostomy. Expeditious consultation of oral surgery and otolaryngology staff is needed. 9.3

Diagnosis and Management

The diagnosis should be suspected on the basis of history and clinical findings. A history of recent odontogenic pain, dental infection, or extraction is often elicited. A full dental examination including radiographs should be done. However, in the presence of severe trismus, intraoral examination and intraoral radiographs may not be possible. A panographic film may be very useful and simple to obtain. Computed axial tomography (CT) or magnetic resonance imaging (MRI) can be used to evaluate the extent of infection, displacement of the trachea, and need for surgical intervention. A chest radiograph to assess for pleural effusions and mediastinal widening should be done.

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Antibiotics with activity against anaerobes and streptococci should be initiated immediately. Such regimens may include parenteral penicillin and metronidazole or broaderspectrum agents such as ceftriaxone and clindamycin, ampicillin/sulbactam (Unasyn), piperacillin/tazobactam sodium (Zosyn), or meropenem (Merrem). 10

SALIVARY GLAND INFECTION

Swellings of the major salivary glands may be the result of infection, obstruction, a combination of the two, or neoplasia. Sudden unilateral swelling associated with meals is usually suggestive of obstruction. Unilateral painful swelling arising over the course of several days in the setting of debilitation, dehydration, or use of antisialagogue medications, such as diuretics, antihistamines, or anticholinergics, is suggestive of infection. The most common salivary gland infection occurs in the parotid. Patients experience acute painful swelling over the angle of the jaw, fever, and systemic toxicity. The submaxillary gland is more susceptible to stone formation; infection is secondary to obstruction. The typical history is one of acute painful swelling beneath the angle of the lower jaw at or around mealtime. In cases of obstruction without infection, the swelling usually decompresses slowly only to recur at succeeding meals. Lingering swelling with increasing pain and onset of fever point to secondary infection. Evaluation of major salivary gland swelling consists of a careful history, gentle but firm palpation of the gland, and an intraoral examination of the duct orifices. Comparison of ducts for the presence of edema, erythema at the orifice, quality and gross quantity of salivary flow, as well as presence of purulence or inspissation is important. Bimanual palpation can sometimes reveal the presence of a sialolith, particularly in the submaxillary gland. Occlusal and panographic radiographs can be useful screening films for stones, although most parotid duct stones are not radiopaque. Treatment includes antibiotics, analgesia, and hydration. Changing medications to nonantisialagogue alternatives is recommended whenever possible. In community acquired parotitis, the most common offending organism is S. aureus. Outpatient antibiotic therapy may include dicloxacillin sodium (Dynapen) or cephalexin (Keflex) 500 mg orally qid. Parenteral agents such as cefazolin 1 g q8h may be used for patients who require hospitalization. Gentle probing and dilation of the duct with a sterile lacrimal duct probe can help relieve obstruction and allow drainage. If salivary flow cannot be elicited, the use of warm packs and a bland diet is suggested. Once salivary flow has been established, the use of sialagogues such as pilocarpine hydrochloride (Salagen) 5 mg qid or sour candies such as lemon drops, in addition to antibiotics and hydration, is recommended. If obstruction persists or if the infection is refractory, a CT scan may be helpful to confirm the diagnosis. Persistent obstruction and chronic infection may require surgical intervention. BIBLIOGRAPHY Eisen D. The clinical characteristics of intraoral herpes simplex virus infection in 52 immunocompetent patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 86(4):432–437, 1998. Glick M, Siegal MA. Viral and fungal infections of the oral cavity in immunocompetent patients. Infect Dis Clin North Am 13(4):817–831, 1999. Li X, Kolltveit K, Tronstad L, Olsen I. Systemic diseases caused by oral infection. Clin Microbiol Rev 13(4):547–558, 2000. Wu T et al. Periodontal disease and risk of cerebrovascular disease. Arch Intern Med 160:2749, 2000. 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics.

12 Community-Acquired Pneumonia and Bronchitis John G. Bartlett Johns Hopkins University, Baltimore, Maryland, U.S.A.

Christopher J. Grace University of Vermont, Burlington, Vermont, U.S.A.

1

INTRODUCTION

Pneumonia is the sixth leading cause of death in the United States. It is the primary cause of infection-related mortality. The frequency of community-acquired pneumonia (CAP) in the United States is approximately 2–3 million cases/year with about 600,000 hospitalizations. The inference is that about 75% of patients with CAP are managed as outpatients. Guidelines were published in the summer of 2000 by both the Infectious Diseases Society of America (IDSA) and the Canadian Community Acquired Pneumonia Working Group to aid the practitioner in diagnosis and treatment. Acute bronchitis is the cause of approximately 12 million physician visits annually. Approximately 5% of adults self-report symptoms consistent with acute bronchitis. The vast majority of these persons seek medical attention. Inappropriate antibiotic therapy for this predominantly viral infection is contributing to the growing problem of bacterial resistance. Chronic bronchitis affects 10%–25% of the adult population. Exacerbations of chronic bronchitis contribute to increased hospitalizations and mortality rate. Determining who should be treated symptomatically or with antibiotics is a daily challenge to the primary care provider. The goal of this chapter is to provide guidelines for managing these infections. A summary algorithm of the approach to the patient with cough, concentrating on CAP and bronchitis, is presented in Figure 1. 2

PNEUMONIA

2.1 2.1.1

Evaluation History

Typical clinical features of CAP are cough and fever of acute onset. These symptoms frequently are accompanied by signs and symptoms of a viral-like respiratory tract infec227

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Figure 1 Approach to the patient with pneumonia or bronchitis. Patients who have bronchitis or pneumonia usually report cough. The patient should be assessed by duration of cough and whether the history and examination findings are suggestive of a viral-like upper respiratory tract infection. If pneumonia or bronchitis is suggested, chest radiography is indicated, especially if the patient has abnormal vital signs. Patients who have pneumonia and most who have exacerbations of chronic bronchitis need antibiotic therapy, those who have acute bronchitis generally do not. CBC, complete blood count; LFT, liver function test, e.g., aminotransferase levels; BUN, blood urea nitrogen; HIV, human immunodeficiency virus; AECB, acute exacerbation of chronic bronchitis. 1Temperature

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PNEUMONIAa Approach to the patient with suspected pneumonia (Figure 1) Acute onset of cough and fever associated with abnormal vital signs Chest radiograph often needed to differentiate from bronchitis Risk assessment to estimate potential mortality and need for hospitalization (Table 1) Site of care by risk category (Table 2) Bacteriological characteristics of CAP (Table 3) Concern about increasing resistance to antibiotics (Table 4) Importance of pneumococcal and influenza vaccines Outpatient therapy (Table 5) Doxycycline Macrolide Fluoroquinolone Influenza therapy (Table 6) Reasons for persistent (>5–7 days) fever (Table 7) Patients requiring hospitalization (category 4, 5) ABG or O2 saturation CBC, renal, hepatic function HIV testing Third-generation cephalosporin ⫹ macrolide or fluoroquinolone a

CAP, community acquired pneumonia; ABG, arterial blood gas; CBC, complete blood count; HIV, human immunodeficiency virus.

tion with nasal congestion, pharyngitis, laryngitis, or acute bronchitis. The cough may be accompanied by the production of sputum that may be mucoid or purulent, or may be dry. Pleurisy is sometimes present and may be the major reason for physician consultation. Another feature that sometimes prompts individuals to seek medical attention is hemoptysis, which is most commonly due to acute bronchitis rather than pneumonitis. Many patients have other nonspecific findings such as nausea, vomiting, diarrhea, and headache. Findings suggesting involvement of other organs are found in more than half of cases. Constitutional symptoms that are frequent include fever, malaise, chills, sweats, and fatigue. 2.1.2

Physical Examination

Physical examination almost invariably reveals abnormalities in vital signs with fever, tachypnea, and/or tachycardia. Rales or ‘‘crackles’’ are present in 50%–70% of patients, but this characteristic feature, according to multiple reviews, is not sufficiently sensitive or specific to confirm a diagnosis of pneumonia when compared to radiographic results that demonstrate a pulmonary infiltrate.

>38⬚C, pulse > 100 beats/min, respiratory rate > 24 breaths/min. 2No underlying lung disease, acute onset of symptoms, self-limited, generally viral. 3Exacerbation of chronic bronchitis, FEV1 > 50%, fewer than four exacerbations per year, often bacterial. 4AECB, FEV1 = 5%–65%, advanced age, more than four exacerbations per year, comorbid conditions, often bacterial. 5Patients with suspected pertussis may be treated to reduce transmission.

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Chest Radiograph

The critical test for the diagnosis of pneumonia is a chest radiograph. This virtually always indicates a pulmonary infiltrate. There are four frequently cited reasons for a false-negative chest radiograph finding: Dehydration: This finding does not make sense simply because dehydration does not limit an inflammatory response at other anatomical sites, does not prevent the evolution of a pulmonary infiltrate in experimental animals, and has not been demonstrated to be a limitation in clinical studies. Neutropenia: There is some evidence that profound neutropenia prevents or reduces the evolution of a pulmonary infiltrate, but these studies are limited to a very specific patient population and have not yet been confirmed. Chest radiograph findings that lag behind clinical illness: Classic studies of pneumonia often indicated that the first 24 hours of acute pneumonia was commonly accompanied by the lack of a pulmonary infiltrate. This apparent lag in changes on chest radiography never exceeds 24 hours and is regarded as rare. Pneumonia involving Pneumocystis carinii: P. carinii pneumonia (PCP) continues to be common in patients with human immunodeficiency virus (HIV) infection either because the disease is not controlled in those who are aware of HIV infection or because the individuals affected have not been tested. Chest radiograph results are falsely negative in up to 30% of patients with PCP. 2.1.4

Other Laboratory Tests

The chest radiograph is the only test that is considered routine for virtually all patients with suspected CAP. Other common tests are the complete blood count (CBC) and chemical profile. Anemia specifically suggests an associated comorbid condition, chronic pneumonia or pneumonia due to Mycoplasma pneumoniae. The white blood count (WBC) may be high or low; a low WBC suggests either severe bacterial pneumonia (usually with increased band forms) or a viral infection (usually associated with a right shift). The purpose of the chemical panel is to determine the status of associated conditions, which is particularly important in patients with established chronic diseases such as renal or hepatic failure, diabetes, alcoholism, and other common chronic conditions. 2.2

Differentiating Pneumonia from Bronchitis

The preceding review indicates the critical role of chest radiography in differentiating pneumonia and acute bronchitis since they present similar symptoms. In general, the patient with an acute cough syndrome with a demonstrated infiltrate on chest radiography is a candidate for antibiotic therapy. The same patient with a negative chest radiograph result usually has a viral infection and should not be treated with antibiotics. The use of antibiotics in the latter group accounts for about 10% of all prescriptions for antibiotics and is commonly viewed as a major source of antibiotic abuse. Surveys of physicians and patients indicate that both groups consider antibiotics appropriate for acute bronchitis, and review of outpatient records indicates that antibiotics are prescribed for about 70%–80% of persons with the diagnosis of ‘‘acute bronchitis.’’ These data emphasize the importance of the distinction between acute bronchitis and pneumonitis and the pivotal role of chest radiography in making this distinction. With regard to the chest radiograph, surveys of patients who have an acute cough syndrome have pneumonia in about 5% of cases, asthma accounts for another 5%, and

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most of the rest have symptoms commonly associated with an upper respiratory tract infection (URI), indicating a viral infection. The issue of the necessity of a chest radiograph in all such cases is frequently raised. Prior surveys show that abnormalities in vital signs are a useful clue since these are abnormal in virtually all patients with pneumonitis. Thus, the patient with an acute cough and typical features of a URI does not need a chest radiograph if there are no abnormalities in temperature ( 4 ␮g/ml) and cephalosporins (MIC > 8 ␮g/ml) or for a patient who is ␤-lactam–allergic, newer fluoroquinolones, vancomycin, linezolid (Zyvox), or quinupristin-dalfopristin (Synercid) can be used. All persons older than 65 years of age and those younger patients at high risk for pneumococcal pneumonia should be vaccinated (see Chapter 43, Table 1). Revaccination every 5–7 years is recommended. 2.5.2 Mycoplasma pneumoniae Mycoplasma pneumoniae is a relatively common cause of pneumonia in young and previously healthy adults. The infection is characteristically less severe and less abrupt in onset when compared to pneumococcal pneumonia. It is transmitted person to person by aerosol. After an incubation period of 2–4 weeks fever, headache, and pharyngitis develop; they are followed by cough with sputum that is mucoid. The cough may be worse at night. Symptoms can last for 3–4 weeks. A characteristic feature of Mycoplasma sp. infection are its high rates of extrapulmonary complications including rash, aseptic meningitis, hemolytic anemia, hepatitis, and myocarditis. The diagnosis can be made by culture for M. pneumoniae, but virtually no laboratory does this. More practical, but less reliable, are serological tests and the cold agglutinin assay. A cold agglutinin titer >1:64 combined with a complement fixation antibody titer >1:64 is supportive of the diagnosis. Initiation of therapy is most often based on clinical suspicion. 2.5.3 Chlamydia pneumoniae Chlamydia pneumoniae is a relatively newly detected agent of pneumonia that occurs primarily in the same population susceptible to Mycoplasma sp. pulmonary infections:

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young, previously healthy adults. It is estimated that C. pneumoniae causes 5%–15% of CAP. Older patients, however, can become ill with C. pneumoniae, and it is this population who account for most of the hospitalization due to this pathogen. As with Mycoplasma sp., the course is usually benign. Symptoms of upper airway involvement (sore throat, hoarseness, and sinusitis) are the rule. The diagnosis is difficult to confirm. C. pneumoniae can be cultured in tissue cultures, but this is done only in research laboratories. The same applies to serological tests, which are not generally available and are not very accurate when they are. Initiation of therapy is most often based on clinical suspicion. 2.5.4 Legionella pneumophila It is important to recognize L. pneumophila as a cause of pneumonia because legionnaires’ disease is serious and potentially lethal. Initial reports emphasized the frequency of gastrointestinal complications, especially diarrhea and central nervous system (CNS) changes; however, subsequent reports suggest that these symptoms cannot reliably differentiate Legionella sp. from other CAP pathogens. Legionnaires’ disease may occur in epidemics. It is the only important cause of CAP besides S. pneumonia that kills people. Populations at risk include persons over 60 years; those who smoke or who have chronic lung disease; those who have diabetes or renal or hepatic failure; and those who have compromised cell-mediated immunity such as individuals receiving cancer chemotherapy, organ transplantation recipients, those receiving chronic corticosteroid therapy, and persons with human immunodeficiency virus (HIV) infection. There is a common impression that legionnaires’ disease is always sufficiently severe to require hospitalization (it accounts for approximately 2%–6% of patients hospitalized with pneumonia), but there are some recent reports suggesting that at least some ‘‘walking pneumonia’’ is due to Legionella sp. An initial clue to the diagnosis may be a sputum Gram stain result without demonstrable bacteria; although Legionella sp. is a Gram-negative rod, it does not Gram stain well. The diagnosis is preferably made with a urinary antigen assay or culture of respiratory secretions. The urinary antigen assay detects only L. pneumophila serogroup 1 but is a rapid, specific, and sensitive test easily done by most microbiology laboratories, and this strain accounts for about 70% of all cases of legionnaires’ disease. The culture is offered by many laboratories, but most are not very good at it. The laboratory must be informed that Legionella sp. is being sought since special agar (charcoal yeast extract) must be used. 2.5.5 Haemophilus influenzae H. influenzae causes about 3%–15% of CAP, though this may be an underestimation because of the high rate of false-negative sputum culture results. Most cases are seen in persons with underlying COLD. Although most cases of childhood infection with H. influenza have been due to type B, most CAP in adults is due to nontypable strains. Resistance to ampicillin is due to the production of ␤-lactamase. Recent studies suggest that more than 30% of strains are ␤-lactamase producers. If H. influenzae is isolated from sputum or blood, empirical therapy with a TGC or fluoroquinolone is suggested until antibiotic sensitivity results are available. 2.5.6

Influenza Virus

The influenza virus is responsible for about 20,000 deaths/year in the United States, primarily in persons over 65 years and often as a complication of other conditions (see Chapter 14). Primary influenza pneumonia is relatively rare. Most patients with serious disease have bacterial superinfections (most often with S. pneumoniae or Staphylococcus

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aureus) or deterioration of other chronic diseases such as COLD, asthma, diabetes, or hepatic or renal failure. Influenza A generally causes more serious illness than influenza B. There are several rapid diagnostic tests that can be used in office practice, which have a sensitivity of about 70%, cost about $30, and provide results in 15–20 minutes. Clinical studies indicate that a good clinician can make the diagnosis with comparable accuracy on the basis of the presence of an epidemic of influenza and typical flulike symptoms including fever, myalgias, headache, rhinitis, and pharyngitis. The issue of this diagnosis has taken on special importance because of the availability of antiviral agents to treat influenza, including the direct-to-consumer promotion that has magnified patient queries and demands. Nevertheless, it should be emphasized that prevention with vaccination is clearly preferred (see Chapter 43, Table 1). This is due to the fact that even those who are treated often have abnormal pulmonary function test results for several weeks, antiviral agents must be given within 48 hours of the onset of symptoms, and therapeutic trials indicate that the expected benefit is a reduction in acute symptoms of about 1–1.5 days. 2.5.7

Other Viruses

Most patients with viral pneumonia do not have an etiological diagnosis established. Viral infections, though, may account for a substantial number of enigmatic pneumonias when the full menu of diagnostic tests are done. The major agents are influenza virus (discussed previously), parainfluenza virus, and respiratory syncytial virus. These and other respiratory viruses are thought to be common causes of ‘‘benign’’ pneumonitis in young adults. They are, though, an important source of morbidity and mortality in older persons and those with serious underlying conditions. 2.5.8

Anaerobic Bacteria

Aspiration pneumonia is thought to account for about 10% of CAP. It should be suspected in persons who have a predisposition to aspiration that is due to compromised consciousness (alcoholism, anesthesia, or drug abuse) or dysphagia including gastroesophogeal reflux disease (GERD). There are three forms of aspiration pneumonia, which are quite different in terms of pathophysiological characteristics, clinical presentation, and management. Mendelson’s syndrome reflects aspiration of gastric acid, which results in an acute chemical burn of the lung. Most patients have an abrupt onset of symptoms and may be critically ill. This applies to those originally described in 1946 by Mendelson, who had observed aspiration during obstetrical anesthesia. Many now believe that there is a much more subtle form of Mendelson’s syndrome, the so-called mini–Mendelson pneumonia, which only requires supportive care and is probably self-limited. A second form of aspiration pneumonia involves aspiration of foreign material, primarily vegetable material such as peas and beans. If this causes obstruction, there may be atelectasis or ‘‘downstream pneumonia.’’ Removal of the foreign body with bronchoscopy may be necessary. The third and most common form of aspiration pneumonia is infection involving the anaerobic bacteria that predominate as the normal flora in the gingival crevice. The major pathogens are Peptostreptococcus, Fusobacterium, and Prevotella spp. Early signs are a clinically subtle pneumonitis with an infiltrate in a dependent pulmonary segment (usually the superior segment of a lower lobe or posterior segment of an upper lobe) in a patient who is aspiration-prone. Late complications include putrid sputum, cavitation with lung abscess, and/or empyema.

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Etiological Diagnosis

Most patients with CAP who do not require hospitalization do not have diagnostic tests for an etiological agent, in compliance with the recommendations for management of pneumonia of the IDSA and American Thoracic Society. Surveys of office practice indicate that no attempt is made to establish an etiological agent in 90%–95% of cases of CAP; empirical treatment is now well accepted as the standard of care. Nevertheless, the clinician may find benefit in getting a heat-fixed slide of expectorated sputum for subsequent staining in the event that the ‘‘walking pneumonia’’ patient subsequently requires hospitalization. This would represent the pretreatment specimen that is preferred since once antibiotics are given, results of Gram stains and cultures of respiratory secretions are notoriously misleading. It may also be appropriate to confirm the diagnosis of influenza and to distinguish between influenza A and B if antiviral drugs are to be given. The distinction between types is relevant if the preferred agent is rimantadine or amantadine since these drugs are active only against influenza A. By contrast, oseltamivir phosphate and zanamivir have the advantage of activity against both influenza A and influenza B. 2.7

Treatment

The mainstay of therapy for outpatients with CAP is antibiotics. The earlier the antibiotic is started, the better. A retrospective study of 14,069 Medicare patients by Meehan and colleagues showed that mortality rate increased with increasing delay of antibiotic initiation. A delay of 8 hours was associated with a statistically significant increased mortality rate. The favorite drugs for outpatient treatment of CAP are doxycycline, the macrolides, and fluoroquinolones (see Table 5). 2.7.1

Doxycycline

The drug doxycycline is active against the major treatable causes of bacterial pneumonia, including 80%–90% of strains of S. pneumoniae, most H. influenzae, and the atypical agents, M. pneumoniae and C. pneumoniae. It is also active against Legionella sp., but the experience is limited. Advantages of this drug include a long track record with a good safety profile and an extremely low price tag. It also has the advantage of a convenient dosing schedule of twice daily administration. The major disadvantage is the reluctance of some physicians to use a drug that has been around for 20 years, costs 7 cents a pill, and is used primarily for acne. Nevertheless, the experience with doxycycline, which is quite extensive, indicates that doxycycline has good in vitro activity against the likely pathogens of CAP and a lack of significant side effects. The most legitimate concern is the resistance by S. pneumoniae, which averages 10%–20% in most areas but may be substantially higher in others. As noted, side effects are sparse, but the patient should be warned of the possibility of sun sensitivity. Women who are pregnant or breast-feeding should not use the drug because of potential dental discoloration of the child. 2.7.2

Macrolides

The macrolide group includes erythromycin, azithromycin, and clarithromycin. These drugs are active against 70%–85% of strains of S. pneumoniae, although the exact frequency of resistance is controversial. S. pneumoniae may appear resistant to macrolides in routine laboratory testing, although it may well be susceptible in vivo. This distinction between in vitro resistance and in vivo activity can be determined by demonstrating pneumococcal sensitivity to clindamycin. It should be noted that macrolides generally show

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Table 5 Antibiotic Treatment of Community Acquired Pneumonia Agent

Dose (oral)

Costa

Comment

$21b

10%–20% Of S. pneumoniae resistant Active against atypical pathogens Dose-related gastrointestinal toxicity Poor activity vs. H. influenzae Better tolerated than erythromycin

Macrolide class Erythromycin

500 mg qid

Clarithromycin

1 g qd or 500 mg bid 500 mg, then 250 mg/day x 4 days

Azithromycin

Tetracycline class Doxycycline Fluoroquinolone class Levofloxacin

$140 $39c

100 mg bid

$4

500 mg qd

$140

400 mg qd 400 mg qd

$87 $62

Amoxicillin

500 mg tid

$12

Amoxicillinclavulanate Cefpodoxime Cefprozil Cefuroxime Miscellaneous Clindamycin

875 mg bid

$97

Gatifloxacin Moxifloxacin

␤-Lactam class

Co-trimoxazole

400 mg bid 500 mg d day 500 mg bid

$146 $115 $160

300 mg tid

$155

Double strength bid

$26

Better tolerated than erythromycin

10%–20% Of S. pneumoniae resistant Well tolerated Single daily dose Active against atypical pathogens Active against >98% of S. pneumoniae Active against all H. influenzae No activity vs. atypical pathogens Variable activity vs. S. pneumoniae Poor activity vs. H. influenzae Oral ␤-lactam preferred for S. pneumoniae Good activity vs. H. influenzae High rate of diarrhea Preferred cephalosporins for S. pneumoniae Also active vs. H. influenzae Active vs. most S. pneumoniae Good activity vs. anaerobes Poor activity vs. S. pneumoniae

a

Average wholesale price, (2000 Drug Topics, Redbook) for 10 days of therapy. There are many alternative erythromycins (see Chapter 3, Table 8). c Z-pack: 500 mg on day 1 then 250 mg days 2–5. b

‘‘class activity’’ against likely pulmonary pathogens so that strains of S. pneumoniae or S. aureus that are resistant to one tend to be resistant to all three agents in the class. A notable exception is H. influenzae, which is resistant to erythromycin, is probably susceptible to clarithromycin, and is usually susceptible to azithromycin. Macrolides are universally active against atypical agents including M. pneumoniae, C. pneumoniae, and Legionella sp. There are substantial differences in these drugs in terms of cost and tolerance. Erythromycin commonly causes gastric distress. This side effect may lead to dosage noncompliance. Clarithromycin and azithromycin, although better tolerated, are substantially more expensive. The macrolides may cause antibiotic-associated diarrhea, but this is infrequent and is rarely due to C. difficile.

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Fluoroquinolones

The fluoroquinolone drugs are expanding rapidly as a result of the introduction of new agents. They are simultaneously contracting because of the withdrawal of several agents (trovafloxacin, gemifloxacin, and grepafloxacin) because of their side effects. The newer fluoroquinolones, which have enhanced activity against S. pneumoniae, include gatifloxacin, levofloxacin, gemifloxacin, and moxifloxacin. These drugs are more active than ciprofloxacin against S. pneumoniae and are consequently favored for infections involving the respiratory tract including pneumonitis. Advantages of this class are the extraordinary activity against S. pneumoniae and good activity against virtually all other treatable bacterial pathogens that cause pneumonia (H. influenzae, M. catarrhalis, most strains of S. aureus, and all three atypical agents). They are given once daily, are well tolerated, and have an extraordinary track record in therapeutic trials. In addition, studies have shown that fluoroquinolones have produced equal, and in some instances better, outcomes for patients hospitalized with CAP when compared to ceftriaxone or combinations of thirdgeneration cephalosporins plus macrolides. There are two potential disadvantages of this class. First, there is concern that excessive use of these drugs will eventually lead to resistance by S. pneumoniae as well as other pathogens. The argument against this concern is that over 200 million persons have received fluoroquinolones and yet S. pneumoniae has retained susceptibility despite very extensive antibiotic pressure. In addition, many believe that the real concern about resistance is related to the use of fluoroquinolones for other respiratory tract infections such as sinusitis, acute bronchitis, and exacerbations of chronic bronchitis, which account for over 50% of all antibiotic prescriptions. By contrast, pneumonitis accounts for less than 1% of prescriptions. Despite these arguments, there has been a slight shift upward in the rate of resistance of S. pneumoniae in recent years, suggesting that the concern is legitimate even though the overall resistance rate remains at less than 2% of strains. The second concern about this class is the cost since the average wholesale price for a course of most fluoroquinolones is $70–$80. Given these issues some authorities prefer to reserve fluoroquinolones for clinical settings in which the patient has a documented lack of response to alternative antibiotics or has intolerance to the alternative drugs. 2.7.4

Other Antibiotics

␤-Lactams are commonly used for pneumonitis. The favored drugs in this class, in terms of activity against S. pneumoniae, are amoxicillin, amoxicillin-clavulanate, cefpodoxime, cefuroxime, and cefprozil. None of these agents has activity against atypical strains so they are generally favored when these agents are considered unlikely. For aspiration pneumonia in outpatients, anaerobic bacteria are the most frequent pathogens, and the preferred drugs are clindamycin and amoxicillin-clavulanate. Clindamycin has the most extensive published experience with anaerobic pulmonary infections. Amoxicillin-clavulanate has a modest and favorable published experience and is active in vitro against nearly all oral anaerobes. Metronidazole should not be used in these infections because it is not active against aerobic and microaerophilic streptococci, which are commonly concurrent pathogens with anaerobes. 2.7.5

Antiviral Agents

As noted, there are now four agents that are effective and Food and Drug Administration (FDA) approved for the treatment of influenza. The relative merits of these drugs are summarized in Table 6. Amantadine and rimantadine are active only against influenza A,

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Table 6 Antibiotic Treatment of Influenzaa

Treatment regimen Influenza activity Efficacy Treatment Must start within 48 hrs Days of symptom reduction Side effects Efficacy Prophylaxis FDA approval for prophylaxis a b

Amantadine

Rimantadine

Zanamivir

Oseltamivir phosphate

100 mg bidb ⫻ 5 days A

100 mg bidb ⫻ 5 days A

10 mg inhaled bid ⫻ 5 days A⫹B

75 mg bid ⫻ 5 days A⫹B

⫹ ⫹ 1–1.5 Days

⫹ ⫹ 1–1.5 Days

⫹ ⫹ 1–1.5 Days

⫹ ⫹ 1–1.5 Days

CNS

CNS

Wheezing

GI intolerance

⫹ ⫹

⫹ ⫹

⫹ ⫺

⫹ ⫺

CNS, central nervous system; GI, gastrointestinal; FDA, U.S. Food and Drug Administration. 100 mg qd for age >65 yrs.

although this agent was responsible for over 95% of all influenza infections from 1997 through 2000. Many authorities prefer rimantadine because of its lower rate of CNS toxicity. Neuraminidase inhibitors, zanamavir and oseltamivir, are relatively new and expensive and have the advantage of activity against both influenza A and influenza B. All four agents appear to have comparable efficacy, with a reduction in the duration of flulike symptoms by 1–1.5 days. They all must be given within 48 hours of the onset of symptoms for demonstrable benefit. Providers must be aware of the differences in these agents in terms of price and side effect profiles (also see Chapter 14, Table 4). They must also be aware that bacterial superinfections are potential problems with influenza. Some patients may require antibacterial agents with attention to the major organisms that cause superinfections in this setting, including S. pneumoniae, followed by S. aureus and H. influenzae.

2.8

Follow-Up

Most patients with CAP respond to antibiotic therapy within 3–5 days with subjective improvement and objective evidence of decrease in fever. Most patients are afebrile by 5–7 days, but the time required for full recovery is often 1–2 months. Patients with influenza generally have abnormal pulmonary function test results for 1–2 months as well. It is appropriate to warn them about this persistence of fatigue and sometimes cough as well. Patients who have persistent fever need to be evaluated for the factors that can explain nonresponse to antibiotic treatment of pneumonia as summarized in Table 7. For patients who respond, the usual duration of antibiotic treatment is 1–2 weeks but may be less with azithromycin because of its long half-life. Follow-up radiographs are advocated for patients who do not respond, for patients who smoke, and for those above 40 years of age. The purpose of this follow-up film is to detect potential underlying lung disease including bronchogenic neoplasms.

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Table 7 Reasons for Antibiotic Failure in Community-Acquired Pneumonia Reason Wrong diagnosis (not pneumonia)

Wrong microbial class

Inadequate host

Noncompliance with medication Wrong antibacterial agent Wrong dose Drainage required Associated condition that confounds response Pulmonary superinfection

Complicated infection with extrapulmonary involvement Complication of antibiotic treatment

2.9

Comment Many other possibilities: Atelectasis Congestive heart failure Bronchiolitis obliterans and organizing pneumonia Wegener’s granulomatosis or vasculitis, Lymphoma Viral Fungal Mycobacterial Most common cause of antibiotic failure; Mortality rate 15%–20% for pneumococcal bacteremia disease despite appropriate antibiotics Mortality rate 15%–30% for legionnaires’ disease despite appropriate antibiotics Primarily among outpatients Many strains of S. pneumoniae now multiply resistant Atypical pathogens not susceptible to ␤-lactams Rare problem except with aminoglycosides Applies to empyemas (noted in about 1% of patients hospitalized for community-acquired pneumonia) Applies primarily to proximal obstruction due to neoplasm, foreign body, or bronchostenosis Infrequent Expectorated sputum culture results often suggestive of ‘‘superinfection’’ because of selective antibiotic pressure Rare but well established complications of pneumococcal pneumonia, e.g., meningitis, septic arthritis, or endocarditis C. difficile–associated colitis Drug fever

Treatment for the Patient Requiring Hospitalization

Patients admitted to a hospital for treatment of CAP generally are older, have more comorbid conditions, and appear more ill at presentation with greater abnormalities of vital signs and initial laboratory test results (see Table 1). In addition to attempting to obtain sputum for Gram stain and culture, two sets of blood cultures should be drawn, and a complete blood count, assessment of renal and hepatic function, and electrolyte and glucose measurements should be done. If the patient has underlying COLD or appears dyspneic, an arterial blood gas specimen should be drawn or oxygen saturation determined. Those patients at potential risk for HIV infection, including all those between the ages of 15 and 54, should have serological testing. Urine for L. pneumophila type 1 antigen should be obtained. If a pleural effusion is present, consideration should be given to performing thoracentesis to rule out an empyema. Pleural fluid should be sent for Gram stain, culture, white blood cell count, and pH. All diagnostic culturing should be performed prior to the initiation of antibiotics.

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For patients admitted to the general medical floor, empirical antibiotic therapy should begin with a TGC such as ceftriaxone 1 g/da and a macrolide. This combination covers penicillin-resistant pneumococci; Haemophilus spp., Moraxella, Legionella, and Chlamydia spp., and the less likely, but possible, aerobic gram-negative rod (GNR) such as Escherichia coli, Klebsiella spp., or Enterobacter spp. Alternatively, a fluoroquinolone such as levofloxacin (Levaquin) can be used as monotherapy. Patients ill enough to be admitted to the intensive care unit should be treated with a third-generation cephalosporin and a macrolide or a combination of a third-generation cephalosporin or ␤-lactam/␤-lactamase inhibitor and a fluoroquinolone. In patients at risk for Pseudomonas sp. infection such as those with frequent hospital admissions for COLD exacerbations, cystic fibrosis, or bronchiectasis, a TGC that has Pseudomonas sp. activity such as ceftazidime should be used. 3

BRONCHITIS

3.1

Acute

Acute bronchitis is an inflammatory condition of the tracheobronchial tree characterized by cough. Acute uncomplicated bronchitis is illness that lasts for less than 3 weeks in otherwise healthy individuals who do not have evidence of chronic pulmonary disease. Acute uncomplicated bronchitis is part of a continuum of viral illnesses that can involve the upper and/or lower respiratory tract systems. Upper respiratory infections (URIs) such as pharyngitis, otitis, and sinusitis are reviewed in Chapter 10; influenza and the common cold are reviewed in Chapter 14. Acute bronchitis is generally a self-limited viral infection BRONCHITIS AND COUGHa Classification, microbiological aspects, and treatment (Table 10) Approach to the patient with pneumonia or bronchitis (Figure 1) Acute Normal host Most common in winter Normal vital signs Viral origin predominant 10% Due to Mycoplasma spp., Chlamydia spp., B. pertussis Diagnostic testing often not needed (Table 8) Antibiotic therapy not needed except for potential influenza or pertussis (Table 9) Chronic Cough > 3 mo/yr for 2 years Often associated with airway obstruction (COLD) AECB often caused by bacteria Severity/risk classification used to judge microbiological features and therapy (Table 10) Cough Differential diagnosis by duration of symptoms (Table 11) Need to consider noninfectious causes, e.g., CHF, asthma, GERD Most common causes of chronic cough in nonsmoker (Table 12) a

COLD, chronic obstructive lung disease; CHF, congestive heart failure; GERD, gastroesophageal feflux disease; AECB, acute exacerbation of chronic bronchitis.

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most commonly seen during the winter months. Despite that fact, up to 70% of patents with acute bronchitis are inappropriately treated with antibiotics. Patients have cough and often other typical coldlike symptoms of rhinitis, hoarseness, and fever. In contrast to that of the common cold, though, cough is the most predominant symptom in acute bronchitis. Although acute bronchitis usually lasts for several weeks, some patients may have symptoms that persist for more than a month. The cough is productive of sputum, which may be purulent, in 50% of patients. Cigarette smokers may have a more prolonged illness with greater amounts of purulent secretions. Fever may be seen in infections due to influenza or adenoviruses but is uncommon with rhinoviruses. Although physical examination may reveal clear lung fields, rales, rhonchi, and wheezing may occasionally be present. The major causes of acute bronchitis are summarized in Table 8. Influenza A virus accounts for the majority of infections. Other viruses include influenza B, adenoviruses, parainfluenza virus, respiratory syncytial virus, and viruses more commonly thought to cause URI such as rhinoviruses, coronaviruses, and coxsackievirus. Bacterial infection by M. pneumoniae, Bordetella pertussis, and C. pneumoniae causes about 5%–10% of acute bronchitis. For patients with cough lasting more than 3 weeks these latter bacteria account for 10%–20% of infections. Although S. pneumoniae, H. influenzae, and M. catarrhalis are able to colonize the upper respiratory tract in normal hosts, there is no evidence that they produce acute bronchitis in adults without underlying lung disease. Special mention of pertussis is warranted. B. pertussis, the etiological agent of whooping cough, is an important consideration in adults with prolonged symptoms. Studies indicate that up to 25% of adults with severe persistent coughing of acute onset have pertussis. Although vaccinated in childhood, most adults are not immune. Whooping cough in the adult is characterized by a severe, persistent cough that begins after an incubation period of 1–3 weeks. Initially patients may report coldlike symptoms of rhinitis, pharyngitis, conjunctivitis, and low-grade fever. Thereafter, the cough worsens to the point that it may induce vomiting. It is characteristically worse at night. In adults the classic ‘‘whoop’’ does not occur.

Table 8 Major Pathogens in Acute Bronchitis and Diagnostic Tests Pathogen Influenza virus

Other viruses Mycoplasma pneumoniae Chlamydia pneumoniae Bordetella pertussis

a

Diagnostic testa Rapid antigen detection tests: 70% sensitivity Clinical criteria: 70% specificity Culture of nasopharyngeal swab: hospitalized patients and epidemiological studies Cultures for parainfluenza and other viruses (rarely done) RSV-DFA test (pediatric only) IgM (diagnostic criteria unclear) MIF with 4-fold rise Calcium alginate nasopharyngeal swabb PCR (experimental) Serologic

RSV, Respiratory syncytial virus; DFA, direct fluorescent antibody; MIF, microimmunofluorescence; PCR, polymerase chain reaction; IgM, immunoglobulin M. b Plate as soon as possible onto Regan-Lowe medium; discuss with the clinical microbiology laboratory.

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The diagnosis of acute bronchitis is a clinical one. Vitals signs are usually normal in these patients. Abnormalities such as heart rate > 100 beats/min, respiratory rate > 24 breaths/min, oral temperature > 38⬚C, or the finding of rales, fremitus, or egophony on physical examination would raise the concern of pneumonia and prompt a chest radiograph. Purulent sputum does not necessarily indicate a bacterial pathogen since both viral and bacterial agents can cause an influx of white blood cells into pulmonary secretions that is that cause of the purulence. Many patients have airway hyperresponsiveness and abnormalities on spirometry. Although these abnormalities usually resolve in 2–3 weeks, they may persist for several months. Laboratory confirmation is usually not indicated for most instances of uncomplicated acute bronchitis (see Table 8). It may be indicated if influenza is suspected, especially if inhalational anthrax is considered in the differential diagnosis or if patients are living in a nursing home. The diagnosis of pertussis should be confirmed prior to treatment. This can be done with nasopharyngeal culture taken with a calcium alginate swab or nasopharyngeal aspiration. The sample should be plated as soon as possible on appropriate medium (consult your clinical microbiology laboratory). B. pertussis is slow growing and may take up to 1 week to grow. Gonzales and associates (2001) have summarized guidelines for managing acute bronchitis from two panels, one representing the Centers for Disease Control and Prevention (CDC) and the other representing the American Chest Physicians/American Society of Internal Medicine (ACP/ASIM). Key points from both groups regarding antibiotic therapy are nearly identical, including a summary of eight clinical trials that did not show any benefit of antibiotic use. Of the nonviral microbial pathogens, C. pneumoniae, M. pneumoniae, and B. pertussis, only B. pertussis requires treatment with antibiotics. Treatment for the great majority of patients with acute bronchitis, therefore, is symptomatic (see Table 9). Antibiotics are rarely indicated. The cough can be treated with nonsteroidal antiinflammatory agents and brompheniramine every 12 hours or with dextromethorphancontaining cough suppressants (e.g., Robitussin DM). Expectorants and inhaled or oral corticosteroids have not been proved to be very helpful. ␤2-adrenergic bronchodilators such as albuterol have been shown to reduce the severity and duration of cough. Influenza A can be treated with amantidine, rimantidine, or the newer neuraminidase inhibitors, as outlined earlier (see Chapter 14, Table 4). These agents can also be used prophylactically to control spread within nursing homes or families for high-risk or nonvaccinated individuals. Pertussis can be treated with erythromycin or co-trimoxazole. Usual

Table 9 Treatment of Acute Bronchitis Cause Influenza Upper respiratory infection

Allergic rhinitis Asthma Pertussis

Treatment Rimantadine, zanamivir, or oseltamivir phosphate (see Table 6) Start within 48 hr of symptom onset Cough medications with codeine or dextromethorphan Dexbrompheniramine ⫹ sedating (first-generation) antihistamine (Actifed, Contac, Dimetapp) Naproxen and/or ipratropium nasal spray Nonsedating antihistamine (second-generation) Inhaled bronchodilator Erythromycin or co-trimoxazole

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therapeutic doses should be given for 2 weeks. Macrolides can also be used prophylactically to prevent spread of pertussis to exposed individuals. Treatment of pertussis does not reduce the duration or severity of illness if initiated after 7–10 days of symptoms but helps reduce transmission to others. There may be great pressure on the provider to prescribe antibiotic therapy by the patient, family, or friend. With direct consumer advertising this demand may increase. It is worthwhile reviewing realistic expectations about the duration of symptoms, the viral nature of the illness, the lack of antibiotic efficacy for the great majority of patients, the concern about adverse drug events, and the growing concern about bacterial resistance in our communities. One study suggested that referring to acute bronchitis as a ‘‘chest cold’’ reduced the patient’s belief that antibiotic therapy was necessary. 3.2

Chronic

The pathophysiological and microbiological characteristics and approach to diagnosis and treatment of chronic bronchitis are very different from those of acute bronchitis. Chronic bronchitis is defined as cough with excessive secretions on most days for at least 3 months of the year for 2 successive years. This clinical syndrome is often associated with airflow obstruction and is referred to as COLD. COLD affects 20% of the population and is the fourth leading cause of death in the United States. Cigarette smoking is the most significant risk factor, though occupational and environmental exposure to dusts and allergens, past childhood respiratory tract infection, and passive exposure to cigarette smoke also contribute. Acute exacerbation of chronic bronchitis (AECB) is episodic worsening of chronic cough, shortness of breath, and/or purulent sputum production without evidence of pneumonia. If underlying lung function is severely compromised, these exacerbations can lead to respiratory failure, need for mechanical ventilation, and prolonged hospitalization. Other risk factors for poor outcomes include age >65 years, need for corticosteroid use, and concomitant cardiac disease. Although bacterial infection is thought to cause 50%–70% of AECB, this topic is much debated. Anthonisen and colleagues (1987) demonstrated in 1986 that antibiotic therapy, in select patients with AECB, leads to improved outcomes. They conducted a double-blind placebo-controlled trial of 362 chronic bronchitis exacerbations. Clinical success occurred in 68% of the antibiotic group, as compared to 55% in the placebo group. This was statistically significant though just barely so. A meta-analysis of nine randomized placebo-controlled trials using antibiotics for AECB by Saint and associates published in 1995 demonstrated a small but statistically significant overall benefit of antibiotic therapy. Defining the bacteriological characteristics of AECB is difficult since the majority of these patients are chronically colonized with S. pneumoniae, H. influenzae, or M. catarrhalis. These same pathogens have been isolated from lower airway secretions with bronchoscopically protected specimen brush techniques, suggesting they are the causative bacterial pathogens in the majority of patients with AECB. Other potential pathogens include H. parainfluenzae, C. pneumoniae, B. pertussis, M. pneumoniae, anaerobes, and Corynebacterium pseudodiphtheriticum. This latter organism has been recently recognized as an important pathogen, especially in immunocompromised patients and those with underlying cardiopulmonary disease. In patients with frequent exacerbations and antibiotic usage, colonization and subsequent infection may occur with aerobic GNRs, including P. aeruginosa. It is important to recognize that viral infection is an important cause of acute exacerbations as it is in acute uncomplicated bronchitis. Because of the difficulty of differentiating colonized patients from those actively infected and the need to identify patients at risk for respiratory failure and to help deter-

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mine who should receive antibiotic therapy, several stratification schemes have been developed to aid the clinician. All schemes utilize severity of underlying lung function, history of recurrent exacerbations, and age to provide an educated guess about the bacteriological features and risk of bacterial resistance and to give the clinician recommendations about empirical antibiotic therapy. Generally, the sicker the patient the more broadspectrum the antibiotic recommendation. None of these schemes has been validated in prospective randomized trials. A recent classification scheme by Ball and associates is summarized in Table 10. For patients with acute exacerbations of chronic bronchitis, antibiotics are frequently recommended. For the patient with good lung function, infrequent exacerbations, and low risk of antibacterial resistance, amoxicillin, doxycycline, or a macrolide can be used as in the treatment of CAP. For patients with more severe lung disease, frequent exacerbations, and increased risk for bacterial resistance, a newer fluoroquinolone such as levofloxacin, gatifloxacin, or moxifloxacin or an oral TGC such as cefixime can be used. If resistant GNR or P. aeruginosa is suspected or documented on culture, ciprofloxacin is a more appropriate choice (see Table 10). Other therapeutic interventions can include a ␤-agonist such as albuterol inhaler, an anticholinergic agent such as ipratropium inhaler (2 puffs qid), and a topical steroid such as triamcinolone inhaler (2–4 bid–qid). For more severe decompensation, oral corticosteroids or leukotriene inhibitors such as montelukast sodium (10 mg/da) or zafirlukast (20 mg bid) can be used. 3.3

Approach to the Patient with Cough

Cough is the most prominent symptom not only of pneumonia and bronchitis but also of myriad other infectious and noninfectious causes. If pneumonia can be excluded by chest radiograph, the differential diagnosis can be approached in terms of the duration of cough, as suggested by Irwin and Madison (2000); acute cough lasts less than 3 weeks, subacute cough lasts 3–8 weeks, and chronic cough lasts >8 weeks. Noninfectious causes such as left ventricular heart failure, asthma, and aspiration should also be considered (see Table 11). The most common cause of acute cough is viral rhinosinusitis. Antibiotics are not indicated. Patients generally respond to symptomatic treatment with dexbrompheniramine maleate; pseudoephedrine sulfate (Drexophed, Dexaphen S.A., Pharmadrine), intranasal ipratropium, or a combination of first-generation (sedating-type) antihistamines and naproxen. Lack of response to symptomatic therapy suggests a bacterial sinusitus, especially if associated with maxillary toothache, purulent nasal secretions, or clinical evidence of sinus consolidation. Indications for antibiotic therapy include bacterial sinusitis, AECB, and pertussis. Subacute cough is most often due to persistence after an acute upper respiratory infection (postinfectious cough), bacterial sinusitis, pertussis, or asthma. Postinfectious cough is due to postnasal drip or persistence of viral rhinitis or tracheobronchitis. It usually resolves spontaneously and antibiotic therapy is not indicated. Evidence of pertussis or sinusitis would warrant the use of antibiotic (see Table 10 and Chapter 10). In cough variant asthma, cough may be the only manifestation of asthma. The vast majority of chronic cough syndromes in immunocompetent persons are due to postnasal drip, asthma, GERD, chronic bronchitis, bronchiectasis, eosinophilic bronchitis, or use of angiotensin-converting enzyme (ACE) inhibitors. Less often lung cancer, sarcoidosis, left ventricular heart failure, or chronic aspiration is the cause. A chest radi-

FEV1 > 50% Increased sputum and purulence Fewer than four exacerbations yearly Same as simple plus FEV1 = 50%–65% Advanced age More than four exacerbations yearly Significant comorbidityg Same as complicated plus Continuous sputum production throughout year

Simple chronic bronchitis

c

Same as complicated bronchitis plus GNRs, including P. aeruginosa

Virale S. pneumoniae H. influenzae M. catarrhalis S. pneumoniaef H. influenzaef M. catarrhalis

Viral, noninfluenza Influenza Mycoplasma Chlamydia Pertussisd

Pathogens

Amoxicillin Macrolide Doxycycline Amoxicillin-clavulanate Levofloxacin Gatifloxacin Moxifloxacin Cefixime Cetibuten Fluoroquinalone Ciprofloxacin Adjustment of antibiotics based on sputum culture

Not indicated See Table 6 Not indicated Not indicated Erythromycinh Co-trimoxazole

Antibiotic treatment

b

FEV1 , forced vital capacity in 1 second; DS, double strength. Costs: see Table 5. c Viral infections account for 90%. d More often recovered (10%–20%) in patients with persistent cough. Therapy does not shorten duration of symptoms but reduces transmission. e Viral infection may precede bacterial. f Concern for bacterial resistance. g Diabetes mellitus, congestive heart failure, chronic renal or liver disease. h There are many alternative erythromycins; see Chapter 3, Table 8. Source: Adapted from Grossman 1997.

a

Chronic bronchial infection

Complicated chronic bronchitis

No underlying structural disease

Risk

Acute bronchitis (self-limited, benign)

Clinical status

Table 10 Classification Scheme and Treatment for Patients with Bronchitisa,b

500 mg tid As above 100 mg bid 875 mg bid 500 mg qd 400 mg qd 400 mg qd 400 mg qd 400 mg bid As above 500 mg bid

400 mg qid Double strength bid

Dose

Community-Acquired Pneumonia and Bronchitis 247

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Table 11 Differential Diagnosis of Cough Acute Viral upper respiratory tract infection Sinusitis Pertussis Acute exacerbation of chronic bronchitis Rhinitis due to allergy or environmental irritant Left ventricular heart failure Asthma Aspiration Subacute Postinfectious cough Bacterial sinusitis Asthma Pertussis Chronic Postnasal drip Gastroesophageal reflux Chronic bronchitis Bronchiectasis Eosinophilic bronchitis Angiotensin-converting enzyme inhibitors Bronchogenic carcinoma Sarcoidosis Left ventricular heart failure Source: Adapted from Irwin and Madison 2000.

Table 12 Causes of Cough Syndrome in Nonsmoking Patients Condition

Frequency

Diagnosis

Postnasal drip syndrome

40%–50%

Subclinical asthma

20%–25%

Gastroesophageal reflux

20%–25%

Sensation of posterior drainage and frequent clearing of throat Radiographic evidence of sinusitis Nasopharyngeal evidence of mucoid/purulent secretions Episodic wheezing, dyspnea with cough Physical examination with wheezing Pulmonary function test result evidence of reversible airway obstruction Heartburn or sour taste in mouth Reflux demonstrated by radiography, endoscopy, or esophageal monitoring

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ograph can usually exclude carcinoma, pneumonia, and bronchiectasis. A nonsmoking person with a clear chest radiograph finding who is not using an ACE inhibitor most likely has postnasal drip from chronic nasal or sinus abnormalities, asthma, GERD, or eosinophilic bronchitis. Postnasal drip is usually diagnosed by therapeutic trial, treating sinusitis, allergic, or vasomotor rhinitis or removing environmental irritants. Cough variant asthma can be excluded by a negative methacholine challenge test result. GERD can be treated with H2-blockers, proton pump inhibitors, and/or metoclopramide. It is important to recognize, though, that chronic cough can have more than one cause in 18%–93% of cases. Causes and diagnosis of the most common types of cough are summarized in Table 12. BIBLIOGRAPHY Anthonisen NR, Manfreda J, Warren CPW, Hershfield ES, Harding GKM, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 106:196, 1987. Bartlett JG. Treatment of community acquired pneumonia. Chemotherapy 46 (suppl 1):24–31, 2000. Bartlett JG, Dowell SF, Mandell LA, File TM, Musher DM, Fine MJ. Guidelines from the Infectious Diseases Society of America: Practice Guidelines for the Management of Community-Acquired Pneumonia in Adults. Clin Infect Dis 31:347–382, 2000. Doern G, Brueggman AB, Huynh H, Wingert E. Antimicrobial resistance with Streptococcus pneumoniae in the United States, 1997–1998. Emerg Infect Dis 5:757–765, 1999. Fahey T, Stocks N, Thomas T. Quantitative systemic review of randomized controlled trials comparing antibiotic with placebo for acute cough in adults. Br Med J 316:906, 1998. Fine MJ, Aulde TE, Yearly DM, et al. A prediction rule to identify low risk patients with communityacquired pneumonia. New Engl J Med 336:243, 1997. Gonzales R, Bartlett JG, Besser RE, et al. Principles for appropriate antibiotic use for treatment of uncomplicated acute bronchitis: Background. Ann Intern Med 134:521, 2001. Grossman RF. Guidelines for the Treatment of Acute Exacerbations of Chronic Bronchitis. Chest 112:310S–313S, 1997. Irwin R, Madison JM. The diagnosis and treatment of cough. N Engl J Med 343:1715, 2000. Mandell LA, Marrie TJ, Grossman RF, Chow AW, Hyland RH et al. Canadian Guidelines for the Initial Management of Community-Acquired Pneumonia: An Evidence based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. Clin Infect Dis 31: 383–421, 2000. Meehan TP, Fine MJ, Krumholz HM, et al. Quality of care, process and outcomes in elderly patients with pneumonia. J Am Med Assoc 278:2080–2084, 1997. Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical exam. JAMA 278:1440, 1997. Saint S, Bent S, Bent S, Vittinghoff E, Grady D. Antibiotics in chronic obstructive pulmonary disease exacerbations: A meta-analysis. JAMA 273:957, 1995. 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics.

13 Tuberculosis C. Fordham von Reyn Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, U.S.A.

1

EPIDEMIOLOGICAL CHARACTERISTICS

Tuberculosis is now an uncommon disease in most regions of the United States. As a result, the diagnosis may not be considered promptly and isolation and treatment may be delayed. Early recognition of tuberculosis requires that the clinician know both the disease syndromes and the epidemiological features of tuberculosis, especially groups who are at risk. Stated briefly, most cases of tuberculosis in the United States now occur in older Americans, members of minority groups, foreign-born persons (50% of U.S. cases), institutionalized persons, and those with predisposing disease such as infection with the human immunodeficiency virus (HIV). Table 1 summarizes groups at risk for active tuberculosis in the United States. Rates of active tuberculosis disease are expressed as an annual incidence per 100,000 population. In the United States the rate was 87/100,000 in 1945 and had fallen to 6.4/ 100,000 by 1999. Thus, both active tuberculosis disease (i.e., culture-positive disease) and latent tuberculosis infection (i.e., positive tuberculin skin test result) are more common in Americans who were born when community rates of tuberculosis were higher. In 1945 approximately 50% of Americans had positive tuberculin skin test results. In the year 2000 this figure had fallen to 10 mm between two PPD test results performed within 2 years of each other is considered a PPD conversion and is interpreted as evidence of new infection with M. tuberculosis. When evaluating a change in two skin test results separated in time, several issues must be considered. First, the original PPD may have only been recorded as ‘‘negative’’ without an exact measurement of the size of the PPD in millimeters of induration. This nonspecific ‘‘negative’’ result makes it impossible to determine whether a second positive test result represents a true conversion or not. For example, a 9-mm reaction could be recorded as a negative result for low-risk persons. A subsequent PPD result of 14 mm would be considered a conversion if the actual measurement of the first test were not known (a false-positive result). In fact, the 14-mm result should not be considered a conversion at all since it is less than a 10-mm increase from the original 9-mm reaction. The second is the inherent variability in PPD skin test interpretation. Variations up to 2–5 mm can be seen when two experienced readers measure the same test result. The third is the booster phenomenon. Individuals with prior mycobacterial infection (including immunization with live bacille Calmette-Gue´rin [BCG] or prior asymptomatic infection with nontuberculous mycobacteria) may have a negative result or an insignificant area of induration on initial PPD testing. A second skin test administered within weeks of the first may demonstrate significant induration since the cellular immune response has been ‘‘boosted’’ by the first PPD. Of note, repeated PPD testing does not cause a positive TB test result in persons without prior mycobacterial infection. The second result of this two-step method can be used as a true baseline for comparison in the future, for example, for immunocompromised patients, elderly patients, or health care workers. Without such testing, an initial negative test result that is followed by a positive test result could be misinterpreted as a new conversion. Establishing a true baseline, with two tests for those who have not been tested in recent years, is a key component for interpreting annual tests. Target groups for two-step testing include persons from tuberculosis endemic countries, persons with prior BCG, and older persons. Figure 2 demonstrates how the booster phe-

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Figure 2 For each patient, one with remote TB infection occurring before two annual skin tests (patient 1) and one with TB infection occurring between two annual skin tests (patient 2), the figure shows the results of testing at 0 and 1 week versus testing at 0 week and 1 year. The third test of patient 1 at one year is included to help illustrate the booster effect (since the patient had been shown to be PPD-positive at 1 week, repeat testing would generally not be required). PPD, purified protein derivative; TB, tuberculosis.

nomenon can improve the interpretation of annual PPD testing and how two-step testing can help establish baseline reactivity. Because of the many variables involved in accurate identification of a PPD conversion, practitioners should be conservative about interpreting such results unless the subject is in a high-risk group for tuberculosis. 3.1.3

Chest Radiography

A small proportion of persons with latent tuberculosis have a small calcified granuloma in the lung parenchyma (Ghon focus), sometimes with associated hilar adenopathy and/or calcification (Ranke complex). Other findings may include apical or pleural scarring or calcification and areas of upper zone fibrosis (Simon foci). 3.2 3.2.1

Active Tuberculosis Disease Respiratory Tract Specimens

Testing of expectorated sputum is the most important and expeditious method of supporting and ultimately confirming the diagnosis of pulmonary tuberculosis (see Table 4). Three sputum samples collected on separate days should be sent for stain and culture. The clinician should confirm with the laboratory that each sample is adequate for testing. Several alternative diagnostic approaches are possible when the patient is unable to expectorate sputum or the sample is inadequate. Sputum induction should be attempted first. If this is unsuccessful and the clinical suspicion of tuberculosis remains high, bronchos-

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259

Table 4 Diagnostic Evaluation for Active Tuberculosis Diseasea HIV-negative (or unknown HIV status) Sputum ⫻ 3 for AFB stain, amplified DNA probe, and culture Chest radiograph PPD skin test HIV ELISA HIV-positive As above, plus Mycobacterial blood culture (lysis-centrifugation or automated) a

HIV, human immunodeficiency virus; AFB, acid-fast bacillus; DNA, deoxyribonucleic acid; PPD, purified protein derivative; ELISA, enzymelinked immunosorbent assay.

copy with bronchoalvelolar lavage should be performed. Transbronchial or percutaneous lung biopsy may be useful in selected cases. Sputum stains for AFB yield positive findings in approximately 40%–50% of patients with pulmonary tuberculosis. A positive AFB stain result supports a diagnosis of tuberculosis but does not confirm it since nontuberculous mycobacteria and some other bacteria (e.g., Nocardia species) may also be acid-fast. Specimens that are AFB-positive can be tested with one of two licensed and highly specific nucleic acid amplification (NAA) tests to determine whether the organism is MTB or another acid-fast organism. NAA testing is available at larger laboratories throughout the United States, and results should be available to the clinician within a few days. AFBnegative sputum samples can also be tested by using one licensed NAA test (Amplified Mycobacterium Tuberculosis Direct Test [MTD], Gen-Probe, San Diego, CA). A positive NAA test result on AFB-negative sputum is highly specific for tuberculosis, but a negative NAA test result on AFB-negative sputum does not exclude the diagnosis of tuberculosis. If a sputum is AFB-negative and NAA-positive, a presumptive diagnosis of tuberculosis is established, but repeat sputum evaluation should be done to confirm the NAA results. Approximately 70% of patients with pulmonary tuberculosis have a positive culture result for MTB. In laboratories that use conventional media, such growth typically occurs at 3 weeks but may take up to 8 weeks. Automated culture systems typically detect MTB in 2 weeks. Susceptibility testing should be performed routinely on all initial isolates of M. tuberculosis. Many AFB-positive, NAA-negative sputum samples from patients in the United States grow a NTM, most commonly organisms of the Mycobacterium avium complex (MAC). Growth of these organisms may be detected at least a week earlier than for MTB. 3.2.2

Sterile Site Culture

Blood cultures for mycobacteria should be obtained from patients with HIV infection, other immunosuppressed patients, and patients with suspected miliary tuberculosis. Special methods are used for mycobacterial blood cultures (e.g., automated, lysis-centrifugation) so the microbiology laboratory should be consulted before the culture is obtained. If focal extrapulmonary tuberculosis is suspected sterile site cultures may be obtained from urine, CSF, and other normally sterile sites (e.g., bone, liver). Polymerase chain reaction (PCR) testing should be considered for patients with suspected tuberculous meningitis, although the sensitivity of such testing is only 50% and test reliability has been shown to vary among laboratories.

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3.2.3

Chest Radiography

Primary disease due to M. tuberculosis may be associated with hilar adenopathy and/or pleural effusion as well as with acute infiltrates. Reactivation disease typically produces infiltrates in the upper lobes or superior segments of the lower lobes. Signs of prior tuberculosis may be evident (see Section 3.1.3). Cavities may also be seen and are typically thin-walled without an associated air fluid level. Miliary tuberculosis usually involves the lung, where the pattern of multiple ‘‘millet seeds’’ produces a diffuse reticulonodular infiltrate.

3.2.4

Other Studies

Chest computer assisted tomography (CT) scans may be used to delineate pulmonary lesions associated with tuberculosis further but are not required for the diagnosis in most cases. CT scans may be useful in distinguishing NTM pulmonary disease from tuberculosis since small nodules ( 7 suggests infection with a ureasplitting organism such as Proteus or Klebsiella spp. The reliability of the microscopic

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Table 2 Causes of Sterile Pyuria Infectious Sexually transmitted diseases Fungal infection Genitourinary tuberculosis Leptospirosis Viral cystitis Low-titer bacterial UTI ( HSV-1 Spontaneous resolution Recurrence common Primary infection worse than recurrence; possible association with systemic symptoms (Table 5) Painful clustered vesicles progressing to ulcers Diagnosis by tissue culture or HSV antigen Need to rule out other sexually transmitted diseases (STDs) (Table 6) Testing for human immunodeficiency virus (HIV) Treatment (Table 7) Primary syphilis Painless ulcer (chancre) Spontaneous resolution; may be followed by secondary syphilis (rash) Treatment with benzathine penicillin G 2.4 million U IM ⫻ 1 dose Also see Chapter 16, Table 11

Treponema pallidum, the infectious agent of syphilis, causes a mild primary infection (ulcer) that is accompanied by clinically inapparent bacteremia and dissemination throughout the body. Secondary syphilis develops when the concentration of spirochetes in infected tissues reaches a threshold, triggering an inflammatory response. The manifestations of primary and secondary syphilis resolve even if untreated, but infection persists in numerous organs, including the central nervous system, with the potential to lead to neurosyphilis and manifestations of tertiary syphilis. Chancroid is caused by Haemophilus ducreyi. It is uncommon in the United States ( vesicle

2– days

Herpes

Not erythematous

Papule

Primary lesions

Diameter of lesions Edges

9–90 days

Usual incubation period

Syphilis

Table 4 Clinical Features of Genital Ulcers

Tender; may suppurate; loculated; usually unilateral; occasionally may involve inguinal and femoral nodes Erythematous

Soft Very tender

Excavated Purulent, ready bleeding

Variable Undermined, ragged, irregular

Often multiple

Pustule

1–14 days

Chancroid

Pelvic/perirectal abscesses, rectal fistulae and strictures, lymphatic occlusion

Multiple, tender and matted, may suppurate, usually unilateral; may involve inguinal and femoral nodes Erythematous

Occasionally firm Variable

Variable Variable, nonvascular

Papule, vesicle, or pustule Usually one (ulcer usually not seen) 2–10 mm Elevated, round or oval

3 days–6 weeks

LGVa

Lymphatic occlusion; inguinal masses due to spread of inflammation

None (pseudobuboes due to subcutaneous extension of granulomatous process) N/A

Firm Uncommon

Elevated Red, velvety, ready bleeding

Variable (usually not presenting feature) Variable Elevated, irregular

1–4 weeks (occasionally longer) Papule

Donovanosis

Male Urogenital Syndromes

329

Table 5 Characteristics of Symptomatic Genital Herpes Infection Type of infection Lesions

Urethritis (e.g., dysuria) Neurological complications Regional lymphadenopathy Systemic manifestationsc Typical duration

Primarya Many, bilateral, widely spaced Common Common Usual Usual 2–3 weeks

Initial nonprimaryb

Recurrent

Few

Fewer, unilateral

Occasional Uncommon Occasional Occasional 1–2 weeks

Uncommon Rare Rare Rare 5–10 days

a

First recognized infection with no serological evidence of previous infection. First recognized infection with positive serological evidence of previous infection. c Fever, aseptic meningitis, myalgia, and extragenital lesions on buttock, groin, and thigh. Source : Fox, 1999. Used by permission of Oxford University Press, Inc. b

inous ulcers. Therefore, regardless of the appearance of the lesion, there should be a low threshold for diagnostic testing to confirm the presence of herpes simplex. Most ulcers clinically diagnosed as due to syphilis or chancroid are typically due to herpes. Patients with genital HSV-1 infection typically have 0–1 recurrences per year; the first year after symptomatic HSV-2 infection, men have an average of 5 recurrences per year and 20% have 10 or more outbreaks. The rate of recurrence declines in subsequent years. Reactivation of HSV-2 has been associated with recurrent aseptic meningitis (Mollaret’s syndrome). Syphilis is classically associated with a painless ulcer (chancre) that is indurated and has a clean base. Lymph nodes are typically small and rubbery or absent. The chancre and lymphadenopathy usually resolve in a few weeks even without treatment. Secondary syphilis usually does not develop for 2–4 months after primary infection but may overlap occasionally with primary infection and therefore is described briefly in this chapter. The classic rash, which is ‘‘papulosquamous’’ and nonpruritic, involves the trunk, palm, and soles. However, syphilis is the ‘‘great imitator’’ and the rash can be confused with that of psoriasis, scabies, pityriasis rosea, and nonspecific dermatitis. Patchy hair loss on the scalp, painless mucous membrane lesions in the mouth, and genital condyloma lata (sometimes confused with warts) may also be present. Aseptic meningitis and other neurological manifestations can also occur with secondary syphilis. Secondary syphilis also typically resolves without treatment over time. The skin rash may recur within the first year after infection. Latent (asymptomatic) syphilis follows and is detectable on the basis of reactive serological testing. Latent syphilis may progress to neurosyphilis and occasionally classic late manifestations of tertiary syphilis such as syphilitic aortitis and gumma formation. CDC guidelines provide additional information regarding diagnosis and treatment of latent syphilis, tertiary syphilis, and neurosyphilis (http://www.cdc.gov/nchstp/dstd/dstdp.html). Chancroid is classically described as painful. The ulcer edge may be ragged and the base rough and purulent. Associated inguinal adenopathy is not common. 3.2

Laboratory Diagnosis

Clinically differentiating genital ulcer disease is difficult. Laboratory testing is therefore important and should include a serological test for syphilis as well as diagnostic testing for herpes simplex (see Table 6).

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Table 6 Laboratory Evaluation of Sexually Active Patients with Genital Ulcer Diseasea Lesions typical of genital herpes Culture or direct fluorescent antibody for HSV (optional; warrants strong consideration) Screening tests for other STDs (syphilis, HIV, chlamydia, and gonorrhea) Other genital ulcers Culture or direct fluorescent antibody test or PCR for HSV Dark-field microscopy for T. pallidum, if available Syphilis serological testing (RPR, VDRL) Selected cases Culture for H. ducreyi Culture for pyogenic bacteria Biopsy Type-specific HSV serological testing a

HSV, herpes simplex virus; STD, sexually transmitted disease; HIV, human immunodeficiency virus; PCR, polymerase chain reaction; RPR, rapid plasma reagin; VDRL, Venereal Disease Research Laboratories. Source : Fox, 1999. Used by permission of Oxford University Press, Inc.

3.2.1

Syphilis

Dark-field microscopy requires very specialized training and is not available in most clinical laboratories including urban medical centers. Referral to a local health department if dark-field microscopy is available should be considered for possible primary syphilis. Nontreponemal serological tests such as the Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR) do not distinguish present from past infection. These tests have positive results in about 80% of cases of primary syphilis. Results are reported as reactive to a dilutional titer. The degree of titer elevation is not necessarily reliable for staging syphilis, but appropriate titer decline does define a successfully treated case. Virtually all patients with primary syphilis have a positive serological test finding by the time the ulcer heals. All patients with secondary syphilis have positive serological results. Reactive nontreponemal tests require confirmation with a specific treponomal test such as the fluorescent treponemal antibody-absorbed (FTA-abs) or microhemagglutination–T. pallidum (MHA-TP) test to rule out biological false-positive results, which may occur in the setting of injection drug use (IDU), acute viral infections, and autoimmune disease. A lumbar puncture (LP) is indicated for primary and secondary syphilis only if there is evidence of neurological involvement such as meningitis, ophthalmic or auditory symptoms, or cranial nerve palsies. Patients with ocular symptoms should have a slit lamp exam to rule out uveitis. It is often advisable to refer patients with suspected neurosyphilis to a specialist for evaluation and follow-up. If LP is performed, 3–5 cc of cerebrospinal fluid (CSF) should be frozen in the event additional diagnostic studies are needed. 3.2.2

Herpes Simplex Virus

Because herpes simplex is by far the most common cause of genital ulceration, failure to perform diagnostic testing for atypical ulcerations often leads to misdiagnosis. Testing is particularly useful when diagnostic uncertainty is present or for firm establishment of the diagnosis before beginning long-term suppressive therapy. The presence of HSV can be confirmed by tissue culture, HSV antigen detection by enzyme immunoassay (EIA), or direct or indirect fluorescent antibody (IF). Type-specific testing may be helpful as the prognosis for recurrence varies between HSV-1 and HSV-2 (see previous discussion). The

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Tzanck test smear is a simple cytological test used to detect multinucleate giant cells characteristic of herpes infection. It is performed by scraping the base of the ulcer with a swab or scalpel and transferring the specimen onto a slide for staining (e.g., Gram or Wright’s stain). Sensitivity compared to that of culture ranges from 50% in the ulcer stage to 67% in the vesicle stage, with a specificity of about 95%. Herpes cultures obtained more than 48 hours after ulcer onset usually yield negative results. Polymerase chain reaction (PCR) for genital herpes simplex is extremely sensitive and may become commercially available in the near future. If chancroid is suspected, the patient’s ulcer should be cultured for H. ducreyi or a specimen sent for PCR. Unfortunately, most clinical laboratories do not have the appropriate culture media for this organism and H. ducreyi PCR is not currently available commercially. Multiplex PCR detects HSV, T. pallidum, and H. ducreyi and may soon be commercially available for clinical use. HIV testing is recommended for any patient newly diagnosed with a STD and should always be performed in patients with primary and secondary syphilis or chancroid. If HIV results are negative, testing should be repeated in 3–6 months if possible. 3.3

Treatment

Treatment of genital ulcer disease is often initiated empirically. It is prudent to treat for the more likely diagnosis (HSV or syphilis) and see the patient again in 7 days. Many experts recommend presumptive treatment for syphilis particularly in the setting of community outbreaks. Repeat serological testing for syphilis may be useful at follow-up as a change in titer from negative to positive virtually assures the diagnosis of syphilis. The regimen of choice for primary syphilis is benzathine penicillin G 2.4 million U intramuscularly (IM) in a single dose. For those with penicillin allergies, doxycycline 100 mg orally bid for 2 weeks or tetracycline 500 mg orally qid for 2 weeks can be used. If the patient is penicillin-allergic and tetracycline-intolerant, erythromycin 500 mg orally qid for 2 weeks or ceftriaxone 1 g IM daily for 8–10 days can be substituted. Patients should be reevaluated clinically and serologically at 6 and 12 months. A fourfold change in titer is required to demonstrate a significant difference. Follow-up syphilis serological tests should be performed in the same lab because simultaneously obtained titers may vary two- to fourfold between labs. A fourfold increase in titer or recurrence of signs or symptoms suggests treatment failure or reinfection; a LP should be performed and HIV serological characteristics checked. If neurosyphilis is excluded, the patient should be retreated with benzathine penicillin G 2.4 million U IM weekly for 3 weeks. The Jarisch-Herxheimer reaction (JHR) is an acute febrile reaction that occurs after treatment of syphilis with penicillin. It may occur in up to 70%–90% of patients with secondary syphilis and less often in those of other stages. Treatment is supportive. An expert should be consulted regarding use of prednisone to abort JHR in patients with cardiovascular or symptomatic neurosyphilis. Treatment to reduce the duration and severity of symptoms is recommended for all primary genital herpes infections if started within 1 week of symptom onset (see Table 7). Treatment may also be indicated for severe recurrences. Chancroid may be treated with single-dose azithromycin 1 g orally or ceftriaxone 250 mg IM. Alternatives include oral ciprofloxacin 500 mg orally bid for 3–5 days or erythromycin 500 mg orally qid for 7 days. Patients with suspected syphilis and chancroid should generally be managed in cooperation with the local health department.

5 Days

Months to years

7–10 Days or until clinical resolution

Recurrentc,d

Suppressivee,f

Severe diseaseg,h (meningitis, neurological dysfunction)

mg mg mg mg mg mg

5⫻/day tid 5⫻/day tid bid bid

5–10 mg/kg IV q8h until clinical resolution Then completion of 7–10 day course with oral therapy

200 400 200 400 800 400

Acyclovira

250 bid 500 mg qd 1 g qd

500 mg bid

1 g bid–tid

Valacyclovir

250 mg bid

125 mg bid

250 mg tid

Famciclovir

b

Topical treatment with acyclovir is far less effective than systemic therapy, and use is strongly discouraged. First episode: Treatment should be initiated early (within a week of onset) for all patients with a first episode (presumed or confirmed) of genital herpes. Treatment decreases duration of pain, viral shedding, and systemic symptoms but has no effect on rate or frequency of relapse. c Recurrent episodes: Treatment should be started with the prodome or within 1 day of lesion onset. Patients should be provided with a prescription so that treatment can be promptly initiated at onset of prodrome or genital lesions as this is more effective than physician-initiated treatment. Valacyclovir 500 mg once daily may be less effective than other valacyclovir doses in patients with >10 recurrences/year. d The mechanism of reactivation is not well understood. The role of stress and fatigue as risk factors for recurrence has not been proved. e Suppressive therapy: Consider with ⱖ6 episodes a year and for severely psychologically affected patients. Safety and efficacy are documented for continuous prophylaxis with acyclovir for up to 10 years without cumulative toxicity or risk of resistance. There is also a significant reduction in viral shedding with prophylactic therapy. f Intermittent or suppressive treatment is commonly needed in those with HIV infection. g Obtain expert consultation in patients with severe disease. h Resistance is rarely seen in immunocompetent patients; refer patients with genital lesions that progress on high-dose therapy for further evaluation.

a

7–10 Days

First episodeb

Duration

Table 7 Treatment Options for Genital Herpes Simplex Virus Infections

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Counseling and Partner Notification

3.4.1

Syphilis and Chancroid

Patients should be counseled that prevention of genital ulcer disease due to STD is achieved by abstinence or use of condoms. Reporting of cases of chancroid and syphilis, as required by state regulations, may help ensure that partner notification and treatment occur. 3.4.2

Herpes

Depression, fear of rejection, and anxiety may accompany the diagnosis of genital herpes. These symptoms may be best addressed after resolution of symptoms related to the acute illness. Patients should be reassured that the diagnosis of herpes simplex is compatible with ongoing intimate relationships. Key points to emphasize during counseling are listed in Table 8. Counseling patients about use of condoms when having sexual intercourse is probably prudent, although use of the latex condom in males has not been demonstrated to provide complete protection in discordant couples. If available, type-specific serological testing of the patient’s partner may prove helpful as it may demonstrate that the partner has HSV infection of the same serotype. If so, the use of condoms to prevent infection of the partner is presumably unnecessary.

4

GENITAL WARTS

Human papillomavirus (HPV) cause numerous clinical syndromes including cutaneous and anogenital warts (condyloma acuminata). More than 20 HPV types infect the genital tract and are increasingly recognized to play a role in genital tract cancers including penile squamous intraepithelial neoplasia and anal carcinoma in men who have sex with men. Subtypes 6 and 11 cause most clinical episodes of anogenital warts. Subtypes 16, 18, 31, 33, and 35 are strongly associated with malignant transformation.

Table 8 Key Points to Be Emphasized in Counseling Patients with Genital Herpes Patients who have genital herpes should be told about the natural history of the disease with emphasis on the potential for recurrent episodes, asymptomatic viral shedding, and sexual transmission. Patients should be advised to abstain from sexual activity when lesions or prodromal symptoms are present and encouraged to inform their sex partners that they have genital herpes. The use of condoms during all sexual exposure with new or uninfected sex partners should be encouraged. In stable relationships, the annual rate of transmission is estimated to be 5% if the source patient is female and 19% if the source patient is male. Sexual transmission of HSV can occur during asymptomatic periods. Asymptomatic viral shedding occurs more frequently in patients who have genital HSV-2 infection than HSV-1 infection and in patients who have had genital herpes for 10,000 organisms/ml. Repeat PPMT evaluation after a 3-day course of nitrofurantoin (which typically clears cystitis but does not penetrate the prostate well) may help establish an underlying prostatic focus of infection. a

b

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Table 14 Treatment of Bacterial Prostatitis Infection

Duration

Drugs and dose

Acute bacterial

4 weeks Initial therapy intravenously until stable then orally

Chronic bacterial

4–12 Weeks

Ampicillin 2 g IV q6h plus gentamicin Ciprofloxacin 400 mg IV q8h then 500 mg PO bid Ofloxacin 400 mg IV q12h then 300 mg PO q12h TMP-SMX ds bida Ciprofloxacin 500 mg PO bid Levofloxacin 500 mg/day PO Doxycycline 100 mg PO bid

a

TMP-SMX, trimethoprim-sulfamethoxazole.

of treatment, and follow-up in these studies make comparisons of different regimens difficult. Optimal therapy and duration of treatment for CBP have not been clearly established. Most authors recommend 4 to 12 weeks of continuous treatment. In most situations, therapy need not be urgently initiated and should be based on results of culture and sensitivity (see Table 14). One randomized controlled trial demonstrated improved outcome and reduced recurrence rate for patients with CBP treated with ␣1-adrenergic receptor antagonists (e.g., 1–10 mg terazosin daily) in addition to antibiotics. Clinical response to the ␣-antagonist may take 4–6 weeks. Relapse after treatment for CBP occurs in 10%–70% of cases in the form of either recurrent UTI or prostatitis symptoms. If the initial course of curative therapy was 12 weeks repeated full-dose regimens have not been shown to result in increased rates of cure. Patients with refractory or relapsing CBP require urological evaluation to rule out abscess, seminal vesicle abnormality, or infected calculi. Evidence to support the common practice of chronic ‘‘suppression’’ using low-dose antibiotic therapy is lacking. Surgical, dietary, and life-style modifications do not have established benefit in the treatment of CBP. Minimal evidence is available to guide the management of NBP/CPPS. On the basis of available data, empirical treatment of this syndrome with antibiotics is not indicated, although trials of antibiotic therapy, especially to cover atypical bacteria such as Ureaplasma and Mycoplasma spp., are common in many settings. One randomized controlled trial (RCT) suggests a possible benefit of ␣1-adrenergic receptor antagonists in this setting. The benefits of other treatments for chronic nonbacterial prostatitis such as benzodiazepines, nonsteroidal antiinflammatory agents, allopurinol, prostatectomy, sitz baths, dietary modifications, frequent ejaculation, prostatic massage, dietary supplements (e.g., saw palmetto, zinc), microwave therapy, bladder neck incision, and psychotherapy have not been established. Progressive symptoms or new physical or laboratory findings should prompt reevaluation of the diagnosis and referral to a urologist. Otherwise, reassurance and periodic follow-up are reasonable. Granulomatous prostatitis may be idiopathic; it may occur in the setting of infection with Mycobacterium tuberculosis, Cryptococcus neoformans, Coccidioides immitis, or Histoplasma capsulatum or after an episode of acute bacterial prostatitis. Symptoms are variable, ranging from asymptomatic to those typical of acute bacterial prostatitis. Exami-

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nation usually reveals a firm or nodular prostate suggestive of prostatic carcinoma. Granulomatous prostatitis is a pathological diagnosis established by biopsy with special stains required to detect fungi or acid-fast bacilli. Referral to a specialist is recommended for management of this condition. 6

EPIDIDYMITIS

Epididymitis is a common condition, accounting for more lost days of military service than any other disease. Epididymitis causes unilateral pain, swelling, and tenderness of the epididymis. Onset is usually over hours to days. Early in the course of disease, pain and swelling may be localized to the epididymis, though involvement of the testes is frequent, ultimately resulting in epididymo-orchitis. Fever and dysuria are common. Sexually active men aged ⱕ35 years typically have a STD such as C. trachomatis or N. gonorrhoeae as the cause of epididymitis. Asymptomatic urethritis due to STD may also be present. Gram-negative rods (GNRs) are the most common cause of epidydimitis in men who are older than 35, have anatomical abnormalities, or have had recent urinary tract procedures or instrumentation. Men who have sex with men, of any age, who are insertive partners during anal intercourse are likely to have infection with GNRs as well as N. gonorrhoeae and C. trachomatis. Complications of epididymitis are uncommon but can include scrotal abscess, testicular infarction, chronic epididymal pain, and infertility. Rarely, epididymitis is caused by Behc¸et’s disease, amiodarone, or granulomatous disease of multiple causes (e.g., sarcoid, idiopathic, infectious). History should include questions regarding sexual exposures, past UTI, and urological malformation or instrumentation. Physical examination often reveals tenderness and erythema of the posterior scrotum. In more advanced cases epididimo-orchitis, spermatic cord tenderness, or hydocele (due to inflammatory fluid between the layers of the tunica vaginalis) is present and may result in an enlarged painful hemiscrotum with difficult to identify landmarks. Urethral discharge may be elicited by ‘‘stripping’’ the urethra even in men without urethral symptoms. EPIDYDIMITIS AND ORCHITIS Epidydimitis Unilateral pain and swelling, fever, dysuria Age 35 years: history of gonococcal urethritis (GU) abnormalities or instrumentation; aerobic gram-negative rods (GNRs) Need to rule out testicular torsion (Table 15) Diagnosis Urethral smear Urinalysis and culture Antibiotic treatment (Table 16) Orchitis Testicular pain and fever Viral cause most common Coxsackie B virus or mumps Bacterial cause uncommon Usually caused by spread from epididymal infection

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The most urgent and challenging diagnostic issue in young men with pain or swelling of the scrotal contents is ruling out of testicular torsion. Younger men with a sudden onset of pain in the testis and others in whom the diagnosis of torsion is under consideration require urgent surgical consultation as testicular viability may be at risk. Distinguishing features are outlined in Table 15. Surgical correction of the torsion has a good chance of salvaging a viable testicle within the first 12 hours of torsion, some chance for salvage between 12 and 24 hours of torsion, and almost no chance for salvage after 24 hours. Most cases of testicular torsion result from congenital lack of fixation of the testicle within the scrotum and therefore occur during late adolescence as the testes enlarge. Among sexually active teenagers with testicular pain, both torsion and STD-associated epididymitis should be considered likely diagnoses. 6.1

Laboratory Evaluation

A Gram stain of urethral discharge (if present) should be collected. Presence of more than 5 WBCs per high-powered field in urethral discharge is abnormal and suggests chlamydia or gonorrhea as the cause. Specific testing for chlamydia and gonorrhea should be performed with urethral swab or first-void urine. Urine microscopic examination and culture should also be performed. When urinary tract infection is present, accompanying epidydimitis is highly likely to be caused by the same organism. The CDC recommends syphilis serological testing and HIV testing and counseling for all men with epididymitis. Color flow Doppler and radionuclide scanning may be used to rule out testicular torsion, because it demonstrates reduced or absent blood flow to the testicle in torsion and increased blood flow in epididymitis. However, delay of surgical evaluation and management should not occur while waiting for such testing. 6.2

Management

Empirical therapy should be instituted while waiting for culture results (see Table 16). Treatment should be adjusted on the basis of culture and sensitivity results.

Table 15 Clinical Features of Epidydimitis and Testicular Torsion Epididymitis Age group

Adults

Onset

Days to weeks

Associated symptoms

Often fever Dysuria

Physical findings

Sometimes discharge Predominant epididymal tenderness

Laboratory Imaging

Pyuria common Enhanced blood flow

Testicular torsion Adolescents Most cases 12–18 years Usually sudden Prior episodes with spontaneous resolution in many patients Vomiting in most cases Fever Dysuria rare Testis often elevated with abnormal lie Cremasteric reflex absent Pyuria in approximately 15% Blood flow usually reduced or absent in Doppler or nuclear studies

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Table 16 Treatment of Epididymitis If epididymitis most likely due to Chlamydia and/or gonorrhea

Gram-negative rods

Drugs Ceftriaxone 250 mg IM ⫻ 1 dose plus Doxycycline 100 mg PO bid for 10 days or Ofloxacin 300 mg PO bid for 10 days Ciprofloxacin 500 mg PO bid or 400 mg IV for 10–14 days or Ofloxacin 200 mg PO or IV for 10–14 days

Costs $45.00 $10.00 $98.00 $83.00 (PO) $600.00 (IV) $78.00 (PO) $260.00 (IV)

Hospitalization and intravenous treatment should be considered when inflammation is advanced, the patient appears systemically ill, or noncompliance with outpatient antibiotic therapy is expected. In addition to antibiotics, bedrest, scrotal elevation on a towel, and analgesics are recommended. Once appropriate treatment has begun, clinical improvement should be rapid. A follow-up examination should be performed to assure the return of scrotal contents to normal. If significant resolution of symptoms has not occurred within 3 days of antibiotic treatment or testicular enlargement persists for more than 1 week, alternative diagnoses, including testicular cancer, abscess, infarction, tuberculosis, or fungal infection, should be considered. Abnormalities of the genitourinary tract should be ruled out when epididymitis is caused by GNRs without precipitating factors such as recent urinary tract instrumentation. Sexual contacts within the past 60 days of partners with a sexually transmitted cause of epididymitis should be evaluated and treated. Sexual intercourse with partners should be avoided until the patient and partner have completed therapy and no longer have symptoms. 7

ORCHITIS

Viruses are the major pathogens causing orchitis, usually in the setting of viremia related to mumps or less commonly coxsackie B virus infection. Approximately 25% of postpubertal males with mumps have evidence of orchitis. The onset occurs 4–6 days after parotiditis and may be subclinical in up to 40% of cases. Orchitis in this setting is usually unilateral but may progress to involve the epididymis or both testes. Symptoms, including pain, nausea, vomiting, and fever, may be mild or quite severe. Resolution occurs within days to several weeks. Treatment is symptomatic. Some atrophy occurs in approximately half of cases but sterility appears now to be uncommon. Bacterial orchitis is very unusual and almost always occurs as a result of extension from epididymal infection. Patients with bacterial orchitis appear very ill and often have high fever, nausea, and vomiting. Skin overlying the tender and swollen testicle is typically erythematous and boggy and there may be an associated acute hydrocele. Empirical intravenous antibiotic therapy should cover the most common causative pathogens including

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Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, staphylococci, and streptococci. Initial empirical therapy could include ceftazidime 2 g q8h or ciprofloxacin 400 mg q8h and vancomycin 15 mg/kg q12h, with subsequent adjustment on the basis of culture results. Complications include testicular infarction and abscess formation. Urological consultation is advised for patients suspected of having bacterial orchitis. BIBLIOGRAPHY Ballard RC. Genital ulcer adenopathy syndrome. In: Holmes KK, Mardh P, Sparling PF, et al., eds. Sexually Transmitted Diseases, New York: McGraw-Hill, 1999, pp 887–892. Barbalias GA, Nikiforidis G, Liasikos N. Alpha blockers for the treatment of chronic prostatitis in combination with antibiotics. J Urol 159(3):883–887. CDC. 2002 Guidelines for treatment of sexually transmitted diseases. MMWR 51 (No. RR-6), 2002. Fox KK, Cohen MS. Gonococcal and chlamydial urethritis. In: Armstrong D, Cohen J, eds. Infectious Diseases, Mosby International, 1999. Fox KK, Isbey SF, Cohen MS, Carson CC. Urethritis, epidydimitis, orchitis, prostatitis. In: Root R, et al., eds. Clinical Infectious Diseases: A Practical Approach. Oxford University Press, 1999, pp 669–678. Handsfield HH. Genital herpes, syphilis, and genital ulcer disease. In: Root R, et al., eds. Clinical Infectious Diseases: A Practical Approach. Oxford University Press, 1999, pp 657–668. Krieger JN. Prostatitis syndromes. In: Holmes KK, Mardh P, Sparling PF, et al., eds. Sexually Transmitted Diseases. New York: McGraw-Hill, 1999, pp 859–871. Krieger JN. Prostatitis, epididymitis, and orchitis. In: Mandell G, Bennett J, and Dolin R, eds. Principles and Practice of Infectious Diseases. Churchill Livingstone, 2000, pp 1243–1250. Krieger JN, Graney DO. Clinical anatomy, histology, and physical exam of the male genital tract. In: Holmes KK, Mardh P, Sparling PF, et al., eds. Sexually Transmitted Diseases. New York: McGraw-Hill, 1999, 699–709. Lipsky BA. Prostatitis and UTI in men: What’s new; What’s true. Am J Med 106(3):327–334. Martin DM, Bowie WR. Urethritis in males. In: Holmes KK, Mardh P, Sparling PF, et al., eds. Sexually Transmitted Diseases. New York: McGraw-Hill, 1999, pp 833–845. Nickel, JC. Prostatitis: Evolving management strategies. Urol Clin North Am 26(4):737–751, 1999. 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics.

18 Endocarditis JoAnn Tufariello Albert Einstein College of Medicine, Bronx, New York, U.S.A.

Franklin D. Lowy Columbia University, New York, New York, U.S.A.

1

INTRODUCTION

Infective endocarditis (IE) is a condition in which microorganisms invade the endothelial lining of the heart. Although typically referring to infection of the heart valves, the term also encompasses infection of septal defects and of the mural endocardium. Because the clinical manifestations of IE can be quite varied, the condition may be encountered by internists, family medicine practitioners, and members of the various medical subspecialties. Despite the varied presentation, prompt recognition of IE with institution of appropriate antimicrobial therapy and in some cases adjunctive surgical intervention is critical to a favorable outcome. Although morbidity and mortality rates remain considerable, advances in both antibiotic therapy and surgical approaches have now rendered curable what had been a uniformly fatal disorder in the preantibiotic era. Since the first comprehensive description of IE provided by William Osler in an address to the Royal College of Physicians in London in 1885, this disease has attracted considerable attention from clinicians and scientific investigators. 2

EPIDEMIOLOGICAL CHARACTERISTICS

The incidence of IE is on the order of ⬃1 patient per 1000 hospital admissions in the United States, or an estimated 10,000 to 20,000 new cases per year. Although this incidence has remained largely unchanged over the past 30 to 40 years, the mean age of patients with IE has increased throughout the antibiotic era, from below 30 years in 1926 to above 50 years at present. Although almost any structural heart disease can predispose to the development of endocarditis, certain cardiac conditions are associated with IE more frequently than others. Acquired valvular dysfunction due to rheumatic heart disease (RHD) was a common predisposing condition in the past, involving the mitral valve in 85% of cases, either alone or in combination, and the aortic valve in about half of cases. However, rheumatic valvular disease is now much less common in Western countries, found in fewer than 15% of patients in many recent series. In developing nations, RHD remains a common disorder 347

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and a frequent predisposing factor in the development of IE. Congenital cardiac conditions including patent ductus arteriosus, ventricular septal defect, primum atrial septal defect, bicuspid aortic valve, coarctation of the aorta, tetralogy of Fallot, and pulmonic stenosis together account for approximately 6%–24% of cases. The congenitally bicuspid aortic valve is a common condition, found in 1%–2% of the general population, and is becoming an increasingly important predisposing factor for native valve endocarditis. IE involving bicuspid aortic valves tends to be severe, requiring surgery in 80%–90% of cases, and carries a significant mortality rate even with prompt surgical intervention. The mitral valve prolapse (MVP) syndrome is also associated with endocarditis. This relatively common condition is found in 0.5%–20% of otherwise healthy individuals, particularly young women. The risk of IE appears to be increased in the group of patients who manifest the holosystolic murmur, rather than those with the isolated midsystolic click, presumably because it is the regurgitant flow and not the valve prolapse itself that creates the turbulence that predisposes to IE. Patients exhibiting myxomatous degeneration of the mitral valve, with mitral valve leaflet thickening and redundancy on echocardiogram, are also at increased risk for IE. Idiopathic hypertrophic subaortic stenosis (IHSS) is another cardiac condition that can lead to IE, which occurs in 5% of patients with IHSS. This has been attributed to turbulent flow at the aortic valve, which is distal to the hypertrophied portion of the interventricular septum, as well as to coexisting mitral regurgitation due to displacement of the anterior leaflet by the abnormally shaped ventricle. The role of ‘‘degenerative’’ cardiac conditions such as calcified lesions due to arteriosclerotic cardiovascular disease or a calcified mitral annulus in predisposition to IE remains unclear. In a number of series, the majority of patients with acute IE had no known underlying cardiac disease. As these degenerative conditions are common in the elderly population, it is possible though unproved that they play a role in the development of IE. The presence of implanted foreign material within the heart or arterial system is also a risk factor for the development of IE. As will be discussed further, prosthetic valve endocarditis (PVE) is a distinct form of IE, occurring in about 3%–6% of patients within 5 years after valve replacement. Intracardiac pacemaker wires and hemodialysis shunts and fistulas also predispose to endocarditis. IE also occurs with increased frequency in hospitalized patients who have undergone invasive vascular access procedures that can lead to bacteremia, including placement of intravenous catheters, hyperalimentation lines, and central venous pressure monitors. Injection drug users (IDUs) are also at increased risk for IE. In IDUs, the endocarditis is often right-sided, involving the tricuspid valve. Infection in these subjects often occurs on previously undamaged valves. A number of theories have been proposed to explain the predominance of right-sided endocarditis in this population, including damage to the endothelium of right-sided valves by injected particulate material; physiological effects of injected substances, including vasospasm, ischemia, tissue injury, and thrombus formation; and direct injection of large bacterial loads, which cause a high-grade bacteremia. An additional trend has been the increasing incidence of nosocomial native and prosthetic valve endocarditis. These infections, frequently related to the use of intravascular devices, are often difficult to detect as a result of supervening medical problems and the intermittent administration of antibiotics. 3

PATHOPHYSIOLOGICAL CHARACTERISTICS

The development of IE is the result of complex interplay among a damaged valvular surface, local hemodynamic factors, transient bacteremia with certain microorganisms, and

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host defenses. Nonbacterial thrombotic endocardial lesions are regions of fibrin deposition and platelet aggregation that result from trauma to the valve surface. In experimental models, many types of stresses can produce these lesions, including high-velocity jet streams of blood, high cardiac output states, and infection. Nonbacterial thrombotic endocarditis (NBTE) has been found to occur in patients with malignancy, especially lung, gastric, and pancreatic cancers, as well as uremia, collagen vascular disease, congenital heart disease, and in those who have undergone placement of Swan-Ganz catheters. On the basis of these associated conditions, either endothelial trauma or a hypercoagulable state is thought to underlie the condition. Hemodynamic factors are also important to the development of IE. Infected vegetations are usually located on the atrial surface of the atrioventricular valves or the ventricular surface of the semilunar valves when associated with insufficiency. That is, when flow occurs through the valve orifice from a region of high to low pressure, the favored location for deposition of bacteria is just beyond the low-pressure side of the orifice. Lesions associated with high degrees of turbulence such as jet streams through small ventricular septal defects (VSDs) also favor bacterial colonization. In contrast, lesions associated with low-pressure flow abnormalities such as ostium secundum, atrial septal defects, or pure mitral stenosis are rarely associated with IE. The NBTE lesions become colonized with bacteria when skin or mucosal integrity is breached, leading to transient bacteremia. Many manipulations that involve the oropharyngeal, gastrointestinal, and genitourinary tracts result in bacteremia (see Table 1). The bacteremia is relatively low-grade and transient; sterilization of blood cultures occurs within about 30 minutes. The bacteremias are due to the indigenous microbial flora at the site involved—often viridans streptococci after oropharyngeal procedures and gramnegative bacilli and enterococci after gastrointestinal and genitourinary manipulations. The specific adherence characteristics of the organisms play an important role in the colonization of nonbacterial thrombotic lesions, which leads to endocarditis. Many strains of viridans streptococci produce a complex extracellular polysaccharide, called dextran, which is thought to promote the adherence of the organisms to NBTE lesions. The ability to produce dextran has been correlated with ability to adhere to damaged valvular tissue in vitro and to induce IE in vivo in a rabbit model. Viridans streptococci also express a surface protein, FimA, which is located at the tips of the fimbriae and is involved in attachment to NBTE lesions. 4

CLINICAL PRESENTATION

The clinical manifestations of IE can be highly varied and involve multiple organ systems (see Table 2). In the past, bacterial endocarditis was classified as acute (ABE) or subacute (SBE) on the basis of the tempo of progression of the disease, although this distinction has now been in large part superseded by classification based on the specific microbiological cause. In general, ABE follows a rapidly progressive course characterized by high fevers, systemic toxicity, and death within days to several weeks if untreated. The causative organisms, usually highly virulent, include Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes (group A streptococcus), and Neisseria gonorrhoeae. In contrast, SBE follows a more indolent course over weeks to several months with lowgrade fever, sweats, fatigue, and weight loss and is typically caused by viridans streptococci. This constellation of symptoms can lead to erroneous diagnoses of tuberculosis, malignancy, or collagen vascular disease. In some cases an antecedent event likely to produce bacteremia (for example, a dental procedure) can be identified. The varied signs and symptoms seen in IE are the result of (1) local destruction of the valve and intracardiac

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Table 1 Incidence of Bacteremia: Various Procedures Procedure/manipulation Dental Dental extraction Periodontal surgery Chewing of candy or paraffin Tooth brushing Oral irrigation device Upper airway Bronchoscopy (rigid) Tonsillectomy Nasotracheal suctioning/intubation Gastrointestinal (GI) Upper GI endoscopy Sigmoidoscopy/colonoscopy Barium enema Percutaneous needle biopsy of liver Urological Urethral dilatation Urethral catheterization Cystoscopy Transurethral prostatic resection Obstetrical/gynecological Normal vaginal delivery Punch biopsy of cervix Removal/insertion of intrauterine device (IUD)

Positive blood culture results, % 18–85 32–88 17–51 0–26 27–50 15 28–38 16 8–12 0–9.5 11 3–13 18–33 8 0–17 12–46 0–11 0 0

Source: Adapted from Everett and Hirschmann 1977.

extension of the infection, (2) septic embolization to distant organs or vessels, (3) bacteremia that causes metastatic seeding of distant sites, and (4) prolonged antigenic stimulation that leads to formation of circulating antigen-antibody complexes. 4.1

Fever

Fever is present in the vast majority of patients with IE; therefore, absence of documented fever in a patient not on antipyretic agents calls the diagnosis into question. However, fever may be absent in the setting of prior antibiotic use, severe congestive heart failure, or renal failure and in elderly or debilitated patients. Fever usually remits with antibiotic treatment within 1–2 weeks in approximately 90% of patients. Fever beyond 2 weeks of appropriate antibiotic therapy may be due to embolization (either major vessel or microvascular phenomena) or intracardiac abscess formation. Prolonged fever may presage the need for cardiac surgery and higher mortality rate. In addition to the endocarditis or its complications, persistent fever may be due to intravenous catheter–related phlebitis, drug fever, or superimposed nosocomial infection. 4.2

Cardiac Manifestations

An audible heart murmur is found in 85% of patients. IE in the absence of a murmur can occur with isolated tricuspid involvement (as in IDUs), with infection of the mural en-

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MANIFESTATIONS AND DIAGNOSIS Clinical manifestations (Table 2) Acute (days) or subacute (months) onset of fever, sweats, weight loss, and myalgias Cardiac Murmur in 85% of subacute cases Congestive heart failure (CHF), heart block Peripheral stigmata such as splinter hemorrhage, Osler’s nodes, Janeway lesions, Roth spots uncommon Renal involvement with glomerulonephritis, abscess, or emboli causing hematuria Neurological involvement due to emboli or ruptured mycotic aneurysm that accompanies stroke Emboli to spleen, mesenteric arteries, extremities, and lung (in injection drug user [IDU] with tricuspid valve infection) Laboratory Blood culture results positive in 85%–95% Normochromic, normocytic anemia Elevated erythrocyte sedimentation rate (ESR) Microscopic hematuria and proteinuria Elevated immunoglobulin, low complement levels Positive rheumatoid factor finding Diagnosis Two or three sets of blood cultures from different venipunctures prior to antibiotics (i.e., persistent bacteremia) Duke criteria: Tables 3 and 4 Use of echocardiography: Figure 1

docardium rather than valvular tissue, and very early in the course of ABE that occurs on previously normal valves. The appearance of new murmurs or of obvious changes in preexisting murmurs, although considered characteristic of IE, is actually uncommon. When present, new murmurs often signify an acute staphylococcal disease with valve destruction leading to aortic or mitral insufficiency and often presage the development of congestive heart failure (CHF), which is now the foremost cause of death in IE. The infection can spread locally from valve leaflets to surrounding structures, producing ring abscesses and mycotic aneurysms. This is especially of concern with staphylococcal endocarditis. Myocardial abscesses can involve the conduction system and produce heart blocks. Septic pericarditis is uncommon and occurs predominantly in the setting of myocardial abscess formation with fistulas to the pericardial sac in S. aureus infection. Myocarditis can occur and lead to arrythmias and to CHF. Coronary artery emboli usually arise from the aortic valve and can produce myocardial infarction. Rarely, very large vegetations can result in valvular stenosis. 4.3

Cutaneous, Peripheral, and Intraocular Findings

A number of cutaneous and peripheral manifestations have been described in IE. As many of these findings are immunologically mediated and increase with duration of untreated illness, they are more common in SBE than in ABE. These peripheral signs were more prevalent in the preantibiotic era. Petechiae occur with prolonged infection and can be

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Table 2 Clinical Manifestations of Infective Endocarditis Symptoms

Patients affected, %

Fever Chills Weakness Dyspnea Sweats Anorexia Weight loss Malaise

80 40 40 40 25 25 25 25

Cough Skin lesions Stroke Nausea/vomiting

25 20 20 20

Headache Myalgia/arthralgia Edema Chest pain Abdominal pain Delirium/coma Hemoptysis Back pain

20 15 15 15 15 10–15 10 10

Signs Fever Heart murmur Changing murmur New murmur Embolic phenomena Skin manifestations Osler nodes Splinter Hemorrhages Petechiae Janeway lesions Splenomegaly Septic complications (pneumonia, meningitis, etc.) Mycotic aneurysms Clubbing Retinal lesions Signs of renal failure

Patients affected, % 90 85 5–10 3–5 >50 18–50 10–23 15 20–40 0.1 and 0.1 and Aqueous crystalline 12–18 million U/24 hr IV ei0.1 and Vancomycin hy0.5 ␮g/ml, (3) nutritionally variant viridans streptococci, or (4) prosthetic valve endocarditis caused by viridans streptococci or Streptococcus bovis. Antibiotic dosages are for patients with normal renal function. IV, intravenous; IM, intramuscular. b For specific dose adjustment and issues concerning gentamicin (obesity of patients, relative contraindications), see Table 5 footnotes. c For specific dosing adjustment and issues concerning vancomycin (obesity of patients, length of infusion), see Table 5 footnotes. Source: Wilson WR et al. 1995.

terococci are relatively resistant to penicillin (median MIC 2 ␮g/ml), ampicillin, and vancomycin. These agents are bacteriostatic against enterococci and must be administered in combination with aminoglycosides to achieve bactericidal activity (see Table 6). Combination therapy is typically given for at least 4–6 weeks. Enterococci are resistant to cephalosporins. Enterococcal strains exhibit highly variable resistance to aminoglycosides; MIC greater than or equal to 2000 ␮g/ml of streptomycin or 500–2000 ␮g/ml of gentamicin is used as the cutoff value to distinguish between low- and high-level resistance. Enterococci that have high-level resistance to one of the aminoglycosides are not killed synergistically with combination therapy. Good therapeutic alternatives do not exist and expert consultation is suggested. Enterococcal penicillin resistance can be due to ␤-lactamase production or to altered penicillin binding proteins (PBPs). ␤-Lactamase production can be countered by adding sulbactam to ampicillin (Unasyn); PBP mutations require the use of vancomycin. Unfortunately, vancomycin-resistant enterococci have emerged as significant pathogens in recent years. Consultation with experts is recommended for these very difficult cases.

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Staphylococci

Most S. aureus strains causing IE, whether acquired in the community or in the hospital, produce ␤-lactamase and are resistant to penicillin G. The recommended regimens include a semisynthetic penicillinase-resistant penicillin such as nafcillin or oxacillin or a firstgeneration cephalosporin given for 4–6 weeks (see Table 7). Addition of gentamicin causes synergistic killing in vitro and in animal models and a more rapid clearing of bacteremia has been observed in clinical trials. Cure rates, though, are not improved with combination

Table 7 Therapy for Endocarditis Due to Staphylococcus in the Absence of Prosthetic Materiala Antibiotic

Dosage and route

Duration

Comments

Methicillin-susceptible staphylococci Regimens for non-␤lactam-allergic patients Nafcillin sodium or oxacillin sodium With optional addition of gentamicin sulfateb Regimens for ␤-lactamallergic patients Cefazolin (or other first-generation cephalosporins in equivalent doses) With optional addition of gentamicin Vancomycin hydrochloridec

2 g IV every 4 hr

4–6 wk

1 mg/kg IM or IV every 8 hr

3–5 days

2 g IV every 8 hr

4–6 wk

1 mg/kg IM or IV every 8 hr 30 mg/kg per 24 hr IV in two equally divided doses, not to exceed 2 g/24 hr unless serum levels are monitored

3–5 days 4–6 wk

Benefit of additional aminoglycosides has not been established As above

Cephalosporins should be avoided in patients with immediate-type hypersensitivity to penicillin As above Recommended for patients allergic to penicillin

Methicillin-resistant staphylococci Vancomycin hydrochloridec

30 mg/kg per 24 hr IV in two equally divided doses, not to exceed 2 g/24 hr unless serum levels are monitored

4–6 wk

For treatment of endocarditis due to penicillin-susceptible staphylococci (minimal inhibitory concentration ⱕ0.1 ␮g/ ml), aqueous crystalline penicillin G sodium (Table 5, first regimen) can be used for 4–6 wk instead of nafcillin or oxacillin. Shorter antibiotic courses have been effective in some IDUs with right-sided endocarditis due to Staphylococcus aureus. IV, intravenous; IM, intramuscular. b For specific dose adjustment and issues concerning gentamicin (obesity of patients, relative contraindications), see Table 5 footnotes. c For specific dosing adjustment and issues concerning vancomycin (obesity of patients, length of infusion), see Table 5 footnotes. Source: Wilson WR et al. 1995. a

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therapy. Therefore, some authorities recommend addition of gentamicin for the first 3 to 5 days of therapy, especially for severe cases of left-sided S. aureus IE, with the objective of reducing metastatic seeding and abscess formation while minimizing the toxicities associated with more prolonged courses of aminoglycoside (see Korzeniowski and Sande 1982, and reviewed in Bayer and Scheld 2000 and in Wilson et al. 1995). Shorter courses of therapy, consisting of an antistaphylococcal semisynthetic penicillin plus an aminoglycoside given for 2 weeks, have yielded high cure rates (90% or greater) in IDUs with uncomplicated right-sided S. aureus IE (for example, Chambers et al. 1988). These abbreviated regimens are not recommended for IDUs with any evidence of left-sided involvement or metastatic infection. In patients with allergies to penicillin and cephalosporins and in cases when the S. aureus isolate is methicillin-resistant, the recommended therapy is vancomycin. However, both in vitro studies and clinical data have shown that vancomycin is an inferior antistaphylococcal agent when compared with the semisynthetic penicillins (discussed in Bayer and Scheld 2000). For penicillin-allergic patients who do not respond to vancomycin therapy for a methicillin-susceptible S. aureus, one can consider ␤-lactam desensitization. For patients infected with methicillin-resistant strains who are responding suboptimally to vancomycin therapy, one may consider adding rifampin, or gentamicin, or both agents (if the isolate is sensitive), or a number of alternative regimens relying on quinolones, trimethoprim-sulfamethoxazole, or minocycline. Infectious disease consultation is advisable in these difficult cases. 7.2.4

HACEK

In the past, the HACEK microorganisms exhibited a consistent susceptibility to ampicillin. However, more recently ␤-lactamase-producing strains have emerged, rendering third-generation cephalosporins the treatment of choice for IE that is due to these organisms. Native valve infections are treated for 4 weeks; prosthetic valve infections require 6 weeks of therapy (see Table 8).

Table 8 Therapy for Endocarditis Due to HACEK Microorganisms (Haemophilus parainfluenzae, Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae)a Antibiotic

Dosage and route

Duration, wk

Ceftriaxone sodiumb

2 g once daily IV or IM

4

Ampicillin sodiumc

12 g/24 hr IV either continuously or in six equally divided doses 1 mg/kg IM or IV every 8 hr

4

With gentamicin sulfated a

Comments Cefotaxime sodium or other third-generation cephalosporins may be substituted

4

Dosages recommended are for patients with normal renal function. IV, intravenous; IM, intramuscular. Patients should be informed that IM injection of ceftriaxone is painful. c Ampicillin should not be used if laboratory tests show ␤-lactamase production. d For specific dose adjustment and issues concerning gentamicin (obesity of patients, relative contraindications), see Table 5 footnotes. Source: Wilson WR et al. 1995. b

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PROSTHETIC VALVE ENDOCARDITIS Pathogens

Within the first 5 years after surgery, PVE occurs in about 3%–6% of patients who have had valve replacement. The incidence is highest during the initial 6–12 months after surgery and declines thereafter to a low but constant rate of about 0.4% per year. PVE can be divided into cases occurring early (within 2 months after surgery) and late (more than 12 months after valve replacement) with an additional intermediate group (2–12 months post surgery). The early cases are often due to coagulase-negative staphylococci (30%–35%) and S. aureus (⬃17%), although Enterbacteriaceae, Pseudomonas aeruginosa, enterococci, diphtheroids, and fungi each account for a small proportion of cases. The early cases are thought to be the result of intraoperative contamination at the time of valve implantation or of seeding of the valve during an early postoperative bacteremia from intravenous catheters and skin or wound infections. The vast majority of the coagulasenegative staphylococci isolated in these early infections are methicillin-resistant. In the intermediate period, the spectrum of organisms is similar, although streptococci are more often involved and gram-negative bacilli and diphtheroids less so. These cases represent a mixture of nosocomial infections with delayed presentation as well as some community-acquired cases. Late PVE is often due to viridans streptococci, enterococci, and HACEK organisms as well as coagulase-negative staphylococci and S. aureus. In these late cases, the coagulase-negative staphylcococci are often methicillin-sensitive and a variety of non–S. epidermidis species are isolated. Fungi account for about 4%–6% of cases of PVE; Candida albicans is responsible for most cases. The clinical presentation of PVE is similar to that of native valve endocarditis especially when it develops several months or more after surgery. However, the diagnosis of PVE in the early postoperative period can be challenging given the variety of surgical and postoperative complications that may give rise to fever and to bacteremia. Patients with early PVE may have fever in the absence of prosthetic valve dysfunction or peripheral manifestations. Diagnosis rests on maintaining high suspicion, obtaining multiple sets of blood cultures, and imaging the valve by echocardiography. When blood cultures sporadically yield organisms such as coagulase-negative staphylococci and diphtheroids, which could represent either PVE pathogens or contaminants, molecular techniques may be pursued to determine whether the isolates are indeed clonal in origin, a source that would make endocarditis more likely. Evaluation of a prosthetic valve for infection requires imaging by both TTE and TEE in order to afford adequate imaging of all valvular surfaces. TEE is especially useful for diagnosis of periprosthetic leaks, abscesses, and fistulas. 8.2

Treatment

The treatment of PVE rests on the same considerations outlined for native valve endocarditis. In general, a bactericidal combination of antimicrobial agents is administered for a minimum of 6 weeks; see Table 9 for regimens for treatment of staphylococcal PVE. Regimens for other organisms are outlined in Karchmer (2000). In contrast to the treatment of NVE, in therapy of staphylococcal PVE, rifampin plays a critical role. This recommendation is based on results from animal models and clinical experience (reviewed in Karchmer, 2000). Resistance to this drug can develop very rapidly, especially if it is given as monotherapy. It is preferable to administer two effective antistaphylococcal agents along with rifampin; if the isolate is resistant to gentamicin or an alternative aminoglycoside, then consideration should be given to substitution of a fluoroquinolone to which the strain is susceptible.

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Table 9 Therapy for Staphylococcal Endocarditis in the Presence of a Prosthetic Valve or Other Prosthetic Materiala Antibiotic

Dosage and route

Duration, wk

Comments

Regimen for methicillin-resistant staphylococci Vancomycin hydrochlorideb

ⱖ6

With rifampinc

30 mg/kg per 24 hr IV in two or four equally divided doses, not to exceed 2 g/24 hr unless serum levels are monitored 300 mg orally every 8 hr

And with gentamicin sulfated,e

1.0 mg/kg IM or IV every 8 hr

Nafcillin sodium or oxacillin sodium

2 g IV every 4 hr

ⱖ6

With rifampinc And with gentamicin sulfated,e

300 mg orally every 8 hr 1.0 mg/kg IM or IV every 8 hr

ⱖ6 2

ⱖ6

Rifampin increases the amount of warfarin sodium required for antithrombotic therapy

2

Regimen for methicillin-susceptible staphylococci First-generation cephalosporins or vancomycin should be used in patients allergic to ␤-lactam Cephalosporins should be avoided in patients with immediate-type hypersensitivity to penicillin or with methicillin-resistant staphylococci

a

Dosages recommended are for patients with normal renal function. IV, intravenous; IM, intramuscular. For specific dosing adjustment and issues concerning vancomycin (obesity of patients, length of infusion), see Table 5 footnotes. c Rifampin plays a unique role in the eradication of staphylococcal infection involving prosthetic material; combination therapy is essential to prevent emergence of rifampin resistance. d For specific dose adjustment and issues concerning gentamicin (obesity of patients, relative contraindications), see Table 5 footnotes. e Use during initial 2 wk. Source: Wilson WR et al. 1995. b

Despite antimicrobial therapy, patients with PVE often experience complications that require surgical intervention. Such complications include periprosthetic dehiscence, CHF due to valvular dysfunction, paravalvular extension of infection, persistent bacteremia despite antibiotic treatment, and very large, highly mobile vegetations. 9

SURGERY IN INFECTIVE ENDOCARDITIS

Surgery is necessary in approximately 25% of cases of infective endocarditis. The indications for surgery have remained relatively constant, although several newer indications have been suggested. The traditionally accepted indications are summarized in Table 10. The hemodynamic status of the patient remains the primary determinant of the need for surgery. Heart failure is the most common indication for surgery and is the most common cause of death in this population. Patients with severe failure unresponsive to medical management, even in the presence of continued active infection, should have surgery

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Table 10 Indications for Surgery 1. 2. 3. 4. 5.

Congestive heart failure (CHF) unresponsive to medical therapy or severe valvular disease resulting from infection Multiple systemic emboli Infection caused by an antimicrobial-resistant organism such as fungi, Enterobacteriaceae, and Pseudomonas aeruginosa Prolonged bacteremia or relapse after appropriate therapy Most patients with prosthetic valve endocarditis

without delay. The indication for surgery due to recurrent emboli is less clear. The frequency of embolic disease decreases rapidly after institution of appropriate therapy. Patients with embolic disease who have persistent, large left-sided vegetations appear to be at increased risk of additional systemic emboli. Mitral valve lesions are associated with the highest risk of embolization. The studies on vegetation size and the risk of emboli as documented by echocardiography are inconclusive: some studies suggest that size increases risk, and others do not support this conclusion. Infections caused by certain bacterial species including Enterobacteriaceae, Pseudomonas sp., and staphylococci are often poorly responsive to therapy. Recent retrospective studies suggest that patients with left-sided S. aureus endocarditis have an improved outcome if they have a combination of medical and surgical therapy. In patients with early (1/2 inch from the scalp represent empty eggshells. Treatment alternatives for NIX- or RID-resistant lice may include the following: Ovide (5% malathione lotion): apply to dry hair; do not cover. Wash out in 8–12 hours. Caution: it is flammable. Elimite (5% permethrin cream): apply to wet hair at bedtime, wrap in towel, and wash out the next morning. Lindane: apply to wet hair at bedtime, wrap in towel, and wash out in the morning. Trimethoprim-sulfamethoxazole (Bactrim DS): take once orally every day for 3 days; repeat in 10 days.

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395

Petrolatum or mayonnaise: thickly applied, it should be covered with a shower cap overnight. Shampoo out with Dawn dish detergent. Shave hair. 2.1.3

Pubic Lice

The chance of acquiring Phthirius pubis from a single sexual contact is about 95%. Pubic, thigh, and eyelash hair may be infected. The lice attach tightly to the bases of hair and clinically resemble multiple small freckles. Patients complain of pruritis in affected areas. Erythematous macules and papules may be present along with excoriations. Occasionally, feeding sites develop peculiar slate blue colored macules that may persist for many months. Partners should be treated and the possibility of other sexually transmitted diseases investigated. Clothing and bedding should be washed as described for head lice. Treatment for pubic lice may include the following: Lindane lotion applied to affected areas overnight NIX applied to affected areas as for head lice and repeated in 10 days Elimite cream applied to affected areas overnight Shaving of hair The preceding treatments should not be applied to the eyelids or lashes. Treatment for eyelashes may include thick application of petrolatum twice a day for 10 days and mechanical removal of nits. Symptomatic pruritis can be treated with antihistamines or topical corticosteroids. 2.2

Scabies

Scabies is caused by infestation with the mite Sarcoptes scabiei var. hominis. These arthropods belong to the class Arachnida. The adults are 1/3 mm long, are rounded, and have four pairs of legs. Scabies is generally transmitted through close personal contact with an infected individual, although rarely transmission via clothing or linens may occur. The incubation period is about 1 month. The female mites burrow superficially into the stratum corneum and lay eggs daily for several weeks before dying. Larvae hatch in a few days and then molt to adults, which then deposit more eggs. Infections therefore may persist for long periods if untreated. The itch of scabies is severe and generally worst at nighttime. Affected individuals have many small red papules, excoriations, and dermatitis prominent on the hands, axilla, breasts, abdomen, and genitalia. Pruritic red papules on the penis should be considered scabies until proved otherwise. Very close inspection is needed to see the characteristic small burrows best noted between the fingers and on the wrists. Only about 10 mites are present on the average host and are best found in these burrows. Definitive diagnosis requires demonstrating the characteristic mite and/or eggs or feces in a skin scraping. 2.2.1

Scabies Preparation Technique

A number 15 scalpel blade should be used to shave the superficial epidermis firmly over burrows and papules between the fingers and on the wrists. Proper sampling often causes a small amount of bleeding. Multiple sites should be scraped and the material put together on one slide. Add one drop of mineral oil or KOH and cover with a coverslip. Mites, eggs, and feces are easily visible at 10⫻ magnification. Because many forms of dermatitis mimic scabies clinically, a scraping should always be performed. If a skin scraping finding is negative and clinical suspicion of scabies is

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high, empirical treatment may be undertaken. However, if empirical treatment fails, an alternative diagnosis should be considered. After successful eradication of the mites, pruritis and rash may continue for up to 4 weeks as part of the so-called postscabetic syndrome. Symptoms after this time should prompt reinvestigation for continued infestation. Crusted or Norwegian scabies may be seen in immunocompromised or immobile patients; it is characterized by thick, crusted plaques that may resemble psoriasis. These individuals are extremely infectious as the lesions are teeming with mites. Treatment is more difficult and usually must be repeated numerous times until clearing. The treatment of choice for scabies is permethrin 5% cream (Elimite) applied before bedtime to the entire cutaneous surface except the face and scalp with meticulous attention to the hands, including under the nails. It is essential that the instructions for application are understood and that medication is applied to all skin and not just symptomatic areas. In the morning, the bed linens should be removed and washed. Mites generally die within 48 hours off a human host so avoidance of usual clothing or furniture for 1–2 days after treatment may decrease the potential for reinfection. Disinfection of furniture or other clothing is generally not necessary. It is important that all close contacts be treated, preferably at the same time, even if they are asymptomatic. Lindane is now used less frequently, partly because of concerns about potential neurotoxic side effects. Toxicity, however, only results from excessive and inappropriate usage and does not occur if the medication is used as directed. Symptomatic treatment with antihistamines and topical anti-itch preparations including topical steroids should also be given as needed. For individuals with resistant disease and particularly those with crusted scabies, oral ivermectin (Stromectol) can be used. It is now available in the United States and is indicated for the treatment of onchocerciasis and Strongyloides sp. infections. Studies in humans show that two doses 1 week apart are effective for uncomplicated infestation and are equal in efficacy to a single application of permethrin cream (see Table 1). 2.3

Other Mites

A variety of mites may be found on most animals and plants, where they generally complete their life cycle. On occasion, these mites may temporarily try to burrow or bite into

Table 1 Treatment of Scabies FDA indication

Pregnancy category

Permethrin 5% cream (Elimite)

Yes >6 months of age

B

Lindane 1%

Yes

B

Ivermectin

No

C

Medication

a

Directions Apply at night to all skin; repeat in 1 week Apply at night to all skin; repeat in 1 week 200 ␮g/kg as a single dose, repeat in one week

Costa $24.00 (60 g)

$15.00 (60 ml)

$10.00 (6-mg tab) $5.00 (3-mg tab)

Average wholesale price, 2000 Drug Topics Red Book. FDA, U.S. Food and Drug Administration.

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397

a human, often causing an immune reaction in the process. The most common of these are fleas and chiggers. 2.3.1

Fleas

Fleas exist universally among animals and humans and may be vectors of serious disease, particularly the rat flea, which serves as the vector of plague and endemic typhus. Currently in the United States, however, the most common problem associated with fleas is the cutaneous irritation caused by bites from Pulex irritans, the human flea; Ctenocephalides felis, the cat flea; and Ctenocephalides canis, the dog flea. Fleas are small brown wingless insects about 1 mm long and are extraordinary jumpers. Bites are most common around the legs and waist and are often in clusters. Not everyone reacts to flea bites, and in some households, only one individual may be affected. In some sensitized individuals, a generalized pruritic eruption of red papules, sometimes called papular urticaria, may occur. In addition to treatment of affected pets, all infested areas such as pet bedding, carpets, and furniture need to be treated. Successful eradication often requires multiple treatments. 2.3.2

Chiggers

The trombiculid mites known as chiggers, harvest mites, or red bugs are common in the southern United States. Mites are about 0.5 mm long and live in hay, grass, and bushes. They are the potential vectors of scrub typhus. Shortly after contact, they cause hemorrhagic punctae surrounded by erythema and sometimes urticaria. The mite usually then drops off and is not seen. Bites are most frequent under constrictive clothing such as at the beltline or around the ankles. Treatment is symptomatic with oral antihistamines or topical corticosteroids. 2.3.3 Cheyletiella Species Also called ‘‘walking dandruff,’’ Cheyletiella spp. are parasites on dogs, cats, and rabbits. They cause small itchy red bumps, generally on the arms of humans who handle animals. The pet should be examined and treated by a veterinarian.

FUNGAL INFECTIONS Dermatophytes (tinea) Circular scaly plaques, dandruff on scalp, thickened discolored nails Therapy Cutaneous: treat topically (Table 3) Hair: treat orally (Table 5) Nails: treat orally (Table 6) Candidal infections Bright red, oozing, painful rash in intertriginous areas Therapy Topical (Table 3) If severe, orally (Table 6) Pityriasis Large coalescing white, red, or brown painless macules Therapy: Table 7

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FUNGAL INFECTIONS

Superficial fungal infections of the skin can be caused by either dermatophytes or yeast. Infection with the dermatophyte or ringworm fungi cause the ‘‘tinea’’ infections. The most common yeast infections are caused by Candida sp. and by Pityrosporum ovale, the causative agent of pityriasis versicolor. 3.1

Dermatophyte Infections (Ringworm or Tinea)

The dermatophytes are molds that include three genera (Trichophyton, Microsporum, and Epidermophyton) and 39 species that may be acquired from other humans, animals, or soil. They invade the stratum corneum of the skin, most commonly in the groin and on the feet, but may also invade hair and nails. Humans become infected after contact with the fungal arthrospore, which then invades the skin. These vegetative spores can live outside the host for 15 months. Therefore, host-to-host contact is not necessary. Classically, the tinea infections are circular lesions with raised scaling edges that may be inflamed. Infections may be asymptomatic, but generally pruritis is prominent. The name of the infection is completed by the location of the fungus on the body: scalp (tinea capitis), face (tinea facei), body (tinea corporis), groin (tinea cruris), hands (tinea manuum), feet (tinea pedis), and nails (onychomycosis). A secondary rash (id reaction) may develop as an immunological reaction to the dermatophyte infection. These id reactions may occur during therapy. Rarely, dermatophyte infections invade deeper tissues in immune compromised hosts, leading to edema and subcutaneous nodules. See Table 2 for a clinical description and diagnostic approach. The diagnosis is made by the characteristic lesions and by skin scraping that demonstrates the organisms on KOH preparation or by culture. Some species of dermatophyte, particularly those acquired from animals, may show green fluorescence on Wood’s light examination. However, very few dermatophyte infections can be diagnosed with this method. 3.1.1

Potassium Hydroxide Preparation Technique

Scrape the skin tangentially with a number 15 scalpel blade and collect a good amount of white scales on a microscope slide. Add 1 to 2 drops of 10% KOH and cover with a coverslip. Heat for 5 seconds (a flame under the slide is sufficient) and view. Hyphae are long, slender, frequently branching filaments that cross several keratinocytes. They are much smaller than keratinocytes and are only faintly seen at 10⫻. Easily identifiable ‘‘filaments’’ at 10⫻ are clothing fibers. As an alternative, chlorazole black is a fungusspecific stain that does not need to be heated and stains fungi a light green color. Apply 1 drop of this, cover with a coverslip, and wait 5 minutes before viewing. Dermatophyte infections of the skin often respond to topical therapy. See Table 3 for a listing of topical antifungal preparations. Clotrimazole (Lotrimin) and terbenafine (Lamisil) cream are the most effective OTC products available. Treatment may take up to 4–6 weeks (longer than suggested on the product label). Occasionally widespread or resistant cases may need oral therapy (see Table 4). Tinea capitis (Table 5) and onychomycosis (Table 6) require systemic therapy. Almost 100% of fingernails and a majority of toenails show improvement with oral therapy. Toenail infections require 12 weeks of daily therapy, whereas fingernail infections may respond in 6 weeks. Ten completely normal toenails, however, can only be achieved about 30% to 50% of the time. Recurrences are common and may approach 50% by 3 years. Almost all individuals with onychomycosis have chronic tinea pedis as well; al-

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Table 2 Dermatophyte (Tinea) Infections Location (name) Scalp (tinea capitis)

Clinical

Red boggy plaque(s), often initially misdiagnosed as impetigo, folliculitis, or contact dermatitis Body (tinea corporis; Annular plaques with ringworm) central clearing and peripheral scale

Hand (tinea manuum)

Feet (tinea pedis)

Nail (onychomycosis)

Comments

1. 2.5% Selenium sulfide shampoo for patient and contacts to decrease infectivity 2. Reinfection common; may need to treat contacts Almost always from an Pluck hairs and send animal; look for liveswab from vigorous stock or pets with scraping of pustules for mange fungal smear and culture 1. Obtain KOH from pe- DDX: Nummular dermatitis—especially if riphery of lesion more than a few le2. Send skin scrapings to sions present or nonlab for fungal smear response to therapy and culture 1. Obtain KOH from pe- Examine feet; treating riphery of lesion chronic tinea pedis decreases recurrences 2. Send skin scrapings to lab for fungal smear and culture

Usually resembles diffuse Fungus lives inside hair; pluck several hairs to dandruff; may have send to lab from the scaling, inflammation, edge of a bald spot or and alopecia; more diffusely scaling area common in children of scalp

Face (tinea facei)

Groin (tinea cruris)

Diagnosis

Pink patch with peripheral scale in inguinal area; does not involve scrotum; if scrotum involved, potentially candidal Fine white scaling of palms prominent in skin creases; often unilateral; fingernails often involved Type 1 ‘‘chronic’’: often asymptomatic; fine dry scaling of soles of feet (‘‘athlete’s foot’’) Type 2 ‘‘acute’’: red itchy patches with peripheral scaling, sometimes blisters Type 3 ‘‘interdigitale’’: redness, fissures, and pain between toes Raised nails with subungual debris

Also known as ‘‘two feet, 1. Obtain KOH one hand disease’’; 2. Send skin scrapings to both feet generally lab for fungal smear show chronic white and culture scaling as well 1. Obtain KOH from pe- Type 3 usually has superinfection with yeast riphery and bacteria; to clear 2. Send skin scrapings to infection, important to lab for fungal smear aerate and separate toes and culture with cotton

Send nail clippings and subungual debris (remove with curette) for fungal smear and culture

High rate of false-negative culture results; if positive test result desired, may need to be repeated

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Table 3 Activity of Topical Antifungal Preparations

Clotrimazole (Lotrimin) Econazole (Spectazole) Naftifine (Naftin) Nystatin Terbinafine (Lamisil) Tolnaftate 2.5% Selenium (Selsun Rx)

Tinea/ dermatophyte

Pityriasis versicolor

Candidal

⫹ ⫹ ⫹ ⫺ ⫹ ⫹ ⫺

⫹ ⫹ ⫺ ⫺ ? ⫺ ⫹

⫹ ⫹ ⫺ ⫹ ? ⫺ ⫺

though it is not proved, many believe that recurrences may be decreased by regular prophylactic application of topical antifungals to the feet. 3.2

Yeast Infections

There are two major yeastlike fungi that cause skin disease: candidal and pityrosporum. 3.2.1

Candidal Infections

Candida albicans is a normal commensal organism of the skin, mucous membranes, and gastrointestinal tract that may become pathogenic under certain conditions. These conditions include increased moisture, maceration and occlusion, and host factors such as diabetes mellitus, pregnancy, immunosuppression, or antibiotic use. Common sites of infection include the intertriginous areas, axillae, and areas beneath the breasts and in the groin and genitals. Although both candida and dermatophytes can infect the inguinal creases, only candida involves the scrotum and penis—a clinical finding that can help differentiate the two. Classic candidal infections are bright red, glistening, or oozing and have characteristic red papules and pustules at the periphery of the plaques (‘‘satellite lesions’’). The diagnosis can be made by a KOH preparation showing budding spores and/or by culture. Candida sp. grows quickly and culture results are often available in about 48 hours. For most labs, a bacterial culturette swab with ‘‘Fungus culture, suspect yeast’’ written on the requisition slip is recommended. If both bacteria and yeast are in the differential, a bacterial culture should be requested and two swabs sent with a note on the slip that yeast is also suspected. Most available topical antifungal preparations treat both yeast and dermatophyte infections; however, some agents have primarily antidermatophyte activity and these

Table 4 Oral Treatment for Dermatophyte Skin Infections Agent Fluconazole (Diflucan) Griseofulvin Itraconazole (Sporanox) Terbinafine (Lamisil) a

Dose

Duration

Costa

150–300 mg one dose/wk 500 mg qd 200–400 mg qd 250 mg qd

4–6 Weeks 4–8 Weeks 7 Days 10 Days

$72–$144 $37–$75 $99–$198 $76

Average wholesale price, 2000 Drug Topics Red Book.

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Table 5 Treatment of Tinea Capitis Cost (for 20-kg child)a

Drug

Daily dose

Duration

Griseofulvin Itraconazole (Sporanox)

20–25 mg/kg 5 mg/kg

Fluconazole (Diflucan)

6 mg/kg 5 mg/kg 10–20 kg–62.5 mg 20–40 kg–125 mg >40 kg–250 mg

6–8 Weeks 4–6 Weeks 1 week/month pulse for 3 months 20 Days 4–6 Weeks 2–4 Weeks

Terbinafine (Lamisil)

$200 $140

$170 $60

a

Average wholesale price, 2000 Drug Topics Red Book.

should not be prescribed when a yeast is suspected (see Table 3). For severe or widespread infections or for severely eroded skin, oral therapy with fluconazole or ketoconazole 100– 200 mg/day for 1–5 days or itraconazole 200 mg/day for 5 days may be used. For candidal infections, care should be given to addressing the underlying physical causes (occlusion, maceration, etc.) to minimize recurrences. 3.2.2

Pityriasis Versicolor

In some individuals, under stimulation from heat and sweat, the normal and ubiquitous follicular commensal yeast Pityrosporum ovale changes from its usual spore form to a mycelial form and becomes the agent of pityriasis versicolor (PV). PV is sometimes also

Table 6 Treatment of Onychomycosis Drug

Dose

Duration

Penlac (topical) Terbinafine

Daily 250 mg/day 250 mg bid ‘‘Pulse’’

Fluconazole

150–400 mg; one dose/wk 200 mg/day 200 mg bid ‘‘Pulse’’

Until clear 12 Weeks For 7 days, then off 21 days; repeat for a total of four ‘‘pulses’’ for toenails and three pulses for fingernails 3–12 months (continue until clear) 90 Days For 7 days, then off 21 days; repeat for a total of three ‘‘pulses’’ for toenails and two pulses for fingernails

Itraconazole

a

Average wholesale price, 2000 Drug Topics Red Book.

Improvement rate, %

Costa

20 70–80

$90 $644 $350

50–80

$143–$1269

60–85

$1287 $600

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called tinea versicolor, which is an unfortunate misnomer since Pityrosporum ovale (previously called Malassezia furfur) is not a tinea (dermatophyte) but a yeastlike organism. PV is more common in the summer and in tropical climates. PV is characterized by white, pink, or brown macules, which may or may not have obvious scale. The spots coalesce into larger patches and are classically located in the sebaceous areas of the torso, particularly on the upper back, anterior chest, and upper abdomen. The fungus secretes a chemical that prevents pigmentation of the underlying skin. For this reason, white spots remain after treatment, particularly in tanned individuals. They can be reassured that their skin color will normalize with the fading of the tan. Diagnosis can easily be made by a KOH preparation that shows abundant small fat hyphae and spores (‘‘spaghetti and meatballs’’). The organism does not grow in routine culture media. The fungus is fairly easy to eradicate; however, recurrences are guaranteed. Treatment options are summarized in Table 7. PV generally responds to topical azole creams. A single 400-mg dose of ketoconazole may suffice, though 5–10 days of 200 mg/day is sometimes needed.

4

VIRAL INFECTIONS

Viral infections localized to the skin include molluscum contagiosum and herpes family viruses including Herpes simplex and varicella zoster. 4.1

Warts

Warts are epidermal neoplasms caused by human papillomavirus (HPV). Characteristically, warts are raised exophytic nodules that are generally asymptomatic but may be painful or bleed. HPV is only found on humans; although it is contagious, transmission is rather difficult. There are at least 89 serotypes of HPV, most of which have a predilection for specific anatomical areas. For example, types 1 and 2 cause plantar warts; types 3 and 10 cause flat warts. Although HPV-induced warts are generally considered benign, infection has been implicated in the development of some squamous cell carcinomas (SCCs), particularly cervical carcinoma (see Chapter 16 concerning genital HPV), anal carcinoma in patients with human immunodeficiency virus (HIV) and SCC in patients who have had organ transplantation. Since death from SCC is a major concern for patients on long-term immunosuppression, it is reasonable to make an attempt to eradicate warts prior to transplantation. However, it must be noted that studies have not been done to prove this therapy effective and that warts can be notoriously difficult to eradicate.

Table 7 Treatment of Pityriasis Versicolor Agent Ketoconazole Clotrimazole cream 2.5% Selenium sulfide lotion a

Dose 400 mg ⫻ 1 dose; repeat if necessary bid ⫻ 1 Month Daily for 10 minutes, shower off; ⫻ 7 days

Average wholesale price, 2000 Drug Topics Red Book.

Pregnancy category

Costa

C

$6

B C

$8 (16-g Tube) $13 (120 ml)

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VIRAL INFECTIONS Warts Nodules may be verrucous or flat, generally painless, caused by HPV Treatment: may resolve spontaneously Over-the-counter (OTC) salicylic acid topically Destruction by liquid nitrogen, laser, cautery Molluscum contagiosum Small flesh-colored or red papules with umbilication Contagious Treatment: may resolve spontaneously Topical treatment with imiquimod Mechanical removal Herpes simplex Usually recurrent vesicles or ulcerations on lips, face, genitals, or buttocks Treatment: Table 8 Varicella zoster Chickenpox possibly followed by shingles in later age or in immune compromised host Treatment: Table 9

Individuals without clinical evidence of warts show an active immune reaction and cytotoxic response against HPV that prevent its expression. Although individuals with clinical warts initially do not show much response to HPV-infected cells, almost all children and a majority of adults with warts eventually mount a successful immune reaction if followed over several years. Clinically, this is represented by a spontaneous and fairly rapid disappearance of lesions. 4.1.1

Common Wart (Verruca Vulgaris)

One or multiple warty papules may be present anywhere but are most frequent on the hands, around the fingers, and on the extensor extremities. Some lesions may have multiple black-tipped finger-like projections. 4.1.2

Flat Warts

Flat warts are characterized by small, red-brown, 1- to 3-mm nonscaling papules that are usually found in clusters. They are common on the face, especially in the beard area; on the backs of the hands; and on the legs. Shaving with a metal razor causes spreading and should be avoided. Acceptable alternatives to a razor blade include an electric razor (which does not shave as closely) and chemical depilatories. The warts can be treated with a light application of liquid nitrogen; however, possible permanent hyper- or hypopigmentation may occur. Approved for use in genital warts, topical imiquimod (Aldara) can be useful for widespread infections; however, the cost may be prohibitive. 4.1.3

Plantar Warts

Often it is difficult to determine whether a keratotic lesion on the sole of the foot is a wart or a corn or callus. This is usually best resolved by paring the top of the lesion. A wart has small black dots representing virally altered blood vessels, whereas a corn has

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a single glassy kernel-like center. It is important to make this distinction because a corn cannot be removed by destructive methods. Plantar warts are often painful as a result of the thick overlying callus. Paring or sanding away this material may be sufficient to provide relief and the patient can be instructed to repeat this as needed for comfort. Treatment is not always necessary, particularly if the lesions are asymptomatic. Reassurance alone is often appropriate, particularly in children. Multiple treatments, all of which have significant limitations, are available (discussed later). OTC salicylic acid should be tried as a first-line agent. Destruction by nitrogen, cautery, or laser is painful, creates open wounds, and may leave permanent pigmentation changes or scars. 4.1.4

Therapy of Warts

Liquid Nitrogen. Apply with a cotton applicator or spray gun until the entire lesion turns white and remains white for 20 to 60 seconds, allow to thaw, and then repeat. Multiple freeze/thaw cycles are superior to one. Blistering is to be expected. Risks include permanent pigmentation changes as well as scarring. Treatments should be repeated every 2 to 4 weeks as necessary. The 3-month cure rate is 40%–80%. Salicylic Acid. Salicylic acid is available OTC as a paint-on liquid or as patches in strengths from 17% to 40%. The stronger concentrations should be used with occlusion for plantar warts. The cure rate is 30%–70%. Cautery. After achieving local anesthesia, the wart can be removed with a curette and the base cauterized. This has a cure rate of about 70% for a single treatment and leaves a permanent scar. Laser. The carbon dioxide laser is often used as a treatment of last resort. This causes a significant thermal injury and wounds are quite slow in healing. Risks include significant pain during recovery and a permanent scar. The cure rate is about 80%. The pulse dye or vascular laser may also be used. It is fairly painful and usually causes blistering but rarely causes scarring or pigment changes. It is most practical for treating multiple lesions on the hands. Cimetidine. There are several anecdotal reports of oral cimetidine at doses of 20– 40 mg/kg for 3 to 4 months. It is theorized that this medication works by stimulating host immune responses. Placebo-controlled studies, however, have shown no statistically significant benefit. Imiquimod (Aldara). Imiquimod topical cream is approved for the treatment of genital warts with a cure rate of about 65% at 4 months. It is an immune-response modifier, which up-regulates host recognition and destruction of HPV infected cells. There are anecdotal reports of benefit in flat warts and some common warts. It is applied three times a week for 3 to 4 months. It does not penetrate keratin, so thick warts need to be pared or pretreated with salicylic acid and the medication applied under occlusion. The cost is about $100/month. 4.2

Molluscum Contagiosum

Molluscum contagiosum is a flesh- to red-colored papule with a characteristic central depression or ‘‘dell’’ in some but not all papules. It is caused by the molluscum contagiosum virus, a deoxyribonucleic acid (DNA) virus of the Poxviridae family. Young children are most frequently affected; although lesions may occur anywhere on the body, they are most common on the head and face. Children with atopic dermatitis appear to be particularly prone, often with more widespread and longer-lasting lesions. As

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the name suggests, they are contagious and are readily spread to siblings and other children. Occasionally a lesion becomes severely inflamed, presenting as a red, painful, large (up to 1 cm) and sometimes purulent nodule. Genital and perianal lesions may be present in children and frequently represent autoinoculation; however, sexual abuse should be considered. In children, routine treatment is generally discouraged since the natural history is that most infections spontaneously clear in 6 to 9 months. Indications for treatment are pain, inflammation, rapid spreading of lesions, or secondary infection. Studies suggest that topical Aldara applied three times a week may clear 80% of infections in 2–3 months. Lesions can also be treated by curettage, light electrocautery, or liquid nitrogen; however, these therapies carry a small risk of permanent pigmentation changes or scarring. Also, destructive procedures may be traumatic for small children as they often require the use of physical restraint. Molluscum contagiosum in adults is almost always sexually transmitted with lesions primarily seen on the genitalia, pubis, abdomen, and thighs. The latent period from acquisition of the virus to the appearance of clinical lesions is around 30 days. In adults, treatment is recommended, and often several office visits are necessary to eradicate all lesions. Liquid nitrogen is generally the treatment of choice. Partners need to be treated to prevent reinfection. Evaluation for other sexually transmitted diseases should be considered. In contrast to that in children, molluscum on the face of an adult is highly unusual and HIV infection should be strongly suspected. Effective antiretroviral therapy is the only successful treatment for HIV-related molluscum. 4.3

Herpes Family Infections

The Herpesviridae is a family of large DNA viruses that include Herpes simplex virus types 1 and 2 (HSV), varicella zoster virus (VZV), cytomegalovirus, Epstein-Barr virus, human herpes 6, 7, and 8 viruses, and simian B virus. The major causes of cutaneous infections in adults are HSV and VZV. These latter infections are characterized by a severe primary infection (primary mucocutaneous lesions or chickenpox, respectively), followed by a clinically silent latency and then episodic recurrence in the form of less severe infections (orolabial or genital ulceration or zoster, respectively). Humans are the only reservoir for HSV and VZV. 4.3.1

Herpes Simplex Virus

There are two types of herpes simplex viruses. HSV-1 predominately affects the oral cavity; HSV-2 affects the genitals. There is wide overlap of anatomical location, and patients may have HSV-1 genital ulcerations and/or HSV-2 oral lesions. Ninety percent of adults are infected with HSV-1 by the age of 50 years. Recurrent herpes infection affects up to 40% of the U.S. population. HSV is spread by direct contact from individual to individual. See also Chapters 11, 16, and 17. Primary or first-episode herpetic gingivostomatitis is a severe orofacial infection characterized by erosions and crusting of the lips, tongue, buccal mucosa, nasal mucosa, hard and soft palate, and/or pharynx. Fever, pain, and cervical lymphadenopathy are common. Resolution generally occurs within 7–14 days. Recurrent oral lesions are characterized by grouped painful vesicles that readily rupture, leaving small ulcerations. These generally occur on the vermilion border of the lips. The recurrence is never as severe as the primary infection and, unless the patient is immunosuppressed, does not involve the tongue, buccal mucosa, or pharynx. Recurrent ulcers in these locations are most likely aphthous ulcers and should not be treated with antiviral

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therapy. The number of recurrences ranges widely but generally decreases in frequency over time. Recurrent cutaneous infections may occur at any site and are most common on the cheeks, neck, buttocks, and thighs. Most cases of presumed recurrent herpes zoster are actually recurrent cutaneous HSV infections. Excessive sun exposure, illness, immunosuppression, and stress are often associated with occurrences. Clinically, one commonly sees a thick serum crust, resembling impetigo. Under the crust are multiple coalescent 1to 2-mm punched-out ulcerations. Only rarely are the initial small tense vesicles seen. An underlying herpes infection should always be considered in all cases of ‘‘impetigo.’’ It is important to recognize that patients may shed HSV during an asymptomatic recurrence. In these occurrences, ulcers or vesicles are not present but the patient is still potentially contagious. Recurrences in immune compromised hosts, such as people with HIV or recipients of organ transplantation, may be more frequent and severe. Transmission to any mucosal surface or abraded cutaneous surface can occur either between people or as autoinoculation. An example of this is herpetic whitlow, an HSV-1 or -2 infection of the finger due to direct contact of the patient with active HSV lesions or secretions in the case of health care workers. Whitlow is manifested as pain and swelling associated with a purulent or vesicular lesion generally of the finger tip. Fever and regional lymphadenopathy may be present. It may be difficult to differentiate from a bacterial infection such as a paronychia, cellulitis, or abscess. Eczema herpeticum is a form of widespread cutaneous HSV infection that occurs in individuals with atopic dermatitis and clinically somewhat resembles chickenpox. Hundreds of crusted papules and erosions may be seen on the face, torso, and extremities, sometimes coalescing into large plaques. It is usually painful (in contrast to the usual itch of atopic dermatitis) and individuals may be febrile. The diagnosis of HSV infection is generally based on the clinical appearance of the eruption. Antibody detection is not helpful because of the common occurrence of positive serological results. Confirmation of a herpes infection and typing (HSV-1 vs. HSV-2) can be accomplished as outlined later. Detection of HSV and VZV requires the collection of cells from the base of lesions. Several skin lesions should be scraped with a number 15 scalpel blade or a Papanicolaou smear spatula. This scraping should be fairly firm; collecting blister fluid or wiping a culturette swab over skin lesions is insufficient. Cells can be sent for cytological examination (Tzanck test smear). HSV- or VZVinfected cells appear as distinctive multinucleated giant cells, and this finding is reported as a positive viral change. A Tzanck test preparation can be obtained rapidly and has a sensitivity of about 70%. Viral culture is needed to distinguish the type of infection (VZV, HSV-1, or HSV2). For culture, cells must to be sent in viral transport media (obtain from your local lab and keep refrigerated). HSV grows in 2–7 days, whereas VZV often takes 7–14 days. With optimal collection and handling, the sensitivity is about 90%. In some areas (check with your local lab), detection by direct fluorescent antibody test (DFA) can be performed with rapid results. Treatment of both primary and recurrent infections is usually accomplished orally (see Table 8). Occasionally, intravenous therapy may be required for a severe primary infection that is not responding to oral treatment. Topical medications, though less effective than oral agents, can reduce the duration of symptomatic outbreaks. Systemic therapy with intravenous acycolvir (5 mg/kg q8h) is indicated for eczema herpeticum and in severe outbreaks in the immune compromised host.

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Table 8 Treatment of Cutaneous Herpes Simplex Virus Infections Agent

Dose

Penciclovir ointment (Denavir) Acyclovir

Apply q2h while awake 200 mg 5/d ⫻ 5 days

Pregnancy category

Costa

B B

$23 (1.5-g Tube) $25

or 400 mg tid ⫻ 5 days

$30

or Valacyclovir (Valtrex) Famciclovir (Famvir)

800 mg bid ⫻ 5 days 500–1000 mg bid ⫻ 3 days 250–500 mg bid ⫻ 5 days

B B

$38 $33–$44 $35–$70

a

Average wholesale price, 2000 Drug Topics Red Book.

Frequent relapses can be suppressed by chronic use of acyclovir (400 mg bid), valacyclovir (500 mg/day), or famciclovir (250 mg/day). Occasionally higher doses are necessary. 4.4 4.4.1

Varicella Zoster Virus Infections Chickenpox

Chickenpox or primary varicella infection is acquired through respiratory particles primarily in the winter and spring. The incubation period is 10–23 days. A person is infectious from 1 day before the rash appears until all lesions have crusted (approximately 7– 10 days). A child may not attend school or day care until all lesions have crusted. A prodrome of fever and sore throat may precede the appearance of pink macules, which tend to be more dense on the torso and scalp than on the face and extremities. Within 24 hours, small tense clear vesicles appear and resemble ‘‘dew drops on rose petals.’’ The vesicles quickly become cloudy and then crust. New crops of lesions appear for several days so that the three variations of lesions (vesicles, pustules, and crusting) are seen simultaneously. Prior to the release of the OKA varicella vaccine, 90% of cases were seen in children less than 10 years old. The vaccine is recommended by the American Academy of Pediatrics for all children and can be given at 1 year of age. Antiviral therapy (discussed later) of mild, uncomplicated infections is not indicated; however, therapy should be used for severe cases and for immunocompromised patients. Attention should be given to frequent skin cleansing to prevent secondary staphylococcal infection. If a bacterial infection is suspected, oral antibiotics should be promptly initiated. 4.4.2

Zoster (Shingles)

VZV is neurotropic. In most individuals, after a primary infection, the virus enters a dormant state in the dorsal root ganglia of the cranial, cervical, thoracic, or lumbrosacral spinal nerves. Zoster or shingles is the reemergence of active virus from these sites, causing pain along the sensory nerve and cutaneous lesions in the nerve’s dermatome. The lesions are chickenpox-like vesicles and pustules that then crust over. Complications of facial infection include deafness, tinnitus, vertigo, or facial palsy (Ramsey Hunt syndrome), pharyngeal and/or laryngeal lesions. Ophthalmic zoster is a medical emergency because of VZV involvement of the first branch of the fifth cranial nerve characterized by keratitis, conjunctival lesions, or uveitis (characteristic large dendritic cells seen on slit lamp examination). A clue to the presence of keratitis is the presence

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Table 9 Treatment for Varicella Infections Agent Acyclovir Valacyclovir (Valtrex) Famciclovir (Famvir)

Dose 800 mg PO 5 times/day ⫻ 7 days 10 mg/kg IV q8h 1 g tid ⫻ 7 days 500 mg tid ⫻ 7 days

Pregnancy category

Costa

B

$45

B B

$92 $164

a

Average wholesale price, 2000 Drug Topics Red Book.

of lesions on the tip of the nose, indicating involvement of the first branch of the fifth nerve. Immediate ophthalmological evaluation is indicated when there is any suspicion of ophthalmic involvement. Treatment (see Table 9) initiated within 72 hours of the start of the cutaneous lesions decreases pain, the number of lesions, and time to healing. However, other than analgesics and good local care, an uncomplicated infection in an individual below age 50 does not necessarily require treatment. In contrast, after the age of 50, there is evidence that treatment may decrease the risk of postherpetic neuralgia. In the very old or immunocompromised patient, early systemic therapy is indicated to reduce the risk of disseminated infection. For pain during acute zoster, oral analgesics can be used. Topical lidocaine gel may also be effective. Topical capsacin (Zostrix) should be avoided if the skin is not intact. Pain after zoster is common and the risk increases with age. For most individuals below age 60, pain has resolved by 6 months. However, of those older than age 60, a significant number experience pain lasting over 1 year. There is evidence that, in addition to antiviral therapy, prophylactic treatment of high-risk patients (elderly, severe infections) with a lowdose tricyclic antidepressant may be effective in decreasing the incidence of postherpetic neuralgia. Amitriptyline or desipramine 10–25 mg at bedtime for 1–3 months is recommended. Several studies have investigated whether a short course of oral steroids during acute zoster is helpful in decreasing subsequent pain, unfortunately with contradictory results. For pain remaining when the skin lesions have cleared, topical lidocaine or capsacin (Zostrix) may be tried. First-line treatment for established postherpetic neuralgia is usually tricyclic antidepressants (increase dose every 5–7 days till effective or maximal dose is obtained) or neurontin (300–3600 mg/day). Other possibilities include anticonvulsants and referral for neural blockade. BIBLIOGRAPHY Allen AL, Siegfried EC. What’s new in human papillomavirus infection. Curr Opin Pediatr 2000 Aug; 12(4):365–369. Benton EC. Therapy of cutaneous warts. Clin Dermatol 15:449–455, 1997. Chosidow O. Scabies and pediculosis. Lancet 355:819–826, 2000. Goldstein AO, Smith KM, Ives TJ, Goldstein B. Mycotic infections. Geriatrics 55:40–52, 2000. Hengge UR, Esser S, Schultewolter T, Behrendt C, Meyer T, Stockfleth E, Goos M. Self-administered topical 5% imiquimod for the treatment of common warts and molluscum contagiosum. Br J Dermatol 2000 Nov; 143(5):1026–1031. Johnson R. Herpes zoster—predicting and minimizing the impact of post-herpetic neuralgia. J Antimicrob Chemother 2001 Feb; 47 Suppl T1:1–8. Wood AJJ. Post-herpetic neuralgia. N Engl J Med 335:32–42, 1996. 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics.

21 Ocular Infections Martin Mayers Bronx Lebanon Hospital Center and Albert Einstein College of Medicine, Bronx, New York, U.S.A.

Essene Bell Bronx Lebanon Hospital Center, Bronx, New York, U.S.A.

Michael H. Miller Albany Medical College, Albany, New York, U.S.A.

1

INTRODUCTION

Differentiating infectious from noninfectious causes of eye disease is a challenging yet crucial task for primary care providers. Regardless of whether the cause of the ocular disease is infectious or noninfectious, patients with diseases of the anterior segment of the eye and adnexae often experience a ‘‘red eye’’ and varying degrees and qualities of ocular discomfort. Diseases limited to the posterior segment of the eye (e.g., vitreous, retina, and choroid) generally do not cause redness or discomfort but do cause visual disturbances and rarely pain. The goal of this chapter is to help the primary care provider identify those situations that can be appropriately treated without referral and those requiring prompt care by an ophthalmologist (see Table 1). A diagram of the eye is provided to assist the primary care provider with the language of ophthalmological infections (see Figure 1).

2

APPROACH TO THE PATIENT WITH ‘‘RED EYE’’

Although most patients with a ‘‘red eye’’ do not have a vision-threatening problem, a red eye may be a warning sign of potential visual loss secondary to acute glaucoma, uveitis, scleritis, or keratitis. All patients with ocular complaints should have their visual acuity measured, a close examination of the external eye with a penlight, instillation of fluorescein into the tear film to look for abnormalities in the corneal epithelium, and measurement of intraocular pressure. An overview of the differential diagnosis of the red eye is presented in Table 2. Differentiating the pattern of inflammation is critical in determining the cause of a ‘‘red eye.’’ The eye becomes noticeably red or injected when the superficial blood vessels of the conjunctiva, episclera, or sclera become dilated in response to vasoactive mediators. The primary site of the inflammation may be either these tissues or an adjacent site such as eyelid, cornea, iris, or ciliary body. 409

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Table 1 Patients with ‘‘Red Eye’’ Requiring Immediate Referral to an Ophthalmologist Symptoms, signs, or risks Visual acuity decreased to less than 20/25 Pain Photophobia Contact lens use Recent eye surgery Pupil middilated or nonresponsive Hyperpurulent conjunctivitis Circumlimbal injection Corneal opacity Corneal edema Hypopyon Elevated intraocular pressure

Comment Suggestive of uveitis or angle closure glaucoma Conjunctivitis potentially uncomfortable, not painful Symptom of keratitis or anterior uveitis Risk of severe keratitis (e.g., Pseudomonas, Acanthamoeba spp.) Risk of postoperative endophthalmitis Concern for acute glaucoma or anterior uveitis; measure intraocular pressure Possibility of gonorrheal conjunctivitis Sign of keratitis or anterior uveitis Sign of corneal infection Sign of angle closure glaucoma Sign of uveitis and endophthalmitis ‘‘Normal’’ ⱕ21 mm Hg

Diffuse hyperemia with relatively less redness in the perilimbal area (the conjunctiva adjacent to the cornea) is the typical pattern of inflammation in common bacterial and viral conjunctivitis (see Figure 2). Ciliary flush refers to primarily circumlimbal (surrounding the cornea) hyperemia and is suggestive of corneal inflammation or iridocyclitis (anterior uveitis or iritis) (see Figure 3). Focal or sectoral hyperemia is localized injection that can be seen in episcleritis (inflammation of the connective tissue between the sclera and conjunctiva) and scleritis. Inflammation of a pterygium (a triangular patch of fibrovascular tissue often found extending from the inner canthus onto the cornea) or a pinguecula (connective tissue thickening of the conjunctiva appearing as a yellowish spot on either side of the cornea) can also cause a focal hyperemia. Unilateral hyperemia that lasts more than 2 days suggests that the disease process is not conjunctivitis. Although conjunctivitis may be asymmetrical, a unilateral inflamed eye should be promptly referred to an ophthalmologist. 3

CONJUNCTIVITIS

Conjunctivitis refers to inflammation of the moist, translucent mucous membrane that covers the sclera (bulbar conjunctiva), the undersurface of the eyelids (palpebral conjunctiva), and the interconnecting forniceal conjunctiva (see Figure 4). It is classified on the basis of cause (infectious, allergic, toxic, or tear insufficiency). Infectious conjunctivitis is commonly called ‘‘pink eye’’; the term has been variously associated with S. pneumoniae in temperate climates, H. aegyptius in hot climates, and viral conjunctivitis (adenoviral) on the Internet. Bulbar conjunctival injection, varying degrees of bulbar and forniceal conjunctival edema (chemosis), and a papillary reaction on the tarsal conjunctivae are general findings in conjunctivitis. Papillae are composed of a tiny central fibrovascular core of vessels that vasodilate in response to inflammatory chemical mediators. Eversion of the lids to inspect for a papillary response is requisite to making the diagnosis of conjunctivitis. On slit lamp examination papillae appear as fine elevated nodular areas of inflammation. Although papillae are a nonspecific sign of conjunctival inflammation their

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Figure 1 Anatomical characteristics of the normal eye: (A) external anatomical characteristics; (B) cross section of the eye illustrating the anterior and posterior sections of the globe.

absence on the tarsal, especially upper tarsal, conjunctiva precludes a diagnosis of conjunctivitis. Examination of a normal upper lid tarsal conjunctiva reveals distinct blood vessels running perpendicular to the lid margin. Obscuration of these blood vessels by hyperemia and papillae is the basis of a grading scale.

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‘‘RED EYE’’ Most often benign but may represent sight-threatening infection When to refer to an ophthalmologist (Table 1) Differential diagnosis (Table 2) Examination Close examination of external eye Visual acuity Intraocular pressure Fluorescein test of cornea Bacterial and viral conjunctivitis with diffuse hyperemia Circumlimbal hyperemia suggestive of iridocyclitis Unilateral hyperemia lasting >2 days not suggestive of viral conjunctivitis but should prompt ophthalmological consultation

P1: distinct outline of blood vessels (see Figure 5) P2: blood vessels that appear partially obscured (see Figure 6) P3: blood vessels obscured by overlying hyperemia and papillae Giant papillae (>1 mm) give the tarsal conjunctiva a cobblestone appearance and are suggestive of allergic mechanisms (vernal conjunctivitis or contact lens–related giant papillary conjunctivitis [GPC]).

Table 2 Differential Diagnosis of ‘‘Red Eye’’a Conjunctivitis Conjunctival erythema Discharge Chemosis Decreased vision Pain Photophobia Corneal opacity/ulcer Ocular pressure Pupillary reaction Hypopyon a

⫹⫹⫹c

Blepharitisb

Keratitis

⫹⫹ to ⫹⫹⫹e ⫹⫹⫹ ⫺ ⫹/⫺ ⫹/⫺ ⫺ N N

⫹⫹ (eyelid margin) ⫹ ⫹⫹ ⫺ ⫹/⫺ ⫹ ⫺a N N

⫹⫹d ⫹ to ⫹/⫺ ⫹ to ⫹ to ⫹ to ⫹ to N N

⫺

⫺

⫺ to ⫹⫹

⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹

Anterior uveitis

Acute angle glaucoma

⫹⫹d

⫹ to ⫹⫹d

⫺ ⫺ ⫹⫹ ⫹ to ⫹⫹⫹ ⫹⫹⫹ ⫺ N Miotic, sluggish ⫺ to ⫹⫹

⫺ ⫺ ⫹⫹ ⫹ to ⫹⫹⫹ ⫹⫹ ⫺ ⇑ Middilated ⫺

Symptoms may occur concurrently, such as blepharoconjunctivitis, keratoconjunctivitis, or blepharokeratoconjunctivitis. ⫹, mild; ⫹⫹, moderate; ⫹⫹⫹, severe; ⫺, not present; N, normal. b May be associated with recurrent or chronic chalazia or styes. c Diffuse hyperemia. d Circumlimbal hyperemia. e Bacterial is generally purulent, viral generally watery.

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Figure 2 Diffuse bulbar conjunctival hyperemia with less inflammation near the limbus, suggestive of conjunctivitis.

Follicles are small lymphocytic aggregates that appear clinically as pale, round-oval elevated structures. Presence of a few follicles in the fornix is of little clinical importance. Finding numerous follicles on the bulbar or palpebral conjunctiva is clinically significant as they are not found in routine bacterial conjunctivitis. Follicular conjunctivitis is a sign of viral infection (adenovirus, Herpes simplex, and Molluscum contagiosum), chlamydial infection, Lyme disease, and occasionally Moraxella conjunctivitis (see Figure 7). The distinct properties of membranous layers that form in some patients with conjunctivitis help to differentiate among causes. ‘‘True’’ membranes are more adherent and when removed cause extensive bleeding; they may form in conjunctivitis caused by Corynebacterium diphtheriae, Neisseria gonorrhoeae, and S. pyogenes or be associated with Stevens-Johnson syndrome. A pseudomembrane is a less adherent inflammatory co-

Figure 3 Circumlimbal injection with less inflammation distal to limbus, suggestive of iritis or keratitis. Not the pattern of inflammation seen in conjunctivitis.

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CONJUNCTIVITIS Differential diagnosis (Table 2) Bulbar conjunctiva injection Papillary reaction of tarsal (especially upper tarsal) conjunctiva (Figure 4) Grading system based on extent of obscuration of upper plate conjunctiva (Figures 5 and 6) Follicular conjunctivitis suggestive of viral, Chlamydia sp., Lyme disease, or Moraxella sp. (Figure 7) May have concomitant keratoconjunctivitis or blepharokeratoconjunctivitis Viral Unilateral to bilateral in 2–10 days Commonly caused by adenovirus Epidemic keratoconjunctivitis Pharyngoconjunctival fever Also enterovirus, herpes simplex virus (HSV), and influenza virus Treatment Topical lubricants Steroids used cautiously (Table 3) Bacterial Unilateral to bilateral in 24 hours Hyperacute: N. gonorrhoeae, N. meningitidis, Streptococcus spp., Staphylococcus spp. Acute to subacute: Streptococcus spp., Staphylococcus spp., H. influenzae Chronic: Staphylococcus spp., S. pneumoniae, Moraxella spp. Topical therapy (Table 4)

agulum and bleeds less than a true membrane when removed. Pseudomembranes may occur with severe viral or bacterial conjunctivitis and alkali burns. Many of the pathogens that cause conjunctivitis may also cause simultaneous infection in the cornea (keratoconjunctivitis), eyelid (blepharoconjunctivitis), or all three areas (blepharokeratoconjunctivitis). In addition, conjunctivitis may be acute or chronic and be predominantly follicular or papillary in nature. 3.1 3.1.1

Viral Conjunctivitis Symptoms and Signs

Patients who have viral conjunctivitis experience acute onset of redness, tearing, or light mucoid discharge, irritation or foreign body sensation, and mild to moderate light sensitivity. There may be recent or current symptoms of upper respiratory infection (URI) as well as a history of exposure to sick contacts. Viral conjunctivitis typically begins unilaterally with involvement of the contralateral eye within 2 to 10 days. On careful examination, conjunctivitis shows a follicular response. The bulbar conjunctiva shows hyperemia, varying degrees of chemosis, and petechial or subconjunctival hemorrhages. Pseudomembranes may occur on the forniceal or tarsal conjunctival surfaces. Superficial keratitis can be the cause of decreased vision. The eyelids become edematous, and a preauricular lymphadenopathy is to be expected.

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Figure 4 Normal eye with limbus, bulbar conjunctiva, forniceal conjunctiva, and lower tarsal conjunctiva identified.

3.1.2

Cause

Acute follicular conjunctivitis is commonly caused by adenovirus, including such syndromes as epidemic keratoconjunctivitis (EKC) and pharyngoconjunctival fever (PCF). PCF is characterized by conjunctivitis, low-grade fever, pharyngitis, lid edema, and preauricular lymphadenopathy. Other causes of acute follicular conjunctivitis include acute hemorrhagic conjunctivitis caused by enterovirus 70, coxsackievirus, and primary herpes simplex virus (HSV). Influenza virus infection is associated with a watery conjunctivitis in 40%–60% of patients that accompanies the usual symptoms of cough, fever, and myalgia. Other less common viral causes of conjunctivitis include varicella zoster virus (VZV or chickenpox), human papillomavirus (warts), measles and mumps viruses, and Newcastle’s disease due to paramyxovirus. 3.1.3

Course and Management

Viral conjunctivitis is generally a self-limited illness of 10 days or less. Occasionally patients with adenovirus keratoconjunctivitis may have a foreign body sensation and reduced vision lasting weeks to months. Treatment is supportive with topical lubricants or vasoconstrictors and cold compresses. There is no commercially available ophthalmic antiinfective preparation for treating adenovirus. In EKC, topical corticosteroid use is controversial but may be prescribed

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Figure 5 Normal upper tarsal conjunctiva exposed after eversion of upper eyelid. Easily identifiable blood vessels running perpendicular to lid margin categorize this as a P1 reaction.

Figure 6 Upper tarsal conjunctiva in a patient with bacterial conjunctivitis. The obscuration of blood vessels by the micropapillary hypertrophy categorize this as a P2 reaction.

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Figure 7 Follicular conjunctivitis.

by the ophthalmologist to decrease corneal opacities and pseudomembranes after a definitive diagnosis has been made. Corticosteroids should be used cautiously by patients with conjunctivitis (see Table 3). Although HSV conjunctivitis may be self-limited, it is generally associated with keratitis. Use of topical trifluridine is appropriate. Oral acyclovir, famciclovir, or valacyclovir should decrease the rate of recurrence when taken on a long-term basis. Topical corticosteroid use is contraindicated in patients with herpes simplex keratoconjunctivitis. Viral conjunctivitis is highly contagious, and patients should be instructed to employ strict hygiene, including hand washing, avoidance of sharing of towels and bedding, and absence from school, work, and direct personal contact in general for at least the first 7 days. Spread can also occur in an office or clinic setting so health care workers should take precautions to prevent spread to other patients and themselves. It is important to keep in mind that a viral conjunctivitis–like illness with recent upper respiratory tract infection and conjunctival pseudomembrane formation may also occur with streptococcal infections. 3.2

Bacterial Conjunctivitis

Bacteria infect the conjunctiva from airborne fomites, upper respiratory tract secretions, hand to eye contact, and least commonly contiguous spread from a facial infection. The

Table 3 Caveats Regarding the Use of Corticosteroid-Containing Eyedrops Do not use when the diagnosis is uncertain. Never use if herpes simplex virus is in the differential diagnosis until ruled out. Do not use if corneal ulceration is present. They can cause open angle glaucoma in patients at risk. They can cause posterior subcapsular cataracts if used for extended periods. By suppressing the immune response, they increase the risk for infection.

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onset of bacterial conjunctivitis can be classified as hyperacute (onset 3–4 weeks). 3.2.1

Signs and Symptoms

Symptoms usually begin unilaterally and become bilateral within 24 to 48 hours. Severity of symptoms, inflammation, and discharge vary with pathogen and host. Patients generally complain of irritation, tearing, redness, and mucopurulent or purulent discharge. Vision should not be significantly affected. Hyperacute conjunctivitis presents with abrupt onset of profuse purulent discharge, lid edema, chemosis, subconjunctival hemorrhages, and preauricular lymphadenopathy. If there is an associated keratitis, progression of corneal ulceration can lead to corneal perforation in 30 days) usually have illnesses of lower toxicity and are less likely to be infectious. Protozoan infections, including Giardia lamblia infections, are common causes of persistent and chronic diarrhea (see Table 2 for a comprehensive list of causes). A broad range of pathogens cause chronic diarrhea in immunocompromised patients with AIDS (discussed later). Evaluation of the patient includes a detailed history of the symptoms of the diarrheal illness, to help determine the severity of clinical illness and possible microbial causes. Patients should be asked about the onset and duration of diarrhea and associated fever, cramps, tenesmus, or vomiting. Additional important clinical clues to the diagnosis of diarrhea include a food and water intake history, timing of symptoms (duration and onset), season, geographical location, medications, sexual practices, and history of chronic illnesses and hospitalizations (see Table 3). Physical examination of the patient with diarrhea is often nonspecific. Careful evaluation of the vital signs, including orthostatic blood pressure and heart rate, yields important clues to the degree of dehydration. Skin tenting and mucous membrane dryness may not be reliable indicators of dehydration in an adult. In the elderly, lethargy is often a manifestation of severe dehydration. Fever and tachycardia may indicate systemic infection. Abdominal tenderness on examination is often found with inflammatory colitis. Most diarrheal illnesses can be organized into syndromes, classified by common symptoms, frequency and volume of stools, and infectious causes (see Table 4). This approach often helps guide diagnostic tests and management.

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Figure 1 Approach to the patient with diarrhea. Patients should be assessed for degree of toxicity and dehydration. Risk factors and epidemiological clues should be gathered from the history and physical examination. Most patients with acute diarrhea do not need laboratory work-up or antibiotic therapy. Patients with systemic toxicity or inflammatory diarrhea should be rapidly evaluated with fecal leukocytes and stool cultures. Empirical therapy may be begun, though caution is suggested since some pathogens (e.g., Escherichia coli 0157:H7) should not be treated with antibiotics. (1) Fecal leukocytes can be identified by direct stain of the stool or by demonstration of lactoferrin. (2) Ova and parasites should be added if risk for exposure to Giardia spp., homosexual sex, or international travel. (3) Stool should be sent for C. difficile toxin assay for those who are currently on or recently received antibiotics. O&P, ova and parasite; ELISA, enzyme-linked immunosorbent assay.

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Table 2 Causes of Chronic Diarrhea Infectious or presumed infectious Protozoa (e.g., Cryptosporidium, Giardia spp.) ‘‘Bacterial overgrowth’’ syndrome Tropical sprue Whipple’s disease Intestinal tuberculosis Noninfectious Noninflammatory Laxatives, alcohol Antibiotics Celiac sprue Partial bowel obstruction or resection Hormone-producing tumors (e.g., carcinoid, gastrinoma, medullary carcinoma of the thyroid) Addison’s disease Lactase deficiency Irritable bowel syndrome Pancreatic exocrine deficiency Food allergies Inflammatory Inflammatory bowel disease Collogenous colitis Eosinophilic gastroenteritis Radiation enterocolitis Chronic graft-versus-host disease Behc¸et’s syndrome

5.2

Diagnostic Testing

A specific microbial diagnosis and tailored antimicrobial therapy are the goal of the diagnostic work-up for diarrhea (see Table 5). This is increasingly important in light of increasing bacterial antibiotic resistance (particularly in Salmonella, Shigella, and Campylobacter spp.), the risks of empirical therapy [i.e., hemolytic-uremic syndrome after antibiotics are given for E. coli 0.157:H7, prolongation of the Salmonella spp. carrier state and suprainfections after antibiotic use (C. difficile colitis, Candida spp. vaginitis)]. With these principles in mind, however, diagnostic tests are not always indicated, useful (e.g., viral pathogens), or cost-effective. Clinical evaluation and examination of the patient also determine when empirical therapy is necessary before diagnostic test results are available (see later discussion). Routine stool cultures, using a variety of agars, are designed to detect Salmonella, Shigella, Campylobacter, and Yersinia spp. and E. coli 0157:H7. Vibrio spp. can be detected when stool is plated onto specific (thiosulfate-citrate-bile salts [TCBS]) media. When stool cultures are indiscriminately ordered for patients with diarrhea, however, the yield of these cultures is very low (2 weeks); exposure to infants or day care; potential exposure to a water-borne outbreak, including shallow home wells; international travelers; and homosexual men. Ova and parasite (O&P) exams are useful in the identification of helminth eggs, G. lamblia, and Entamoeba histolytica (amebiasis), but not of other protozoan pathogens such as Cryptosporidium or Cyclospora spp. or Isospora belli. In the United States, the most common pathogen detected on O&P examination is G. lamblia. A downfall of the inappropriate use of ova and parasite examinations is the confusion caused by the identification of a wide variety of protozoa that are believed to be nonpathogenic (e.g., Blastocystis hominis and Entamoeba coli). Commercially available diagnostic techniques such as enzyme immunoassays may be more sensitive than microbial studies and are available for the evaluation of Cryptosporidium spp., G. lamblia, and E. histolytica. Viral cultures are rarely indicated in the assessment of infectious diarrhea. If diarrhea is of public health importance (i.e., the initial case in a potential outbreak), a microbial cause should always be sought and the health department notified.

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Table 4 Infectious Diarrhea Syndromes Syndrome

Common symptoms

Location

Select microbial causesa Many noninflammatory enteric pathogens, including viruses, Giardia spp., and ETEC Shigella, Campylobacter, Salmonella spp.; E. coli 0157:H7; EIEC; E. histolytica; C. difficile

Acute watery diarrhea

Large-volume stools Abdominal cramps

Small intestine

Colitis, dysentery

Frequent small-volume stools Tenesmus Blood and mucus in stools Fever, cramps Same as colitis

Colon

Proctitis

Persistent (>14 days) and chronic (>4 weeks) diarrhea

Gastroenteritis (in foodborne disease) a

Variable, usually watery diarrhea May have signs of weight loss Vitamin deficiency Vomiting, nausea Watery diarrhea

Rectum

Small intestine and/or colon

Stomach, small intestine

N. gonorrhoeae, herpesviruses, Chlamydia trachomatis, syphilis Protozoa (Cryptosporidium, Cyclospora, Isospora, Microsporidium spp.), EPEC Preformed toxins of S. aureus, B. cereus, and viral pathogens

ETEC, enterotoxigenic E. coli; E. coli 0157:H7, enterohemorrhagic E. coli; EPEC, enteropathogenic E. coli; EIEC, enteroinvasive E. coli.

Table 5 Diagnostic Tests Pathogen/marker

Diagnostic testa

Salmonella spp. Shigella spp. Campylobacter spp. E. coli 0157:H7

Routine stool cultures, including special media for Campylobacter spp. (at 42 C), E. coli 0157:H7

Vibrio cholerae Yersinia species C. difficile

Stool culture for Vibrio spp. (TCBS agar) Stool culture with cold enrichment C. difficile toxin assay or culture

Cryptosporidium parvum Cyclospora species Isospora belli

Acid-fast stain (Kinyoun) of stool

Giardia lamblia Cryptosporidium parvum

Stool antigen assay (may be offered together or as separate tests)

Giardia lamblia Entamoeba histolytica

Ova and parasites

Fecal leukocytes Fecal blood

Lactoferrin test, stool stained for WBC Guaiac testing of stool

a

TCBS, thiosulfate-citrate-bile salts; ELISA, enzyme linked immunosorbent assay; WBC, white blood cells.

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MANAGEMENT

6.1

Rehydration

The cornerstones of therapy are the restoration and maintenance of adequate hydration. This is particularly important in the elderly or immunocompromised patient. In otherwise healthy patients with mild to moderate diarrhea, increasing intake of most fluids is usually adequate to replace fluid losses. In moderate to severe diarrhea, juices and sports drinks may not adequately replace electrolyte losses. For dehydrating diarrhea, aggressive rehydration with electrolyte solutions or intravenous fluids is required. The formulation of ‘‘oral rehydration solutions’’ as determined by the World Health Organization (WHO) includes the addition of sodium, potassium, chloride, citrate, and glucose to meet fluid and electrolyte needs. Home recipes, which approximate WHO recommendations, are listed in Table 6. Use of these solutions may help preclude the need for intravenous fluid administration. 6.2

Antimotility Agents

Antimotility drugs, such as loperamide (Imodium), can be used safely for symptomatic relief in most cases of acute diarrhea. The number of diarrheal stools is reduced by 80% with this agent. Lomotil (diphenoxylate hydrochloride; atropine sulfate) should be avoided because of the central opiate effect, risk of overdosage, and anticholinergic effects of the atropine, including urinary retention, mucosal and cutaneous dryness, tachycardia, and hyperthermia. All antimotility drugs should be avoided when there are symptoms of dysentery (fever, cramps, blood and pus in stool). In general, when fever or other systemic signs are present with diarrhea, antimotility drugs should only be used concurrently with appropriate antibiotic therapy. The antisecretory properties of salicylate in bismuth subsalicylate (Pepto-Bismol) can decrease diarrheal stools by 50% and are effective in decreasing symptoms of vomiting due to enteric viral infections. Salicylate overdose and bismuth encephalopathy have occurred after excessive use of bismuth subsalicylate. 6.3

Antibiotic for Specific Pathogens

Specific antimicrobial therapy is used when a pathogen is confirmed and in selected cases of empirical treatment (discussed later). Agents and dosages are listed in Table 7. Diagnosis and treatment of Entamoeba histolytica are reviewed in Chapter 32.

Table 6 Home Recipes for Oral Rehydration Solutions Recipe 1 3/4 teaspoon salt 1 teaspoon baking soda 1 Cup orange juice or two bananas 4 Tablespoons sugar Add to 1 liter of clean water Recipe 2 Mix in one cup

Mix in another cup Drink alternately from the two cups

8 ounces of orange or apple juice 1/2 teaspoon of honey 1 pinch salt 8 ounces clean water 1/4 teaspoon baking soda

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Table 7 Therapya Pathogen

Antimicrobial agent

Special circumstances

Bacterial Nontyphoid Salmonella species

Not recommended routinely

Campylobacter species

Erythromycin 500 mg PO bid ⫻ 5 days for severe disease Co-trimoxazole ds PO bid ⫻ 3 days (if sensitive) Ciprofloxacin 500 mg bid ⫻ 3 days, if resistant

Shigella species

Escherichia coli ETEC

E. coli 0157:H7 Yersinia species

Vibrio cholerae

Clostridium difficile

Ciprofloxacin 1.0 g PO ⫻ 1 or 500 mg PO bid ⫻ 3 days Not recommendedc Antibiotics not required

Doxycyline 300 mg PO ⫻ 1 or Ciprofloxacin 1 g PO ⫻ 1 Metronidazole 500 mg PO tid ⫻ 10–14 days

Ciprofloxacin 500 mg PO bid for 5 days Treat 14 days if patient immunocompromisedb

Treat immunocompromised patient ⫻ 7–10 days

For serious infections or bacteremia: ciprofloxacin IV or PO or Doxycycline with aminoglycoside

For severe infections, vancomycin 125 mg PO qid ⫻ 10–14 days Metronidazole 500 mg IV q8hd ⫻ 10–14 days

Parasitic Cryptosporidium parvum

Giardia lamblia Cyclospora cayentanenis Isospora belli a

No therapy useful Self-limited illness in immunocompetent hosts Metronidazole 250 mg PO tid ⫻ 5–10 days Co-trimoxazole DS bid ⫻ 3 days Co-trimoxazole 2 DS PO bid ⫻ 2–4 wk

Immunocompromised hosts: try paromomycin 500 mg PO tid ⫻ 2–4 wk

ETEC, enterotoxigenic E. coli; E. coli 0157:H7, enterohemorrhagic E. coli; DS, double-strength. See text for recommendations. c Increased risk of hemolytic uremic syndrome. d If unable to take orally. b

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Empirical Therapy

Several practice guidelines including those of the American College of Gastroenterology (1997) and the Infectious Disease Society of America (Guerrant et al., 2001) support the use of empiric antibiotic therapy in the treatment of diarrhea in three specific patient populations: (1) patients with traveler’s diarrhea, (2) suspected giardiasis, and (3) patients with acute inflammatory diarrheas. Traveler’s diarrhea is frequently due to enterotoxigenic E. coli. In acute, moderate, to severe travel-related diarrhea, empirical therapy with a quinolone antibiotic is appropriate, without stool culture (see Table 7). In giardiasis, patients often have watery diarrhea that lasts 10 days to more than 4 weeks but do not have fever or symptoms of dysentery. Empirical therapy with metronidazole may be considered in these patients. Finally, patients with fever and acute inflammatory diarrhea (confirmed by lactoferrin testing) and signs of systemic illness should also be considered for empirical antibiotic therapy, usually with ciprofloxacin 500 mg bid orally, while confirmatory microbiological results are pending. This decision should be carefully made in cases of bloody diarrhea that may be due to E. coli 0157:H7.

7 CLOSTRIDIUM DIFFICILE AND ANTIBIOTIC-ASSOCIATED DIARRHEA Almost all antibiotics can cause diarrhea. The majority of cases are benign and resolve on discontinuation of the antibiotic. The organism best known to cause antibiotic-associated diarrhea (AAD) is Clostridium difficile, the second most frequently isolated enteric pathogen, after Campylobacter jejuni. C. difficile accounts for 10%–20% of cases of AAD and is the most common cause of nosocomial diarrhea. However, most cases of AAD, especially in outpatients, are not due to C. difficile. The cause of non–C. difficile AAD has not been fully elucidated, although both S. aureus and Candida species have been implicated in association with altered metabolism of carbohydrates and fatty acids.

ANTIBIOTIC-ASSOCIATED DIARRHEA Can be caused by any antibiotic Often resolves with discontinuation of antibiotic 10%–20% Due to C. difficile C. difficile–associated diarrhea Increased risk in elderly, immune suppressed, hospitalized, and those undergoing gastrointestinal (GI) surgery Abdominal pain, fever, blood/mucus in stool Leukocytosis Fecal leukocytes possibly present Diagnosis by immunoassay on stool for toxin A and B, endoscopy, or stool culture Therapy (Table 8) Relapse in 20% of patients Associated with Continued antibiotic use Elderly, recent GI surgery, renal failure patients

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C. difficile is a toxin-producing obligate anaerobic gram-positive bacillus. It is not part of the normal adult intestinal flora; only 1%–3% of normal hosts are colonized with C. difficle. C. difficile is able to survive in the environment in a spore form for up to 5 months on a hospital floor. The organism is thought to be acquired from the environment after alteration of protective gut flora by antibiotics rather than from antibiotic-enhanced overgrowth of a natural carrier state. The majority of hospitalized patients who acquire C. difficile are clinically asymptomatic and undiagnosed, thus representing a reservoir for nosocomial transmission. Almost all antibiotics have been linked to C. difficile–associated diarrhea (CDAD), including vancomycin and metronidazole, the usual treatments for the infection. The most commonly implicated agents are clindamycin and the cephalosporins. Risk factors for acquiring CDAD include advanced age, immunosuppression, hospitalization, and alteration of intestinal flora or motility. A strong link between gastrointestinal surgery, hospitalization, and narcotic-impaired gastrointestinal motility has been made with pseudomembraneous colitis (PMC). The pathogenesis of CDAD depends on disruption of normal bowel flora by antibiotics, acquisition of C. difficile, and secretion of toxins A (an enterotoxin) and B (a cytotoxin). After attaching to intestinal epithelium, the toxins cause disruption of the cellular skeleton, cell death, mucosal inflammation, and increased intracolonic secretion of fluid. Toxin A is thought to cause most of the clinical manifestations of CDAD, but synergy of the two toxins may be necessary for disease expression. 7.1

Clinical Manifestations

Symptoms of AAD often begin 5–10 days after the onset of antibiotic use. The majority of patients have mild diarrhea, which abates spontaneously with discontinuation of the antibiotic. Patients with CDAD often experience more severe symptoms and signs. Crampy abdominal pain, nausea, and vomiting are common. Diarrhea may occur 10–20 times a day and is often associated with mucus and blood in the stool. Fever and leukocytosis (up to 20,000 white blood cells/mm3) is expected. In leukemoid reactions the white blood cell (WBC) count may exceed 40,000/mm3. Cases of toxic megacolon or colonic perforation are rare. Clinically these patients may have rebound tenderness and lack of bowel sounds on physical examination. 7.2

Diagnosis

CDAD should be suspected in all patients in whom diarrhea develops while they are receiving antibiotics or shortly afterward. The presence of fever, systemic toxicity, and leukocytosis should further raise concern. Inflammatory cells (as indicated by either lactoferrin or fecal leukocyte examination) may be present in the stool, although a negative test finding does not exclude the diagnosis of CDAD. Megacolon with mucosal thumbprinting may be seen on plain radiograph. Computed tomography (CT) scans may reveal colonic thickening and pericolonic inflammation. CT scans may be especially helpful in those who have abdominal pain without diarrhea and right-sided colonic involvement. Diagnosis of CDAD by visualization of pseudomembranes is useful, and sigmoidoscopy is often adequate. Colonoscopy may be needed, however, if right-sided involvement of the colon is suspected. On endoscopy, most CDAD patients have normal or mildly inflamed mucosa. In those with colitis, friable, red, and edematous mucosa is found in the left colon in 70%–95% of cases. Classic patchy pseudomembranous plaques are 2–5 mm and are limited to the colon. The pseudomembranes are composed of neutrophils, sloughed epithelial cells, mucus, and fibrin. Though pseudomembranes may be extensive, histolog-

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ical findings do not necessarily correlate with severity of symptoms. CDAD should be differentiated from other pathogens that cause a dysentery-like illness, inflammatory bowel disease, and ischemic colitis. With the use of selective media, culture for C. difficile is a sensitive test but is not performed in many hospital labs. Since many hospitalized patients are colonized with C. difficile, a positive culture result is not equivalent to clinical disease. Latex agglutination assays for detection of the C. difficile bacterium in stool are rapid and simple to perform but are not sensitive or specific and do not differentiate toxin-producing from non-toxinproducing strains. Clinically, the diagnosis of CDAD is usually made by demonstrating the presence of C. difficile toxin A or B in stool from a patient with diarrhea. The gold standard toxin assay is a test for tissue cytotoxicity. Although sensitive and specific, this assay is cumbersome and expensive. Most clinical laboratories use a straightforward enzyme-linked immunosorbent toxin assay (ELISA) to detect toxin A or A and B. These tests are very specific but miss 10%–20% of cases. Some authors have suggested that repeating the ELISA two or three times may increase the sensitivity. Assays that detect both A and B toxins have a higher sensitivity than those assays that detect only toxin A. 7.3

Treatment

The initial step in treatment of ADD is to discontinue antibiotic therapy whenever possible. Up to 25% of patients respond to this measure alone. Asymptomatic carriers of C. difficile should not be treated, since colonization is usually transient. The initiation of therapy for CDAD should depend on the clinical severity of the illness and confirmation of the diagnosis by ELISA, cytotoxicity assay, or endoscopy. The presence of fecal leukocytes or lactoferrin in a patient with a history compatible with CDAD may warrant empirical therapy while awaiting laboratory confirmation. Therapy is aimed at using antibiotics effective against C. difficile, eliminating toxins, and restoring gut flora (see Table 8). Antimotility agents such as Imodium should be avoided.

Table 8 Treatment of Clostridium difficile Colitis Drug Metronidazole orally Vancomycin orally Bacitracin

Metronidazole intravenouslyc Vancomycin intrarectally a

Costsa

Comment

500 mg qid ⫻ 7–10 days 750 mg tid ⫻ 7–10 days 125 mg qid ⫻ 7–14 days

$12.00–$18.00 $19.00–$28.99 $239.00–$478.00

500 mg qid ⫻ 7–10 days 20,000–25,000 U PO qid ⫻ 10 days

$602.00–$860.00 $76.00

Considered the drug of choice For patients unable to tolerate metronidazoleb Severely ill patients Less effective than metronidazole or vancomycin Associated with more relapses Inability to take oral antibiotics Less effective than oral

Dose

500 mg q8h ⫻ 7–10 days 500 mg q4–8h ⫻ 7–10 days

Average wholesale price. 2000 Drug Topics Red Book. Continued alcohol use or pregnancy, severe nausea, and vomiting. c Add oral vancomycin by nasogastric tube if possible. b

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Both metronidazole and vancomycin are highly efficacious. Metronidazole is less expensive and generally considered the drug of choice. In very ill patients, however, highdose oral vancomycin is preferred. When oral antibiotics cannot be used, intravenous (IV) metronidazole is the best choice since IV vancomycin penetrates the colon poorly and should not be used. Nasogastric tube delivery of vancomycin and vancomycin retention enemas have been used with success. With successful therapy, patients often feel better within 2–3 days with cessation of diarrhea within 1 week. Results of tests for toxin, however, remain positive for weeks, and a ‘‘test for cure’’ is not indicated. Surgical intervention is infrequently necessary but is a critical step for patients with toxic megacolon unresponsive to antibiotics or perforation. The operative mortality rate of patients with perforations due to severe colitis is high. Despite appropriate antibiotic therapy, approximately 20% of patients with C. difficile colitis relapse after discontinuation of therapy. Risk factors for CDAD relapse include the continued use of antibiotics despite the presence of C. difficile infection, advanced age, recent abdominal surgery, chronic renal failure, and community-acquired disease. Retreatment with the same regimen is effective in about half of these patients. A variety of other approaches are used for patients with repeated relapses, including ‘‘pulsing’’ or tapering of vancomycin, combinations of vancomycin and rifampin, use of anion-exchange resins (cholestyramine), rectal infusions of bacteria or feces (often avoided for aesthetic reasons), and oral probiotics such as Lactobacillus GG and Saccharomyces boulardii to restore normal flora. Except Lactobacillus sp. therapy, is the only therapy approaches that has been subjected to clinical trial. For patients admitted to the hospital, infection control is very important. The main techniques of preventing nosocomial spread are isolation of patients, handwashing (before and after patient contact), contact precautions with gloves and gowns, and environmental decontamination. 8

ACQUIRED IMMUNODEFICIENCY SYDROME

Approximately 50% of AIDS patients have gastrointestinal tract involvement with a wide variety of pathogens. In the early 1990s, 30%–60% of patients with AIDS reported diarrhea, frequently associated with malnutrition and progressive weight loss. Unlike in other populations, diarrhea is often (⬃30%) due to more than one pathogen and specific causes are difficult to determine. The use of highly active antiretroviral therapy (HAART) has

ACQUIRED IMMUNODEFICIENCY SYNDROME–RELATED DIARRHEA Approach to patient (Figure 2) Common with protease inhibitors Infection associated with advanced immune suppression (CD 4 < 100) Increased risk for nontyphoidal Salmonella spp. Protozoan infections common cause of chronic, noninflammatory diarrhea Cryptosporidium, Cyclospora, Isospora spp. diagnosed with acid-fast stain (Kinyuon) of stool Microsporidia diagnosed by biopsy/electron microscopy, histopathological evaluation, or stool trichrome stain

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Figure 2 Approach to the patient with AIDS and diarrhea. Patients with advanced immune suppression are at highest risk for infectious diarrhea. Protease inhibitors commonly cause diarrhea. If there are signs of an inflammatory process (fever, fecal leukocytes) in a patient with acute-onset diarrhea, then empirical therapy with ciprofloxacin should be initiated. If the diarrhea is persistent and undiagnosed, then upper endoscopy for parasites or mycobacterium pathogens should be done. Upper or lower endoscopy with biopsy may be needed to make a diagnosis. (1) Patients with CD4 >200–300 cells/mm3 usually can be managed as immunologically normal hosts (Figure 1). (2) Short duration of several days; may last up to 14 days. (3) More than 14 days. (4) Large-volume, watery diarrhea without blood or mucus. (5) Small, frequent stools with tenemus; blood or mucus may be present. AIDS, acquired immunodeficiency syndrome; EM, electron microscopy; O&P, ova and parasite; AFB, acid-fast bacillus; CMV, cytomegalovirus.

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markedly decreased the incidence of gastrointestinal opportunistic infections. However, debilitating diarrhea can be caused by HAART, especially as a result of the use of protease inhibitors. Figure 2 demonstrates a basic algorithm for evaluating acute diarrhea in patients with AIDS. Several pathogens are more common in patients with AIDS, predominantly as a result of changes in cell-mediated immunity. Leading causes of diarrhea in patients with AIDS include cytomegalovirus, Cryptosporidium spp., Microsporidium spp., E. histolytica, G. lamblia, Salmonella spp., Campylobacter spp., Shigella spp., C. difficile, Vibrio parahaemolyticus, and Mycobacterium spp. Before the era of HAART, Cryptosporidium parvum infected up to 20% of patients with very low CD4 counts ( 1.5) and/or the development of any degree of encephalopathy warrants hospitalization and monitoring for fulminant hepatic failure, preferably in a center that offers liver transplantation. Otherwise, outpatient monitoring is preferred. 3.1.2

Diagnosis

HAV infection should be suspected in the context of potential contaminated food or water ingestion, unexpected breaches in public health sanitation (such as with flooding), contacts with children in day care facilities, or subjects with a recent history of travel to endemic areas. The infection rate is particularly high among young Native Americans. Confirmation of HAV is performed by the presence of immunoglobulin M (IgM) anti-HAV titers in serum during the acute illness. Decreases in IgM with a rise and persistence of IgG antiHAV levels occur after several months. After recovery, the IgG antibodies persist for life and provide protection from future infections. An acute, self-limited infection is the usual clinical course for HAV. An estimated 99% of those infected recover without residual sequelae. A prolonged or relapsing cholestatic hepatitis may occur in up to 15% of cases. Fulminant hepatic failure that results in encephalopathy and death within 12 weeks of acute infection is rare. Cases compatible with chronic infection or carrier states for hepatitis A have only rarely been reported.

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Prevention

Prevention of HAV is based on the principles of avoidance, passive immunization, and vaccination. Hands should be washed with soap and water after bowel movements, changing of diapers, and before food preparation. Diaper changing tables in day care centers, if not cleaned properly or changed after each use, can be a source of contamination and transmission of the virus. Strict isolation in the home has no significant benefit as household members have usually been exposed before the clinical infection is observed. Hepatitis A vaccine (Havrix, SmithKline Beecham or VAQTA, Merck) is highly effective in preventing acute infection and can have a substantial impact on eliminating disease burden. The vaccine is made from inactivated HAV and stimulates persistent natural immunoglobulin production, thus conferring long-term immunity. Protection against HAV is conferred as early as 2–4 weeks after vaccination in over 95% of individuals. Immunization of children (2–18 years of age) consists of two or three doses of the vaccine at a dose of 0.5 ml each. Adults need a booster dose 6–12 months after an initial vaccine dose of 1.0 ml. The vaccine is thought to be effective for at least 15–20 years. Adverse reactions, which are rare, may include pain or tenderness at the injection site. Hypersensitivity reactions have not been described. At-risk individuals who should be vaccinated include persons engaging in anal-oral sex, users of illegal injectable drugs, children living in communities experiencing repeated HAV epidemics, certain institutional workers, workers in day-care centers, and laboratory workers who handle live HAV. Patients with chronic liver disease and clotting factor disorders should be vaccinated against HAV. Persons traveling internationally should be vaccinated 4 weeks prior to their travel. The use of immune globulin for passive immunization against HAV can provide global protection through the stable antigenic composition of the virus. Immune globulin should be used if the traveler is unable to tolerate the HAV vaccine or is traveling immediately. Protection through passive immunization (60%–70%) is not as good as that through the vaccine. Temporary immunity (less than 3 months) is provided by 0.02 ml/kg immune globulin administered intramuscularly. Screening for IgG antibodies to HAV before immunization among prospective travelers may detect preexisting immunity and is a cost-saving maneuver to prevent unnecessary immune globulin use. For those exposed to HAV, immune globulin (0.02 ml/kg) should be given as soon as possible and no later than 2 weeks after initial exposure. Transmission rates can be decreased by 90% if the immune globulin is given within this 2-week period. 3.2

Hepatitis B Virus

Hepatitis B virus (HBV) is an enveloped, double-stranded deoxyribonucleic acid (DNA) hepadnavirus that exists as a 42-nm particle in serum. Hepatocyte injury in HBV infection is thought to be secondary to host immune system response rather than a direct cytopathic effect. Major routes of transmission among adults in Western countries are intravenous drug use and sexual contact. The risk of HBV infection is notably high in homosexual men but is also transmitted among heterosexual partners. Transmission may be prevented by correct use of condoms. Health care workers and patients receiving hemodialysis are also at increased risk of infection. Mucous membrane or nonintact skin contact also poses a small theoretical increased risk for virus acquisition. The blood supply in developed countries has been screened for HBV for many years, and, at present, transmission by transfusion of blood products is extremely rare. The rate of HBV infection had been increasing through 1985. Then, through 1993, there was a 55% decline in the number of identified cases. This decrease in new infections

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HEPATITIS B VIRUS Transmission Sexual Injection drug use Clinical presentation Incubation, 45–160 days Subclinical to fulminant hepatic failure (⬃2%) Fever, fatigue, abdominal pain ⬃10% Chronic carriers Chronic infection asymptomatic or leads to cirrhosis, hepatocellular carcinoma (HCC) Diagnosis Acute HbsAg ⫹, HbeAg ⫹, immunoglobulin M (IgM) HbcAb ⫹ Transition from acute infection HBcAb ⫹ Resolution of HBsAg, IgM HBcAb HBsAb ⫹ Chronic, immune HbsAb ⫹ and HBcAb ⫹ Chronic infection Replicative HBsAg ⫹, HBeAg ⫹, HBeAb ⫺ Very infectious Higher risk of cirrhosis and HCC Nonreplicative HBsAg ⫹, HBeAg ⫺, HBeAb ⫹ Treatment For patients with active hepatitis B virus (HBV) replication and elevated liver tests (AST and/or ALT levels) Interferon, lamivudine, famciclovir in combination Prevention Nonimmune patient exposed to HBV HBV vaccine and Hepatitis B immune globulin (HBIG) (0.06 ml/kg IM) HBV vaccine for those at risk Three 1-ml injections IM at 0, 1, 6 months

is thought to be due to increased vaccination rates among adults, modification of highrisk practices, and possibly a decrease in the number of susceptible persons. Since 1993, increases in incidence are now observed among the three major risk groups: nonmonogamous sexually active men and women as well as injection drug users. Each year in the United States, an estimated 200,000 people have new HBV infections; of them, more than 11,000 are hospitalized and 20,000 remain chronically infected. Overall, an estimated 1.25 million people in the United States have chronic HBV infection; 4000 to 5000 people die each year of HBV-related chronic liver disease or liver cancer.

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461

Clinical Presentation

The incubation period for HBV is 45 to 160 days. Acute HBV infection can range from subclinical disease to fulminant hepatic failure. In many acutely infected individuals, clinically apparent acute hepatitis develops with loss of appetite, nausea, vomiting, fever, and abdominal pain. Fatigue, which is often worse in the evening, is the most common symptom. Jaundice can occur but is considered rare. Similar clinical findings can be observed with acute HAV or HCV infection. Fulminant hepatic failure occurs in ⬃2% of cases. More than 90% of immunocompetent adults with acute HBV infection recover uneventfully and resolve the infection. In the remaining 10% of cases, either chronic HBV infection or fulminant hepatic failure develops. In cases of fulminant hepatic failure, liver transplantation may be a lifesaving procedure. The mortality rate for acute HBV is estimated between 1% and 2%. The natural history of chronic HBV infection varies dramatically among individuals. Some have clinically insignificant liver disease and never experience complications, whereas others have progressive fibrosis leading to cirrhosis. Others become asymptomatic chronic carriers. These are patients with normal liver biochemical profiles who are nevertheless potentially infectious. Their serological testing results are positive for hepatitis B surface antigen and negative for hepatitis B surface antibody. Young age and immunosuppressed states are known risk factors associated with the development of chronic active or persistent disease. Individuals with chronic HBV (as well as HCV) in whom cirrhosis develops may also experience an asymptomatic condition with no physical abnormalities. With advanced disease, the characteristic findings associated

Figure 1 Natural history of hepatitis B virus infection during the first year after infection. ALT, alanine aminotransferase.

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with cirrhosis such as spider angiomata, muscle wasting, ascites, peripheral edema, encephalopathy, and asterixis can occur. Patients with cirrhosis are also at increased risk for the development of hepatocellular carcinoma (HCC): ⬃1%–2%/year. Semiannual screening with an ␣-fetoprotein and ultrasound examination of the liver are therefore recommended for patients with cirrhosis secondary to chronic hepatitis B infection. A smaller increased risk for HCC exists among chronic asymptomatic carriers of HBV. 3.2.2

Diagnosis

The diagnosis of HBV infection is generally made on the basis of serological results. Virtually all individuals infected with active HBV infection, either acutely or chronically, have detectable serum hepatitis B surface antigen (HBsAg). Other markers that determine the duration (acute vs. chronic) and activity (replicative vs. nonreplicative) of infection include hepatitis B surface antibody (HBsAb), core antibody (HBcAb) with IgM or IgG, nucleocapsid (e) antigen (HBeAg), and (e) antibody (HBeAb). The time course and clinical significance of these markers are described in the following and are shown in Figures 1 and 2: Serological marker • HBsAg • HBsAb

• IgG HBcAb

• IgM HBcAb • HBeAg • HBeAb

Interpretation Acute or chronic HBV infection: Persistence for 6 months after acute infection indicates progression to chronic HBV. These patients are infectious. Individual has been vaccinated, has received immune globulin, was infected but recovered, or is an infant who has received antibodies from its mother. These patients are immune, do not need vaccination, and are not infectious. Indicates past infection and lasts indefinitely. Also may be detected in someone who has received immune globulin or an infant who has received antibodies from its mother. Can be positive in the absence of HBsAg or HbsAb; patients with isolated HbcAb are not immune and should be vaccinated. Indicates recent infection with HBV within the past 4–6 months. Can be positive in the absence of HBsAg or HbsAb. Indicates active viral replication and high infectivity. Seen in association with (⫹) HbsAg. Indicates seroconversion from the active replicative state. Seen in the chronic carrier in association with (⫹) HbsAg.

Acute HBV infection is diagnosed by the presence of serum hepatitis B surface antigen (HBsAg) and IgM antibody to hepatitis B core antigen (HBcAb-IgM) in the early stages of infection, which coincide with the onset of clinical symptoms. HBeAg is also detectable in acute infection, signifying the increased rate of viral replication. Subsequently, IgG antibodies against core antigen (HBcAb) are detectable in serum once the acute infection resolves. IgM-associated HBcAb and HBsAg become undetectable once IgG antibody (HBcAb) production is sustained. In subjects who mount an immune response against HBV, antibodies to surface antigen (HBsAb) develop. Complete resolution of acute infection results in IgG-associated HBcAb for life. The gradual loss of HBsAb in select individuals may result in an increased susceptibility to future infection. Acutely infected individuals who do not clear HBV continue to have serum HBsAg. In most cases,

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Figure 2 Natural history of hepatitis B virus infection over 10 years.

the chronic infection becomes nonreplicative with the loss of serum HBeAg and development of HBeAb. In replicative chronic infection, the presence of detectable HBeAg is usually observed. Patients with chronic replicative hepatitis B infection, defined by detectable HBeAg or HBV DNA, have a greater chance of developing cirrhosis and/or hepatocellular carcinoma than those without evidence of active HBV replication. Among individuals suspected of having chronic HBV infection, the appropriate screening test is for serum HBsAg. Other clinical scenarios that may warrant screening for HBV include the following: Presence of symptoms related to chronic liver disease Abnormal laboratory test results suggesting liver disease Individuals from countries where HBV infection is endemic (e.g., China) Risk factors such as past intravenous drug use or unprotected promiscuous sex Children of HBV-infected parents or household contacts Health care workers Patients on hemodialysis Consideration of serving as a living organ donor 3.2.3

Treatment

Most cases (⬃90%) of acute HBV infection resolve spontaneously with the development of long-lasting natural immunity to subsequent infection. Although the successful treatment of fulminant hepatic failure secondary to HBV with lamivudine is known, antiviral therapy is not recommended in acute cases. Two approved treatments for chronic HBV infection are currently available: recombinant interferon alpha-2b (INF-␣) and lamivudine (3 TC). Despite the approval of these agents for the treatment of chronic HBV infection, no treatment strategy has been consistently successful. Recent data point to combination therapy with lamivudine plus INF-␣ or famciclovir as more efficacious than

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monotherapy with either lamivudine or INF-␣. Studies of triple therapy (INF-␣ ⫹ lamivudine ⫹ famciclovir) are under way. Adefovir dipivoxil is still the subject of clinical trials. Only patients with active HBV replication and elevated serum liver transaminase levels are usually considered to be candidates for antiviral therapy. Because the standard of therapy is still evolving, treatment of HBV infection should always be on an individual basis and initiated by a subspecialist with expertise in treating chronic viral hepatitis. 3.2.4

Prevention

Hepatitis B virus vaccination prevents both primary infection and those diseases related to HBV infection. HBV vaccines (Recombivax HB, Merck and Engerix B, SmithKline Beecham) currently available in the United States are made by using recombinant DNA technology and do not contain any live components. The vaccine is given as a series of three intramuscular doses of 1 ml over a 6-month period (at 0, 1, and 6 months). A missed dose should result in the administration of the second and third doses 3 to 5 months apart. It can also be given at the same time as other vaccinations. The most common side effects of vaccination are pain at the injection site and mild to moderate fever. Serious side effects are very uncommon. Adequate antibody titers develop after the three-dose series in more than 95% of children and 90% of young healthy adults. In immunocompromised hosts protective antibody titers develop in 50% to 70% of cases. Protection is conferred for a minimum of 15 years and possibly much longer. Persons who respond to hepatitis B vaccine are protected against acute hepatitis B as well as the chronic consequences of HBV infection, including cirrhosis and liver cancer. There is currently a universal child vaccination policy in the United States. Most schools require evidence of vaccination for registration. Adults at increased risk for HBV infection who should receive the vaccine include sexually active heterosexual adults with more than one sex partner in the prior 6 months, persons with a history of a sexually transmitted disease, homosexual men, illicit injectable drug users, persons at occupational risk of infection, hemodialysis patients, clients and staff of institutions for the developmentally disabled, and household and sexual contacts of persons with chronic HBV infection. Unvaccinated individuals exposed to HBV-infected persons through contact with infected blood or body fluids should receive an intramuscular injection of hepatitis B virus immune globulin (HBIG) 0.06 ml/kg within 48–72 hours of exposure. The window of efficacy for HBIG, however, may be as long as 2 weeks after exposure to HBV. Exposed nonvaccinated patients should also receive the HBV vaccine. All women should be screened for HBsAg during early pregnancy to determine whether they are infectious and capable of transmitting HBV to their infants. If not treated, 85% to 95% of infants born to HbsAg-positive mothers may become carriers. This can be prevented by giving the infants of HbsAg-positive mothers HBIG and their first dose of HBV vaccine within 12 hours of delivery. Completion of the vaccination series by 6 months is then recommended. This treatment prevents 90% of vertically transmitted chronic HBV infections. The vaccine is safe to be given during pregnancy. 3.3

Hepatitis C Virus

Hepatitis C virus (HCV) is a single-stranded RNA virus with characteristics similar to those of the Flaviviridae family (yellow fever, dengue, Japanese, St. Louis, and tick-borne encephalitis viruses). On successful molecular cloning of the hepatitis C virus, it was

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HEPATITIS C VIRUS Transmission Injection drug use, blood products Sexual transmission less common Clinical presentation Incubation period, 14–180 days Chronic infection in 85% Cirrhosis in 20%–30% Increased risk of hepatocellular carcinoma (HCC) Associated with Porphyria cutanea tarda Membranoproliferative glomerulonephritis Cryoglobulinemia Diagnosis Anti-HCV antibody: no differentiation of acute and chronic infection Active disease determined by presence of hepatitis C virus ribonucleic acid (HCV RNA) Therapy Decrease of other hepatotoxins, especially alcohol Treatment of active disease only if associated with elevated liver tests (AST and/or ALT levels) or abnormal liver biopsy result Pegylated ␣ interferon ⫹ ribavirin HCV genotype influence on response to therapy Prevention No vaccine or immunoglobulin

discovered that this was responsible for most cases of posttransfusion non-A, non-B hepatitis. The pathogenic mechanism of HCV appears to be related to lymphocyte recognition of viral antigen in hepatocytes with a subsequent inflammatory response. Transmission of HCV is primarily blood-borne via parenteral routes (transfusions, intravenous drug use) but also occurs by sexual and perinatal routes. Since the advent of blood supply testing for HCV in the early 1990s, the risk of transfusion-related HCV infection is less than 1%. Most new infections (60%) are related to illicit injection drug use. The incidence of HCV in the United States is approximately 36,000 new infections annually (1996 estimates), down from a peak of 175,000 new cases per year. However, only 25%–30% of infections present in a symptomatic fashion. HCV is estimated to have infected 3.9 million Americans (1.8% of the U.S. population), of whom 2.7 million are chronically infected. Chronic infection develops in approximately 85% of individuals who are acutely infected with HCV. Cirrhosis develops in 20% to 30% of cases. Between 8000 and 10,000 deaths occur annually secondary to chronic HCV infection. HCV-associated end-stage liver disease is now the leading indication for liver transplantation in the United States. Despite these figures, there exists a commonly held misconception that hepatitis C is a benign condition. Although it may be for a substantial proportion of chronically infected individuals, HCV infection is associated with considerable morbidity and mortality rates.

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Clinical Presentation

The incubation period of HCV varies between 14 and 180 days. The average time from transmission to seroconversion, however, is between 6 and 8 weeks. The clinical manifestations of acute HCV infection are indistinguishable from those of nonfulminant cases of HAV and HBV infection. Jaundice occurs in only 25% of acute HCV infections, making the clinical detection of recent infection difficult. Complete resolution of acute HCV infection, with clearance of HCV RNA from serum, occurs in ⬃15% of instances within 4 months of infection. Manifestations of chronic HCV infection range from the asymptomatic state to endstage liver disease. Fatigue, which may be accompanied by right upper quadrant abdominal discomfort, is the most common subjective complaint. Although fluctuating levels of serum transaminases are common, up to 25% of individuals with chronic HCV infection have normal serum liver biochemical findings. The correlation between serum transaminase levels and histological severity of chronic HCV infection is poor. Porphyria cutanea tarda, skin lesions consistent with leukocytoclastic vasculitis, membranoproliferative glomerulonephritis, osteopetrosis, and cryoglobulinemia are associated with HCV infection as well. Diabetes mellitus has also been putatively associated with chronic HCV infection. The natural history of HCV is unpredictable. The risk of progressive disease is cumulative and influenced by host and viral factors. Despite an indolent presentation, cirrhosis may develop over a 10- to 20⫹-year period after infection. Hepatocellular carcinoma is also strongly associated with chronic HCV infection, almost always in the setting of cirrhosis. The annual risk of hepatocellular carcinoma in patients with cirrhosis secondary to HCV is 1%–2%. For this reason, semiannual screening with ␣-fetoprotein and ultrasound examination of the liver are recommended. Currently, almost one-half of adult liver transplantations in the United States are performed for end-stage liver disease from HCV. One-tenth of these transplant recipients die or require retransplantation in the first 5 years postoperatively because of recurrent HCV infection. 3.3.2

Diagnosis

The array of tests available for the diagnosis of HCV infection is limited in comparison to those available for hepatitis B. Because HCV antibodies are usually not neutralizing, the detection of antibody to HCV (anti-HCV) does not distinguish between acute and chronic infection. Approximately ⬃85% of individuals with detectable anti-HCV have active infection vs. 15% who have resolved prior infection (HCV RNA no longer present). In the acute setting, anti-HCV is only detectable in ⬃60% of patients in the first 4 weeks after infection. Although up to 12 months can elapse before HCV antibodies become detectable, seroconversion generally occurs within 2 to 6 months of infection in ⬃90% of individuals. The presence of anti-HCV antibodies is detected by either enzyme-linked immunosorbent assay (ELISA) or recombinant immunoblot assay (RIBA). These tests are equivalent in terms of sensitivity and specificity. Detection of anti-HCV antibody should be followed up with a test to determine whether HCV RNA is still present in serum, i.e., whether HCV infection persists. Either qualitative or quantitative assays for HCV RNA by polymerase chain reaction (PCR) amplification may be used. The quantitative PCR assays are generally preferable as they now enjoy similar sensitivity to that of the qualitative assays. Quantitation of HCV RNA may also be performed by a branched DNA (bDNA) hybridization assay. Despite considerable promotional literature to the contrary, none of the PCR or bDNA tests has clear superiority over its competitors. It is worth bearing in mind that the assays are not interchangeable, however, as HCV RNA is reported

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in different units. Immunocompromised patients (e.g., transplantation recipients, others receiving corticosteroids, or patients with renal failure) may not generate HCV antibodies. Such patients should undergo PCR or bDNA testing to screen for HCV infection. In addition, a very small minority of immunocompetent HCV-infected individuals test negative for anti-HCV antibody but have HCV RNA detectable in serum. HCV RNA testing is indicated when the level of suspicion is high for HCV infection despite negative antiHCV antibody test findings. There are six major HCV genotypes (1a,b,c; 2a,b,c; 3a,b; 4; 5; 6). As HCV genotype influences responsiveness to therapy (the only definitive clinical implication of HCV genotype), this test is of utility when treatment is being considered. The utility of liver biopsies in patients with chronic HCV infection is increasingly equivocal. Biopsies may be helpful in determining disease activity and stage, factors that often influence patient willingness to undergo therapy. The presence of cirrhosis does not meaningfully affect likelihood of response to antiviral therapy. 3.3.3

Treatment

Only two drugs have been approved by the Food and Drug Administration for the treatment of chronic HCV infection: recombinant interferon-alpha (INF-␣) (pegylated and standard) and ribavirin. The addition of polyethylene glycol (pegylation) to INF-␣ results in more sustained bioavailability of interferon, facilitating once-weekly dosage and having superior efficacy to that of standard interferon. Combination therapy with pegylated INF-␣ and ribavirin for 48 weeks is now the standard of care for treatment of chronic hepatitis C infection in adults. The overall sustained virological response rates (undetectable levels of HCA RNA in serum for ⱖ6 months after completion of therapy) is over 50%. Ultimate response to therapy can usually be determined after 24 weeks of treatment with pegylated INF-␣ and ribavirin (only 1:400 likelihood of clearing HCV RNA after 24 weeks of treatment). Sustained virological response rates vary substantially with HCV genotype (42% genotype 1 vs. 75% non-1 genotypes). Sustained virological response rates are also greater for patients who have no or minimal fibrosis indicated on liver biopsy and who have lower (less than 2 ⫻ 106 IU/ml) viral levels at initiation of treatment. Patients with compensated cirrhosis can expect an overall likelihood of sustained virological response of 44%. Side effects of therapy are common; they include flulike symptoms, depression, cytopenias, and thyroid dysfunction secondary to INF-␣ and hemolysis secondary to ribavirin. Dosage reductions are required in ⬃40% of patients receiving combination treatment with pegylated INF-␣ and cessation of therapy in 14%. Only adult patients with active HCV infection, as determined by the detection of HCV RNA in serum, elevated serum liver transaminase levels, and abnormal histological findings on liver biopsy, are considered to be clear-cut candidates for antiviral therapy. Because the treatment of chronic HCV is evolving so rapidly, therapy for hepatitis C should be initiated by a subspecialist. Promising new agents in various stages of clinical trials include ribozyme, interleukin-2, recombinant vaccine products, and HCV-specific helicase and protease inhibitors. Studies of thymosin, interleukin-10, mycophenolate mofetil, silymarin (milk thistle), vitamin E, amantadine, extracorporeal hyperthermia, and ursodeoxycholic acid either have not shown a benefit or have been inconclusive. 3.3.4

Prevention

Currently no effective vaccine exists for HCV. As a result, continued surveillance of the donated blood supply and counseling to reduce or modify high-risk practices remain a

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mainstay. Patients with chronic HCV infection should be advised to limit or eliminate their alcohol intake to prevent the increased risk for cirrhosis in this setting. Screening for anti-HCV among uninfected individuals in monogamous long-term sexual relationships is advised if one of the partners is known to be HCV-positive. Populations at increased risk for HCV infection are similar to those for HBV and to some extent HIV. These patients include injection drug users, hemodialysis patients, surgical and emergency room health care workers, sexual contacts of infected persons, persons with multiple sex partners, recipients of blood transfusions before July 1992, recipients of clotting factors before 1987, and infants born to infected women. 3.4

Hepatitis D Virus

Hepatitis D (HDV) is a defective RNA virus that requires coinfection with HBV for replication. HBsAg production is required for HDV to produce its outer envelope and begin replication. Its pathogenesis remains uncertain as reinfection in liver transplantation recipients with HDV can occur without recurrent HBV or signs of histological damage. Transmission is similar to that of HBV but less often by sexual or perinatal transmission. The highest seroprevalence rates for HDV occur in Italy, South America, Africa, and the Middle East. Up to 50% of individuals carrying HBsAg in these areas may have antibody to HDV. Injecting drug users and patients with a history of multiple transfusions are at highest risk for HDV in the United States. 3.4.1

Clinical Presentation

The development of acute, chronic, and fulminant hepatitis is known to occur in the presence of HDV. Patients with acute HBV and HDV are described as coinfected. Superinfection with HDV occurs in those who have existing chronic HBV infections (HbsAgpositive). Among patients with chronic HBV infection in whom fulminant hepatic failure or an unexplained hepatic decompensation develops, superinfection with HDV should be suspected.

HEPATITIS D AND E VIRUSES Hepatitis D virus (HDV) Requires hepatitis B virus (HBV) coinfection (HbsAg ⫹) Transmission usually parenteral Hepatic failure potentially triggered by superinfection of HBV with HDV Diagnosis with immunogloblin M (IgM) and IgG antibodies Treatment with alpha-interferon No vaccine or immunoglobulin Hepatitis E (HEV) Fecal-oral or water-borne transmission Self-limited without chronicity Diagnosis by anti-HEV IgM No treatment, vaccine, or immunoglobulin

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Diagnosis

The diagnosis of HDV infection is most commonly made by serological methods. Elevated titers of both IgG and IgM anti-HDV antibodies are usually found in combination. Titers greater than 1:100 of anti-HDV are indicative of chronic HDV infection. Paradoxically, titers of HBV as measured by HBV DNA or HBeAg fall after HDV superinfection. 3.4.3

Treatment

The only approved treatment for chronic HDV is INF-␣. Only patients with elevated serum liver transaminase levels and appropriate histological findings on liver biopsy are considered potential treatment candidates. Formal assessment and acceptance for treatment on an individual basis should be initiated by referral to a subspecialist with expertise in treating chronic viral hepatitis. 3.4.4

Prevention

Vaccination against HBV can prevent HDV infection. There is no vaccine directed at HDV. Immunoglobulin therapy is not protective. 3.5

Hepatitis E Virus

Hepatitis E virus (HEV) is a single-stranded RNA virus that causes acute episodes of hepatitis. The pathogenic mechanism of HEV is related either to a viral cytopathic effect or to immune system–mediated damage. Its mode of transmission is by waterborne or fecal-oral routes. Epidemics of infection from HEV have occurred primarily in Southeast and Central Asia, India, Africa, and Central America. Originally described as a disease of young adults and children, it has a prevalence in developed countries that is low but measurable (1% to 2%). There have been no known epidemics of HEV infection acquired within the United States to date. 3.5.1

Clinical Presentation

The incubation period for HEV is between 15 and 60 days. In general, HEV infection is a self-limited illness with no evidence of chronicity. The clinical course of HEV resembles that seen with HAV infection. Jaundice may occur but is less often seen in children. Fulminant hepatic failure from HEV has been observed in pregnant women during their third trimester with an associated 30% mortality rate. 3.5.2

Diagnosis

A serological test for the detection of anti-HEV IgM antibody is now available. Anti-HEV IgM antibody is often undetected at presentation and usually disappears within 3 months after the onset of jaundice. IgG titers may also disappear over time, raising the concern of recurrent infection. Testing for anti-HEV is usually reserved for returning travelers from the developing world in whom hepatitis is present but other hepatitis viruses cannot be detected. 3.5.3

Treatment

Currently there is no specific medial treatment for HEV as it is self-limited. 3.5.4

Prevention

No vaccine to confer antibody protection against HEV is available. Immunoglobulin therapy is not protective.

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3.6.

Other Agents of Viral Hepatitis

Many of the herpesvirsues—varicella-zoster, herpes simplex types 1 and 2, Epstein-Barr virus, and cytomegalovirus—may also cause hepatitis. Hepatitis secondary to these agents is much less common than that to hepatitis A–E. Of these, varicella-zoster and herpes simplex may cause severe liver dysfunction in previously healthy individuals. Transaminase levels are usually greatly increased with relatively less abnormal bilirubin levels. In contrast to that in other forms of acute viral hepatitis, liver biopsy may be diagnostic in this setting because of the presence of inclusion bodies. An appropriate antiviral therapy (acyclovir, penciclovir, or famciclovir) may be lifesaving. 3.7

New Viral Agents: Hepatitis F, Hepatitis G, TT-Virus, and SEN-Virus

The advent of techniques such as polymerase chain reaction and representational difference analysis has facilitated the discovery of new viruses. Whereas some recently discovered viruses are of clear importance as agents of human disease (hepatitis C), others are not. Hepatitis F, initially described in France and thought to be a new fecal-enteric virus, seems not to exist at all. Hepatitis G (also referred to as GBV-C) is a parenterally transmitted single-stranded RNA virus originally isolated from the serum of a surgeon with non-a, non-B, non-C hepatitis. Despite the initial transmissibility of hepatitis to chimpanzees from the original serum from which hepatitis G was isolated, hepatitis G has yet to be unequivocally demonstrated to cause liver disease or to be hepatotropic. TT-virus, a highly prevalent member of the circoviridae (single-stranded circular DNA virus) family that bears the initials of the first patient from whom it was isolated, may be parenterally and enterally transmitted. TT-virus, although initially linked to posttransfusion hepatitis, appears neither to be hepatotropic nor to be associated with any form of liver disease. Most recently the SEN-virus, also named after the first patient from whom it was recovered, has been touted as an agent of parenterally transmitted hepatitis. Similarly to TT-virus, however, there is no conclusive evidence that this prevalent new virus either is hepatotropic or causes liver disease. There is no clinical setting that warrants routine testing for any of these new viruses (hepatitis G, TT-virus, and SEN-virus). 4

EVALUATION OF POTENTIAL OCCUPATIONAL EXPOSURE TO VIRAL HEPATITIS

Almost every physician practicing in the ambulatory care setting is called on to evaluate an employee or patient who has sustained a needle-stick injury or similar potential occupational exposure to viral hepatitis (also see Chapter 42). Investigation of the exposure incident should include documentation of the route(s) of exposure, the circumstance under which the exposure incident occurred, and identification and documentation of the source individual, if possible. Testing of the source individual’s blood, with permission, for hepatitis B and C viruses and HIV infection should be done as soon as possible. The great majority of source individuals are eager to assist with postexposure testing. If the source individual is already known to be infected with a viral hepatitis agent or HIV, retesting is not needed. The results of the source individual’s testing should be made available to the exposed employee. Confidentiality concerning the identity and infectious status of the source individual needs to be stressed. When the source individual refuses testing or cannot be otherwise tested, the procedure outlined for an exposure to an unknown source should

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be followed. Refusal to be tested must be documented. Exposed employees should be offered baseline viral hepatitis and HIV testing. When medically indicated, postexposure prophylaxis should be provided as soon as possible to the employee. 4.1

HBV Risk Assessment and Treatment

The risk of transmission from a HBsAg-positive/HBeAg-positive patient is 25%–30%. If the source patient is HBsAg-positive/HBeAg-negative, then the transmission risk is 5%– 10%. If an employee is exposed to a source individual found to be positive for HBsAg, the employee needs to be tested for HBsAb (see Chapter 42, Table 4). If the employee is HBsAb positive, no prophylaxis is required. If the HbsAb titer is negative, the employee should be given a single dose of HBIG (0.06 mg/kg, intramuscularly) within 48–72 hours if possible. If the employee has not previously received the HBV vaccination, the series should be initiated at this time. Employees who refuse vaccination should be given a second dose of hepatitis B immune globulin at 1 month. If the employee has previously received hepatitis B vaccine and is hepatitis B surface antibody–negative and has been previously antibody-positive, he or she should receive one dose of the hepatitis B vaccine and hepatitis B surface antibody rechecked at 1 month. If the antibody titer is negative at that time, a second complete vaccine series should be provided. If the employee has had the HBV vaccine and is not known to be HBsAb-positive (HBsAb titer > 10 mIU/ml), he or she should receive HBIG and a booster dose of the vaccine. 4.2

Hepatitis C Virus Risk Assessment

The risk of transmission of HCV to a health care worker is estimated to be about 3.5% (0%–6%) after a needle-stick injury from a HCV-positive patient. Postexposure prophylaxis with immune globulin does not appear to be effective in preventing HCV and is not recommended. A vaccine for HCV is not available. After a potential exposure to HCV infection, the employee’s anti-HCV status should be determined by ELISA or RIBA. If the status is positive, the presence of HCV RNA should be determined by PCR. If the initial screening finding is negative, repeat screening should be performed at 1 and 6 months post exposure. A negative screening finding at 6 months post exposure is generally accepted as indicative that infection has not occurred.

BIBLIOGRAPHY Alter MJ, Hadler SC, Margolis HS, et al. The changing epidemiology of hepatitis B in the United States: Need for alternative vaccination strategies. JAMA 263:1218–1222, 1990. Boyer N, Marcellin P. Pathogenesis, diagnosis and management of hepatitis C. J Hepatol 32(suppl 1):98–112, 2000. Centers for Disease Control and Prevention. Protection against viral hepatitis: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 39:5–22, 1990. Di Bisceglie AM. Natural history of hepatitis C: Its impact on clinical management. Hepatology 31: 1014–1018, 2000. Dusheiko GM. Rolling review—the pathogenesis, diagnosis, and management of viral hepatitis. Aliment Pharmacol Ther 8:229–253, 1994. Francis DP, Hadler SC, Thompson SE, et al. Prevention of hepatitis B vaccine: Report from the Centers for Disease Control multi-center efficacy trial among homosexual men. Ann Intern Med 97:362–366, 1982.

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Hadler SC, Margolis HS. Hepatitis B Immunization: vaccine types, efficacy, and indications for immunization. In: Remington JS, Swartz MN, eds. Current Clinical Topics in Infectious Diseases. Boston: Blackwell Scientific, 1992, pp 282–308. Margolis HS, Alter MJ, Hadler SC. Hepatitis B: Evolving epidemiology and implications for control. Semin Liver Dis 11:84–92, 1991. Noskin GA, et al. Prevention, diagnosis, and management of viral hepatitis. Arch Fam Med 4:923– 934, 1995. Szmuness W, Stevens CE, Harley EJ, et al. Hepatitis B vaccine: Demonstration of efficacy in a controlled clinical trial in a high risk population in the United States. N Engl J Med 303: 833–841, 1980.

24 Intra-Abdominal Infections Neil H. Hyman and Christopher J. Grace University of Vermont, Burlington, Vermont, U.S.A.

1

INTRODUCTION

Intra-abdominal infections run the gamut from relatively minor problems that respond promptly to oral antibiotics to imminently life-threatening intra-abdominal catastrophes. Such infections may be the cause of major morbidity and mortality, particularly if not diagnosed and treated promptly. Abdominal pain has been reported to be the most common reason for admission to the hospital in the United States. Although many such cases are clear-cut intra-abdominal catastrophes that are seen in the emergency department, many other intra-abdominal infections appear in a much more subtle fashion and are seen in the office of the primary care provider. In this chapter, an approach to the patient with abdominal pain is outlined. The management principles for common intra-abdominal infections, including diffuse peritonitis, cholecystitis, cholangitis, appendicitis, diverticulitis that causes localized peritonitis, and solid organ abscesses, are discussed. Current thoughts on prophylaxis for surgical infections are addressed, as are the evolving controversies regarding treatment of Heliobacter pylori infection. Other infectious causes of abdominal pain such as dysentery and food poisoning (Chapter 22), pyelonephritis (Chapter 15), gynecological infections (Chapter 16) and male genitourinary tract infections (Chapter 17) are covered in other sections of the text. 2

APPROACH TO THE PATIENT WITH ABDOMINAL PAIN

Despite major technological advances, the cornerstone of appropriate diagnosis and treatment rests on a thorough history and physical examination coupled with the practitioner’s clinical acumen, rather than any imaging studies. 2.1

History

A thorough history includes the age of the patient, onset and duration of the pain, location and character of the pain, and whether or not the pain radiates in any particular direction or fashion. An appropriate review of systems requires a search for associated gastrointestinal, gynecological, or genitourinary symptoms. The presence of fever, chills, and sweats suggests an infectious cause. Pain of sudden onset often suggests a gastrointestinal source 473

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such as perforation or obstruction. A more insidious onset suggests an inflammatory process such as appendicitis or diverticulitis. Crampy or colicky pain often signifies mechanical obstruction of a hollow viscus such as renal colic or small bowel obstruction. Bilious vomiting more strongly suggests a ‘‘surgical’’ cause of abdominal pain than nonbilious vomiting. Patients may describe ‘‘coffee ground’’ emesis, which on closer questioning is simply nonbilious in nature. Past medical and surgical history is also of considerable importance. Previous lower abdominal surgery in a patient with crampy abdominal pain suggests a diagnosis of small bowel obstruction. Patients with risk factors or known atherosclerotic vascular disease or atrial fibrillation need to be considered for the possibility of mesenteric ischemia. 2.2

Physical Examination

Simple observation of the patient may be particularly helpful. Patients with renal colic frequently writhe, searching for a comfortable position. On the other hand, patients with peritoneal irritation attempt to lie as still as possible. Vital signs are most helpful in terms of screening for a true intra-abdominal catastrophe. Although nonspecific, tachycardia should increase the level of suspicion for an intra-abdominal infection. Hypotension suggests septic shock or a ruptured abdominal aortic aneurysm. Auscultation of the abdomen can often provide important clues as to the diagnosis and management. Hyperactive high-pitched bowels sounds suggest bowel obstruction, whereas a quiet abdomen typically indicates an ileus associated with an infectious process. Bruits are a marker for vascular disease. It is usually best to avoid the area of maximal pain when starting the abdominal examination. Vigorous palpation of the area of maximal tenderness often precludes completion of the examination. If simple percussion causes pain, there is probably no reason to pursue palpation. If coughing causes severe pain in a specific area, it is likely that vigorous palpation will be intolerable. Diffuse tenderness is most often noninfectious in origin; exceptions include primary peritonitis in the cirrhotic patient and secondary peritonitis from a perforation. The psoas sign is elicited by extending the patient’s thigh. This maneuver stretches the ipsilateral psoas muscle, causing pain if the muscle is in contact with an abscess or inflamed appendix. The obturator sign is performed by flexing the knee and rotating the lower leg laterally. This causes internal rotation of the femur, stretching the obturator muscle. An inflamed appendix in this area causes pain during the maneuver. Peritoneal signs such as rebound tenderness and involuntary guarding suggest intraabdominal infection. Rebound tenderness is elicited when release of the palpating hand causes an obvious involuntary spasm of pain that is visually evident to the practitioner. Voluntary guarding implies that the muscles of the abdominal wall are contracted but the patient is capable of voluntarily relaxing them. Involuntary guarding denotes inability to relax the abdominal musculature and is a sign that raises much more concern. Patients suspected of having an intra-abdominal infection generally require a rectal examination. A rectal or bimanual exam may identify a pelvic abscess associated with diverticulitis, appendicitis, or pelvic inflammatory disease. Patients with Crohn’s disease may have fistulas and abscesses. Frank rectal blood suggests colonic bleeding from ischemia, diverticular disease, infectious colitis, inflammatory bowel disease, or tumor. Melena raises the concern for upper gastrointestinal bleeding. Occult bleeding (as detected by guaiac testing) can be seen with infectious colitis in addition to noninfectious causes.

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If the patient does not appear toxic and does not have tachycardia or show involuntary guarding, then a course of outpatient oral antibiotics is likely to be appropriate. Alternatively, for a patient with fever, tachycardia, and involuntary guarding triage for admission for intravenous antibiotics is probably best. If the patient exhibits more diffuse tenderness, surgical evaluation and possibly even urgent surgical intervention are often required. 2.3

Laboratory and Radiological Assessment

Patients should have a complete blood count (CBC) with differential performed. Although some patients with an intra-abdominal infection may have a normal white blood cell count, most have a polymorphonuclear predominance. A patient with epigastric or right upper quadrant pain usually requires evaluation of liver transaminases, alkaline phosphatase, and lipase or amylase. Young women with right lower quadrant pain usually require urinalysis and urine pregnancy test. The urinalysis may also be helpful in excluding urinary tract infection and nephrolithiasis. If a confident diagnosis cannot be made on the basis of history, physical examination, and laboratory evaluation, then radiological studies are warranted and appropriate. A simple plain film of the abdomen can be useful to look for kidney stones, or gallstones, evidence of small bowel obstruction, or an appendicolith. Upright films may reveal free intraperitoneal air, indicative of perforation. In selected circumstances, imaging studies are very useful when guided by specific clinical concerns. If the diagnosis is not clear from the history, physical examination, and laboratory studies, a computed tomographic (CT) scan with oral, intravenous, and occasionally rectal contrast media may be helpful. In many circumstances, it may not be possible to secure a diagnosis on the basis of a ‘‘snapshot’’ in time. With continuing observation, often in an outpatient setting, the signs and symptoms become more focused and allow for an accurate diagnosis. The only decisions that are required initially are whether the patient requires an urgent operation or admission to the hospital. A patient who is tachycardic and toxic with local peritoneal signs is best admitted to the hospital for observation. Alternatively, a patient who does not appear particularly ill and has a short history of right lower quadrant pain without peritoneal signs can often be followed as an outpatient with follow-up telephone contact and/or repeated physical examination. An approach to the patient with suspected intra-abdominal infection is given in Figure 1.

3

PERITONITIS

The peritoneal membrane surrounds most of the intra-abdominal organs. It extends from the diaphragm to the pelvis. The kidneys, postbulbar duodenum, pancreas, and portions of the colon are retroperitoneal. Intra-abdominal infection may therefore reside within the peritoneal cavity or the retroperitoneal space. Peritonitis is inflammation of the peritoneal membrane. Within the peritoneum, the infection may be localized or diffuse. Diffuse peritonitis can be caused by bacterial seeding of ascites fluid (primary peritonitis) or a perforation of an abdominal viscus (secondary peritonitis). Localized peritonitis can occur next to an inflamed organ such as the appendix, gallbladder, or colonic diverticula. Peritonitis complicating peritoneal dialysis is reviewed in Chapter 36.

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DIFFUSE PERITONITIS Primary or spontaneous bacterial peritonitis (SBP) Most common in patients with advanced alcoholic liver disease, cirrhosis, and ascites Abdominal pain and fever, though patients may be afebrile and less commonly may not experience abdominal pain Ascitic fluid polymorphonuclear neutrophil (PMN) > 250/mm3 Monobacterial with aerobic gram-negative rods (GNRs) and S. pneumoniae most common Empirical therapy with ceftriaxone Secondary peritonitis Due to intra-abdominal viscus perforation Sudden onset of pain, fever, nausea, and vomiting May progress rapidly to septic shock Free peritoneal air sometimes seen on acute abdominal series Urgent surgical intervention required Antibiotic therapy (Table 2)

3.1

Diffuse Primary Peritonitis

Primary or spontaneous bacterial peritonitis (SBP) is an infection predominantly seen in patients with alcohol-induced hepatic cirrhosis and ascites. Less commonly, primary peritonitis can develop in patients with ascites due to other causes of liver failure, congestive heart failure, or malignancy. Bacteria enter the peritoneal fluid either hematogenously, from the lymphatic circulation, or directly from transmigration across the intact bowel wall. The damaged reticuloendothelium of the cirrhotic liver is unable to clear bacteria from the blood as it normally should. Bacteria entering the blood from any source are therefore not cleared and have a higher rate of seeding of the ascitic fluid in the peritoneum. Since the peritoneal fluid infection is not due to a perforated viscus, the peritonitis is classically monobacterial. Gastrointestinal aerobic gram-negative rods (GNRs) such as Escherichia coli, Klebsiella spp., Proteus spp., and Enterobacter spp. account for the

< Figure 1 Approach to the patient with abdominal pain due to infection. Abdominal pain that has an infectious cause may produce localized or diffuse discomfort. Patients with diffuse abdominal pain should be admitted to the hospital for surgical evaluation and CT imaging as needed. If spontaneous bacterial peritonitis is suspected, the patient should undergo paracentesis. Patients with suspected diverticulitis or cholecystitis who are not acutely ill can be managed with oral antibiotics as long as close follow-up and surgical consultation are arranged. Patients with moderate or severe infection require hospitalization. The type of antibiotic empiricism is based on the severity of illness. Those who appear more ill should receive a broader spectrum of antibiotics. Patients with suspected parenchymal abscesses should undergo CT imaging. (1) Mild: abdominal pain controlled with oral analgesics, ability to take oral medications and maintain hydration. (2) Anaerobic agents include clindamycin or metronidazole (3) See Table 2 for dosage. (4) Moderate illness is severe enough to warrant hospitalization, but patient is not hypotensive or requiring intensive care (ICU) monitoring. (5) Severe illness requires ICU monitoring and blood pressure support. GU, genitourinary tract; LDH, lactate dehydrogenase; PMN, polymorphonuclear neutrophil; ICU, intensive care unit; CT, computed tomography. (Adapted from Grace and Ahern 2001.)

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majority of infections. Less commonly seen today are infections from Streptococcus pneumoniae, other Streptococcus spp., and Enterococcus spp. Staphylococcus aureus accounts for about 4% of infections. Anaerobic bacteria such as Bacteroides spp. are uncommon. In about a third of patients with SBP, the ascites culture finding is negative. Typically, the patient reports acute onset of diffuse abdominal pain, fever, nausea, and vomiting. Patients may be afebrile and on occasion have no abdominal tenderness. Therefore, all patients with cirrhosis-related ascites should have paracentesis to exclude SBP. Fluid obtained by paracentesis should be sent for protein analysis and cell count. An accepted definition of SBP is an ascites fluid neutrophil count >250 polymorphonuclear neutrophils/mm3. An ascites fluid lactate of ⱖ25 mg/dl and a pH 60 years, recurrent cholecystitis, and history of postcholecystectomy jaundice or common bile duct exploration or instrumentation. In the periphery of the liver there are direct connections between the branches of the bile duct and the hepatic venous system, which allow direct access of infected bile to the systemic circulation. A patient with acute cholangitis typically experiences epigastric or right upper quadrant pain, nausea, fever, and jaundice. The classic Charcot’s triad of fever, jaundice, and right upper quadrant pain is seen in only 19% of patients. Liver transaminases and alkaline phosphatase are often very abnormal. Leukocytosis can be marked. Patients with cholangitis are often quite ill, tend to have positive blood culture findings, and are frequently hemodynamically unstable.

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All patients with suspected cholangitis require hospital admission for vigorous fluid resuscitation, intravenous antibiotics, and careful observation. Prompt endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic sphincterotomy and biliary drainage allows for prompt relief of obstruction and clinical improvement in the vast majority of cases. Laparoscopic cholecystectomy may then be undertaken at a later date to prevent recurrence of cholangitis or biliary symptoms. For elderly or chronically ill patients, cholecystectomy may not be required as many such patients have no further biliary tract problems. If endoscopic decompression is not successful or available, then prompt surgical management via cholecystectomy is warranted. 3.3.3

Appendicitis

Appendicitis occurs when a fecalith or lymphatic swelling causes obstruction of the appendiceal orifice. The appendix becomes swollen, engorged, and infected. The classic presentation is vague periumbilical pain that migrates over time to the right lower quadrant as visceral inflammation progresses to parietal peritoneal inflammation. There are generally anorexia, nausea, low-grade fever, and a modest leukocytosis. When appendicitis occurs in this manner, the diagnosis is usually straightforward and an appendectomy is performed. However, many cases present atypical features that readily lead the clinician astray. Patients may have urinary symptoms or abnormalities on a urinalysis suggestive of a urinary tract infection or diarrhea suggestive of gastrointestinal infection. In women of childbearing age the differential diagnosis includes ovarian cyst, ectopic tubal pregnancy, and tubo-ovarian abscess. Acute appendicitis is the second most common cause of surgical abdominal disease in older adults. These patients may have atypical symptoms, plus the diagnosis is often not entertained early enough by the clinician. As compared to younger patients, they have a higher incidence of delayed diagnosis with subsequent perforation. A ruptured appendix can be a serious and life-threatening emergency. A patient with a ruptured appendix usually requires more prolonged hospitalization and is subject to a higher rate of postoperative abscess or wound infection. Long-term sequelae such as small bowel obstructions and infertility of women of childbearing age are real concerns. Historically, surgeons have been trained to ‘‘shoot for’’ an accuracy rate of approximately 85% when operating on a patient with presumed appendicitis. The rate of finding a normal appendix at appendectomy in women of childbearing age has commonly been in the range of 30%–40%. This is one area where radiological imaging, most notably CT scanning, has represented a major advance. When the diagnosis is not straightforward, CT scan has emerged as a very accurate modality to make the diagnosis. Another use of CT scan is to exclude appendicitis in patients that are thought to have a low likelihood of the disease, thereby preventing unnecessary surgical exploration to rule out appendicitis. A normal CT scan result may prevent admission from the primary care physician’s office. An appendiceal mass may be due to a periappendiceal abscess or phlegmon. The patient may report right lower quadrant pain that has waxed and waned for days to weeks. A right lower quadrant mass may be found on palpation of the abdomen. A CT scan usually shows a phlegmon of matted loops of intestine or a discrete collection of pus around the base of the cecum (abscess cavity). If there is an appendiceal phlegmon, intravenous antibiotics frequently suffice. A true abscess may be managed by radiographically guided percutaneous drainage coupled with appropriate antibiotics. In both of these scenarios, interval appendectomy can be performed 6 to 12 weeks later, often with laparoscopic assistance and a short hospital stay. A evaluation to exclude other causes of a

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right lower quadrant mass such as a perforated cecal neoplasm, Crohn’s disease, or cecal diverticulitis is usually warranted. This can be achieved by colonoscopy with ileal intubation or alternatively by barium enema and/or small bowel series. 3.3.4 Diverticulitis Diverticula are herniations of the mucosa and submucosa through the colonic wall where the branches of the marginal arteries penetrate the colonic tunica muscularis. Strictly speaking, these are actually pseudodiverticula since the muscle is not part of the herniated sac. Diverticula are most commonly found in the sigmoid and descending colon in persons of Western societies, although they can occur anywhere throughout the large intestine. In Asian societies, diverticula are more common in the ascending colon. Diverticula are typically small (5–10 mm) and number from very few to hundreds. Diverticulosis appears to have been relatively rare before the 20th century. However, with the advent of refineries and the marked reduction in dietary fiber, diverticulosis has become a very common condition. Although the true incidence of diverticulosis in Western societies is not clear, the condition clearly increases in frequency with age and probably occurs in at least two-thirds of adults older than 85. Patients with uncomplicated diverticular disease may experience intermittent abdominal pain and bloating that can be exacerbated by eating and relieved with defecation. There are no signs of peritoneal inflammation. Diverticulitis is probably better termed peridiverticulitis since the infection results from micro- or macroperforations of a diverticulum with an associated inflammatory response in the surrounding soft tissue. Presumably undigested food and bacteria collect in the diverticula, leading to ischemia, obstruction, and inflammation. Perforation of the fundus of the herniation can lead to limited pericolonic inflammation or more seriously to a diffuse secondary peritonitis or abscess formation. Diverticulitis occurs in up to 20% of patients with diverticulosis; the risk increases with age and the larger number of diverticula. The disease is more common in men than in women and occurs most commonly in the sigmoid colon. Patients with diverticulitis typically experience left lower quadrant pain associated with altered bowel habits, nausea, vomiting, and a low-grade fever. Urinary frequency or urgency can occur when there is a diverticular mass irritating the urinary bladder. Concommitant gastrointestinal bleeding is rare. On physical examination, there is generally left lower quadrant tenderness, although the maximal tenderness may be in the suprapubic area or even to the right of midline. Guarding and rebound may be present, and a mass is occasionally palpable. There may be tenderness in the left lower quadrant on rectal exam. It should be remembered that the sigmoid colon often deviates well to the right of midline, and the distinction between diverticulitis and appendicitis may be difficult in this setting. A WBC can be helpful in assessing severity of infection and response to treatment, but in many cases leukocytosis is absent. Patients who have classic signs and symptoms do not necessarily require any imaging studies during the acute illness. Sigmoidoscopy and colonoscopy are usually contraindicated in acute conditions because of the risk of perforation from air insufflation. Patients with localized tenderness who do not appear toxic and do not have a high fever or peritoneal signs can often be managed as outpatients with oral antibiotics. Although somewhat controversial, a low-residue diet is probably better tolerated by the patient in the acute phase. Patients should be advised to report new or worsening symptoms. Should the situation worsen or fail to resolve on oral antibiotics, surgical consultation is warranted. Hos-

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pitalization for intravenous antibiotics (Table 2) may be required. If there is no response to antibiotic therapy in 48–72 hours, a CT scan is frequently very helpful to assess for an abscess. Water-soluble contract studies can also make the diagnosis, but CT scanning is generally more accurate and provides more clinically useful information. Although these scans reliably demonstrate abscesses that occur outside the colon, they often do not reveal abscesses contained within the leaves of the mesentery or in the bowel wall itself. If the diagnosis of diverticulitis appears secure and there is no response to appropriate antibiotic therapy, surgical resection is appropriate even though an abscess is not demonstrable by CT scan. When a CT scan does show an overt abscess, it can be drained percutaneously. This approach can prevent urgent surgery, which often necessitates temporary colostomy formation. Successful drainage often relieves symptoms and allows for bowel preparation and an elective single-stage surgical procedure (resection and anastomosis). Once an episode of diverticulitis has been successfully treated with antibiotics, subsequent work-up with sigmoidoscopy and/or barium enema is appropriate to document the presence of diverticula and to exclude a colonic neoplasm. Once the acute symptoms have resolved, there is some evidence that a high-fiber diet may decrease the risk of subsequent episodes. Patients who have recurrent episodes should be evaluated for elective surgical resection. A recommendation for surgery is often made on the basis of the fear of perforation with a subsequent episode. However, this possibility, although legitimate, is probably overestimated. Most patients who experience a perforation usually do so on the initial episode of diverticulitis. It is rather uncommon for a patient who has previously been treated for diverticulitis to experience perforation. In a 10-year review at our institution, there was only one case of diverticular perforation in a patient who had previously been treated for an episode of acute diverticulitis (unpublished data). Therefore, the decision for elective surgery is probably best made on a case-by-case basis. Surgery is highly effective in preventing recurrent diverticulitis, with postsurgical recurrence rates less than 10% if the procedure is performed properly. However, the surgeon must also consider the short-term risks of colectomy and the potential longer-term problems such as ventral hernias and adhesive small bowel obstruction. Probably the most important factors are the difficulty of treating the patient’s episodes, their frequency, and their effect on the patient’s quality of life. 3.4

Antimicrobial Therapy for Localized and Secondary Peritonitis

The bacteriological characteristics of appendicitis and diverticulitis reflect the bacterial flora of the colon, whereas the pathogens of cholecystitis reflect duodenal bacteria. The stomach and upper small bowel generally contain a sparse flora (1010 bacteria/ml). Intra-abdominal infections therefore are polymicrobic, and antimicrobial therapy must be directed at this diverse flora. Although enterococci are part of the normal bowel flora and may be involved in 15%–20% of intra-abdominal abscesses, there is controversy regarding the need to treat enterococci in all patients with intra-abdominal infections.

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Empirical therapy for Candida spp. is generally not indicated. The antimicrobial activities of various agents that may be used to treat intra-abdominal sepsis are summarized in Table 1. Antimicrobial therapy should be used in addition to surgery except in mild diverticulitis. Antibiotics should be started after blood cultures have been drawn but before surgery. Most antibiotic regimens include agents active against aerobic GNRs (gentamicin, trimethoprim & sulfamethoxazole, ceftriaxone, ciprofloxacin) and anaerobes (clindamycin or metronidazole). Agents that have activity against both aerobes and anaerobes (ampicillin with clavulanic acid, cefotetan, ampicillin with sulbactam, imipenem with cilastatin, piperacillin with tazobactam) may be used with equal efficacy. Enterococcal activity can be added with ampicillin or vancomycin or as part of the spectrum of piperacillin or imipenem-cilastatin for life-threatening infections. Therapy should generally be continued for 24–48 hours, depending on improvement of clinical features such as normalization of the WBC, defervescence of fever, and resolution of the associated ileus. Longer courses may be needed if the patient is not improving. Suggested regimens for outpatient and inpatient management are outlined in Table 2. 4 4.1

INTRAPARENCHYMAL ABSCESSES Hepatic Abscess

Pyogenic liver abscess (PLA) is a focal collection of purulent material caused by bacteria or fungi and less commonly by parasitic agents such as Entamoeba histolytica. Agents

Table 1 Relative Activitiesa of Antimicrobial Agents Used to Treat Intra-Abdominal Infections

Antibiotic

Non-pseudomonas species Gram-negative gram-negative aerobes anaerobes

Aminoglycoside Ampicillin Ceftazidime Cefotetan Ceftriaxone Ciprofloxacin Clindamycin Co-trimoxazole Imipenem/meropenem Metronidazole Piperacillin

⫹⫹⫹ ⫹ ⫹⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹⫹ ⫺ ⫹⫹ ⫹⫹⫹ ⫺ ⫹⫹

⫺ ⫺ ⫺ ⫹⫹ ⫺ ⫺ ⫹⫹⫹ ⫺ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹

Piperacillin/tazobactam

⫹⫹⫹

⫹⫹⫹

Trovafloxacin Vancomycin Amoxicillin/clavulanate Cefpodoxime

⫹⫹⫹ ⫺ ⫹⫹ ⫹⫹

⫹⫹⫹ ⫺ ⫹⫹ ⫺⫺⫺

Pseudomonas aeruginosa

Enterococcus species

⫹⫹⫹ ⫺ ⫹⫹⫹ ⫺ ⫺ ⫹⫹⫹ ⫺ ⫺ ⫹⫹ ⫺ ⫹⫹ (Use w/ aminoglycoside) ⫹⫹ (Use w/ aminoglycoside) ⫹⫹⫹ ⫺ ⫺⫺⫺ ⫺⫺⫺

⫺ ⫹⫹ ⫺ ⫺ ⫺ ⫹ ⫺ ⫺ ⫹⫹ ⫺ ⫹⫹

a ⫺, no activity; ⫹, limited activity; ⫹⫹, moderate activity; ⫹⫹⫹, high activity. Source: Adapted from Grace CJ et al. 1999.

⫹⫹⫹ ⫹ ⫹⫹⫹ ⫹⫹⫹ ⫺⫺⫺

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Table 2 Antimicrobial Therapy for Intra-Abdominal Infections Dosagea

Regimen Oral therapy for mild diverticulitis or cholecystitis Amoxacillin-clavulanic acid Co-trimoxazole or cefpodoxime proxetil or ciprofloxacin and metronidazole or clindamycin Intravenous Moderate illness (see text and Figure 1) Cefotetan Gentamicin or ceftriaxone or co-trimoxazole plus metronidazole or clindamycin Severe illness (sepsis, shock, ICU admission) Gentamicin or ceftriaxone and metronidazole as above and ampicillin Piperacillin-tazobactam and gentamicin as above Ciprofloxacin and metronidazole, ampicillin as above

875 mg bid Double-strength bid 400 mg bid 500 mg bid 500 mg tid 300 mg qid

2 g q12h 7 mg/kg/dayb 1 g/day 10 mg/kg/day In divided doses 500 mg q8h 600 mg q8h

1 g q6h 3.375 g q6h

400 g q8h

a

Assuming normal renal function. ICU, intensive care unit. See Chapter 4, Tables 3 and 4.

b

may be single or multiple. It is an uncommon but potentially life-threatening infection intra-abdominal infection. Bacteria or fungi gain access to the liver parenchyma via the portal vein from appendicitis or diverticulitis or via the hepatic artery during a systemic bacteremia. There can be contiguous spread from an infected gallbladder or obstructed biliary tree. The most common cause of PLA is biliary tract disease. Patients at increased risk include those with diabetes mellitus, cirrhosis, malignancy, inflammatory bowel disease, immune suppression, chronic granulomatous disease, and malnutrition. Patients with chronic indwelling central venous catheters and those who have had hepatobiliary instrumentation are also at higher risk. PLAs are most often polymicrobic, reflecting the frequent origin from biliary and bowel lesions. Aerobic GNRs, anaerobes, and enterococci are often

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INTRAPARENCHYMAL ABSCESS Hepatic Related to biliary or colonic disease or bacteremia Days to weeks of symptoms Right upper quadrant (RUQ) pain, fever Diagnosis by computed tomography (CT) scan or sonography Drainage and prolonged antibiotics Repair of underlying gastrointestinal source Splenic Caused by bacteremia, most often from endocarditis Acute onset of left upper quadrant (LUQ) pain radiating to shoulder and fever Diagnosis by CT scan or sonography Antibiotics and splenectomy (less commonly percutaneous drainage) Pancreatic Caused by bacterial contamination of severe pancreatitis Difficult to differentiate from sterile pseudocyst Diagnosis by CT scan Renal Perinephric Ascending genitourinary (GU) infection Increased risk with renal stones and/or obstruction Persistent flank pain and fever Urinalysis and culture results most often positive except with complete obstruction Aerobic gram-negative rods (GNRs) most often Percutaneous drainage and antibiotics Intrarenal Hematogeneous in origin S. aureus most common Concern for bacteremia and renal abscess raised by S. aureus in urine Urinalysis result possibly normal Diagnosis by CT scan Percutaneous drainage and antibiotics

involved. Monobacterial infections with Staphylococcus aureus, Yersinia spp., and Candida spp. can occur. Patients with PLA generally experience several weeks of nonspecific symptoms including fever, malaise, weight loss, and abdominal pain. The discomfort is not always localized to the right upper quadrant. Physical examination may reveal abdominal tenderness, hepatomegaly, and, less often, jaundice and right lower lung abnormalities. Laboratory assessment generally shows a leukocytosis and elevations of alkaline phosphatase and, less often, transaminases. Diagnosis is confirmed with ultrasonography or CT scan imaging. CT performed with intravenous contrast medium has a sensitivity of approximately 95% and is best for detecting multiple lesions. Treatment generally requires percutaneous drainage, antibiotics, and management of the underlying cause of the PLA. Surgery may be required if percu-

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taneous drainage is unsuccessful and/or for treatment of the causative biliary or intestinal infection. Empirical antibiotics should cover aerobic and anaerobic GNRs and enterococci (see Tables 1 and 2). If S. aureus or streptococci are suspected because of the possibility of endocarditis, nafcillin or vancomycin can be used alone or added to the current regimen (see Table 2). The initial antibiotic selection should be adjusted on the basis of blood and abscess culture results. 4.2

Splenic Abscess

Splenic abscess is a rare complication of bacteremia that commonly originates from endocarditis. Patients at increased risk include those who have sickle cell disease and those who use injection drugs. S. aureus and streptococci are the most common pathogens, though aerobic and anaerobic GNRs have also been involved. Twenty-five percent are polymicrobic. Patients have fever and left upper quadrant (LUQ) pain that may be referred to the left shoulder. Physical examination reveals tenderness in the LUQ and occasionally pulmonary rales and evidence of a left pleural effusion. Seventy percent of patients have positive blood culture results. Diagnosis is confirmed by CT scan imaging. Initial empirical antibiotics should include a combination of 1) ceftriaxone or ciprofloxacin, and 2) ampicillin or vancomycin, and 3) metronidazole or clindamycin. Single agents such as piperacillin with tazobactam or imipenem with cilastatin can also be used. The initial antibiotic selection should be based on blood and abscess culture results. Splenectomy is generally required, although percutaneous drainage may be attempted in selected circumstances. 4.3

Pancreatic Abscess

The majority of cases of pancreatitis resolve without sequelae. However, pancreatic abscesses may originate as a complication of severe pancreatitis. The necrotic pancreatic tissue becomes secondarily infected from the biliary tree, duodenum, or transverse colon. Therefore, most of these infections are polymicrobic, reflecting the regional bowel flora. Patients have fever and midabdominal pain that radiates to the back. The abscess may develop acutely during a severe episode of pancreatitis. Amylase or lipase is often elevated. Pancreatic ‘‘abscesses’’ are quite different from other intra-abdominal abscesses in regard to the nature of the problem and management. The digestive pancreatic enzymes obtain access to the peripancreatic space, causing necrosis of the retroperitoneal fat. There is essentially a retroperitoneal ‘‘burn’’ with a severe inflammatory response, potentially causing massive fluid shifts and extensive cytokine release. These patients are often hemodynamically unstable and at considerable risk for progressive multiorgan failure. Initial treatments for this necrotizing infection are hemodynamic support and intensive care. Serial CT scanning is very useful to follow the course of the inflammatory response and assess for the development of infected necrosis. Although somewhat controversial, antibiotics probably are helpful in selected cases of severe pancreatitis associated necrosis (see Tables 1 and 2). Clinical deterioration, positive blood culture findings, or the appearance of gas bubbles around the pancreas suggests the development of infection, complicating the intrinsic inflammatory nature of the pancreatitis. CT-guided fluid aspiration can confirm the presence of infection. It is at this point that drainage may be helpful. As opposed to other intra-abdominal ‘‘abscesses’’ that are confined collections of purulent material, large amounts of infected retroperitoneal soft tissue, when present, limit the efficacy of CT-

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guided percutaneous drainage. Surgical de´bridement, often done repetitively as further necrosis ensues, is often required to salvage these challenging patients. On other occasions, an episode of pancreatitis may resolve, leaving a loculated collection of pancreatic fluid (pancreatic pseudocyst). Many resolve with expectant management, but others may require radiological, endoscopic, or surgical drainage. 4.4

Renal Abscess

Renal abscesses may be perinephric or intrarenal in location. Perinephric abscesses are generally seen in patients with diabetes mellitus and/or kidney stones. There is often obstruction of the genitourinary tract. These infections are most often due to aerobic GNRs. Intrarenal abscesses originate from a bacteremia and are most often due to S. aureus. Patients report fever and unilateral flank pain. They may have originally been treated for pyelonephritis but either did not respond or quickly relapsed. The urinalysis may yield normal results, especially with intrarenal abscesses. Diagnosis is confirmed with CT or sonographic imaging. Therapy consists of percutaneous drainage and antibiotics aimed at the offending pathogen. 5

SURGICAL PROPHYLAXIS

In recent years, there has been an increasing emphasis on ‘‘tightening up’’ the indications for antibiotic usage both to prevent and to treat surgical infections. There is increasing concern about resistant bacteria, and multiple studies have shown the lack of benefit and possible detriment of prolonged courses of antibiotics. The ‘‘more must be better’’ ap-

Table 3 Categories of Surgical Procedures Type of surgery Clean Elective surgery No inflammation or break in sterile technique No entry of a contaminated cavity such as the gastrointestinal or genitourinary tract Clean-contaminated Otherwise clean surgery done emergently Controlled entrance into a colonized body cavity Contaminated Acute nonpurulent inflammation Major contamination from a colonized body cavity Dirty Overt purulence encountered Preoperative perforation of a colonized body cavity Source: Adapted from Grace and Ahern 2001.

Example

Infection risk

Hernia repair

1%

Elective colon resection

8%

Colon resection for acute diverticulitis

15%

Colon resection for perforated diverticulitis

40%

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proach is steadily being replaced by a more judicious and focused approach. One example of this is in surgical prophylaxis. The goal of perioperative antibiotics is to prevent wound infection. The probability of wound infection in any particular case can be predicted on the basis of category of procedure (Table 3). It is clear that antibiotic prophylaxis is effective in reducing the wound infection rates for clean, uncontaminated cases but should only be administered perioperatively. A more prolonged course of antibiotics should be used for contaminated or dirty cases since there are generally residual bacteria in the peritoneal cavity. Prophylactic antibiotics should be administered on induction of anesthesia to provide high tissue levels during the surgical procedure. Antibiotics with short half-lives may need redosage during the surgical procedure. Postoperative antibiotics should be limited to 24 hours if given at all. The antibiotic chosen should have a narrow spectrum specific to the expected pathogens. See Figure 2 for antibiotic suggestions based on the type of surgery being performed. Luminal antibiotics should probably be used in addition to parenteral agents for colorectal prophylaxis. A common regimen includes 1 gram of oral erythromycin base and oral neomycin given at 1 p.m., 2 p.m., and 11 p.m. the day before surgery.

6 HELICOBACTER PYLORI INFECTION Heliobacter pylori (formerly Campylobacter pylori) is a motile, urease-producing gramnegative rod that lives in the mucus layer overlying the gastric mucosa. Humans are the major and possibly the only reservoir. It is a very common pathogen, infecting most people living in third world countries and 50%–60% of persons above 60 years of age living in the United States. H. pylori has been associated with gastritis, peptic ulcer disease, atrophic gastritis, gastric carcinoma, and gastric mucosa-associated lymphoid tissue (MALT) lymphomas. H. pylori does not appear to be tissue-invasive, and the mechanism of tissue damage is not clear. The microbial urease produces ammonia that protects the organism from gastric acid and may potentiate neutrophil-induced gastric injury. The identification and eradication of H. pylori–associated duodenal ulcer disease have been a major advance. Whereas recurrent ulceration after cessation of antisecretory treatment was extremely common in the past, successful eradication of H. pylori has now dramatically reduced the rate of recurrent ulcers.

HELIOBACTER PYLORI Associated with peptic duodenal or gastric ulcer, gastric carcinoma, and lymphoma Protective for gastroesophageal reflux disease (GERD), Barrett’s esophagus, adenocarcinoma of esophagogastric junction Testing Patients with peptic ulcer disease Endoscopy, serological analysis, or urease breath test Not for asymptomatic patients Treatment (Table 3) Peptic ulcer disease in H. pylori–positive patients Mucosa-associated lymphoid tissue (MALT) lymphoma

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Figure 2 Surgical prophylaxis. Antibiotics used to prevent surgical wound infections should be given immediately before skin incision. The type of antibiotic(s) used depends on the types of bacteria expected to be encountered. Operations should be considered to be clean, clean-contaminated, contaminated, or dirty (see Table 3). Suggested antibiotics and dosages are provided in the figure. For prolonged procedures, repeat dosage may be needed. Postoperative prophylaxis is not effective. (1) Some authorities add gentamicin for head and neck surgery. (2) For penicillin allergy. (Adapted from Grace and Ahern 2001.)

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The question remains whether or not H. pylori should be routinely sought after and eradicated even when it is not producing a specific complication such as peptic ulcer disease. The argument for routine treatment is prevention of peptic ulcer disease and possibly carcinoma of the stomach. With the apparent decrease in H. pylori infections in some Western societies, there has been a parallel decrease in the incidence of distal gastric malignancies. However, despite the link between H. pylori and gastric malignancy, evidence is lacking that eradicating infection actually reduces the risk of gastric carcinoma. There are potential downsides of routine H. pylori treatment. These include the obvious risk of selecting for resistant bacteria and the development of antibiotic complications such as C. difficile colitis. Certain strains of H. pylori have been epidemiologically

Table 4 Treatment Regimens for Helicobacter pylori Infection Regimen 7–10 Days Proton pump inhibitor omeprazole 20 mg bid or lansoprazole 30 mg bid plus Clarithromycin (500 mg PO bid) plus Amoxicillin (1 g PO bid) or Metronidazole (500 mg PO bid) 7–10 Days Ranitidine 300 mg bid plus Clarithromycin 500 mg bid plus Amoxicillin 1000 mg PO bid or Metronidazole 500 mg PO bid 2 Weeks Pepto-Bismol 2 tab qid plus Tetracycline 500 mg qid plus Metronidazole 500 mg tid Combination packets Helidac qid Bismuth 262.4 mg Metronidazole 250 mg Tetracycline 500 mg Prevpac bid Lansoprazole 30 mg Amoxicillin 500 mg Clarithromycin 500 mg a

Costsa $78.00 For 10 days

$74.00 For 10 days $72.00 For 10 days $18.40 For 10 days $60.00 For 10 days $64.00 For 10 days As above As above As above Over-the-counter $5.00 For 14 days $84.00 For 14 days $80.48 For 14 days

$252.00 For 14 days

Average wholesale price, Drug Topics 2000 Red Book.

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associated with protection against gastroesophageal reflux disease (GERD), Barrett’s esophagus, and adenocarcinoma of the esophagogastric (EG) junction. Routine treatment of H. pylori may decrease the risk of distal gastric malignancies at the expense of increasing the risk of GE junction malignancy. Therefore, routine eradication of H. pylori is not recommended at this time except in the treatment of symptomatic ulcer disease. Eradication may be reasonable in selected patients such as those with a history of cigarette smoking and family history of distal gastric adenocarcinoma. The routine testing and treatment of dyspeptic patients without endoscopic or radiographic documentation of ulcer disease have been suggested, though this course remains controversial. There are no data concerning postoperative treatment for H. pylori in patients who have undergone surgery for ulcer disease. Testing for H. pylori may be performed in three ways, all of which have excellent accuracy: 1) upper endoscopy and biopsy with samples taken for culture and staining of the organism and detection of preformed urease; 2) the urease breath test, involving the ingestion of radiolabled urea13 or urea14 containing meal and breath testing for CO213 or 14; and 3) serological testing for immunoglobulin G (IgG) and less commonly IgM antibodies to H. pylori. Drug therapy involves a bismuth salt combined with a type 2 histamine (H2) blocker (ranitidine) or proton pump inhibitor (PPI) (omeprazole 20 mg bid or lansoprozole 30 mg bid), together with two antibiotics. The PPI not only reduces gastric acidity but may also inhibit the bacterial urease. Antibiotics with clinical activity include amoxicillin, tetracycline, metronidazole, and clarithromycin. Several suggested treatment regimens are outlined in Table 4. Commercially available combination packets can simplify administration and improve compliance. Eradication rates approaching 80%–90% can be achieved. The urease breath test is the simplest follow-up test to prove eradication. Serological evaluation should not be used for posttreatment test of cure. If eradication is not achieved, a second-line treatment should be instituted. If clarithromycin and ampicillin are used in the primary treatment, then the second-line regimen should include a 7-day course of a PPI, bismuth subsalicylate (PeptoBismol), tetracycline, and metronidazole. If failure persists, H. pylori antimicrobial testing is warranted. BIBLIOGRAPHY Arnbjornsson E. Management of appendiceal abscess. Curr Surg 4:4–8, 1994. De Boer WA, Tytgat NJ. Treatment of Heliobacter Pylori infection. Br Med J 320:31–43, 2000. Dellinger EP, Gross PA, Barnett TL, Krause PJ, Martone WJ, et al. Quality standard for antimicrobial prophylaxis in surgical procedures. Clin Infect Dis 18:422–427, 1994. Elsakr ER, Johnson DA, Younes Z, Oldfield EC. Antimicrobial treatment of intra-abdominal infections. Dig Dis 16;47–60, 1998. Grace C, Ahern J. Guide to Antimicrobial Therapy for Adults. Burlington, VT: Fletcher Allen Health Care, 2001. Grace CJ, Alston WK, Ramundo MB. Pyogenic liver abscess. In: Medical Management of Liver Disease. New York: Marcel Dekker, 1999. Hardin DM. Acute appendicitis: Review and update. Am Fam Physician 60:2027–2034, 1999. Johnston DE, Kaplan MM. Pathogenesis and treatment of gallstones. N Engl J Med 328:412–424, 1993. Kohler L, Sauerland S, Neugebauer E. Diagnosis and treatment of diverticular disease: Results of a consensus development conference: The Scientific Committee of the European Association for Endoscopic Surgery. Surg Endosc 13:430–436, 1999.

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Lillemore KD. Surgical treatment of biliary tract infections. Am Surg 66:138–144, 2000. Parks TG. Natural history of diverticular disease of the colon. Clin Gastroenterol 4:53–61, 1975. Stollman NH, Raskin JB. Diverticular disease of the colon. J Clin Gastroenterol 29:241–252, 1999. Westphal JF, Brogard JM. Biliary tract infections: A guide to drug treatment. Drugs 57:81–91, 1999. Williams MP, Pounder RE. Heliobacter pylori: From the benign to the malignant. Am J Gastroenterol 94(suppl):511–516, 1999. 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics, 2000.

25 The Patient with Human Immunodeficiency Virus Infection Recognition, Testing, and Initial Assessment Kenneth H. Mayer Brown University, and The Miriam Hospital, Providence, Rhode Island, U.S.A.

Daniel E. Cohen Fenway Community Health, Boston, Massachusetts, U.S.A.

1 1.1

INTRODUCTION The Epidemic of Human Immunodeficiency Virus

In the early 1980s, clinicians in San Francisco, Los Angeles, and New York began reporting the appearance of unusual malignancies and opportunistic infections among men who had sex with men (MSM) and intravenous drug use (IDU), suggesting a syndrome of acquired, not endogenous, immune deficiency possibly due to a transmissible agent. In 1984 the human immunodeficiency virus (HIV) was identified independently by laboratories in the United States and France. HIV originated on the African continent and is the cause of acquired immunodeficiency syndrome (AIDS). Tremendous strides have been made in the treatment of HIV infection since 1996, primarily related to the advent of highly active antiretroviral therapy (HAART). The AIDSrelated mortality rate and opportunistic illnesses among HIV-infected patients have decreased and patients’ quality of life has improved. However, the advent of new therapies, monitoring schema, and drug toxicities has complicated the management of HIV infection as a chronic disease. The standard of care changes almost on a monthly basis, as results from ongoing clinical trials are reported, and even optimally treated patients may not respond appropriately to therapy. HIV-positive patients are still at greater risk of illness and death than the population at large. For these reasons patients with HIV infection have better outcomes when under the care of clinicians with experience in the management of HIV disease. Although specialists may play an increasingly central role in managing patients once they are found to be HIV-infected, well-informed primary care providers are an essential part of any effective HIV treatment and prevention program. The prompt identification of HIV infection by primary care providers is vitally important, since they may be the first clinicians to have contact with at risk individuals soon after they are infected. Multiple 495

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studies have demonstrated that earlier entry into care is associated with improved outcomes for HIV-infected patients. Of the 750,000 to 900,000 Americans living with HIV infection, more than one-third are unaware of their infection and an almost equal number know they are HIV-infected are not receiving state-of-the-art care. Primary providers can play a vital role in identifying these individuals and triaging them to colleagues who can provide appropriate services. In addition to identifying HIV-infected patients who are unaware of their serostatus, primary providers can play a crucial role in HIV risk reduction and thus in slowing the spread of the epidemic. Over the past few years, the rate of new HIV infections has plateaued at 30,000–50,000 per year. The majority of men and women in ‘‘high-risk groups’’ are uninfected. Therefore, clinical encounters with primary providers provide an important opportunity to convey information about the patient’s risk of infection and ideally to impart skills and motivation to help him or her reduce that risk. 1.2

Virological Characteristics

HIV is a retrovirus, meaning that its genome is composed of ribonucleic acid (RNA) but that its life cycle includes a deoxyribonucleic acid (DNA) intermediate (the provirus) that integrates into target cells, necessitating the transcription of DNA from RNA (so-called reverse transcription). The virus has several unique steps in its life cycle that offer opportunities for effective antiretroviral therapy. HIV can be transmitted as a cell-free viral particle or through cell-to-cell contact. The highest concentrations of the virus are found in blood, semen, and cervicovaginal secretions, thus explaining its epidemiological characteristics. The virus can enter the body through parenteral exposures or binding of mucosal cells that have CD4 receptors that can bind HIV. Anal sex and traumatic vaginal sex may potentiate HIV transmission through mucosal abrasions that can allow the virus more direct access to submucosal tissues. The leukocyte subpopulations that are most readily infected by HIV include T-helper cells (also called CD4⫹ T lymphocytes) and monocyte/macrophage cells, including follicular dendritic cells in the genital tract mucosa. Once the virus has contact with a target cell, the viral envelope fuses with the cell membrane, discharging the viral core into the cell’s cytoplasm. The viral RNA immediately begins the process of reverse transcription; DNA templates are produced and are integrated into the host cell’s genome and used for subsequent protein synthesis and virion assembly. Daughter virions then bud off from the cell membrane with potential to infect new target cells. The replication process is remarkably efficient and highly inaccurate. Approximately 1010 new virions are produced each day in an HIV-infected individual, but a large proportion of this viral progeny contains genetic errors of transcription. Although many of these mutant offspring will be nonfunctional, a fraction contain mutations that confer advantages such as resistance to antiretroviral medications. The clinical implication of this finding is that even before the initiation of antiretroviral therapy, virions that are not inhibited by single or double antiretroviral drug therapy are present. However, it is unlikely that mutants that are able to resist combinations of three or more drugs will be generated at the onset of infection; hence the rationale for combination antiretroviral therapy (discussed later). Another implication of the kinetics of HIV replication is that millions of HIV-infected white blood cells are formed and destroyed every day. Thus, for the majority of individuals, HIV infection is a dynamic infection in which retrovirally induced immune destruction is compensated by the host’s ability to generate new immune effector cells. The onset of

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HUMAN IMMUNODEFICIENCY VIRUS RECOGNITION Need for prompt recognition Treatment of the patient Risk reduction education Importance of detailed history Sexual Injection drug use Blood products Indications for testing Risk behavior Others (see Table 1) Acute human immunodeficiency virus (HIV) infection (see Table 2) Differential diagnosis of acute HIV infection (see Table 3)

opportunistic infections or malignancies signals the host’s inability to compensate for the high level of cellular turnover induced by chronic HIV infection (see Chapter 26). The next sections of this chapter are designed to describe the approach to the patient at risk for HIV, the detection of acute HIV infection, and the subsequent management of infected patients. 2 2.1

COUNSELING AND DISCUSSION Recognition of Those at Risk

In the early years of the HIV epidemic in the United States, the infection was detected primarily in specific populations who were considered to be at high risk, including IDU and MSM populations and patients with hemophilia and other blood product recipients. This terminology implies that certain individuals are less susceptible than others to infection. Since HIV infection now routinely affects persons in a wide spectrum of socioeconomic and behavioral categories, it is more helpful to think in terms of ‘‘risk behavior’’ than ‘‘risk group.’’ Identifying patients at risk therefore means determining an individual patient’s risk-taking behavior. This determination depends on a thorough history of sexual practices and patterns of drug use. This history should be obtained in a detailed and nonjudgmental fashion. Since persons of any age may be newly diagnosed with HIV infection, this history should be obtained from all adult patients. Since several hundred thousand asymptomatic patients in the United States are unaware that they are HIV-infected, it is incumbent on the medical provider to recognize people who are infected or at increased risk and to provide counseling and recommend testing when appropriate. The rationale for prompt detection of HIV infection is twofold: infected people are more likely to benefit from antiretroviral therapy and opportunistic infection prophylaxis the earlier they are identified, and they will be more amenable to protecting their partners if they are aware of their HIV status. 2.2

Risk Reduction

When discussing issues relating to potential HIV transmission, it is important to convey the concept of relative risk. Often when patients are counseled about the inadvisability of ‘‘high-risk’’ behavior they perceive a message that most of the activities that they enjoy

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are dangerous and hence forbidden. This may instill a sense that nothing short of complete abstinence is of any benefit and undermine the patient’s will to avoid risk. A more profitable strategy is to discuss the fact that some kinds of behavior (such as unprotected anal intercourse) is associated with a high risk of infection, others (such as intercourse with a latex condom) are much less risky, and still others (such as fellatio) are intermediate in risk. The actual per contact rates of HIV transmission are not well established, given the ethical and logistical issues involved in determining when a person has become infected with HIV. Cohort studies suggest that the average per contact rate may vary from less than 1 per 1000 contacts to more than 1 in 10 for unprotected anal or vaginal intercourse. An infected man is four times more likely to transmit HIV to his female partner than vice versa, and a male engaging in receptive anal intercourse is far more likely to acquire HIV from his insertive partner than the converse. The reasons for the variability include the fact that different tissues are more or less susceptible to HIV infection because of the numbers and types of cells that are present that can bind or transmit HIV. Other factors may alter HIV susceptibility or infectiousness, including the presence of concomitant genital tract infection, sexual trauma, the level of HIV in the infected partner’s genital secretions, and the strain of the virus to which one is exposed. Additional factors that play a role include circumcision (the foreskin contains more cells that can bind or transmit HIV) and a woman’s prepubertal or postmenopausal status (estrogen thickens the cervicovaginal epithelium and protects against HIV). Finally, oral exposure to HIV appears to be much less risky than anal or vaginal intercourse, possibly because of endogenous anti-HIV compounds that are present in the oropharynx. However, it is important to note that there are several well-documented case reports describing HIV infection after oral exposure to ejaculate; therefore, fellatio is not as risky as unprotected anal or vaginal intercourse but is not risk-free. It is up to the well-informed patient to make his or her own decision regarding acceptance of risk with the physician serving as a nonjudgmental adviser. Attempts to assign numerical values to the risk associated with a single act are not likely to be helpful as they may be misleading or leave the patient with the impression that the physician has given leave to engage in certain types of behavior because the individual risk is low. Patients at risk for HIV infection may be in relatively stigmatized groups including IDU and MSM individuals. Accurate assessment of HIV risk and appropriate counseling for risk reduction depend on complete reporting of all potential risky behavior, including activities that may be socially unacceptable or illegal or that the clinician may find personally objectionable. In such circumstances it is essential that the clinician remain absolutely objective in his or her questioning. Such marginalized patients are not likely to be forthcoming with accurate information if they believe that their medical provider disapproves of specific behavior or is inclined to judge them on the basis of what they relate about themselves. Conversely, once a bond of trust is established between physician and patient, the patient is more likely to discuss high-risk behavior frankly and to accept the physician’s counseling regarding risk reduction. 2.3

Testing

Since a large number of HIV-infected individuals are unaware of their infection, it is critical that all clinicians assess risk for HIV and offer testing when appropriate. Obtaining a thorough history, including nonjudgmental but specific questioning about sexual activity and drug use, has become even more important in identifying patients at risk for HIV infection.

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HIV testing should be performed for any patient who requests it. Other indications for voluntary testing include sexually transmitted diseases, pregnancy, and active tuberculosis. Testing should be considered in young adults with shingles or women with refractory or recurrent vaginal candidiasis. Oral candidiasis should prompt HIV testing, especially if not explained by antibiotic use or diabetes mellitus. Although a common symptom, chronic unexplained fatigue should prompt consideration of HIV testing. Voluntary testing is also recommended for adults hospitalized in facilities where the seroprevalence exceeds 1% or where the AIDS case rate exceeds 1 per 1000 discharges. Finally, HIV testing should be considered for patients who have generalized lymphadenopathy, unexplained dementia, aseptic meningitis, peripheral neuropathy, chronic and unexplained fever, diarrhea, weight loss, generalized herpes simplex infection, or multidermatomal herpes zoster; unexplained cytopenias, including chronic disease anemia, leukopenia, and thrombocytopenia; infection with hepatitis C virus; B-cell lymphoma; or other opportunistic conditions suggestive of cell-mediated immunodeficiency (see Table 1). 2.4

Pre- and Posttest Counseling

All patients who are being tested for HIV antibodies should receive counseling before the test is performed. This should include information about what the test is actually measuring (i.e., antibodies to HIV) and the significance of positive, negative, and indeterminate results. It is important to explain that HIV infection can occur without seropositivity because

Table 1 Indications for Voluntary Human Immunodeficiency Virus Testing Patient request Sexually transmitted diseases Pregnancy Active tuberculosis Herpes zoster in young adult or multidermatomal herpes zoster Recurrent vaginal candidiasis Oral candidiasis Generalized lymphadenopathy Infection with hepatitis C virus Unexplained chronic fatigue Unexplained dementia Aseptic meningitis Peripheral neuropathy Chronic unexplained fever, diarrhea, or weight loss Generalized herpes simplex infection Unexplained cytopenias Chronic disease anemia Leukopenia Thrombocytopenia B-cell lymphoma Opportunistic illness suggesting defective cell-mediated immunity Adults hospitalized in facilities where Seroprevalence exceeds 1% or acquired immunodeficiency syndrome (AIDS) case rate exceeds 1 per 1000 discharges

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of a possible delay in the development of anti-HIV antibodies after exposure (the ‘‘window period’’), which may last for weeks or even months. All patients should give informed consent in writing before HIV testing. Posttest counseling includes providing and explaining test results and is a good opportunity to reemphasize the potential for seronegative infection during the window period. If the patient’s result is seronegative, this is often a convenient time to schedule an appointment for repeat HIV testing. Reinforcement of risk reduction behavior and further education should be provided. It is advisable to deliver all HIV test results to the patient in person, and not by telephone or correspondence. This policy minimizes miscommunication and maximizes the chance for effective risk reduction counseling. Confidentiality about the testing should be stressed. To be confident that HIV infection is not present, repeated testing should be offered approximately 6 months after the initial test if the result is negative or indeterminate. However, the patient must understand that the repeat test will be most helpful if he or she has not had any additional potential exposures during that interval. For this reason preand posttest counseling must also address risk behavior and the patient must understand exactly what behavior might cause exposure to infection. Likewise, patients may erroneously believe that sexual intercourse with penetration is only risky if ejaculation has occurred or that anal or vaginal intercourse is risky for the receptive but not for the insertive partner. Patients using injection drugs should be referred for counseling and rehabilitation. They should be educated about using sterile needles if available and techniques to clean their ‘‘works’’ (see Chapter 35, Table 3). Persons found to be HIV-positive should be referred to a clinician experienced in the management of HIV disease. This diagnosis can represent a severe psychological stress, and the patient may be at risk for depression, social withdrawal, and suicide. The provider should be alert for these symptoms and have access to social work and psychiatry support. 3 3.1

CLINICAL PRESENTATION OF HUMAN IMMUNODEFICIENCY VIRUS Acute Human Immunodeficiency Virus Infection

Acute HIV-1 infection is symptomatic in a large proportion of patients. The prevalence of symptomatic primary HIV infection, referred to as acute retroviral syndrome, varies from series to series; up to 90% of patients may manifest some symptoms. Because of a lack of awareness among susceptible patients and a low index of suspicion among health care providers, HIV-1 infection is probably still underreported. Clinical manifestations of acute retroviral illness appear within days to weeks of exposure to HIV, most commonly at 2 and 6 weeks (see Table 2). Common symptoms include fever, frequently in excess of 102⬚F; night sweats; headache; fatigue; and a nonpruritic erythematous maculopapular rash. This rash may be variable in appearance and may be evanescent; the patient may not notice it. In dark-skinned individuals it may not be readily apparent. Other common findings include lymphadenopathy and pharyngitis, occasionally with exudates. The overall syndrome may thus be indistinguishable from infectious mononucleosis. Oral or genital ulcers and oral candidiasis are occasionally seen; these findings are considered particularly suggestive of acute HIV infection by some investigators. Neurological findings may occasionally predominate, including a syndrome of aseptic meningitis. Laboratory findings are nonspecific and may include cytopenias and elevated liver enzyme levels. HIV antibody testing at this stage most often yields negative findings.

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Table 2 Signs and Symptoms Associated with Acute Retroviral Syndrome Clinical finding

Patients, %

Fever Fatigue Weight loss Pharyngitis Myalgia Night sweats Diarrhea Rash Lymphadenopathy Headache Nausea, vomiting Aseptic meningitis Oral or genital ulcers Thrombocytopenia Leukopenia Elevated liver enzyme levels

>80% >70% 70% 50%–70% 50%–70% 50% 50% 40%–80% 40%–70% 32%–70% 30%–60% 24% 10%–20% 45% 40% 21%

Source: Adapted from Schacker et al. 1996 and Kahn and Walker 1998.

Occasionally an indeterminate HIV antibody result, consisting of a reactive enzyme immunoassay and fewer than two reactive bands on the confirmatory Western blot, occurs. Because of the nonspecific nature of the syndrome, the differential diagnosis for patients with acute retroviral syndrome can be broad (see Table 3). Most often it includes infectious mononucleosis, streptococcal pharyngitis, and viral respiratory tract infections. Depending on which symptoms are predominant, acute HIV infection can be confused with secondary syphilis, acute toxoplasmosis, viral hepatitis, or viral meningitis. None of the initial clinical findings or laboratory results is pathognomonic for acute retroviral illness. Therefore, acute HIV infection should be considered for any patient who is experi-

Table 3 Differential Diagnosis of Acute Retroviral Syndrome Infectious mononucleosis (Epstein-Barr virus or cytomegalovirus) Toxoplasmosis Streptococcal pharyngitis Rubella Secondary syphilis Viral meningitis Other viral infections (e.g., influenza) Viral hepatitis Disseminated gonococcal infection Primary herpes simplex infection Drug reaction

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encing a compatible syndrome. Making the diagnosis depends on identifying a potential HIV exposure in the preceding few weeks. Therefore, patients who have such an illness should be questioned about potential risk behavior, including sexual activity or injection drug use in the previous 6–8 weeks. If high suspicion is generated by this history, but the antibody test result is negative or indeterminate, the diagnosis can be confirmed by testing plasma or serum for the presence of HIV RNA by one of the sensitive newer amplification techniques, i.e., polymerase chain reaction (PCR), branched DNA assay (bDNA), or nucleic acid sequence based analysis (NASBA). HIV RNA testing is not recommended for screening of lower-risk populations because nucleic acid amplification assays are costly, laborious, and prone to false-positive results. After the acute retroviral syndrome, HIV-infected patients often remain asymptomatic for many years before the onset of immunodeficiency. They need careful primary care to manage any common comorbidities such as sexually transmitted diseases, tuberculosis, or viral hepatitis and to monitor their immune function to determine when antiretroviral and prophylactic antimicrobial therapies are indicated. 3.2

Natural History of Human Immunodeficiency Virus

The clinical course of untreated HIV infection has by now been well established. In most cases HIV causes progressive loss of T-helper cells, which eventually renders the patient unable to mount an immune response against a variety of opportunistic pathogens. A hypothetical patient’s clinical course over time is illustrated in Figure 1. The actual time course of this decline is highly variable from one patient to another. Indeed, in a small minority of cases, no loss of immunological function is detectable even after 10 years or more of untreated infection. Antiretroviral drug therapy is generally not indicated for this population, referred to as long-term nonprogressors. In these individuals, the immune system appears able to control HIV replication. In most cases, however, T-helper cell counts eventually decline to the point that clinical illness is imminent. This fact is the rationale for the use of HAART. However, that decline may take place in as few as 1–2 years or after 8–10 years of infection. During most of this time patients generally remain asymptomatic and are usually unaware of their infection. One powerful predictor of the rate of eventual T-cell decline and subsequent risk of progression to AIDS is the baseline plasma HIV RNA level. This value tends to be relatively stable after the acute HIV infection has subsided, when an equilibrium of sorts is established between viral replication, on one hand, and T-helper cell generation, on the other. The amount of virus present in the patient’s plasma is determined by a balance between viral replication and destruction. This steady-state level of virus (viral load) varies individually from 100,000 (log 105) copies/mm3. With time, though, the viral load steadily increases, in conjunction with progressive immune destruction and a fall in the CD4⫹ lymphocyte count. There is a fairly well-defined correlation between a patient’s T-helper cell count and the particular infections to which he or she is susceptible. In general, more virulent pathogens such as Mycobacterium tuberculosis and Streptococcus pneumoniae may cause disease at relatively high T-helper cell counts in excess of 300 cells/mm3. Other opportunistic pathogens, such as Pneumocystis carinii, seldom present a threat until counts are below 250 cells/mm3. Finally, organisms such as Toxoplasma gondii and Mycobacterium avium complex may be life-threatening when counts are below 100 cells/mm3. The advanced stage of HIV infection, acquired immunodeficiency syndrome (AIDS), is defined by the acquisition of opportunistic illnesses or a T-helper cell count below 200 cells/mm3.

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Figure 1 Natural history of infection and response. On initial infection with HIV there is rapid replication of HIV, sometimes up to 106 (1,000,000) virions/mm3 of blood. Immunological destruction begins with a fall in CD4⫹ helper lymphocytes. During this time the patient may experience the acute retroviral syndrome. A steady state is finally reached, in which the CD4 count and viral load remain relatively stable despite high levels of HIV replication and destruction. Most patients are asymptomatic during this time. With time HIV replication continues, in association with progressive immunological damage, placing the patient at risk for opportunistic infections. CD4 count, cells/cubic millimeters; viral load log 10. HIV, human immunodeficiency virus; TB, tuberculosis.

4 4.1

INITIAL MANAGEMENT OF THE HUMAN IMMUNODEFICIENCY VIRUS–POSITIVE PATIENT History

Critical portions of the initial medical history of a patient with HIV infection include the date of his or her first positive HIV result, his or her last negative HIV test result (if available), and any prior CD4⫹ lymphocyte counts and quantitative HIV RNA measurements. It is helpful to obtain documentation of the patient’s HIV status as there have been cases of factitious HIV infection in which patients seek to be wrongly identified as HIVpositive for secondary gain. It is also helpful to ascertain why the patient was tested and what the presumed mode of acquisition was. Occasionally a patient does not know how he or she became HIV-infected, and this situation can serve as an initial opportunity for education about methods of HIV transmission. Aside from a general past medical history and review of systems, the HIV-specific medical history should inquire about typical presenting symptoms of HIV, including fevers, night sweats, weight loss, generalized lymphadenopathy, diarrhea, and oral candidiasis. Questions should also address any history of opportunistic illnesses, especially including recurrent bacterial pneumonias, Pneumocystis carinii pneumonia, tuberculosis (including extrapulmonary disease), cryptococcal meningitis, herpes zoster, cytomegalovirus infec-

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INITIAL MANAGEMENT History Fever, night sweats Chronic diarrhea Weight loss Geographical exposure risk Sexually transmitted diseases Tuberculosis (TB) Medications Physical exam Lymphadenopathy Hepatosplenomegaly Oral Thrush Kaposi’s sarcoma Poor dentition Pelvic exam and Papanicolaou (Pap) smear Anorectal Laboratory (see Table 4) Immunizations (see Table 5) Prophylaxis (see Table 6) Indications for antiretroviral therapy (see Table 6) Available antiretroviral agents (see Table 7)

tion, Mycobacterium avium infection, invasive cervical cancer, and Kaposi’s sarcoma. A geographical history should be obtained since regionally prevalent illness such as histoplasmosis, blastomycosis, and coccidioidomycosis may occur as reactivation disease after a patient has left an endemic region. Because of the nature of HIV transmission, a detailed sexual history should also be included and any history of specific sexually transmitted diseases should be elicited. Included in this category are viral hepatitides, which should also be asked about specifically. 4.1.1

Tuberculosis History

A detailed tuberculosis (TB) exposure history should include: any known exposure to TB including a family history; date of the patient’s last tuberculin skin test; history of a reactive skin test result and, if present, duration of therapy for latent TB (chemoprophylaxis), if any, and date of the last chest radiograph (if any). 4.1.2

Medication and Drug History

A thorough medication history is essential, especially if antiretroviral therapy is going to be initiated. Patients should be asked about all medications they are currently taking, including over-the-counter medications, herbal preparations, and nutritional supplements. There is a tendency for many patients to consider herbal medications benign and therefore not mention their use. Patients should be reminded that any pharmacologically active substance may have unwanted side effects or interactions with other medications. Use of tobacco, alcohol, and illicit drugs should be accurately ascertained in a nonjudgmental manner.

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Physical Examination

A thorough physical examination should be done at the initial visit, focusing on organ systems likely to be affected by opportunistic illnesses. Height and weight should be measured at baseline; in particular, changes in weight can be a sensitive marker of systemic illness. With regard to the vital signs, fever may suggest infection, or hemodynamic instability may suggest hypovolemia or adrenal insufficiency. A thorough skin examination should look for lesions suggesting Kaposi’s sarcoma (purple nodules or plaques) and other opportunistic illnesses. The ocular fundi should be visualized, looking for retinal lesions. In the oropharynx, candidiasis and oral hairy leukoplakia are sensitive markers of immune suppression; Kaposi’s sarcoma is often seen first in the mouth; and dental and gingival health should be carefully noted. An assiduous search should be made for enlarged lymph nodes in all accessible chains. Hepatomegaly or splenomegaly may suggest a number of systemic infections. A detailed anogenital examination is imperative since many HIVinfected patients are also at risk for other sexually transmitted diseases. In the MSM population the anus should be closely examined for lesions of herpes simplex and human papillomavirus infection. Women should have a thorough pelvic examination with Papanicolaou (Pap) smear, and annually thereafter. Women with an abnormal Pap smear result or a history of human papillomavirus infection should have more frequent exams and should be referred for colposcopy. A careful neurological exam should also be done on all patients at baseline. 4.3

Laboratory Studies

A baseline laboratory evaluation of a new HIV-positive patient (Table 4) should include complete blood count and routine chemistry testing to assess liver and kidney function.

Table 4 Recommended Baseline Laboratory Evaluationa HIV serological tests (if not documented) CBC with differential Chemical panel including liver enzyme levels CD4⫹ cell count Quantitative HIV RNA (PCR or bDNA) Serological test for syphilis Tuberculin skin test HBsAg, HBsAb, HBcAb Hepatitis C antibody Anti-Toxoplasma gondii IgG Anti-CMV IgG G-6-PD (in appropriate populations) Papanicolaou smear (for women) a

HIV, human immunodeficiency virus; CBC, complete blood count; RNA, ribonucleic acid; PCR, polymerase chain reaction; bDNA, branched deoxyribonucleic acid assay; HBsAg, hepatitis B surface antigen; HBcAb, hepatitis B core antibody; IgG, immunoglobulin G; CMV, cytomegalovirus; G-6PD, glucose-6-phosphate dehydrogenase; CMV, cytomegalovirus.

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4.3.1 T Cells A CD4⫹ lymphocyte count is the most readily available quantitative measure of the status of the cell-mediated immune system and should be checked at baseline and periodically (discussed later). 4.3.2

Viral Load

A quantitative plasma HIV RNA assay should also be performed periodically. There is still some controversy over whether ultrasensitive assays, with lower limits of detection below 100 copies/mm3, offer any real clinical benefit over standard assays. The HIV RNA level should be measured before any planned change in antiretroviral therapy and at least every 4 weeks after a change until it has reached a stable level. Measurements every 3 months thereafter are usually adequate. Because transient states of immune activation may elevate HIV RNA levels, levels should not be measured within 4 weeks of receiving a vaccination or during an intercurrent illness unless there is concern that the illness is due to failure of antiretroviral therapy. 4.3.3

Concomitant Infections

New HIV patients should also be tested for concomitant infections that may be transmitted in a similar fashion such as hepatitis B and C virus infection and those which present particular problems for HIV-infected patients, such as tuberculosis, cytomegalovirus infection, and toxoplasmosis. At a minimum, baseline testing should include serological testing for prior and active hepatitis B infection (hepatitis B surface antigen and antibody and core antibody) and for hepatitis C antibodies. Patients who are not hepatitis B–seropositive should be given the hepatitis B vaccine series (see Chapter 43). Antibodies against Toxoplasma gondii and cytomegalovirus should be measured at baseline. These assays are performed only for evidence of prior exposure, which would indicate latent infection and risk for subsequent reactivation. Therefore, a single titer of immunoglobulin G (IgG) antibodies is adequate. This is in contrast with testing of symptomatic patients for acute toxoplasmosis, in whom acute and convalescent antibodies or IgM antibody fraction is measured. 4.3.4

Syphilis

All HIV-infected patients should be tested for syphilis and treated if a serological test is reactive. This population is at increased risk of complications from syphilis, including neurosyphilis, rapid progression of disease, and failure of treatment. For this reason, a lumbar puncture should be strongly considered for all HIV-infected patients diagnosed with syphilis of unknown duration. The use of tetracyclines for treating syphilis in HIVpositive patients is discouraged and penicillin desensitization is preferred in penicillinallergic individuals because of the predilection of the spirochete to disseminate early to the central nervous system in the setting of HIV infection. 4.3.5

Tuberculosis

Tuberculin skin testing at baseline and every year should also be routine for HIV-infected patients. Any HIV-positive patient with a reactive tuberculin skin test (at least 5-mm in diameter) result should receive antituberculous therapy for latent TB for 1 year (see Chapter 13). Declining CD4⫹ cell counts are associated with an increased rate of anergy. Therefore, in patients at particularly high risk of TB exposure (such as family members of

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infected persons) consideration should be given to antituberculous prophylaxis even in the absence of skin test reactivity. 4.4

Immunization

Although some immunizations for the HIV-infected population are still controversial, there are many that carry little risk and are likely to benefit patients (see Table 5). Current recommendations suggest that all patients with a CD4⫹ lymphocyte count of 200 cells/ mm3 or greater receive a single dose of 23-valent pneumococcal vaccine if they have not received one in the prior 5 years. In patients with fewer than 200 CD4⫹ cells/mm3, the likelihood of development of an effective humoral response to the vaccination is lower; however, the vaccination is safe and should still be considered. Yearly influenza vaccinations are warranted for all HIV-infected patients. Investigators had been concerned because plasma HIV RNA measurements obtained immediately after influenza vaccination may show a transient rise in viral load. However, there is no evidence that such transient ‘‘blips’’ lead to a sustained rise in viral load or to subsequent development of antiretroviral resistance; thus the risk associated with influenza vaccination is negligible. HIV-infected patients should receive tetanus-diphtheria booster vaccinations every 10 years in accordance with the recommendation for the general adult population. Vaccination against hepatitis B virus is recommended for all adults who do not have evidence of prior immunization or prior hepatitis B infection. Certain patient populations, such as MSM individuals and persons with chronic hepatitis C, should be immunized against hepatitis A. For young patients who are unlikely to have preexisting hepatitis A immunity,

Table 5 Adult Vaccinations in the Human Immunodeficiency Virus Populationa Vaccination

Recommended for whom

When

Influenza

All adults

Yearly

Pneumococcal (23valent)

All adults

At first visit

Diphtheria-tetanus (dT) booster Hepatitis A

All adults

Every 10 years

Comments Best response when CD4⫹ >200 cells/mm3 but vaccination of everyone No significant risk of sustained viral load increase after immunization Repeat every 5 years If first dose given when CD4⫹ 200 cells/mm3 on HAART

MSM; chronic Months 0 and 6 liver disease Hepatitis B All non-immune Months 0, 1, 6 adults Measles-mumps-rubella Contraindicated Adverse reactions reported; avoid (MMR) use Oral polio vaccine Contraindicated Avoid use in household contacts Varicella-zoster virus Contraindicated a

MSM, men who have sex with men; HAART, highly active antiretroviral therapy.

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it is usually more cost-effective simply to vaccinate against hepatitis A virus (HAV) rather than test for HAV antibodies. Live virus vaccines should not be used for HIV-positive adults. These include oral polio vaccine, varicella-zoster vaccine, and vaccines for measles, mumps, and rubella. Furthermore, household members of an HIV-infected patient should not receive oral polio vaccine, because of the risk of infection due to fecal shedding of live poliovirus. If someone in the patient’s household has received oral polio vaccine, the patient should avoid contact with that person for the next month. 4.5

Prophylaxis for Opportunistic Infections

Prophylaxis may be primary to prevent occurrence of infection or secondary to prevent recurrence of established infection (see Table 6).

Table 6 Prophylaxis a Infection

Indications

Agents

Pneumocystis carinii CD4⫹ 200: more likely chronic pneumonia with upper lobe infiltrates CD4 < 200: more likely disseminated or miliary Toxoplasmosis Most common human immunodeficiency virus (HIV)-related brain mass Serological result negative in 5%–10% Diagnosis by therapeutic trial

ings are common, including pneumothoraces and even a normal radiograph result. The diagnosis is often suggested by oxygen desaturation with exertion, easily measured in the outpatient evaluation with a pulse oximeter. Lactate dehydrogenase (LDH) level is generally elevated. Pulmonary function test results showing decreased carbon monoxide (CO) diffusing capacity are characteristic but nonspecific findings and should not be considered diagnostic. Use of trimethoprim & sulfamethoxazole (TMP-SMZ) as prophylaxis against PCP argues against the diagnosis since breakthrough infection is exceedingly rare. PCP breakthrough is associated more frequently with second-line medications such as aerosolized pentamidine, dapsone, or atovaquone. The diagnosis of PCP may be made by concentration and staining of an induced sputum sample or may require bronchoscopy with bronchial alveolar lavage. A definitive diagnosis is important since empirical treatment for PCP can be toxic and misdirected. Other pulmonary processes may have characteristics similar to those of PCP, including bacterial pneumonia, influenza, tuberculosis or other mycobacterial infections, histoplasmosis, Kaposi’s sarcoma, and pulmonary emboli. In 10%–15% of patients more than one opportunistic process may occur simultaneously. Standard therapy for PCP is a 21-day course of TMP-SMZ, either orally or intravenously, depending on the severity of illness. For patients with sulfa allergy there are a number of alternative agents including intravenous pentamidine, atovaquone, and clinda-

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mycin plus primaquine. Significant hypoxemia (PaO2 < 70 mm Hg or A-a gradient > 35) should be managed with adjunctive steroids along with specific antimicrobial therapy. All patients who have had PCP should then receive prophylaxis at completion of acute therapy (see Chapter 25, Table 6). 3.2

Esophageal Candidiasis

Esophageal candidiasis typically causes odynophagia with pain centered in the substernal area. Patients may also report that food and pills become stuck when swallowed. This dysphagia may progress to difficulty in swallowing liquids. Although the diagnosis may be suggested by the presence of oropharyngeal thrush, a substantial number of patients with esophageal infection have no findings on oral exam. Treatment may be given empirically with fluconazole 200 mg daily for 14 days. Topical agents are not absorbed and therefore should be used only for infection limited to the oropharynx. Diagnostic uncertainty or lack of a response to empirical therapy should lead to further evaluation by endoscopy. The diagnosis may then be made by direct visualization of the fungal plaques and confirmed by biopsy. This procedure also allows differentiation of esophageal candidiasis from other causes of odynophagia (e.g., cytomegalovirus [CMV], herpes simplex virus [HSV], aphthous ulcers) and detection of drug (azole-) resistant fungal infection. Azole-resistant infection necessitates the use of amphotericin B. 3.3

Cryptococcal Meningitis

Cryptococcus neoformans is ubiquitous encapsulated yeast that may cause infection in the lung, skin, bone, or genitourinary tract but is manifested most commonly in the central nervous system as meningitis. Cryptococcal meningitis commonly causes subacute to acute (95%. Definitive diagnosis requires lumbar puncture (LP) for testing for cerebrospinal fluid (CSF) cryptococcal antigen. The LP classically shows a lymphocytic pleocytosis with an elevated protein level and a depressed glucose level. The CSF result must be interpreted with care since the protein and glucose may be normal and white blood cells (WBCs) absent or present in low numbers. Results of CSF cultures are almost invariably positive. India ink staining of CSF may be useful for initial diagnosis but should not supplant the use of antigen testing since the sensitivity is only 60%–80%. Markers of poor prognosis include age gram-negative rod (GNR) Diagnosis Painful swollen joint Decreased passive and active range of motion (ROM) Arthrocentesis White blood cell (WBC) count generally >50,000 cells/m3 Gram stain and culture Suspected gonococcal: Thayer-Martin agar Analysis for birefringent crystals Computed tomography/magnetic resonance imaging (CT/MRI) scan to assess for abscess, osteomyelitis, or fistula as needed Therapy (see Table 3) Repeated arthrocentesis vs. open drainage Gonococcal IV for 24–48 hr after improvement then PO for a total of 3–4 wk Nongonococcal IV for 2 wk then PO for total of 4–6 wk

1.2

Routes of Joint Infection

Hematogenous seeding of the highly vascularized synovium and epiphyseal bone is the most common route to pyarthrosis. Sources leading to hematogenous spread of bacteria often include skin sites, intravenous catheters, and injection drug use (IDU). However, Table 1 Affected Joint Distribution in Adults with Nongonococcal Bacterial Arthritis Joint Knee Hip Ankle Shoulder Wrist Elbow Others Multiple joints

Cases, % 55 11 8 8 7 6 5 12

Source: Adapted from Goldenberg 1997.

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Table 2 Principal Microorganisms Causing Nongonococcal Bacterial Arthritis Microorganisms

Percentage

Staphylococcus aureus Streptococcus spp. Gram-negative bacilli Miscellaneous

55 27 14 4

Source: Adapted from Smith 1990.

infection of any organ system, most notably the genitourinary, gastrointestinal, or cardiovascular, could lead to bacteremia and joint seeding. Thus, the evaluation of patients with pyarthrosis must include a detailed history and physical examination directed at identifying a potential extra-articular source of infection. Pyarthrosis can also result from contiguous spread from an adjacent soft tissue infection or a juxta-articular osteomyelitis. Contamination of a joint can also occur by direct inoculation via joint aspiration, injection of a joint space, arthrography, or penetrating wound. Postoperative infections can result from arthroscopy and prosthetic joint replacement (see Sec. 1.9.1). 1.3

Pathogenesis

Within minutes of gaining entry into a joint, virulent bacteria such as S. aureus and Streptococcus spp. provoke a proliferation of synovial cells, macrophages, and polymorphonuclear leukocytes. Over the course of several hours, synovial hypertrophy and elaboration of synovial fluid result in joint swelling, effusion, and pain. At this stage, physical examination and conventional radiological imaging may demonstrate the presence of interosseous distension and signs of effusion (see Figure 1[2] and Figure 2). Over the course of 3 to 4 days, leukocyte production of cytokines and proteolytic enzymes leads to hydrolysis of cartilage. Additionally, the development of a growing synovial pannus further erodes and undermines the cartilage. Destruction of cartilage and erosion of bone can be seen radiologically as joint space narrowing and a poorly defined rim of juxta-articular bone, respectively (see Figure 1[3,4] and Figure 3a and 3b[1,2]). If the inflammatory process is allowed to proceed, bony bridging (ankylosis) ensues (see Figure 1[5] and Figure 4). Infection can spread into juxta-articular soft tissue, causing abscesses, sinus tracts, pyomyositis, fasciitis, and rupture of adjacent tendons and ligaments. Joint distension caused by an enlarging effusion can impair local blood flow, leading to avascular necrosis. The suppurative inflammatory model of septic arthritis described previously does not appear to explain the pathophysiological mechanisms of joint inflammation associated with all microorganisms. Viruses, chlamydia, mycobacteria, fungi, Borrelia spp., and other bacteria cause associated joint inflammation in ways that are not well understood. The term reactive arthritis, categorized as one of several seronegative spondyloarthropathies, has been applied to a number of infection-associated inflammatory processes. As the name implies, it reflects a poorly understood interplay between the inciting pathogen and host immune reaction. In many instances of reactive arthritis, infection appears to occur at a site distant from the joint and viable microorganisms are absent from the inflammatory joint tissues. Some of these pathophysiological mechanisms appear to be

Amoxicillin/clavulanate 500 mg tid

Ampicillin/sulbactam 1.5 g q6h or cefotaxime 1.0 g q8h or ceftriaxone 1.0 g q12h As in anti–S. aureus regimen; P. aeruginosa, ceftazidime or piperacillin or ticarcillin Ceftriaxone 2.0 g qd or penicillin G 20 million units qd, 14 to 30 days

IVDA, MRSA, INH, RIF, PZA, ETH, Source: Adapted from Smith and Shabaz 2000.

a

Foreign or domestic exposure: Mycobacterium tuberculosis

Ingestion of unpasteurized dairy products: Brucella spp.

Tick exposure: Borrelia burgdorferi

IVDA: S. aureus, Pseudomonas aeruginosa

Amoxicillin/clavulanate 500 mg tid

Ampicillin/sulbactam 1.5 g q6h

Human bite: mixed flora, including Streptococcus spp., S. aureus, Eikenella corrodens, Fusobacterium nucleatum Dog and cat bite: mixed flora, including Pasteurella multocida

Doxycycline 200 mg qd for 6 wk, plus either streptomycin 1.0 g IM qd for 3 wk or gentamicin 5 mg/kg IV or IM qd for 10 days INH and RIF for 9 to 12 mo, plus either PZA or ETH for 2 mo

Doxycycline 100 mg bid or amoxicillin 500 mg qid, 30 to 60 days

As in anti–S. aureus regimen; P. aeruginosa, ciprofloxacin 500 mg bid

Oral therapy easier to administer and less expensive; if symptoms of neuroborreliosis present, IV regimen preferred No comparative efficacy data for streptomycin and gentamicin regimens; may add rifampin 300 mg PO tid after completion of aminoglycoside course If drug resistance suspected or documented additional agents possibly required

If monobacterial infection caused by P. multocida switch to penicillin G IV or penicillin VK PO If MRSA suspected, vancomycin

Doxycycline 100 mg bid or clindamycin plus either a fluoroquinolone or trimethoprim & sulfamethoxazole No firmly established regimen. Consideration of clindamycin plus fluoroquinolone If S. aureus, vancomycin

Ciprofloxacin 500 mg bid or spectinomycin 2.0 g IM q12h

IV antibiotic continued 24– 48 hr after clinical improvement begins, then oral regimen E. corrodens resistant to oxacillin, nafcillin, and clindamycin

Penicillin allergic Vancomycin

Comments If MRSA suspected, vancomycin 1.0 g q12h

Antimicrobial

Dicloxacillin 500 mg qid, or first-generation cephalosporin Cefixime 400 mg bid or ciprofloxacin 500 mg bid

Oxacillin (or nafcillin) 2.0 g q4h or cefazolin 2.0 g q8h Ceftriaxone 1.0 g qd or cefotaxime 1.0 g q8h or ceftizoxime 1.0 g q8h

Cutaneous source: Staphylococcus aureus or Streptococcus spp. Sexually active young adult: Neisseria gonorrhoeae

Oral

Intravenous

Epidemiological features and microorganism

Table 3 Epidemiologic Associations and Antimicrobial Regimens in Septic Arthritisa

538 Tobin and Brecher

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Figure 1 Septic arthritis: Pathological abnormalities: 1, Normal synovial joint; 2, an edematous swollen and hypertrophic synovial membrane becomes evident; 3, 4, accumulating inflammatory pannus leads to chondral destruction and to marginal and central osseous erosions; 5, bony ankylosis eventually can result. (Adapted from Resnick and Niwayama 1995.)

due to a sharing of antigenic determinants between microorganism and host that leads to an autoimmune inflammatory reaction. 1.4

Risk Factors

Individuals who have preexisting joint disease (e.g., RA, crystal-induced arthritis, and degenerative arthritis) or joint trauma are at significantly higher risk for hematogenously acquired suppurative arthritis. Increased rates of pyarthrosis also occur in immunosuppressed patients, diabetics, and patients with chronic renal failure. Individuals with sickle cell anemia are at higher risk for development of pyarthrosis due to Salmonella spp. Bacterial inoculation of the blood stream by IDU increases the risk of septic arthritis. For reasons that are not understood, menstruating or pregnant women with gonorrhea are predisposed to acquisition of gonococcal arthritis.

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Figure 2 Conventional radiograph of the knee obtained in the lateral projection demonstrating a large joint effusion (arrows).

Figure 3 Pyarthrosis of first metatarsophalangeal joint: Conventional radiographs of the first metatarsophalangeal joint performed in the anteroposterior projection obtained 15 days apart. a, The initial radiograph demonstrates subtle subchondral sclerosis (arrow); b, the follow-up radiograph reveals rapid destruction of the joint manifested by joint space narrowing and marginal erosive changes.

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Figure 4 Pyarthrosis of interphalangeal joint with ankylosis: Anteroposterior conventional radiograph demonstrates bony fusion of the interphalangeal joint (arrow), a late radiographic feature of pyarthrosis, signifying end-stage joint destruction.

The presence of particular histocompatibility antigens significantly increases the risk of certain types of infection-associated arthritis. Individuals with human leukocyte antigen B27 (HLA-B27) are at increased risk of development of reactive arthritis after sexually transmitted chlamydia infection and after gastrointestinal infections due to Salmonella, Campylobacter, Shigella, and Yersinia spp. Chronic Lyme arthritis is significantly more likely to occur in individuals who have the HLA-DRB1*0401 gene. Any activity that results in direct inoculation of the joint, such as bites, punctures, injections, aspiration, and surgery, may cause pyarthrosis. Risk factors for the development of prosthetic joint infection include the development of superficial infection at the surgical site, a high surgical risk index score, and a history of malignant disease. 1.5

Clinical Manifestations, History, and Physical Examination

The acuity and severity of symptoms and signs depend on the virulence of the infecting microorganism, the underlying health and immune function of the host, and the anatomical location of the infected joint. History should be directed to identification of risk factors and possible sources of infection as well as recognition of conditions that can mimic septic arthritis (see Table 3 and Figure 5). On the basis of clinical manifestations and the natural history of disease, bacterial septic arthritis has historically been subdivided into nongonococcal and gonococcal forms. 1.5.1

Nongonococcal Septic Arthritis

Suppurative arthritis due to staphylococci and streptococci occurs abruptly with pain and swelling of the joint. Monoarticular arthritis is significantly more common than involve-

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Figure 5 Algorithm for the differential diagnosis of the painful swollen joint.

ment of multiple joints. Fever occurs commonly but is usually low-grade. Peripheral joints that can be easily examined demonstrate an effusion and are often erythematous, warm, and exquisitely tender. In deep joints (e.g., hip, shoulder) clinical signs of effusion are not usually apparent but can often be evaluated by various diagnostic imaging modalities. Pain due to pyarthrosis causes a marked limitation in both passive and active range of motion. This is in contrast to tenosynovitis, in which pain and limitation are worse with active range of motion. Similarly, whereas juxta-articular pain, erythema, and swelling can occur with osteomyelitis, septic bursitis, and cellulitis, there is minimal limitation in passive range of joint motion. When infection involves the hip or sacroiliac joint (SIJ), pain is frequently referred to the buttock, lower back, groin, or leg, often resulting in a delayed diagnosis. Clinical signs of SIJ infection include tenderness over the joint; pain with the combined maneuver of flexion, abduction, external rotation, and extension (FABERE maneuver) of the ipsilateral leg; and pain with pelvic compression. Physical findings that

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help localize hip joint infection include pain with weight bearing and movement of the joint. Sternoclavicular joint infection causes anterior chest pain that frequently radiates to the neck and ipsilateral shoulder. Physical findings demonstrate swelling and tenderness over the involved sternoclavicular joint. Joint infection due to aerobic gram-negative bacilli can result from gastrointestinal and genitourinary tract sources as well as IDU. Anaerobic and polymicrobial bacterial pyarthrosis can result from open trauma and bite wounds. Brucella arthritis occurs more frequently in parts of the world where nonpasteurized dairy products are consumed. Joint infections due to Borrelia spp. and mycobacteria should be considered when epidemiological associations are identified (Table 3). 1.5.2

Gonococcal Arthritis

Gonococcal infection occurs most often in healthy, sexually active young adults. Indeed, it is this feature that should prompt awareness and consideration of this microorganism in the appropriate clinical and epidemiological setting. In a minority of individuals with gonorrhea, bacteremia and disseminated gonococcal infection (DGI) develop. Dissemination typically results in a syndrome characterized by fever, rash, tenosynovitis, and migratory polyarthritis, often involving knee, ankle, wrist, and metacarpophalangeal joints. After 1 to 4 days, systemic manifestations wane and tenosynovitis and arthritis involving one to several joints become the predominant features. Occasionally, gonococcal arthritis occurs in individuals without an obvious history of full-blown DGI. In this form, gonococcal arthritis is clinically indistinguishable from other types of pyogenic arthritis. In most cases of DGI and arthritis, symptoms associated with infection at the primary mucosal site (e.g., cervix, urethra, rectum, pharynx) are absent, although cultures of these sites frequently yield positive results.

1.6

Differential Diagnosis

Because of the potential for rapid joint destruction, any painful swollen joint should be considered infected until proved otherwise. However, it is important to appreciate that a variety of disease entities can cause clinical manifestations that mimic pyarthrosis. The epidemiological setting, clinical history, physical findings, and synovial fluid analysis can establish a diagnosis of septic arthritis in the majority of cases. An algorithm (see Figure 5) provides an approach to considering the differential diagnosis. It is important to remember that periarticular infection and inflammation can cause symptoms that may suggest pyarthrosis; a thorough physical examination should help to distinguish one from the other. Crystal-induced arthropathy (gout and pseudogout) is relatively common, and its clinical features are indistinguishable from those of pyarthrosis. Diagnosis depends on the presence of birefringent crystals (monosodium urate monohydrate or calcium pyrophosphate dihydrate) in synovial fluid. However, joint infection and crystal-induced arthropathy may coexist. Thus synovial fluid analysis for the presence of crystals should always include Gram’s stain and cultures. Patients with RA are at increased risk of both monoarticular and polyarticular infection. Pyarthrosis should be considered when RA patients experience a flare in joint symptoms, particularly single-joint or multiple-asymmetrical-joint inflammation. The epidemiological and clinical presentations of gonococcal arthritis and reactive arthritis due to Chlamydia trachomatis can be identical.

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Approach to Establishing the Diagnosis Synovial Fluid Analysis

The diagnosis of septic arthritis is established when microorgansisms are identified in synovial fluid. However, not all joints are easily accessible for fluid aspiration, and not all microorganisms causing arthritis are readily cultured or present in the joint at the time patients reach clinical attention. Culture of blood and extra-articular sites of primary infection may provide presumptive microbiological diagnosis. When septic arthritis is being considered, joint aspiration should be performed before antibiotic therapy. If antibiotics have been administered before joint aspiration, the yield of positive cultures can decrease significantly. Since joint destruction can occur within a few days of infection, there should be no delay in performing an arthrocentesis. The ease of aspiration depends on the joint involved; the knee is the most accessible. Arthrocentesis of other joints often requires the expertise of rheumatologists or orthopedic surgeons or guidance by radiological imaging (Figure 6). Gram stains have positive results in only 30% of nongonococcally infected joints and very rarely in gonococcal arthritis. Cultures yield positive findings in 90% of joints with nongonococcal pyarthrosis and 50% with gonococcal arthritis. Blood cultures yield positive results in 10% to 60% of patients with nongonococcal arthritis but less than 10% of patients with gonococcal infection. When gonococcal arthritis is being considered, cultures of mucosal sites (urethra, cervix, rectum, and pharynx) should also be obtained, immediately inoculated onto selective growth medium (Thayer-Martin agar), and placed in an enriched CO2 environment. The yield from these mucosal sites is approximately 85%. Polymerase chain reaction (PCR) can measure N. gonorrhoeae deoxyribonucleic acid (DNA) in synovial fluid and may prove to be a rapid, sensitive, and readily available technique.

Figure 6 Needle aspiration of infected left sternoclavicular joint: A nonenhanced axial computerized tomography (CT) scan displayed with soft tissue window of the thorax demonstrates the tip of an aspiration needle within the left sternoclavicular joint (solid arrow). Subtle asymmetrical enlargement of the left pectoralis major muscle is seen (open arrow). Gram’s stain and culture of synovial fluid yielded gram-positive cocci and Staphylococcus aureus, respectively.

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The total white blood cell count in synovial fluid can be determined rapidly, but its ability to distinguish among pyogenic, reactive, and noninfectious inflammatory processes is limited. Pyogenic infections tend to have relatively high cell counts (>50,000 cells/mm3) and a predominance of neutrophils; however, similar findings can occur in RA and crystalinduced arthritis. Septic arthritis with relatively low synovial fluid cell counts (20% (see Table 5) Positive blood culture or tissue biopsy result needed to secure diagnosis and guide therapy Empirical therapy for hematogenous osteomyleitis (see Table 6) Definitive therapy based on blood or tissue culture results (see Table 7) Intravenous antibiotics given for 6–8 weeks Orthopedist or neurosurgeon consulted early to assess spinal stability, cord compression, and need for abscess drainage

diagnosis is missed, and is most often seen at the outset by the primary care physician. Vertebral osteomyelitis is considered rare, accounting for only 2%–4% of all bone infections. The annual incidence rate is about 1 to 2 cases per 200,000 adults. These figures are probably misleading as the true incidence is almost certainly higher and appears to be increasing. Men outnumber women in most series by at least 2:1. Infection occurs in all ages, but the incidence rises after the age of 50. 3.1

Anatomical and Pathophysiological Characteristics

With the exception of cases related to trauma or instrumentation, vertebral osteomyelitis almost always results from hematogenous seeding of the spine. Batson’s plexus, a lowpressure network of valveless veins, drains the vertebral column. Until recently, Batson’s plexus was thought to play a major role in the spread of urinary tract bacteria to the spinal column. Despite numerous experimental attempts, spinal infection via this retrograde venous route has never been demonstrated and is probably rare. Instead, an arterial bacteremia is nearly always involved. Initially, segmental arteries arise from the vertebral, intercostal, or lumbar vessels to supply corresponding vertebrae in the cervical, thoracic, and lumbar regions, respectively (see Figure 2). Paired anterior segmental arteries course along the middle of each vertbebra supplying blood to the body. Each segmental vessel also gives off numerous ascending and descending collateral branches that supply blood to the upper or lower poles (the metaphyseal regions) of the vertebra. The metaphyseal regions of adult vertebrae represent watershed areas where collaterals between the anterior segmental and posterior spinal circulations are sparse. For this reason, a few ascending or descending branches always span more than one level, bridging the intervertebral disk space to supply the metaphyseal region of a neighboring vertebra located one spinal segment above or below. Despite crossing the disk space, these bridging vessels supply no blood to the disk itself, which is completely avascular in adults.

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Figure 2 Blood supply to the vertebral bodies. Paired segmental arteries (SA), arising from the aorta (A), course along the middle of each vertebra. Ascending and descending collateral branches (CB) arise from each segmental artery to supply the metaphyseal regions (M) of the vertebral body. The metaphyseal regions of adult vertebrae represent watershed areas where the collateral circulation is sparse. A few bridging arteries (BA) always cross the disk space (D), supplying blood to the metaphyseal region of a neighboring vertebra located one spinal segment above or below. Pathologically, these bridging arteries provide a route for the rapid spread of infection between adjoining vertebral bodies.

Bacteria gaining access to the bloodstream may lodge in these metaphyseal watershed regions, to produce small areas of infarction. Once infarction occurs, infection is quickly established and rapidly spreads via the bridging arteries to involve the metaphyseal region of an adjoining vertebra. Simultaneously, bacteria directly invade the intervening disk, which is then rapidly destroyed. As shown in Figure 3, the earliest changes seen on plain radiographs include a loss of disk height combined with anterior endplate erosion of the two adjoining vertebral bodies. Left untreated, infection may not only spread to involve additional segments, but also result in paravertebral abscess, cord compression, vertebral column instability, and death of uncontrolled sepsis. Successful outcome depends on early diagnosis and treatment. 3.2

Risk Factors

Table 1 lists the major risk factors for vertebral osteomyelitis. In younger adults, sickle cell disease, renal failure, long-term vascular access, and perhaps early-onset type I diabetes mellitus represent the major risks. When these conditions are excluded, intravenous drug use is the most important factor, accounting for nearly all the remaining cases. Among ambulatory adults above the age of 50, the risks are less well defined and more controversial. Diabetes is the only well-established risk factor, present in roughly 20% of cases.

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Figure 3 The radiographic appearance of vertebral osteomyelitis. A, Loss of disk height may be apparent as early as 10 days after symptom onset. B, Superior and inferior end-plate erosion of adjoining vertebrae is often visible by 2 to 3 weeks. C, Advanced disease is characterized by ballooning of the disk space due to extensive destruction of the vertebral bodies. At this stage, vertebral column instability and paravertebral abscesses are common.

Table 1 Risk Factors for Vertebral Osteomyelitis Well established Age above 50 years Diabetes mellitus Sickle cell disease Hemodialysis Intravenous drug use Long-term vascular access Nosocomial bacteremia Probable increased risk Collagen vascular disease Malignancy Malnutrition Alcoholism Corticosteroids Other immunosuppressive agents Proposed Preceding minor trauma or fall Human immunodeficiency virus (HIV) infection Infective endocarditis

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Other proposed risks include preexisting collagen vascular disease, long-term steroid use, use of other immunosuppressive agents, alcoholism, malnutrition, and malignancy. A history of minor trauma or fall within the preceding month is also common. Recently, venous– and urinary catheter–related bacteremia has emerged as a major risk factor among hospitalized elderly adults and residents of long-term care facilities. 3.3

Presenting Symptoms and Signs

The patient usually experiences localized back or neck pain that has been present anywhere from 2 to 8 weeks before seeking treatment. The pain is usually constant, often severe, and unaffected by position or movement. Sometimes there is a radicular component. The upper lumbar or lower thoracic spine is usually involved. Neck pain is rare except in intravenous drug users, in whom cervical spine involvement occurs 25% of the time. Invariably, the pain persists and usually worsens during a 2-week trial of conservative management. In addition to pain, loss of appetite is surprisingly common when specifically sought. Problems of leg weakness or difficulty of urination occur less often but are not rare. On physical exam, the patient usually appears uncomfortable and may have visible or palpable paraspinous muscle spasm. Localized percussion tenderness is usually present and reflects the level of involvement. As many as 20%–40% of patients have a demonstrable neurological deficit (lower extermity weakness, hyperreflexia, or paresthesias) if carefully examined. Fever occurs in fewer than half of all patients, and its absence should not dissuade the clinician from entertaining the diagnosis. Table 2 lists the frequencies of these signs and symptoms. 3.4

Laboratory Tests

Table 3 lists the most useful laboratory studies and the expected findings. Although yielding positive results in only 20%–50% of the time, two sets of blood cultures should always be drawn. As discussed shortly, if the findings are positive, they may spare the patient an invasive diagnostic procedure. Although nonspecific, the erythrocyte sedimentation rate (ESR) and the C-reactive protein (CRP) level are almost always elevated. Serial measurements of these parameters are useful in monitoring the response to therapy. The complete blood count (CBC) is very nonspecific but may show a mild normochromic normocytic anemia. Leukocytosis is seen only 40%–60% of the time. Measuring the serum alkaline phosphatase level is seldom helpful.

Table 2 Presenting Signs and Symptoms Symptom or sign Localized pain (severe or progressive) Location Lumbar Thoracic Cervical Percussion tenderness Fever Anorexia Lower extremity weakness Septic picture

Percentage >90 60 35 5 85 50 90 20 10

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Table 3 Laboratory Tests Testa

Frequency abnormal

Blood cultures (two sets)

Positive result in 20%– 50%

ESR

Elevated rate in >95%

CRP CBC

Elevated level in >98% Increased WBC count in 40%–60%, mild anemia Elevated level in 50%– 60%

Alkaline phosphatase a

Comment Always draw before giving antibiotics; if finding positive, bone biopsy may not be needed Often over 80 mm/h; if normal, diagnosis is suspect; useful in monitoring response to therapy Has similar utility to ESR Nonspecific. WBC increase thought to suggest paravertebral abscess Requires fractionation; seldom helpful

ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; CBC, complete blood count; WBC, white blood cell.

3.5

Radiographic Studies

Table 4 lists the radiographic studies routinely used to evaluate the spine and gives estimates of their sensitivity and specificity. Plain films should be the initial study whenever the diagnosis is suspected. The earliest changes, seen after about 2 weeks, are disk space narrowing combined with anterior end-plate erosion (see Figure 3). In young healthy adults with a compatable clinical history, these changes raise suspicion and are reasonably specific. Conversely, otherwise healthy young adults who have back pain but who lack risk factors, are afebrile, and have no percussion tenderness or neurological deficits indicated on exam are exceedingly unlikely to have osteomyelitis if their plain film results are normal. Unfortunately in older adults, many benign diseases can produce similar radiographic findings. Furthermore, although these changes may be present after only 2 weeks, they are often subtle and may not be evident for up to 2 months. Thus, although useful, given the difficulties with interpretation combined with a rising incidence of disease with advancing age, plain films should not be relied on to make or exclude the diagnosis for patients above age 50. Magnetic resonance imaging (MRI) has excellent sensitivity and specifity even very early in the disease process. It has the added advantage of producing detailed soft tissue images to allow for prompt diagnosis of serious complications such as paravertebral ab-

Table 4 Radiographic Studies Modality Plain radiograph Three-phase bone scan Gallium scan Gallium ⫹ bone scans Magnetic resonance imaging

Sensitivity, %

Specificity, %

78–82 86–92 89–92 90 92–96

57 49–78 85–100 78 92

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scesses or cord compromise. For these reasons MRI is now the imaging procedure of choice. Nuclear medicine studies are also sensitive and remain useful, particularly when MRI is unavailable or contraindicated. Gallium scanning (alone or combined with a three-phase bone scan) is the nuclear study of choice. The indium white cell scan, although highly specific, is very insensitive and should not be used as a screening study. Newer modalities such as radiolabeled antigranulocyte antibody studies appear promising but lack clinical experience and are not widely available. Areas of abnormality seen on plain radiograph or nuclear scans can be followed up by MRI or computed tomographic (CT) scanning. CT scanning is considerably less sensitive than nuclear scanning, especially for early disease; it should not used as a screening test. 3.6

Diagnostic Approach

The patient who reports severe back pain, percussion tenderness, fever, and a neurological deficit presents little diagnostic confusion (other than malignancy) and is likely to undergo prompt and appropriate evaluation (see Figure 4). The diagnosis should be considered whenever the folowing criteria have been met: (1) the patient has severe or persistent back pain, (2) common causes have been excluded, (3) localized percussion tenderness is present on exam, and (4) one or more of the risk factors outlined in Table 2 are present. Although the standard admittedly is arbitrary, moderately severe pain that persists or progresses over a 2-week period of observation should heighten clinical suspicion. Ultimately the decision to proceed with imaging studies rests on thoughtful clinical judgment guided by a thorough history and physical examination. A definitive microbiological diagnosis depends on isolating an organism from either blood cultures or a bone biopsy. Blood cultures must be drawn before starting antibiotics. Similarly, clinically stable patients without evidence of abscess or instability on MRI can safely remain off antibiotics until after the bone biopsy. Even under optimal conditions, percutaneous bone or disk space biopsy is successful in identifying the microbiological pathogens in only 40%–70% of cases. Ideally, if the first attempt was unsuccessful in identifying microorganisms, either a second attempt should follow or an open biopsy should be performed. In addition to Gram stain and aerobic culture, material obtained by open biopsy should have anaerobic culture as well as staining and culture for acid-fast bacilli and fungus. Even when following this aggressive approach, at least 30% of cases remain undiagnosed, making a prolonged course of empirical therapy unavoidable. 3.7

Microbiological Characteristics

Table 5 lists the microbes likely to be recovered from the majority of immunocompetent adults. A few points deserve emphasis. First, even though Staphylococcus aureus remains the most common organism, it is being recovered in proportionally fewer cases, underscoring the need for biopsy. Second, even though methicillin-resistant S. aureus (MRSA) is being reported more frequently than in the past, community-aquired disease is very rare. Third, although S. epidermidis can certainly be a real pathogen, it may also contaminate blood cultures and biopsy samples. Fourth, Pseudomonas aeruginosa is a very common pathogen among intravenous drug users but is rarely encountered in other patients. Finally, although polymicrobial infections are being reported more frequently (probably because more patients are undergoing biopsy), if blood culture results are positive, tissue biopsy is still unnecessary.

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Figure 4 Approach to the patient with possible vertebral osteomyelitis. The approach to the patient with back pain, suspected of having osteomyelitis, should proceed in a stepwise fashion, assessing the risk factors for infection, laboratory tests, and radiological testing. Focal neurological findings should raise the concern of spinal cord compression; this is a surgical emergency requiring orthopedic and/or neurosurgical consultation. Empirical antibiotics should be avoided before microbiological diagnosis is established.

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Table 5 Microbiological Characteristics Gram stain result Gram-positive: 71%

Gram-negative: 23%

Other: 6%

Mixed

3.8

Pathogen

Percent

S. aureus Methicillin-sensitive (MSSA) Methicillin-resistant (MRSA) S. epidermidis Streptococci (except group D) Group D Streptococcus spp. Enterococcus spp. Diphtheroids (Corynebacterium spp.) Pseudomonas spp. Escherichia coli Other gram-negative rods Anaerobes M. tuberculosis Brucella spp. Candida spp. Polymicrobial

45 (88) (12) 13 11 2 100⬚ F Ulcer Purulent discharge WBC > 10,000/mm3 Positive blood culture result Osteomyelitis a

Percentage a 79 90 44 100 77 50 4 68

Ninety two patients with 97 events. WBC, white blood cell count. Source: Adapted from Grayson et al. 1994.

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Besides any specific stated complaints, the elements of the patient history that are most important include a pattern of numbness or sensory loss suggesting neuropathy or pain. Early neuropathy may often be painful and difficult to distinguish from ischemic rest pain, although neuropathic discomfort commonly has a stocking-glove distribution. Pain may be localized to the site of an ulcer, but, more commonly, in the neuropathic foot, there is an absence of pain, which is a large part of the problem. Pain from ischemia typically involves the heel, forefoot, or toes (not the calf or ankle) and is associated with an absence of pedal pulses. Dependent rubor is present on physical examination in the toes or forefoot (rubor has a deep purple discoloration compared to erythema from infection, which tends to be a brighter red hue). Patients may have claudication pain or a sense of tiredness in the large bulky muscles of the calf, thigh, or buttocks when walking. The history should include some investigation regarding the patient’s preferred footwear to be sure it is comfortable and has adequate support. Table 2 contains questions that may be used to screen diabetes patients for potential foot problems. 3.2

Physical

Physical examination always begins with inspection, including the heel and the area between the toes. Areas of redness from shoe irritation that could be potential trouble spots should be noted. Be sure to examine the first and fifth metatarsal heads, heel, and points of bony prominence. Typically, patients with neuropathy have (or will have) Charcot-type deformities, including loss of the arch, bunions, and hammertoes. This condition alters the weight-bearing mechanics of the foot and places the patient at risk for cutaneous injury and ulceration, particularly when sensation is diminished. Note the skin color (normal pink, pale white, rubor), condition of the nails, and presence of any lesions. The diabetic foot is often dry, warm, and insensate. The skin is hyperkeratotic and the veins dilated. The toes may become clawlike. The pedal pulses are good unless there is also advanced peripheral vascular disease, as described previously. One should also feel pulses at the femoral, popliteal, dorsalis pedis, and posterior tibial locations in the leg and foot as this may be the first clue that the patient has an ischemic problem (with or without neuropathy).

Table 2 Foot Care Screening Questions Do your feet feel numb? Do your feet feel excessively cold or hot? Do you have ‘‘pins and needles’’ sensations in your feet or legs? Do you have any stabbing pain in your feet and legs? Do you have any deep dull pain (like a toothache) in your feet and legs?

No No No

Yes Yes Yes

No

Yes

No

Yes

No

Yes

No No

Yes Yes

When? Do you have any burning sensation in your feet and legs? Do the bedclothes irritate your feet or legs? Have you ever had an infection or ulcer of your leg or foot that did not heal or healed very slowly?

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Patients who have calluses (preulcerative lesions) or early neuropathic changes should have evaluation with the Semmes-Weinstein monofilament. This is a simple nylon filament calibrated to bend at 10 g. of force, which is a pressure associated with protective sensation. Examination proceeds by touching the patient in the areas at risk in the foot (metatarsal heads, bony prominences, ulcer area) and noting whether the patient can feel the touch. If not, the foot is at risk of development of ulceration and the patient should have special footwear. An evaluation by a podiatrist or orthopedist with an interest in problems of the diabetic foot should be sought. The neuropathic ulcer is usually surrounded by hyperkeratotic skin. The base may reveal pink granulation tissue and can bleed easily. It is painless. The arterial pulses of the foot are intact. The ischemic ulcer develops in areas of tissue atrophy without the associated hyperkeratotic buildup typical of the neuropathic ulcer; the foot is cool and pulses poorly palpated. The presence of the typical signs of infection (erythema, odor, drainage, lymphangitis) should be noted. In general, infections in the diabetic foot may be classified as follows: 3.2.1 Type I: Mild Type I infection is characterized by a superficial ulcer or minor break in the skin surrounded by a slight amount of erythema of the skin, usually extending less than 2 cm in diameter from the ulcer. There is no systemic toxicity or evidence of osteomyelitis, tissue necrosis, or deep plantar infection. 3.2.2

Type II: Moderate or Limb-Threatening

Type II infections are chronic deeper ulcers extending to the subcutaneous tissues. There is no bone exposed. The lesion may be draining small amounts of serous or purulent fluid, but no deep collection is suspected on the basis of inability to express pus from the wound and lack of edema in the arch of the foot. There may be erythema extending to the forefoot. Osteomyelitis may be present. Larger (more than 2 cm2 in diameter) and deeper ulcers (more than 3 mm2 in depth) are more commonly associated with a contiguous osteomyelitis. 3.2.3

Type III: Severe

Limb and life-threatening. The type III infections are extensive infections with large deep ulcers. Cellulitis may be widespread and associated with lymphangitis. There is malodorous, purulent drainage. Suspicion of a deep infection or abscess collection is based on ability to express pus from the ulcer. The ulcer and surrounding tissue may be necrotic with blackened dead skin and subcutaneous tissue. Bone may be visible or easily palpated with probing. Signs and symptoms of systemic involvement such as fever, elevated white blood cell count, and hyperglycemia are present. Typically, tissue destruction is extensive under the intact skin. 3.2.4

Osteomyelitis

The diagnosis of osteomyelitis by physical exam can be challenging. Bone infection related to diabetic foot infections is due to contiguous spread from the ulcer to bone. The bone is not infected hematogenously; usually it is by direct extension from a large deep ulcer or a fistulous tract from the ulcer to the bone. Therefore, demonstration of a fistulous tract or ulcer extending to the bone or in the direction of the bone (if the bone is not visible) is useful circumstantial evidence that the bone is involved. This may be particularly helpful

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when trying to differentiate an osteomyelitis of the midfoot tarsal bones from a Charcot joint. Lack of a tract to the suspected bone should raise doubt about a diagnosis of bone infection. Palpation of the bone with a sterile probe can be a valuable test for the detection of osteomyelitis. According to Grayson and associates (1994), the palpation of bone through the ulcer has a sensitivity of 66%, a specificity of 85%, and a positive predictive value of 89% in predicting the presence of osteomyelitis. The inability to palpate bone does not rule out bone infection, though. Osteomyelitis is typically associated with type II or type III infections, but long-standing type I infections can develop this complication as well. It is important to recognize that some patients with limb- or life-threatening diabetic foot infections do not appear toxic and are not febrile. Blood culture findings often are negative. Pain and tenderness are not consistent findings and should not be used to judge the presence of infection, especially in view of the peripheral neuropathy present in the majority of patients. 3.3

Laboratory

Results of the routine laboratory assessment including a complete blood count are generally nonspecific, although some patients with type II or III infection may have a leukocytosis. Despite bone destruction the alkaline phosphatase level is not elevated. Most patients have an elevated erythrocyte sedimentation rate (ESR) and C-reactive protein level. Investigators have found osteomyelitis in 100% of patients with ESR >100 mm/hr. Others (Lipsky, 1995) have found a 12-fold increased risk of osteomyelitis in patients with ESR >40 mm/hr. Glycemic control may be lost during infections. 3.4

Radiological Evaluation

Radiographic modalities used to look for osteomyelitis include plain radiography; nuclear imaging, including bone and leukocyte tagged scans, and computed tomographic (CT) and magnetic resonance imaging (MRI) scans. The sensitivity, specificity, and costs of these tests vary greatly; they all have practical use in the diagnosis of deep tissue infection and osteomyelitis (see Table 3). If bone is visible or palpated through the ulcer and there is no evidence of a deeper abscess, radiological imaging is not necessary. If there is doubt about the presence of osteomyelitis, a plain radiograph may demonstrate periosteal reaction, focal osteopenia, bone destruction, and islands of dead bone (sequestra) that are characteristic of bone infection. The sensitivity of a plain radiograph is limited and a negative film result does not rule out bone infection. Repeating radiography in 2–3 weeks may demonstrate changes consistent with osteomyelitis. A technetium Tc 99 bone scan shows increased uptake in areas of osteoblastic activity or increased blood flow. Scans are more sensitive than plain film and can provide evidence for osteomyelitis weeks before changes can be seen on plain radiographs. Unfortunately, they are nonspecific and false-positive test findings can occur because of fractures; previous bone surgery, partially treated bone infection; Charcot joints; and tumors. Although leukocyte tagged scans such as indium-111 and Tc-99m-HMPAO are specific for infections, the degree of anatomical resolution is poor and differentiating bone infection from overlying cellulitis may be difficult. Some authorities recommend combining bone and leukocyte scans to improve the diagnostic specificity for bone infections. The accuracy of this double-scan approach nears 90%. This approach, however, is expensive and timeconsuming and does not yield adequate detail about soft tissue involvement.

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Table 3 Imaging the Diabetic Foot for Evidence of Osteomyelitis Imaging technique

Sensitivity, %

Specificity, %

PPV,a %

Comment

Plain radiograph

60 (28–93)

66 (50–92)

74–87

Bone scan b

86 (68–100)

45 (0–79)

43–87

Leukocyte scan c

89 (45–100)

78 (29–100)

75–85

MRI scan

99 (29–100)

83 (71–100)

50-100

Need 40%–70% bone resorption to visualize changes, which can lag up to 2 weeks False-positive results from diabetic osteopathy, fractures, and healing bone infections; false negative results are unusual and may be due to poor blood flow. Poor anatomical resolution; false-positive result due to overlying cellulitis Not as good as CTd scan for detecting cortical lesions but better for imaging bone marrow and soft tissue

a

Positive predictive value. Technecium Tc 99m diphosphonate three-phase bone scan. c Indium-111 or Tc 99m HMPAO leukocyte tagged scan. d Computed tomography. Source: Adapted from Lipsky 1997. b

Overall the most sensitive and specific imaging technique is MRI scanning. It can give excellent anatomical detail of the bone and soft tissue, helping in assessment not only for osteomyelitis but also for deep tissue abscess and fasciitis. Bone involvement shows a low T1 and high T2 signal. The improved sensitivity and specificity of the MRI scan must be weighed against the cost of the exam and its limited availability. MRI scanning should be reserved for patients whose diagnosis is in doubt after plain radiographs or nuclear scanning or for patients with suspected deep tissue involvement. The MRI scan may not be able to differentiate between osteomyelitis and a Charcot joint. An approach to the diagnosis to osteomyelitis is outlined in Figure 2. 4 4.1

BACTERIOLOGICAL CHARACTERISTICS Pathogens

The bacteria isolated from a diabetic ulcer can generally be predicted from the severity of the ulcer and the culturing technique used. Superficial or type I ulcers are usually monobacterial with cultures growing S. aureus or streptococci. As the severity of the infection worsens, the wounds (type II and III) are more likely to be polymicrobic, involving not only staphylococci and streptococci but also aerobic gram-negative rods (GNRs) and anaerobes. In a study by Lipsky and colleagues (1990) of 60 patients treated as outpatients for infections not involving abscess formation or osteomyelitis the average number of pathogens isolated per patient was 2.1. Monobacterial infections were found in 42% of patients; predominant isolates were S. aureus, coagulase-negative staphylococci, and strep-

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Figure 2 Diagnosis of osteomyelitis. All patients who have a diabetic foot ulceration, particularly one that does not heal with appropriate medical care, should be suspected of having an underlying osteomyelitis. Bone involvement occurs from a contiguous ulceration. Generally a pathway from cutaneous ulcer to bone can be demonstrated. The use of magnetic resonance imaging (MRI) or white blood cell (WBC) tagged nuclear scanning may be helpful when there is strong suspicion of osteomyelitis when initial plain foot film findings are nondiagnostic. Palpation or visualization of bone is highly predictive of osteomyelitis. (Adapted from Lipsky 1999, Figure 1.)

tococci. Aerobic GNRs were isolated from 23%; Klebsiella spp., Proteus spp., and Pseudomonas aeruginosa predominated. In more severe infections, multiple pathogens are isolated in up to 90% of patients. The number of bacteria isolated in these more severe infections averaged three to five, depending on the study. Most of the infections were due to an admixture of staphylococci, including S. aureus and coagulase-negative staphylococci; streptococci, including S. pyogenes, aerobic GNRs, including Escherichia coli, Proteus spp., Klebsiella spp., Enterobacter spp., and P. aeruginosa; and anaerobes such as Bacteroides spp., Clostridium spp., and Peptostreptococcus spp. Diabetic osteomyelitis is also usually polymicrobic; 70%–85% of patients have multiple pathogens isolated from bone biopsy culture. Staphylococci, streptococci, diphtheroids, and enterococci are often isolated along with aerobic GNRs and anaerobes. Pseudomonas spp. have been isolated from 10%–15% of patients. Anaerobes are more frequently isolated from more severe or long-standing infections. Although coagulase-negative staphylococcus, diphtheroids, and Enterococcus spp. are often considered colonizers or contaminants, in the patient with diabetic osteomyelitis they are often true pathogens.

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Culturing

The accuracy of the cultures from diabetic foot ulcers is dependent on the technique used to obtain the specimen. It is well recognized that swab cultures of superficial ulcers are inaccurate, overrepresent pathogenic bacteria, and should not be done. Cultures should be taken from tissue, bone, or loculated abscesses. Frequently, only the ulcer can be cultured. Comparisons of deep cultures (surgical biopsy or abscess aspiration) to those taken from the open ulcer showed a correlation in only 17%–27%. The rate of both false-positive and false-negative culture results from the ulcers was 50%. When only the ulcer is available for culturing, the base should first be cleaned with saline solution, povidine-iodine, or alcohol. A sample for culture is then taken by curettage of the base of the ulcer with a scalpel blade or curette. The scraping should be sent for aerobic and anaerobic culture. De´bridement of the ulcer may also produce suitable tissue for culture. Ideally, bone suspected of being infected should be cultured. This is easier said than done, especially in the outpatient setting. The ability to predict accurately the results of bone cultures from soft tissue cultures is extremely limited. One study showed identical pathogens from bone and soft tissue in only 13% of patients (Laveny, 1995). The difficulty of identification of true bone pathogens is compounded by the frequent use of antibiotics before biopsy, which makes interpretation of cultures challenging. 5

APPROACH TO THE PATIENT WITH A DIABETIC FOOT ULCER

The approach to the patient with a diabetic foot infection is summarized in Figure 3. The patient should have a thorough history and physical examination. The history should include duration and level of glycemic control, complications of diabetes such as peripheral neuropathy, and cigarette smoking. The ulcer should be probed to determine depth of the

DIABETIC FOOT INFECTION: 2 Approach to the patient with a diabetic foot ulcer (see Figure 3) Type I or mild Shallow ulcer 256, a fourfold increase in antibody on acute and convalescent sera, or seroconversion represents a positive test finding. Similar criteria, based on laboratory control samples, may be used for HGE, although a single IFA titer of ⱖ80 is considered a positive result. The tests should include both IgM and IgG antibodies. Additional serological tests (ELISA, immunoblot, recombinant protein ELISA) are also now in use. 3.4

Treatment

Doxycycline (100 mg bid for 7 days) is the treatment of choice and is highly effective. Rifampin may have a role in the treatment of pregnant women and children. Quinolones may also be effective, but clinical data are limited. Response to treatment is usually rapid. The persistence of fever or other symptoms in a patient treated for suspected ehrlichosis should lead to consideration of other infectious causes, including opportunistic infection facilitated by HGE or coinfection by other tick-borne agents. 4

BABESIOSIS

Babesia microti is a malaria-like intraerythrocytic protozoon. Human infection was first recognized in the United States in 1969 on Nantucket Island, Massachusetts. A related illness had been previously described in Europe. Early epidemiological studies demonstrated the deer tick was the vector in the eastern United States. Although white tailed deer are not infected with Babesia spp., their proliferation allowed the spread of the deer tick. The nymph and larva tick stages feed on white-footed mice, which serve as the reservoir for Babesia microti. With the spread of deer ticks, babesiosis has been recognized in other northern coastal sites and in Wisconsin. In addition, two newly recognized Babesia species have been reported from splenectomized patients in Washington state, California, and Missouri. Although most cases of babesiosis result from tick bites, a small number of transfusion-acquired cases have been reported. Babesiosis, when symptomatic, is usually a mild disease in the United States, characterized by indolent but recurring fatigue, fever, and malaise. Asymptomatic infection is common. Most symptomatic cases are reported in elderly patients. Physical exam may reveal a relative bradycardia and splenomegaly. Hemolytic anemia and hemoglobinuria may be present. In immunocompromised or splenectomized patients, the infection can become fulminant and life-threatening. Laboratory findings include mild anemia, lymphopenia, and/or thrombocytopenia. Elevations of alkaline phosphatase or transaminase levels are common. Parasitemia of red blood cells usually ranges between 1% and 10%. Coinfection with Lyme disease or HGE may occur. Because symptomatic babesiosis has nonspecific signs and symptoms the disease is often not suspected by physicians. The diagnosis is often first considered when intraerythrocytic inclusions are noted by laboratory personnel examining a Giemsa- or Wrightstained blood smear. Definitive diagnosis can be made by examination of thick and thin blood smears in a similar manner to the diagnosis of malaria. Although intracellular organisms are present in most patients with symptomatic babesiosis, low-level parasitemia may make diagnosis a challenge. The intraerythrocytic inclusions of babesiosis can be distinguished from malaria by the presence of extracellular merozoite and tetrad forms, but these are not always present. Indirect immunofluorescent antibody tests may confirm

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Babesia spp. infection. Patients with active infection usually have serum antibody titers of 1:1024 or greater with a gradual decrease in titer to 1:256 over several months. PCR for Babesia spp. DNA has a high sensitivity when used on blood in acute cases. Many infected patients are asymptomatic or only mildly ill and recover without therapy. Occasionally untreated infection can persist from months to years. Treatment is usually effective, though persistence of parasitemia for several weeks after treatment has been documented. Standard treatment includes the combination of quinine and clindamycin for 7–10 days. Toxicities due to quinine and clindamycin make this regimen difficult. Atovaquone with azithromycin is an alternative, less toxic combination. In patients with severe illness and parasitemias of >5–10%, exchange transfusion has been reported to be an effective adjunct to treatment.

5

ROCKY MOUNTAIN SPOTTED FEVER

Rocky Mountain spotted fever (RMSF) is caused by Rickettsia rickettsii, a member of the spotted fever group Rickettsiae. The illness appears misnamed since most infections occur in the south central and southeastern United States. RMSF was first described in Idaho and was not recognized outside the western United States until 1931. It has occurred in all but a few states (see Figure 7). R. rickettsii is an obligate intracellular bacterium that targets endothelial cells and can cause a multiorgan disease through these vasculitic effects. Fatality rates without treatment reach 25%. As its presenting features are those of a nonspecific febrile illness, high suspicion and willingness to start empirical antibiotic treatment are essential in endemic areas. 5.1

Ecological and Epidemiological Characteristics

RMSF is transmitted by the dog tick Dermacentor variabilis in most of the United States except the western mountain states, where the wood tick, Dermacentor andersoni, is the vector (see Figure 8). The ticks serve as both reservoir and vector for R. rickettsii. Although these ticks are ubiquitous in many areas of the United States, RMSF tends to occur regularly in particular geographical foci. Dermacentor spp. ticks, unlike deer ticks, are abundant in grassy open areas as well as brushy habitats. Although R. rickettsii can be transmitted transovarially and from stage to stage in the tick, only the adult Dermacentor spp. ticks bite humans. In Central and South America, other tick genera including Amblyomma and Rhipicephalus spp. are vectors. RMSF may be transmitted by tick bites in 500 Eosinophils/␮L blood (see Table 2) >10% Eosinophilia Tissue-invasive parasites Hookworm and cutaneous larva migrans Ascariasis and visceral larva migrans (toxocariasis) Schistosomiasis Stronglyloidiasis Trichinosis Filariasis Echinococcosis Drug reactions Primary eosinophilic disorders Parasitic infections Occupational and travel history (see Table 3) Skin exam (see Table 4) Elevated immunoglobulin E (IgE) level Stool ova and parasite exam

ceral (Toxocara canis or cati, dog or cat ascarid) larval migrans syndromes or strongyloidiasis. Exposure to insects may suggest filariasis (infections due to tissue dwelling nematodes such as Wucheria bancrofti and Brugia malayi). Unsatisfactory preparation of foods, particularly salads, has been linked to cysticercosis (tissue infection with larval cysts of the tapeworm Taenia solium) and fascioliasis (infection with the liver fluke Fasciola hepatica). Ingestion of snails, slugs, freshwater crabs, or shrimp suggests angiostronylosis (abdominal pain, right lower quadrant mass due to Angiostrongylus costaricensis or A. cantonensis). Ingestion of poorly cooked pork or large wild mammals may be linked to trichinosis (fever and myalgia due to infection with the tissue roundworm Trichinella spiralis). Physical examination should be directed to the involved organ system. Cutaneous lesions are often the first sign of parasitic infection (see Table 4). Skin rash is seen with cutaneous larva migrans syndromes. Skin thickening syndromes, subcutaneous nodules, and lymphatic enlargement are seen with filariasis. Wheezing and shortness of breath occur with tropical pulmonary eosinophilia. Muscle swelling and periorbital edema are symptoms of trichinosis. Diagnostic tests are limited. Stool exam for parasitic ova and larva may be useful in schistosomiasis, strongyloidiasis, fascioliasis, hookworm, enterobiasis, and ascariasis (roundworm, Ascaris lumbricoides). Biopsy of subcutaneous nodules may be diagnostic for onchocerciasis (river blindness caused by Onchocerca volvulus). Generally serological tests indicate prior exposure and are not useful for patients from endemic areas. Peripheral blood smears and skin snips may help in detecting microfilaria due to infection with Wucheria sp. or Brugia sp. filariasis.

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Table 1 Parasite Classification Protozoa

Helminths (worms)

Amoebae Entamoeba histolytica (amebiasis), E. hartmani, E. coli, Endolimax nana Free-living amoebae Acanthamoeba, Naegleria spp. Flagellates Giardiasis Trichomoniasis Blood/tissue flagellates Leishmaniasis Trypanosomiasis Babesiosis Cilophora Balantidium Coccidia Toxoplasmosis Cryptosporidiosis Isosporiasis Cyclosporiasis Sarcocystis Blastocystis Plasmodium (malaria) Babesiosis Microsporidia

Intestinal nematodes (roundworms) Trichuriasis (whipworm) Enterobiasis (pinworm) Strongyloidiasis (threadworm) Hookworm: Necator, Ancylostoma spp. Animal hookworm (cutaneous larva migrans), Ancylostoma braziliense Ascariasis (giant intestinal worm) Animal ascarids (visceral larva migrans): Toxocara canis, T. cati Tissue nematodes (filaria) Wucheria Brugia Onchocerciasis (river blindness) Loa loa Dracunculus Trichinosis Cestodes (tapeworms) Cysticercosis; Taenia solium and T. saginata Echinococcosis Hymenolepis Diphyllobothriasis Trematodes (flatworms or flukes) Schistosomiasis Clonorchiasis Fascioliasis Paragonimiasis

Table 2 Differential Diagnosis of Eosinophilia Allergy Asthma Allergic rhinitis Drug reactions Food allergy Insect bites Invasive helmintic parasites Hookworm and cutaneous larva migrans Ascariasis and viseral larva migrans (toxocariasis) Schistosomiasis Strongyloidiasis Trichinosis Filariasis Echinococcosis

Skin disorders Eczema Acute urticaria Pemphigoid Pemphigus Malignancy Lymphoma Acute myelogenous leukemia Mycosis fungoides Carcinoma of lung, stomach, pancreas, ovary Angioimmunoblastic lymphadenopathy

Collagen vascular disease Systemic lupus erythematosus (SLE) Rheumatoid arthritis Polyarteritis nodosa Allergic angiitis Miscellaneous Job’s syndrome Churg-Strauss syndrome Loeffler’s syndrome Chronic granulomatous disease Hypoadrenalism Eosinophic gastroenteritis Hypereosinophilic syndrome

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Table 3 Eosinophilia Secondary to Helminthic Parasitic Disease (Eosinophilia ⱖ3,000/(␮L) Exposure Raw or lightly cooked snails, slugs, freshwater crabs, or prawns or unwashed vegetables

Barefoot contact with soil

Parasite

Eosinophilia present/clinical syndrome

Angiostrongylus cantonensis

Larva migration into the brain; meningoencephalitis

Angiostrongylus costaricensis

All stages of infection; abdominal pain, fever, appendicitis Early transpulmonary larval migration mild in mature worms; pulmonary infiltrates, iron deficiency anemia Early transpulmonary larval migration pronounced during hyperinfection syndrome; pulmonary infiltrates Pronounced during stage of encystment of larvae in muscles; fever, myalgia, periorbital edema Visceral larva migrans; fever, cough, hepatomegaly, or asymptomatic Only during early transpulmonary larval migration; pulmonary infiltrates During early infection in nonimmune hosts; fever, cough, hepatosplenomegaly, lymphadenopathy (Katayama fever) Parasite migration in soft tissues; cutaneous larva migrans, meningitis Severe infestation of large bowel; iron deficiency anemia, rectal prolapse Asymptomatic or during acute phase of disease; may be absent in chronic disease; lymphangitis, fever, orchitis, tropical pulmonary eosinophilia Raised serpiginous pruritic rash (cutaneous larva migrans) Early phase of localization in biliary tract; asymptomatic, cholangitis Migration of adult worms into liver with heavy infestation; fever, hepatomegaly, right upper quadrant pain

Hookworm

Strongyloides stercoralis

Ingestion of undercooked pork or meat of wild carnivores

Trichinella spiralis

Geophagic children

Toxocara canis and T. cati Ascaris lumbricoides

Freshwater exposure

Schistosoma spp.

Ingestion of improperly cooked fish, frogs, birds, and snakes Uncooked vegetables from gardens fertilized with human excreta Insect bites in Southeast Asia

Gnathostoma spinigerum

Trichuris trichiuria

Brugia malayi, Wucheria bancrofti

Dog or cat feces

Ancylostoma braziliense

Ingestion of raw fish

Clonorchis sinensis

Consumption of aquatic plant in tropical area

Fasciola hepatica

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Table 4 Cutaneous Lesions Associated with Parasites Clinical syndromes Severely pruritic serpiginous tract (cutaneous larva migrans) Pruritic erythematous rash on exposed areas Pruritic follicular dermatitis Subcutaneous swelling, worm migration across conjunctiva, large hives Pruritis with maculopapular rash, predominantly on buttocks and back; lesions potentially hyperkeratotic and severely pruritic Chronic lymphadema, acute lymphangitis with fever, orchitis, funiculitis Subcutaneous nodules, painless fixed nodules around bony prominences; also chronic pruritic dermatitis, lymphadema Painful erythematous papule or furuncle with opening for fly maggot (myiasis) Painless ulcer, raised edges, slow healing on face, limbs Perianal and perineal nocturnal pruritus

3

Exposure/contact Skin exposed to contaminated soil

Cause

Geographical locale

Ancylostoma spp., Gnathostoma spinigerum Strongyloides spp.

Worldwide, tropics

Avian schistosomiasis Loa loa

North American Great Lakes Northern West Africa

Simulium fly bite

Onchocerca volvulus

Central and West Africa, Latin America, and Arabian peninsula

Mosquito bite

Brugia malayi, Wucheria bancrofti

Southeast Asia

Blackfly (Simulium sp.) bite Skin exposed to contaminated soil

Onchocerca volvulus

Rural Africa, Central and South America

Fly bite transmitting larvae (ecoparasite)

Dermatoba hominis (botfly), Cordylobia anthrophaga (tumba fly) Leishmania spp.

Skin exposed to contaminated soil Skin exposed to contaminated water Fly (Chrysops spp.) bite

Sandfly bite

Person-to-person in families and institutions

Worldwide, tropics, and subtropics

Gnathostoma spinigerum

Enterobius vermicularis

Central and South America, Africa

Africa, Central and South America, Middle East Children, worldwide

DIARRHEA

Diarrhea that lasts for more than 1 week or acquired during international travel should prompt a search for a parasitic infection. Most commonly, these infections are acquired from contaminated food or water. Diagnosis is generally by stool exam for ova and parasites. Treatment is available for the majority of infections (see Table 5). The most commonly encountered parasites include Giardia lamblia, Entamoeba histolytica, Cryptospor-

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DIARRHEA (Also see Chapter 22 and Chapter 39) Generally chronic May be associated witih weight loss, steatorrhea, nausea, abdominal pain, flatulence Giardiasis Amebiasis Also acute proctocolitis Hepatic abscess, ameboma Cryptosporidiosis, cyclosporiasis, isosporiasis, microsporidia, balantidiasis, Blastocystis hominis More common in immune compromised patient Diagnosis by stool ova and parasite or antigen detection May need samples on 3 different days Therapy (see Table 5)

Table 5 Treatment of Intestinal Protozoa Intestinal protozoon Giardiasis

Treatment Metronidazole 2 g/day ⫻ 3 days or 250 mg tid ⫻ 7 days or paromomycin 10 mg/kg tid ⫻ 5–10 days

or albendazole 400 mg/day ⫻ 5 days Amebiasis Asymptomatic cysts

Invasive colitis

Cryptosporidiosis

Cyclosporiasis Isoporiasis Microsporiasis a b

Iodoquinol 650 mg tid ⫻ 20 days or paromomycin 10 mg/kg tid ⫻ 5–10 days

or metronidazole 750 mg tid ⫻ 10 days metronidazole 750 mg IV/PO tid ⫻ 5–10 days then iodoquinol or paromomycin as above Paromomycin 500 mg tid ⫻ 7 days or azithromycin 600 mg/day ⫻ 4 wk TMP-SMZ2 DSa bid ⫻ 7 days TMP-SMZ DS qid ⫻ 10 days Albendazole 400 mg bid ⫻ 21 days

TMP-SMZ, trimethoprim & sulfamethoxazole (co-trimoxazole); DS, double-strength. Average wholesale price: 2000 Drug Topics Redbook.

Costb $36.00 $63.00 $113.00–$226.00 For 70-kg person $10.00 $31.50 $113.00–$226.00 For 70-kg person

$180.00

$133.00 $486.00 $18.00 $52.00 $84.00

Manifestations of Parasitic Infections

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idium parvum, Isospora belli, Cyclospora cayetanenis, Microsporidia spp., Balantidium coli, and Blastocystis hominis. 3.1

Giardiasis

Giardiasis, an enteric infection caused by the flagellated protozoon Giardia lamblia (also called G. duodenalis or intestinalis), is the most common gastrointestinal parasitic infection in the United States. Giardia spp. have been found in 2%–5% of stool samples in the industrialized world and in 20%–30% of samples from the developing world. Giardia spp. are spread by ingestion of oocysts usually from contaminated water but also from person-to-person contact and from contaminated foods. After ingestion, excystation occurs in the small bowel, allowing attachment and proliferation of the trophozoite in the gut. High-risk groups for giardiasis include infants, young children, travelers, and those who have common variable immunodeficiency human immunodeficiency virus (HIV) infection, and gastric surgery or hypochlorhydria. Although giardiasis accounts for less than 5% of traveler’s diarrhea, travelers to certain areas such as St. Petersburg, Russia, have an attack rate as high as 30%–40%. Even within the United States, prevalence is quite variable, as outbreaks have been associated with drinking from clear mountain streams. Immunodeficiency predisposes to chronic infection. The ability of the cyst to survive in fresh water and its relative insensitivity to chlorination are responsible for water-borne epidemics. Human-to-human transmission occurs in day care centers, schools, and residential institutions. Food handlers have been implicated in epidemics, and there is evidence to suggest that there is a reservoir in wild and domestic animals. The clinical syndromes include an asymptomatic carrier state and acute and chronic diarrhea. The incubation period is generally 1 to 2 weeks. Acute giardiasis causes a voluminous and watery diarrhea though without associated blood or mucus. Mild weight loss occurs in 60%–70% of patients. Other symptoms may include abdominal discomfort, nausea, flatulence, mild fever, and lassitude. Steatorrhea may be present. The vast majority of infections are self-limited and last 2–4 weeks. In 25% of patients chronic diarrhea, lasting months with associated weight loss, malabsorption, steatorrhea, macrocytic anemia, and secondary lactase deficiency, develops. Periods of normal stools and/or constipation may be interspersed during this chronic infection. The appropriate clinical history suggests the diagnosis. Stool sample findings should be negative for blood and fecal leukocytes. The detection of Giardia sp. cysts or trophozoites in the stool confirms the diagnosis. The sensitivity of parasitic detection in the stool rises to 85% when specimens are submitted on 3 different days. Commercially available antigen detection assays have sensitivities of 87%–100%. An immunofluorescence test for both Giardia spp. and Cryptosporidium spp. is available. Therapy is summarized in Table 5. The drug of choice is metronidazole, which has an 80%–95% cure rate. Albendazole has been used successfully, though experience is limited. Paromomycin may be the drug of choice in pregnant women with severe symptomatic disease. Consideration should be given to delaying treatment until after delivery or at least during the first trimester if symptoms are not severe and hydration can be maintained. 3.2

Amebiasis

Amebiasis, caused by the pseudopod forming protozoa Entamoeba histolytica, is most often manifested clinically as acute colitis. Less commonly, systemic invasion results in

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hepatic abscess formation. E. histolytica infects more than 100 million people worldwide, contributing to significant morbidity and mortality rtes. In the United States the overall serological prevalence is 4% of the population. Institutionalized populations, especially the mentally challenged, have a higher incidence of infection. The prevalence of this infection in men who have sex with men is high, although many are actually infected with Entamoeba dispar, which is morphologically identical to E. histolytica but does not produce clinical disease. The clinical spectrum of intestinal amebiasis includes asymptomatic infection, symptomatic noninvasive infection, invasive protocolitis (amebic dysentery), fulminate colitis, toxic megacolon, and ameboma. Symptomatic noninvasive disease occurs 2 to 6 weeks after exposure and produces lower abdominal pain and mild diarrhea. This may progress to dysentery and, rarely, fulminant colitis characterized by bloody diarrhea, abdominal pain, fever, and leukocytosis. Proctocolitis, more common in malnourished persons, pregnant women, and recipients of steroid therapy, is associated with a high mortality rate. Perianal infection of skin with fistula formation can rarely occur. Less commonly, patients may have symptoms and signs of an intestinal mass (ameboma) mimicking carcinoma or an abscess. Extraintestinal disease such as a liver abscess is a rare complication. The finding of either the cyst or the trophozoites in the stool confirms the diagnosis. Administration of three stool exams increases the sensitivity to 70%–90%. Other amebas such as E. dispar, E. hartmanni, Endolimax nana, and Chilomastix mesnili are considered nonpathogenic. The stool is always heme-positive. Serological tests such as the indirect hemagglutination antibody (IHA) tests are useful for the diagnosis of invasive disease. Antibody levels indicated by IHA may remain elevated for years after acute invasive infection. E. dispar cannot be distinguished microscopically from E. histolytica, but infection with E. dispar does not generate serum antibodies. Therefore, asymptomatic patients with presumed E. histolytica oocysts or trophozoites in their stool should have antibody testing performed to rule our E. dispar. Antibody-negative patients do not require treatment. Therapy is summarized in Table 5. Asymptomatic E. histolytica cyst passers should be treated with luminal agents such as iodoquinol or paromomycin. Invasive colitis is treated with metronidazole plus a luminal agent. All patients should have follow-up stool testing to confirm eradication of the parasite. 3.3

Cryptosporidiosis

Cryptosporidium parvum is an intracellular coccidian protozoon. It can be transmitted by the fecal-oral route to humans from other humans and animals and by contaminated water. The oocysts are resistant to standard water purification techniques and chlorination and can survive for many months outside the host. After ingestion, the oocysts excyst and replicate in the bowel lumen, leading to a repeating cycle of autoinfection. Seroprevalence studies in industrialized nations suggest that up to 25%–35% of the population have been infected and stool studies show that 3% of patients with diarrhea are infected with Cryptosporidium spp. The rates are considerably higher in nonindustrialized nations. After an incubation period of 7–10 days, cryptosporidiosis produces bloating, abdominal pain, and diarrhea. Diarrhea is usually voluminous and can total 12–17 liters a day. In addition, patients may report low-grade fever, general malaise, nausea, fatigue, and anorexia. The diarrhea is usually self-limited but may become chronic in immunocompromised patients. Acalculous cholecystitis and cholangitis have been reported in patients with AIDS.

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The diagnosis is confirmed by finding oocysts in the stool by direct examination or antigen detection. Stools are concentrated and then stained by a modified acid-fast method or examined for antigen by immunofluorescent antibody tests. The stool is heme-negative. There is no reliable curative or palliative treatment for cryptosporidiosis. In the immunocompetent host, it is a self-limited illness. Supportive measures including hospitalization for hydration may be necessary. In immunocompromised patients, including those with HIV infection, paromomycin and azithromycin have been used with variable efficacy (see Table 5). 3.4

Isosporiasis

Isospora belli is a coccodidian protozoon related to Cryptosporidium, Cyclospora, and Toxoplasma spp. Fecally contaminated food or water transmits the infection. Isospora spp. have worldwide distribution but are more common in the tropics. In the United States infection is more common in persons who have HIV or are institutionalized, attend day care, or are immigrants from tropical areas. After ingestion, the parasite excysts and replicates in the small bowel. After a brief incubation period of 1 to 2 days, the acute illness begins with low-grade fever; profuse watery, nonbloody diarrhea; and abdominal cramps. In the immunologically normal host, the disease can be self-limited or less commonly can become chronic. In patients with HIV infection and other immune suppressed states, isosporiasis can lead to chronic diarrhea refractory to treatment. The diagnosis is made by identification of oocysts in the stool. Multiple stool samples may be needed to identify the parasite. The cysts are elliptical in shape and much larger in size than those of Cryptosporidium spp. Modified acid-fast staining or autofluorescence under ultraviolet light is used to identify the oocysts from stool concentrates. The treatment is trimethoprim & sulfamethoxazole (TMP-SMZ or co-trimoxazole) (see Table 5). Immune-suppressed patients, especially those with AIDS, may need lifelong suppressive therapy with TMP-SMZ three times weekly. 3.5

Cyclosporiasis

Infection with Cyclospora cayetanenis causes a diarrheal illness similar to that caused by Cryptosporidium and Isospora spp. It occurs worldwide and is relatively uncommon in the United States. Infections have been reported in travelers, children, and those with HIV infection. Local outbreaks in the United States due to ingestion of imported fruit and vegetables have been reported. Person-to-person transmission has not been reported. The clinical features are similar to those produced by other coccidian protozoa. The incubation period can be as short as several days but averages about 1 week. Symptoms include fever, watery diarrhea, fatigue, crampy abdominal pain, and flatulence. Diagnosis requires identification of the oocyst in the stool. The modified acid-fast stain is the preferred method. Fluorescent microscopy is rapid and sensitive. The treatment of choice is TMP-SMZ (see Table 5). For patients with AIDS, TMP-SMZ should be used qid for 10 days and chronic suppression should be considered. 3.6

Microsporidia

The microsporidia are a group of small, obligate intracellular spore-forming protozoa. They have a worldwide distribution and produce serious infections, most commonly in immunocompromised patients such as those with HIV infection and organ transplantation. Reports have been made of infection in travelers. Person-to-person transmission and water-

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borne transmission are the primary modes of transmission. Eleven species of micropsoridia have caused infection in humans. Infection can occur in the gastrointestinal, respiratory, and urinary tracts. Infection with Enterocytozoan bieneusi and Encephalitizoon intestinalis can cause chronic diarrhea associated with wasting, anorexia, abdominal pain, nausea, and fever. Stool microscopy with special staining techniques such as the Weber chromotrope stain are necessary for confirmation of diagnosis. Species identification with electron microscopy or polymerase chain reaction may be important since only some species respond to therapy. Intestinal disease due to Encephalitozoon spp. can be treated with albendazole (see Table 5). 3.7

Balantidiasis

Balantidium coli is a large ciliated protozoan parasite. Pigs are the major reservoir. Human infection is uncommon, though achlorhydria increases risk. Most patients are asymptomatic. If clinical infection occurs, it is characterized by chronic diarrhea, weight loss, and abdominal pain. Less commonly, infection can mimic amebic dysentery. Doxycycline, iodoquinol, and metronidazole can be used for treatment. 3.8

Blastocystis hominis

Many questions about taxonomic characteristics, number of species, morphological features, and virulence remain about the protozoan parasite Blastocystis hominis. This protozoon should not be considered a pathogen unless all other intestinal infections have been ruled out, it is found in multiple stool samples, and the patient continues to be symptomatic. If symptomatic infection occurs, it is generally self-limited and does not require treatment. Reports of treatment are anecdotal. Metronidazole and iodoquinol have been used with variable efficacy. 4

WORMS SEEN IN THE STOOL

Rarely a patient may report seeing a worm or fragment of a worm in feces. Generally the patient does not have other symptoms. A luminal helminthic infection should be considered. These patients do not have blood eosinophilia. If the worm is described as similar to an earthworm, Ascaris sp. is likely. If the description is of segments of a worm, then the intestinal tapeworms Diphyllobothrium latum, Tania soluim, and Tania saginata should be considered. Fresh stool should be submitted for ova and parasite examination. The lab

WORMS IN STOOL Wormlike: Ascaris lumbricoides Worm segments: intestinal tapeworms (Cestodes) Diphyllobothrium latum Tania solium, T. saginata Stool ova and parasite exam Worm to parasitology laboratory Therapy with mebendazole, albendazole, or praziquantel Hysterical parasitosis?

Pruritic rash, Loeffler’s syndrome, diarrhea, abdominal pain, autoinfection in immune-compromised

Small bowel

Small bowel

Southeastern United States; transmission from contaminated soil through skin Southeastern United States; transmission from contaminated soil through skin

Hookworm (Acylostoma duodenale, Necator americanus) Threadworm (Strongyloides stercoralis)

Average wholesale price: 2000 Drug Topics Redbook.

a

Asymptomatic, Loeffler’s syndrome, malabsorption, bowel obstruction, ‘‘passing of worms’’ Pruritic rash, Loeffler’s syndrome, iron deficiency anemia

Small bowel; migration to lungs and heart

Southeastern United States

Giant intestinal worm (Ascaris lumbricoides)

Cecum, perianal area

Family and institutional spread

Asymptomatic, rectal prolapse, iron deficiency anemia Asymptomatic, perianal pruritis

Syndromes

Pinworm (Enterobiasis vermicularis)

Cecum

Anatomic location

Southeastern United States

Risks

Whipworm (Trichuris trichuria)

Common name (genus and species)

Table 6 Helminth Infections Endemic to the United States

$2.80

Mebendazole 100 mg ⫻ 1 day; repeat in 2 wk Albendazole 400 mg ⫻ 1 day; repeat in 2 wk Mebendazole 100 mg bid ⫻ 3 days

$6.00

Albendazole 400 mg/ day ⫻ 3 days or ivermectin 200 ␮g/kg ⫻ 1 day

$25.00 For 70-kg person

As above

Mebendazole or albendazole ⫻ 1 day

$4.00 As above

$8.50

Costsa

Mebendazole 100 mg bid ⫻ 3 days

Therapy

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should be informed of the possible diagnosis under consideration. If the finding is negative, the patient should submit a stool that he or she thinks shows the characteristic parasite. This should be confirmed by the parasitology lab. If helminthic infection cannot be confirmed, parasitosis, a hysterical disorder, should be considered. Luminal helminthic infection can be treated with mebendazole (100 mg bid ⫻ 3 days) and albendazole (400 mg once) for Ascaris sp. and praziquantel (5–10 mg/kg once) for tapeworms. 5

HELMINTH INFECTIONS ENDEMIC IN THE UNITED STATES

The parasites that cause endemic U.S. helminth infections have the following characteristics in common: (1) they are intestinal nematodes called roundworms; (2) they are mostly seen in the southern United States with the exception of pinworms, which are seen throughout the United States; (3) they are transmitted by ingestion of ova from fecally contaminated food and hands, with the exception of Stronglyloides spp. and hookworm; and (4) they are most common in children. Infections may present a variety of symptoms but may also be asymptomatic. Eosinophilia may be present during certain stages of parasite migration (hookworm and Strongyloides spp.) through the human host, though absence of eosinophilia does not exclude infection. Diagnosis is generally made by detection of ova and parasite in the stool. Risk factors for infection, clinical manifestations, and therapy are summarized in Table 6. Infection with Strongyloides spp. in the immune-compromised host (as a result of AIDS, organ transplantation, high-dose corticosteroid use, lymphoma, or leukemia) can be life-threatening as a result of superinfection and dissemination of the parasite. These patients may experience pneumonia, severe abdominal pain, shock, eosinophilia, and gramnegative bacteremia superinfection. BIBLIOGRAPHY Ackers JP. Gut coccidia—isospora, cryptosporidium, cyclospora and sarcocystis. Semin Gastrointest Dis 8(1):33–44, 1997. Fauci AS, Harley JB, Roberts WC, Ferrans VJ, Gralnick HR, Bjornson BH. The idiopathic hypereosinophilic syndrome: Clinical, pathophysiologic, and therapeutic considerations. Ann Intern Med 97:78–92, 1982. Goodgame RW. Understanding intestinal spore forming protozoa: Cryptosporidium, Microsporidium, Isospora and Cyclospora. Ann Intern Med 124(4):429–441, 1996. Herwalt BL. Cyclospora cayetanensis: A review, focusing on the outbreaks of cyclosporiasis in the 1990s. Clin Infect Dis 31:1040-1057, 2000. Maguire JH, Keystone JS, eds. Parasitic Diseases. Infect Dis Clin North Am 7(3), 1993. Mahmoud AA. Strongyloidiasis. Clin Infect Dis 23(5):949–952, 1996. Ortega TR, Adam RD. Giardia: Overview and update. Clin Infect Dis 25(3):545–549, 1997. Petri WA, Singh U. Diagnosis and management of amebiasis. Clin Infect Dis 29:1117–1125, 1999. Sarinas PS, Chitkara RK. Ascariasis and hookworm. Semin Respir Infect 12(2):130–137, 1997. 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics.

33 The Pregnant Patient Mary-Margaret Andrews Dartmouth-Hitchcock Medical Center, and Dartmouth Medical School, Lebanon, New Hampshire, U.S.A.

1

INTRODUCTION

Primary care providers are often ill at ease about infections that occur during pregnancy; a working knowledge of how to approach infectious complications during the prenatal, perinatal, and postpartum periods can streamline care delivered in the outpatient clinic. The range of infections complicating pregnancy includes common infections not unique to pregnant patients but seen with increased frequency in pregnant women such as urinary tract infections (UTIs), infections that have more severe sequelae during pregnancy (hepatitis E virus, influenza, or varicella pneumonia) and infections unique to pregnant women (chorioamnionitis and endometritis). Pregnant women can also have common infections such as pneumonia, cellulitis, and gastroenteritis during pregnancy. These infections are managed as in the nonpregnant patient and are reviewed in other chapters; special attention to antibiotic selection is required. A broad array of pathogens can cause perinatal or congenital infection of the neonate (Table 1). Subclinical infection of the upper genital tract may be responsible for infertility, premature labor, and low-birth-weight deliveries. The lower female genital tract is colonized by a diverse microbial flora. This normal flora includes Lactobacillus spp., streptococci, Staphylococcus epidermidis, Bacteroides and Prevotella spp., and Gardnerella vaginalis. Typical aerobic and anaerobic bacteria dominate the flora; however, atypical bacteria (Chlamydia, Mycoplasma, and Ureaplasma species), yeast (Candida albicans), viruses (herpes simplex virus), and parasites (Trichomonas vaginalis) may also reside in the lower genital tract. Many of these species are true colonizers but can become pathogens in the appropriate clinical setting. The upper female genital tract is normally sterile. Lower tract flora can ascend in the context of surgery, instrumentation, or childbirth. Infections of the uterine cavity (endometritis), the gravid uterus and amniotic sac (chorioamnionitis), and fallopian tubes and ovaries (salpingitis, tubo-ovarian abscess, and pelvic peritoneum) are generally polymicrobial. Sexually transmitted pathogens also can play a significant role. This chapter reviews the principles of antibiotic selection for the pregnant woman and the more common infectious syndromes encountered. Table 2 outlines some general principles regarding the approach to infections in the pregnant patient. 645

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Table 1 Agents That Cause Congenital Infections Bacteria Listeria monocytogenes Treponema pallidum (syphilis) Leptospirosis spp. Mycobacterium tuberculosis Viruses Rubella Cytomegalovirus Herpes simplex virus Varicella zoster virus Parvovirus B19 Human immunodeficiency virus (HIV) Hepatitis B virus Enteroviruses Protozoa Toxoplasma gondii Plasmodium spp. (malaria)

2

ANTIBIOTIC SELECTION IN THE PREGNANT PATIENT

Pharmacokinetic principles of antibiotic use in pregnancy are unique. The physiological changes of pregnancy result in a net lowering of drug bioavailability. Drug absorption may vary with altered gastrointestinal motility and gastric emptying. The blood volume is expanded by as much as 50%, resulting in an expanded volume of drug distribution. Renal clearance of many drugs is increased by the increased renal blood flow and glomerular filtration rates of pregnancy. Elevated progesterone levels may affect hepatic metabolism of some drugs. Consequently, there is a tendency to underdosage of antibiotics during pregnancy. Antibiotics are distributed in all body compartments. Concentration gradients, low molecular weight, and low protein binding favor excretion of all antibiotics into breast milk and transfer across the placenta to the fetus. Adverse effects on neonates from antibiotic exposure, however, are rare. The U.S. Food and Drug Administration (FDA) developed risk categories for drugs (see Table 3). Most antibiotics can be used safely in pregnancy (see Table 4). ␤ -Lactams are core agents used to treat infections during pregnancy. In particular, ampicillin continues to be an excellent choice for UTIs and for polymicrobial infections involving lower genital

Table 2 Infections in Pregnant Patients: General Principles Consider potential pregnancy in female patients. Take a complete sexual, travel, and exposure history. Search for common illnesses first. Test and treat at a lower threshold. Prevent underdosage of antibiotics. Coordinate care with obstetrical service providers.

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Table 3 Pregnancy Risk Categories Pregnancy risk category X

D

C

B

A

Descriptiona Studies in animals or human beings have demonstrated fetal abnormalities, or there is evidence of fetal risk based on human experience, or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant. There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective). Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus. Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters). Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote.

a

The descriptions for the risk categories are those used by the Food and Drug Administration. Source: Federal Register 1980; 44:37434–37467.

tract flora because of its activity against streptococci, including group B streptococci (GBS), enterococci, and enteric gram-negative rods (GNRs) such as Escherichia coli. It can be combined with additional agents (e.g., clindamycin) or with a ␤ -lactamase inhibitor (clavulanate or sulbactam) to expand coverage to include anaerobes, Klebsiella spp., resistant E. coli, and Staphylococcus aureus. Cefotetan and cefoxitin are excellent drugs that can be used to treat polymicrobial lower genital tract infections. Other ␤ -lactam antibiotics such as imipenem, a carbapenem, and aztreonam, a monobactam, have both been used safely during pregnancy. Additional agents can be used during pregnancy with a few cautionary notes. Macrolides (erythomycin, azithromycin, and clarithromycin) may be indicated for respiratory infections in the pregnant or lactating woman and have been used successfully. Metronidazole in combination with gentamicin or a ␤ -lactam can be used for mixed aerobicanaerobic infections. Metronidazole can be used as a single agent for bacterial vaginosis but solely during the second or third trimester. Because it is a mutagen, it is used more stringently during the first trimester. Trimethoprim & sulfamethoxasole can be used safely during pregnancy, although the trimethoprim component should also be avoided during the first trimester. Sulfonamides should be avoided near the time of delivery to prevent fetal hyperbilirubinemia. Aminoglycosides are not contraindicated in pregnancy but are used cautiously. In the past, rare instances of eighth nerve damage were reported in women treated for tuberculosis with long courses of streptomycin.

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Table 4 Antibiotic Risk During Pregnancy Risk category Antimicrobials generally considered to be safe in pregnancy Amphotericin B Azithromycin Aztreonam Cephalosporins Clindamycin Erythromycin Famciclovir Metronidazole Nitrofurantoina Penicillins Valacyclovir Antimicrobials to be used with caution in pregnancy Acyclovir Aminoglycosides Clarithromycin Ganciclovir Fluconazole Imipenem-cilastatin Indinavir Ketoconazole Lamivudine Nelfinavir Nevirapine Nystatin Rifampin Ritonavir Sulfonamidesa,b Stavudine Trimethroprim & sulfamethoxazolea,b Trimethoprim Zalcitabine Vancomycin Zidovudine Amprenavir Didanosine Lopinavir/r Delavirdine Antimicrobials which should be avoided in pregnancy Efavirenz Quinolones Ribavirin Tetracyclines a

B B B B B B B B B B B C D C C C C C C C B C C C B B C B C C C C C B C C C C X D

Do not administer to pregnant patients who have (G-6-PD) deficiency because of the risk of hemolysis to the mother and fetus. b Risk factor D applies if administered near term. Source: Briggs G et al. Drugs in Pregnancy and Lactation. Fifth edition. Philadelphia: Lippincott, Williams & Wilkins, 1998; Department of Health & Human Services. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. February 4, 2002. http://www.hivatis.org.

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Acyclovir can be safely used to treat genital herpes simplex infections and disseminated varicella zoster infection, including pneumonia. In general women with human immunodeficiency virus (HIV) infection should be managed in a similar manner to nonpregnant patients (as discussed later). Several antimicrobials should be avoided during pregnancy and breast-feeding, especially for empirical treatment. Ciprofloxacin and other newer quinolones are not recommended because of an arthropathy demonstrated in animal studies associated with drug deposition in bone. Tetracyclines, including doxycycline, can inhibit long bone growth and may cause deposition in teeth with subsequent lifelong discoloration. Fluconazole and ribavirin have been associated with fetal malformations, and their use in pregnancy is not recommended. 3

URINARY TRACT INFECTIONS

UTIs are the most common medical complication associated with pregnancy. Acute symptomatic cystitis occurs in up to 1.3% of pregnant women, and acute pyelonephritis complicates 1%–2.5% of pregnancies. The incidence of asymptomatic bacteriuria (ASB), defined as >105 colonies/mL of a single organism, is at least 4%–7%. Pregnant women with ASB have a 20%–30% risk of development of acute pyelonephritis, associated with morbidity and potential mortality risks to both the mother and the fetus, including premature labor. Of pyelonephriits cases 70%–80% can be prevented by screening and treatment for ASB. Women are predisposed to UTI by the proximity of the urethra to the gastrointestinal tract and the urethra’s short length. In pregnancy urine flow is diminished as a result of decreased ureteral peristalsis and ureteral and bladder compression by the gravid uterus. The bladder also empties incompletely because of relaxed detrusor muscle tone. During

URINARY TRACT INFECTIONS Approach to asymptomatic bacteriuria (see Figure 1) Screening of all asymptomatic women for bacteriuria during first trimester Bacteriologic features same as for nonpregnant patients Treatment of all women with asymptomatic bacteriuria Treatment of symptomatic cystitis as a complicated urinary tract infection (UTI) (see Chapter 15) Goal of urine sterility throughout pregnancy Contraindicated antibiotics (see Table 4) Quinolones Tetracyclines Sulfa drugs (Bactrim) in third trimester Trimethoprim in first trimester Pyelonephritis Parenteral therapy Ampicillin and gentamicin Outpatient treatment of clinically and psychosocially stable patients without comorbidities Amoxicillin-clavulanate (Augmentin) Trimethoprim & sulfamethoxazole (Bactrim)

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pregnancy, bacterial growth in urine is enhanced by increasingly alkaline pH and relative glucosuria. These changes result in a significant risk for UTI for the pregnant patient. UTI pathogens in pregnant women are similar to those seen in nonpregnant women. E. coli is detected in 60%–90%. Proteus mirabilis, Klebsiella species, enterococci, and GBS are also major pathogens in this setting. Bacterial virulence factors combined with host genetic characteristics likely explain why some bacteria are particularly good at adhering to the uroepithelium. For example, strains of E. coli possessing P fimbriae are uniquely able to bind to the uroepithelium and ascend to cause upper tract disease. ASB should be assessed at the first prenatal visit and reassessed later in pregnancy for those with treated ASB early in pregnancy or those with a history of frequent or recurrent UTI. Women without these risk factors are generally not rescreened because 18 hours, or intrapartum temperature 38⬚C are recommended to receive intrapartum penicillin G (5-mU IV load, then 2.5-mU IV q4h until delivery). Current practice has been hampered by the relatively poor sensitivity of GBS culture and nonculture screening; these are influenced by timing of testing, collection methods, and specimen handling. Polymerase chain reaction (PCR) assays have promise for improving rapid screening. During pregnancy, there is a slight impairment of cell-mediated immunity, placing the pregnant women at risk for Listeria monocytogenes bacteremia; Listeria sp. meningitis is uncommon. This infection is most common in the third trimester, during the height of immune suppression. Women experience fever, headache, and myalgias. The infection can cause amnionitis and precipitate premature labor and may result in neonatal death in 22% of cases. Treatment is with intravenous ampicillin. 6

HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 AND PREGNANCY

As the human immunodeficiency virus type 1 (HIV-1) epidemic continues, the number of HIV-positive women who become pregnant continues to grow. The effects of HIV on pregnancy are not usually clinically apparent. Similarly, the effects of pregnancy on the course of HIV infection do not appear to be significant in the majority of individuals. In developed countries, antiretroviral therapy during pregnancy is recommended to maintain the mother’s health, as indicated by the CD4 cell count and HIV viral load. The oldest antiretroviral, zidovudine (ZDV) has the best proven track record during pregnancy. How-

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HUMAN IMMUNODEFICIENCY VIRUS INFECTION AND PREGNANCY All pregnant women should be tested for human immunodeficiency virus (HIV) (consent required). HIV infection does not alter the outcome of pregnancy. Pregnancy does not alter HIV infection. Pregnant women with HIV should be treated with antiretroviral agents similarly to nonpregnant women (see Table 4). Antiretroviral therapy markedly decreases perinatal transmission. Goal of therapy is to suppress to undetectable viral load. Those women who are not otherwise candidates for antiretroviral therapy should be treated with at least zidovudine (see Table 8).

ever, most drugs now employed in combination therapy have been used to treat pregnant women. If a woman becomes pregnant while taking an antiretroviral regimen, that combination of medications is usually continued if she has had a good clinical response. Small clinical cohorts and a national registry document the use of many additional antiretroviral agents. Efavirenz, a nonnucleoside reverse transcriptase inhibitor, is a teratogen, however, and is contraindicated in pregnancy. Women should have joint follow-up by their HIV specialists and obstetrical care giver. HIV treatment is reassessed with CD4 cell count and viral load testing each trimester. Mother-to-child transmission of HIV occurs in up to 25% of untreated births in developed country settings and in up to 40% in developing countries where women routinely breast-feed after delivery. A minority of HIV transmissions occur in utero or during breast-feeding. Most perinatal HIV transmission occurs during labor and delivery, when the normal maternal-fetal blood admixture is disrupted. Transmission rates are greater in those with placental inflammation or ulcerative lesions in the genital tract. Transmission rate has a positive correlation with the HIV viral load of the mother. A series of interventions in the United States and Europe have dramatically reduced perinatal HIV transmission rates since 1992. HIV counseling and testing with consent are now recommended for all pregnant women regardless of HIV risk factors. This standard arose from data about the pitfalls of HIV risk assessments in women, as many do not realize they have been exposed to HIV. In addition, identification of maternal HIV infection would justify ZDV to prevent perinatal transmission and other antiretroviral therapy as indicated for maternal health. Although these screening practices have been implemented successfully in many parts of the United States, local practice patterns vary widely and stigmas persist. Because laws about HIV counseling, testing, and reporting are unique to each state, each practitioner needs to be informed about local practice. The AIDS Clinical Trials Group (ACTG) study 076 showed that ZDV given to the mother and child can reduce perinatal transmission from 25% to 8% (67% reduction). ZDV is given during the second and third trimesters, through labor and delivery, and to the neonate during the first 6 weeks of life (see Table 8). In the era of enhanced prenatal testing for HIV and with the use of combinations of highly active antiretroviral agents, the U.S. HIV perinatal transmission rate has fallen to 1%–2%. In response to the findings of several large U.S. and European studies, cesarean delivery is now recommended for HIV-positive women who are not on antiretroviral therapy or who have unsuppressed HIV viral load (>1000 copies/mL.) The risks of cesarean

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Table 8 Zidovudine Perinatal Transmission Prophylaxis Regimen Antepartum

Intrapartum Postpartum

Initiation at 14–34 weeks of gestation and continuation throughout pregnancy 100 mg 5 times daily 200 mg tid 300 mg bid During labor, zidovudine (ZDV) 2 mg/kg IV for 1 hour, followed by continuous infusion of 1 mg/kg/hr until delivery Oral administration of ZDV to newborn (ZDV syrup 2 mg/kg q6h) for first 6 weeks of life, beginning at 8–12 hours after birth

Source: CDC. Recommendations of the Public Health Service Task Force on the use of Zidovudine to reduce perinatal transmissions of HIV. MMWR, 43(No. RR-4):1–20, 1994.

delivery include infection, bleeding, and longer recovery period than in vaginal birth. For women who are successfully taking combination antiretroviral therapy and have suppressed HIV replication in the blood, the added benefit of cesarean delivery is expected to be low. False-positive screening test results during pregnancy are becoming increasingly common as the tests are applied to the broader population of pregnant women. The screening HIV enzyme-linked immunosorbent assay (ELISA) and the HIV Western blot are required to confirm HIV-1 infection. Repeat testing in 1–3 months is indicated to rule out HIV seroconversion if a woman has been exposed to HIV during pregnancy. False-positive test results have been a particular problem with rapid HIV tests now in use in some acute care facilities and sexually transmitted disease clinics in the United States. The benefit of rapid HIV testing in this setting is its ability to target ZDV therapy to HIV-positive women who may not have received prior prenatal care in order to attempt to prevent perinatal HIV transmission.

7

VACCINATIONS

In general, vaccinations during pregnancy should be avoided; however, vaccinations for tetanus, hepatitis B virus, and influenza are acceptable. Live vaccines such as measles, mumps, rubella (MMR); oral poliovirus; oral typhoid; and yellow fever vaccines are contraindicated. The pregnant woman needs immunity to tetanus for prevention of neonatal infection. If she is not immune, vaccination with diphtheria/tetanus should be provided. If she is expected to be in the second or third trimester during the influenza season (October through March), she should be vaccinated against influenza virus (also see Chapter 43).

BIBLIOGRAPHY Centers for Disease Control and Prevention. Sexually transmitted diseases. Treatment Guidelines 2002. Morb Mortal Wkly Rep 51(No. RR-6):1–79, 2002. Centers for Disease Control and Prevention. Prevention of perinatal group B streptococcal disease: A public health perspective. Morb Mortal Wkly Rep 45(No. RR-7):1–24, 1996. Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIVinfected adults and adolescents, February 4, 2002. http://www.hivatis.org. Goldenberg RL, Hauth JC, Andrews WW. Mechanism of disease: Intrauterine infection and preterm delivery. N Engl J Med 324(20):1500–1507, 2000.

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Public Health Service Task Force recommendations for use of antiretroviral drugs in pregnant HIVI-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States. August 30, 2002. Available at http://www.hivatis.org. Sweet RL, Gibbs RS, eds. Infectious Diseases of the Female Genital Tract, 3rd ed. Baltimore: Williams & Wilkins, 1995. Tuomala RE, Cox SM, eds. Infections in obstetrics. Infect Dis Clin North Am 11(1):1–239, 1997.

34 The Immune-Compromised Patient Robert W. Lyons University of Connecticut, Farmington, Saint Francis Hospital, Hartford, and Yale University, New Haven, Connecticut, U.S.A.

1

INTRODUCTION

The diagnosis of infection in the immune-compromised adult can be difficult. Both the infecting organisms and their manifestations may be different from those in the normal patient. By considering what sort of immune defect a patient has, however, one can often narrow the infection to a few likely organisms. Certain immune defects render a person particularly susceptible to certain infections while not impairing ability to resist others. In the same way the presence of certain infections may be a clue that the patient has an unsuspected immune defect and help in its diagnosis (see Table 1). The immune system is conventionally divided into the humoral immune system, the phagocytic system, and the cell-mediated immune system. The humoral system comprises circulating antibody, complement, and other circulating substances that serve to coat microorganisms and either destroy them or enable phagocytic cells to engulf them. The phagocytic system consists of circulating phagocytes (polymorphonuclear neutrophils) and tissue macrophages that ingest and kill infecting organisms. The cell-mediated immune system, in which thymus-derived lymphocytes (T lymphocytes) play a major role, recognizes new antigens, especially those within cells, and assists in destroying or containing intracellular pathogens. To these three I would add the ‘‘anatomical immune system,’’ which consists of those anatomical structures that by their presence and adequate function protect the body against infection. Examples of the anatomical system include the spleen, intact skin, gastric acid, the neurological reflexes that control swallowing and the function of the epiglottis, the ciliary cells of the bronchi, and the elaborate architecture of the nasal sinuses. I consider in this chapter the organisms that are usually associated with specific immune defects and the signs and symptoms a patient might present that might lead to a suspicion of an immune defect. An approach to the management of the immune-compromised host (ICH), including prevention and recognition of infection, is summarized. Finally an approach to the patient with staphylococcal furuncles is presented. The acquired immunodeficiency syndrome (AIDS), the major immunodeficiency disease in the world, is discussed in more detail in Chapters 25 and 26. The infected immune-suppressed patient presents a complex diagnostic and therapeutic challenge to the clinician. The potential pathogens may be unusual and the signs 661

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Table 1 Immune Defects and Their Infectionsa Defect

Disease

Organisms/diseases

Splenectomy

Postsurgical Idiopathic Sickle cell disease

Pneumococcal sepsis Severe babesiosis Sepsis after dog bite

Achlorhydria

Postsurgical Medication-induced

Enteric pathogens Salmonella, Shigella spp.

IgG deficiency

Common variable immunodeficiency Acquired hypogammaglobinemia Multiple myeloma CLL

Recurrent sinusitis Recurrent pneumonia Bronchiectasis Pneumococcal infection Chronic diarrhea Relapsing giardiasis Severe enteroviral infection

Hyper-IgE syndrome

Job’s syndrome

Chronic eczema Recurrent pneumonia ‘‘Cold’’ S. aureus abscesses Dental abnormalities

Neutropenia

Leukemia Chemotherapy Cyclic neutropenia

S. aureus bacteremia Gram-negative rod infections Pseudomonas sp. Fungal infections (late) Candida, Aspergillus spp.

Neutrophil dysfunction

Chronic granulomatous disease

S. aureus infections Aspergillus spp. infections Serratia spp. infections, osteomyelitis Burkholderia cepacia infection

Neutrophil dysfunction

Leukocyte adhesion defects

‘‘Cold’’ skin abscesses Poor pus formation, elevated WBC Severe gingivitis, tooth loss

Cell-mediated immunity defects

Lymphoma Steroid therapy HIV/AIDS Organ transplantation Immunosuppressive medications Cyclosporine, OKT3, tacrolimus

Thrush Disseminated herpes zoster Cytomegalovirus Cryptococcal meningitis Pneumocystis carinii pneumonia Listeria spp. meningitis Nocardia spp. infections Mycobacterial infections Strongyloidiasis

a

IgG, immunoglobulin G; CLL, WBC, white blood cell count; HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome.

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IMMUNE COMPROMISING CONDITIONS Anatomical defects Asplenia Achlorhydria Humoral defects Common variable immunodeficiency Acquired hypogammaglobulenemia Multiple myeloma Chronic lymphocytic leukemia Hyper–immunoglobulin E (IgE) syndrome (Job’s syndrome) Phagocytic defects Neutropenia with absolute neutrophil count (ANC) 5.0 g/L. This can usually be done with monthly injections of 400 mg/kg of IgG. 3.2

Acquired Hypogammaglobinemia

As noted, a hallmark of acquired hypogammaglobinemia is repeated or unusual infection with encapsulated organisms. In that respect patients with this problem are like asplenic patients, but, unlike asplenic patients, they do not usually have overwhelming sepsis. Acquired hypogammaglobinemia may progress to development of bronchiectasis, as does common variable immunodeficiency, but affected patients usually receive medical attention before the disease becomes chronic. Although acquired hypogammaglobinemia may be idiopathic, two important causes to consider are multiple myeloma and chronic lymphocytic leukemia. Patients with these disorders may need immunoglobulin replacement as well as therapy for their primary disease. Recurrent pneumococcal infection, especially in an elderly patient who has back pain or anemia, should raise the suspicion of multiple myeloma. Immunoglobulin electrophoresis is warranted in such a patient. 3.3

Hyper–Immunoglobulin E Syndrome (Job’s Syndrome)

The first point to be clear about is that Job did not have Job’s syndrome. Job, the biblical figure for whom the syndrome is named, had the acute onset of boils, together with a large number of financial reverses and personal tragedies, that came upon him in middle life. Previously he had apparently been in good health. The syndrome that bears his name is a congenital abnormality that manifests itself in infancy with chronic eczema, pneumonia, and cold skin abscesses due to Staphylococcus aureus. These patients usually have hypereosinophilia and levels of IgE in excess of 2000 IU/mL. Attention has recently been drawn to dental abnormalities and craniofacial and skeletal abnormalities in many patients. The patients do not shed their primary teeth, and the permanent teeth erupt behind or in front of the retained primary teeth. Many patients have hyperextensible joints, abnormalities of midline facial development, and frequent bone fractures. The disease is inherited in an autosomal dominant manner but with variable expressivity. Some patients with Job’s syndrome may survive into adulthood and seek care in an adult medicine office. Most patients with recurrent boils, however, do not have Job’s syndrome, just as he did not. The diagnosis should only be considered when patients report recurrent skin and pulmonary infections since early childhood. 3.4

Complement Deficiency

Deficiencies in complement are relatively rare. They can be inherited (0.03% of the population) or acquired. Acquired defects can occur during acute infection or are related to rheumatological disease. There is an association between deficiencies of the terminal com-

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ponents of the complement cascade (C5, C6, C7, C8) and increased infections due to Neisseria gonorrhoeae and N. meningitidis. Patients who have recurrent neisserial infections may warrant evaluation for complement deficiency. 4

PHAGOCYTIC DEFECTS

Defects in the phagocytic arm of the immune system can be further subdivided into those in which the number of phagocytic cells is decreased and those in which the number is normal, but the cells do not function efficiently. Patients with phagocytic defects are susceptible to a broader variety of bacterial infections than those that infect patients with humoral defects, but they are not particularly susceptible to some of the organisms that may afflict patients with defects in cell-mediated immunity. These distinctions between infecting organisms may become blurred in some patients, such as those on cancer chemotherapy, who may have defects in more than one branch of the immune system. 4.1

Neutropenia

The most common phagocytic defect is a decrease in the absolute number of circulating phagocytes. This is commonly measured as the absolute neutrophil count (ANC). The ANC can be calculated by multiplying the white blood cell count per cubic millimeter by the fraction of the count made up of mature neutrophils and band forms. Thus in a patient receiving systemic chemotherapy who has a white blood cell count of 1000 cells/mm3 of which 25% are mature neutrophils and 5% are band forms, the ANC is 1000 ⫻ (0.25 ⫹ 0.05) = 300 cells/mm3. It is not until the ANC falls below 1000 that problems with infection begin to arise. The problems become both more frequent and more severe when the ANC is less than 500. Patients with severe neutropenia are predominantly at risk for infection, especially bacteremia, with aerobic gram-negative rods (GNRs) from their own GI tract and Staphylococcus aureus. In some reports Pseudomonas aeruginosa has been a major pathogen in such patients, although it is my clinical impression that bacteremia with this organism is not as common as it once was. Bacteremia with anaerobic organisms is remarkably infrequent in such patients. Patients with neutropenia are usually not at increased risk for viral or fungal infections in the early stages of neutropenia. Fungi (Candida spp. and Aspergillus spp.) usually become important pathogens in such patients only after they have been neutropenic for prolonged periods and have received multiple courses of antibiotic therapy that have eliminated their normal microbial flora. The most commonly seen individuals with severe neutropenia are acute myelogenous leukemia patients and cancer patients on chemotherapy. These patients are especially susceptible to infection with bowel organisms, probably because of the deleterious effect of chemotherapy on the bowel mucosa. Patients with severe neutropenia from other causes such as cyclic neutropenia or aplastic anemia seem somewhat less susceptible to infection, but when they become infected, it is usually with the same organisms as other neutropenic patients: aerobic GNRs and S. aureus. Management of the febrile neutropenic patient is reviewed in Chapter 2. In the past, management usually necessitated hospitalization of the febrile patient if the ANC fell below 1000 cells/mm3 (some experts use 500 cells/mm3). With the advent of well-absorbed oral antibiotics with activity against P. aeruginosa (ciprofloxacin) and gram-positive bacteria (amoxicillin-clavulanic acid), outpatient oral therapy is possible for low-risk patients.

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Such patients include those receiving chemotherapy for solid organ tumors who have an expected duration of neutropenia of less than 1 week, are nontoxic, are able to tolerate oral antibiotics, and have close follow-up. 4.2

Neutrophil Dysfunction

There are a variety of defects of phagocytic function in which the patient’s white blood cell (WBC) count is normal or even high, but in which the patient’s neutrophils do not function efficiently enough to protect their host from infection. They are rarely seen in adult practice because most patients so afflicted die of infection in childhood. Two forms of neutrophil dysfunction merit brief consideration: chronic granulomatous disease and leukocyte adhesion defects. 4.2.1

Chronic Granulomatous Disease

The neutrophils of patients with chronic granulomatous disease (CGD) are able to ingest bacteria normally but are unable to kill them because of inability to generate hydrogen peroxide. With some species of bacteria the neutrophil can, however, utilize the hydrogen peroxide made by the bacteria itself to kill it. Bacteria (and fungi) that escape this fate are those that dispose of their own hydrogen peroxide by making the enzyme catalase. Streptococci that are unable to produce catalase are killed normally. Catalase producing bacteria such as S. aureus can cause chronic and severe infections in these patients. There are several genetic forms of CGD. Patients with the X-linked form are most severely infected and usually do not survive into adulthood. There are also several forms of autosomal inheritance, however, that are less severe. Patients who have one of these forms may survive into adulthood. Severe, prolonged, and recurrent infections of soft tissue, bone, and lungs with S. aureus, Burkholderia (Pseudomonas) cepacia, Serratia marcescens, or species of Aspergillus are the hallmark of CGD. The diagnosis should be considered when a patient has recurrent infections of this sort and a history of such infections since childhood. The most widely used test for CGD is the nitroblue tetrazolium (NBT) test. 4.2.2

Leukocyte Adhesion Defects

The neutrophils of leukocyte adhesion defect (LAD) patients adhere poorly to vascular epithelium and have difficulty in migrating to an area of infection. This is due to a defect in the cell wall of the neutrophil. Most patients die in childhood, but some patients with less severe manifestations survive to adulthood. These patients suffer from frequent skin infections in which they have ‘‘cold abscesses’’ or necrotic infections with little or no pus formation. They also experience visceral infections with similar manifestations. Gingivitis is a universal problem, and alveolar bone reabsorption and tooth loss are problems for adults. The patients typically run a high white blood cell count, 20,000 cells/mm3 or more. As in CGD, the diagnosis of LAD should be considered when someone has a history of recurrent bacterial infections from childhood, especially if accompanied by chronic gingivitis and chronic leukocytosis. Unlike in CGD there is no simple test for LAD, and patients suspected of having the disease should be referred to a center specializing in the disorder. 5

CELL-MEDIATED IMMUNE DEFECTS

The major disease in which cell-mediated immune (CMI) dysfunction predisposes to infection is, of course, acqired immunodeficiency syndrome (AIDS), which is discussed in

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Chapters 25 and 26. I would like to consider here the results of the lymphocyte dysfunction seen in lymphoma, that associated with chronic use of adrenocortical steroids and with organ transplantation. 5.1

Lymphoma

Generally speaking, lymphoma patients have a lower risk of severe bacterial infections (with the exception of Listeria, Nocardia, and Legionella spp.) than patients with neutrophil abnormalities, unless they are receiving chemotherapy that renders them neutropenic. The infections seen in these patients are more often mycobacterial, fungal, viral, or, occasionally, parasitic. Listeria monocytogenes is a gram-positive rod usually acquired by ingestion of infected food, often cheese or other milk products. In the normal host it usually causes a mild disease. In a pregnant woman it may cause a devastating infection of the fetus. In patients with lymphoma or in the elderly it can cause a bacteremia and/or severe meningitis. Listeria spp. should always be borne in mind when confronted with a bacterial meningitis in a patient with lymphoma. The organism is sensitive to ampicillin but resistant to the third-generation cephalosporins so often used to treat bacterial meningitis. Nocardia asteroides is a filamentous branching bacterium that resembles a fungus on Gram stain. It causes cavitary lung lesions that may be mistaken for tuberculosis. It may also cause nodular skin lesions and frequently spreads to the brain, where it causes mass lesions and abscesses. It responds to therapy with various sulfa drugs. Legionella spp. (L. pneumophila is most common) are aerobic gram-negative rods transmitted by aerosol commonly related to potable water systems. The most common clinical syndrome is pneumonia with fever, dry cough, and pleuritic chest pain. In the immune-compromised host the cough may be minimal. Diagnosis is by culture on charcoal yeast extract agar or urinary antigen detection (L. pneumophila serogroup 1 only). Therapy employs a macrolide or flouroquinolone. Of the fungal infections the ones most likely to be encountered among outpatient lymphoma patients are oral thrush due to Candida albicans and meningitis due to Cryptococcus neoformans. Such infections may be the first manifestation of lymphoma. Oral thrush in the absence of steroid or preceding antibiotic use always raises the question of a defect in cell-mediated immunity. If there is no obvious cause, its presence should prompt the search for lymphoma, leukemia, or human immunodeficiency virus (HIV) infection. Cryptococcal meningitis can be surprisingly indolent. It may present in an outpatient who reports persistent headache for several weeks with gradual changes in mental acuity or personality changes. A positive blood test result for cryptococcal antigen may suggest the diagnosis, but a negative test result does not exclude it. The only method that makes or excludes the diagnosis with certainty is spinal tap. Although some patients with apparently normal immune systems may acquire cryptococcal meningitis, the finding should prompt a search for an immune defect. Pneumocystis carinii, once thought to be a parasite, is a fungus. It may cause pneumonia in lymphoma patients just as it does in AIDS patients, although not as commonly. The manifestations of the pneumonia—a bilateral interstitial infiltrate with slowly progressive hypoxia—are much the same as those seen in AIDS, although the disease may be even more indolent. Of the viral infections the Herpesviridae family, including herpes simplex virus (HSV 1 and HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpes 6, 7, and 8, are of greatest concern. Disseminated herpes zoster

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(more than 10 lesions outside the principal dermatome) may be a first manifestation of a lymphoma, as may severe herpes simplex infection. CMV infections are usually not an early manifestation of lymphoma, but CMV pneumonia may be a problem as the disease progresses. Parasitic infections include Toxoplasma gondii, Cryptosporidium parvum, and Strongyloides stercoralis infections. Of these Strongyloides sp. infection merits special attention. This nematode can persist in its human host for decades, and when cell-mediated immunity declines, it can disseminate to lung, brain, and other organs as the number of worms expands exponentially in what is called the hyperinfection syndrome. If a patient is from the Caribbean, Southeast Asia, or the tropics and has a defect in cell-mediated immunity, it is worth checking the stool for Strongyloides spp. and treating it if found. 5.2

Glucocorticosteroid Therapy

Therapy with glucocorticosteroids can cause a variety of immune defects, including interference with neutrophil migration and impairment of antibody response to new antigens, but the effect on cell-mediated immunity is probably the major one. Significant defects in cell-mediated immunity are not seen with low-dose therapy (ⱕ10 mg. of prednisone per day) or even with high-dose therapy for a few days. It has been shown that cumulative doses of ⱕ700 mg of prednisone are not associated with increase in infection risk. With higher doses and prolonged therapy the risks of infection mimic those seen with lymphoma. Of particular concern are infections with the bacteria Listeria and Nocardia spp.; with fungus, especially Candida species, Cryptococcus neoformans, and Pneumocystis carinii; with the herpesvirus group; and with Strongyloides stercoralis in a host from the appropriate geographical area. Patients who use steroids are probably not particularly susceptible to infection with M. tuberculosis, but they are more susceptible to disease with that organism. They are more likely to experience reactivation of old quiescent tuberculosis lesions and development of active disease after high-dose steroid administration than they would be if they were not receiving that drug. 5.3

Organ Transplantation

With the introduction of effective immune suppressing agents such as glucocorticosteroids, azathioprine, and cyclosporine (Neoral), and more recently tacralimus (Prograf), mycophenolate mofetil (Cellcept), and muromonab/CD3 (Orthoclone OKT3), the number of patients receiving organ transplantation has markedly increased. The primary care provider needs to be vigilant about infections in these patients. The posttransplantation patient is at risk for bacterial infections, Listeria spp., mycobacteria, and Legionella sp.; fungal infections, Pneumocystis carinii, Cryptococcus, Aspergillus, and Candida spp.; and viral infections, HSV, VZV, EBV, and CMV. In addition to causing infectious mononucleosis, EBV can cause a posttransplantation lymphoproliferative disorder, including extranodal lymphoma. Patients who receive lung or heart-lung transplantation are at highest risk for infection and infection-related mortality. Also at very high risk are liver transplantation recipients. At somewhat lesser, though still quite serious, risk are heart and kidney transplantation recipients. The most important pathogen for the transplantation recipient is CMV. As does all herpesviruses, CMV can establish latency and later reactivate. Infections can therefore be

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primary in a nonimmune transplantation recipient, a reactivation of dormant virus in the recipient, or suprainfection with a second strain from the donor into the recipient who has CMV infection. Primary CMV infection occurs when the organ recipient who is CMV antibody– negative receives a CMV-positive organ or blood transfusion. Primary infection can cause fever, leukopenia, thrombocytopenia, atypical lymphocytosis, myalgia, and arthralgia. Other manifestations can include colitis, interstitial pneumonitis (especially in allogeneic bone marrow transplantation), and hepatitis (especially in liver transplantation). In the organ transplantation recipient who has had previous CMV infection, reactivation of CMV or superinfection can cause a febrile mononucleosis-like illness that is generally less severe than the primary infection. Diagnosis can be made by histological demonstration of CMV intranuclear inclusion bodies and by detection of CMV antigen in neutrophils. Reliance on CMV culture is problematic since growth of the virus in urine and sputum does not differentiate active CMV disease from asymptomatic infection. CMV infection may also make the transplantation recipient at greater risk for Pneumocystis carinii, Nocardia spp., and Listeria spp. infections and can contribute to allograft injury, leading to increased rejection. Allograft rejection and drug toxicities can mimic infection, and differential diagnosis can be challenging.

6 6.1

THE IMMUNE-SUPPRESSED PATIENT Presentations Suggestive of Immunodeficiency

The patient at risk for immune suppression and opportunistic infection can be approached from two different directions. One approach involves assessment of the type of immune defect the patient has on the basis of underlying illness. Subsequent infection risk can be judged by the type of immune defect present (see Table 1). The other approach is retrospective when the patient has an infection. Certain infections raise the possibility that a patient has an undiscovered immunodeficiency and may call for further evaluation (see Table 2). Repeated infections with Streptococcus pneumoniae suggest that the patient may have an immunoglobulin G (IgG) deficiency. When these occur in an elderly patient or an elderly patient has an unusual pneumococcal infection such as pneumococcal arthritis, the possibility of a hitherto undiscovered multiple myeloma or chronic lymphocytic leukemia should be considered. Recurrent sinusitis accompanied by recurrent bronchitis since childhood may be a late manifestation of common variable immunodeficiency in an adult and warrants an immunoglobulin electrophoresis. Most recurrent skin infections are not due to an immune defect. Chronic eczema and recurrent Staphylococcal spp. abscesses with little inflammation around them (‘‘cold abscesses’’), however, may suggest either hyper-IgE syndrome or a leukocyte adhesion defect, especially if there is a history of such infections since childhood and the patient also has dental or gingival abnormalities. Recurrent staphylococcal infections are also seen in patients with chronic granulomatous disease. Osteomyelitis caused by Serratia marcescens is seen in this disease and is virtually unheard of in any other situation. The occurrence of oral thrush is a marker for a cell-mediated immune defect. Its occurrence in an adult who is neither on antibiotics or glucocorticoids nor diabetic should raise the question of HIV infection or lymphoma. This is even more true of Pneumocystis

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IMMUNE-COMPROMISED PATIENTS May have unusual pathogens and life-threatening infections; specialty consultation suggested Approach to the patient Prevention of infection Immunizations Pneumovax Hepatitis A, B Influenza (yearly) Trimethoprim & sulfamethoxazole (TMP-SMZ) for Pneumocystis carinii pneumonia (PCP)/Toxoplasma spp. prophylaxis Quinolones and fluconazole for organ transplantation recipient Type of immune defect Immune defect that can be predicted by underlying illness (see Table 1) Immune defect that can predict type of opportunistic infection (see Table 1) Type of infection that may identify immune defect (see Table 2) Degree of immune abnormality Prolonged high-dose steroid use First 6 months post organ transplantation Absolute neutrophil count (ANC) 1 week ANC 50 for influenza. HIV, human immunodeficiency virus. b Screen for immunity before administering.

Although injection drug use itself is not an indication for pneumococcal vaccination, IDUs who have HIV infection, cirrhosis, or chronic alcoholism should be immunized (Table 1). 5.2

Tuberculosis

IDUs are at high risk for exposure to tuberculosis as a result of their life-style. Once tuberculosis infection has occurred, IDUs are also at high risk of development of active tuberculosis regardless of HIV status. The incidence of active tuberculosis among IDUs with positive tuberculin skin test results is presented in Table 2. These high rates even among HIV-uninfected IDUs may reflect increased transmission or more recent infection. Screening for tuberculosis infection and disease is an important aspect of routine care of IDUs. Screening for tuberculosis (TB) infection is covered in Chapter 13, and aspects of tuberculin screening in the IDU are summarized in Table 2. Because of the high risk of active disease, treatment of latent infection is indicated for all IDUs regardless of age or HIV status. The most recent CDC guidelines for treatment of latent TB infection advocate short course therapy with 2 months of rifampin and pyrazinamide. Unfortunately there have been cases of severe liver toxicity, including several fatalities with this regimen. Therefore 9 months of isoniazid is the preferred regimen unless close (biweekly) monitoring of clinical and laboratory status can be assured. Short course therapy may be appropriated in settings such as jails, prisons, or methadone maintenance programs where follow-up is certain. It is important to note that rifampin has significant interactions with many antiretroviral drugs and may be contraindicated. Rifabutin may be substituted when antiretroviral therapy is used, but adjustments of rifabutin and antiretroviral therapy dosages may be required. TB preventive therapy may be given as directly observed preventive

Table 2 The Tuberculin Skin Test in the Injection Drug User

HIV-uninfected HIV-infected a

Positive TST result

Risk of active TB with positive TST result

Latent infection regimen a

10-mm Induration 5-mm Induration

10/1000 patient-years 76/1000 patient-years

INH 300 mg/day ⫻ 9 mo Same

INH may be administered twice weekly in the setting of directly observed preventive therapy. TST, tuberculin skin test; TB, tuberculosis; HIV, human immunodeficiency virus; INH, isoniazid.

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therapy (DOPT). Isoniazid or rifampin and pyrazinamide may all be administered twice weekly if DOPT is planned. DOPT is especially appropriate in the setting of methadone maintenance and can be required as a condition of continued participation. Several studies in the early 1990s reported that anergic HIV-infected IDUs had a risk of TB high enough to warrant preventive therapy. Subsequent studies have not supported this and routine anergy testing is not recommended for any population. The IDU with active tuberculosis should be considered a public health hazard, and the clinician should inform the local health department as soon as the diagnosis is made. The patient should be started on at least four antituberculous drugs, usually isoniazid, rifampin, pyrazinamide, and ethambutol. In some communities the incidence of drug resistance among IDUs is high enough to necessitate inclusion of more drugs in the initial regimen, although this is becoming rare as tuberculosis control has improved nationally. Drug treatment of the IDU who has active tuberculosis presents numerous challenges. To improve adherence, directly observed therapy is imperative, and the clinician should always enlist the help of experts in administration of antituberculosis therapy. Enablers and incentives such as access to drug treatment, housing, food vouchers, or even cash should be used to improve compliance. Therapy should be administered in conjunction with methadone treatment if possible. 6

HEPATITIS

Injection drug use is the classic risk factor for acquisition of the blood-borne viral hepatitides. IDUs tend to acquire hepatitis B and C early in their drug-using history, when needle sharing is more common. An important goal of the physician caring for an injection drug user is prevention of acquisition and further spread of these infections. 6.1

Hepatitis C Virus

The seroprevalence of hepatitis C virus (HCV) infection in IDUs in the United States ranges from 64%–90%. IDUs rarely have clinical manifestations of acute HCV infection. HCV is more likely to be diagnosed serologically in asymptomatic persons or when liver disease becomes clinically significant. Therapeutic options for hepatitis C are covered in Chapter 23. The decision to initiate hepatitis C therapy should be made in consultation with an expert in HCV treatment. The likelihood of development of liver disease with HCV infection is increased with use of alcohol and other hepatotoxic substances; thus the patient should be advised to limit exposure. 6.2

Hepatitis B and D Viruses

Some series report the prevalence of serological markers of hepatitis B virus (HBV) exposure to be as high as 60%–80% in IDUs who share needles. The clinical manifestations, diagnosis, and treatment of HBV are covered in Chapter 23. Vaccination against HBV is indicated for all IDUs who share needles. Because of the high seroprevalence of hepatitis B, IDUs should be tested for antibody to HBV prior to immunization. There is no specific recommendation for which antibody test to administer. Testing for hepatitis B core antibody (HBcAb) identifies all previously infected persons but does not distinguish between carriers and noncarriers. Testing for hepatitis B surface antibody (HBsAb) identifies previously infected persons; however, levels of HBsAb may wane over time. Any IDU who does not have HBsAb or HBcAb should be vaccinated with the three-dose series. Exact adherence to the recommended dosage schedule may be difficult in IDUs, and immunity

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HEPATITIS, HUMAN IMMUNODEFICIENCY VIRUS, HUMAN T-LYMPHOTROPIC VIRUS, AND SEXUALLY TRANSMITTED DISEASE Hepatitis Hepatitis C virus (HCV), HBV High incidence in injection drug users (IDUs) Transmitted parenterally HBV vaccine for those at risk: HBsAb < 10 IU/mL Avoidance of other hepatotoxins such as alcohol Therapy for HBV, HCV (see Chapter 23) HAV Fecal-oral spread Vaccination of all IDUs Human immunodeficiency virus (HIV) Testing all IDUs for HIV Methadone drug interactions with antiretrovirals Role of postexposure prophylaxis unclear (see Chapter 41) Human T-lymphotropic virus (HTLV) Low overall incidence HTLV-I T-cell leukemia HTLV-associated myelopathy tropical spastic paraparesis HTLV-II Up to 10% Of IDUs No clear disease associations Sexually transmitted disease (STD) See Chapters 16 and 17 Increased risk of HIV transmission Risk of false-positive rapid plasma reagin (RPR) result Screening for asymptomatic chlamydia and gonorrhea in female IDU

may be conferred by other dosage schedules. Immunization Practices Advisory Committee (ACIP) publications (CDC 1991, 1999) should be consulted for specific questions. HIVinfected IDUs should have postimmunization testing for HBsAb, and revaccination should be provided if levels are 100 white blood cells (WBCs)/mm3 Culture and Gram stain of fluid Most commonly due to S. aureus and S. epidermidis; less commonly gram-negative rods (GNRs) and yeast Polymicrobic infection suggestive of viscus perforation Empirical antibiotics that include cefazolin and an aminoglycoside delivered intraperitoneally (see Table 3) Catheter removal sometimes necessary

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alysis (PD) cycler at night and one disconnection in the morning. As a result, the peritonitis rate for CCPD is lower than that for CAPD. Second, the likelihood of intraluminal contamination during each exchange may be reduced. Advances in ‘‘connection technology,’’ especially the introduction of the Y system in the 1980s, have led to a reduction in peritonitis rates. A discussion of connection technology is beyond the scope of this chapter. The peritoneal dialysis procedure itself may predispose to peritonitis. Peritoneal dialysis fluid is not physiological. In order to achieve ultrafiltration (fluid removal) across the peritoneum, dialysis fluid is hyperosmolar with glucose concentrations of 1500, 2500, or 4250 mg/dL. Dialysis fluid pH is low. The presence of large volumes of dialysis fluid in the peritoneal cavity dilutes peritoneal macrophages and cytokines. In addition, activated macrophages and cytokines are removed with each exchange. Patients classically have abdominal pain accompanied by cloudy effluent dialysis fluid. Fever (often low-grade) is present in about one-half of cases and diffuse abdominal tenderness is detected in the majority. The white blood cell count in the peritoneal fluid typically exceeds 100/mm3. Most of these cells are neutrophils. Gram stain of the peritoneal fluid is usually nondiagnostic, but culture of the peritoneal fluid yields a positive result in 80% to 90% of patients. The method for culturing the peritoneal fluid varies among institutions. At some institutions, 10 mL of spent dialysis fluid is placed into each of two blood culture bottles. At the author’s institution, up to 50 mL of spent dialysis fluid is transported to the laboratory in a sterile container. The fluid is centrifuged and the sediment is planted onto culture medium and inoculated into thioglycolate broth. Blood cultures should be obtained in severely ill patients but usually have a negative result. Although the diagnosis of peritonitis is straightforward in most cases, four important points must be made. First, abdominal pain may be accompanied by clear effluent dialysis fluid. In these cases, the dialysis fluid often turns cloudy within a day. Repeated peritoneal fluid cell counts may be necessary when a peritoneal dialysis patient has abdominal pain. Second, the peritoneal fluid differential cell count is important. Not all cloudy dialysate is due to infection. Eosinophilic peritonitis usually occurs soon after peritoneal catheter placement and is thought to result from chemicals leached from the catheter, dialysate containers, or tubing. Peritoneal fluid cultures typically yield no growth (although fungal and parasitic peritonitis may cause peritoneal fluid eosinophilia) and peritoneal fluid eosinophilia typically resolves within 2 to 6 weeks. Third, not all abdominal pain in peritoneal dialysis patients is due to peritonitis. The increased intra-abdominal pressure that results from peritoneal dialysis leads to formation of hernias. In addition, a perforated viscus (as from diverticulitis) may be responsible for peritonitis and should be strongly suspected if peritoneal fluid culture indicates a polymicrobic infection with enteric organisms or anaerobes. Free intraperitoneal air is often present in peritoneal dialysis patients and is presumably due to leakage of air through the catheter insertion site. Thus detection of free air under the diaphragm by an upright film of the abdomen is not diagnostic of a ruptured viscus in a peritoneal dialysis patient. Finally, the peritoneal fluid culture may yield no growth if the culture is obtained early in the course of the illness (before organisms are present in high numbers) or if too little peritoneal fluid is cultured. Staphylococcus epidermidis and Staphylococcus aureus are the most pathogens. About 15% of cases are due to gram-negative bacilli. Polymicrobial infection and fungal infection are much less common. Cases of peritonitis caused by vancomycin-resistant enterococci (VRE) appear to be on the rise. In 10% to 20% of cases, the peritoneal fluid culture yields no growth. Drug is transported across the peritoneum from dialysate to blood. Therefore, antibiotics may be administered through the peritoneum. Patients with peritonitis may be

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treated as outpatients. Admission to a hospital is indicated for patients who are severely ill or who do not improve within the first 24 to 48 hours of therapy. Intraperitoneal antibiotic therapy should be initiated after the peritoneal fluid culture has been obtained (Table 3). If the Gram stain result is negative, a first-generation cephalosporin (cefazolin or cephalothin) and an aminoglycoside should be administered in the same dialysate bag. The loading dose for the cephalosporin is 1000 mg and the maintenance dose 125 mg/L in each bag. The loading dose for gentamicin and tobramycin is 1.7–2 mg/kg in the dialysate bag and the maintenance dose is 4–6 mg/L. In order to reduce the risk of otovestibulotoxicity, the maintenance dose of the aminoglycoside may be administered as a single daily dose. For gentamicin and tobramycin, the dose is 20 mg/ L in one bag each day. If one chooses to add gentamicin or tobramycin to each dwell at a concentration of 4–6 mg/L, care must be taken to prevent otovestibulotoxicity. It is the author’s practice to administer this regimen for 5 days, hold aminoglycoside therapy for 2 days, obtain an aminoglycoside blood level, and administer, if necessary, another loading dose. It is hoped that this practice will prevent severe otovestibulotoxicity. If the patient appears very ill, the loading doses of the cephalosporin and aminoglycoside should be administered intravenously rather than intraperitoneally. Because of the emergence of VRE, vancomycin is no longer recommended as initial empirical therapy for peritonitis. Its use should be limited to cases due to MRSA, ␤lactam-resistant S. epidermidis, and gram-positive organisms for patients allergic to ␤lactam antibiotics. In some dialysis centers, however, vancomycin should be part of the

Table 3 Antibiotic Dosage for Peritoneal Dialysis Patients Antibiotic Cephalosporins Cefazolin Cephalothin Ceftazidime Vancomycin Penicillins Ampicillin Quinolones Ciprofloxacin Aminoglycosides Gentamicin

Maintenance dose

1000 mg 1000 mg 1000 mg 1000–2000 mg

125 mg/L In each bag 125 mg/L In each bag 125 mg/L In each bag 15–25 mg/L In each bag or 1000–2000 mg/week

1000–2000 mg IV

125 mg/L In each bag

400 mg IV

25 mg/L In each bag

1.7–2 mg/kg

4–6 mg/L In each bag or 20 mg/L in one bag each dayb,c 4–6 mg/L In each bag or 20 mg/L in one bag each dayb,c 6–7.5 mg/L In each bag or 60 mg/L in one bag each dayb

Tobramycin

1.7–2 mg/kg

Amikacin

5.0–7.5 mg/kg

Antifungals Fluconazole Flucytosine a

Loading dosea

2000 mg PO

150 mg IP every other day 1000 mg PO/day

Unless otherwise specified, loading doses are given as milligrams per bag of dialysis solution. The volume of dialysis solution is not important. b See text for details of dosage if aminoglycoside is to be administered in each bag. c Consider maintenance dose of 6–8 mg/L in each bag if culprit organism is Pseudomonas or Xanthomonas sp. Source: Keane et al. 1996.

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initial empirical regimen. All peritoneal dialysis centers should monitor the susceptibilities of the isolates from cases of peritonitis and devise an empirical regimen that will be effective in the great majority of cases. In cases of gram-positive pathogen peritonitis, the cephalosporin may be administered for 3 weeks in S. aureus infections and for 2 weeks in S. epidermidis infections. In cases of ␤-lactam resistance, vancomycin should be administered. The loading dose of vancomycin is 1000–2000 mg and the maintenance dose 15–25 mg/L of dialysate. Alternatively, 1000–2000 mg may be administered every 7 days. In patients who have significant residual renal function, however, serum vancomycin levels may become subtherapeutic (10 IU/L) in 95% of normal adults but in only 50%–60% of chronic hemodialysis patients. Nevertheless, administration of the hepatitis B vaccine substantially reduces the risk of hepatitis B infection in chronic hemodialysis patients. The CDC has recommended that all susceptible dialysis patients receive the hepatitis B vaccine. In order to increase the likelihood of an immune response, a higher dose is given to dialysis patients than to healthy adults. Engerix-B (SmithKline Beecham) is given as an intramuscular injection of 40 ␮g at 0, 1, and 6 months. Recombivax HB (recombinant hepatitis B virus vaccine) is given as an intramuscular injection of 40 ␮g at 0, 1, and 6 months. HBsAb should be tested 1 to 2 months after the series of injections. If there is an inadequate immune response (HBsAb 10 IU/L) is achieved, HBsAb level should be monitored yearly. If HBsAb subsequently falls below 10 IU/L, a single booster dose of 40 ␮g should be administered. If HBsAb level remains below 10 IU/L in spite of revaccination or booster administration, HBsAg level should be tested monthly. The presentation, diagnosis, and treatment of HBV infection are reviewed in Chapter 23. 4.2

Hepatitis C Virus

Three forms of renal disease may be seen in association with hepatitis C virus (HCV) infection: mixed cryoglobulinemia, membranoproliferative glomerulonephritis, and membranous nephropathy. All three may lead to ESRD. HCV is transmitted by exposure to blood or other body fluids. Hemodialysis patients are at risk for nosocomial infection. The prevalence of anti–hepatitis C virus antibody among dialysis patients in the United States is about 19% but varies widely among dialysis centers. The incidence and prevalence of HCV infection among dialysis patients are falling. Three major factors are responsible. Screening of blood donors for anti-HCV antibody and the use of erythropoietin therapy have reduced the risk of posttransfusion hepatitis. Implementation of infection control measures has reduced nosocomial transmission of HCV infection within dialysis centers. The CDC does not recommend patient isolation and dedicated machines and does not prohibit dialyzer reuse for patients with HCV infection. There are two major reasons. HCV is less infective than is HBV since it circulates in low levels in serum and is rapidly degraded at room temperature. In addition, a positive test result for anti–hepatitis C virus antibody does not distinguish between past and present infection, and a negative test result does not exclude infection. Detection of HCV ribonucleic acid (RNA) by polymerase chain reaction would be helpful in this regard but is not practical. Nosocomial transmission of HCV infection in dialysis centers is best prevented by strict adherence to universal precautions and by careful sterilization of dialysis machines. HCV infection in dialysis patients can be overlooked. Symptoms of ESRD may mask or mimic those of HCV. Additionally, the alanine aminotransferase (ALT) level may be normal even when liver disease is advanced. Use of second- or third-generation enzyme immunoassays for hepatitis C virus RNA testing will enhance diagnostic abilities. Interferon-␣ appears to be effective for dialysis patients with chronic active hepatitis. Interferon ␣-2b at a dose of 3 million units subcutaneously three times per week for 6 to 12 months has been effective in reducing ALT levels and in inducing clearance of HCV RNA from serum. Improvement in liver histological features has been reported as well (Huraib et al., 1999). However, discontinuation of therapy due to side effects appears to

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be more likely in patients who have ESRD. In addition, recurrence of viremia is frequent after discontinuation of therapy, and long-term benefits of therapy have not been established. Nevertheless, interferon-␣ therapy should be considered for selected dialysis patients, especially those who have chronic active hepatitis indicated by liver biopsy or those who are candidates for renal transplantation. The posttransplantation course in these patients depends largely on the pretransplantation severity of liver disease. Liver biopsy is mandatory for kidney transplant candidates. Ribavirin therapy is not recommended for patients who have ESRD as clearance of the drug is reduced and drug is not removed by hemodialysis. The presentation, diagnosis, and treatment of HCV are further reviewed in Chapter 23. 5

HUMAN IMMUNODEFICIENCY VIRUS

Several forms of renal disease are associated with human immunodeficiency virus (HIV) infection. The most common form is collapsing focal glomerulosclerosis. This form of HIV-associated nephropathy is much more common in blacks and in males. Heavy proteinuria or the nephrotic syndrome is typically present at the onset. Rapid progression to ESRD has been the rule, but preliminary evidence indicates that combined highly active antiretroviral therapy may improve the prognosis of this disorder. Prolonged survival on maintenance dialysis is possible. Combined highly active antiretroviral therapy should be administered to HIV-infected patients with ESRD. However, the dosages of didanosine (give one-fourth of the total daily dose for normal renal function once a day) and zidovudine (100 mg q8h) must be adjusted. The risk of patient-to-patient transmission of HIV infection in a hemodialysis center is extremely low. Neither dedicated hemodialysis machines nor patient isolation is necessary. 6

VACCINATIONS

Recommendations for administration of the hepatitis B virus vaccine have been given. The Advisory Committee on Immunization Practices (ACIP) recommends that the 23valent pneumococcal polysaccharide vaccine be administered to all adult dialysis patients. More than 75% of dialysis patients mount an adequate immune response to the pneumococcal vaccine, but antibody levels often decline within 5 years. Revaccination is recommended in 5 years. The immune response to the influenza vaccine of chronic dialysis patients is similar to that of controls. Yearly influenza vaccination is recommended for all chronic dialysis patients. 7

URINARY TRACT INFECTIONS

Pyuria in the absence of infection is common in patients with ESRD. Nevertheless, urinalysis is frequently requested during the evaluation of the febrile dialysis patient. In the absence of symptoms of urinary tract infection (dysuria, flank pain, abdominal pain), pyuria should not lead one to conclude that a urinary tract infection (UTI) is the cause of the fever. Antibiotic therapy for UTI should be limited to patients with symptoms of UTI or a positive urine culture finding. Pyocystis denotes pus in the bladder and may cause fever in anuric dialysis patients. Symptoms include suprapubic pain and purulent urethral discharge. Bladder catheterization

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yields pus, and urine culture frequently yields multiple organisms. Treatment consists of catheter drainage of the bladder and irrigation of the bladder with antibiotic solutions. If systemic symptoms or signs are present, parenteral antibiotic therapy should be administered. Urological consultation and cystoscopy are recommended. Cystoscopy may reveal a structural lesion of the bladder for which surgical intervention or even cystectomy is indicated. Autosomal dominant polycystic kidney disease accounts for 2.5% of cases of ESRD in the United States. Renal cyst infections are characterized by fever, flank pain, and flank tenderness. Pyuria may be absent and urine culture may yield no growth. Ciprofloxacin and trimethoprim-sulfamethoxazole are able to penetrate cysts and are the antibiotics of choice for cyst infections. Chloramphenicol is also able to penetrate cysts.

BIBLIOGRAPHY Aronoff GR, Berns JS, Brier ME, Golper TA, Morrison G, Singer I, Swan SK, Bennett WM. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults, 4th ed. Philadelphia: American College of Physicians, 1999. Barth RH, DeVincenzo N. Use of vancomycin in high-flux hemodialysis: Experience with 130 courses of therapy. Kidney Int 50:929–936, 1996. Berkoben M, Provenzale J. A hemodialysis patient with excruciating back pain. Semin Dial 9:286– 288, 1996. Berkoben M, Schwab SJ. Hemodialysis vascular access. In: Henrich WL, ed. Principles and Practice of Dialysis, 2nd ed. Baltimore: Williams & Wilkins, 1999, pp 41–59. Fogel MA, Nussbaum PB, Feintzeig ID, Hunt WA, Gavin JP, Kim RC. Cefazolin in chronic hemodialysis patients: A safe, effective alternative to vancomycin. Am J Kidney Dis 32:401– 409, 1998. Herwaldt LA. Reduction of Staphylococcus aureus nasal carriage and infection in dialysis patients. J Hosp Infect 40:S13–S23, 1998. Huraib S, Tanimu D, Romeh SA, Quadri K, Al Ghandi G, Iqbal A, Abdulla A. Interferon-alpha in chronic hepatitis C infection in dialysis patients. Am J Kidney Dis 34:55–60, 1999. Keane WF, Alexander SR, Bailie GR, Boeschoten E, Gokal R, Golper TA, Holmes CJ, Huang CC, Kawaguchi Y, Piraino B, Riella M, Schaefer F, Vas S. Peritoneal dialysis-related peritonitis treatment recommendations: 1996 update. Perit Dial Int 16:557–573, 1996. Levin A, Mason AJ, Jindal KK, Fong IW, Goldstein MB. Prevention of hemodialysis subclavian vein catheter infection by topical povidone-iodine. Kidney Int 40:934–938, 1991. Marr KA, Kong LK, Fowler VG, Gopal A, Sexton DJ, Conlon PJ, Corey GR. Incidence and outcome of Staphylococcus aureus bacteremia in hemodialysis patients. Kidney Int 54:1684–1689, 1998. Marx MA, Frye RF, Matzke GR, Golper TA. Cefazolin as empiric therapy in hemodialysis-related infections: Efficacy and blood concentrations. Am J Kidney Dis 32:410–414, 1998. Miller ER, Alter MJ, Tokars JI. Protective effect of hepatitis B vaccine in chronic hemodialysis patients. Am J Kidney Dis 33:356–360, 1999. Murphy BVR, Pereira BJG. Hepatitis and human immunodeficiency virus infections in end-stage renal disease patients. In: Henrich WL, ed. Principles and Practice of Dialysis. 2nd ed. Baltimore: Williams & Wilkins, 1999, pp 285–304. NKF-DOQI Clinical Practice Guidelines for Vascular Access. New York: National Kidney Foundation, 1997, pp 62–65. Rangel MC, Coronado VG, Euler GL, Strikas RA. Vaccine recommendations for patients on chronic dialysis. Semin Dial 13:101–107, 2000. Schwab SJ, Beathard G. The hemodialysis conundrum: Hate living with them, but can’t live without them. Kidney Int 56:1–17, 1999.

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Sesso R, Barbosa D, Leme IL, Sader H, Canziani ME, Marfredi S, Draibe S, Pignatari AC. Staphylococcus aureus prophylaxis in hemodialysis patients using central venous catheter: effect of mupirocin ointment. J Am Soc Nephrol 9:1085–1092, 1998. Sieradzki K, Roberts RB, Haber SW, Tomasz A. The development of vancomycin resistance in a patient with methicillin-resistant Staphylococcus aureus infection. N Engl J Med 340:517– 523, 1999. Smith TL, Pearson ML, Wilcox KR, Cruz C, Lancaster MV, Robinson-Dunn B, Tenover FC, Zervos MJ, Band JD, White E, Jarvis WR for the Glycopeptide-Intermediate Staphylococcus aureus Working Group. Emergence at vancomycin resistance in Staphylococcus aureus. N Engl J Med 340:493–501, 1999. Tokars JI, Miller ER, Alter MJ, Arduino MJ. National surveillance of diaylsis-associated diseases in the United States, 1997. Semin Dial 13:75–85, 2000.

37 Infections in the Patient with Animal Contact Anthony L. Esposito and George Abraham Saint Vincent Hospital at Worcester Medical Center, and University of Massachusetts, Worcester, Massachusetts, U.S.A.

1

INTRODUCTION

The remarkable spectrum of human infections acquired from animals continues to expand and to capture the attention of medical professionals and the general public. For example, innumerable news reports and public health announcements accompanied the New York City outbreak of West Nile viral disease, a mosquito-transmitted infection, which initially appeared in North America in the summer of 1999. It produced deaths in birds, horses, and humans and rapidly spread into the neighboring states of New Jersey, Maryland, Connecticut, and Massachusetts. Obviously, the number and complexity of animal-associated illnesses preclude a comprehensive review of the entire subject in a single chapter. Moreover, most of these conditions remain uncommon, even for the infectious disease consultant, and many produce such catastrophic manifestations that afflicted patients require immediate hospitalization. Accordingly, this chapter focuses on conditions potentially encountered by a primary care physician treating adults in an ambulatory setting in the United States. Of note, some prevalent infections, such as Lyme disease and Rocky Mountain spotted fever, are addressed in detail in Chapter 30 along with ehrlichiosis, tick-borne relapsing fever, tularemia, and babesiosis. Additional information on animal-acquired diseases associated with life-threatening syndromes, such as arbovirus encephalitis and hantavirus pulmonary syndrome, is reviewed in Chapter 31. An awareness of the mechanisms through which microbes can be transmitted from vertebrate animals to humans provides insight into the clinical syndromes with which patients present. In brief, infections derived from vertebrates (or zoonotic diseases) can be acquired through direct contact, the inhalation of infectious aerosols, the ingestion of contaminated products, or the bite of an arthropod vector. Consequently, the ensuing clinical syndromes include soft tissue infections (e.g., cellulitis due to Pasteurella multocida after a cat bite), lymphadenopathy (e.g., cat-scratch disease resulting from contact with a kitten), lower respiratory tract infections (e.g., pneumonia due to Chlamydia psittaci in a bird fancier), gastrointestinal disorders (e.g., diarrhea caused by Salmonella spp. acquired from contaminated poultry products), and cutaneosystemic disorders (e.g., Lyme disease or Rocky Mountain spotted fever transmitted by a tick bite). 709

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ZOONOSIS History Animal contact Hunting Occupation Water exposure Travel Consumption of raw milk Presentations with pneumonia, lymphadenopathy, diarrhea, and fever (see Table 1) Animal bite wounds (see Figure 1) Increased concern with cat bites, wounds involving bones and joints, and immune compromised hosts Cleaning and de´bridement Assessment of need for antibiotic prophylaxis or therapy Assess need for tetanus and rabies immunotherapy Reassessment in 24–48 hours Rabies vaccination (see Figure 2 and Table 3) Cat scratch disease (see Figures 3 and 4) Regional lymphadenopathy associated with kitten scratch Diagnosis with antibodies to Bartonella henselae Generally self-limited

2

EPIDEMIOLOGICAL CLUES TO ZOONOTIC INFECTIONS

The possibility that a patient who has pneumonia, diarrhea, lymphadenopathy, or fever has an animal-associated problem is raised by the nature and course of the illness. Accordingly, in those circumstances in which the cause of the problem remains enigmatic or in which simple diagnostic tests are unrevealing, an epidemiological or ‘‘exposure’’ history should be secured. In short, is the patient at risk for a zoonotic illness through exposure to the necessary source or vector? Important diagnostic clues in the epidemiological histories of patients with specific clinical syndromes are outlined in Table 1. Details concerning these disorders, including antimicrobial therapies, can be found in standard texts of medicine or infectious diseases. The discussion that follows centers on the clinical problems of animal bites and catscratch disease. The authors recognize that in some geographical regions of the country, other animal-associated conditions may be more common or more nettlesome to practitioners than the topics selected. Nevertheless, limitations of space and the importance of a detailed discussion on the more prevalent zoonotic illnesses demand a narrow focus. 3

ANIMAL BITES

Epidemiologists estimate that 1–2 million Americans experience an animal bite annually. Dogs or cats are involved in the vast majority of these episodes; however, the spectrum of animal bite–associated human infections is broad; it is illustrated in Table 2. Thus, although the following discussion is devoted to the management of dog and cat bites and addresses the more common soft tissue infections complicating these insults, the clinician

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should be aware that any vertebrate bite can lead to human disease. Consequently, every bite wound requires thoughtful and thorough attention. The management of the patient who has an animal bite is guided by the presence or absence of frank infection at the time of presentation, the nature and location of the wound, the risk of rabies, and a few other factors. Of note, the traditional medical reasons for recording a detailed history and physical examination are augmented in the setting of an animal bite, since the injury can lead to litigation. Accordingly, sketches or even photographs may be necessary in order to provide the most accurate description of the wound. Patients may seek medical care immediately after an animal bite because of pain, blood loss, crush injury, or the need for suturing, prophylactic antibiotics, or rabies vaccination. An approach to the uninfected bite wound is outlined in Figure 1. Later presentations (after 8 hours) are usually due to the onset of infections. The patient may experience pain, erythema, swelling, fever, and/or purulent wound discharge. The risk of infection can be 10-fold greater in cat versus dog bites. The higher infection rate is related, in part, to the fact that cats more commonly produce puncture wounds and that cats more frequently harbor Pasteurella multocida in their oropharynx. Accordingly, except in cosmetically important areas such as the face, cat bites should not be primarily closed with sutures. Equally importantly, since cellulitis caused by Pasteurella spp. typically begins 24–48 hours after the injury, an assessment of the patient’s status should be made soon after the initial visit, regardless of whether or not antimicrobial chemoprophylaxis has been administered. Persons immunologically impaired by splenectomy, lymphoproliferative disease, corticosteroid use, or alcoholism are at risk of experiencing serious infection due to Capnocytophaga canimorsus (formerly termed dysgonic fermenter, type 2 [DF-2]). This is a gram-negative bacillus that is carried in the oropharynx of some dogs and cats. In normal hosts, C. canimorsus rarely causes disease, although in immunosuppressed patients, the bacterium can cause a fulminant illness characterized by bacteremia, sepsis, disseminated intravascular coagulation, adrenal and renal failure, and peripheral gangrene. Of note, about a quarter of patients infected with C. canimorsus report an antecedent exposure to a dog but no actual bite. Obviously, once the full sepsis syndrome evolves, these patients require admission to an intensive care unit. Penicillin represents the antimicrobial treatment of choice. Infected dog or cat bites should be managed similarly to uninfected wounds (Figure 1). Infected wounds should never be closed and therapeutic antimicrobials are indicated. In general, wound cultures should be obtained, especially for patients who require admission to a hospital. By employing appropriate techniques, three to five bacteria can be isolated. The microbes most commonly recovered include P. multocida or P. canis, aerobic streptococci, staphylococci, Moraxella spp., and a variety of anaerobes, such as Fusobacterium spp. and Bacteroides spp. Although the antimicrobial therapy of infected wounds is be guided by the results of deep wound cultures, the initial regimen should have activity against the most common pathogens, especially Pasteurella spp., which is usually resistant to semisynthetic penicillins (i.e., dicloxacillin), first-generation cephalosporins (i.e., cephalexin), and clindamycin. Amoxicillin-clavulanate possesses sufficient in vitro activity against the pathogens usually associated with these infections and is often recommended. Penicillin in combination with a first-generation cephalosporin (e.g., cephalothin) or with penicillinase-resistant penicillin (e.g., dicloxacillin) may also be considered. For the patient with disease requiring parenteral therapy in an inpatient or ambulatory setting, ampicillinsulbactam or penicillin plus oxacillin provides the necessary coverage. Treatment can be modified as microbiological information becomes available. In the penicillin-allergic pa-

Fever

Diarrhea

Pneumonia

Clinical syndrome

Q fever

Tularemia

Pneumonic plague

Cattle, sheep, goats

Wild rabbits, beaver, squirrels, muskrats

Wild rodents or fleas in Western states

Murine typhus

Giardiasis

Water potentially contaminated with animal excreta

Fleas

Campylobacteriosis, salmonellosis

Poultry products

Calves and other neo- Cryptosporidiosis natal ruminants

Psittacosis

Possible diagnosis

Birds

Exposure history

Both psittacine (i.e., parrots, parakeets) and other birds (i.e., canaries, ducks, geese, pigeons) potential sources of infection Shedding of microbe in milk, urine, and birth products by infected domesticated ungulates (hoofed animals) Landscapers, hunters, farmers, laboratory workers, and veterinarians at risk

Comment

Usually secondary to septicemic plague, pneumonia fatal if therapy delayed; condition a public health emergency Examination of stool for oocysts of Crypto- Household pets (dogs, cats) also sources of infecsporidium spp. tion; farmers, veterinarians, and abattoir workers at risk Culture of stool for Campylobacter, Salmo- Young dogs and cats (Campylobacter spp.) and nella spp. turtles and snakes (Salmonella spp.), household sources of disease Examination of stool for cysts and trophozo- Individuals who consume water from streams or ponds contaminated by beaver, cattle, or sheep ites of Giardia intestinalis, or antigen deat risk tection assays, or rarely sampling of duodenal fluid Serological tests for Rickettsia typhi Disease largely confined to southern California or south Texas; thrombocytopenia, leukopenia, and elevated hepatic transaminase level clues to diagnosis; maculopapular, truncal rash present in most cases

Serological tests for Francisella tularensis; isolation in laboratory possible but risky to personnel Smear and culture of bubo aspirate; culture of blood and sputum for Yersinia pestis

Serological tests for Coxiella burnetti

Serological tests for Chlamydia psittaci

Laboratory tests

Table 1 Elements of an Epidemiological History That Raise the Possibility of a Zoonotic Disease a

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Serological tests for Ehrlichia; review of blood smears for intraleukocytic inclusions (morulae) although test insensitive; PCR of peripheral blood Serological tests for Francisella tularensis

Ehrlichiosis

Tularemia

Serological tests for Coxiella burnetti

Sheep, goats, cattle

Q fever

Serological tests for Brucella spp.; blood cultures with selective media

Serological tests for Leptospira spp.

Serological tests for Colorado tick fever virus; immunofluorescent staining for intraerythrocytic viral antigen

Colorado tick fever

Leptospirosis

Microscopic exam of blood smears for Babesia microti; serological tests also available

Babesiosis

Cattle, sheep, goats; Brucellosis unpasteurized milk or cheese

Animal urine

Ticks

Elderly and splenectomized patients at risk of severe disease; most prevalent on islands and along coast of Massachusetts, Rhode Island, and New York; hemolytic anemia and hemoglobinuria possible Self-limited illness endemic in mountainous regions of Colorado, Montana, Wyoming, Utah and Idaho; hunters, hikers, and campers at risk; headache, photophobia, abdominal pain; rash present in 10% of cases More common in southern and south-central states; clues to diagnosis include leukopenia, thrombocytopenia, and abnormal hepatic transaminase results; maculopapular rash present in about 30% of cases Tick transmission less common than direct contact; high-risk groups similar (as above) Microbe carried by wide range of domesticated and wild animals, especially rodents; laboratory mice implicated in many outbreaks; cough, diarrhea and conjunctival suffusion; rash present during late stage; hepatic and renal involvement in severe illness Although reported in all states, incidence highest in Texas, California, Florida, and Virginia; farmers, veterinarians, and abattoir workers at risk; consumption of contaminated fresh dairy products are also a risk Parturient sheep implicated in many cases (as above)

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Fever and lymphadenopathy

Clinical syndrome

Smear and culture of bubo aspirate for Yersina pestis

Bubonic plague

Wild rodents or fleas in western states

Serological tests for Toxoplasma gondii

Toxoplasmosis

Serological tests for Francisella tularensis

Serological tests for Bartonella henselae

Culture of blood for Yersina pestis; smear and culture of bubo aspirate

Laboratory tests

Cat-scratch disease

Septicemic plague

Possible diagnosis

Wild rabbits, beaver, Ulceroglandular squirrels, muskrats; tularemia ticks

Cats

Wild rodents or fleas in western states

Exposure history

Table 1 Continued

Septicemic plague that may be primary or secondary to progression of untreated bubonic disease; hunters, trappers at risk Disease also associated with noncontact cat exposure; adenopathy regional, tender and persistent for months; fever low-grade and transient Cats as the definitive host able to shed oocysts in feces; oocyst sporulation in a few days, producing infectious forms that can persist for weeks in soil, poorly maintained litter boxes, etc.; protozoan parasite potentially acquired through fecal-oral route Inoculation of skin through contact (i.e., skinning) that produces ulcer on hand or forearm and regional tender adenopathy; inoculation via tick, which produces ulcer at bite site and local node enlargement Buboes (enlarged, painful lymph nodes) usually present in groin or axilla; lesions extremely tender; course fulminant without appropriate therapy

Comment

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Anthrax

Rat bite fever

Rats

Cattle, sheep, donkeys, goats

Rickettsial pox Recovery of Streptobacillus moniliformis or Spirillium minor from blood or synovial fluid Culture for Bacillus anthracis from vesicle

Serological tests for Rickettsia akari

Direct immunofluorescence of skin biopsy; serological tests for Rickettsia rickettsii

Rocky Mountain spotted fever

Mice or mouse mites

(As above) (As above) Serological tests for Borrelia burgdorferi

Colorado tick fever Ehrlichosis Lyme disease

Ticks

(As above)

Murine typhus

Fleas

PCR, polymerase chain reaction.

Papules

Fever and Rash — — Most cases reported in Connecticut, New York, Massachusetts, Rhode Island, Pennsylvania, Wisconsin, Minnesota, and California; present in 75% of cases, rash (erythema migrans) typically expanding red lesion with central clearing found in axilla, groin, or thigh; secondary lesions possible over chest and trunk Disease reported in every state; rash present in 90% of cases; initially maculopapular and appearing on wrists and ankles; cutaneous lesion that spread to trunk and become petechial as disease progresses Disease in urban areas; chickenpox suggested by generalized papulovesicular rash Myalgias and migratory polyarthritis suggestive; maculopapular or morbilliform rash present over palms, soles, and extremities Painless, prurutic papule with vesicles, generally on extremities or face; agent that can be used in biological warfare. Inhalation of spores manifested by pneumonia.

—

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Table 2 Spectrum of Pathogens Recovered from Humans Infected Through Uncommon Animal Bites Source Alligator Dolphin Ferret Hamster Horse Lion Monkey Pig Piranha Rat Shark Tiger Wolf

Microbe Aeromonas hydrophila, Pseudomonas aeurginosa a Mycobacterium marinum a Mycobacterium bovis a Acinetobacter sp.b Pasteurella sp., Actinobacillus sp.a Pasteurella multocida a Herpesvirus simiae c Pasteurella sp., Actinobacillis suis a Aeromonas hydrophila a Streptobacillus moniliformis,d Leptospira sp.d Vibrio carchariae a Pasteurella multocida a Pasteurella multocida a

a

Soft tissue infection. Osteomyelitis. c Nervous system infection. d Systemic infection. b

tient, clindamycin plus a tetracycline or quinolone, which are agents possessing appropriate in vitro activity against P. multocida, provides acceptable therapy. Of course, the potential toxicities of tetracyclines and quinolones limit their use for pregnant or lactating women. Erythromycin, clarithromycin, and azithromycin exhibit variable activity against Pasteurella spp. and should not be used. Prophylactic antimicrobial therapy for the noninfected wound may be administered for 3–5 days, whereas for infected wounds, treatment should be continued for 10–14 days. 4

RABIES PROPHYLAXIS

Few discussions produce greater frustration than do those initiated by distraught patients concerning the need for rabies prophylaxis after animal contact. Fear of a universally fatal disease usually sweeps aside thoughtful consideration of the actual risks and the scientifically based recommendations. In fact, the decision concerning the need for antirabies immunoprophylaxis for an animal bite should be guided by a number of simple factors including the presence or absence of rabies in the region where the injury occurred, the circumstances of the bite, and the availability of the animal for observation or for sacrifice and brain harvesting (Figure 2). The following are considered to indicate a ‘‘provoked’’ bite: trespassing through an animal’s territory; playing with, petting, or feeding an animal; intervening in a fight; caring for an injured animal; handling an animal in a veterinary facility; and running, riding, or walking past an animal. Although the animal’s vaccination status should be determined, a history of rabies immunization does not exclude the possibility of the disease. Deaths due to rabies have occurred in travelers bitten outside the United States by dogs believed to have been immunized. In addition, the patient should

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Figure 1 Management of the adult with an uninfected animal bite. PCN, penicillin; Td, tetanus and diphtheria toxoid; TIG, tetanus immunoglobulin.

be assessed for tetanus immunization (intramuscular, tetanus and diphtheria toxoid [Td], 0.5 mL) and tetanus immune globulin ([TIG], 250–500 IU intramuscularly) (see Figure 1; also see Chapter 42). Bats and carnivorous animals (raccoons, skunks, foxes, and coyotes) are most likely to be infected with the virus. Any person who has the bite wound of a wild carnivorous mammal should be considered at risk for rabies unless immunofluorescent staining of the animal’s brain tissue yields a negative finding for the virus. As for all bite wounds, these lesions must be cleaned thoroughly with soap and water, a simple procedure that in experimental circumstances is extremely effective in reducing the transmission of the rabies virus. Previously unvaccinated patients should be given passive and active immunization (Table 3). Local reactions such as pain, swelling, and redness occur in up to 70% of vaccine recipients. Systemic reactions are less common and tend to be mild. Human rabies

Figure 2 Guidelines concerning rabies immunoprophylaxis for patients with animal bites.

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Table 3 Postexposure Rabies Immunoprophylaxis Protocol a Component Human rabies immune globulin (HRIG) Human diploid cell vaccine (HDCV)b

Dosage

Comment

20 IU/kg

Infiltrate as much of dose as possible around wound; give the balance IM into gluteal region Give IM into deltoid, the only acceptable sitec; doses administered on days 0, 3, 7, 14, and 28

1.0 mL

a

Previously immunized individuals should receive a dose of the human diploid cell vaccine on days 0 and 3. HRIG and HDCV should never be mixed in the same syringe. c HDCV must never be administered in the gluteal region. In young children, HDCV can be given in the outer aspect of the thigh. b

acquired in the United States is usually attributed to nonbite contact with bats. Thus patients who have a history of close contact with bats but no bite injury may nevertheless be candidates for rabies prophylaxis. Additional details concerning postexposure rabies prophylaxis can be obtained from state public health departments. 5

ZOONOSES MANIFESTING WITH LYMPHADENOPATHY

The causes of lymphadenopathy are myriad; the documentation of antecedent animal exposure can limit the list of potential causes (Figure 3). Thus, a history of outdoor activities or of recent catching or skinning a rabbit or other wild animal, especially in the late winter, raises the possibility of tularemia (Table 1). A history of travel to the Southwest and fleabites brings into focus the diagnosis of bubonic plague. Manifested 2–8 days after the bite of a rat flea, the syndrome is one of febrile lymphadenopathy (Table 1). Of note, with increasing intercontinental travel, diseases associated with enlarged lymph nodes can be acquired abroad. Thus, travelers to the African continent bitten by the tsetse fly can experience West or East African trypanosomiasis (caused by Trypanosoma rhodesiense and T. gambiense, respectively). Voyagers to Central or South America bitten by a reduviid insect (kissing bug) can contract Chagas disease (caused by T. cruzi). 6

CAT-SCRATCH DISEASE

With an estimated 25,000 cases annually in the United States, cat-scratch disease represents the most common animal-associated cause of lymphadenopathy likely to be encountered by a primary care physician (Figure 4). The incidence of the problem is greater in warm, humid regions of the country, where the prevalence of cats infected with Bartonella henselae, the etiological agent, is greatest. Remarkably, in some regions, about 50% of normal cats less than 1 year of age have been shown to be bacteremic with Bartonella sp. and 90% have antibodies against the microbe. Fleas have been implicated in the dissemination of Bartonella sp. among cats but do not appear to transmit the bacterium to humans. The symptoms of cat-scratch disease develop 2–3 weeks after exposure, typically to a recently acquired kitten. In more than 90% of cases in immunocompetent hosts, lymphadenopathy represents the cardinal manifestation of the disease. Fever and other constitutional symptoms tend to be mild. In about a third of patients, a local reaction in the form of a red or brown papule is noted. The course of the papule tends to parallel that of the adenopathy. Anatomically related to the inoculation site, the lymphadenopathy is usually unilateral and localized. The most commonly involved regions include the axillary

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Figure 3 Diagnostic clues to zoonotic diseases in the patient with lymphadenopathy. HIV, human immunodeficiency virus; EBV, Epstein-Barr virus; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.

and epitrochlear nodes (⬃50%), the cervical and submandibular nodes (⬃25%), and the femoral and inguinal nodes (⬃20%). Rarely, the adenopathy may be generalized and associated with severe constitutional symptoms and with hepatic, splenic, or abdominal node involvement. Atypical cat-scratch disease manifestations include Parinaud’s oculoglandular syndrome (preauricular adenopathy with an ipsilateral conjunctivitis), encephalopathy with seizures, and endocarditis. Individuals infected with the human immunodeficiency virus (HIV) and other immunosuppressed patients are at risk of experiencing a disseminated Bartonella sp. infection that is characterized by cutaneous, subcutaneous, and visceral proliferative vascular lesions (bacillary angiomatosis) and that can be fatal without antimicrobial therapy. The available diagnostic tests for cat-scratch disease include the in vitro cultivation of the microbe on synthetic medium, the identification of the organism in tissues or other

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Figure 4 Management of the patient with suspected cat-scratch disease.

clinical specimens by polymerase chain reaction (PCR), and the detection of serum immunoglobulin G (IgG) and IgM antibodies by immunofluorescent or enzyme-linked immunosorbent assay (ELISA) techniques. In general, the diagnosis of cat-scratch disease is suggested by the clinical picture and usually confirmed by the indirect immunofluorescent antibody (IFA) assay for Bartonella henselae. Of note, since serological test results may be negative in 15%–20% of cases if specimens are secured within the first two 2 weeks of the onset of symptoms, repeated testing at 4–8 weeks may be necessary to detect antibodies to confirm the diagnosis. Uncomplicated cases of cat-scratch disease do not warrant antimicrobial therapy. The adenopathy can be expected to persist 3–4 months (range, 1–12 months) and resolve spontaneously. Serial assessments to document regression are essential, and if the diagnosis remains uncertain, a biopsy should be performed to exclude the presence of other problems, especially lymphoma. On occasion, massive suppuration and the threat of rupture

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necessitate needle aspiration to decompress the lesions. On the basis of one controlled trial, administration of azithromycin appears to be the treatment of choice. Other agents possessing in vitro activity and occasionally utilized include erythromycin, clarithromycin, doxycycline, rifampin, and ciprofloxacin. The prognosis is good and most patients recover without sequelae. BIBLIOGRAPHY Bass JW, Vincent JM, Person DA. The expanding spectrum of Bartonella infections. II. Cat scratch disease. Pediatr Infect Dis J 16:193–179, 1997. Bass JW, Freitas BC, Freitas AD, Sisler CL, Chan DS, Vincent JM, Person DA, Claybaugh JR, Wittler RR, Weisse ME, Regnery RL, Slater LN. Prospective randomized double blind placebo-controlled evaluation of azithromycin for the treatment of cat-scratch disease. Pediatr Infect Dis J 17:447–452, 1998. Centers for Disease Control and Prevention. Human rabies prevention—United States, 1999: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 48(RR-1):1–21, 1999. Goldstein EJC. Household pets and human infections. Infect Dis Clin North Am 5:117–130, 1991. Hicklin H, Verghese A, Alvarez S. Dysgonic fermenter-2 septicemia. Rev Infect Dis 9:884–890, 1987. Noah DL, Drenzek CL, Smith JS, Krebs JW, Orciari L, Shaddock J, Sanderlin D, Whitfield S, Fekadu M, Olson JG, Rupprecht CE, Childs JE. Epidemiology of rabies in the United States, 1980 to 1996. Ann Intern Med 128:922–930, 1998. Talan DA, Citron DM, Abrahamian FM, Moran GJ, Goldstein EJ. Bacteriologic analysis of infected dog and cat bites. N Engl J Med 340:85–92, 1999. Tan JS. Human zoonotic diseases transmitted by dogs and cats. Arch Intern Med 157:1933–1943, 1997. Weber DJ, Rutala WA. Zoonotic infections. Occup Med 14:247–284, 1999. Weber DJ, Wolfson JS, Swartz MN, Hooper DC. Pasteurella multocida infections: Report of 34 cases and review of the literature. Medicine 63:133–154, 1984. Weinberg AN. Ecology and epidemiology of zoonotic pathogens. Infect Dis Clin North Am 5:1– 17, 1991.

38 The Patient with Fatigue Irving E. Salit Toronto General Hospital and University of Toronto, Toronto, Ontario, Canada

1

INTRODUCTION

In clinical practice, patients may present with the following common symptoms: fatigue, insomnia, dizziness, constipation, or pain. These symptoms are often considered to be ‘‘soft,’’ difficult to quantify, and may have no obvious underlying organic cause. Etiologically these symptoms are usually more often associated with psychosocial factors than organic ones. Because of that association there is a perception that these presentations represent more minor problems that may even be an irritant to some physicians. This irritation arises from the fact that these patients are often the ‘‘worried well’’ who may ‘‘medicalize’’ symptoms; the diagnosis is obscure and attempts at treatment are unsuccessful. Medical training is geared to ruling out organic diagnoses, so medical textbooks usually focus on ‘‘interesting’’ organic illnesses and may outline long, exotic differential diagnoses for such problems, but these are rarely the causes. The symptoms described, in particular fatigue, are in fact not minor and may be associated with functional impairment comparable to or greater than caused by many organic conditions. Patients with chronic fatigue can be helped, but the process is often a frustrating one for the doctor, the patient, the loved ones, and insurance companies.

2

BACKGROUND

Fatigue is a very common symptom in the community as well as among those who seek medical attention. Large community surveys have found that 20% of men and 25% of women ‘‘always feel tired,’’ yet only a fraction of these people perceive the fatigue as a medical problem and seek medical attention. Approximately 20% of primary care patients report that they suffer from fatigue, and about 15% report fatigue as either their chief complaint or a secondary complaint. Self-limited fatigue, which generally lasts up to 4 to 6 weeks, very commonly occurs after acute medical illnesses and after surgical operations. For example, follow-up studies of patients who have had lower respiratory tract infections indicate that persisting cough and fatigue last a median of 2 weeks and longer in those with more severe infections. Similarly, fatigue is well known to occur after influenza, infectious mononucleosis, aseptic meningitis, myocardial infarction, and cardiovascular surgery. Other, more clearly psycho723

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FATIGUE Common, often incapacitating symptom Can be acute or chronic, including chronic fatigue syndrome (CFS) (Table 1) CFS True clinical syndrome, of unknown cause Centers for Disease Control (CDC) definition (see Table 2) Unrefreshing sleep, postexertional fatigue Cognitive dysfunction Myalgia Patient characteristics (see Table 4) Female Aged 20–45 years Normal physical and laboratory results Management (see Table 5) Guarded prognosis (see Table 6)

social stressors, such as motor vehicle accidents (in the absence of physical injury), major job changes, serious family illness, moving to a new house, and major changes in a relationship, can all be associated with fatigue. It is important for the physician to help provide the necessary insight and reassurance in order to help prevent these subacute forms of fatigue from developing into chronic fatigue. Community studies have found a prevalence of chronic fatigue of almost 40/100,000 population with a female-to-male ratio of 1.3:1 and a mean age of 34 years. Other studies have found little variation with age. Those with chronic medical illness and those with psychiatric illness were more likely to have had fatigue. Conversely those with fatigue have a higher prevalence of lifetime and current psychiatric disorders such as major depression, somatization disorder, and dysthymia. Those in the community with fatigue also have a greater number of medically unexplained symptoms and more health care visits, especially if there is an associated psychiatric diagnosis. Similarly, patients who report fatigue in the primary care setting have a significantly higher lifetime prevalence of depressive or anxiety disorders and perceive that they have undergone significantly more stress over the preceding 3 months than have control subjects (Figures 1 and 2). Most patients who report fatigue in the primary care setting do acknowledge a psychosocial contribution to their fatigue and an association with self-perceived emotional vulnerability. Women are more likely to report fatigue even after adjusting for psychosocial distress. Those patients with more than 6 months of fatigue have experienced more somatic symptoms, greater worry about their illness and have lower recovery rates. Although fatigue is common in the primary care setting, very few patients with fatigue actually mention the chronic fatigue syndrome (CFS) as the cause. Many studies in patients who were examined in tertiary care centres further document the high rates of current major depression as well as a lifetime history of depression in patients with chronic fatigue. Chronic fatigue is not a new condition but has been described in many forms over the centuries. In 1750, febricula, or little fever, was described as ‘‘listlessness with great lassitude and weariness all over the body.’’ These patients also had myalgias, arthralgias,

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Figure 1 Etiological diagnoses of 200 patients with chronic fatigue (Demitrack and Abbey, 1996).

and forgetfulness. In 1869, George Beard, an American neurologist, described ‘‘neurasthenia,’’ which had all of the features of chronic fatigue syndrome: it was a condition of ‘‘nervous exhaustion . . . undue fatigue on slightest exertion, both physical and mental . . . headache, . . . and subjective sensations of all kinds.’’ Later, chronic fatigue was described as occurring after brucellosis, influenza, and infectious mononucleosis, but the association was controversial. In the 1950s, there was mounting evidence that prolonged morbidity after infections was often due to psychological disorders and not due to a continuing infection. For example, in a prospective evaluation of male employees at Fort Detrick in whom Asian flu developed, premorbid psychological vulnerability predicted influenza illness and a longer recovery time. More recently a prospective cohort study of primary care demonstrated that prolonged fatigue after flulike illnesses was related to premorbid psychological distress. Furthermore, in carefully controlled cold virus challenge studies there was an increase in the rates of both documented infection and clinical illness caused by these viruses with increases in the degree of psychological stress. For many patients seen in the office it may be difficult to determine whether fatigue has led to

Figure 2 Psychiatric diagnoses of 200 patients with chronic fatigue (Demitrack and Abbey, 1996).

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psychological distress or psychological factors have led to fatigue (or both). It is, however, clear that in prospective studies psychological factors can predispose to infection and especially persisting ill health. Thus chronic fatigue syndrome (CFS) can be viewed as a classical association involving the mind, body, and environment; in traditional Chinese medicine this is conceptualized as yin and yang. In addition to the more sporadic forms of CFS noted, outbreaks of CFS-like illness have also been described. Epidemics of a fatiguing illness in association with other symptoms came to be known as epidemic neuromyasthenia, and outbreaks came to be known by different designations based on the location (e.g., Royal-Free disease, Iceland disease, Lake Tahoe epidemic). Twenty-three such epidemics were reported from 1934 to 1958. The origin of these outbreaks is uncertain, but it was alleged that there was a strong element of mass hysteria in many of these outbreaks. These apparent outbreaks seem to be much less frequent in recent decades and attention has turned to sporadic cases. Sporadic forms of chronic fatigue bear some resemblance to the cases in these epidemics, but the relationship between sporadic and epidemic fatigue is uncertain. Our focus in this chapter is on sporadic fatigue, especially chronic fatigue that lasts more than 6 months. 3

DEFINITIONS AND CRITERIA

The main presentations to be delineated are subacute fatigue, chronic fatigue, and chronic fatigue syndrome (CFS) (see Table 1). Short-lived or subacute fatigue generally lasts up to several weeks but can last for months and is associated with acute precipitating causes. These causes may be related to organic illness, psychosocial stressors, psychiatric disorders, surgery, or trauma. Chronic fatigue is fatigue lasting more than 6 months that can be explained on the basis of a medical or psychiatric diagnosis. Alternatively, it is fatigue that is chronic but not extremely debilitating. For example, from a large group of patients suffering from chronic fatigue, one can make a psychiatric diagnosis in about 75%, a

Table 1 Forms of Fatigue Acute/subacute Up to 4–6 weeks Very common in community After acute medical illness (e.g., post pneumonia) Posttraumatic Chronic Variable severity Very common in community May or may not have associated symptoms Several to many months High prevalence of psychiatric disorders Chronic fatigue syndrome Much less frequent form of fatigue >6 Months Very severe fatigue Myalgia Sleep disorder Cognitive dysfunction Depressive symptoms

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medical diagnosis in 2%, and a medical and psychiatric diagnosis in 3% (see Figure 2). We are then left with a subset of patients (perhaps up to 20%) who have idiopathic chronic fatigue; many of those patients have chronic fatigue syndrome. In 1994 a case definition was developed by the Centers for Disease Control and Prevention (CDC) to encompass the syndrome known as chronic fatigue syndrome (CFS) (Fukuda et al., 1994). The value of this noncommittal label is that it did not attribute the fatigue to any particular cause or pathological condition, unlike the terms chronic EpsteinBarr virus (EBV) and myalgic encephalomyelitis (see Tables 2 and 3). CFS overlaps with other conditions. It is likely that CFS is identical to the conditions known as chronic Epstein-Barr virus syndrome, postviral fatigue, chronic fatigue and immunodeficiency syndrome (CFIDS), and myalgic encephalomyelitis. There is also considerable overlap of CFS with fibromyalgia. Furthermore, many subjects with CFS also have other medically unexplained illnesses such as temporomandibular joint pain, irritable bowel syndrome, and chronic headaches. The role of a case definition for CFS is to assist in proper diagnosis and appropriate investigations to rule out other conditions. CFS is defined solely on the basis of patientreported symptoms, so other causes of such symptoms have to be excluded. Although chronic fatigue and chronic fatigue syndrome are differentiated, it really is not clear that these two patient groups differ substantially. 4

THE CHRONIC FATIGUE SYNDROME PATIENT

Characteristically the CFS patient is a female between the ages of 20 and 45. The patient enters your office in a very characteristic fashion. Especially if the patient is unfamiliar to you there may be several phone calls to your office before the appointment because the patient often has concerns about the appointment related to location of the office, the duration of the visit, and what the visit entails. The patient usually arrives with a friend or family member who may have driven him or her to the appointment and who may wish to participate in the interview. It is generally preferable to interview the patient alone in order to assess better his or her ability to tell the history and to observe the patient’s cognitive functioning. Any gaps in the story can subsequently be filled in with the help of the accompanying person. The patients usually state that they have cognitive problems and require a friend or family problem to help them. It is actually rare, though, for the patient to encounter any difficulties with the ability to recount his or her history in considerable detail. Patients with CFS may arrive with a binder that includes detailed documentation of symptoms, medical history, and day-to-day functional ability that they themselves have catalogued. They may also have information from the Internet, newspapers, or magazines that alleges a new cause or cure for CFS. The patient may indicate that the main complaint is ‘‘tiredness’’ but you must determine exactly what the patient means by this term; you should differentiate between sleepiness, fatigue, lack of muscle power, depression, and other causes. All patients with CFS have very profound mental and physical fatigue that exceeds anything they have ever experienced and in fact often defies description. The hallmark of the fatigue is worsening after simple activities that the patient could have done quite easily in the past. It is made worse by stress, exertion, or mental functioning and is not very much improved by prolonged rest. The other predominant symptoms include problems with sleep, achiness, headaches, depression, and irritability. For the first few months of the illness the patients may be sleeping excessively (‘‘all day long’’), but later in the illness there may be frequent reawakenings and even when sleep does improve somewhat, patients are still unrefreshed in the morning.

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Table 2 Chronic Fatigue Syndrome: Centers for Disease Control Case Definition Clinically evaluated, unexplained, persistent, or relapsing chronic fatigue that Is new or has a definite onset (that is, has not been lifelong) Is not the result of ongoing exertion Is not substantially relieved by rest Results in a substantial reduction in previous levels of occupational, educational, social, and/or personal activities Concurrent presence of four or more of the following symptoms that have persisted or recurred during 6 or more consecutive months of illness and did not predate the fatigue Self-reported impairment in short-term memory or concentration severe enough to cause substantial reduction in previous levels of activity Sore throat Tender cervical or axillary lymph nodes Muscle pain Multijoint pain in absence of arthritis Headaches of new type, pattern, or severity Unrefreshing sleep Postexertional malaise lasting more than 24 hours

Attention should be paid to the circumstances under which the illness started or the precipitating factors (Figure 3). As noted in Figure 3, there may be one or more apparent precipitants that act on a background of psychosocial factors and result in the symptoms of CFS. Poor coping, misinformation, and abnormal illness behavior amplify and prolong the symptoms; it is the severity and chronicity of the illness that lead to a diagnosis of CFS. The debilitating illness may again lead to flulike symptoms and worsening; this stage completes the cycle. Patients often indicate that they were feeling perfectly well until they

Table 3 Chronic Fatigue Syndrome: Exclusionary Conditions Any active medical condition that explains the fatigue Any prior chronic medical condition whose resolution has not been documented (e.g., chronic hepatitis C) Past or current major depression with psychotic or melancholic features, bipolar affective disorders, schizophrenia, delusional disorders, dementias, anorexia nervosa, or bulimia Substance abuse within 2 years before onset Severe obesity

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Figure 3 A hypothesis of the generation and perpetuation of chronic fatigue syndrome (CFS).

had the initial or precipitating flulike illness, which seemed unremarkable. Indeed, they have usually been very active in exercise, social life, and family life and may have been working very long hours. However, after the acute, usually respiratory symptoms disappear in a week or so, they are left with overwhelming fatigue. Attempts to return to school or the workplace are unsuccessful because of the fatigue and cognitive dysfunction. Their boss or coworker may tell them to go home and not return until they are feeling much better. The clinician should inquire whether there were major changes in the workplace before the onset of the illness. A determination should be made as to prior coping strategies. Many patients in fact relate that in the year or so preceding the onset of the illness there were a number of psychosocial stressors, they were finding it increasingly difficult to cope, and they had to cut back on other activities. During the first year of the illness many patients are extremely incapacitated and may only be able to lie in bed or lie on the couch, or they may have great difficulty in even going to the washroom (some have to crawl on their hands and knees to do so). The physical examination findings are generally normal. There may be some redness of the throat, which is of uncertain significance. Although patients may describe tender, swollen lymph glands there is rarely palpable lymphadenopathy. It is more likely that any cervical tenderness relates to some tenderness of the sternomastoid muscles. Generalized muscle tenderness and tenderness of the tendon insertions are not infrequent, and there may be classical fibromyalgia tender points. Anxiousness during the examination is common and may be associated with tachycardia, moist palms, and jumpiness. There is no muscle weakness and no neurological abnormalities are found in CFS. Simple tests of cognitive functioning such as the mini–mental test yield normal findings. As a further assessment of cognition you should make note of the patient’s ability to relate the medical history in a careful and chronological fashion with attention to detail; there is usually no impairment at all in this regard.

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Patients should be observed for any signs of fatigue during the comprehensive history taking and examination. It is perplexing that patients rarely have any signs of overt fatigue during this process but indicate that they will be wiped out for a day or two after the office visit (see Table 4).

5

INVESTIGATIONS

Only a very small minority of patients who have typical CFS have evidence of an underlying organic disorder that can be uncovered by investigations. One has to reach a balance between doing too few tests and missing a rare organic cause and doing too many tests that may increase the patient’s concerns about a nonexistent underlying disorder; furthermore, doing more testing increases the likelihood that one will uncover some irrelevant abnormalities by chance alone. One useful approach is to do a minimal battery of laboratory screening tests to include a complete blood count; liver function tests; calcium, phosphorus, glucose, creatinine, thyrotropin (TSH) levels; and a urinalysis. It also may be useful to pursue more detailed targeted investigations when patients have a predominant symptom or sign that points to a possible underlying organic disorder; for example, if there has been abdominal pain, then perhaps a screening ultrasound would be of use. Many other kinds of tests have been reported to yield abnormal findings in CFS, and patients may be aware of these test abnormalities from their reading. Some of the reported immunological changes involve every aspect of lymphoid cell function, yet the changes are small and inconsistent, and it is uncertain whether they are truly different from normal. For example, expansion of CD45RO with adhesion markers suggests that immunologically mediated processes and cytokine production may be responsible for the clinical picture of CFS. One of the most documented and reproducible findings is a defect in natural killer (NK) cell function. A neuroendocrine explanation for CFS is suggested by low basal evening cortisol levels, which appear to be caused by a central nervous system– (CNS)-mediated failure to activate the hypothalamic-pituitary-adrenal axis. These changes can be induced by stress, infections, and/or psychiatric disorders. The neuroendocrine and immune findings may be central to the causation of CFS or may be epiphenomena resulting from fatigue, prolonged physical activity, and other symptoms such as psychological problems. By and large, these are research tests, which have no place in the general evaluation of such patients. Other tests that are not recommended include a computed tomography (CT) scan, single photon emission CT (SPECT) brain scanning, magnetic resonance imaging (MRI), antibodies to Candida spp., red blood cell magnesium, sleep studies, and the tilt table test.

6

MANAGEMENT

Optimal management of CFS lies primarily in the areas of empathy, education, and counseling. The CFS patient is very frustrated. Such a patient would definitely like to get better and return to his or her previous life-style but is confused by different messages as to how to do so. These patients are not malingering. They have an illness that needs attention and they need validation of their illness. It is not helpful to tell them that there is ‘‘nothing wrong’’ with them or that ‘‘it is all in their head.’’ It should be explained that this is not an infectious disease. There is no evidence for a continuing infection despite the way they feel. This illness is multifactorial in origin, so all possible contributory causes (e.g., psychosocial stressors) and solutions have to be explored.

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Table 4 The Chronic Fatigue Syndrome Patient Female Aged 20–45 years Normal physical examination findings Unrefreshing sleep, postexertional fatigue, cognitive dysfunction, achiness, headaches Normal routine blood test results

Patients may well have unfounded concerns that they have a terminal illness, a dementing illness, or an illness that is progressive and will not show any improvement. They must be educated that this is not the case at all. It should be emphasized that there has not been and will not be any permanent damage to any part of the body since their activities are often restricted by a fear that they will harm themselves. One should emphasize that this is an illness in which function is impaired without destruction of any organs or tissues. The doctor, however, should acknowledge the very severe impact that this condition has had on the patient’s life and emphasize that it is a real illness with real symptoms even though blood test results may be normal. It is important to review the process through which this illness has likely occurred so that the patient can gain some insight. This can be done by reviewing the history and pointing out how typical their illness is when compared to other cases of CFS and demonstrating the role for precipitating factors that may be obvious to you. Patients often want to know whether they actually have CFS. If they have had severe fatigue continuing for months, then the answer is virtually always, Yes, you do have chronic fatigue, but the issue now is how the illness occurred and how best to manage it. The actual label itself is less important than proper education and management. Although some with chronic fatigue may not actually fulfill the Centers for Disease Control (CDC) criteria for CFS, management is the same. The patients should be encouraged to regularize their life-style by getting out of bed at a reasonable hour every morning and getting dressed. Even though they may have to rest before and after activities, they should plan to do some activities in the morning and afternoon even though these may be very simple tasks. Furthermore, patients should be encouraged to leave the house for even brief walks, the duration of which can be built up in a very gradual fashion. They should be encouraged to continue to work or attend school although they may not be able to function on a full-time basis. If there are significant abnormalities in sleep and especially if depressive symptoms are present, they should be encouraged to take very small doses of antidepressants. Patients with CFS may tell you that they are hypersensitive to medication, and they are usually philosophically opposed to any antidepressant therapy. The low-dose antidepressants should be offered as medication that may benefit sleep and achiness. Start with the smallest possible dosage and then try to build up to therapeutic dosage, but this will be a challenge. Many patients who do accept such an approach show considerable improvement. If nonprescription medication is more acceptable to them, then they can start on St. John’s wort, which in some studies has been shown to be equivalent in efficacy to tricyclic antidepressants. Some patients also benefit from a sedative-hypnotic to help their sleep. The patients should be discouraged from seeking many medical opinions and seeing many specialists. Detailed, exotic, and expensive testing should also be discouraged. Out of desperation and perhaps because of philosophical differences with traditional medicine, most patients with CFS have tried alternative treatments such as anti–Candida therapy,

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echinacea, or evening primrose oil. Although these do not appear to be of any consistent benefit, one should support the patients in trying some of these remedies for a brief period if only to show them that there will be no benefit and to discourage them from spending excessive time, money, and energy on researching alternative therapies. It should be emphasized to patients that they can and will very likely improve over time by using some of the approaches advocated and by avoiding the harmful approaches. The role of formal exercise is uncertain in altering outcomes in CFS, but simple stretching exercises and perhaps exercising in a warm therapeutic pool may be of some symptomatic benefit for the muscle aching; the exercise also gives the patients some confidence that they are indeed able to exercise without having a setback. These activities may help their sleep and may improve their social interactions if these activities are done outside the home. Overall, patients should be encouraged to take increasing responsibility and not allow well-meaning family members to do too much for them. The approaches outlined are also aimed at moving patients out of the sick role and reducing illness behavior. It is also helpful for some patients to have more formal counseling by a psychologist, psychiatrist, occupational therapist, or social worker to give them support in their attempts at recovery. Some studies have shown that cognitive behavioral therapy is effective in improving outcomes. Many different therapies have been reported to be beneficial in CFS, but these either have not been confirmed or have been refuted. Some reportedly beneficial therapies of the past have included efamol, magnesium, and immunoglobulin injections. Because of this long history of allegedly beneficial therapies one has to be quite skeptical about the most recent ‘‘cures’’ that you may read about or that patients draw to your attention (see Table 5).

7

OUTCOME

The most favorable prognosis in chronic fatigue occurs in those for whom an organic cause is found, those with symptoms of less than 4 months in duration, and those who have only one or two symptoms and an absence of a lifetime history of dysthymia. Unfortunately, in CFS none of these conditions commonly applies so the prognosis is fairly poor. The worst outcomes occur among those who have a fixed belief in a physical or viral cause of the CFS and those who deny that psychosocial factors may be playing a role. Furthermore, there is a poor prognosis for those who are members of a CFS support

Table 5 Management of Chronic Fatigue Syndrome Validate the illness (the symptoms are real and severely limiting) Educate about causation (not a virus) Alleviate concerns (nonfatal, will not worsen) Increase activities slowly Regulate daily schedule Encourage antidepressants, hypnotics as needed Provide cognitive-behavioral therapy Discourage excessive reliance on alternative therapies

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group. Recovery is also independent of virological and immunological results and more related to psychosocial morbidity. Avoidance of physical activity plays a part in perpetuating symptoms. If some of the appropriate management strategies are applied within the first few months of the fatiguing illness, it is possible that chronic fatigue can be averted. There is, however, no confirmation that this is the case. Fully developed CFS (by definition, it has been present >6 months) is a severely disabling and generally very chronic condition that commonly lasts for years. If there was an acute onset of fatigue, patients are generally at their worst in the first 3 months or so, after which there may be some improvement. With the proper approach and a committed patient there may be a 50% improvement in the functional ability during the first 1 to 2 years. After 2 to 3 years only 5% or so of subjects have fully recovered. Only 2% of subjects have another medical diagnosis that can explain the fatigue, whereas in about 20% an alternative psychiatric diagnosis becomes likely. On a positive note, patients rarely worsen over time. Patients should be made aware of the likely outcomes (without undue pessimism) because this knowledge will allow more realistic planning and will actually prevent frustration caused by unexpectedly slow improvement. When improvement does occur, patients should be encouraged to increase their activities and possibly return to school or the workplace on at least a part-time basis. Many patients may be reluctant to increase their activities because they may believe that their improvement has been due to major life-style changes and severe limitation of activities. They may be afraid to go back to some of their previous activities and therefore maintain a stagnant low level of activity (see Table 6).

8

ASSESSMENT FOR INSURANCE PURPOSES

Because of severe disabling fatigue, many subjects who have CFS are unable to work on a full-time basis. The insurance assessment should be considered an integral part of the management of patients with CFS. The overall aim should be for the patients to remain in the workplace or return to the workplace whenever possible. Assessments should be based on the symptoms and the degree of disability and not necessarily on the fulfillment of any diagnostic criteria for CFS. The difficulty for insurance companies is that the manifestations of CFS are based on subjective criteria only; there are no specific laboratory test result abnormalities or other objective criteria. Patients state that any difficulties with insurance companies and involvement of attorneys increase their stress and makes their illness worse. What may compound their uncertainty is that after years of illness patients often do not have the same job or any job to return to.

Table 6 Outcome of Chronic Fatigue Syndrome after Several Years Improvement Full recovery Worsening Another medical diagnosis Psychiatric diagnosis

50% 5% 2% 2% 20%

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SUMMARY

CFS is a form of chronic fatigue associated with cognitive impairment, myalgias, arthralgias, headaches, unrefreshing sleep, and postexertional malaise. CFS likely has a multifactorial cause, and it requires a multifaceted approach to management. Improvement is very slow, but most patients have the capability of improving considerably over a period of 2 to 3 years. BIBLIOGRAPHY Beard GM. Neurasthenia or nervous exhaustion. Boston Med Surg J 3:217–220, 1869. Demitrack MA, Abbey SE, eds. Chronic Fatigue Syndrome. New York: The Guilford Press, 1996. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: A comprehensive approach to its definition and study. Ann Intern Med 121:953–959, 1994. Imboden J, Canter A, Cluff L. Convalescence from influenza: A study of the psychological and clinical determinants. Arch Intern Med 108:393–399, 1961. Kruesi MJP, Dale JK, Straus SE. Psychiatric diagnoses in patients who have chronic fatigue syndrome. J Clin Psychiatry 50:53–56, 1989. Manu P, Matthews DA, Lane TJ, Tennen H, Hesselbrock V, Mendola R, Affleck G. Depression among patients with a chief complaint of chronic fatigue. J Affect Dis 17:165–172, 1989. Pawlikowska T, Chalder T, Hirsch S, Wallace P, Wright D, Wessely S. A population based study of fatigue and psychological distress. Br Med J 308:763–766, 1994. Salit IE. Sporadic postinfective neuromyasthenia: Persistent illness after acute infections. Can Med Assoc J 133:659–663, 1985. Salit IE. The chronic fatigue syndrome: An overview of important issues. J Musculoskeletal Pain 3:17–24, 1995. Salit IE. Precipitating factors for the chronic fatigue syndrome. J Psych Res 31:59–65, 1997. Sharpe MC, Hawton KE, Simkin S, Surawy C, Klimes I, Peto TEA, Warrell D, Seagroatt V. Cognitive therapy for chronic fatigue syndrome: A randomized controlled clinical trial. Br Med J 312:22–26, 1996. Taerk GS, Toner BA, Salit IE, Garfinkel PE, Ozersky S. Depression in patients with neuromyasthenia (benign myalgic encephalomyelitis). Int J Psychiatry Med 17:49–56, 1987. Wessely S, Chalder T, Hirsch S, Pawlikowska T, Wallace P, Wright DJ. Postinfectious fatigue: Prospective cohort study in primary care. Lancet 345:1333–1338, 1995.

39 Epstein-Barr Virus Infection and Infectious Mononucleosis–Like Illnesses Irving E. Salit Toronto General Hospital and University of Toronto, Toronto, Ontario, Canada

1

INTRODUCTION

In the strict sense, mononucleosis refers to a marked increase in the peripheral blood mononuclear cells (monocytes and lymphocytes) usually accompanied by atypical lymphocytes. This in turn can be caused by a variety of infections and other conditions. However, the term has come to be synonymous with acute infectious mononucleosis (IM), or ‘‘mono,’’ which is caused by the Epstein-Barr virus (EBV). The focus in this chapter is on EBV-induced acute infectious mononucleosis, also called glandular fever in the United Kingdom. The differential diagnosis of EBV mononucleosis is also reviewed. There were clinical descriptions of infectious mononucleosis in the 1880s. The recognition of the atypical lymphocyte as a hematological marker for the disease led to more specific diagnostic criteria. In the 1930s it was noted that heterophile antibodies (human antibodies that react to cells from other animals) developed during the course of infectious mononucleosis, and a diagnostic test that was the forerunner of the current rapid diagnostic tests was developed. The Epstein-Barr virus was described in 1964, and in the 1960s and 1970s large-scale epidemiological studies demonstrated that heterophile-positive IM occurred in patients who did not have preexisting EBV antibody but who later acquired antibody to EBV. These epidemiological studies allowed the recognition of subclinical EBV infections. It became apparent that 10%–20% of the cases of heterophile-negative mononucleosis were caused by other conditions, including cytomegalovirus infection. It is now recognized that EBV is also associated with nasopharyngeal carcinoma, Burkitt’s lymphoma, Hodgkin’s disease, and B-cell lymphoma in immune-compromised patients. 2

EPSTEIN-BARR VIRUS

The name Epstein-Barr virus reflects the work of Epstein, Barr, and Achong, who discovered a herpesvirus in the tissues of African patients who had Burkitt’s lymphoma. EBV has the characteristic features of other members of the Herpesviridae. It is an enveloped virus containing an icosohedral nucleocapsid enclosing double-stranded deoxyribonucleic acid (DNA). The EBV genome codes for more than 100 proteins. The viral capsid antigen (VCA) and early antigen (EA) are expressed during the lytic phase of infection; the nuclear 735

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EPSTEIN-BARR VIRUS INFECTIONS Most infections asymptomatic in childhood (see Figure 1) Clinical illness more often seen in teenagers and adults By adulthood 95% of population immune No association with chronic fatigue syndrome Clinical illness (see Table 1) Sore throat, malaise, headache, fever (see Table 2) Lymphadenopathy, pharyngitis, splenomegaly (see Table 3) Laboratory diagnosis Leukocytosis and atypical lymphocytes (>10%) Elevated liver function test (LFT) results Thrombocytopenia Positive heterophile antibody (monospot test) finding in 80%–90% Antibodies to Epstein-Barr virus (EBV) antigens (see Table 5) Positve IGM to viral capsid antigen (VCA) Older patients Less pharyngitis, lymphadenopathy May have 50% Mononuclear cells >10% Atypical lymphocytes Serological Transient appearance of heterophile antibodies Permanent emergence of antibodies to Epstein-Barr virus (EBV)

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Table 2 Symptoms of Infectious Mononucleosis Symptom Sore throat Malaise Headache Anorexia Myalgias Chills Nausea Abdominal discomfort Cough Vomiting Arthralgias

Percentage 80–90 50–75 40–55 10–30 10–20 10–20 2–15 2–15 5 5 2

The tonsillar enlargement can be quite striking as occasionally the tonsils may meet at the midline (‘‘kissing tonsils’’) and may even result in pharyngeal obstruction. Palatal petechiae may be seen in about half of the cases, and they usually occur at the junction of the hard and soft palate. Posterior cervical lymphadenopathy is almost universal; it is symmetrical and is usually not very tender to palpation. Lymphadenopathy may also occur in other areas, although occipital lymphadenopathy is uncommon. Hepatomegaly occurs in only 10%–15% of cases, but ‘‘punch tenderness’’ of the liver is somewhat more frequent. Splenomegaly is clinically detectable in about half of patients but can be seen by ultrasonography in 100% of patients, especially by the second week of the illness. A rash is very infrequent and nonspecific in appearance. Ampicillin can produce a pruritic maculopapular eruption in 90%–100% of IM patients, which begins 7–10 days after the start of the drug. This does not necessarily indicate that the patient is allergic to penicillin. Results of routine laboratory tests can be strongly suggestive of IM. At least one of the liver function test results is abnormal in almost all cases of IM. These elevations are usually mild with individual values in the range of two to three times the upper limit of normal. Bilirubin level is only mildly elevated and frank jaundice is rare. Abnormalities

Table 3 Signs of Infectious Mononucleosis Sign Lymphadenopathy Pharyngitis Fever Splenomegaly Hepatomegaly Palatal enanthem Jaundice Rash

Percentage 100 70–90 100 50–65 5–15 25–60 5–10 0–15

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found on urinalysis, seen in 16% of patients, include proteinuria, pyuria, and microscopic hematuria. Presence of mixed cryoglobulins is extremely common. The hematological manifestations are usually very suggestive of IM. The peak white blood cell count can be up to about 20,000/mm3. There is a relative lymphocytosis in about 70% of the cases as monocytes and lymphocytes account for 60%–70% of the total white blood cells. Atypical lymphocytes are the hematological hallmark of IM. In acute EBV infection there are >10% atypical lymphocytes, though there is a wide range of response, from 5% to 90% of the circulating lymphocytes. The atypical lymphocytes are larger than the mature lymphocytes encountered in peripheral blood, and the cytoplasm is often vacuolated and basophilic. The edges have a ‘‘rolled-up’’ appearance. The presence of atypical lymphocytes in conjunction with the history and the physical findings noted previously are virtually pathognomonic of IM caused by EBV. Mild neutropenia and thrombocytopenia are also quite common. Atypical lymphocytes, however, can occur in other circumstances, but the clinical scenarios are so different that this finding hardly provides a diagnostic dilemma (Table 4) (also see the discussion of the differential diagnosis of IM). All patients who have had IM or EBV infection have lifelong immunity. There is no clear evidence that classical IM is dangerous during pregnancy to either the mother or the fetus. Most patients recover without sequelae. Studies have shown, though, that up to 38% of patients are still symptomatic (as self-reported) at 2 months and 12% at 6 months. There were no objective measures that characterized patients who self-reported failure to recover fully. Occasionally patients may present with atypical symptoms, causing diagnostic confusion. Patients above 40 years of age experience less pharyngitis and lymphadenopathy and often have fever lasting more than 2 weeks. These older patients have increased rates of hepatitis with higher levels of transaminases and bilirubin and hepatomegaly. Older patients may also have a less significant lymphocytosis. In one study, 16% of patients above age 40 had 90% of patients and persist for life. Antibodies to the EA can be of two types: EA-D pattern is a diffuse immunfluorescent staining of the nucleus and cytoplasm; the EA-R pattern shows staining restricted to the cytoplasm only. EA-D antibodies appear after 3–4 weeks of symptoms and are present

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Table 5 Serological Diagnosis of Epstein-Barr Virus Infection

Phase of illness, months Acute infection (1–3) Convalescent (3–6) Past infection (6–12)

Heterophile antibody (Monospot) ⫹ ⫾b ⫺b

Viral capsid antigen (VCA)

Early antigen (EA)

IgM

IgG

EA-D EA-R

⫹c ⫾d ⫺

⫹ ⫹ ⫹

⫹e ⫹f ⫺

⫺g ⫾h ⫾

Nuclear antigen (NA) ⫺ ⫹i ⫹

⫹, present; ⫾, present sometimes; ⫺, absent; EA, early antigen; EA-D, diffuse pattern; EA-R, restricted pattern. Finding may remain positive for 3–12 months. c Diagnostic of acute Epstein-Barr virus (EBV) infection. d Immunoglobulin M (IgM) finding remains positive for 4–8 weeks. e Present after 3–4 weeks. f Present in 70% of patients, especially those with severe disease. Lasts 3–6 months. g Generally absent; if present, appears 2 weeks to months after onset. Appears later then EA-D. h May be seen in severe infections. i Usually appear 6–12 months after initial symptoms. a

b

in about 70% of patients with acute IM, especially those with severe symptoms. Antibodies to EA-D in the presence of IgM to the VCA is suggestive of recent infection. EA-D antibodies are also seen in patients with nasopharyngeal carcinoma. EA-R are rarely present in acute EBV infection but may be seen in patients with African Burkitt’s lymphoma. Antibodies to nuclear antigen are detectable after 3–6 months. They persist for life. The absence of antibody to NA in a patient who is VCA IgG–positive but VGA IgM– negative suggests a recent infection. The finding of anti-EBV NA early in the course of an illness precludes a diagnosis of acute EBV infection. The simplest test to do for confirmation of recent EBV infection is the IgM VCA. It is very sensitive and specific and can be done on serum during acute illness, rather than waiting for a convalescent period. On rare occasions CMV infection of cells latently infected with EBV can cause the production of VCA IgM, causing a false-positive test result. EBV can be cultured from oropharyngeal washings or from circulating lymphocytes, but this culture is certainly not routinely available and is less useful in diagnosing acute IM as the virus may be detectable in healthy persons or those with unrelated illnesses. Viral DNA may also be detectable in oropharyngeal washings or lymphocytes, but this finding is also not diagnostic of acute infection. There are a variety of immune abnormalities that occur during the course of IM. Polyclonal increases in immunoglobulin are a result of the proliferation of infected B cells. These are often associated with abnormal antibodies of the IgM class. These abnormal antibodies include Venereal Disease Research Laboratories (VDRL) test for syphilis antibodies, antinuclear antibodies (ANA), rheumatoid factor (RF), and anti-i antibodies, which may be associated with hemolytic anemia. 4.3

Complications of Infectious Mononucleosis

Most IM patients recover quite uneventfully. The acute symptoms of sore throat and fever usually pass in 1 to 2 weeks. The swollen glands, fatigue, and lack of energy almost always disappear in 2 to 4 weeks. Follow-up studies of university students with IM have established that 20% return to school within 1 week and 50% within 2 weeks. When many

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patients are given a diagnosis of IM they fear that they will be very ill and fatigued for months. They should be reassured that this is not the case at all and that they have a selflimited illness and should be able to return to school or work quickly. Even though complications of IM are quite rare, they have been widely reported because this infection is so common in the community. These complications include autoimmune hemolytic anemia (0.5%–3%), profound thrombocytopenia, and neutropenia with secondary infections. Rupture of the spleen is a popularized complication that is actually very rare (0.1%–0.2% of all cases). Splenic rupture occurs most frequently during the second or third week of illness and should be suspected if there is abdominal pain and/or syncope. Splenectomy is usually required. There often is a history of preceding trauma or Valsalva maneuver in association with straining at stool. Because of this problem, it has been advocated that one should palpate the spleen gently, treat constipation, and avoid contact sports at least in the first few weeks after diagnosis. Neurological complications occur in 3 weeks), especially to areas of poor sanitation or off common tourist routes and those visiting relatives and friends. Japanese encephalitis virus (JEV) is a mosquito-borne virus that may cause viral encephalitis with a high fatality rate (30%) and neurological sequelae in 50% of survivors. Vaccination is recommended for travelers to the rural Indian subcontinent and parts of Southeast Asia with stays of >30 days, especially with rural exposures and during summer months. The CDC ‘‘Yellow Book’’ outlines the seasonal risks of all countries. The JEV vaccine has a rare but serious hypersensitivity reaction in 0.6% of vacinees, which includes urticaria, angioedema, and respiratory distress. The reaction may occur immediately or up to 1 week after vaccinations. It is responsive to epinephrine, antihistamines, and/or steroids. To monitor for side effects, the full course (three doses) of vaccination with JEV vaccine should be completed more than 10 days before travel. Rabies vaccine is usually reserved for animal handlers, cave explorers, and travelers expected to spend prolonged time in areas of significant threat. Vaccines against plague, tick-borne encephalitis, and cholera are rarely recommended for travelers and should be given in consultation with a travel medicine expert. Parenteral cholera vaccine is poorly immunogenic. A newer live oral formulation, CVD 103-HgR, is more immunogenic, but neither vaccine is available in the United States.

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755

Malaria Prophylaxis

Malaria is a parasitic infection caused by Plasmodium spp. characterized by fever, headache, and hemolytic anemia. It is transmitted by the Anopheles mosquito. It is endemic in Central and most of South America, most of Africa, the Middle East, India, and Southeast Asia, including southern China. There are four species: P. malariae, P. vivax, P. ovale, and P. falciparum. The most lethal form of malaria is caused by P. falciparum (see Chapter 2). Most P. falciparum are resistant to the tradition prophylaxis agent, chloroquine. Generally P. malariae, P. vivax, and P. ovale are sensitive to chloroquine. There are, though, increasing reports of chloroquine-resistant P. vivax in Southeast Asia. Approximately 1000 cases of imported malaria in returning travelers are diagnosed annually in the United States. The best prevention against malaria is avoidance of mosquito bites (see section 2.1.3). Travelers to malarious regions should be advised that the Anopheles sp. mosquito bites from dusk to dawn, and nighttime outdoor activity should be limited. Medical prophylaxis against malaria depends on the region of the world, length of stay in the endemic area, and activities of the traveler. Prophylactic agents are taken before travel to ensure adequate blood levels during travel and post travel to eradicate protozoa potentially in the bloodstream. Since prophylaxis is not completely effective and only approximately 50% of travelers fully adhere to their prophylactic regimens, travelers should be educated about the symptoms of malaria (unexplained fever with or without headache, chills, weakness, vomiting, and diarrhea). All travelers to endemic areas need to recognize that malaria can be fatal unless treated early and prompt medical evaluation is necessary for symptoms suggestive of malaria. Areas of drug-resistant P. falciparum malaria are rapidly changing. Throughout most of the world, the traditional prophylactic agent, chloroquine sulfate, can no longer be used to prevent malaria. The CDC web sites (listed later) should be contacted for up-to-date drug resistance information. Agents used for malaria prophylaxis and dosages are listed in Table 3. Areas of chloroquine-sensitive P. falciparum malaria are increasingly few. Chloroquine prophylaxis can be safely used only in Haiti, the Dominican Republic, Central America west of the Panama Canal, Egypt, and parts of the Middle East.

Table 3 Drugs for Malaria Prophylaxis

Drug

Adult dose

Started before travel

Stopped after travel

2 Weeks

4 Weeks

2 Weeks

4 Weeks

Contraindicated

Important side effects Dizziness, depression, anxiety, insomnia Sun sensitivity, esophageal ulceration, vaginitis Abdominal pain, nausea, vomiting, headache Itching, nausea, headache, occasional alopecia, skin eruptions, corneal precipitates

Mefloquine hydrochloride (Lariam) Doxycycline

250 mg Once weekly 100 mg Once daily

Atovaquone; proguanil hydrochloride (Malarone) Chloroquine phosphate (Aralen Phosphate)

One tablet (250/ 100) once daily

3 Days

7 Days

History of seizures, psychosis Pregnant women, children 90%) travelers. However, other vaccines such as oral typhoid vaccine may be only 60%–70% effective, and illness can occur with a high bacterial inoculum.

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Table 7 Selected Causes of Traveler’s Fever by Incubation Period Short incubation period (21 days) Malaria (P. vivax, ovale, malariae) Viral hepatitis (A, B, C, D, E) Tuberculosis Acute human immunodeficiency virus (HIV) Amebic liver abscess Rabies Visceral leishmaniasis Acute schistosomiasis

3.1.4

Medication and Chemoprophylaxis Use During Travel

Infections that have been partially treated, with either antibiotics or prophylactic medications, may have atypical presentations. All medications and chemoprophylaxis during the period of travel should be closely reviewed. The physician interviewing the febrile traveler who has been prescribed malaria prophylaxis should remember that most patients are incompletely compliant with malaria prophylaxis, particularly in the 4 weeks post travel; that no prophylaxis is 100% effective; and that drug resistance patterns are changing rapidly worldwide. Malaria with a low parasite count occurs in individuals with fever who have used malaria prophylaxis. Repeated examinations of thick and thin Geimsa stained malaria smears are indicated in this situation. Adverse drug reactions to any medication should also be considered. 3.1.5

Physical Examination

The thorough physical examination often reveals diagnostic clues to the cause of fever. Examples of physical examination findings and associated causes of fever are shown in Table 9. 3.1.6

Work-up of Undifferentiated Travelers’ Fever

Despite a complete history and examination, many travelers’ fevers remain undifferentiated. An initial approach is shown in Table 10. Acutely ill patients with suspected viral hemorrhagic fever or P. falciparum malaria should be hospitalized. Most individuals without signs of systemic toxicity can be evaluated as outpatients.

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Table 8 Exposures and Selected Causes of Fevera Insects/arthropods Mosquitos: malaria, dengue, yellow fever, JEV, other arboviral infections, lymphatic filaria Ticks: spotted fevers, endemic relapsing fever, Q fever, viral encephalititis, Lyme disease, ehrlichiosis, tularemia, babesia Fleas: plague, murine typhus Sandflies: leishmania, bartonellosis, sandfly fever Flies: onchocerciasis, loa loa, African trypanosomiasis Animal exposures Tularemia, rabies, plague, anthrax, viral hemorrhagic fevers, brucellosis, rat-bite fever Raw meats/seafood Hepatitis A and E, trichinosis, bacterial and viral gastroenteritis, toxoplasmosis, anisakasis, Angiostrongylus spp., Vibrio cholerae, V. vulnificans, pork and beef tapeworms (Taenia solium and T. saginata), Campylobacter jejuni Unpasteurized milk Brucellosis, listeriosis, Q fever, Salmonella spp. Contaminated water/vegetables Amebiasis, hepatitis A and E, leptospirosis, typhoid fever, nontyphoid salmonellosis, shigellosis, viral gastroenteritis Swimming, fresh water Schistosomiasis, leptospirosis Ill contact exposure Shigellosis (bacillary dysentery), typhoid fever, mengingococcal meningitis, flavoviral infections (Ebola, Marburg virus) Sexual contacts Gonorrhea, hepatitis B and C, HIV, HTLV-1, syphilis, chlamydia a

JEV, Japanese encephalitis virus; HIV, human immunodeficiency virus; HTLV-1, human T lymphotropic virus type 1.

3.2

Common Causes of Fever in Returning Travelers

The most common causes of fever in the returning international traveler are malaria, typhoid fever, hepatitis A and E virus infection, and dengue. 3.2.1

Malaria

Malaria is by far the most common cause of tropical fever of travelers. Approximately 1000 cases a year are imported to North America, the majority in Canada. Health care providers treating travelers should remember the axiom ‘‘Fever in the returning traveler is falciparum malaria until proved otherwise.’’ It is a priority to consider, diagnose, and treat malaria expeditiously as P. falciparum or ‘‘malignant’’ malaria can rapidly lead to severe disease with marked hemolytic anemia, renal failure, coma, and death. Even when managed in intensive care units, severe P. falciparum malaria has a mortality rate >20%. Of travelers who have malaria 90% do not have signs or symptoms until they have returned home. Malaria can be a primary infection, recur, or be asymptomatic (only in those with prior immunity). P. falciparum malaria is manifested within the first 2 months of return (90%), whereas P. vivax and P. ovale malaria can appear up to several years post travel and may also recur. Any symptom can be associated with malaria, including fever, chills, malaise, myalgias, headache, gastroenteritis, and cough. The fever pattern is not helpful in early disease

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Table 9 Physical Examination Findings and Selected Causes of Traveler’s Fever Temperature-pulse dissociation High fever, low pulse: typhoid fever, leptospirosis, yellow fever Low fever, high pulse: acute rheumatic fever (carditis), Chagas disease, tetanus (no fever) Hepatomegaly Amebic or bacterial liver abscess, malaria, typhoid, leptospirosis Splenomegly Chronic malaria, schistosomiaisis, visceral leishmaniasis, typhus Lymphadenopathy Acute human immunodeficiency virus (HIV), dengue fever and other arboviruses, visceral leishmaniasis, brucellosis Eschar Anthrax, Lyme disease, typhus Facial edema Trichinellosis Hemorrhage Crimean-Congo hemorrhagic fever, Lassa fever, Ebola virus, Marburg virus, dengue fever, yellow fever, meningococcus, Rocky Mountain spotted fever, Rift Valley fever Jaundice Yellow fever, viral hepatitis, dengue, leptospirosis Joint swelling Loa loa (calabar swelling)

and is not synchronized with the classic tertian or quartan patterns until the parasites have gone through multiple replication cycles. In severe falciparum malaria, parasites sequester in peripheral tissues. Despite a high parasite load, a patient with severe malaria may look well but within a short period can be acutely ill with shock and mental status changes. Patients with severe malaria (or the possibility of it) need immediate intensive care support and urgent consultation by a physician trained in the care of malaria.

Table 10 Initial Workup of Fever in the Returning Traveler Detailed travel and exposure history (see Table 8) ↓ Determination of likely incubation period (see Table 7) ↓ Physical exam findings (see Table 9) ↓ Consideration of the more common infections first (see Table 6) ↓ Thick and thin blood smears (repeat q8–12h) Complete blood count (CBC) with manual differential Blood cultures (twice) Hepatic transaminase levels Stool culture and ova and parasite exam (if diarrhea) Urinalysis and culture Consideration of acute serum for storage

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The diagnosis of malaria is missed in over half of the cases. Many patients see more than three physicians before an accurate diagnosis is made. Malaria is diagnosed by thick and thin blood smears, which take considerable expertise to read correctly. The thin smear is specific for the P. plasmodium species and the thick smear, which is made with more blood, is more sensitive for the presence of malaria parasites. A competent microscopist can detect 5 to 10 parasites/␮L of blood on the thick film. Thick and thin smears that yield negative results should be repeated every 8–12 hours three times in order to rule out malaria. Other diagnostic tests such as the quantitative buffy coat, enzyme-linked immunosorbent assay (ELISA), and histidine-rich parasite antigen (ParasiteF) tests have greater sensitivity than blood smears but are expensive and not readily available in all settings. The treatment of uncomplicated malaria is summarized in Table 11. Medical therapy for malaria depends on the severity of infection, species present, and antibiotic resistance patterns. The most updated data on resistance patterns must be obtained before treatment (CDC Malaria Hotline 404-332-4555). Resistance to antimalarial agents worldwide is rapidly evolving. Globally, most areas have chloroquine-resistant P. falciparum, and some areas such as Southeast Asia have falciparum malaria resistant to all known forms of therapy. Drug-resistant P. vivax has also been reported in Oceania. Mild cases of malaria including most cases of nonfalciparum malaria can be treated orally on an outpatient basis with close follow-up. Severe cases of malaria including most infections with P. falciparum should receive inpatient monitoring and intravenous antibiotics. Many need intensive care unit (ICU) attention. Supportive care of these patients, including transfusions, fluid management, dialysis, and plasmapheresis, may be necessary and must be done in consultation with a malaria expert. Patients diagnosed with either P. vivax or P. ovale are at risk for recurrence of malaria because of the presence of the hypnozoite form of the parasite that resides in the liver, which is not eradicated by routine malarial agents. Primaquin (see Table 11) must also be

Table 11 Therapy of Uncomplicated Malaria a Chloroquine-sensitive Chloroquine b 1 g (Salt) at 0 hr, then 500 mg PO at 6, 24 and 48 hr or 1 g At 0 hr then 500 mg PO at 12, 24, and 36 hr or 1 g At 0 and 24 hr then 500 mg PO at 48 hr Chloroquine-resistant Quinine sulfate 650 mg (base) PO q8h for 3–7 days plus Doxycycline 100 mg PO bid for 7 days or Mefloquine 15 mg/kg PO at 0 hr then 10 mg/kg at 8–24 hr Mefloquine-resistant Quinine and doxycycline (as above) Terminal (hepatic phase) therapy for P. vivax, P. ovale Primaquine 15–30 mg PO/day for 14 daysc a

Severe malaria: consult expert trained in care of severe malaria. 1 g Salt = 600-mg base of chloroquine. c Check G6PD level before use. b

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given when treating P. ovale and P. vivax to prevent relapses. A G6PD level should be checked on all patients before use of primaquin since the drug can cause hemolysis in those with G6PD deficiency. 3.2.2

Hepatitis A and E

Viral hepatitis in the traveler is largely due to HAV infection contracted after ingestion of contaminated food and water. The infection is spread via outbreaks in developed nations but is globally endemic in areas with poor sanitation. After a long incubation period of 2–7 weeks, the infection produces fever, malaise, and nausea in the preictal period. Fever usually disappears after several days with the onset of jaundice. Patients remain infectious from the latter half of the incubation period to approximately after the first week of jaundice. Children are often asymptomatic and mild infections in healthy adults last 1–2 weeks. Severity increases with age, however, and infection may cause months of disability. In healthy hosts, full recovery without sequelae is the norm. Cases of HAV infection in the traveler are expected to decline with the use of the HAV vaccine, which has >90% effectiveness compared to the 60%–70% effectiveness of intravenous (IV) immunoglobulin. The diagnosis of HAV infection is made by demonstrating immunoglobulin M (IgM) anti–hepatitis A antibodies in association with elevated transaminase levels or by demonstrating a fourfold rise in antibody titer. Treatment is symptomatic. Hepatitis E virus (HEV) is found predominantly in the tropics and subtropics. It is spread via the oral-fecal route and cannot be distinguished clinically from HAV infection. Epidemics have been reported in Asia, Africa, the Middle East, and Central America. Pregnant women in the third trimester are at very high risk of fulminant hepatitis and death (30%) of HEV infection. Commercial serological tests for HEV infection are not available. Pregnant women should consider deferring travel to high-risk areas. Vigilant hand washing and attention to food and water precautions are advised for all travelers. 3.2.3

Enteric Fever

Enteric fever due to the gram-negative bacillus Salmonella typhi (typhoid fever) or Salmonella paratyphi (paratyphoid fever) can be contracted worldwide through ingestion of contaminated food and water. Most cases of typhoid fever diagnosed in the United States are contracted in India, Mexico, and Peru. High incidence rates are also found in Pakistan, Chile, and Haiti. The incubation period of typhoid fever varies with the infecting dosage (3–60 days). Clinical features include an initially remittent fever that becomes sustained. Malaise, headache, abdominal pain, and sleep disorders are common. Constipation in adults is common, rather than diarrhea. Hepatosplenomegly, transient ‘‘rose spots’’ on the trunk, and a temperature-pulse dissociation may be found on exam. The leukocyte count is normal. Complications of typhoid fever include gastrointestinal hemorrhage, bowel perforation, mental status changes (‘‘typhoid state’’), and hepatitis. Without appropriate treatment, the mortality rate can be >10%, with a higher rate of complications. Approximately 5%–10% of untreated patients relapse. Patients who excrete S. typhi for over 12 months are considered ‘‘chronic carriers’’ and are the unique reservoir for S. typhi. Diagnosis is made by isolation of the organism. Of blood cultures 80% yield a positive result in the first week while stool culture results are positive in 2 weeks) form often due to parasites (protozoa) May be part of a systemic illness such as malaria, typhoid fever Eosinophilia (see Chapter 32, Tables 2 and 3) Invasive helminth infection, drug reactions Review of duration of travel, exposure to fresh water, ingestion of raw seafood or meat Skin lesions Systemic illnesses associated with rash (see Table 13) Assessment by character of rash (see Table 14) Diffuse Papules/linear lesions Nodules Ulcers and eschars Migratory lesions

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usually acute, self-limited, and of bacterial origin, infectious agents of persistent (>14 days) diarrhea syndromes or those that begin after return home are more likely due to a viral or parasitic pathogen. Posttravel diarrhea may be part of a systemic infection such as malaria or typhoid fever. Noninfectious causes of diarrhea include postinfectious mucosal damage, with malabsorption of fats or carbohydrates (such as lactose), antibiotic-associated colitis (Clostridium difficile), tropical sprue, and unrelated gastrointestinal (GI) diseases. Table 12 shows a selected list of infectious causes of persistent posttravel diarrhea (see Chapter 22). 3.4

Eosinophilia

An elevated eosinophil count in the traveler is classically thought to be due to invasive helminth infections (especially the larvae and adult nematodes, flukes, and tapeworms). However, eosinophilia has many nonparasitic and noninfectious causes, including preexisting rheumatological and allergic conditions (see Chapter 32, Tables 2 and 3). The travel history, duration, and timing of travel are important to determine the incubation periods of possible parasitic infection. Eosinophilia may be due to immature/ larval parasite forms, which cannot be detected in the stool until they have matured to the adult form (i.e., larval nematodes such as hookworm). Duration of travel is important since many of the infections that cause eosinophilia require extensive exposure and are unlikely to affect short-term travelers (e.g., filarial infections). Travelers should be asked about exposures to water (drinking and bathing) and ingestion of raw seafood or meat. A definitive diagnosis of an infection that is causing eosinophilia is difficult, possible in only 38% of one reported series. Regardless, most patients have a normal eosinophil count within 2–4 months. In contrast, some parasitic infections (such as Stronglyoides spp. infection) cause eosinophilia that persists for years. 3.5

Rash

Skin problems of travelers are a common reason for seeking medical advice. Often, travelrelated skin disorders are not due to infection and may represent aggravation of underlying

Table 12 Selected Infectious Agents of Diarrhea in Travelers Acute diarrhea Enterotoxigenic Escherichia coli (ETEC) Salmonella spp. Shigella spp. Campylobacter jejuni Vibrio parahaemolyticus Yersinia enterocolitica Aeromonas hydrophilia Rotavirus Norwalk virus Persistent diarrhea (>14 days) Giardia lamblia Cryptosporidium parvum Entamoeba histolytica Strongyloides stercoralis Cyclospora cayatensis

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skin conditions such as eczema or psoriasis, insect bite reactions, severe sunburns, and nonspecific dermatitis. The common diagnoses among travelers with rash include cutaneous larva migrans, pyodermas, arthropod-reactive dermatitis, myiasis, urticaria, and cutaneous leishmaniasis. Common bacterial infections of the skin such as streptococcal and staphyloccal infections are also more common in tropical climates. Rash may represent a local phenomenon or be part of a systemic illness. Evaluation of a traveler’s rash begins with a detailed travel history (Table 5) with specific emphasis on exposures and life-style issues. Duration of travel is important, since long-term residents may have different responses (e.g., rashes and level of eosinophilia), particularly to helminth infections, from those of transient visitors. Rashes are organized here by appearance: diffuse lesions, papules/linear lesions, ulcers and eschars, nodules/subcutaneous swelling, and migratory lesions (also see Chapter 32, Table 4). 3.5.1

Diffuse Rash

Many types of pathogens that cause systemic illness can be associated with diffuse rashes (see Table 13; also see Chapter 7). Since these infections represent bloodstream invasion, many require immediate attention (e.g., meningococcemia). The rickettsial infections are an important group of infections in this category, although rickettsial rashes vary by species (e.g., tache noir eschar with R. conorii infection vs. a diffuse rash with scrub typhus, R. tsutsugamushi). Dengue fever and vaccine-preventable infections such as measles and rubella can cause other diffuse erythroderma-like rashes. Skin penetration by pathogens also causes systemic rashes; these rashes in general are extremely pruritic. Cercarial dermatitis (‘‘swimmer’s itch’’), for example, is due to penetration of skin by avian or human schistosomal cercariae. Similarly, jellyfish larvae cause ‘‘sea bather’s eruption’’ in a bathing suit distribution after skin penetration.

Table 13 Selected Systemic Infections Associated with Rash Dengue fever Enteroviral infections Erlichiosis Gonococcemia Acute human immunodeficiency virus (HIV) Visceral leishmaniasis Leptospirosis Lyme disease Measles Meningococcemia Rickettsial infections Rubella Strongyloidiasis Syphilis Toxic shock syndromes Typhoid fever Varicella Viral hemorrhagic fevers

768

3.5.2

Kirkpatrick

Papules/Linear Lesions

The most common causes of papules are arthropod bites that cause allergic or local hypersensitivity reactions (see Table 14). Pruritic insect bites may persist for weeks to months after return from the tropics, particularly those from fleas or bedbugs. Many bites are exquisitely painful, including tsetse and blackfly bites. Stinging arthropods include scorpions and brown recluse spiders, both of which may cause considerable local necrosis.

Table 14 Evaluation of Rash by Lesion Type Papules/linear lesions Insect bites Scabies Body or head lice Milaria rubra (prickly heat) Filariasis (onchocerciasis) Drug reaction Candiasis Cercarial dermatitis Sea bather’s eruption Cutaneous larva migrans Nodules and subcutaneous swellings Gnathostomiasis Myiasis Tungiasis Filariasis (loa loa, onchocerciasis, W. bancrofti) Mycobacterium marinum, M. ulcerans, M. leprae Echinococcosis Dracunculiasis Ulcers and eschars Anthrax Diphtheria Leishmania Mycobacterium marinum, M. ulcerans, M. leprae Pyoderma gangrenosum Syphilis Tick eschar Yaws Chancroid Amebiasis Cysticercosis (Taenia solium) Most invasive fungal infections Paracoccidioidomycosis Migratory lesions Cutaneous larva migrans Dracunculiasis Gnathostomiasis Loa loa Strongyloides Myiasis

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Scabies, from the mite Sarcoptes scabiei, is common worldwide and is often found in linear burrows in the finger webs, wrists, and genitalia. Other linear and serpiginous lesions include cutaneous larva migrans (hookworm larvae) and larva currens (Strongyloides spp.). 3.5.3

Ulcers and Eschars

Most tropical ulcers are rare, except the shallow and painful ulcers of ecthyma. These ulcers are due to streptococcal or staphylococcal infections that occur as bacterial suprainfections of underlying insect bites or areas of traumatized skin. In contrast, the classic ‘‘tropical ulcer’’ is caused by infection with the protozoan Leishmania spp. The lesion begins as a nodule and slowly develops into the classic ‘‘heaped-up’’ painless ulcer. Since cutaneous leishmaniasis ulcers are asymptomatic and indolent, they are often ignored for a long period after travel. Diagnosis is made by biopsy and specialized culture. Rectal and genital ulcers may be due to amebiasis or sexually transmitted diseases, including chancroid, granuloma inguinale, and syphilis (see Chapters 16 and 17 regarding sexually transmitted diseases). 3.5.4

Nodules and Subcutaneous Swelling

Nodules occur after lymphatic spread of pathogens or at the site of inoculation. The differential diagnosis of these lesions is broad, and nodules/cystic lesions can occur with all invasive fungal infections and many mycobacterial and parasitic infections. Biopsy of the site is often the most efficient method of diagnosis. Subcutaneous swellings due to furuncular myiasis are common skin lesions in returning travelers and represent an embedded larva of the human botfly Dermatobia hominis. Similarly, the sand flea Tunga penetrans penetrates the skin (usually between toes) and enlarges to approximately 1 cm about 1–2 weeks after penetration (tungiasis). The nodules can be painful and characteristically have a central pore through which the larvae breathes. Both myiasis and tungiasis may be single or multiple infections and are treated by extraction of the larvae or flea. Filarial infections also cause subcutaneous swelling (loa loa) and nodules (Onchocerca spp.) but are usually found among long-term travelers or indigenous populations of endemic areas. 3.5.5

Migratory Lesions

Migratory lesions are unique to parasitic infections and are immensely disconcerting to the patient. Many represent the migration of infecting larvae in an accidental host (human). ‘‘Creeping eruption’’ or cutaneous larva migrans from canine and feline hookworm species is common among returning travelers from beach vacations in the Caribbean. This serpiginous rash is usually found on the feet or exposed skin and is extremely pruritic. Strongyloides spp. also cause a similar but broader rash that is rapidly moving (5–10 cm/hr) and is often found in the rectal area. Most patients with migratory infections have eosinophilia that indicates the immune reaction to tissue invasion.

BIBLIOGRAPHY The Centers for Disease Control. The Yellow Book, CDC Health Information for International Travel. Available at http://www.cdc.gov/travel/yellowbk/home.htm. Blue sheet updates. Available at www.cdc.gov/travel/bluesheet.htm. Malaria Hotline (404) 332-4555.

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Guerrant RL, Walker DH, Weller PF, eds. Tropical Infectious Diseases, Prinicples, Pathogens and Practice. Churchill Livingstone, 1999. Manson’s Tropical Diseases, 12th ed. W.B. Saunders, 1996. U.S. State Department. Counsular information, travel advisories. Available at http://travel.state.gov/ travel㛭warnings.html Virka A. Advice for international travelers. Mayo Clin Proc 76:831–840, 2001. Wilson ME. A World Guide to Infections. Oxford University Press, 1991.

41 The Patient Living in a Nursing Home Henry S. Sacks Mount Sinai School of Medicine, New York, New York, U.S.A.

1

INTRODUCTION

The proportion of the United States population above age 65 (currently 13% or 35 million people) is increasing rapidly and the proportion above age 85 (currently 1.6%) is increasing even more rapidly. Most elderly live in households, but the likelihood of living in a nursing home increases with age. In 1990, nearly 1.6 million of the 31 million persons aged 65 years and above (5%) lived in nursing homes. Three of four residents of nursing homes in 1990 were aged 75 or older and 7 of 10 were women. In 2000 more than an estimated 2 million people resided in nursing homes. It is expected that this number will double or triple in the next few decades. Over one-third of those above 65 years of age will spend at least some time in a nursing home. Nursing home residents tend to be frailer, to have more medical problems, and to use more medications than community-living elderly. The majority of nursing home patients are cognitively impaired and therefore less able both to manage their personal hygiene and to give a clear history when they become sick. Age-related changes that predispose to infection are summarized in Table 1. Because of these health impairments and cognitive limitations, the elderly living in the nursing home may manifest infections in unusual forms (see Table 2). Nursing homes differ from acute care facilities in both the range of diagnostic and therapeutic services they can provide and the flexibility and rapidity with which they can perform these services. Because many nursing home residents may recently have been in a hospital, they are at increased risk of becoming infected with antibiotic-resistant organisms. Because they live in close proximity with other residents, they are at increased risk of transmitting infection to other residents and may also be exposed to infections transmitted either directly or indirectly from resident to resident by nursing home staff. Therefore, outbreaks of respiratory infections, diarrheal illness, conjunctivitis, scabies, and other highly communicable problems are major concerns. It has been estimated that the average nursing home resident experiences one to three infections per year, although there is great individual variability. The elderly also have higher infection-related mortality rates than younger patients (see Table 3). Higher mortality rates are especially significant for older persons residing in long-term care facilities. They account for the most frequent reasons for transfers to acute care facilities. 771

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Sacks

Table 1 Age-Related Changes That Predispose to Infection Thinner and more fragile skin Slower wound healing Impaired cough Impaired swallowing Impaired bladder emptying Impaired humoral immunity: decreased antibody levels and function Impaired cell-mediated immunity Decreased ability to mount a febrile response

Table 2 Atypical Presentations of Infection in Older Persons Any change of temperature in either direction from baseline Any unexplained change in functional status or behavior Worsening cognition Lethargy or agitation Anorexia or change in appetite Falls Incontinence Focal neurological finding Tachypnea

Table 3 Mortality Rate of Infections in Elderly Compared to Young

Infection Pneumonia Upper urinary tract infection Sepsis Appendicitis Cholecystitis Tuberculosis Infective endocarditis Bacterial meningitis Source: Yoshikawa and Norman 1987.

Mortality rate in elderly compared to that in young 3 Times 5–10 Times 3 Times 15–20 Times 2–8 Times 10 Times 2–3 Times 3 Times

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URINARY TRACT INFECTIONS Increased incidence of asymptomatic bacteriuria occurs in male and female elderly adults. Do not treat asymptomatic bacteriuria. Asymptomatic pyuria is not an indication for treatment. All patients with indwelling urinary catheters become colonized. Asymptomatic infection should not be treated. Remove catheter if at all possible. Treat symptomatic cystitis with trimethoprim & sulfamethoxazole (TMP-SMZ), nitrofurantoin, or ciprofloxacin. Vaginal estriol cream and cranberry juice may help prevent colonization and infection in elderly women.

The most common infections, which constitute over 80% of all nursing home infections, are in three categories: Pneumonia, Urinary tract infections, and Soft tissue infections (acronym, PUS). This chapter reviews these entities in addition to herpes zoster infection, tuberculosis, and scabies among nursing home residents. 2

URINARY TRACT INFECTION

Urinary tract infection (UTI) is the most common bacterial infection in nursing home residents. However, it is frequently overdiagnosed and overtreated. 2.1

Asymptomatic Bacteriuria

Significant bacteriuria (>105 colonies/mL) without associated symptoms (fever, dysuria, frequency, or urgency) is common in elderly patients, both male (15%–30%) and female (25%–50%). Whether treatment of asymptomatic bacteriuria is of any benefit has been debated in the literature for years; there is no strong evidence that treatment is of benefit. Randomized controlled trials have shown that rates of recurrence after treatment remain high and rates of development of symptomatic infection do not differ in treated and untreated patients. The only significant differences between treated and untreated patients were higher rates of adverse drug reactions and increased antimicrobial resistance in treated patients. In patients without symptoms, a urinalysis finding negative for white blood cells or a dipstick test result negative for leukocyte esterase can help to identify those patients who do not need to be treated. Foul-smelling urine is not an indication for treatment. Patients who have significant bacteriuria and symptoms of a UTI should be treated. Bacteriuria in elderly women may be prevented with intravaginal estriol cream. One placebo-controlled trial suggested that drinking cranberry juice reduced bacteriuria among elderly women. 2.2

Diagnosis and Treatment

The diagnosis of UTI is easier to establish when patients are able to describe a history of dysuria, frequency, and urgency with or without fever and flank pain. The diagnosis is difficult to make when patients cannot give a clear history since they are likely to have a positive urine culture result. Therefore, culture is recommended only for those who have either clear symptoms or fever. Similarly, pyuria is not helpful since it can occur with

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asymptomatic bacteriuria even in the absence of bacteriuria. The absence of pyuria, however, may be helpful in excluding UTI. Ideally, treatment should be based on knowledge of the sensitivities of the infecting organism. This requires a clean-catch specimen, which may be difficult to obtain. Cultures obtained from bedpan specimens or pedibags are not reliable. Symptomatic infection may be treated (with modification depending on culture results) empirically with trimethoprim-sulfamethoxazole (TMP-SMZ) or nitrofurantoin. The newer quinolones such as ciprofloxacin are widely used but are more expensive and are more likely to lead to the emergence of resistant organisms. Duration of therapy probably should be longer than in younger patients. Seven days is recommended for cystitis, though some authorities believe a 3-day course should suffice; 10 to 14 days of therapy should be used for those with fever or flank pain. Recurrence of bacteriuria is common, so followup cultures are not recommended unless symptoms recur. 2.3

Bacteriuria in Patients with Chronic Drainage Catheters

To date, no method has been found that can reliably prevent the development of bacteriuria in patients with indwelling drainage catheters. Therefore, the first question should always be, Can the patient be managed without the catheter? Alternatives include more frequent offers of toilet or bedpan or for men external (condom) catheters. Use of silver alloy– impregnated catheters may be of some benefit at least for the short term. Well-designed studies have shown little or no benefit from instillation of antimicrobial agents into either the collection bag or the catheter. On the other hand, there is evidence that good aseptic technique and maintenance of a closed drainage system are of benefit, at least in the short term. Despite the best technique, in the majority of patients who have long-term catheterization bacteriuria, which is usually polymicrobial, eventually develops. The presence of bacteriuria, with or without pyuria, is not an indication for treatment unless the patient also has fever or hemodynamic changes. The optimal management of symptomatic infection in patients with chronic catheters is not well studied, but the following recommendations seem reasonable. In patients who develop fever, evidence of infection at other sites should be looked for. Evidence of catheter obstruction or periurethral infection should be sought. If the source of the fever is not clear and the patient’s condition is clinically stable, consider observing off antibiotics for 24–48 hours; many fevers resolve spontaneously during this time. If the patient appears ill, obtain blood and urine cultures and treat for a short period (3–7 days) with TMPSMZ, nitrofurantoin, or ciprofloxacin. The value of changing the catheter is also not clear.

3 3.1

SKIN AND SOFT TISSUE INFECTIONS Pressure Ulcers

Pressure ulcers are unfortunately common among the infirm elderly. It is estimated that 10% of elderly nursing home patients will develop a pressure sore or decubitus ulcers during a 1-year period. Lying in one position for prolonged periods leads to skin necrosis and tissue breakdown. These lesions may remain quite superficial or progress to full-skinthickness necrosis and osteomyelitis of contiguous bone. Associated infections can include cellulitis, abscess formation, fasciitis, myositis, and bacteremia. Prevention works better than treatment. Frequent repositioning of the patient and excellent nursing care cannot be overemphasized (see Table 4). The treatment of pressure sores involves many of the same

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PRESSURE ULCERS, ZOSTER, AND SCABIES Pressure ulcers Prevention (see Table 4) is more effective than treatment (see Table 5) Superficial breakdown can progress to cellulitis, abscess formation, and osteomyelitis. Aerobic and anaerobic polymicrobic bacteria are common. Culture results are difficult to interpret. Topical antibiotics are of limited efficacy. Topical antiseptics (povidine, Dakin’s solution, hydrogen peroxide) can be detrimental. Systemic antibiotics are prescribed for associated fever, abscess formation, osteomyelitis. Zoster Reactivation of dormant varicella zoster virus occurs. Painful vesicles, pustules, and erythema have a dermatomal distribution. Therapy may shorten course (see Chapter 20, Table 9) Postherpetic neuralgia Routine analgesics generally are not helpful. Topical lidocaine or capsaicin cream may help. Low-dose tricyclic antidepressants or gabapentin may be most effective. Scabies Pruritic papules and burrows occur. Fingers, flexor surfaces of wrist, axillae, and genital area are affected. Permethrin 5% cream (Elimite) is applied to the entire body (except head) overnight. Clean all linens and clothes. Itching may persist for weeks despite successful therapy.

Table 4 Prevention of Pressure Ulcers 1. Use a risk assessment tool to identify patients at risk for pressure ulcers. Modify risk factors (immobility, moisture or incontinence, and nutritional deficiencies) as possible. Reassess patients regularly. 2. Use a repositioning schedule to reposition immobile patients—at least every 2 hours for bedbound patients and every hour for chair-bound patients. Prevent positioning directly on the trochanter. Use pillows and other devices to lift heels completely off bed and prevent direct contact with bony prominences. Minimize elevation of head of bed. 3. Use a pressure-reducing seating surface (not the donut-type) for chair-bound patients and a pressure-reducing mattress or mattress overlay for at-risk patients in bed. 4. Provide skin care; inspect skin daily, cleanse regularly with a mild cleanser, use moisturizers for dry skin, and prevent massage over bony prominences. 5. For incontinent patients, cleanse skin at time of soiling and use topical moisture barrier ointment. Use underpads or briefs with a quick-drying surface against the skin. 6. Maintain adequate dietary intake of protein, calories, and fluids. Give daily multivitamin and multimineral supplement to at-risk patients. 7. Optimize activity level, mobility, and range of motion. Institute a rehabilitation program. 8. Educate patients, family, care givers, and health care providers about causes, risk factors, risk assessment, selection and use of support surfaces, skin care, positioning, and documentation. Source: Pressure Ulcers in Adults 1992.

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elements involved in prevention: repositioning, skin care, and nutrition. In addition, cleansing, bandaging, and pain relief must be provided (see Table 5). Topical antibiotics do not penetrate into wounds or surrounding tissues. They may cause local reactions and may lead to overgrowth with resistant organisms. They should be used only for short periods (up to 2 weeks). Topical antibiotics that have been shown in randomized controlled trials to be useful include gentamicin and silver sulfadiazine. However, topical antiseptics such as 1% povidone-iodine, 0.25% acetic acid, 0.5% sodium hypochlorite (Dakin’s solution), and 3% hydrogen peroxide may impair wound healing and should not be used. Pressure sore infections are polymicrobic, a mix of aerobic gram-negative rods (GNRs), anaerobes, streptococci, and staphylococci. Differentiating wound colonizers from pathogens is almost impossible. Wound swabs, even of pus, are of little value. Needle aspiration of a closed space collection or punch biopsy of infected tissue is the preferred method for determining the true bacteriology of a pressure ulcer. Alternatively, a two-step process of (1) thoroughly cleansing the wound with nonantimicrobial solution then (2) swabbing a 1-cm area of the wound base for 5 seconds with pressure sufficient to express fluid from the wound tissue may be tried. Systemic antibiotics are indicated for patients with signs of local (pus, erythema) or systemic (fever, leukocytosis) infection. Before beginning systemic antibiotic therapy obtain blood and wound cultures (as described) if possible. Antibiotics that have polymicrobic activity that may be useful for the treatment of infected ulcers include cefoxitin or cefotetan, ampicillin-sulbactam, ticarcillin-clavulanic acid, and piperacillin-tazobactam. Oral agents with combined aerobic and anaerobic activity include amoxicillin-clavulanate and the newer quinolones such as gatifloxacin, moxifloxacin, temefloxacin, grepafloxacin, and sparfloxacin. Oral antibiotics that have anaerobic activity (clindamycin or metronidazole) and aerobic GNR activity (cefixime, co-trimoxazole, ciprofloxacin) can also be used in combination. If there is no bone involvement a 10- to 14-day course should be adequate.

Table 5 Treatment of Pressure Ulcers 1. Assess ulcer(s) initially and then reassess weekly size (length, width, and depth), description of tunneling, undermining, necrotic tissue, odor, exudate, and cellulitis if present and condition of surrounding skin. 2. Relieve pressure: use a repositioning schedule and pressure-reducing support surface. 3. Assess and manage nutritional status: intake goal of 30–35 cal/kg/day, 1.25–1.50 g protein/kg/ day, and daily high-potency multivitamin, multimineral supplement. 4. Use autolytic, enzymatic, mechanical, or sharp de´bridement to remove necrotic tissue. Dry eschar on heels should be left in place unless evidence of infection is present. 5. Cleanse ulcer at each dressing change with saline solution or other nontoxic cleanser with technique that minimizes mechanical trauma to wound. 6. Select ulcer dressings that keep ulcer bed continuously moist and surrounding skin dry. 7. Bacteremia, sepsis, and cellulitis require systemic antibiotic therapy. Local infection (colonization) does not require systemic antibiotics and is more appropriately treated with topical antibiotics (not topical antiseptics). 8. For nonhealing ulcers, consider adjunctive therapy such as electrical stimulation. 9. Provide adequate pain relief. Source: Bergstrom N et al. 1994.

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777

Herpes zoster (Shingles)

The incidence of herpes zoster increases steadily with advancing age and its associated waning of immunity. In young adults, there may be only 1 or 2 cases per 1000 personyears, whereas in those above age 65, the rates may be 10 times higher. The rash typically occurs unilaterally in one or two adjacent dermatomes on the trunk, upper extremity, or face. The rash, which may or may not be preceded by pain in the same area, begins with erythema and vesicles that coalesce, form pustules, and crust over in 7 to 10 days. Pain is common and may persist for weeks or months after the skin lesions have healed. Acyclovir and its more recent family members, famciclovir and valacyclovir, have all been shown to reduce time of crusting and healing of lesions and postherpetic pain if started within 72 hours of the onset of symptoms (see Chapter 20, Table 9, for dosage and costs). The definition of postherpetic neuralgia (PHN) varies in different studies, leading to widely varying estimates from 2% to 30% of patients. PHN is more common in older patients, in those with more severe rash, and in those who had severe pain during the rash or pain before the rash appeared. Clinically, PHN may be defined as pain that lasts for more than 1 month after onset of the zoster rash. Treatment remains a frustrating problem for both patients and physicians. It is reasonable to start with aspirin and other analgesics, although both aspirin and narcotic analgesics have limited benefit. Topical lidocaine or lidocaine/prilocaine creams may be helpful. Capsaicin cream (0.025%–0.075%) has been shown to be beneficial to some patients but many cannot tolerate it. There is some suggestion that the newer drugs are more effective in reducing the incidence of postherpetic neuralgia, but there is not enough evidence for a clear recommendation of any one drug. Whether or not the addition of corticosteroids is beneficial remains unclear The tricyclic antidepressants amitriptyline and desipramine are generally considered the treatment of choice for refractory PHN. Either drug may be tried, starting with a low dose (12.5–25 mg) at bedtime and increasing the dosage at 1-week intervals until either relief is obtained or unacceptable side effects occur. Anticonvulsant drugs including phenytoin, valproate sodium, and carbamazepine have shown some benefit when added to the antidepressants. Unfortunately, the serotonin reuptake inhibitor antidepressant drugs (such as fluoxetine and paroxetin), which are better tolerated by the elderly than the tricyclics, have so far not been shown to be as useful for PHN. A recent study of gabapentin as monotherapy titrated from 900 mg/day to 3600 mg/ day showed dramatic benefit when compared to placebo and appears to be better tolerated than the tricyclics. There have been no direct comparisons with other symptomatic agents reported. Patients who do not respond to any of these measures may benefit from referral to pain specialists for nonpharmacolgical approaches such as transcutaneous electrical nerve stimulation (TENS). Acute herpes zoster is considered to be infectious until the lesions have crusted over. Those at risk are children or adults who have not had chickenpox (varicella), although over 90% of adults have antibodies to the herpes zoster/varicella virus whether or not they remember having had chickenpox. As the number of children receiving the herpes zoster/ varicella vaccine increases, it is hoped that the number of persons at risk will decrease. 3.3

Scabies

Scabies is a skin infestation with Sarcoptes scabiei that can cause outbreaks in nursing homes or other communal living facilities. The typical eruption consists of pruritic papules or vesicles and burrows where the causative mite has dug into the skin. Areas most likely

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to be affected are the webs between fingers, flexor surface of the wrist, axillae, and genital areas. In the elderly or immunosuppressed, an atypical presentation, including exfoliatve dermatitis, can occur. Therapy involves the application of a topical scabicide such as permethrin 5% cream (Elimite) or lindane on all skin from the neck down with special attention to axillae, groin, perineum, and finger and toe webs (see Chapter 20, Table 1 for dosage and costs). The cream is left on overnight. All clothing and bed clothing should be washed in very hot water. All persons sharing the patient’s room or having close contact should also be treated. Itching may persist for some time after treatment because of residual allergic reaction to the infestation. The decision whether or not to re-treat may be difficult. 4

RESPIRATORY INFECTIONS

In the elderly, as in the younger population, respiratory infections are the most common conditions for which medical attention is sought. 4.1

Influenza

Influenza occurs in annual cycles, usually in the fall and winter months, and varies greatly in its extent and severity (see Chapter 14). The illness begins abruptly with fever, myalgias, headache, runny nose, sore throat, cough, and malaise. In the elderly, chills, myalgia, sore throat, and runny nose are less common, whereas sputum production, cough, and dyspnea are more common. In more severe cases viral pneumonia or secondary bacterial pneumonia can develop. The disease is typically self-limited and usually lasts 3 to 5 days but may

PULMONARY INFECTIONS Influenza Fever, myalgia, pharyngitis, cough Can progress to viral pneumonia Can be complicated by secondary bacterial pneumonia with S. pneumoniae or S. aureus Diagnosis by rapid test of nasal swab or oropharyngeal wash treatment (see Chapter 14, Table 4) Importance of yearly influenza vaccination Pneumonia Atypical presentations without fever or cough (see Table 1) Increased risk related to feeding tubes, incontinence, recent viral infection, immobility, and stroke (see Table 2) S. pneumoniae, H. influenzae, M. catarrhalis, S. aureus, and gram-negative rods (GNRs) Can generally be treated in the nursing home; rapid initiation of therapy potentially more important than hospitalization Therapy (see Table 7) Importance of pneumococcal vaccine Tuberculosis Reactivation of dormant infection more common than acquisition of new infection Surveillance of nursing home patients (see Table 8) Purified protein derivative (PPD) testing of all new residents (see Chapter 13, Figure 2) Treatment of latent and active infection (see Table 9)

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persist for up to 2 weeks. The elderly, smokers, and those with cardiac or pulmonary disease, diabetes, or other chronic diseases are at higher risk for complications, including death. During influenza epidemics, up to 90% of the deaths attributed to pneumonia and influenza occur in those above age 65. Much of the morbidity and mortality can be prevented with influenza vaccination. As the virus is continually evolving, the vaccine must be updated and provided annually. Viral and secondary bacterial pneumonia are major concerns in the elderly. Viral pneumonia may develop early in the disease course with bloody sputum and tachypnea and may progress to respiratory failure. Secondary bacterial pneumonia may occur later in the course, often after initial improvement and defervescence. Streptococcus pneumoniae and Staphyloccus aureus are the bacterial pathogens most commonly reported. In patients with preexisting cardiac disease, influenza may cause worsening of heart failure and an increased likelihood of myocardial infarction. The diagnosis is usually made clinically on the basis of the time of year, knowledge of influenza reported in the area, and a compatible clinical picture. However, in nursing homes, where there is concern about outbreaks and the need to provide prophylaxis, laboratory information may be helpful to decision making. Three rapid (10–20 minutes) diagnostic tests for influenza A and B have recently been approved by the United States Food and Drug Administration: FLU O1A (Biostar), Quikone Influenza test (Quidel), and Zstatflu (ZymeTx). All have good specificity (93%–99%). The sensitivity of Zstatflu (57%–65%) is less than that of the other two (73%–81%). These join the already released Directigen Flu A, which detects only influenza A. All cost $15–$20. There have been no direct comparisons of the tests. A positive test result in the appropriate clinical setting can be highly predictive of influenza. A negative test finding does not rule out the diagnosis. Four drugs are currently available in the United States for the treatment and prevention of influenza. Amantadine and rimantadine block viral replication but are active only against influenza A (the most common variety). Both are highly effective in preventing illness in exposed subjects and in shortening the duration of illness if given within 48 hours of onset of symptoms. Both can cause nausea, vomiting, nervousness, anxiety, lightheadedness, and, rarely, seizures. Rimantadine may have fewer side effects. The dosage of both drugs should be reduced to 100 mg daily in the elderly. Two new drugs that act by inhibiting viral have recently been approved in the United States: Zanamivir (Relenza) and Oseltamvir (Tamiflu). They are active against both influenza A and influenza B and appear to be better tolerated than amantadine but are more expensive. Comparative trials have not yet been completed. Zanamivir is taken by inhaler twice daily; Oseltamivir 75 mg is taken orally twice daily. The treatment course is 5 days for both (see Chapter 14, Table 4, for dosage and costs). 4.2

Pneumonia

Pneumonia is much more frequent in nursing homes than in the community (see Chapter 12). It is the leading cause of death in patients living in long-term care facilities. Most of what is known about pneumonia in elderly adults is derived from studies of communityacquired pneumonia (CAP) of patients living at home rather than in nursing homes. Where important differences in nursing home–acquired pneumonia (NHAP) are clear, they will be noted. The case fatality rates of pneumonia remain around 20% in patients above age 65 and 40% in those above 85. Outbreaks of pneumococcal pneumonia have been reported in nursing homes, often in association with low rates of pneumococcal vaccination.

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It has been suggested since the days of Sir William Osler that older patients who have pneumonia may experience nonrespiratory symptoms. A large multicenter study has recently confirmed this impression. Patients older than 75 reported significantly fewer of the typical symptoms of pneumonia such as cough, dyspnea, sputum production, and hemoptysis. Pleuritic chest pain was only half as likely to be reported compared to reports by younger patients. Similarly, nonrespiratory symptoms (fatigue, fever, sweats, myalgia, inability to eat) were also less likely to be reported by elderly patients with pneumonia. Women reported fewer symptoms than men and nonsmokers reported fewer symptoms than smokers. These findings emphasize the need for a heightened level of suspicion. Predisposing factors include declining immunity; oropharyngeal colonization with potentially pathogenic bacteria, including S. aureus and GNRs; decreased clearance of respiratory secretions; chronic obstructive pulmonary disease; and recent viral respiratory infection, especially influenza. Additional risk factors for NHAP include declining immunity, urinary incontinence, tracheotomy or nasogastric feeding tube, bedbound status, and difficulty with swallowing and secretions. Unfortunately neither gastrostomy nor jejunostomy seems to reduce the risk of pneumonia. Establishing with certainty the cause of NHAP is often challenging because of difficulties in obtaining and interpreting sputum cultures. S. pneumoniae is the most frequently isolated pathogen in many studies, followed by Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and GNRs such as Klebsiella pneumoniae. Pathogens occasionally isolated included Legionella species and Chlamydia species. In many studies, over half of the cases have no specific etiological agent identified. Viruses that have been shown to cause pneumonia in nursing homes include influenza and parainfluenza viruses, respiratory syncytial virus (RSV), and adenovirus (see Table 6). Up to 50% of nursing home patients who have pneumonia are transferred to acute care hospitals. There are many factors considered in this decision including the wishes of the patient and family; the availability (or lack) of intravenous therapy, supplemental oxygen, and other treatment modalities at the nursing home; and the severity of the illness. It is worth noting that there is no evidence that transfer per se improves outcome. On the basis of the CAP studies it seems more likely that prompt initiation of therapy has a greater impact on outcome. If transfer delays the start of therapy, it can actually be counterproductive. Guidelines for treatment of CAP and hospital-acquired pneumonia have been published by several groups. There are currently no specific guidelines for NHAP. Antibiotic

Table 6 Causes of Nursing Home–Acquired Pneumonia Organism Streptococcus pneumoniae Staphylococcus aureus Gram-negative rods Legionella spp. Mycoplasma spp. Chlamydia spp. Other Viruses

Cases, % 5–39 2–33 3–50 0–6 0–1 0–6 6–20 0–10

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selection is empirical. Patients who are mildly to moderately ill may be treated with oral agents including cefaclor, amoxicillin/clavulanate, gatifloxacin, or levofloxacin. Intramuscular cefamandole or ceftriaxone can also be used. For patients who appear more ill or who have unstable vital signs (respiratory rate greater than 30/min, systolic blood pressure less than 90 mm Hg, or pulse greater than 120/min), intravenous antibiotics are recommended. Suitable choices include the newer quinolones (gatifloxacin or levofloxacin), second- or third-generation cephaloporins (cefotetan, cefuroxime, or ceftriaxone), and ␤-lactam/␤-lactamase inhibitor combinations (ampicillin/sulbactam, piperacillin/tazo-bactam). Ciprofloxacin has excellent activity against GNRs, but poor streptococcal activity and should not be used empirically because of the concern for S. pneumoniae. Aminoglycosides have limited activity in respiratory secretions and may cause greater nephrotoxicity in the elderly and should not be used to treat NHAP. TMP-SMZ has good activity against most bacteria that cause NHAP but may not have activity against penicillin-resistant pneumococci. The addition of a macrolide such as erythromycin or azithromycin to a ␤-lactam agent has been suggested for moderate to severe CAP to treat for Legionella and Chlamydia spp. Their use may be reasonable in NHAP also, although there is no clear evidence for or against their use. The newer quinolones have activity against atypical pathogens and may be used as single agents to cover both typical and atypical bacteria. Treatment options for mild to moderate infection are summarized in Table 7. Ancillary measures include supplemental oxygen, adequate hydration, pain control, and nutrition. 4.3

Tuberculosis

Tuberculosis (TB) is an uncommon cause of infection in nursing homes (see Chapter 13). However, most people who are elderly today grew up at a time and in places where tuberculosis was much more common than it is today and before antituberculosis drugs were available. Thus they may harbor asymptomatic infection that can reactivate as immunity declines. New infection can also be acquired from unrecognized cases, and outbreaks of tuberculosis in nursing homes have been reported. Rates of tuberculosis in elderly community residents are two to three times higher than in younger people. Rates in residents of long-term care facilities are higher still. Approximately 5% of the population above age 65 lives in extended care facilities, where 20% of the cases of TB occur. Recommendations for TB surveillance of nursing home patients are summarized in Table 8. All patients entering nursing homes should have baseline tuberculin skin testing; those who have negative test findings should have repeat testing in 10–14 days to detect false-negative results. The ‘‘booster phenomenon’’ is more common in elderly (see Chapter 13, Figure 2). Anergy testing is not recommended. Tuberculosis is often overlooked in the differential diagnosis of pneumonia in the nursing home patient. The presentation may be nonspecific, with less frequent occurrence of night sweats and hemoptysis and more common weight loss, cough, and weakness. Asymptomatic patients with recent skin test conversion are candidates for treatment of latent infection with a 9-month course of isoniazid (INH). Therapy for active tuberculosis in the elderly is essentially the same as for younger patients. Because of high rates of drug resistance, a four-drug regimen is recommended by the Centers for Disease Control and Prevention. The main drugs used are INH, rifampin, pyrazinamide, and ethambutol. The usual duration is 9 months (see Table 9). Many practitioners believe that since most cases in elderly adults are recurrences of infection acquired many years before, patients

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Table 7 Treatment of Mild to Moderate Nursing Home–Acquired Pneumonia Medication Oral antibiotics Azithromycin Cefuroxime axetil Amoxicillinclavulanate Levofloxacin Moxifloxacin Gatifloxacin Doxycycline Erythromycin Intramuscular antibiotics Ceftriaxone Cefotetan Intravenous antibiotics Cefuroxime Ampicillin-sulbactam Levofloxacin Gatifloxacin Piperacillin-tazobactam Ticarcillin-clavulanate

Dosage a

Costb

500 mg On day 1 then 250 mg once daily on days 2–5 c 250–500 mg bid 500 mg tid 500 mg/day 400 mg/day 400 mg/day 100 mg/day 250–500 mg qid d

$39

500 mg–1 g/day 1 g q12h

$250–$450 $290

750 mg q8h 1.5 g q8h 500 mg/day 400 mg/day 3.375 g q6h 3.1 g q6h

$282 $204 $390 $380 $660 $616

$81–$148 $106 $85 $87 $70 $24 $10–$20

a

Assuming normal renal function. Average wholesale price for a 10-day course of antibiotics. c Equivalent to a 10-day course. d Other preparations of erythromycin can be found in Chapter 3, Table 8. b

are unlikely to harbor resistant mycobacteria and therefore can be treated with a two- or three-drug regimen. Patients being treated for active TB should have monthly sputum samples collected for acid-fast bacillus (AFB) smear and culture. It is important to try to establish whether the patient was ever treated in the past for tuberculosis and with which drugs since retreatment should generally employ at least two new drugs. The risk of isoniazid hepatitis increases with age. Although it usually occurs within the first few weeks of treatment, it may occur at any time. Therefore, monitoring for signs and symptoms of INH toxicity (anorexia, nausea, vomiting, jaundice) should continue

Table 8 Surveillance of Tuberculosis in Nursing Home Patients All new residents should have two-step tuberculin testing. Repeat in 7–10 days if the first test result is negative (see Chapter 13, Figure 2). Chest radiography for all positive reactors. Annually retest all nonreactors (or retest whenever a case of active disease is diagnosed). Recent converters (an increase of >10 mm in duration) should receive therapy for latent infection. Anergy testing is not recommended.

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Table 9 Treatment for Tuberculosis Treatment for latent infection Isoniazida Treatment for active disease Isoniazid a Rifampin Pyrazinamide Ethambutal a

300 mg/day 300 mg/day 600 mg/day 25 mg/kg/day in two to three divided doses 25 mg/kg/day

Also use pyridoxine 25 mg/day.

throughout treatment. Most authorities do not recommend routine monitoring of liver enzymes because mild (less than five times the upper limit of normal) asymptomatic elevations are relatively common and are not a reason for changing therapy. If patients do not tolerate the first-line regimen, a pulmonary or infectious disease consultant may help in designing alternative regimens. 5 5.1

OTHER INFECTIONS IN THE ELDERLY Central Nervous System Infections

Alterations in consciousness may occur with any serious illness. Conversely, the classic presentation of bacterial meningitis including high fever, headache, and neck stiffness may be absent in the elderly. Time of year is important in determining the potential cause of meningitis. Viral meningitis from enteroviruses is more common in late summer and fall. Bacterial meningitis is more common in winter and early spring. It is most often caused by Streptococcus pneumoniae, Listeria monocytogenes, and less commonly aerobic organisms. Organisms that are more commonly seen in the elderly include Mycobacterium tuberculosis and Cryptococcus neoformans. Signs and symptoms of bacterial meningitis in elderly adults may be less prominent than in younger patients though cerebrospinal fluid (CSF) analysis findings are similar. The elderly confused patient with a stiff neck should be assumed to have meningitis until proved otherwise. Because of the concern of L. monocytogenes, the initial empirical antibiotics should include ampicillin (2 g q4h) in addition to ceftriaxone (2 g q12h). If penicillin-resistant pneumococcal infection is a possibility, vancomycin (15 mg/kg q12h) should be added. Arbovirus encephalitis is more common in late spring, summer, or early fall. St. Louis encephalitis (StLE) was first described in the 1930s and has occurred in both rural and urban areas all across the country. It is transmitted among wild birds by mosquitoes and is occasionally transmitted to humans. Whereas the infection may be asymptomatic in young adults, in the elderly adult symptomatic disease is more common, with altered mental status, fever, and a lymphocytic pleocytosis in the spinal fluid. West Nile virus (WNV) was unknown in the United States before the summer of 1999, when an outbreak was identified in New York City. The clinical manifestations were similar to those of StLE though some patients had a characteristic progressive paralysis. Seven fatalities were reported in New York City. The virus has been found in birds and/or mosquitoes in many parts of the Northeast and may have become more widespread. Treatment is primarily supportive although laboratory studies suggest a possible role for the antiviral drug ribavirin. If either StLE or WNV infection is suspected, blood and/or CSF specimens should be obtained and the local health department consulted urgently.

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Encephalitis due to herpes simplex type 1 (HSV-1) is the most common sporadic encephalitis. There are no seasonal peaks. There is a biphasic age distribution with the second peak in persons above 50 years. In this older population the encephalitis is most likely a reactivation of dormant HSV-1 infection. Patients have fever, altered mental status, focal neurological deficits, or seizures. Magnetic resonance imaging (MRI) scans show abnormalities characteristically in the temporal, parietal, and/or frontal lobes. The CSF shows a nonspecific lymphocytic pleocytosis. The diagnosis can be confirmed by demonstration of viral deoxyribonucleic acid (DNA) in the spinal fluid by polymerase chain reaction. It is the only potentially treatable viral encephalitis. Therapy with high-dose intravenous acyclovir (10 mg/kg q8h) may improve prognosis. Noninfectious causes of altered mental states should be considered for the confused elderly patient including stroke, systemic lupus erythematosus, sarcoidosis, vasculitis, and drugs. 5.2

Methicillin-Resistant Staphyloccus aureus in the Nursing Home

Methicillin-resistant S. aureus (MRSA) is well known to be a frequent cause of serious infection in hospitalized patients. The elderly are at greater risk of colonization and infection. The impact of MRSA on nursing home residents is less clear. MRSA colonization appears to be quite variable, having been found in from 50% in different surveys. Infection caused by MRSA has been documented much less frequently; it can cause skin and soft tissue infection, urinary tract infection, pneumonia, and septicemia. Treatment has been with intravenous vancomycin. Recently, two new agents have been approved for use—intravenous quinupristin; dalfopristin (Synercid), a streptogramin, and linezolid (Zyvox), an oxazolidinone—which can be taken either intravenously or orally (see Table 10). It is important but not always easy to distinguish colonization with MRSA from infection. Agents used to attempt eradication of colonization have included combinations of rifampin and either ciprofloxacin or trimethoprim-sulfamethoxazole. Intranasal 2% mupirocin cream has had success in eliminating nasal MRSA carriage. Relapse of colonization and bacterial resistance remain significant problems. Attempts to eradicate MRSA colonization are unlikely to be successful. Therefore, screening or surveillance cultures are generally not recommended; nor is elaborate environmental decontamination. The importance of regular hand washing after contact with patients who have MRSA cannot be overemphasized. 5.3

Malignant External Otitis

Malignant external otitis (MEO) is an infection of the external ear canal that invades the mastoid or temporal bones or base of the skull and adjacent tissues including cranial nerves. It is caused most commonly by Pseudomonas aeruginosa but can be caused by other bacteria, including staphylococci, and fungi, including Candida and Aspergillus species. It is called malignant because of the high mortality rate of invasive and subsequent central nervous system infection. MEO must be considered when patients do not rapidly respond to treatment of ear complaints. MEO occurs mostly in elderly diabetics. Ear pain is the most common symptom. It is typically severe and unrelenting. Purulent discharge is also usually present. Examination of the ear canal may show variable amounts of discharge, sometimes greenish, and the presence of granulation tissue. Swelling or erythema outside the ear canal should raise suspicion that the problem is more than superficial external otitis. Cranial nerve involve-

The Patient Living in a Nursing Home

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Table 10 Treatment of Methicillin-Resistant Staphylococcus aureus Dosage a

Toxicity

Vancomycin

15 mg/kg IV q12h; Adjust for decreased renal function

Quinupristin; dalfopristin (Synercid)

5–7.5 mg/kg IV q8h

Linezolid (Zyvox)

600 mg PO or IV q12h g

Fever Phlebitis Redman syndrome c Auditory nerve damage Nephrotoxicity d Myalgia, arthralgia Phlebitis Nausea, vomiting Diarrhea Hypertension f Leukopenia Liver biochemical abnormalities Tongue discoloration

Drug

Cost for 10 days of therapy b $550

$4830 e

$800 $1440 (IV)

a

Assuming normal renal function. Average wholesale price. c Tingling, flushing, and redness of head, neck, and chest. d Now relatively uncommon. e For a 70-kg person. f Linezolid has monoamine oxidase inhibitory properties. It can raise blood pressure with certain drugs and tyramine-containing foods (see Chapter 3). g No adjustment for abnormal renal function is needed. b

ment, especially facial nerve weakness and involvement of nerves IX, X, and XII, should raise the possibility of MEO and be an indication for cranial imaging. Routine skull films or mastoid series may show bony involvement. Computed tomography (CT) is superior for evaluating the extent of bone involvement. MRI may give a better picture of soft tissue involvement. The erythrocyte sedimentation rate is typically elevated but is very nonspecific. Intravenous administration of an antipseudomonal antibiotic such as ceftazadime, cefepime, piperacillin, or ciprofloxacin should be started. Further therapy should be guided by culture results. Therapy should continue for 6 to 8 weeks. If the condition is improving, changing to oral ciprofloxacin can be considered. Surgical de´bridement of involved areas may be a useful adjunct. BIBLIOGRAPHY Ahronheim JC. Handbook of Prescribing Medications for Geriatric Patients. Boston: Little, Brown, 1992. Bentley DW, Bradley S, High K, et al. Practice guidelines for evaluation of fever and infection in long-term care facilities. Clin Infect Dis 31:640–653, 2000. Bergstrom N, Bennett MA, Carlson CE, et al. Treatment of pressure ulcers. Clinical Practice Guideline No. 15. AHCPR Publication No. 95-0652. Rockville, MD, U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, 1994. Dutt AK, Stead WW. Tuberculosis in the elderly. Med Clin North Am 77:1353–1368, 1993.

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Gleckman RA, Ganz NM, eds. Infection in the Elderly. Boston: Little, Brown, 1983. Metlay JP, Schulz R, Li Y, et al. Influence of age on symptoms at presentation in patients with community-acquired pneumonia. Arch Intern Med 157:1453–1459, 1997. Muder RR. Pneumonia in residents of long-term care facilities: Epidemiology, etiology, management and prevention. Am J Med 105:319–330, 1998. Nicolle LE. Urinary tract infection in long-term-care facility residents. Clin Infect Dis 31:757–761, 2000. Pressure ulcers in adults: Prediction and prevention. Clinical Practice Guideline No. 3. AHCPR Publication No. 92-0047. Rockville, MD, U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, 1992. Yoshikawa TT, Dean NC, eds. Infectious Disease in the Aging: A Clinical Handbook. Totowa, NJ: Humana Press, 2000. Yoshikawa TT, Norman DC, eds. Aging and Clinical Practice: Infectious Diseases: Diagnosis and Treatment. New York: Igaku-Shoin Medical, 1987, p 6.

42 Postexposure Prophylaxis Judith L. Steinberg Boston University, Boston, and Neponset Health Center, Dorchester, Massachusetts, U.S.A.

1

INTRODUCTION

The primary care physician may be called on to manage the care of health care workers or patients who have been exposed to potentially infectious blood and body fluids. Each incident needs to be analyzed individually as to the type of exposure, the history and risk factors of the source, and the medical history of the exposed. In the process, an assessment of risk is made. Exposures to blood and body fluids present risks for transmission of human immunodeficiency virus (HIV) as well as hepatitis B and C viruses. Thus, exposure episodes must be managed in a way that addresses each of these pathogens. When caring for patients who have sustained an occupational or nonoccupational exposure, it is important to utilize a clearly outlined exposure protocol for the following reasons: (1) comprehensive management must address all three viruses, each with its own set of guidelines; (2) an exposure episode is a stressful event for all involved that can lead to errors and confusion if a protocol is not followed; and (3) there may be potential legal issues. In addition to the administration of postexposure prophylaxis (PEP), such a protocol must include the counseling, support, and follow-up of exposed individuals. 2 2.1

HUMAN IMMUNODEFICIENCY VIRUS EXPOSURE Occupational Exposure

Occupational exposures to HIV-infected blood and body fluids in which PEP should be considered include percutaneous injury, contact with mucous membrane or nonintact skin with blood, tissue, or other potentially infectious body fluids; the latter include semen and vaginal secretions or other body fluids contaminated with visible blood. Cerebrospinal, synovial, pleural, peritoneal, pericardial, and amniotic fluids should also be considered potentially infectious, although they pose an undetermined risk of transmission. Exposures to saliva, tears, sweat, breast milk, nasal secretions, sputum, vomitus, urine, or feces are not considered risks for HIV transmission when visible blood is not apparent in these fluids. Any direct contact with concentrated HIV from a laboratory setting is considered a significant exposure. Through prospective studies, the average risk of HIV transmission after percutaneous exposure to HIV-infected blood has been estimated to be 0.3%. After mucous membrane 787

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Steinberg

HUMAN IMMUNODEFICIENCY VIRUS POSTEXPOSURE PROPHYLAXIS Approach (see Figure 1) Risk of transmission dependent on type of exposure Occupational exposure Baseline human immunodeficiency virus (HIV) test Expert consultation suggested Determination of need for postexposure prophylaxis (PEP) Assessment of type of exposure (see Tables 1 and 2) Determination of HIV status of source (see Tables 1 and 2) PEP recommendations: dual or triple therapy; dual therapy warranted for most exposures Often not needed If PEP used Begin as soon as possible (ASAP) (