Harrison's Infectious Diseases

HARRISON’S Infectious Diseases Derived from Harrison’s Principles of Internal Medicine, 17th Edition Editors ANTHONY...

Author: Dennis Kasper | Anthony Fauci

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HARRISON’S Infectious Diseases

Derived from Harrison’s Principles of Internal Medicine, 17th Edition

Editors ANTHONY S. FAUCI, MD

EUGENE BRAUNWALD, MD

Chief, Laboratory of Immunoregulation; Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda

DENNIS L. KASPER,

Distinguished Hersey Professor of Medicine, Harvard Medical School; Chairman,TIMI Study Group, Brigham and Women’s Hospital, Boston

STEPHEN L. HAUSER, MD

MD

William Ellery Channing Professor of Medicine, Professor of Microbiology and Molecular Genetics, Harvard Medical School; Director, Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Boston

Robert A. Fishman Distinguished Professor and Chairman, Department of Neurology, University of California, San Francisco

J. LARRY JAMESON, MD, PhD

DAN L. LONGO, MD Scientific Director, National Institute on Aging, National Institutes of Health, Bethesda and Baltimore

JOSEPH LOSCALZO,

Professor of Medicine; Vice President for Medical Affairs and Lewis Landsberg Dean, Northwestern University Feinberg School of Medicine, Chicago

MD, PhD

Hersey Professor of the Theory and Practice of Medicine, Harvard Medical School; Chairman, Department of Medicine; Physician-in-Chief, Brigham and Women’s Hospital, Boston

HARRISON’S Infectious Diseases Editors

Dennis L. Kasper, MD William Ellery Channing Professor of Medicine, Professor of Microbiology and Molecular Genetics, Harvard Medical School; Director, Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Boston

Anthony S. Fauci, MD Chief, Laboratory of Immunoregulation; Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda

New York Chicago San Francisco Lisbon London Madrid Mexico City Milan New Delhi San Juan Seoul Singapore Sydney Toronto

Copyright © 2010 by The McGraw-Hill Companies, Inc. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher. ISBN: 978-0-07-170294-2 MHID: 0-07-170294-6 The material in this eBook also appears in the print version of this title: ISBN: 978-0-07-170293-5, MHID: 0-07-170293-8. All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the trademark. Where such designations appear in this book, they have been printed with initial caps. McGraw-Hill eBooks are available at special quantity discounts to use as premiums and sales promotions, or for use in corporate training programs. To contact a representative please e-mail us at [email protected]. This book was set in Bembo by Glyph International.The editors were James F. Shanahan and Kim J. Davis. The production supervisor was Catherine H. Saggese. Project management was provided by Arushi Chawla of Glyph International.The cover design was by Thomas DePierro. Cover, section, and chapter opener illustrations © MedicalRF.com. All rights reserved. TERMS OF USE This is a copyrighted work and The McGraw-Hill Companies, Inc. (“McGrawHill”) and its licensors reserve all rights in and to the work. Use of this work is subject to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate, sell, publish or sublicense the work or any part of it without McGraw-Hill’s prior consent. You may use the work for your own noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the work may be terminated if you fail to comply with these terms. THE WORK IS PROVIDED “AS IS.” McGRAW-HILL AND ITS LICENSORS MAKE NO GUARANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its operation will be uninterrupted or error free. Neither McGraw-Hill nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill and/ or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise.

CONTENTS Contributors . . . . . . . . . . . . . . . . . . . . . . . . xi

14 Approach to the Acutely Ill Infected Febrile Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 Tamar F. Barlam, Dennis L. Kasper

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii

15 Severe Sepsis and Septic Shock . . . . . . . . . . . 162 Robert S. Munford

SECTION I

INTRODUCTION TO INFECTIOUS DISEASES

SECTION III

1 Introduction to Infectious Diseases: Host-Pathogen Interactions. . . . . . . . . . . . . . . . 2 Lawrence C. Madoff, Dennis L. Kasper

INFECTIONS IN ORGAN SYSTEMS 16 Pharyngitis, Sinusitis, Otitis, and Other Upper Respiratory Tract Infections . . . . . . . . 174 Michael A. Rubin, Ralph Gonzales, Merle A. Sande

2 Molecular Mechanisms of Microbial Pathogenesis. . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Gerald B. Pier

17 Pneumonia. . . . . . . . . . . . . . . . . . . . . . . . . . 188 Lionel A. Mandell, Richard Wunderink

3 Immunization Principles and Vaccine Use . . . . 20 Gerald T. Keusch, Kenneth J. Bart, Mark Miller

18 Bronchiectasis and Lung Abscess . . . . . . . . . . 202 Gregory Tino, Steven E.Weinberger

4 Health Advice for International Travel . . . . . . . 43 Jay S. Keystone, Phyllis E. Kozarsky

19 Infective Endocarditis . . . . . . . . . . . . . . . . . . 206 Adolf W. Karchmer

5 Laboratory Diagnosis of Infectious Diseases . . . 54 Alexander J. McAdam,Andrew B. Onderdonk

20 Pericardial Disease . . . . . . . . . . . . . . . . . . . . 220 Eugene Braunwald

6 Microbial Bioterrorism . . . . . . . . . . . . . . . . . . 66 H. Clifford Lane,Anthony S. Fauci SECTION II

21 Infections of the Skin, Muscle, and Soft Tissues. . . . . . . . . . . . . . . . . . . . . . . . . . 230 Dennis L. Stevens

FEVER AND APPROACH TO THE FEBRILE PATIENT

22 Osteomyelitis . . . . . . . . . . . . . . . . . . . . . . . . 237 Jeffrey Parsonnet

7 Fever and Hyperthermia . . . . . . . . . . . . . . . . . 82 Charles A. Dinarello, Reuven Porat

23 Infectious Arthritis . . . . . . . . . . . . . . . . . . . . 244 Lawrence C. Madoff

8 Fever and Rash . . . . . . . . . . . . . . . . . . . . . . . 87 Elaine T. Kaye, Kenneth M. Kaye

24 Intraabdominal Infections and Abscesses. . . . . 252 Miriam J. Baron, Dennis L. Kasper

9 Fever of Unknown Origin . . . . . . . . . . . . . . 100 Jeffrey A. Gelfand, Michael V. Callahan

25 Acute Infectious Diarrheal Diseases and Bacterial Food Poisoning . . . . . . . . . . . . . . . 260 Joan R. Butterton, Stephen B. Calderwood

10 Atlas of Rashes Associated with Fever . . . . . . 108 Kenneth M. Kaye, Elaine T. Kaye

26 Acute Appendicitis and Peritonitis . . . . . . . . . 268 Susan L. Gearhart,William Silen

11 Infections in Patients with Cancer . . . . . . . . . 118 Robert Finberg

27 Urinary Tract Infections, Pyelonephritis, and Prostatitis . . . . . . . . . . . . . . . . . . . . . . . . 272 Walter E. Stamm

12 Infections in Transplant Recipients. . . . . . . . . 130 Robert Finberg, Joyce Fingeroth

28 Sexually Transmitted Infections: Overview and Clinical Approach . . . . . . . . . . . . . . . . . . . . . 283 King K. Holmes

13 Health Care–Associated Infections. . . . . . . . . 144 Robert A.Weinstein

v

vi

Contents

29 Meningitis, Encephalitis, Brain Abscess, and Empyema . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 Karen L. Roos, Kenneth L.Tyler 30 Chronic and Recurrent Meningitis . . . . . . . . 333 Walter J. Koroshetz, Morton N. Swartz

Part 3 Diseases Caused by Gram-Negative Bacteria 44 Meningococcal Infections . . . . . . . . . . . . . . . 450 Lee M.Wetzler 45 Gonococcal Infections . . . . . . . . . . . . . . . . . 459 Sanjay Ram, Peter A. Rice

31 Chronic Fatigue Syndrome . . . . . . . . . . . . . . 341 Stephen E. Straus

46 Moraxella Infections. . . . . . . . . . . . . . . . . . . . 469 Daniel M. Musher

32 Infectious Complications of Burns and Bites . . . 343 Lawrence C. Madoff, Florencia Pereyra

47 Haemophilus Infections . . . . . . . . . . . . . . . . . 472 Timothy F. Murphy

SECTION IV

BACTERIAL INFECTIONS Part 1 Approach to Therapy for Bacterial Diseases 33 Treatment and Prophylaxis of Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . 354 Gordon L.Archer, Ronald E. Polk Part 2 Diseases Caused by Gram-Positive Bacteria 34 Pneumococcal Infections . . . . . . . . . . . . . . . 374 Daniel M. Musher 35 Staphylococcal Infections . . . . . . . . . . . . . . . 386 Franklin D. Lowy 36 Streptococcal and Enterococcal Infections . . . 399 Michael R.Wessels 37 Acute Rheumatic Fever . . . . . . . . . . . . . . . . 412 Jonathan R. Carapetis 38 Diphtheria and Other Infections Caused by Corynebacteria and Related Species . . . . . . . 418 William R. Bishai, John R. Murphy 39 Infections Caused by Listeria Monocytogenes. . . 426 Elizabeth L. Hohmann, Daniel A. Portnoy 40 Tetanus . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429 Elias Abrutyn 41 Botulism . . . . . . . . . . . . . . . . . . . . . . . . . . . 434 Elias Abrutyn 42 Gas Gangrene and Other Clostridial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . 438 Dennis L. Kasper, Lawrence C. Madoff 43 Clostridium Difficile–Associated Disease, Including Pseudomembranous Colitis . . . . . . 445 Dale N. Gerding, Stuart Johnson

48 Infections Due to the HACEK Group and Miscellaneous Gram-Negative Bacteria . . . . . 477 Tamar F. Barlam, Dennis L. Kasper 49 Legionella Infection . . . . . . . . . . . . . . . . . . . . 481 Miguel Sabria,Victor L.Yu 50 Pertussis and Other Bordetella Infections . . . . . 487 Scott A. Halperin 51 Diseases Caused by Gram-Negative Enteric Bacilli . . . . . . . . . . . . . . . . . . . . . . . 493 Thomas A. Russo, James R. Johnson 52 Helicobacter Pylori Infections . . . . . . . . . . . . . . 506 John C.Atherton, Martin J. Blaser 53 Infections Due to Pseudomonas Species and Related Organisms . . . . . . . . . . . . . . . . . 512 Reuben Ramphal 54 Salmonellosis . . . . . . . . . . . . . . . . . . . . . . . . 521 David A. Pegues, Samuel I. Miller 55 Shigellosis . . . . . . . . . . . . . . . . . . . . . . . . . . 530 Philippe Sansonetti, Jean Bergounioux 56 Infections Due to Campylobacter and Related Species . . . . . . . . . . . . . . . . . . . . . . 536 Martin J. Blaser 57 Cholera and Other Vibrioses . . . . . . . . . . . . . 540 Matthew K.Waldor, Gerald T. Keusch 58 Brucellosis . . . . . . . . . . . . . . . . . . . . . . . . . . 547 Michael J. Corbel, Nicholas J. Beeching 59 Tularemia . . . . . . . . . . . . . . . . . . . . . . . . . . . 552 Richard F. Jacobs, Gordon E. Schutze 60 Plague and Other Yersinia Infections . . . . . . . 558 David T. Dennis, Grant L. Campbell 61 Bartonella Infections, Including Cat-Scratch Disease . . . . . . . . . . . . . . . . . . . 569 David H. Spach, Emily Darby

Contents 62 Donovanosis. . . . . . . . . . . . . . . . . . . . . . . . . 574 Gavin Hart Part 4 Miscellaneous Bacterial Infections

vii SECTION V

VIRAL INFECTIONS Part 1 Viral Diseases: General Considerations

63 Nocardiosis . . . . . . . . . . . . . . . . . . . . . . . . . 576 Gregory A. Filice

78 Medical Virology . . . . . . . . . . . . . . . . . . . . . 706 Fred Wang, Elliott Kieff

64 Actinomycosis . . . . . . . . . . . . . . . . . . . . . . . 581 Thomas A. Russo

79 Antiviral Chemotherapy, Excluding Antiretroviral Drugs . . . . . . . . . . . . . . . . . . . 717 Lindsey R. Baden, Raphael Dolin

65 Infections Due to Mixed Anaerobic Organisms . . . . . . . . . . . . . . . . . . . . . . . . . . 586 Dennis L. Kasper, Ronit Cohen-Poradosu Part 5 Mycobacterial Diseases

Part 2 Infections Due to DNA Viruses 80 Herpes Simplex Viruses. . . . . . . . . . . . . . . . . 730 Lawrence Corey

66 Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . 596 Mario C. Raviglione, Richard J. O’Brien

81 Varicella-Zoster Virus Infections . . . . . . . . . . 740 Richard J.Whitley

67 Leprosy (Hansen’s Disease) . . . . . . . . . . . . . . 617 Robert H. Gelber

82 Epstein-Barr Virus Infections, Including Infectious Mononucleosis . . . . . . . . . . . . . . . 745 Jeffrey I. Cohen

68 Nontuberculous Mycobacteria . . . . . . . . . . . 627 C. Fordham von Reyn 69 Antimycobacterial Agents . . . . . . . . . . . . . . . 635 Richard J.Wallace, Jr., David E. Griffith Part 6 Spirochetal Diseases 70 Syphilis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 644 Sheila A. Lukehart 71 Endemic Treponematoses . . . . . . . . . . . . . . . 656 Sheila A. Lukehart 72 Leptospirosis. . . . . . . . . . . . . . . . . . . . . . . . . 660 Peter Speelman, Rudy Hartskeerl 73 Relapsing Fever . . . . . . . . . . . . . . . . . . . . . . 665 David T. Dennis 74 Lyme Borreliosis. . . . . . . . . . . . . . . . . . . . . . 670 Allen C. Steere Part 7 Diseases Caused by Rickettsiae, Mycoplasmas, and Chlamydiae 75 Rickettsial Diseases . . . . . . . . . . . . . . . . . . . . 676 David H.Walker, J. Stephen Dumler, Thomas Marrie 76 Infections Due to Mycoplasmas . . . . . . . . . . . 688 William M. McCormack 77 Chlamydial Infections . . . . . . . . . . . . . . . . . . 692 Walter E. Stamm

83 Cytomegalovirus and Human Herpesvirus Types 6, 7, and 8. . . . . . . . . . . . . 751 Martin S. Hirsch 84 Molluscum Contagiosum, Monkeypox, and Other Poxviruses, Excluding Smallpox Virus . . . . . . . . . . . . . . . . . . . . . . . 757 Fred Wang 85 Parvovirus Infections. . . . . . . . . . . . . . . . . . . 759 Kevin E. Brown 86 Human Papillomavirus Infections . . . . . . . . . 762 Richard C. Reichman Part 3 Infections Due to DNA and RNA Respiratory Viruses 87 Common Viral Respiratory Infections and Severe Acute Respiratory Syndrome (SARS) . . . . . . 766 Raphael Dolin 88 Influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . 776 Raphael Dolin Part 4 Infections Due to Human Immunodeficiency Virus and Other Human Retroviruses 89 The Human Retroviruses . . . . . . . . . . . . . . . 785 Dan L. Longo, Anthony S. Fauci 90 Human Immunodeficiency Virus Disease: AIDS and Related Disorders . . . . . . . . . . . . . 792 Anthony S. Fauci, H. Clifford Lane

viii

Contents

Part 5 Infections Due to RNA Viruses 91 Viral Gastroenteritis . . . . . . . . . . . . . . . . . . . 887 Umesh D. Parashar, Roger I. Glass 92 Acute Viral Hepatitis . . . . . . . . . . . . . . . . . . . 893 Jules L. Dienstag 93 Chronic Hepatitis . . . . . . . . . . . . . . . . . . . . . 917 Jules L. Dienstag 94 Enteroviruses and Reoviruses . . . . . . . . . . . . 939 Jeffrey I. Cohen 95 Measles (Rubeola) . . . . . . . . . . . . . . . . . . . . 947 Anne Gershon 96 Rubella (German Measles) . . . . . . . . . . . . . . 952 Anne Gershon 97 Mumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . 956 Anne Gershon 98 Rabies and Other Rhabdovirus Infections . . . 959 Alan C. Jackson, Eric C. Johannsen 99 Infections Caused by Arthropod- and Rodent-Borne Viruses . . . . . . . . . . . . . . . . . 965 Clarence J. Peters 100 Ebola and Marburg Viruses . . . . . . . . . . . . . . 985 Clarence J. Peters SECTION VI

PRION DISEASES 101 Prion Diseases . . . . . . . . . . . . . . . . . . . . . . . 990 Stanley B. Prusiner, Bruce L. Miller SECTION VII

FUNGAL AND ALGAL INFECTIONS 102 Diagnosis and Treatment of Fungal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . 1000 John E. Edwards, Jr. 103 Histoplasmosis . . . . . . . . . . . . . . . . . . . . . . 1003 Chadi A. Hage, L. Joseph Wheat

107 Candidiasis . . . . . . . . . . . . . . . . . . . . . . . . . 1017 John E. Edwards, Jr. 108 Aspergillosis . . . . . . . . . . . . . . . . . . . . . . . . 1021 David W. Denning 109 Mucormycosis . . . . . . . . . . . . . . . . . . . . . . 1028 Alan M. Sugar 110 Miscellaneous Mycoses and Algal Infections . . . 1031 Stanley W. Chapman, Donna C. Sullivan 111 Pneumocystis Infection . . . . . . . . . . . . . . . . . 1037 A. George Smulian, Peter D.Walzer

SECTION VIII

PROTOZOAL AND HELMINTHIC INFECTIONS Part 1 Parasitic Infections: General Considerations 112 Laboratory Diagnosis of Parasitic Infections . . . . . . . . . . . . . . . . . . . . . . . . . . 1042 Sharon L. Reed, Charles E. Davis 113 Agents Used to Treat Parasitic Infections . . . . . . . . . . . . . . . . . . . . . . . . . . 1050 Thomas A. Moore 114 Pharmacology of Agents Used to Treat Parasitic Infections . . . . . . . . . . . . . 1059 Thomas A. Moore Part 2 Protozoal Infections 115 Amebiasis and Infection With Free-Living Amebas . . . . . . . . . . . . . . . . . . 1070 Sharon L. Reed 116 Malaria. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1077 Nicholas J.White, Joel G. Breman 117 Babesiosis . . . . . . . . . . . . . . . . . . . . . . . . . . 1097 Jeffrey A. Gelfand, Edouard Vannier

104 Coccidioidomycosis . . . . . . . . . . . . . . . . . . 1007 Neil M.Ampel

118 Atlas of Blood Smears of Malaria and Babesiosis. . . . . . . . . . . . . . . . . . . . . . . 1100 Nicholas J.White, Joel G. Breman

105 Blastomycosis . . . . . . . . . . . . . . . . . . . . . . . 1011 Stanley W. Chapman, Donna C. Sullivan

119 Leishmaniasis . . . . . . . . . . . . . . . . . . . . . . . 1104 Barbara L. Herwaldt

106 Cryptococcosis . . . . . . . . . . . . . . . . . . . . . . 1013 Arturo Casadevall

120 Trypanosomiasis . . . . . . . . . . . . . . . . . . . . . 1111 Louis V. Kirchhoff

Contents 121 Toxoplasma Infections . . . . . . . . . . . . . . . . . 1118 Lloyd H. Kasper 122 Protozoal Intestinal Infections and Trichomoniasis . . . . . . . . . . . . . . . . . . . 1127 Peter F.Weller Part 3 Helminthic Infections 123 Trichinella and Other Tissue Nematodes . . . . 1133 Peter F.Weller

ix

126 Schistosomiasis and Other Trematode Infections . . . . . . . . . . . . . . . . . 1154 Adel A.F. Mahmoud 127 Cestodes. . . . . . . . . . . . . . . . . . . . . . . . . . . 1163 A. Clinton White, Jr., Peter F.Weller Appendix Laboratory Values of Clinical Importance . . . . 1173 Alexander Kratz, Michael A. Pesce, Daniel J. Fink

124 Intestinal Nematodes . . . . . . . . . . . . . . . . . 1139 Peter F.Weller,Thomas B. Nutman

Review and Self-Assessment . . . . . . . . . . . . . . 1195 Charles Wiener, Gerald Bloomfield, Cynthia D. Brown, Joshua Schiffer,Adam Spivak

125 Filarial and Related Infections . . . . . . . . . . . 1145 Thomas B. Nutman, Peter F.Weller

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1231

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CONTRIBUTORS Numbers in brackets refer to the chapter(s) written or co-written by the contributor. EUGENE BRAUNWALD, MD, MA (Hon), ScD (Hon) Distinguished Hersey Professor of Medicine, Harvard Medical School; Chairman,TIMI Study Group, Brigham and Women’s Hospital, Boston [20]

ELIAS ABRUTYN, MD† Professor of Medicine and Public Health, Drexel University College of Medicine, Philadelphia [40, 41] NEIL M. AMPEL, MD Professor of Medicine, University of Arizona; Staff Physician, SAVAHCS,Tucson [104]

JOEL G. BREMAN, MD, DTPH Senior Scientific Advisor, Fogarty International Center, National Institutes of Health, Bethesda [116, 118]

GORDON L. ARCHER, MD Professor of Medicine and Microbiology/Immunology;Associate Dean for Research, School of Medicine,Virginia Commonwealth University, Richmond [33]

CYNTHIA D. BROWN, MD Department of Internal Medicine,The Johns Hopkins University School of Medicine, Baltimore [Review and Self-Assessment] KEVIN E. BROWN, MD Consultant Medical Virologist, Health Protection Agency, London [85]

JOHN C. ATHERTON, MD Professor of Gastroenterology; Director,Wolfson Digestive Diseases Centre, University of Nottingham, United Kingdom [52]

JOAN R. BUTTERTON, MD Assistant Clinical Professor of Medicine, Harvard Medical School; Clinical Associate in Medicine, Massachusetts General Hospital, Boston [25]

LINDSEY R. BADEN, MD Assistant Professor of Medicine, Harvard Medical School, Boston [79]

STEPHEN B. CALDERWOOD, MD Morton N. Swartz, MD Academy Professor of Medicine (Microbiology and Molecular Genetics), Harvard Medical School; Chief, Division of Infectious Diseases, Massachusetts General Hospital, Boston [25]

TAMAR F. BARLAM, MD Associate Professor of Medicine, Boston University School of Medicine, Boston [14, 48] MIRIAM J. BARON, MD Instructor in Medicine, Harvard Medical School, Boston [24]

MICHAEL V. CALLAHAN, MD, DTM&H (UK), MSPH Clinical Associate Physician, Division of Infectious Diseases, Massachusetts General Hospital; Program Manager, Biodefense, Defense Advanced Research Project Agency (DARPA), United States Department of Defense,Washington [9]

KENNETH J. BART, MD, MPH, MSHPM Professor Emeritus, Epidemiology and Biostatistics, San Diego State University, San Diego; Consultant, National Vaccine Program Office, Office of the Secretary, Department of Health and Human Services, Washington [3]

GRANT L. CAMPBELL, MD, PhD Division of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, U.S. Public Health Service, Laporte [60]

NICHOLAS J. BEECHING, FFTM (RCPS GLAS) DCH, DTM&H Senior Lecturer in Infectious Diseases, Liverpool School of Tropical Medicine, University of Liverpool; Consultant and Clinical Lead, Tropical and Infectious Disease Unit, Royal Liverpool University Hospital, Liverpool, United Kingdom [58]

JONATHAN R. CARAPETIS, MBBS, PhD Director, Menzies School of Health Research; Professor, Charles Darwin University, Casuarina, Northern Territory,Australia [37]

JEAN BERGOUNIOUX, MD Medical Doctor of Pediatrics, Unité de Pathogénie Microbienne Moléculaire, Paris [55]

ARTURO CASADEVALL, MD, PhD Professor of Microbiology and Immunology and of Medicine; Chair, Department of Microbiology and Immunology,Albert Einstein College of Medicine, New York [106]

WILLIAM R. BISHAI, MD, PhD Professor of Medicine,The Johns Hopkins School of Medicine, Baltimore [38]

STANLEY W. CHAPMAN, MD Professor of Medicine and Microbiology; Director, Division of Infectious Diseases;Vice-Chair for Academic Affairs, Department of Medicine, University of Mississippi School of Medicine, Jackson [105, 110]

MARTIN J. BLASER, MD Frederick H. King Professor of Internal Medicine; Chair, Department of Medicine; Professor of Microbiology, New York University School of Medicine, New York [52, 56]

JEFFREY I. COHEN, MD Chief, Medical Virology Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda [82, 94]

GERALD BLOOMFIELD, MD, MPH Department of Internal Medicine,The Johns Hopkins University School of Medicine, Baltimore [Review and Self-Assessment]

†

Deceased

xi

xii

Contributors

RONIT COHEN-PORADOSU, MD Channing Laboratory, Brigham and Women’s Hospital, Boston [65] MICHAEL J. CORBEL, PhD, DSc(Med), FIBiol Head, Division of Bacteriology, National Institute for Biological Standards and Control, Potters Bar, United Kingdom [58] LAWRENCE COREY, MD Professor of Medicine and Laboratory Medicine; Chair of Medical Virology, University of Washington; Head, Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle [80]

ROBERT FINBERG, MD Professor and Chair, Department of Medicine, University of Massachusetts Medical School,Worcester [11, 12] JOYCE FINGEROTH, MD Associate Professor of Medicine, Harvard Medical School, Boston [12] DANIEL J. FINK, MD, MPH Associate Professor of Clinical Pathology, College of Physicians and Surgeons, Columbia University, New York [Appendix]

EMILY DARBY, MD Senior Fellow, Division of Infectious Diseases, University of Washington, Seattle [61]

SUSAN L. GEARHART, MD Assistant Professor of Colorectal Surgery and Oncology,The Johns Hopkins University School of Medicine, Baltimore [26]

CHARLES E. DAVIS, MD Professor of Pathology and Medicine Emeritus, University of California San Diego School of Medicine; Director Emeritus, Microbiology Laboratory, University of California San Diego Medical Center, San Diego [112]

ROBERT H. GELBER, MD Scientific Director, Leonard Wood Memorial Leprosy Research Center, Cebu, Philippines; Clinical Professor of Medicine and Dermatology, University of California, San Francisco, San Francisco [67]

DAVID W. DENNING, MBBS Professor of Medicine and Medical Mycology, University of Manchester; Director, Regional Mycology Laboratory, Manchester Education and Research Centre,Wythenshawe Hospital, Manchester, United Kingdom [108]

JEFFREY A. GELFAND, MD Professor of Medicine, Harvard Medical School; Physician, Department of Medicine, Massachusetts General Hospital, Boston [9, 117]

DAVID T. DENNIS, MD, MPH Faculty Affiliate, Department of Microbiology, Immunology and Pathology, Colorado State University; Medical Epidemiologist, Division of Influenza, Centers for Disease Control and Prevention, Atlanta [60, 73] JULES L. DIENSTAG, MD Carl W.Walter Professor of Medicine and Dean for Medical Education, Harvard Medical School; Physician, Gastrointestinal Unit, Massachusetts General Hospital, Boston [92, 93] CHARLES A. DINARELLO, MD Professor of Medicine, University of Colorado Health Science Center, Denver [7] RAPHAEL DOLIN, MD Maxwell Finland Professor of Medicine (Microbiology and Molecular Genetics); Dean for Academic and Clinical Programs, Harvard Medical School, Boston [79, 87, 88] J. STEPHEN DUMLER, MD Professor, Division of Medical Microbiology, Department of Pathology,The Johns Hopkins University School of Medicine and Immunology,The Johns Hopkins University Bloomberg School of Public Health, Baltimore [75] JOHN E. EDWARDS, JR., MD Chief, Division of Infectious Diseases, Harbor/University of California, Los Angeles Medical Center; Professor of Medicine, David Geffen School of Medicine at the University of California, Los Angeles,Torrance [102, 107] ANTHONY S. FAUCI, MD, DSc (Hon), DM&S (Hon), DHL (Hon), DPS (Hon), DLM (Hon), DMS (Hon) Chief, Laboratory of Immunoregulation; Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda [6, 89, 90] GREGORY A. FILICE, MD Professor of Medicine, University of Minnesota; Chief, Infectious Disease Section, Minneapolis Veterans Affairs Medical Center, Minneapolis [63]

DALE N. GERDING, MD Assistant Chief of Staff for Research, Hines VA Hospital, Hines; Professor, Stritch School of Medicine, Loyola University, Maywood [43] ANNE GERSHON, MD Professor of Pediatrics, Columbia University College of Physicians and Surgeons, New York [95-97] ROGER I. GLASS, MD, PhD Director, Fogarty International Center;Associate Director for International Research, National Institutes of Health, Bethesda [91] RALPH GONZALES, MD, MSPH Professor of Medicine, Epidemiology and Biostatistics, University of California, San Francisco, San Francisco [16] DAVID E. GRIFFITH, MD Professor of Medicine;William A. and Elizabeth B. Moncrief Distinguished Professor, University of Texas Health Center, Tyler [69] CHADI A. HAGE, MD Assistant Professor of Medicine, Indiana University School of Medicine, Roudebush VA Medical Center, Pulmonary-Critical Care and Infectious Diseases, Indianapolis [103] SCOTT A. HALPERIN, MD Professor of Pediatrics and of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia [50] GAVIN HART, MD, MPH Director, STD Services, Royal Adelaide Hospital; Clinical Associate Professor, School of Medicine, Flinders University,Adelaide, Australia [62] RUDY HARTSKEERL, PhD Head, FAO/OIE,World Health Organization and National Leptospirosis Reference Centre, KIT Biomedical Research, Royal Tropical Institute,Amsterdam,The Netherlands [72] BARBARA L. HERWALDT, MD, MPH Medical Epidemiologist, Division of Parasitic Diseases, Centers for Disease Control and Prevention,Atlanta [119]

Contributors

xiii

MARTIN S. HIRSCH, MD Professor of Medicine, Harvard Medical School; Professor of Immunology and Infectious Diseases, Harvard School of Public Health; Physician, Massachusetts General Hospital, Boston [83]

ELLIOTT KIEFF, MD, PhD Harriet Ryan Albee Professor of Medicine and Microbiology and Molecular Genetics, Harvard Medical School; Senior Physician, Brigham and Women’s Hospital, Boston [78]

ELIZABETH L. HOHMANN, MD Associate Professor of Medicine and Infectious Diseases, Harvard Medical School, Massachusetts General Hospital, Boston [39]

LOUIS V. KIRCHHOFF, MD, MPH Professor, Departments of Internal Mediciene and Epidemiology, University of Iowa; Staff Physician, Department of Veterans Affairs Medical Center, Iowa City [120]

KING K. HOLMES, MD, PhD William H. Foege Chair, Department of Global Health; Director, Center for AIDS and STD; Professor of Medicine and Global Health, University of Washington; Head, Infectious Diseases, Harborview Medical Center, Seattle [28] ALAN C. JACKSON, MD, FRCPC Professor of Medicine (Neurology) and of Medical Microbiology, University of Manitoba; Section Head of Neurology,Winnipeg Regional Health Authority,Winnipeg, Canada [98] RICHARD F. JACOBS, MD, FAAP President,Arkansas Children’s Hospital Research Institute; Horace C. Cabe Professor of Pediatrics, University of Arkansas for Medical Sciences, College of Medicine, Little Rock [59] ERIC C. JOHANNSEN, MD Assistant Professor, Department of Medicine, Harvard Medical School;Associate Physician, Division of Infectious Diseases, Brigham and Women’s Hospital, Boston [98] JAMES R. JOHNSON, MD Professor of Medicine, University of Minnesota, Minneapolis [51] STUART JOHNSON, MD Associate Professor, Stritch School of Medicine, Loyola University, Maywood; Staff Physician, Hines VA Hospital, Hines [43] ADOLF W. KARCHMER, MD Professor of Medicine, Harvard Medical School, Boston [19] DENNIS L. KASPER, MD, MA (Hon) William Ellery Channing Professor of Medicine, Professor of Microbiology and Molecular Genetics, Harvard Medical School; Director, Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Boston [1, 14, 24, 42, 48, 65] LLOYD H. KASPER, MD Professor of Medicine and Microbiology/Immunology; Co-Director, Program in Immunotherapeutics, Dartmouth Medical Schoool, Lebanon [121]

WALTER J. KOROSHETZ, MD Deputy Director, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda [30] PHYLLIS E. KOZARSKY, MD Professor of Medicine, Infectious Diseases; Co-Director,Travel and Tropical Medicine, Emory University School of Medicine,Atlanta [4] ALEXANDER KRATZ, MD, PhD, MPH Assistant Professor of Clinical Pathology, Columbia University College of Physicians and Surgeons;Associate Director, Core Laboratory, Columbia University Medical Center, New York-Presbyterian Hospital; Director,Allen Pavilion Laboratory, New York [Appendix] H. CLIFFORD LANE, MD Clinical Director; Director, Division of Clinical Research; Deputy Director, Clinical Research and Special Projects; Chief, Clinical and Molecular Retrovirology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda [6, 90] DAN L. LONGO, MD Scientific Director, National Institute on Aging, National Institutes of Health, Bethesda and Baltimore [89] FRANKLIN D. LOWY, MD, PhD Professor of Medicine and Pathology, Columbia University, College of Physicians & Surgeons, New York [35] SHEILA A. LUKEHART, PhD Professor of Medicine, University of Washington, Seattle [70, 71] LAWRENCE C. MADOFF, MD Associate Professor of Medicine, Harvard Medical School, Boston [1, 23, 32, 42] ADEL A. F. MAHMOUD, MD, PhD Professor, Molecular Biology, Princeton University, Princeton [126] LIONEL A. MANDELL, MD Professor of Medicine, McMaster University, Hamilton, Ontario [17]

ELAINE T. KAYE, MD Clinical Assistant Professor of Dermatology, Harvard Medical School; Assistant in Medicine, Department of Medicine, Children’s Hospital Medical Center, Boston [8, 10]

THOMAS MARRIE, MD Professor, Department of Medicine; Dean, Faculty of Medicine and Dentistry, University of Alberta, Edmonton [75]

KENNETH M. KAYE, MD Associate Professor of Medicine, Harvard Medical School;Associate Physician, Division of Infectious Diseases, Brigham and Women’s Hospital, Boston [8, 10]

ALEXANDER J. McADAM, MD, PhD Medical Director, Infectious Diseases Diagnostic Division, Children’s Hospital, Boston;Assistant Professor, Department of Pathology, Harvard Medical School, Boston [5]

GERALD T. KEUSCH, MD Associate Provost and Associate Dean for Global Health, Boston University School of Medicine, Boston [3, 57]

WILLIAM M. McCORMACK, MD Distinguished Teaching Professor of Medicine; Chief, Infectious Disease Division, SUNY Downstate Medical Center, Brooklyn [76]

JAY S. KEYSTONE, MD, FRCPC Professor of Medicine, University of Toronto; Staff Physician, Centre for Travel and Tropical Medicine,Toronto General Hospital, Toronto [4]

BRUCE L. MILLER, MD AW and Mary Margaret Clausen Distinguished Professor of Neurology, University of California, San Francisco School of Medicine, San Francisco [101]

xiv

Contributors

MARK MILLER, MD Associate Director for Research, National Institutes of Health, Bethesda [3] SAMUEL I. MILLER, MD Professor of Genome Sciences, Medicine, and Microbiology, University of Washington, Seattle [54] THOMAS A. MOORE, MD Clinical Professor and Associate Program Director, Department of Medicine, University of Kansas School of Medicine, Wichita [113, 114] ROBERT S. MUNFORD, MD Jan and Henri Bromberg Chair in Internal Medicine, University of Texas Southwestern Medical Center, Dallas [15]

CLARENCE J. PETERS, MD John Sealy Distinguished University Chair in Tropical and Emerging Virology, Director for Biodefense, Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch in Galveston, Galveston [99, 100] GERALD B. PIER, PhD Professor of Medicine (Microbiology and Molecular Genetics), Harvard Medical School; Microbiologist, Brigham and Women’s Hospital, Boston [2] RONALD E. POLK, PharmD Chair, Department of Pharmacy, Professor of Pharmacy and Medicine, School of Pharmacy,Virginia Commonwealth University, Richmond [33]

JOHN R. MURPHY, PhD Professor of Medicine and Microbiology; Chief, Section of Molecular Medicine, Boston University School of Medicine, Boston [38]

REUVEN PORAT, MD Professor of Medicine; Director, Internal Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University,Tel Aviv [7]

TIMOTHY F. MURPHY, MD UB Distinguished Professor, Department of Medicine and Microbiology; Chief, Infectious Diseases, State Univerity of New York, Buffalo [47]

DANIEL A. PORTNOY, PhD Professor of Biochemistry and Molecular Biology, Department of Molecular and Cell Biology, University of California, Berkeley [39]

DANIEL M. MUSHER, MD Chief, Infectious Disease Section, Michael E. DeBakey Veterans Affairs Medical Center; Professor of Medicine and Professor of Molecular Virology and Microbiology, Baylor College of Medicine, Houston [34, 46] THOMAS B. NUTMAN, MD Head, Helminth Immunology Section; Head, Clinical Parasitology Unit; Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Insitutes of Health, Bethesda [124, 125] RICHARD J. O’BRIEN, MD Head of Scientific Evaluation, Foundation for Innovative New Diagnostics, Geneva, Switzerland [66] ANDREW B. ONDERDONK, PhD Professor of Pathology, Harvard Medical School and Brigham and Women’s Hospital, Boston [5] UMESH D. PARASHAR, MBBS, MPH Lead, Enteric and Respiratory Viruses Team, Epidemiology Branch, Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta [91] JEFFREY PARSONNET, MD Associate Professor of Medicine and Microbiology, Dartmouth Medical School, Lebanon [22] DAVID A. PEGUES, MD Professor of Medicine, Division of Infectious Diseases, David Geffen School of Medicine at UCLA, Los Angeles [54] FLORENCIA PEREYRA, MD Instructor in Medicine, Harvard Medical School; Division of Infectious Disease, Brigham and Women’s Hospital, Boston [32] MICHAEL A. PESCE, PhD Clinical Professor of Pathology, Columbia University College of Physicians and Surgeons; Director of Specialty Laboratory, New York Presbyterian Hospital, Columbia University Medical Center, New York [Appendix]

STANLEY B. PRUSINER, MD Director, Institute for Neurodegenerative Diseases; Professor, Department of Neurology; Professor, Department of Biochemistry and Biophysics, University of California, San Francisco [101] SANJAY RAM, MD Assistant Professor of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester [45] REUBEN RAMPHAL, MD Professor, Division of Infectious Diseases, Department of Medicine, University of Florida College of Medicine, Gainesville [53] MARIO C. RAVIGLIONE, MD Director, StopTB Department,World Health Organization, Geneva [66] SHARON L. REED, MD Professor of Pathology and Medicine; Director, Microbiology and Virology Laboratories, University of California, San Diego Medical Center, San Diego [112, 115] RICHARD C. REICHMAN, MD Professor of Medicine and of Microbiology and Immunology; Director, Infectious Diseases Division, University of Rochester School of Medicine, Rochester [86] PETER A. RICE, MD Professor of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester [45] KAREN L. ROOS, MD John and Nancy Nelson Professor of Neurology, Indiana University School of Medicine, Indianapolis [29] MICHAEL A. RUBIN, MD, PhD Assistant Professor of Medicine, Division of Epidemiology and Infectious Diseases, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City [16] THOMAS A. RUSSO, MD, CM Professor of Medicine and Microbiology, State University of New York, Buffalo [51, 64]

Contributors MIGUEL SABRIA, MD, PhD Professor of Medicine,Autonomous University of Barcelona; Chief, Infectious Diseases Section, Germans Trias i Pujol Hospital, Barcelona, Spain [49] MERLE A. SANDE,† MD Professor of Medicine, University of Washington School of Medicine; President,Academic Alliance Foundation, Seattle [16] PHILIPPE SANSONETTI Professeur á l’Institut Pasteur, Paris [55]

xv

ALAN M. SUGAR, MD Professor of Medicine, Boston University School of Medicine; Medical Director, Infectious Diseases Clinical Services, HIV/AIDS Program, and Infection Control, Cape Cod Healthcare, Hyannis [109] DONNA C. SULLIVAN, PhD Associate Professor of Medicine and Microbiology, Division of Infectious Diseases, Department of Medicine, University of Mississippi School of Medicine, Jackson [105, 110]

JOSHUA SCHIFFER, MD Department of Internal Medicine,The Johns Hopkins University School of Medicine, Baltimore [Review and Self-Assessment]

MORTON N. SWARTZ, MD Professor of Medicine, Harvard Medical School; Chief, Jackson Firm Medical Service and Infectious Disease Unit, Massachusetts General Hospital, Boston [30]

GORDON E. SCHUTZE, MD Professor of Pediatrics and Pathology, University of Arkansas for Medical Sciences, College of Medicine; Chief, Pediatric Infectious Diseases,Arkansas Children’s Hospital, Little Rock [59]

GREGORY TINO, MD Associate Professor of Medicine, University of Pennsylvania School of Medicine; Chief, Pulmonary Clinical Service Hospital of the University of Pennsylvania, Philadelphia [18]

WILLIAM SILEN, MD Johnson and Johnson Distinguished Professor of Surgery, Emeritus, Harvard Medical School, Boston [26]

KENNETH L. TYLER, MD Reuler-Lewin Family Professor of Neurology and Professor of Medicine and Microbiology, University of Colorado Health Sciences Center; Chief, Neurology Service, Denver Veterans Affairs Medical Center, Denver [29]

A. GEORGE SMULIAN, MB, BCh Associate Professor, University of Cincinnati College of Medicine; Chief, Infectious Disease Section, Cincinnati VA Medical Center, Cincinnati [111] DAVID H. SPACH, MD Professor of Medicine, Division of Infectious Diseases, University of Washington, Seattle [61] PETER SPEELMAN, MD, PhD Professor of Medicine and Infectious Diseases; Head, Division of Infectious Diseases,Tropical Medicine and AIDS; Department of Internal Medicine,Academic Medical Center, University of Amsterdam,The Netherlands [72] ADAM SPIVAK, MD Department of Internal Medicine,The Johns Hopkins University School of Medicine, Baltimore [Review and Self-Assessment] WALTER E. STAMM, MD Professor of Medicine; Head, Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle [27, 77] ALLEN C. STEERE, MD Professor of Medicine, Harvard Medical School, Boston [74] DENNIS L. STEVENS, MD, PhD Chief, Infectious Diseases Section,Veteran Affairs Medical Center, Boise; Professor of Medicine, University of Washington School of Medicine, Seattle [21] †

STEPHEN E. STRAUS, MD Senior Investigator, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases; Director, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda [31]

†

Deceased.

EDOUARD VANNIER, PhD Assistant Professor, Department of Medicine, Division of Infectious Diseases,Tufts-New England Medical Center and Tufts University School of Medicine, Boston [117] C. FORDHAM von REYN, MD Professor of Medicine (Infectious Disease) and International Health; Director, DARDAR International Programs, Dartmouth Medical School, Lebanon [68] MATTHEW K. WALDOR, MD, PhD Professor of Medicine (Microbiology and Molecular Genetics), Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston [57] DAVID H. WALKER, MD The Carnage and Martha Walls Distinguished University Chair in Tropical Diseases; Professor and Chairman, Department of Pathology; Executive Director, Center for Biodefense and Emerging Infectious Disease, University of Texas Medical Branch, Galveston [75] RICHARD J. WALLACE, JR., MD Chairman, Department of Microbiology, University of Texas Health Center at Tyler,Tyler [69] PETER D. WALZER, MD, MSc Associate Chief of Staff for Research, Cincinnati VA Medical Center; Professor of Medicine, University of Cincinnati College of Medicine, Cincinnati [111] FRED WANG, MD Professor of Medicine, Harvard Medical School, Boston [78, 84] STEVEN E. WEINBERGER, MD Senior Vice President for Medical Education Division,American College of Physicians; Senior Lecturer on Medicine, Harvard Medical School;Adjunct Professor of Medicine, University of Pennsylvania School of Medicine, Philadelphia [18]

xvi

Contributors

CHARLES WIENER, MD Professor of Medicine and Physiology;Vice Chair, Department of Medicine; Director, Osler Medical Training Program,The Johns Hopkins University School of Medicine, Baltimore [Review and Self-Assessment] ROBERT A. WEINSTEIN, MD Professor of Medicine, Rush University Medical Center; Chairman, Infectious Diseases, Cook County Hospital; Chief Operating Officer, CORE Center, Chicago [13] PETER F. WELLER, MD Professor of Medicine, Harvard Medical School; Co-Chief, Infectious Diseases Division; Chief,Allergy and Inflammation Division;Vice-Chair for Research, Department of Medicine, Beth Israel Deaconess Medical Center, Boston [122-125, 127] MICHAEL R. WESSELS, MD Professor of Pediatrics and Medicine (Microbiology and Molecular Genetics), Harvard Medical School; Chief, Division of Infectious Diseases, Children’s Hospital, Boston [36] LEE M. WETZLER, MD Professor of Medicine,Associate Professor of Microbiology, Boston University School of Medicine, Boston [44]

L. JOSEPH WHEAT, MD President and Director, MiraVista Diagnostics and MiraBella Technology, Indianapolis [103] A. CLINTON WHITE, JR., MD The Paul R. Stalnaker, MD, Distinguished Professor of Internal Medicine; Director, Infectious Disease Division, Department of Internal Medicine, University of Texas Medical Branch, Galveston [127] NICHOLAS J. WHITE, DSc Professor of Tropical Medicine, Oxford University, United Kingdom; Mahidol University, Bangkok,Thailand [116, 118] RICHARD J. WHITLEY, MD Loeb Scholar in Pediatrics, Professor of Pediatrics, Microbiology, Medicine, and Neurosurgery, University of Alabama, Birmingham [81] RICHARD WUNDERINK, MD Professor, Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Feinberg School of Medicine; Director, Medical Intensive Care Unit, Northwestern Memorial Hospital, Chicago [17] VICTOR L.YU, MD Professor of Medicine, University of Pittsburgh, Pittsburgh [49]

PREFACE Despite enormous advances in diagnosis, treatment, and prevention during the twentieth century, physicians caring for patients with infectious diseases today must cope with extraordinary new challenges, including a neverending deluge of new information, the rapid evolution of the microorganisms responsible for these diseases, and formidable time and cost constraints. In no other area of medicine is the differential diagnosis so wide, and often the narrowing of the differential to a precise infection caused by a specific organism with established antimicrobial susceptibilities is a matter of great urgency. To inform crucial decisions about management, today’s care providers are typically turning to a variety of sources, including colleagues, print publications, and online services. Our goal in publishing Harrison’s Infectious Diseases as a stand-alone volume is to provide practitioners with a single convenient source that quickly yields accurate, accessible, up-to-date information to meet immediate clinical needs and that presents this information in the broader context of the epidemiologic, pathophysiologic, and genetic factors that underlie it. The authors of the chapters herein are acknowledged experts in their fields whose points of view represent decades of medical practice and a comprehensive knowledge of the literature. The specific recommendations of these authorities regarding diagnostic options and therapeutic regimens—including drugs of choice, doses, durations, and alternatives—take into account not just the trends and concerns of the moment but also the longer-term factors and forces that have shaped present circumstances and will continue to influence future developments. Among these forces are the changing prevalence, distribution, features, and management alternatives in different regions of the world; accordingly, these topics are addressed from an international perspective.

Prominent among the 127 chapters in this volume, that on HIV infections and AIDS by Anthony S. Fauci and H. Clifford Lane (Chap. 90) is widely considered to be a classic in the field. Its clinically pragmatic focus, along with its comprehensive and analytical approach to the pathogenesis of HIV disease, has led to its use as the sole complete reference on HIV/AIDS in medical schools. A highly practical chapter by Robert A. Weinstein (Chap. 13) addresses health care–associated infections, a topic of enormous significance in terms of patient care in general and antimicrobial resistance in particular. A superb chapter by Richard C. Reichman (Chap. 86) includes critical information and recommendations regarding the recently licensed human papillomavirus vaccine. Thomas A. Russo and James R. Johnson (Chap. 51) take on the complex area of serious infections caused by gram-negative bacilli, including Escherichia coli. With a full-color design, this volume offers abundant illustrations that provide key information in a readily understandable format. Two chapters comprise atlases of images that can be invaluable in clinical assessments: Chap. 10 presents images of rashes associated with fever, while Chap. 118 shows blood smears of the various stages of the parasites causing malaria and babesiosis. Selfassessment questions and answers appear in an appendix at the end of the book. The Editors thank our authors for their hard work in distilling their experience and the relevant literature into this volume, which we hope you will enjoy using as an authoritative source of current information on infectious diseases. Dennis L. Kasper, MD

xvii

NOTICE Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.

Review and self-assessment questions and answers were selected by Miriam J. Baron, MD, from those prepared by Wiener C, Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J (editors) Bloomfield G, Brown CD, Schiffer J, Spivak A (contributing editors). Harrison’s Principles of Internal Medicine Self-Assessment and Board Review, 17th ed. New York, McGraw-Hill, 2008, ISBN 978-0-07-149619-3.

The global icons call greater attention to key epidemiologic and clinical differences in the practice of medicine throughout the world. The genetic icons identify a clinical issue with an explicit genetic relationship.

SECTION I

INTRODUCTION TO INFECTIOUS DISEASES

CHAPTER 1

INTRODUCTION TO INFECTIOUS DISEASES: HOST-PATHOGEN INTERACTIONS Lawrence C. Madoff Dennis L. Kasper Despite decades of dramatic progress in their treatment and prevention, infectious diseases remain a major cause of death and debility and are responsible for worsening the living conditions of many millions of people around the world. Infections frequently challenge the physician’s diagnostic skill and must be considered in the differential diagnoses of syndromes affecting every organ system.

H5N1 avian influenza, having spread rapidly through poultry farms in Asia and having caused deaths in exposed humans, had reached Europe and Africa, heightening fears of a new influenza pandemic. Many infectious agents have been discovered only in recent decades (Fig. 1-1). Ebola virus, human metapneumovirus, Anaplasma phagocytophila (the agent of human granulocytotropic ehrlichiosis), and retroviruses such as HIV humble us despite our deepening understanding of pathogenesis at the most basic molecular level. Even in developed countries, infectious diseases have made a resurgence. Between 1980 and 1996, mortality from infectious diseases in the United States increased by 64% to levels not seen since the 1940s. The role of infectious agents in the etiology of diseases once believed to be noninfectious is increasingly recognized. For example, it is now widely accepted that Helicobacter pylori is the causative agent of peptic ulcer disease and perhaps of gastric malignancy. Human papillomavirus is likely to be the most important cause of invasive cervical cancer. Human herpesvirus type 8 is believed to be the cause of most cases of Kaposi’s sarcoma. Epstein-Barr virus is a cause of certain lymphomas and may play a role in the genesis of Hodgkin’s disease. The possibility certainly exists that other diseases of unknown cause, such as rheumatoid arthritis, sarcoidosis, or inflammatory bowel disease, have infectious etiologies. There is even evidence that atherosclerosis may have an infectious component. In contrast, there are data to suggest that decreased exposures to pathogens in childhood may be contributing to an increase in the observed rates of allergic diseases. Medical advances against infectious diseases have been hindered by changes in patient populations. Immunocompromised hosts now constitute a significant proportion of the seriously infected population. Physicians immunosuppress their patients to prevent the rejection of transplants and to treat neoplastic and inflammatory diseases. Some infections, most notably that caused by HIV, immunocompromise the host in and of themselves. Lesser degrees of immunosuppression are associated with other infections, such as influenza and syphilis. Infectious agents that coexist peacefully with immunocompetent hosts wreak havoc in those who lack a complete immune system. AIDS has brought to prominence once-obscure

CHANGING EPIDEMIOLOGY OF INFECTIOUS DISEASES With the advent of antimicrobial agents, some medical leaders believed that infectious diseases would soon be eliminated and become of historic interest only. Indeed, the hundreds of chemotherapeutic agents developed since World War II, most of which are potent and safe, include drugs effective not only against bacteria, but also against viruses, fungi, and parasites. Nevertheless, we now realize that as we developed antimicrobial agents, microbes developed the ability to elude our best weapons and to counterattack with new survival strategies. Antibiotic resistance occurs at an alarming rate among all classes of mammalian pathogens. Pneumococci resistant to penicillin and enterococci resistant to vancomycin have become commonplace. Even Staphylococcus aureus strains resistant to vancomycin have appeared. Such pathogens present real clinical problems in managing infections that were easily treatable just a few years ago. Diseases once thought to have been nearly eradicated from the developed world-tuberculosis, cholera, and rheumatic fever, for example-have rebounded with renewed ferocity. Newly discovered and emerging infectious agents appear to have been brought into contact with humans by changes in the environment and by movements of human and animal populations. An example of the propensity for pathogens to escape from their usual niche is the alarming 1999 outbreak in New York of encephalitis due to West Nile virus, which had never previously been isolated in the Americas. In 2003, severe acute respiratory syndrome (SARS) was first recognized.This emerging clinical entity is caused by a novel coronavirus that may have jumped from an animal niche to become a significant human pathogen. By 2006,

2

Diphtheria, 1993

Pertussis, 1993

HIV,1981 Hantavirus, 1993

West Nile virus, 1999 Legionnaire's disease, 1976 Marburg Anthrax, virus, 2005 1993

Pandemic cholera, 1991

FIGURE 1-1 Map of the world showing examples of geographic locales where infectious diseases were noted to have emerged or resurged. (Adapted from Addressing Emerging Infectious

organisms such as Pneumocystis, Cryptosporidium parvum, and Mycobacterium avium.

HOST FACTORS IN INFECTION For any infectious process to occur, the pathogen and the host must first encounter each other. Factors such as geography, environment, and behavior thus influence the likelihood of infection. Although the initial encounter between a susceptible host and a virulent organism frequently results in disease, some organisms can be harbored in the host for years before disease becomes clinically evident. For a complete view, individual patients must be considered in the context of the population to which they belong. Infectious diseases do not often occur in isolation; rather, they spread through a group exposed from a point source (e.g., a contaminated water supply) or from one individual to another (e.g., via respiratory droplets). Thus the clinician must be alert to infections prevalent in the community as a whole. A detailed history, including information on travel, behavioral factors, exposures to animals or potentially contaminated environments, and living and occupational conditions, must be elicited. For example, the likelihood of infection by Plasmodium falciparum can be significantly affected by altitude, climate, terrain, season, and even time of day. Antibiotic-resistant strains of P. falciparum are localized to specific geographic regions, and a seemingly minor alteration in a travel itinerary can dramatically influence the likelihood of acquiring chloroquine-resistant malaria. If such important details in the history are overlooked, inappropriate treatment may result in the death of the patient. Likewise, the chance of acquiring a sexually transmitted disease can be greatly affected by a relatively minor variation in sexual practices, such as the method used for contraception. Knowledge of the relationship between specific risk factors and disease allows the physician to influence a patient’s health even before the devel-

Vancomycin-resistant Staphylococcus aureus,1996

Vibrio cholerae O139,1993 Rift Valley fever, 1993 Ebola virus, 1976 Yellow fever, 1993

Human H5N1 influenza,1997

3

Nipah virus, 1997 Dengue,1992

Disease Threats: A Prevention Strategy for the United States, Department of Health and Human Services, Centers for Disease Control and Prevention, 1994.)

opment of infection by modification of these risk factors and—when a vaccine is available—by immunization. Many specific host factors influence the likelihood of acquiring an infectious disease. Age, immunization history, prior illnesses, level of nutrition, pregnancy, coexisting illness, and perhaps emotional state all have some impact on the risk of infection after exposure to a potential pathogen. The importance of individual host defense mechanisms, either specific or nonspecific, becomes apparent in their absence, and our understanding of these immune mechanisms is enhanced by studies of clinical syndromes developing in immunodeficient patients (Table 1-1). For example, the higher attack rate of meningococcal disease among people with deficiencies in specific complement proteins of the so-called membrane attack complex (see “Adaptive Immunity” later in the chapter) than in the general population underscores the importance of an intact complement system in the prevention of meningococcal infection. Medical care itself increases the patient’s risk of acquiring an infection in several ways: (1) through contact with pathogens during hospitalization, (2) through breaching of the skin (with intravenous devices or surgical incisions) or mucosal surfaces (with endotracheal tubes or bladder catheters), (3) through introduction of foreign bodies, (4) through alteration of the natural flora with antibiotics, and (5) through treatment with immunosuppressive drugs. Infection involves complicated interactions of microbe and host and inevitably affects both. In most cases, a pathogenic process consisting of several steps is required for the development of infections. Since the competent host has a complex series of barricades in place to prevent infection, the successful pathogen must use specific strategies at each of these steps. The specific strategies used by bacteria, viruses, and parasites (Chap. 2) have some remarkable conceptual similarities, but the strategic details are unique not only for each class of microorganism, but also for individual species within a class.

Introduction to Infectious Diseases: Host-Pathogen Interactions

Lassa fever, 1992

SARS, 2003

CHAPTER 1

Escherichia coli O157:H7, 1982

4

TABLE 1-1 INFECTIONS ASSOCIATED WITH SELECTED DEFECTS IN IMMUNITY

SECTION I Introduction to Infectious Diseases

DISEASE OR THERAPY ASSOCIATED WITH DEFECT

COMMON ETIOLOGIC AGENT OF INFECTION

Impaired cough

Rib fracture, neuromuscular dysfunction

Loss of gastric acidity Loss of cutaneous integrity

Achlorhydria, histamine blockade Penetrating trauma, athlete’s foot

Bacteria causing pneumonia, aerobic and anaerobic oral flora Salmonella spp., enteric pathogens Staphylococcus spp., Streptococcus spp. Pseudomonas aeruginosa Staphylococcus spp., Streptococcus spp., gramnegative rods, coagulasenegative staphylococci Streptococcus spp., coagulasenegative staphylococci, Staphylococcus aureus Staphylococcus spp., Streptococcus spp., gram-negative rods Clostridium difficile, Candida spp.

HOST DEFECT

Nonspecific Immunity

Burn Intravenous catheter

Implantable device

Heart valve

Artificial joint

Loss of normal bacterial flora Impaired clearance Poor drainage Abnormal secretions

Antibiotic use Urinary tract infection Cystic fibrosis

Escherichia coli Chronic pulmonary infection with P. aeruginosa

Neutropenia

Hematologic malignancy, cytotoxic chemotherapy, aplastic anemia, HIV infection

Chemotaxis

Chédiak-Higashi syndrome, Job’s syndrome, protein-calorie malnutrition

Gram-negative enteric bacilli, Pseudomonas spp., Staphylococcus spp., Candida spp. S. aureus, Streptococcus pyogenes, Haemophilus influenzae, gram-negative bacilli Bacteria causing skin and systemic infections, gingivitis Streptococcus pneumoniae, H. influenzae H. influenzae, S. pneumoniae, other streptococci, Capnocytophaga spp., Babesia microti, Salmonella spp. Catalase-positive bacteria and fungi: staphylococci, E. coli, Klebsiella spp., P. aeruginosa, Aspergillus spp., Nocardia spp. S. aureus, S. pyogenes Mycobacterium spp., Salmonella spp.

Inflammatory Response

Leukocyte adhesion defects 1 and 2 Phagocytosis (cellular) Splenectomy

Systemic lupus erythematosus (SLE), chronic myelogenous leukemia, megaloblastic anemia —

Microbicidal defect

Chronic granulomatous disease

Chédiak-Higashi syndrome Interferon γ receptor defect, interleukin 12 deficiency, interleukin 12 receptor defect Innate Immunity Complement system C3

Congenital liver disease, SLE, nephrotic syndrome

C5 C6, C7, C8

Congenital Congenital, SLE

Alternative pathway

Sickle cell disease

S. aureus, S. pneumoniae, Pseudomonas spp., Proteus spp. Neisseria spp., gram-negative rods Neisseria meningitidis, N. gonorrhoeae S. pneumoniae, Salmonella spp. (Continued)

TABLE 1-1 (CONTINUED)

5

INFECTIONS ASSOCIATED WITH SELECTED DEFECTS IN IMMUNITY COMMON ETIOLOGIC AGENT OF INFECTION

Congenital Congenital

Gram-negative bacilli S. pneumoniae, S. aureus, other bacteria N. meningitidis, other bacteria

Innate Immunity (Continued) Toll-like receptor 4 Interleukin 1 receptor-associated kinase (IRAK) 4 Mannan-binding lectin

Congenital

Adaptive Immunity T lymphocyte deficiency/ dysfunction

Thymic aplasia, thymic hypoplasia, Hodgkin’s disease, sarcoidosis, lepromatous leprosy

AIDS

B cell deficiency/dysfunction

Mucocutaneous candidiasis Purine nucleoside phosphorylase deficiency Bruton’s X-linked agammaglobulinemia Agammaglobulinemia, chronic lymphocytic leukemia, multiple myeloma, dysglobulinemia

Selective IgM deficiency Selective IgA deficiency Mixed T and B cell deficiency/ dysfunction

Common variable hypogammaglobulinemia

Ataxia-telangiectasia Severe combined immunodeficiency

Wiskott-Aldrich syndrome X-linked hyper-IgM syndrome

THE IMMUNE RESPONSE INNATE IMMUNITY As they have co-evolved with microbes, higher organisms have developed mechanisms for recognizing and responding to microorganisms. Many of these mechanisms, referred together as innate immunity, are evolutionarily ancient, having been conserved from insects to

Listeria monocytogenes, Mycobacterium spp., Candida spp., Aspergillus spp., Cryptococcus neoformans, herpes simplex virus, varicellazoster virus Pneumocystis, cytomegalovirus, herpes simplex virus, Mycobacterium aviumintracellulare, C. neoformans, Candida spp. Candida spp. Fungi, viruses S. pneumoniae, other streptococci H. influenzae, N. meningitidis, S. aureus, Klebsiella pneumoniae, E. coli, Giardia lamblia, Pneumocystis, enteroviruses S. pneumoniae, H. influenzae, E. coli G. lamblia, hepatitis virus, S. pneumoniae, H. influenzae Pneumocystis, cytomegalovirus, S. pneumoniae, H. influenzae, various other bacteria S. pneumoniae, H. influenzae, S. aureus, rubella virus, G. lamblia S. aureus, S. pneumoniae, H. influenzae, Candida albicans, Pneumocystis, varicella-zoster virus, rubella virus, cytomegalovirus Agents of infections associated with T and B cell abnormalities Pneumocystis, cytomegalovirus, Cryptosporidium parvum

humans. In general, innate immune mechanisms exploit molecular patterns found specifically in pathogenic microorganisms. These “pathogen signatures” are recognized by host molecules that either directly interfere with the pathogen or initiate a response that does so. Innate immunity serves to protect the host without prior exposure to an infectious agent, i.e., before specific or adaptive immunity has had a chance to develop.


DISEASE OR THERAPY ASSOCIATED WITH DEFECT

CHAPTER 1

HOST DEFECT

6 Innate immunity also functions as a warning system


that activates components of adaptive immunity early in the course of infection. Toll-like receptors (TLRs) are instructive in illustrating how organisms are detected and send signals to the immune system.There are at least 11 TLRs, each specific to different biologic classes of molecules. For example, even minuscule amounts of lipopolysaccharide (LPS), a molecule found uniquely in gram-negative bacteria, are detected by LPS-binding protein, CD14, and TLR4 (see Fig. 2-3).The interaction of LPS with these components of the innate immune system prompts macrophages, via the transcriptional activator nuclear factor κB (NF-κB), to produce cytokines that lead to inflammation and enzymes that enhance the clearance of microbes. These initial responses serve not only to limit infection but also to initiate specific or adaptive immune responses.

ADAPTIVE IMMUNITY Once in contact with the host immune system, the microorganism faces the host’s tightly integrated cellular and humoral immune responses. Cellular immunity, comprising T lymphocytes, macrophages, and natural killer cells, primarily recognizes and combats pathogens that proliferate intracellularly. Cellular immune mechanisms are important in immunity to all classes of infectious agents, including most viruses and many bacteria (e.g., Mycoplasma, Chlamydophila, Listeria, Salmonella, and Mycobacterium), parasites (e.g., Trypanosoma, Toxoplasma, and Leishmania), and fungi (e.g., Histoplasma, Cryptococcus, and Coccidioides). Usually, T lymphocytes are activated by macrophages and B lymphocytes, which present foreign antigens along with the host’s own major histocompatibility complex antigen to the T-cell receptor. Activated T cells may then act in several ways to fight infection. Cytotoxic T cells may directly attack and lyse host cells that express foreign antigens. Helper T cells stimulate the proliferation of B cells and the production of immunoglobulins. Antigen-presenting cells and T cells communicate with each other via a variety of signals, acting coordinately to instruct the immune system to respond in a specific fashion. T cells elaborate cytokines (e.g., interferon) that directly inhibit the growth of pathogens or stimulate killing by host macrophages and cytotoxic cells. Cytokines also augment the host’s immunity by stimulating the inflammatory response (fever, the production of acute-phase serum components, and the proliferation of leukocytes). Cytokine stimulation does not always result in a favorable response in the host; septic shock (Chap. 15) and toxic shock syndrome (Chaps. 35 and 36) are among the conditions that are mediated by these inflammatory substances. The immune system has also developed cells that specialize in controlling or downregulating immune responses. For example,Treg cells, a subgroup of CD4+ T cells, prevent autoimmune responses by other T cells and are thought to be important in downregulating immune responses to foreign antigens.There appear to be both naturally occurring and acquired Treg cells. The reticuloendothelial system comprises monocytederived phagocytic cells that are located in the liver

(Kupffer cells), lung (alveolar macrophages), spleen (macrophages and dendritic cells), kidney (mesangial cells), brain (microglia), and lymph nodes (macrophages and dendritic cells) and that clear circulating microorganisms. Although these tissue macrophages and polymorphonuclear leukocytes (PMNs) are capable of killing microorganisms without help, they function much more efficiently when pathogens are first opsonized (Greek,“to prepare for eating”) by components of the complement system such as C3b and/or by antibodies. Extracellular pathogens, including most encapsulated bacteria (those surrounded by a complex polysaccharide coat), are attacked by the humoral immune system, which includes antibodies, the complement cascade, and phagocytic cells. Antibodies are complex glycoproteins (also called immunoglobulins) that are produced by mature B lymphocytes, circulate in body fluids, and are secreted on mucosal surfaces. Antibodies specifically recognize and bind to foreign antigens. One of the most impressive features of the immune system is the ability to generate an incredible diversity of antibodies capable of recognizing virtually every foreign antigen yet not reacting with self. In addition to being exquisitely specific for antigens, antibodies come in different structural and functional classes: IgG predominates in the circulation and persists for many years after exposure; IgM is the earliest specific antibody to appear in response to infection; secretory IgA is important in immunity at mucosal surfaces, while monomeric IgA appears in the serum; and IgE is important in allergic and parasitic diseases. Antibodies may directly impede the function of an invading organism, neutralize secreted toxins and enzymes, or facilitate the removal of the antigen (invading organism) by phagocytic cells. Immunoglobulins participate in cell-mediated immunity by promoting the antibody-dependent cellular cytotoxicity functions of certain T lymphocytes. Antibodies also promote the deposition of complement components on the surface of the invader. The complement system consists of a group of serum proteins functioning as a cooperative, self-regulating cascade of enzymes that adhere to—and in some cases disrupt—the surface of invading organisms. Some of these surface-adherent proteins (e.g., C3b) can then act as opsonins for destruction of microbes by phagocytes. The later, “terminal” components (C7, C8, and C9) can directly kill some bacterial invaders (notably, many of the neisseriae) by forming a membrane attack complex and disrupting the integrity of the bacterial membrane, thus causing bacteriolysis. Other complement components, such as C5a, act as chemoattractants for PMNs (see below). Complement activation and deposition occur by either or both of two pathways: the classic pathway is activated primarily by immune complexes (i.e., antibody bound to antigen), and the alternative pathway is activated by microbial components, frequently in the absence of antibody. PMNs have receptors for both antibody and C3b, and antibody and complement function together to aid in the clearance of infectious agents. PMNs, short-lived white blood cells that engulf and kill invading microbes, are first attracted to inflammatory

The clinical manifestations of infectious diseases at presentation are myriad, varying from fulminant lifethreatening processes to brief and self-limited conditions to indolent chronic maladies. A careful history is essential and must include details on underlying chronic diseases, medications, occupation, and travel. Risk factors for exposure to certain types of pathogens may give important clues to diagnosis. A sexual history may reveal risks for exposure to HIV and other sexually transmitted pathogens. A history of contact with animals may suggest numerous diagnoses, including rabies, Q fever, bartonellosis, Escherichia coli O157 infection, or cryptococcosis. Blood transfusions have been linked to diseases ranging from viral hepatitis to malaria to prion disease. A history of exposure to insect vectors (coupled with information about the season and geographic site of exposure) may lead to consideration of such diseases as Rocky Mountain spotted fever, other rickettsial diseases, tularemia, Lyme disease, babesiosis, malaria, trypanosomiasis, and numerous arboviral infections. Ingestion of contaminated liquids or foods may lead to enteric infection with Salmonella, Listeria, Campylobacter, amebas, cryptosporidia, or helminths. Since infectious diseases may involve many organ systems, a careful review of systems may elicit important clues as to the disease process. The physical examination must be thorough, and attention must be paid to seemingly minor details, such as a soft heart murmur that might indicate bacterial endocarditis or a retinal lesion that suggests disseminated candidiasis or cytomegalovirus (CMV) infection. Rashes are extremely important clues to infectious diagnoses and may be the only sign pointing to a specific etiology (Chaps. 8 and 10). Certain rashes are so specific as to be pathognomonic—e.g., the childhood exanthems (measles, rubella, varicella), the target lesion of erythema migrans (Lyme disease), ecthyma gangrenosum (Pseudomonas aeruginosa), and eschars (rickettsial diseases). Other rashes, although

LABORATORY INVESTIGATIONS Laboratory studies must be carefully considered and directed toward establishing an etiologic diagnosis in the shortest possible time, at the lowest possible cost, and with the least possible discomfort to the patient. Since mucosal surfaces and the skin are colonized with many harmless or beneficial microorganisms, cultures must be performed in a manner that minimizes the likelihood of contamination with this normal flora while maximizing the yield of pathogens. A sputum sample is far more likely to be valuable when elicited with careful coaching by the clinician than when collected in a container simply left at the bedside with cursory instructions. Gram’s stains of specimens should be interpreted carefully and the quality of the specimen assessed. The findings on Gram’s staining should correspond to the results of culture; a discrepancy may suggest diagnostic possibilities such as infection due to fastidious or anaerobic bacteria. The microbiology laboratory must be an ally in the diagnostic endeavor. Astute laboratory personnel will suggest optimal culture and transport conditions or alternative tests to facilitate diagnosis. If informed about specific potential pathogens, an alert laboratory staff will allow sufficient time for these organisms to become evident in culture, even when the organisms are present in small numbers or are slow-growing. The parasitology technician who is attuned to the specific diagnostic considerations relevant to a particular case may be able to detect the rare, otherwise-elusive egg or cyst in a stool specimen. In cases where a diagnosis appears difficult, serum should be stored during the early acute phase of the illness so that a diagnostic rise in titer of antibody to a specific pathogen can be detected later. Bacterial and fungal antigens can sometimes be detected in body fluids, even when cultures are negative or are rendered sterile by antibiotic therapy. Techniques such as the polymerase chain reaction allow the amplification of specific DNA sequences so that minute quantities of foreign nucleic acids can be recognized in host specimens.

7


Approach to the Patient: INFECTIOUS DISEASES

less specific, may be exceedingly important diagnostic indicators. The prompt recognition of the early scarlatiniform and later petechial rashes of meningococcal infection or of the subtle embolic lesions of disseminated fungal infections in immunosuppressed patients can hasten life-saving therapy. Fever (Chaps. 7, 8, and 9) is a common manifestation of infection and may be its sole apparent indication. Sometimes the pattern of fever or its temporally associated findings may help refine the differential diagnosis. For example, fever occurring every 48–72 h is suggestive of malaria (Chap. 116). The elevation of body temperature in fever (through resetting of the hypothalamic setpoint mediated by cytokines) must be distinguished from elevations in body temperature from other causes, such as drug toxicity (Chap. 9) or heat stroke (Chap. 7).

CHAPTER 1

sites by chemoattractants such as C5a, which is a product of complement activation at the site of infection. PMNs localize to the site of infection by adhering to cellular adhesion molecules expressed by endothelial cells. Endothelial cells express these receptors, called selectins (CD-62, ELAM-1), in response to inflammatory cytokines such as tumor necrosis factor α and interleukin 1. The binding of these selectin molecules to specific receptors on PMNs results in the adherence of the PMNs to the endothelium. Cytokine-mediated upregulation and expression of intercellular adhesion molecule 1 (ICAM 1) on endothelial cells then take place, and this latter receptor binds to β2 integrins on PMNs, thereby facilitating diapedesis into the extravascular compartment. Once the PMNs are in the extravascular compartment, various molecules (e.g., arachidonic acids) further enhance the inflammatory process.

8

Treatment: INFECTIOUS DISEASES


Optimal therapy for infectious diseases requires a broad knowledge of medicine and careful clinical judgment. Life-threatening infections such as bacterial meningitis or sepsis, viral encephalitis, or falciparum malaria must be treated immediately, often before a specific causative organism is identified. Antimicrobial agents must be chosen empirically and must be active against the range of potential infectious agents consistent with the clinical scenario. In contrast, good clinical judgment sometimes dictates withholding of antimicrobial drugs in a self-limited process or until a specific diagnosis is made. The dictum primum non nocere should be adhered to, and it should be remembered that all antimicrobial agents carry a risk (and a cost) to the patient. Direct toxicity may be encountered—e.g., ototoxicity due to aminoglycosides, lipodystrophy due to antiretroviral agents, and hepatotoxicity due to antituberculous agents such as isoniazid and rifampin. Allergic reactions are common and can be serious. Since superinfection sometimes follows the eradication of the normal flora and colonization by a resistant organism, one invariant principle is that infectious disease therapy should be directed toward as narrow a spectrum of infectious agents as possible.Treatment specific for the pathogen should result in as little perturbation as possible of the host’s microflora. Indeed, future therapeutic agents may act not by killing a microbe, but by interfering with one or more of its virulence factors. With few exceptions, abscesses require surgical or percutaneous drainage for cure. Foreign bodies, including medical devices, must generally be removed in order to eliminate an infection of the device or of the adjacent tissue. Other infections, such as necrotizing fasciitis, peritonitis due to a perforated organ, gas gangrene, and chronic osteomyelitis, require surgery as the primary means of cure; in these conditions, antibiotics play only an adjunctive role. The role of immunomodulators in the management of infectious diseases has received increasing attention. Glucocorticoids have been shown to be of benefit in the adjunctive treatment of bacterial meningitis and in therapy for Pneumocystis pneumonia in patients with AIDS. The use of these agents in other infectious processes remains less clear and in some cases (in cerebral malaria, for example) is detrimental. Activated protein C (drotrecogin alfa, activated) is the first immunomodulatory agent widely available for the treatment of severe sepsis. Its usefulness demonstrates the interrelatedness of the clotting cascade and systemic immunity. Other agents that modulate the immune response include prostaglandin inhibitors, specific lymphokines, and tumor necrosis factor inhibitors. Specific antibody therapy plays a role in the treatment and prevention of many diseases. Specific immunoglobulins have long been known to prevent the development of symptomatic rabies and tetanus. More recently, CMV immune globulin has been recognized as important not only in preventing the transmission of the virus during organ

transplantation, but also in treating CMV pneumonia in bone marrow transplant recipients. There is a strong need for well-designed clinical trials to evaluate each new interventional modality.

PERSPECTIVE The genetic simplicity of many infectious agents allows them to undergo rapid evolution and to develop selective advantages that result in constant variation in the clinical manifestations of infection. Moreover, changes in the environment and the host can predispose new populations to a particular infection.The dramatic march of West Nile virus from a single focus in New York City in 1999 to locations throughout the North American continent by the summer of 2002 caused widespread alarm, illustrating the fear that new plagues induce in the human psyche.The intentional release of deadly spores of Bacillus anthracis via the U.S. Postal Service awakened many from a sense of complacency regarding biologic weapons. “The terror of the unknown is seldom better displayed than by the response of a population to the appearance of an epidemic, particularly when the epidemic strikes without apparent cause.” Edward H. Kass made this statement in 1977 in reference to the newly discovered Legionnaire’s disease, but it could apply equally to SARS, H5N1 (avian) influenza, or any other new and mysterious disease. The potential for infectious agents to emerge in novel and unexpected ways requires that physicians and public health officials be knowledgeable, vigilant, and open-minded in their approach to unexplained illness. The emergence of antimicrobialresistant pathogens (e.g., enterococci that are resistant to all known antimicrobial agents and cause infections that are essentially untreatable) has led some to conclude that we are entering the “postantibiotic era.” Others have held to the perception that infectious diseases no longer represent as serious a concern to world health as they once did. The progress that science, medicine, and society as a whole have made in combating these maladies is impressive, and it is ironic that, as we stand on the threshold of an understanding of the most basic biology of the microbe, infectious diseases are posing renewed problems. We are threatened by the appearance of new diseases such as SARS, hepatitis C, and Ebola virus infection and by the reemergence of old foes such as tuberculosis, cholera, plague, and Streptococcus pyogenes infection. True students of infectious diseases were perhaps less surprised than anyone else by these developments. Those who know pathogens are aware of their incredible adaptability and diversity. As ingenious and successful as therapeutic approaches may be, our ability to develop methods to counter infectious agents so far has not matched the myriad strategies employed by the sea of microbes that surrounds us.Their sheer numbers and the rate at which they can evolve are daunting. Moreover, environmental changes, rapid global travel, population movements, and medicine itself—through its use of antibiotics and immunosuppressive agents—all increase

FURTHER READINGS

CHAPTER 2

MOLECULAR MECHANISMS OF MICROBIAL PATHOGENESIS Gerald B. Pier Over the past three decades, molecular studies of the pathogenesis of microorganisms have yielded an explosion of information about the various microbial and host molecules that contribute to the processes of infection and disease. These processes can be classified into several stages: microbial encounter with and entry into the host; microbial growth after entry; avoidance of innate host defenses; tissue invasion and tropism; tissue damage; and transmission to new hosts. Virulence is the measure of an organism’s capacity to cause disease and is a function of the pathogenic factors elaborated by microbes. These factors promote colonization (the simple presence of potentially pathogenic microbes in or on a host), infection (attachment and growth of pathogens and avoidance of host defenses), and disease (often, but not always, the result of activities of secreted toxins or toxic metabolites). In addition, the host’s inflammatory response to infection greatly contributes to disease and its attendant clinical signs and symptoms.

MICROBIAL ENTRY AND ADHERENCE ENTRY SITES A microbial pathogen can potentially enter any part of a host organism. In general, the type of disease produced by a particular microbe is often a direct consequence of

its route of entry into the body.The most common sites of entry are mucosal surfaces (the respiratory, alimentary, and urogenital tracts) and the skin. Ingestion, inhalation, and sexual contact are typical routes of microbial entry. Other portals of entry include sites of skin injury (cuts, bites, burns, trauma) along with injection via natural (i.e., vector-borne) or artificial (i.e., needlestick) routes. A few pathogens, such as Schistosoma spp., can penetrate unbroken skin. The conjunctiva can serve as an entry point for pathogens of the eye. Microbial entry usually relies on the presence of specific microbial factors needed for persistence and growth in a tissue. Fecal-oral spread via the alimentary tract requires a biology consistent with survival in the varied environments of the gastrointestinal tract (including the low pH of the stomach and the high bile content of the intestine) as well as in contaminated food or water outside the host. Organisms that gain entry via the respiratory tract survive well in small moist droplets produced during sneezing and coughing. Pathogens that enter by venereal routes often survive best on the warm moist environment of the urogenital mucosa and have restricted host ranges (e.g., Neisseria gonorrhoeae, Treponema pallidum, and HIV). The biology of microbes entering through the skin is highly varied. Some organisms can survive in a broad range of environments, such as the salivary glands or

9

Molecular Mechanisms of Microbial Pathogenesis

ARMSTRONG G et al: Trends in infectious disease mortality in the United States during the 20th century. JAMA 281:61, 1999 BARTLETT JG: Update in infectious diseases.Ann Intern Med 144:49, 2006 BLASER MJ: Introduction to bacteria and bacterial diseases, in Principles and Practice of Infectious Diseases, 6th ed, GL Mandell et al (eds). Philadelphia, Elsevier, 2005, p 2319

HENDERSON DA: Countering the posteradication threat of smallpox and polio. Clin Infect Dis 34:79, 2002 HOFFMAN J et al: Phylogenetic perspectives in innate immunity. Science 284:1313, 1999 HUNG DT et al: Small-molecule inhibitor of Vibrio cholerae virulence and intestinal colonization. Science 310:670, 2005 PROMED-MAIL: The Program for Monitoring Emerging Diseases. www.promedmail.org PUCK JM: Primary immunodeficiency diseases. JAMA 278:1835, 1997 TYLER KL, NATHANSON N: Pathogenesis of viral infections, in Fields Virology, DM Knipe, PM Howley (eds). Philadelphia, Lippincott Williams & Wilkins, 2001, pp 199-244 WEISS ST: Eat dirt—the hygiene hypothesis and allergic diseases. N Engl J Med 347:930, 2002

CHAPTER 2

the impact of infectious diseases. Although new vaccines, new antibiotics, improved global communication, and new modalities for treating and preventing infection will be developed, pathogenic microbes will continue to develop new strategies of their own, presenting us with an unending and dynamic challenge.

10 alimentary tracts of arthropod vectors, the mouths of


larger animals, soil, and water. A complex biology allows protozoan parasites such as Plasmodium, Leishmania, and Trypanosoma spp. to undergo morphogenic changes that permit transmission to mammalian hosts during insect feeding for blood meals. Plasmodia are injected as infective sporozoites from the salivary glands during mosquito feeding. Leishmania parasites are regurgitated as promastigotes from the alimentary tract of sandflies and are injected by bite into a susceptible host. Trypanosomes are ingested from infected hosts by reduviid bugs, multiply in the insects’ gastrointestinal tract, and are released in feces onto the host’s skin during subsequent feedings. Most microbes that land directly on intact skin are destined to die, as survival on the skin or in hair follicles requires resistance to fatty acids, low pH, and other antimicrobial factors on skin. Once it is damaged (and particularly if it becomes necrotic), the skin can be a major portal of entry and growth for pathogens

and elaboration of their toxic products. Burn wound infections and tetanus are clear examples. After animal bites, pathogens resident in the animal’s saliva gain access to the victim’s tissues through the damaged skin. Rabies is the paradigm for this pathogenic process; rabies virus grows in striated muscle cells at the site of inoculation.

MICROBIAL ADHERENCE Once in or on a host, most microbes must anchor themselves to a tissue or tissue factor; the possible exceptions are organisms that directly enter the bloodstream and multiply there. Specific ligands or adhesins for host receptors constitute a major area of study in the field of microbial pathogenesis. Adhesins comprise a wide range of surface structures, not only anchoring the microbe to a tissue and promoting cellular entry where appropriate, but also eliciting host responses critical to the pathogenic process (Table 2-1). Most microbes produce multiple adhesins specific for multiple host receptors. These

TABLE 2-1 EXAMPLES OF MICROBIAL LIGAND-RECEPTOR INTERACTIONS MICROORGANISM

TYPE OF MICROBIAL LIGAND

HOST RECEPTOR

Hemagglutinin

Sialic acid

Hemagglutinin Hemagglutinin ? Glycoprotein C Surface glycoprotein Envelope protein Fiber protein Viral coat proteins

CD46/moesin Signaling lymphocytic activation molecule (SLAM) CD46 Heparan sulfate CD4 and chemokine receptors (CCR5 and CXCR4) CD21 (=CR2) Coxsackie-adenovirus receptor (CAR) CAR and major histocompatibility class I antigens

Neisseria spp. Pseudomonas aeruginosa

Pili Pili and flagella Lipopolysaccharide

Escherichia coli Streptococcus pyogenes Yersinia spp. Bordetella pertussis Legionella pneumophila Mycobacterium tuberculosis

Pili Hyaluronic acid capsule Invasin/accessory invasin locus Filamentous hemagglutinin Adsorbed C3bi Adsorbed C3bi

Membrane cofactor protein (CD46) Asialo-GM1 Cystic fibrosis transmembrane conductance regulator (CFTR) Ceramides/mannose and digalactosyl residues CD44 β1 Integrins CR3 CR3 CR3; DC-SIGNa

WI-1 Int1p

Possibly matrix proteins and integrins Extracellular matrix proteins

Merozoite form Erythrocyte-binding protein 175 (EBA-175) Surface lectin

Duffy Fy antigen Glycophorin A

Viral Pathogens Influenza virus Measles virus Vaccine strain Wild-type strains Human herpesvirus type 6 Herpes simplex virus HIV Epstein-Barr virus Adenovirus Coxsackievirus Bacterial Pathogens

Fungal Pathogens Blastomyces dermatitidis Candida albicans Protozoal Pathogens Plasmodium vivax Plasmodium falciparum Entamoeba histolytica a

A novel dendritic cell–specific C-type lectin.

N-Acetylglucosamine

Bacterial Adhesins Among the microbial adhesins studied in greatest detail are bacterial pili and flagella (Fig. 2-1). Pili or fimbriae are commonly used by gram-negative and gram-positive bacteria for attachment to host cells and tissues. In electron micrographs, these hairlike projections (up to several hundred per cell) may be confined to one end of

A

B

C

FIGURE 2-1 Bacterial surface structures. A and B. Traditional electron micrographic images of fixed cells of Pseudomonas aeruginosa. Flagella (A) and pili (B) projecting out from the bacterial poles can be seen. C and D. Atomic force microscopic image of live P. aeruginosa freshly planted onto a

D

smooth mica surface. This technology reveals the fine, three-dimensional detail of the bacterial surface structures. (Images courtesy of Dr. Martin Lee and Dr. Milan Bajmoczi, Harvard Medical School; with permission.)

11


Viral Adhesins (See also Chap. 69) All viral pathogens must bind to host cells, enter them, and replicate within them.Viral coat proteins serve as the ligands for cellular entry, and more than one ligand-receptor interaction may be needed; for example, HIV uses its envelope glycoprotein (gp) 120 to enter host cells by binding to both CD4 and one of two receptors for chemokines (designated CCR5 and CXCR4). Similarly, the measles virus H glycoprotein binds to both CD46 and the membrane-organizing protein moesin on host cells. The gB and gC proteins on herpes simplex virus bind to heparan sulfate; this adherence is not essential for entry, but rather serves to concentrate virions close to the cell surface. This step is followed by attachment to mammalian cells mediated by the viral gD protein. Herpes simplex virus can use a number of eukaryotic cell surface receptors for entry, including the herpesvirus entry mediator (related to the tumor necrosis factor receptor); members of the immunoglobulin superfamily; two proteins called nectin-1 and nectin-2; and modified heparan sulfate.

the organism (polar pili) or distributed more evenly over the surface. An individual cell may have pili with a variety of functions. Most pili are made up of a major pilin protein subunit (molecular weight, 17,000-30,000) that polymerizes to form the pilus. Many strains of Escherichia coli isolated from urinary tract infections express mannose-binding type 1 pili, whose binding to the integral membrane glycoproteins called uroplakins that coat the cells in the bladder epithelium is inhibited by D-mannose. Other strains produce the Pap (pyelonephritis-associated) or P pilus adhesin that mediates binding to digalactose (gal-gal) residues on globosides of the human P blood groups. Both of these types of pili have proteins located at the tips of the main pilus unit that are critical to the binding specificity of the whole pilus unit. It is interesting that, although immunization with the mannose-binding tip protein (FimH) of type 1 pili prevents experimental E. coli bladder infections in mice and monkeys, a trial of this vaccine in humans was not successful. E. coli cells causing diarrheal disease express pilus-like receptors for enterocytes on the small bowel, along with other receptors termed colonization factors. The type IV pilus, a common type of pilus found in Neisseria spp., Moraxella spp., Vibrio cholerae, Legionella pneumophila, Salmonella enterica serovar typhi, enteropathogenic E. coli, and Pseudomonas aeruginosa, mediates adherence of these organisms to target surfaces.These pili tend to have a relatively conserved amino-terminal region and a more variable carboxyl-terminal region. For some species (e.g., N. gonorrhoeae, N. meningitidis, and enteropathogenic E. coli), the pili are critical for attachment to mucosal epithelial cells. For others, such as P. aeruginosa, the pili only partially mediate the cells’ adherence to host tissues.Whereas interference with this stage of colonization would appear to be an effective antibacterial strategy, attempts to develop pilus-based vaccines for human diseases have not been highly successful to date.

CHAPTER 2

adhesins are often redundant, are serologically variable, and act additively or synergistically with other microbial factors to promote microbial sticking to host tissues. In addition, some microbes adsorb host proteins onto their surface and utilize the natural host protein receptor for microbial binding and entry into target cells.

12


Flagella are long appendages attached at either one or both ends of the bacterial cell (polar flagella) or distributed over the entire cell surface (peritrichous flagella). Flagella, like pili, are composed of a polymerized or aggregated basic protein. In flagella, the protein subunits form a tight helical structure and vary serologically with the species. Spirochetes such as T. pallidum and Borrelia burgdorferi have axial filaments similar to flagella running down the long axis of the center of the cell, and they “swim” by rotation around these filaments. Some bacteria can glide over a surface in the absence of obvious motility structures. Other bacterial structures involved in adherence to host tissues include specific staphylococcal and streptococcal proteins that bind to human extracellular matrix proteins such as fibrin, fibronectin, fibrinogen, laminin, and collagen. Fibronectin appears to be a commonly used receptor for various pathogens; a particular amino acid sequence in fibronectin (Arg-Gly-Asp, or RGD) is critical for bacterial binding. Binding of the highly conserved Staphylococcus aureus surface protein clumping factor A (ClfA) to fibrinogen has been implicated in many aspects of pathogenesis. The conserved outer-core portion of the lipopolysaccharide (LPS) of P. aeruginosa mediates binding to the cystic fibrosis transmembrane conductance regulator (CFTR) on airway epithelial cells-an event that appears to be critical for normal host resistance to infection. A number of bacterial pathogens, including coagulase-negative staphylococci, S. aureus, and uropathogenic E. coli as well as Yersinia pestis, Y. pseudotuberculosis, and Y. enterocolitica, express a surface polysaccharide composed of poly-N-acetylglucosamine. One function of this polysaccharide is to promote binding to materials used in catheters and other types of implanted devices; poly-N-acetylglucosamine may be a critical factor in the establishment of device-related infections by pathogens such as staphylococci and E. coli. High-powered imaging techniques (e.g., atomic force microscopy) have revealed that bacterial cells have a nonhomogeneous surface that is probably attributable to different concentrations of cell surface molecules, including microbial adhesins, at specific places on the cell surface (Fig 2-1D). Fungal Adhesins Several fungal adhesins have been described that mediate colonization of epithelial surfaces, particularly adherence to structures like fibronectin, laminin, and collagen. The product of the Candida albicans INT1 gene, Int1p, bears similarity to mammalian integrins that bind to extracellular matrix proteins. Transformation of normally nonadherent Saccharomyces cerevisiae with this gene allows these yeast cells to adhere to human epithelial cells. The agglutinin-like sequence (ALS) adhesins are large cell-surface glycoproteins mediating adherence of pathogenic Candida to host tissues. These adhesins are expressed under certain environmental conditions (often associated with stress) and are crucial for pathogenesis of fungal infections. For several fungal pathogens that initiate infections after inhalation, the inoculum is ingested by alveolar

macrophages, in which the fungal cells transform to pathogenic phenotypes. Eukaryotic Pathogen Adhesins Eukaryotic parasites use complicated surface glycoproteins as adhesins, some of which are lectins (proteins that bind to specific carbohydrates on host cells). For example, Plasmodium vivax binds (via Duffy-binding protein) to the Duffy blood group carbohydrate antigen Fy on erythrocytes. Entamoeba histolytica expresses two proteins that bind to the disaccharide galactose/N-acetylgalactosamine. Reports indicate that children with mucosal IgA antibody to one of these lectins are resistant to reinfection with virulent E. histolytica. A major surface glycoprotein (gp63) of Leishmania promastigotes is needed for these parasites to enter human macrophages—the principal target cell of infection. This glycoprotein promotes complement binding but inhibits complement lytic activity, allowing the parasite to use complement receptors for entry into macrophages; gp63 also binds to fibronectin receptors on macrophages. In addition, the pathogen can express a carbohydrate that mediates binding to host cells. Evidence suggests that, as part of hepatic granuloma formation, Schistosoma mansoni expresses a carbohydrate epitope related to the Lewis X blood group antigen that promotes adherence of helminthic eggs to vascular endothelial cells under inflammatory conditions.

HOST RECEPTORS Host receptors are found both on target cells (e.g., epithelial cells lining mucosal surfaces) and within the mucous layer covering these cells. Microbial pathogens bind to a wide range of host receptors to establish infection (Table 2-1). Selective loss of host receptors for a pathogen may confer natural resistance to an otherwise susceptible population. For example, 70% of individuals in West Africa lack Fy antigens and are resistant to P. vivax infection. S. enterica serovar typhi, the etiologic agent of typhoid fever, uses CFTR to enter the gastrointestinal submucosa after being ingested. As homozygous mutations in CFTR are the cause of the life-shortening disease cystic fibrosis, heterozygote carriers (e.g., 4–5% of individuals of European ancestry) may have had a selective advantage due to decreased susceptibility to typhoid fever. Numerous virus–target cell interactions have been described, and it is now clear that different viruses can use similar host-cell receptors for entry.The list of certain and likely host receptors for viral pathogens is long. Among the host membrane components that can serve as receptors for viruses are sialic acids, gangliosides, glycosaminoglycans, integrins and other members of the immunoglobulin superfamily, histocompatibility antigens, and regulators and receptors for complement components. A notable example of the effect of host receptors on the pathogenesis of infection comes from comparative binding studies of avian influenza A virus subtype H5N1 and influenza A virus strains expressing hemagglutinin subtype H1. The H1-subtype strains, which tend to be highly pathogenic and transmissible from human to human, bind to a receptor composed of two sugar molecules:

Once established on a mucosal or skin site, pathogenic microbes must replicate before causing full-blown infection and disease. Within cells, viral particles release their nucleic acids, which may be directly translated into viral proteins (positive-strand RNA viruses), transcribed from a negative strand of RNA into a complementary mRNA (negative-strand RNA viruses), or transcribed into a complementary strand of DNA (retroviruses); for DNA viruses, mRNA may be transcribed directly from viral DNA, either in the cell nucleus or in the cytoplasm. To grow, bacteria must acquire specific nutrients or synthesize them from precursors in host tissues. Many infectious processes are usually confined to specific epithelial surfaces—e.g., H1-subtype influenza to the respiratory mucosa, gonorrhea to the urogenital epithelium, and shigellosis to the gastrointestinal epithelium. Although there are multiple reasons for this specificity, one important consideration is the ability of these pathogens to obtain from these specific environments the nutrients needed for growth and survival. Temperature restrictions also play a role in limiting certain pathogens to specific tissues. Rhinoviruses, a cause of the common cold, grow best at 33°C and replicate in cooler nasal tissues, but not as well in the lung. Leprosy lesions due to Mycobacterium leprae are found in and on relatively cool body sites. Fungal pathogens that infect the skin, hair follicles, and nails (dermatophyte infections) remain confined to the cooler, exterior, keratinous layer of the epithelium. Many bacterial, fungal, and protozoal species grow in multicellular masses referred to as biofilms.These masses are biochemically and morphologically quite distinct from the free-living individual cells referred to as planktonic cells. Growth in biofilms leads to altered microbial metabolism, production of extracellular virulence factors, and decreased susceptibility to biocides, antimicrobial agents, and host defense molecules and cells. P. aeruginosa growing on the bronchial mucosa during chronic infection, staphylococci and other pathogens growing on implanted medical devices, and dental pathogens growing on tooth surfaces to form plaques represent several examples of microbial biofilm growth associated with human disease. Many other pathogens can form biofilms during in vitro growth, and it is increasingly accepted that this mode of growth contributes to microbial virulence and induction of disease.

Because microbes have probably interacted with mucosal/ epithelial surfaces since the emergence of multicellular organisms, it is not surprising that multicellular hosts have a variety of innate surface defense mechanisms that can sense when pathogens are present and contribute to their elimination. The skin is acidic and is bathed with fatty acids toxic to many microbes. Skin pathogens such as staphylococci must tolerate these adverse conditions. Mucosal surfaces are covered by a barrier composed of a thick mucous layer that entraps microbes and facilitates their transport out of the body by such processes as mucociliary clearance, coughing, and urination. Mucous secretions, saliva, and tears contain antibacterial factors such as lysozyme and antimicrobial peptides as well as antiviral factors such as interferons. Gastric acidity is inimical to the survival of many ingested pathogens, and most mucosal surfaces—particularly the nasopharynx, the vaginal tract, and the gastrointestinal tract—contain a resident flora of commensal microbes that interfere with the ability of pathogens to colonize and infect a host. Pathogens that survive these factors must still contend with host endocytic, phagocytic, and inflammatory responses as well as with host genetic factors that determine the degree to which a pathogen can survive and grow. The growth of viral pathogens entering skin or mucosal epithelial cells can be limited by a variety of host genetic factors, including production of interferons, modulation of receptors for viral entry, and age- and hormone-related susceptibility factors; by nutritional status; and even by personal habits such as smoking and exercise.

ENCOUNTERS WITH EPITHELIAL CELLS Over the past decade, many bacterial pathogens have been shown to enter epithelial cells (Fig. 2-2); the bacteria often use specialized surface structures that bind to receptors, with consequent internalization. However, the exact role and the importance of this process in infection and disease are not well defined for most of these pathogens. Bacterial entry into host epithelial cells is seen as a means for dissemination to adjacent or deeper tissues or as a route to sanctuary to avoid ingestion and killing by professional phagocytes. Epithelial cell entry appears, for instance, to be a critical aspect of dysentery induction by Shigella. Curiously, the less virulent strains of many bacterial pathogens are more adept at entering epithelial cells than are more virulent strains; examples include pathogens that lack the surface polysaccharide capsule needed to cause serious disease.Thus, for Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus agalactiae (group B Streptococcus). and Streptococcus pyogenes, isogenic mutants or variants lacking capsules enter epithelial cells better than the wild-type, encapsulated parental forms that cause disseminated disease. These observations have led to the proposal that epithelial cell entry may be primarily a

13


MICROBIAL GROWTH AFTER ENTRY

AVOIDANCE OF INNATE HOST DEFENSES

CHAPTER 2

sialic acid linked α-2-6 to galactose. This receptor is highly expressed in the airway epithelium.When virus is shed from this surface, its transmission via coughing and aerosol droplets is readily facilitated. In contrast, H5N1 avian influenza virus binds to sialic acid linked α-2-3 to galactose, and this receptor is highly expressed in pneumocytes in the alveoli. Alveolar infection is thought to underlie not only the high mortality rate associated with avian influenza but also the low human-to-human transmissibility rate of this strain, which is not readily transported to the airways (from which it could be expelled by coughing).

14


A

B

FIGURE 2-2 Entry of bacteria into epithelial cells. A. Internalization of P. aeruginosa by cultured human airway epithelial cells expressing wild-type cystic fibrosis transmembrane conductance regulator (CFTR), the cell receptor for bacterial ingestion. B. Entry of P. aeruginosa into murine tracheal epithelial cells after infection by the intranasal route.

manifestation of host defense, resulting in bacterial clearance by both shedding of epithelial cells containing internalized bacteria and initiation of a protective and nonpathogenic inflammatory response. However, a possible consequence of this process could be the opening of a hole in the epithelium, potentially allowing uningested organisms to enter the submucosa.This scenario has been documented in murine S. enterica serovar typhimurium infections and in experimental bladder infections with uropathogenic E. coli. In the latter system, bacterial pilus–mediated attachment to uroplakins induces exfoliation of the cells with attached bacteria. Subsequently, infection is produced by residual bacterial cells that invade the superficial bladder epithelium, where they can grow intracellularly into biofilm-like masses encased in an extracellular polysaccharide-rich matrix and surrounded by uroplakin. This mode of growth produces

structures that have been referred to as bacterial pods. At low bacterial inocula, epithelial cell ingestion and subclinical inflammation are probably efficient means to eliminate pathogens; in contrast, at higher inocula, a proportion of surviving bacterial cells enter host tissue through the damaged mucosal surface and multiply, producing disease. Alternatively, failure of the appropriate epithelial cell response to a pathogen may allow the organism to survive on a mucosal surface where, if it avoids other host defenses, it can grow and cause a local infection. Along these lines, as noted above, P. aeruginosa is taken into epithelial cells by CFTR, a protein missing or nonfunctional in most severe cases of cystic fibrosis. The major clinical consequence is chronic airwaysurface infection with P. aeruginosa in 80–90% of patients with cystic fibrosis. The failure of airway epithelial cells to ingest and promote the removal of P. aeruginosa via a properly regulated inflammatory response has been proposed as a key component of the hypersusceptibility of these patients to chronic airway infection with this organism.

ENCOUNTERS WITH PHAGOCYTES Phagocytosis and Inflammation Phagocytosis of microbes is a major innate host defense that limits the growth and spread of pathogens. Phagocytes appear rapidly at sites of infection in conjunction with the initiation of inflammation. Ingestion of microbes by both tissue-fixed macrophages and migrating phagocytes probably accounts for the limited ability of most microbial agents to cause disease.A family of related molecules called collectins, soluble defense collagens, or pattern-recognition molecules are found in blood (mannose-binding lectins), in lung (surfactant proteins A and D), and most likely in other tissues as well and bind to carbohydrates on microbial surfaces to promote phagocyte clearance. Bacterial pathogens seem to be ingested principally by polymorphonuclear neutrophils (PMNs), whereas eosinophils are frequently found at sites of infection with protozoan or multicellular parasites. Successful pathogens, by definition, must avoid being cleared by professional phagocytes. One of several antiphagocytic strategies employed by bacteria and by the fungal pathogen Cryptococcus neoformans is to elaborate large-molecular-weight surface polysaccharide antigens, often in the form of a capsule that coats the cell surface. Most pathogenic bacteria produce such antiphagocytic capsules. On occasion, proteins or polypeptides form capsule-like coatings on organisms such as Bacillus anthracis. Because activation of local phagocytes in tissues is a key step in initiating inflammation and migration of additional phagocytes into infected sites, much attention has been paid to microbial factors that initiate inflammation. Encounters with phagocytes are governed largely by the structure of the microbial constituents that elicit inflammation, and detailed knowledge of these structures for bacterial pathogens has contributed greatly to our understanding of molecular mechanisms of microbial pathogenesis (Fig. 2-3). One of the beststudied systems involves the interaction of LPS from

15 LPS, mycobacterial products

TLR2

Phagosome lumen

IL-1Rc type 1

TLR4 CD14

MD-2

MyD88

TIRAP/Mal

IRAK4 IRAK1 PI3K

Cytoplasm

TRAF-6

RIP2

Ubc13

UEV1A TAB2

Akt

TAK-1 TAB3

TAB1 MKK (JNK)

IKK-α,β,γ/ NEMO

PP IκBα

MAPK

IκBα p65 p60

DEGRADATION AP-1

NF-κB Nucleus

FIGURE 2-3 Cellular signaling pathways for production of inflammatory cytokines in response to microbial products. Various microbial cell-surface constituents interact with CD14, which in turn interacts in a currently unknown fashion with Toll-like receptors (TLRs). Some microbial factors do not need CD14 to interact with TLRs. Associating with TLR4 (and to some extent with TLR2) is MD-2, a cofactor that facilitates the response to lipopolysaccharide (LPS). Both CD14 and TLRs contain extracellular leucine-rich domains that become localized to the lumen of the phagosome upon uptake of bacterial cells; there, the TLRs can bind to microbial products. The TLRs are oligomerized, usually forming homodimers, and then bind to the general adaptor protein MyD88 via the C-terminal Toll/ IL-1R (TIR) domains, which also bind to TIRAP (TIR domaincontaining adaptor protein), a molecule that participates in the transduction of signals from TLR4. The MyD88/TIRAP complex activates signal-transducing molecules such as IRAK1 and IRAK4 (IL-1Rc-associated kinases 1 and 4); TRAF-6 (tumor necrosis factor receptor–associated factor 6); TAK-1 (transforming growth factor β-activating kinase 1); and TAB1, TAB2, and TAB3 (TAK1-binding proteins 1, 2, and 3). This signaling complex associates with the ubiquitin-conjugating

enzyme Ubc13 and the Ubc-like protein UEV1A to catalyze the formation of a polyubiquitin chain on TRAF6. Polyubiquitination of TRAF6 activates TAK1, which, along with TAB2 (a protein that binds to lysine residue 63 in polyubiquitin chains via a conserved zinc-finger domain), phosphorylates the inducible kinase complex IKK-α, -β, and -γ. IKK-γ is also called NEMO [nuclear factor κB (NF-κB) essential modulator]. This large complex then phosphorylates the inhibitory component of NF-κB, IκBα, resulting in release of IκBα from NF-κB. Phosphorylated (PP) IκB is then degraded, and the two components of NF-κB, p50 and p65, translocate to the nucleus, where they bind to regulatory transcriptional sites on target genes, many of which encode inflammatory proteins. In addition to inducing NF-κB nuclear translocation, TAK1 also activates MAP kinase transducers such as the c-Jun N-terminal kinase (JNK) pathway, which can lead to nuclear translocation of the transcription factor AP1. Via the RIP2 protein, TRAF6 bound to IRAK can activate phosphatidylinositol-3 kinase (PI3K) and the regulatory protein Akt to dissociate NF−κB from IκBα, an event followed by translocation of the active NF-κB to the nucleus. (Figure modified from an original produced by Dr. Terry Means and Dr. Douglas Golenbock.)


MyD88

CHAPTER 2

Mycobacterial products Peptidoglycan Lipoteichoic acid Lipopeptides (spirochetes)

16 gram-negative bacteria and the glycosylphosphatidyli-


nositol (GPI)-anchored membrane protein CD14 found on the surface of professional phagocytes, including migrating and tissue-fixed macrophages and PMNs. A soluble form of CD14 is also found in plasma and on mucosal surfaces. A plasma protein, LPS-binding protein (LBP), transfers LPS to membrane-bound CD14 on myeloid cells and promotes binding of LPS to soluble CD14. Soluble CD14/LPS/LBP complexes bind to many cell types and may be internalized to initiate cellular responses to microbial pathogens. It has been shown that peptidoglycan and lipoteichoic acid from gram-positive bacteria and cell-surface products of mycobacteria and spirochetes can interact with CD14 (Fig. 2-3). Additional molecules, such as MD-2, also participate in the recognition of bacterial activators of inflammation. GPI-anchored receptors do not have intracellular signaling domains. Instead, the mammalian Toll-like receptors (TLRs) transduce signals for cellular activation due to LPS binding. It has recently been shown that binding of microbial factors to TLRs to activate signal transduction occurs not on the cell surface, but rather in the phagosome of cells that have internalized the microbe. This interaction is probably due to the release of the microbial surface factor from the cell in the environment of the phagosome, where the liberated factor can bind to its cognate TLRs.TLRs initiate cellular activation through a series of signal-transducing molecules (Fig. 2-3) that lead to nuclear translocation of the transcription factor nuclear factor κB (NF-κB), a master-switch for production of important inflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukin (IL) 1. Inflammation can be initiated not only with LPS and peptidoglycan, but also with viral particles and other microbial products such as polysaccharides, enzymes, and toxins. Bacterial flagella activate inflammation by binding of a conserved sequence to TLR5. Some pathogens, including Campylobacter jejuni, Helicobacter pylori, and Bartonella bacilliformis, make flagella that lack this sequence and thus do not bind to TLR5. The result is a lack of efficient host response to infection. Bacteria also produce a high proportion of DNA molecules with unmethylated CpG residues that activate inflammation through TLR9.TLR3 recognizes double-strand RNA, a pattern-recognition molecule produced by many viruses during their replicative cycle.TLR1 and TLR6 associate with TLR2 to promote recognition of acylated microbial proteins and peptides. The myeloid differentiation factor 88 (MyD88) molecule is a generalized adaptor protein that binds to the cytoplasmic domains of all known TLRs and also to receptors that are part of the IL-1 receptor (IL-1Rc) family. Numerous studies have shown that MyD88mediated transduction of signals from TLRs and IL-1Rc is critical for innate resistance to infection. Mice lacking MyD88 are more susceptible than normal mice to infection with group B Streptococcus, Listeria monocytogenes, and Mycobacterium tuberculosis. However, it is now appreciated that some of the TLRs (e.g., TLR3 and TLR4) can activate signal transduction via an MyD88independent pathway.

Additional Interactions of Microbial Pathogens and Phagocytes Other ways that microbial pathogens avoid destruction by phagocytes include production of factors that are toxic to phagocytes or that interfere with the chemotactic and ingestion function of phagocytes. Hemolysins, leukocidins, and the like are microbial proteins that can kill phagocytes that are attempting to ingest organisms elaborating these substances. For example, staphylococcal hemolysins inhibit macrophage chemotaxis and kill these phagocytes. Streptolysin O made by S. pyogenes binds to cholesterol in phagocyte membranes and initiates a process of internal degranulation, with the release of normally granule-sequestered toxic components into the phagocyte’s cytoplasm. E. histolytica, an intestinal protozoan that causes amebic dysentery, can disrupt phagocyte membranes after direct contact via the release of protozoal phospholipase A and pore-forming peptides. Microbial Survival inside Phagocytes Many important microbial pathogens use a variety of strategies to survive inside phagocytes (particularly macrophages) after ingestion. Inhibition of fusion of the phagocytic vacuole (the phagosome) containing the ingested microbe with the lysosomal granules containing antimicrobial substances (the lysosome) allows M. tuberculosis, S. enterica serovar typhi, and Toxoplasma gondii to survive inside macrophages. Some organisms, such as L. monocytogenes, escape into the phagocyte’s cytoplasm to grow and eventually spread to other cells. Resistance to killing within the macrophage and subsequent growth are critical to successful infection by herpes-type viruses, measles virus, poxviruses, Salmonella, Yersinia, Legionella, Mycobacterium, Trypanosoma, Nocardia, Histoplasma, Toxoplasma, and Rickettsia. Salmonella spp. use a master regulatory system, in which the PhoP/PhoQ genes control other genes, to enter and survive within cells; intracellular survival entails structural changes in the cell envelope LPS.

TISSUE INVASION AND TISSUE TROPISM TISSUE INVASION Most viral pathogens cause disease by growth at skin or mucosal entry sites, but some pathogens spread from the initial site to deeper tissues.Virus can spread via the nerves (rabies virus) or plasma (picornaviruses) or within migratory blood cells (poliovirus, Epstein-Barr virus, and many others). Specific viral genes determine where and how individual viral strains can spread. Bacteria may invade deeper layers of mucosal tissue via intracellular uptake by epithelial cells, traversal of epithelial cell junctions, or penetration through denuded epithelial surfaces. Among virulent Shigella strains and invasive E. coli, outer-membrane proteins are critical to epithelial cell invasion and bacterial multiplication. Neisseria and Haemophilus spp. penetrate mucosal cells by poorly understood mechanisms before dissemination into the bloodstream. Staphylococci and streptococci elaborate a variety of extracellular enzymes, such as hyaluronidase, lipases,

TISSUE DAMAGE AND DISEASE Disease is a complex phenomenon resulting from tissue invasion and destruction, toxin elaboration, and host response.Viruses cause much of their damage by exerting a cytopathic effect on host cells and inhibiting host defenses. The growth of bacterial, fungal, and protozoal parasites in tissue, which may or may not be accompanied by toxin elaboration, can also compromise tissue function and lead to disease. For some bacterial and possibly some fungal pathogens, toxin production is one of the best-characterized molecular mechanisms of pathogenesis, whereas host factors such as IL-1,TNF-α, kinins, inflammatory proteins, products of complement activation, and mediators derived from arachidonic acid metabolites (leukotrienes) and cellular degranulation (histamines) readily contribute to the severity of disease.

VIRAL DISEASE See Chap. 78. BACTERIAL TOXINS Among the first infectious diseases to be understood were those due to toxin-elaborating bacteria. Diphtheria, botulism, and tetanus toxins are responsible for the diseases associated with local infections due to Corynebacterium diphtheriae, Clostridium botulinum, and Clostridium tetani, respectively. Enterotoxins produced by E. coli, Salmonella, Shigella, Staphylococcus, and V. cholerae contribute to diarrheal disease caused by these organisms. Staphylococci, streptococci, P. aeruginosa, and Bordetella elaborate various toxins that cause or contribute to disease, including toxic shock syndrome toxin 1 (TSST-1); erythrogenic toxin; exotoxins A, S,T, and U; and pertussis toxin. A number of these toxins (e.g., cholera toxin, diphtheria toxin, pertussis toxin, E. coli heat-labile toxin, and P. aeruginosa exotoxins A, S, and T) have adenosine diphosphate (ADP)-ribosyltransferase activity—i.e., the toxins enzymatically catalyze the

17


TISSUE TROPISM The propensity of certain microbes to cause disease by infecting specific tissues has been known since the early days of bacteriology, yet the molecular basis for this propensity is understood somewhat better for viral pathogens than for other agents of infectious disease. Specific receptor-ligand interactions clearly underlie the ability of certain viruses to enter cells within tissues and disrupt normal tissue function, but the mere presence of a receptor for a virus on a target tissue is not sufficient for tissue tropism. Factors in the cell, route of viral entry, viral capacity to penetrate into cells, viral genetic elements that regulate gene expression, and pathways of viral spread in a tissue all affect tissue tropism. Some viral genes are best transcribed in specific target cells, such as hepatitis B genes in liver cells and Epstein-Barr virus genes in B lymphocytes. The route of inoculation of poliovirus determines its neurotropism, although the molecular basis for this circumstance is not understood. The lesser understanding of the tissue tropism of bacterial and parasitic infections is exemplified by Neisseria spp. There is no well-accepted explanation of why N. gonorrhoeae colonizes and infects the human genital tract, whereas the closely related species N. meningitidis principally colonizes the human oropharynx. N. meningitidis expresses a capsular polysaccharide, whereas N. gonorrhoeae

does not; however, there is no indication that this property plays a role in the different tissue tropisms displayed by these two bacterial species. N. gonorrhoeae can use cytidine monophosphate N-acetylneuraminic acid from host tissues to add N-acetylneuraminic acid (sialic acid) to its lipooligosaccharide (LOS) O side chain, and this alteration appears to make the organism resistant to host defenses. Lactate, present at high levels on genital mucosal surfaces, stimulates sialylation of gonococcal LOS. Bacteria with sialic acid sugars in their capsules, such as N. meningitidis, E. coli K1, and group B streptococci, have a propensity to cause meningitis, but this generalization has many exceptions. For example, all recognized serotypes of group B streptococci contain sialic acid in their capsules, but only one serotype (III) is responsible for most cases of group B streptococcal meningitis. Moreover, both H. influenzae and S. pneumoniae can readily cause meningitis, but these organisms do not have sialic acid in their capsules.

CHAPTER 2

nucleases, and hemolysins, that are probably important in breaking down cellular and matrix structures and allowing the bacteria access to deeper tissues and blood. Organisms that colonize the gastrointestinal tract can often translocate through the mucosa into the blood and, under circumstances in which host defenses are inadequate, cause bacteremia. Y. enterocolitica can invade the mucosa through the activity of the invasin protein. Some bacteria (e.g., Brucella) can be carried from a mucosal site to a distant site by phagocytic cells (e.g., PMNs) that ingest but fail to kill the bacteria. Fungal pathogens almost always take advantage of host immunocompromise to spread hematogenously to deeper tissues.The AIDS epidemic has resoundingly illustrated this principle:The immunodeficiency of many HIV-infected patients permits the development of life-threatening fungal infections of the lung, blood, and brain. Other than the capsule of C. neoformans, specific fungal antigens involved in tissue invasion are not well characterized. Both fungal and protozoal pathogens undergo morphologic changes to spread within a host. Yeast-cell forms of C. albicans transform into hyphal forms when invading deeper tissues. Malarial parasites grow in liver cells as merozoites and are released into the blood to invade erythrocytes and become trophozoites. E. histolytica is found as both a cyst and a trophozoite in the intestinal lumen, through which this pathogen enters the host, but only the trophozoite form can spread systemically to cause amebic liver abscesses. Other protozoal pathogens, such as T. gondii, Giardia lamblia, and Cryptosporidium, also undergo extensive morphologic changes after initial infection to spread to other tissues.

18 transfer of the ADP-ribosyl portion of nicotinamide ade-


nine diphosphate to target proteins and inactivate them. The staphylococcal enterotoxins,TSST-1, and the streptococcal pyogenic exotoxins behave as superantigens, stimulating certain T cells to proliferate without processing of the protein toxin by antigen-presenting cells. Part of this process involves stimulation of the antigen-presenting cells to produce IL-1 and TNF-α, which have been implicated in many of the clinical features of diseases like toxic shock syndrome and scarlet fever. A number of gramnegative pathogens (Salmonella, Yersinia, and P. aeruginosa) can inject toxins directly into host target cells by means of a complex set of proteins referred to as the type III secretion system. Loss or inactivation of this virulence system usually greatly reduces the capacity of a bacterial pathogen to cause disease.

ENDOTOXIN The lipid A portion of gram-negative LPS has potent biologic activities that cause many of the clinical manifestations of gram-negative bacterial sepsis, including fever, muscle proteolysis, uncontrolled intravascular coagulation, and shock. The effects of lipid A appear to be mediated by the production of potent cytokines due to LPS binding to CD14 and signal transduction via TLRs, particularly TLR4. Cytokines exhibit potent hypothermic activity through effects on the hypothalamus; they also increase vascular permeability, alter the activity of endothelial cells, and induce endothelial-cell procoagulant activity. Numerous therapeutic strategies aimed at neutralizing the effects of endotoxin are under investigation, but so far the results have been disappointing. One drug, activated protein C (drotrecogin alfa, activated), was found to reduce mortality by ∼20% during severe sepsis—a condition that can be induced by endotoxin during gram-negative bacterial sepsis. INVASION Many diseases are caused primarily by pathogens growing in tissue sites that are normally sterile. Pneumococcal pneumonia is mostly attributable to the growth of S. pneumoniae in the lung and the attendant host inflammatory response, although specific factors that enhance this process (e.g., pneumolysin) may be responsible for some of the pathogenic potential of the pneumococcus. Disease that follows bacteremia and invasion of the meninges by meningitis-producing bacteria such as N. meningitidis, H. influenzae, E. coli K1, and group B streptococci appears to be due solely to the ability of these organisms to gain access to these tissues, multiply in them, and provoke cytokine production, leading to tissue-damaging host inflammation. Specific molecular mechanisms accounting for tissue invasion by fungal and protozoal pathogens are less well described. Except for studies pointing to factors like capsule and melanin production by C. neoformans and (possibly) levels of cell wall glucans in some pathogenic fungi, the molecular basis for fungal invasiveness is not well defined. Melanism has been shown to protect the fungal cell against death caused by phagocyte factors

such as nitric oxide, superoxide, and hypochlorite. Morphogenic variation and production of proteases (e.g., the Candida aspartyl proteinase) have been implicated in fungal invasion of host tissues. If pathogens are effectively to invade host tissues (particularly the blood), they must avoid the major host defenses represented by complement and phagocytic cells. Bacteria most often avoid these defenses through their cell surface polysaccharides—either capsular polysaccharides or long O-side-chain antigens characteristic of the smooth LPS of gram-negative bacteria. These molecules can prevent the activation and/or deposition of complement opsonins or limit the access of phagocytic cells with receptors for complement opsonins to these molecules when they are deposited on the bacterial surface below the capsular layer. Another potential mechanism of microbial virulence is the ability of some organisms to present the capsule as an apparent self antigen through molecular mimicry. For example, the polysialic acid capsule of group B N. meningitidis is chemically identical to an oligosaccharide found on human brain cells. Immunochemical studies of capsular polysaccharides have led to an appreciation of the tremendous chemical diversity that can result from the linking of a few monosaccharides. For example, three hexoses can link up in more than 300 different and potentially serologically distinct ways, whereas three amino acids have only six possible peptide combinations. Capsular polysaccharides, which have been used as effective vaccines against meningococcal meningitis as well as against pneumococcal and H. influenzae infections, may prove to be of value as vaccines against any organisms that express a nontoxic, immunogenic capsular polysaccharide. In addition, most encapsulated pathogens become virtually avirulent when capsule production is interrupted by genetic manipulation; this observation emphasizes the importance of this structure in pathogenesis.

HOST RESPONSE The inflammatory response of the host is critical for interruption and resolution of the infectious process, but also is often responsible for the signs and symptoms of disease. Infection promotes a complex series of host responses involving the complement, kinin, and coagulation pathways. The production of cytokines such as IL-1, TNF-α, and other factors regulated in part by the NF-κB transcription factor leads to fever, muscle proteolysis, and other effects, as noted above. An inability to kill or contain the microbe usually results in further damage due to the progression of inflammation and infection. In many chronic infections, degranulation of host inflammatory cells can lead to release of host proteases, elastases, histamines, and other toxic substances that can degrade host tissues. Chronic inflammation in any tissue can lead to the destruction of that tissue and to clinical disease associated with loss of organ function; an example is sterility from pelvic inflammatory disease caused by chronic infection with N. gonorrhoeae. The nature of the host response elicited by the pathogen often determines the pathology of a particular

As part of the pathogenic process, most microbes are shed from the host, often in a form infectious for susceptible individuals. However, the rate of transmissibility may not necessarily be high, even if the disease is severe in the infected individual, as transmissibility and virulence are not linked traits. Most pathogens exit via the same route by which they entered: respiratory pathogens by aerosols from sneezing or coughing or through salivary spread, gastrointestinal pathogens by fecal-oral spread, sexually transmitted diseases by venereal spread, and vector-borne organisms by either direct contact with the vector through a blood meal or indirect contact with organisms shed into environmental sources such as water. Microbial factors that specifically promote transmission are not well characterized. Respiratory shedding is facilitated by overproduction of mucous secretions, with consequently enhanced sneezing and coughing. Diarrheal toxins such as cholera toxin, E. coli heat-labile toxins, and Shigella toxins probably facilitate fecal-oral spread of microbial cells in the high volumes of diarrheal fluid produced during infection. The ability to produce phenotypic variants that resist hostile environmental factors (e.g., the highly resistant cysts of

FURTHER READINGS CAMILLI A, BASSLER BL: Bacterial small-molecule signaling pathways. Science 311:1113, 2006 FINLAY BB, MCFADDEN G: Anti-immunology: Evasion of the host immune system by bacterial and viral pathogens. Cell 124:767, 2006 HAN J, ULEVITCH RJ: Limiting inflammatory responses during activation of innate immunity. Nat Immunol 6:1198, 2005 KAWAI T, AKIRA S: Innate immune recognition of viral infection. Nat Immunol 7:131, 2006 KNIREL YA et al: Structural features and structural variability of the lipopolysaccharide of Yersinia pestis, the cause of plague. J Endotoxin Res 12:3, 2006 MENDES-GIANNINI MJ et al: Interaction of pathogenic fungi with host cells: Molecular and cellular approaches. FEMS Immunol Med Microbiol 45:383, 2005 PIZARRO-CERDA J, COSSART P: Bacterial adhesion and entry into host cells. Cell 124:715, 2006 SPEAR PG et al: Different receptors binding to distinct interfaces on herpes simplex virus gD can trigger events leading to cell fusion and viral entry.Virology 344:17, 2006 TAKAHASHI K et al: The mannose-binding lectin: A prototypic pattern recognition molecule. Curr Opin Immunol 18:16, 2006

19


TRANSMISSION TO NEW HOSTS

E. histolytica shed in feces) represents another mechanism of pathogenesis relevant to transmission. Blood parasites such as Plasmodium spp. change phenotype after ingestion by a mosquito-a prerequisite for the continued transmission of this pathogen. Venereally transmitted pathogens may undergo phenotypic variation due to the production of specific factors to facilitate transmission, but shedding of these pathogens into the environment does not result in the formation of infectious foci. In summary, the molecular mechanisms used by pathogens to colonize, invade, infect, and disrupt the host are numerous and diverse. Each phase of the infectious process involves a variety of microbial and host factors interacting in a manner that can result in disease. Recognition of the coordinated genetic regulation of virulence factor elaboration when organisms move from their natural environment into the mammalian host emphasizes the complex nature of the host-parasite interaction. Fortunately, the need for diverse factors in successful infection and disease implies that a variety of therapeutic strategies may be developed to interrupt this process and thereby prevent and treat microbial infections.

CHAPTER 2

infection. Local inflammation produces local tissue damage, whereas systemic inflammation, such as that seen during sepsis, can result in the signs and symptoms of septic shock. The severity of septic shock is associated with the degree of production of host effectors. Disease due to intracellular parasitism results from the formation of granulomas, wherein the host attempts to wall off the parasite inside a fibrotic lesion surrounded by fused epithelial cells that make up so-called multinucleated giant cells. A number of pathogens, particularly anaerobic bacteria, staphylococci, and streptococci, provoke the formation of an abscess, probably because of the presence of zwitterionic surface polysaccharides such as the capsular polysaccharide of Bacteroides fragilis. The outcome of an infection depends on the balance between an effective host response that eliminates a pathogen and an excessive inflammatory response that is associated with an inability to eliminate a pathogen and with the resultant tissue damage that leads to disease.

CHAPTER 3

IMMUNIZATION PRINCIPLES AND VACCINE USE Gerald T. Keusch Kenneth J. Bart Mark Miller

Vaccines play a special role in the health and security of nations. The World Health Organization (WHO) cites immunization and the provision of clean water as the two public health interventions that have had the greatest impact on the world’s health, and the World Bank notes that vaccines are among the most cost-effective health interventions available. Over the past century, the integration of immunization into routine health care services in many countries has provided caregivers with some degree of control over disease-related morbidity and mortality, especially among infants and children. Despite these extraordinary successes, vaccines and their constituents (e.g., the mercury compound thimerosal, formerly used as a preservative) have come under attack in some countries as causes of neurodevelopmental disorders such as autism and attention-deficit hyperactivity disorder, diabetes, and a variety of allergic and autoimmune diseases. Although millions of lives are saved by vaccines each year and countless cases of postinfection disability are averted, some segments of the public are increasingly unwilling to accept any risk whatsoever of vaccine-associated complications (severe or otherwise), and resistance to vaccination is growing. No medical procedure is absolutely risk-free, and the risk to the individual must always be balanced with benefits to the individual and to the population at large. This dichotomy poses two essential challenges for the medical and public health communities with respect to vaccines: (1) to create more effective and ever-safer vaccines, and (2) to educate patients and the general public more fully about the benefits as well as the risks of vaccine use. Because immunity to infectious diseases is acquired only by infection itself or by immunization, sustained vaccination programs for each birth cohort will continue

to be necessary to control vaccine-preventable infectious diseases until and unless their etiologic agents can be eradicated from every region of the world. An unwavering scientific and public health commitment to immunization is essential in countering public distrust and political pressure to legislate well-intentioned but ill-informed vaccine safety laws in response to the concerns of organized antivaccine advocacy groups. Ironically, it is the public health success of vaccines that has created a significant part of the problem: because the major fatal and disabling diseases of childhood are only rarely seen today in the United States, parents and young practitioners most likely will never have seen tetanus, diphtheria, Haemophilus influenzae disease, polio, or measles. Under these circumstances, the risks of immunization can easily (if erroneously) be perceived to outweigh the benefits, and this perception can be fueled by inaccurate information, poor science, and zealous advocacy. Caregivers must be prepared to educate parents about the importance of childhood immunization and to address their concerns effectively. The medical community must also appreciate public concern about the sheer number of vaccines now licensed and the attendant fear that the more vaccines are administered, the more likely it is that complications and adverse immunologic consequences will occur. More than 50 biologic products are presently licensed in the United States, and dozens of antigens (many of them components of vaccine-combination products) are recommended for routine immunization of infants, children, adolescents, and adults (Figs. 3-1 and 3-2). Moreover, new vaccines are continually becoming available—e.g., human papillomavirus (HPV) vaccine for use in adolescent girls to prevent cervical cancer (Chap. 86) and a herpes zoster vaccine to prevent zoster (Chap. 81). Still other vaccines

20

Hepatitis B 1

HepB

HepB

see footnote 1

HepB

Rota

Rota

Rota

Diphtheria,Tetanus,Pertussis 3

DTaP

DTaP

DTaP

Haemophilus influenzae type b4

Hib

Hib

Hib 4

Hib

Pneumococcal 5

PCV

PCV

PCV

PCV

Inactivated Poliovirus

IPV

IPV

HepB Series

DTaP

DTaP Hib PCV PPV

IPV

Influenza 6

4–6 years

IPV Influenza (Yearly)

Measles, Mumps, Rubella 7 Varicella 8 Hepatitis A 9

MMR

MMR

Varicella

Varicella

HepA (2 doses)

Meningococcal 10

HepA Series MPSV4

A

Range of recommended ages

FIGURE 3-1 These schedules indicate the recommended ages for routine administration of currently licensed childhood vaccines, as of December 1, 2006, for children aged 0–6 and 7–18 years. For updates see http://www.cdc.gov/mmwr/preview/mmwrhtml/ mm5751a5.htm?s_cid=mm5751a5_. Any dose not administered at the recommended age should be administered at any subsequent visit, when indicated and feasible. Additional vaccines may be licensed and recommended during the year. Licensed combination vaccines may be used whenever any components of the combination are indicated and other components of the vaccine are not contraindicated and if approved by the Food and Drug Administration for that dose of the series. Providers should consult the respective Advisory Committee on Immunization Practices statement for detailed recommendations. Clinically significant adverse events that follow immunization should be reported to the Vaccine Adverse Event Reporting System (VAERS). Guidance about how to obtain and complete a VAERS form is available at http://www.vaers.hhs.gov or by telephone, 800-822-7967. A. Recommended immunization schedule for persons aged 0–6 years—United States, 2006–2007. 1. Hepatitis B vaccine (HepB). (Minimum age: birth) At birth: Administer monovalent HepB to all newborns before hospital discharge. If mother is hepatitis surface antigen (HBsAg)–positive, administer HepB and 0.5 mL of hepatitis B immune globulin (HBIG) within 12 hours of birth. If mother’s HBsAg status is unknown, administer HepB within 12 hours of birth. Determine the HBsAg status as soon as possible and if HBsAg-positive, administer HBIG (no later than age 1 week). If mother is HBsAg-negative, the birth dose can only be delayed with physician’s order and mother’s negative HBsAg laboratory

Catch-up immunization

Certain high-risk groups

report documented in the infant’s medical record. After the birth dose: The HepB series should be completed with either monovalent HepB or a combination vaccine containing HepB. The second dose should be administered at age 1–2 months. The final dose should be administered at age ≥24 weeks. Infants born to HBsAg-positive mothers should be tested for HBsAg and antibody to HBsAg after completion of ≥3 doses of a licensed HepB series, at age 9–18 months (generally at the next well-child visit). 4-month dose: It is permissible to administer 4 doses of HepB when combination vaccines are administered after the birth dose. If monovalent HepB is used for doses after the birth dose, a dose at age 4 months is not needed. 2. Rotavirus vaccine (Rota). (Minimum age: 6 weeks) Administer the first dose at age 6–12 weeks. Do not start the series later than age 12 weeks. Administer the final dose in the series by age 32 weeks. Do not administer a dose later than age 32 weeks. Data on safety and efficacy outside of these age ranges are insufficient. 3. Diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP). (Minimum age: 6 weeks) The fourth dose of DTaP may be administered as early as age 12 months, provided 6 months have elapsed since the third dose. Administer the final dose in the series at age 4–6 years. 4. Haemophilus influenzae type b conjugate vaccine (Hib). (Minimum age: 6 weeks) If PRP-OMP (PedvaxHIB or ComVax [Merck]) is administered at ages 2 and 4 months, a dose at age 6 months is not required. TriHiBit (DTaP/Hib) combination products should not be used for primary immunization but can be used as boosters after any Hib vaccine in children aged ≥12 months. 5. Pneumococcal vaccine. (Minimum age: 6 weeks for pneumococcal conjugate vaccine (Continued)

Immunization Principles and Vaccine Use

Rotavirus 2

21

CHAPTER 3

Vaccine

Recommended Immunization Schedule for Persons Aged 0–6 Years UNITED STATES • 2007 1 2 4 6 12 15 18 19–23 2–3 Birth month Age months months months months months months months years

22

Recommended Immunization Schedule for Persons Aged 7–18 Years UNITED STATES • 2007

SECTION I

Age

Vaccine

Tetanus, Diphtheria, Pertussis 1

see footnote 1

Human Papillomavirus 2

see footnote 2

Meningococcal 3

11–12

7–10 years

YEARS

MPSV4

Introduction to Infectious Diseases

Pneumococcal 4

15 years

Tdap

Tdap

HPV (3 doses)

HPV Series

MCV4

MCV4 3 MCV4

16–18 years

PPV

Influenza 5

Influenza ( Yearly )

Hepatitis A 6

HepA Series

Hepatitis B 7

HepB Series

Inactivated Poliovirus 8 Measles, Mumps, Rubella 9 B

13–14 years

Varicella 10

IPV Series MMR Series Varicella Series

Range of recommended ages FIGURE 3-1 (CONTINUED) [PCV]; 2 years for pneumococcal polysaccharide vaccine [PPV]). Administer PCV at ages 24–59 months in certain highrisk groups. Administer PPV to children aged ≥2 years in certain high-risk groups. See MMWR 2000;49(No. RR-9):1–35. 6. Influenza vaccine. (Minimum age: 6 months for trivalent inactivated influenza vaccine [TIV]; 5 years for live, attenuated influenza vaccine [LAIV]). All children aged 6–59 months and close contacts of all children aged 0–59 months are recommended to receive influenza vaccine. Influenza vaccine is recommended annually for children aged ≥59 months with certain risk factors, health care workers, and other persons (including household members) in close contact with persons in groups at high risk. See MMWR 2006;55(No. RR-10):1–41. For healthy persons aged 5–49 years, LAIV may be used as an alternative to TIV. Children receiving TIV should receive 0.25 mL if aged 6–35 months or 0.5 mL if aged ≥3 years. Children aged 1 million persons are infected. Antibodies to HTLV-I are present in the serum of up to 35% of Okinawans, 10% of residents of the Japanese island of Kyushu, and 95% of affected patients showing serologic evidence of HTLV-I infection. The latency period between infection and the emergence of disease is 20–30 years for ATL. For HAM, the median latency period is ~3.3 years (range, 4 months to 30 years). The development of ATL is rare among

CHAPTER 89

c-rel/NF-κB, ets-1 and -2, and members of the fos/jun family), cytokines [e.g., interleukin (IL) 2, granulocytemacrophage colony-stimulating factor, and tumor necrosis factor (TNF)], and membrane proteins and receptors [major histocompatibility (MHC) molecules and IL-2 receptor α].The genes activated by tax are generally controlled by transcription factors of the c-rel/NF-κB and cyclic AMP response element binding (CREB) protein families. It is unclear how this induction of host gene expression leads to neoplastic transformation; tax can interfere with G1 and mitotic cell-cycle checkpoints, block apoptosis, inhibit DNA repair, and promote antigen-independent T-cell proliferation. Induction of a cytokine-autocrine loop has been proposed; however, IL2 is not the crucial cytokine. The involvement of IL-4, IL-7, and IL-15 has been proposed. In light of the irregular expression of tax in ATL cells, it has been suggested that tax is important in the early phases of transformation but is not essential for the maintenance of the transformed state. As is clear from the epidemiology of HTLV-I infection, transformation of an infected cell is a rare event and may depend on heterogeneous second, third, or fourth genetic hits. No consistent chromosomal abnormalities have been described in ATL; however, individual cases with p53 mutations and translocations involving the T-cell receptor genes on chromosome 14 have been reported. Tax may repress certain DNA repair enzymes, permitting the accumulation of genetic damage that would normally be repaired. However, the molecular pathogenesis of HTLV-I–induced neoplasia is not fully understood.

790 persons infected by blood products; however, ~20% of

SECTION V

patients with HAM acquire HTLV-I from contaminated blood. ATL is more common among perinatally infected individuals, whereas HAM is more common among persons infected via sexual transmission. Associated Diseases ATL

Viral Infections

Four clinical types of HTLV-I–induced neoplasia have been described: acute, lymphomatous, chronic, and smoldering. All of these tumors are monoclonal proliferations of CD4+ post-thymic T cells with clonal proviral integrations and clonal T-cell receptor gene rearrangements. Acute ATL

About 60% of patients who develop malignancy have classic acute ATL, which is characterized by a short clinical prodrome (~2 weeks between the first symptoms and the diagnosis) and an aggressive natural history (median survival period, 6 months). The clinical picture is dominated by rapidly progressive skin lesions, pulmonary involvement, hypercalcemia, and lymphocytosis with cells containing lobulated or “flower-shaped” nuclei. The malignant cells have monoclonal proviral integrations and express CD4, CD3, and CD25 (lowaffinity IL-2 receptors) on their surface. Serum levels of CD25 can be used as a tumor marker. Anemia and thrombocytopenia are rare. The skin lesions may be difficult to distinguish from those in mycosis fungoides. Lytic bone lesions, which are common, do not contain tumor cells, but rather are composed of osteolytic cells, usually without osteoblastic activity. Despite the leukemic picture, bone marrow involvement is patchy in most cases. The hypercalcemia of ATL is multifactorial; the tumor cells produce osteoclast-activating factors (TNF-α, IL-1, lymphotoxin) and can also produce a parathyroid hormone–like molecule. Affected patients have an underlying immunodeficiency that makes them susceptible to opportunistic infections similar to those seen in patients with AIDS (Chap. 90). The pathogenesis of the immunodeficiency is unclear. Pulmonary infiltrates in ATL patients reflect leukemic infiltration half the time and opportunistic infections with organisms such as Pneumocystis and other fungi the other half. Gastrointestinal symptoms are nearly always related to opportunistic infection. Strongyloides stercoralis is a gastrointestinal parasite that has a pattern of endemic distribution similar to that of HTLV-I. HTLV-I–infected persons also infected with this parasite may develop ATL more often or more rapidly than those without Strongyloides infections. Serum concentrations of lactate dehydrogenase (LDH) and alkaline phosphatase are often elevated in ATL. About 10% of patients have leptomeningeal involvement leading to weakness, altered mental status, paresthesia, and/or headache. Unlike other forms of central nervous system (CNS) lymphoma, ATL may be accompanied by normal CSF protein levels. The diagnosis depends on finding ATL cells in the CSF.

Lymphomatous ATL

The lymphomatous type of ATL occurs in ~20% of patients and is similar to the acute form in its natural history and clinical course, except that circulating abnormal cells are rare and lymphadenopathy is evident.The histology of the lymphoma is variable but does not influence the natural history. In general, the diagnosis is suspected on the basis of the patient’s birthplace (see “Epidemiology” earlier in the chapter) and the presence of skin lesions and hypercalcemia.The diagnosis is confirmed by the detection of antibodies to HTLV-I in serum. Chronic ATL

Patients with the chronic form of ATL generally have normal serum levels of calcium and LDH and no involvement of the CNS, bone, or gastrointestinal tract. The median duration of survival for these patients is 2 years. In some cases, chronic ATL progresses to the acute form of the disease. Smoldering ATL

Fewer than 5% of patients have the smoldering form of ATL. In this form, the malignant cells have monoclonal proviral integration; 97% of cases due to HTLV-II. The seroprevalence of HTLV-II was higher in the Southwest and the Midwest than in the Northeast. In contrast, the seroprevalence of HIV-1 was higher in the Northeast than in the Southwest or the Midwest. Approximately 3% of the cohort members were infected with both HTLV-II and HIV-1.The seroprevalence of HTLV-II increased linearly with age. Women were significantly more likely to be infected with HTLV-II than were men; the virus is thought to be more efficiently transmitted from male to female than from female to male. Associated Diseases Although HTLV-II was isolated from a patient with a Tcell variant of hairy cell leukemia, this virus has not been consistently associated with a particular disease and in fact has been thought of as “a virus searching for a disease.” However, evidence is accumulating that HTLV-II may play a role in certain neurologic, hematologic, and dermatologic diseases. These data require confirmation, particularly in light of the previous confusion regarding the relative prevalences of HTLV-I and HTLV-II among injection drug users.

791

The Human Retroviruses

Other Putative HTLV-I–Related Diseases

In areas where HTLV-I is endemic, diverse inflammatory and autoimmune diseases have been attributed to the virus, including uveitis, dermatitis, pneumonitis, rheumatoid arthritis, and polymyositis. However, a causal relationship between HTLV-I and these illnesses has not been established.

promising but is not widely available. Patients with the chronic or smoldering form of ATL may be managed with an expectant approach: treat any infections, and watch and wait for signs of progression to acute disease. Patients with HAM may obtain some benefit from the use of glucocorticoids to reduce inflammation. Antiretroviral regimens have not been effective. In one study, danazol (200 mg three times daily) produced significant neurologic improvement in five of six treated patients, with resolution of urinary incontinence in two cases, decreased spasticity in three, and restoration of the ability to walk after confinement to a wheelchair in two. Physical therapy and rehabilitation are important components of management.

CHAPTER 89

of HAM patients, where titers are often higher than in the serum. The pathophysiology of HAM may involve the induction of autoimmune destruction of neural cells by T cells with specificity for viral components such as Tax or Env proteins. One theory is that susceptibility to HAM may be related to the presence of human leukocyte antigen (HLA) alleles capable of presenting viral antigens in a fashion that leads to autoimmunity. Insufficient data are available to confirm an HLA association. However, antibodies in the sera of HAM patients have been shown to bind a neuron-specific antigen [heteronuclear ribonuclear protein A1 (hnRNP A1)] and to interfere with neurotransmission in vitro. It is unclear what factors influence whether HTLV-I infection will cause disease and, if it does, whether it will induce a neoplasm (ATL) or an autoimmune disorder (HAM). Differences in viral strains, the susceptibility of particular MHC haplotypes, the route of HTLV-I infection, the viral load, and the nature of the HTLV-Irelated immune response are putative factors, but few definitive data are available.

792 Prevention

FURTHER READINGS

SECTION V

Avoidance of needle sharing, adherence to safe-sex practices, screening of blood (by assays for HTLV-I, which also detect HTLV-II), and avoidance of breast-feeding by infected women are important principles in the prevention of spread of HTLV-II.

GHEZ D et al: Neuropilin-1 is involved in human T-cell lymphotropic virus type 1 entry. J Virol 80:6844, 2006 KASHANCHI F, BRADY JN: Transcriptional and post-transcriptional gene regulation of HTLV-1. Oncogene 24:5938, 2005 LEE SM et al: HTLV-1 induced molecular mimicry in neurological disease. Curr Top Microbiol Immunol 296:125, 2005 MANEL N et al: HTLV-I tropism and envelope receptor. Oncogene 24:6016, 2005 MATSUOKA M, JEANG KT: Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation. Nat Rev Cancer 7:270, 2007 PELOPONESE JM et al: Modulation of nuclear factor-κB by human T cell leukemia virus type 1 Tax protein. Immunol Res 34:1, 2006 PROIETTI FA et al: Global epidemiology of HTLV-I infection and associated diseases. Oncogene 24:6058, 2005 TAYLOR GP, MATSUOKA M: Natural history of adult T-cell leukemia/lymphoma and approaches to therapy. Oncogene 24:6047, 2005

HUMAN IMMUNODEFICIENCY VIRUS Viral Infections

HIV-1 and HIV-2 are members of the lentivirus subfamily of Retroviridae and are the only lentiviruses known to infect humans. The lentiviruses are slow-acting by comparison with viruses that cause acute infection (e.g., influenza virus) but not by comparison with other retroviruses. The features of acute primary infection with HIV resemble those of more classic acute infections.The characteristic chronicity of HIV disease is consistent with the designation lentivirus. For a detailed discussion of HIV, see Chap. 90.

CHAPTER 90

HUMAN IMMUNODEFICIENCY VIRUS DISEASE: AIDS AND RELATED DISORDERS Anthony S. Fauci Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .793 Etiologic Agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .793 Morphology of HIV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .794 Replication Cycle of HIV . . . . . . . . . . . . . . . . . . . . . . . . . . . . .794 HIV Genome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .797 Molecular Heterogeneity of HIV-1 . . . . . . . . . . . . . . . . . . . . . .798 Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .799 Sexual Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .799 Transmission by Blood and Blood Products . . . . . . . . . . . . . .801 Occupational Transmission of HIV: Health Care Workers, Laboratory Workers, and the Health Care Setting . . . . . . . .802 Maternal-Fetal/Infant Transmission . . . . . . . . . . . . . . . . . . . . .803 Transmission by Other Body Fluids . . . . . . . . . . . . . . . . . . . .804 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .805 HIV Infection and AIDS Worldwide . . . . . . . . . . . . . . . . . . . . .805 AIDS in the United States . . . . . . . . . . . . . . . . . . . . . . . . . . . .807 Pathophysiology and Pathogenesis . . . . . . . . . . . . . . . . . . . .808 Primary HIV Infection, Initial Viremia, and Dissemination of Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . .809 Establishment of Chronic and Persistent Infection . . . . . . . . .810 Advanced HIV Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . .812 Long-Term Survivors and Long-Term Nonprogressors . . . . . .813 Lymphoid Organs and HIV Pathogenesis . . . . . . . . . . . . . . . .814 Cellular Activation and HIV Pathogenesis . . . . . . . . . . . . . . . .815

H. Clifford Lane

The Cytokine Network in HIV Pathogenesis . . . . . . . . . . . . . .818 Lymphocyte Turnover in HIV Infection . . . . . . . . . . . . . . . . . .818 The Role of Co-Receptors in HIV Pathogenesis . . . . . . . . . . .819 Cellular Targets of HIV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .819 Abnormalities of Mononuclear Cells . . . . . . . . . . . . . . . . . . . .820 Genetic Factors in HIV Pathogenesis . . . . . . . . . . . . . . . . . . .823 Neuropathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .826 Pathogenesis of Kaposi’s Sarcoma . . . . . . . . . . . . . . . . . . . .827 immune Response to HIV . . . . . . . . . . . . . . . . . . . . . . . . . . .827 Humoral Immune Response . . . . . . . . . . . . . . . . . . . . . . . . .828 Cellular Immune Response . . . . . . . . . . . . . . . . . . . . . . . . . .829 Diagnosis and Laboratory Monitoring of HIV Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .830 Diagnosis of HIV Infection . . . . . . . . . . . . . . . . . . . . . . . . . . .830 Laboratory Monitoring of Patients with HIV Infection . . . . . . .834 Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .836 The Acute HIV Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . .836 The Asymptomatic Stage—Clinical Latency . . . . . . . . . . . . . .837 Symptomatic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .837 Idiopathic CD4+ T Lymphocytopenia . . . . . . . . . . . . . . . . . . .865 HIV and the Health Care Worker . . . . . . . . . . . . . . . . . . . . . .882 Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .883 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .884 Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .885

DEFINITION 793 The current CDC classification system for HIV-infected adolescents and adults categorizes persons on the basis of clinical conditions associated with HIV infection and CD4+ T-lymphocyte counts. The system is based on three ranges of CD4+ T-lymphocyte counts and three clinical categories and is represented by a matrix of nine mutually exclusive categories (Tables 90-1 and 90-2). Using this system, any HIV-infected individual with a CD4+ T-cell count of 500/µL 200–499/µL 13 years) with documented HIV infection. Conditions listed in categories B and C must not have occurred. Asymptomatic HIV infection Persistent generalized lymphadenopathy Acute (primary) HIV infection with accompanying illness or history of acute HIV infection Category B: Consists of symptomatic conditions in an HIV-infected adolescent or adult that are not included among conditions listed in clinical category C and that meet at least one of the following criteria: (1) The conditions are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or (2) the conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection. Examples include, but are not limited to, the following: Bacillary angiomatosis Candidiasis, oropharyngeal (thrush) Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy Cervical dysplasia (moderate or severe)/cervical carcinoma in situ Constitutional symptoms, such as fever (38.5ºC) or diarrhea lasting >1 month Hairy leukoplakia, oral Herpes zoster (shingles), involving at least two distinct episodes or more than one dermatome Idiopathic thrombocytopenic purpura Listeriosis Pelvic inflammatory disease, particularly if complicated by tuboovarian abscess Peripheral neuropathy Category C: Conditions listed in the AIDS surveillance case definition. Candidiasis of bronchi, trachea, or lungs Candidiasis, esophageal Cervical cancer, invasivea Coccidioidomycosis, disseminated or extrapulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis, chronic intestinal (>1 month’s duration) Cytomegalovirus disease (other than liver, spleen, or nodes) Cytomegalovirus retinitis (with loss of vision) Encephalopathy, HIV-related Herpes simplex: chronic ulcer(s) (>1 month’s duration); or bronchitis, pneumonia, or esophagitis Histoplasmosis, disseminated or extrapulmonary Isosporiasis, chronic intestinal (>1 month’s duration) Kaposi’s sarcoma Lymphoma, Burkitt’s (or equivalent term) Lymphoma, primary, of brain Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary) Mycobacterium, other species or unidentified species, disseminated or extrapulmonary Pneumocystis jiroveci pneumonia Pneumonia, recurrenta Progressive multifocal leukoencephalopathy Salmonella septicemia, recurrent Toxoplasmosis of brain Wasting syndrome due to HIV

Viral Infections a

Added in the 1993 expansion of the AIDS surveillance case definition. Source: MMWR 42(No. RR-17), December 18, 1992.

West African patients and was originally confined to West Africa. However, a number of cases that can be traced to West Africa or to sexual contacts with West Africans have been identified throughout the world. Both HIV-1 and HIV-2 are zoonotic infections.The Pan troglodytes troglodytes species of chimpanzees has been established as the natural reservoir of HIV-1 and the most likely source of original human infection. HIV-2 is more closely related phylogenetically to the simian immunodeficiency virus (SIV) found in sooty mangabeys than it is to HIV-1. The taxonomic relationship among primate lentiviruses is shown in Fig. 90-1.

MORPHOLOGY OF HIV Electron microscopy shows that the HIV virion is an icosahedral structure (Fig. 90-2A) containing numerous external spikes formed by the two major envelope proteins, the external gp120 and the transmembrane gp41. The virion buds from the surface of the infected cell and incorporates a variety of host proteins, including major histocompatibility complex (MHC) class I and II antigens, into its lipid bilayer. The structure of HIV-1 is schematically diagrammed in Fig. 90-2B (Chap. 89). REPLICATION CYCLE OF HIV HIV is an RNA virus whose hallmark is the reverse transcription of its genomic RNA to DNA by the enzyme reverse transcriptase. The replication cycle of HIV begins with the high-affinity binding of the gp120 protein via a portion of its V1 region near the N terminus to its receptor on the host cell surface, the CD4 molecule (Fig. 90-3). The CD4 molecule is a 55-kDa protein found predominantly on a subset of T lymphocytes that are responsible for helper function in the immune system. It is also expressed on the surface of monocytes/macrophages and dendritic/Langerhans cells. Once gp120 binds to CD4, the gp120 undergoes a conformational change that facilitates binding to one of a group of co-receptors. The two major co-receptors for HIV-1 are CCR5 and CXCR4. Both receptors belong to the family of seven-transmembrane-domain G protein–coupled cellular receptors, and the use of one or the other or both receptors by the virus for entry into the cell is an important determinant of the cellular tropism of the virus (see below for details). Certain dendritic cells express a diversity of C-type lectin receptors on their surface, one of which is called DC-SIGN, that also bind with high affinity to the HIV gp120 envelope protein, allowing the dendritic cell to facilitate the binding of virus to the CD4+ T cell upon engagement of dendritic cells with CD4+ T cells. After binding of the envelope protein to the CD4 molecule associated with the above-mentioned conformational change in the viral envelope gp120, fusion with the host cell membrane occurs via the newly exposed gp41 molecule penetrating the plasma membrane of the target cell and then coiling upon itself to bring the virion and target cell together. After fusion, the preintegration complex, composed of viral RNA and viral enzymes and surrounded by a capsid

HIV-1, chimpanzee and gorilla

795

Mandrill SMNDGB1

L’hoest

CHAPTER 90

SIVLHOEST

HIV-1 Group M

HIV-1H HIV-1F HIV-1I HIV-1E HIV-1A HIV-1G

CPZ-EK505 SIVCPZUS SIVCPZGAB SIVCPZANT HIV-1N HIV-1J

HIV-1C

HIV-2 subtype B

HIV-2 subtype A Gorilla HIV-1 O ANT70

HIV-2, Sooty Mangabey

STMM83293 HIV-1 O MVP5180

SMNE SMM251 SMM9 S6P12

SSAB1C STAN1 SVER155 SVER9063 SVERTYO SVERAGM3

SGRI677 0.10

SIVSYK173

Sykes

African green monkey FIGURE 90-1 A phylogenetic tree, based on the complete genomes of primate immunodeficiency viruses. The scale at the bottom (0.10) indicates a 10% difference at the nucleotide level.

(Prepared by Brian Foley, PhD, of the HIV Sequence Database, Theoretical Biology and Biophysics Group, Los Alamos National Laboratory.)

gp41

Matrix

Lipid membrane

Capsid

RNA

gp120

A

Reverse transcriptase

B

FIGURE 90-2 A. Electron micrograph of HIV. Figure illustrates a typical virion after budding from the surface of a CD4+ T lymphocyte, together with two additional incomplete virions in the process of budding from the cell membrane. B. Structure of HIV-1, including the gp120 outer membrane, gp41

transmembrane components of the envelope, genomic RNA, enzyme reverse transcriptase, p18(17) inner membrane (matrix), and p24 core protein (capsid) (copyright by George V. Kelvin). (Adapted from RC Gallo: Sci Am 256:46, 1987.)

Human Immunodeficiency Virus Disease: AIDS and Related Disorders

HIV-1D HIV-1B CPZ-MB66,LB7

796

Cellular DNA

SECTION V

Unintegrated linear DNA

Integrase

Reverse transcriptase

Viral Infections

Integrated proviral DNA

gp120

CD4 Genomic RNA

mRNA Genomic RNA

HIV Co-receptor

Fusion

Mature HIV virion

FIGURE 90-3 The replication cycle of HIV. See text for description. (Adapted from Fauci, 1996.)

protein coat, is released into the cytoplasm of the target cell (Fig. 90-4). As the preintegration complex traverses the cytoplasm to reach the nucleus (Fig. 90-3), the viral reverse transcriptase enzyme catalyzes the reverse transcription of the genomic RNA into DNA, and the protein coat opens to release the resulting double-stranded HIV-DNA. At this point in the replication cycle, the viral genome is vulnerable to cellular factors that can block the progression of infection. In particular, the cytoplasmic TRIM5-α protein in rhesus macaque cells blocks SIV replication at a point shortly after the virus fuses with the host cell. Although the exact mechanisms of action of TRIM5-α remain unclear, the human form is inhibited by cyclophilin A and is not effective in restricting HIV replication in human cells. The recently

described APOBEC family of cellular proteins also inhibits progression of virus infection after virus has entered the cell. APOBEC proteins bind to nascent reverse transcripts and deaminate viral cytidine, causing hypermutation of HIV genomes. It is still not clear whether (1) viral replication is inhibited by the binding of APOBEC to the virus genome with subsequent accumulation of reverse transcripts, or (2) by the hypermutations caused by the enzymatic deaminase activity of APOBEC proteins. HIV has evolved a powerful strategy to protect itself from APOBEC.The viral protein Vif targets APOBEC for proteasomal degradation. With activation of the cell, the viral DNA accesses the nuclear pore and is exported from the cytoplasm to the nucleus, where it is integrated into the host cell

Budding

Protein synthesis, processing, and assembly

CD4+ T cell

CCR5 CD4

gp120

Receptor binding

Membrane fusion

gp41 HIV virion

FIGURE 90-4 Binding and fusion of HIV-1 with its target cell. HIV-1 binds to its target cell via the CD4 molecule, leading to a conformational change in the gp120 molecule that allows it to bind to the co-receptor CCR5 (for R5-using viruses). The virus then firmly attaches to the host cell membrane in a coiled-spring fashion via the newly exposed gp41 molecule. Virus-cell

fusion occurs as the transitional intermediate of gp41 undergoes further changes to form a hairpin structure that draws the two membranes into close proximity (see text for details). (Adapted from D Montefiori, JP Moore: Science 283:336, 1999; with permission.)

vif: Viral infectivity factor (p23) Overcomes inhibitory effects of APOBEC, preventing hypermutation and viral DNA degradation

HIV GENOME Figure 90-5 illustrates schematically the arrangement of the HIV genome. Like other retroviruses, HIV-1 has genes that encode the structural proteins of the virus: gag encodes the proteins that form the core of the virion (including p24 antigen); pol encodes the enzymes responsible for protease processing of viral proteins, reverse transcription, and integration; and env encodes the envelope glycoproteins. However, HIV-1 is more complex than other retroviruses, particularly those of

vpu: Viral protein U Promotes CD4 degradation and influences virion release

eny: gp 160 envelope protein Cleaved in endoplasmic reticulum to gp 120 (SU) and gp41 (TM) gp 120 mediates CD4 and chemokine receptor binding, while gp41 mediates fusion Contains RNA response element (RRE) that binds Rev

5' U3 R U5

gag: Pr55gag Polyprotein processed by PR MA, matrix (p17) Undergoes myristylation that helps target gag polyprotein to lipid rafts; CA, capsid (p24) Binds cyclophilin A NC, nucleocapsid (p7) Zn finger, RNA-binding protein p6 Interacts with Vpr; contains late domain (PTAP) that binds TSG101 and participates in terminal stops of virion budding

nef: Negative effector (p27) Promotes downregulation of surface CD4 and MHC 1 expression Blocks apoptosis Enhance virion infectivity Alters state of cellular activation Progression to disease slowed significantly in absence of NEF

U3 R U5 3'

pol: Polymerase vpr: Viral protein R (p15) Encodes a variety of viral Promotes G2 enzymes, including PR (p10), cell-cycle arrest RT, and RNAase H Facilitates HIV infection of (p66/51), and IN (p32) macrophages all processed by PR

rev: Regulator of viral gene expression (p19) Binds RRE Inhibits viral RNA splicing and promotes nuclear export of incompletely spliced viral RNAs

tat: Transcriptional activator (p14) Binds TAR In presence of host cyclin T1 and CDK9 enhances RNA Pol II elongation on the viral DNA template

FIGURE 90-5 Organization of the genome of the HIV provirus together with a summary description of its nine genes encoding 15 proteins. (Adapted from Greene and Peterlin.)

797


LTR: Long terminal repeat Contains control regions that bind host transcription factors (NF-κB, NFAT, Sp.1, TBP) Required for the initiation of transcription Contains RNA trans-acting response element (TAR) that binds Tat

virion occurs through specialized regions in the lipid bilayer of the host cell membrane known as lipid rafts, where the core acquires its external envelope (Chap. 89). The virally encoded protease then catalyzes the cleavage of the gag-pol precursor (see below) to yield the mature virion. Progression through the virus replication cycle is profoundly influenced by a variety of viral regulatory gene products. Likewise, each point in the replication cycle of HIV is a real or potential target for therapeutic intervention (see below). Thus far, the reverse transcriptase, protease, and integrase enzymes as well as the process of virus–target cell binding and fusion have proven clinically to be susceptible to pharmacologic disruption (see below). Inhibitors of the maturation process of virions during the latter phase of the replication cycle are currently being evaluated in clinical trials.

CHAPTER 90

chromosomes through the action of another virally encoded enzyme, integrase. HIV provirus (DNA) selectively integrates into the nuclear DNA preferentially within introns of active genes and regional hotspots. This provirus may remain transcriptionally inactive (latent) or it may manifest varying levels of gene expression, up to active production of virus. Cellular activation plays an important role in the replication cycle of HIV and is critical to the pathogenesis of HIV disease (see below). After initial binding and internalization of virions into the target cell, incompletely reverse-transcribed DNA intermediates are labile in quiescent cells and do not integrate efficiently into the host cell genome unless cellular activation occurs shortly after infection. Furthermore, some degree of activation of the host cell is required for the initiation of transcription of the integrated proviral DNA into either genomic RNA or mRNA. This latter process may not necessarily be associated with the detectable expression of the classic cell surface markers of activation. In this regard, activation of HIV expression from the latent state depends on the interaction of a number of cellular and viral factors. After transcription, HIV mRNA is translated into proteins that undergo modification through glycosylation, myristylation, phosphorylation, and cleavage. The viral particle is formed by the assembly of HIV proteins, enzymes, and genomic RNA at the plasma membrane of the cells. Budding of the progeny

798 the nonprimate group, in that it also contains at least six

SECTION V Viral Infections

other genes (tat, rev, nef, vif, vpr, and vpu), which code for proteins involved in the modification of the host cell to enhance virus growth and the regulation of viral gene expression (Chap. 89). Several of these proteins are thought to play a role in the pathogenesis of HIV disease; their various functions are listed in Fig. 90-5. Flanking these genes are the long terminal repeats (LTRs), which contain regulatory elements involved in gene expression (Fig. 90-5). The major difference between the genomes of HIV-1 and HIV-2 is the fact that HIV-2 lacks the vpu gene and has a vpx gene not contained in HIV-1.

MOLECULAR HETEROGENEITY OF HIV-1 Molecular analyses of HIV isolates reveal varying levels of sequence diversity over all regions of the viral genome. For example, the degree of difference in the coding sequences of the viral envelope protein ranges from a few percent (very close, between isolates from the same infected individual) to 50% (extreme diversity, between isolates from the different groups of HIV-1, M, N, and O; see below).The changes tend to cluster in hypervariable regions. HIV can evolve by several means, including simple base substitution, insertions and deletions, recombination, and gain and loss of glycosylation sites. HIV sequence diversity arises directly from the limited fidelity of the reverse transcriptase.The balance of immune pressure and functional constraints on proteins influences the regional level of variation within proteins. For example, Envelope, which is exposed on the surface of the virion and is under immune selective pressure from both antibodies and cytolytic T lymphocytes, is extremely variable, with clusters of mutations in hypervariable domains. In contrast, Reverse Transcriptase, with important enzymatic functions, is relatively conserved, particularly around the active site.The extraordinary variability of HIV-1 is in marked contrast to the relative stability of HTLV-I and -II. There are three groups of HIV-1: group M (major), which is responsible for most of the infections in the world; group O (outlier), a relatively rare viral form found originally in Cameroon, Gabon, and France; and group N, first identified in a Cameroonian woman with AIDS; only a few cases of the latter have been identified. Among primate lentiviruses, HIV-1 is most closely related to viruses isolated from chimpanzees and gorillas. The chimpanzee subspecies Pan troglodytes troglodytes has been established to be the natural reservoir of the HIV-1 M and N groups. The HIV-1 O group is most closely related to viruses found in Cameroonian gorillas. The M group comprises nine subtypes, or clades, designated A, B, C, D, F, G, H, J, and K, as well as a growing number of major and minor circulating recombinant forms (CRFs). CRFs are generated by infection of an individual with two subtypes that then recombine and create a virus with a selective advantage. These CRFs range from highly prevalent forms such as the AE virus, CRF01_AE, which is predominant in southeast Asia and often referred to simply as E, despite the fact that the

CRF01_AE CPZ-MB66 CPZ-LB7

G C

A2 A1

B D

CPZ-ANT GOR-CP684 GOR-BQ664 HIV-1 O HIV-1 O

J

K H

F1

F2

CPZ-US CPZ-CAM5 N CPZ-EK505

10% CPZ-GAB

FIGURE 90-6 Phylogenetic tree constructed from representative viral envelope sequences of the subtypes and CRF01 in HIV-1 group M, some isolates from groups N and O (also HIV-1 human), CPZ (chimpanzee), and gorilla (GOR). The scale bar at the bottom indicates the genetic distances between the sequences. A1 and A2, F1 and F2 are subtypes; CRF01_AE is unique in the envelope gene but similar to subtype A in the rest of the genome. (Courtesy of Brian Foley, PhD, Bette Korber, PhD, and Thomas Leitner, PhD, HIV Database, Los Alamos National Laboratory; with permission.)

parental E virus has never been found, and CRF02_AG from west and central Africa, to a large number of CRFs that are relatively rare. The subtypes and CRFs create the major lineages of the M group of HIV-1. The picture has been complicated somewhat when it was found that some subtypes are not equidistant from one another, whereas others contained sequences so diverse that they could not properly be considered to be the same subtype.Thus the term sub-subtype was introduced, and subtypes A and F are now subdivided into A1 and A2, F1 and F2. It has also been argued that subtypes B and D are really too close to be separate subtypes and should be considered sub-subtypes; it was decided, however, not to increase the confusion by renaming the clades (Fig. 90-6). The global patterns of HIV-1 variation likely result from accidents of viral trafficking. Subtype B viruses, which now differ by up to 17% in their env coding sequences, are the overwhelmingly predominant viruses seen in the United States, Canada, certain countries in South America, western Europe, and Australia. Other subtypes are also present in these countries to varying degrees. It is thought that, purely by chance, subtype B was seeded into the United States in the late 1970s, thereby establishing an overwhelming founder effect. Subtype C viruses (of the M group) are the most common form worldwide; many countries have co-circulating viral subtypes that are giving rise to new CRFs. Figure 90-7 schematically diagrams the worldwide distribution of HIV-1 subtypes by region. Seven strains account for the majority of HIV infections globally: HIV-1 subtypes A, B, C,D,G and two of the CRFs,CRF01_AE and CRF02_AG. The predominant subtype in Europe, Australia, and the Americas is subtype B. In Sub-Saharan Africa, home to

799

CHAPTER 90

A B C

F,G,H,J,K CRF01_AE CRF02_AG CRF03_AB Other combinations 10% 12% 50%

8% 5% 5% 3% 7%

FIGURE 90-7 Geographic distribution of HIV-1 subtypes and recombinants. The prevalence of HIV-1 genetic subtypes varies by geographic region. The proportions of subtypes in different

approximately two-thirds of all individuals living with HIV/AIDS, >50% of infections are caused by subtype C, with smaller proportions of infections caused by subtype A, subtype G, CRF02_AG, and other subtypes and recombinants. In Asia, HIV-1 isolates of the CRF01_AE lineage and subtypes C and B predominate. CRF01_AE accounts for most infections in south and southeast Asia, whereas subtype C is prevalent in India (see “HIV Infection and AIDS Worldwide” later in the chapter). Sequence analyses of HIV-1 isolates from infected individuals indicate that recombination among viruses of different clades likely occurs as a result of infection of an individual with viruses of more than one subtype, particularly in geographic areas where subtypes overlap.

TRANSMISSION HIV is transmitted by both homosexual and heterosexual contact; by blood and blood products; and by infected mothers to infants either intrapartum, perinatally, or via breast milk. After >25 years of scrutiny, there is no evidence that HIV is transmitted by casual contact or that the virus can be spread by insects, such as by a mosquito bite.

SEXUAL TRANSMISSION HIV infection is predominantly a sexually transmitted disease (STD) worldwide. In the United States, ~49% of the HIV/AIDS cases diagnosed in 2005 among adults and adolescents were attributed to male-to-male sexual contact. Heterosexual contact accounted for another 32%.

regions are indicated by pie charts. (From J Hemelaar et al: AIDS 20:W13, 2006.)

Worldwide, the most common mode of infection, particularly in developing countries, is clearly heterosexual transmission. Furthermore, the yearly incidence of new cases of AIDS attributed to heterosexual transmission of HIV is steadily increasing in the United States, mainly among minorities, particularly women in minority groups (Fig. 90-8). HIV has been demonstrated in seminal fluid both within infected mononuclear cells and in cell-free material. The virus appears to concentrate in the seminal fluid, particularly in situations where there are increased numbers of lymphocytes and monocytes in the fluid, as in genital inflammatory states such as urethritis and epididymitis, conditions closely associated with other STDs (see below). The virus has also been demonstrated in cervical smears and vaginal fluid. There is a strong association of HIV transmission with receptive anal intercourse, probably because only a thin, fragile rectal mucosal membrane separates the deposited semen from potentially susceptible cells in and beneath the mucosa and trauma may be associated with anal intercourse. Anal douching and sexual practices that traumatize the rectal mucosa also increase the likelihood of infection. It is likely that anal intercourse provides at least two modalities of infection: (1) direct inoculation into blood in cases of traumatic tears in the mucosa; and (2) infection of susceptible target cells, such as Langerhans cells, in the mucosal layer in the absence of trauma (see below). Although the vaginal mucosa is several layers thicker than the rectal mucosa and less likely to be traumatized during intercourse, it is clear that the virus can be transmitted to either partner through vaginal intercourse.


D

800

70

60

Male-to-male sexual contact

Viral Infections

Cases, %

SECTION V

50

40

30

Injection drug use (IDU)

20 High-risk heterosexual contact 10

Male-to-male sexual contact and IDU

0 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Year of report

FIGURE 90-8 AIDS cases among U.S. adults and adolescents by exposure category and year of diagnosis. The proportion of AIDS cases attributed to heterosexual contact with a person known to have or at high risk for HIV infection (high-risk

heterosexual) increased from 3% in 1985 to 31% in 2005. IDU, injection drug use. [From The Centers for Disease Control and Prevention (CDC).]

Studies in the United States and Europe have found that male-to-female HIV transmission is usually more efficient than female-to-male transmission, but small numbers of HIV-positive female index partners limit conclusive sex-specific estimates of transmission probabilities per sex act. The differences in reported transmission rates between men and women may be due in part to the prolonged exposure to infected seminal fluid of the vaginal and cervical mucosa, as well as the endometrium (when semen enters through the cervical os). By comparison, the penis and urethral orifice are exposed relatively briefly to infected vaginal fluid. Among various cofactors examined in studies of heterosexual HIV transmission, the presence of other sexually transmitted diseases (STDs; see below) has been strongly associated with HIV transmission. In this regard, there is a close association between genital ulcerations and transmission, from the standpoints of both susceptibility to infection and infectivity. Infections with microorganisms such as Treponema pallidum (Chap. 70), Haemophilus ducreyi (Chap. 47), and herpes simplex virus (HSV; Chap. 80) are important causes of genital ulcerations linked to transmission of HIV. In addition, pathogens responsible for nonulcerative inflammatory STDs such as those caused by Chlamydia trachomatis (Chap. 77), Neisseria gonorrhoeae (Chap. 45), and Trichomonas vaginalis (Chap. 122) are also associated with an increased risk of transmission of HIV infection. Bacterial vaginosis, an infection related to sexual behavior, but not strictly an STD, may also be linked to an increased risk of transmission of HIV infection. Several studies suggest that treating other STDs and genital tract syndromes may help prevent transmission of HIV. This effect is most prominent in populations in which the prevalence of HIV infection is

relatively low. In studies conducted in Uganda, the chief predictor of heterosexual transmission of HIV was the level of plasma viremia. In a cohort of couples in which one partner was HIV-infected and one was initially uninfected, the mean serum HIV RNA level was significantly higher among HIV-infected subjects whose partners seroconverted than among those whose partners did not seroconvert. In fact transmission was rare when the infected partner had a plasma level of 9300 individuals in the United States who survived the illness for which they received HIV-contaminated blood transfusions, blood components, or transplanted tissue had developed AIDS. Virtually all these cases were due to HIV infection before the spring of 1985, when mandatory testing of donated blood for HIV-1 was initiated. It is estimated that 90–100% of individuals who were exposed to HIV-contaminated products became infected. Transfusions of whole blood, packed red blood cells, platelets, leukocytes, and plasma are all capable of transmitting HIV infection. In contrast, hyperimmune γ globulin, hepatitis B immune globulin, plasma-derived hepatitis B vaccine, and Rho immune globulin have not been associated with transmission of HIV infection.The procedures involved in processing these products either inactivate or remove the virus. In addition to the above, an estimated 8000–10,000 individuals in the United States with hemophilia or other clotting disorders were infected with HIV by receipt of HIV-contaminated fresh-frozen plasma or concentrates of clotting factors; by the end of 2005, >5400 of these individuals had developed AIDS. Currently, in the United States and in most developed countries, the following measures have made the risk of transmission of HIV infection by transfused blood or blood products extremely small: (1) the screening of all blood for HIV nucleic acid, p24 antigen, and/or anti-HIV antibodies; (2) the selfdeferral of donors on the basis of risk behavior; (3) the screening out of HIV-negative individuals with positive surrogate laboratory parameters of HIV infection, such as hepatitis B and C; and (4) serologic testing for syphilis. The chance of infection of a hemophiliac via clotting factor concentrates has essentially been eliminated because of the added layer of safety resulting from heat treatment of the concentrates.


Transmissions per 1000 coital acts

16

802

SECTION V Viral Infections

It is currently estimated that the risk of infection with HIV in the United States via transfused screened blood is approximately 1 in 1.5 million donations. Therefore, among the ~15 million donations collected in the United States each year, about 10 infectious donations are available for transfusion. Thus, despite the best efforts of science, one cannot completely eliminate the risk of transfusion-related transmission of HIV since current technology cannot detect HIV RNA for the first 1–2 weeks after infection due to the low levels of viremia. There have been several reports of sporadic breakdowns in routinely available screening procedures in certain countries, where contaminated blood was allowed to be transfused, resulting in small clusters of patients becoming infected. In China, a disturbingly large number of persons have become infected by selling blood in situations where the collectors reused needles that were contaminated and, in some instances, mixed blood products from a number of individuals, separated the plasma, and reinfused red blood cells back into individual donors. There have been no reported cases of transmission of HIV-2 in the United States via donated blood or tissues, and, currently, donated blood is screened for both HIV-1 and HIV-2 antibodies.Transmission of HIV (both HIV-1 and HIV-2) by blood or blood products is still an ongoing threat in certain developing countries, particularly in Sub-Saharan Africa, where routine screening of blood is not universally practiced. Before the screening of donors, a small number of cases of transmission of HIV via semen used in artificial insemination and tissues used in organ transplantation were documented. At present, donors of such tissues are prescreened for HIV infection. However, laboratory errors can occur, and in 2007 an incorrect screening report led to the transplantation in Italy of two kidneys and a liver to three recipients from a deceased donor who was later discovered to have been HIV positive. With regard to HIV sero-discordant couples (male, HIV infected; female, HIV-uninfected) who wish to conceive a child, assisted reproductive techniques using spermwashing to reduce the risk of HIV transmission have been successfully employed, with only one well-documented seroconversion in the uninfected female partner, reported in 1990.

OCCUPATIONAL TRANSMISSION OF HIV: HEALTH CARE WORKERS, LABORATORY WORKERS, AND THE HEALTH CARE SETTING There is a small, but definite, occupational risk of HIV transmission to health care workers and laboratory personnel and potentially others who work with HIV-containing materials, particularly when sharp objects are used.An estimated 600,000–800,000 health care workers are stuck with needles or other sharp medical instruments in the United States each year. Exposures that place a health care worker at potential risk of HIV infection are percutaneous injuries (e.g., a needle stick or cut with a sharp object) or contact of

mucous membrane or nonintact skin (e.g., exposed skin that is chapped, abraded, or afflicted with dermatitis) with blood, tissue, or other potentially infectious body fluids. Large, multi-institutional studies have indicated that the risk of HIV transmission after skin puncture from a needle or a sharp object that was contaminated with blood from a person with documented HIV infection is ~0.3% and after a mucous membrane exposure it is 0.09% (see “HIV and the Health Care Worker” later in the chapter). HIV transmission after non-intact skin exposure has been documented, but the average risk for transmission by this route has not been precisely determined; however, it is estimated to be less than the risk for mucous membrane exposure. Transmission of HIV through intact skin has not been documented. In addition to blood and visibly bloody body fluids, semen and vaginal secretions are also considered potentially infectious but have not been implicated in occupational transmission from patients to health care workers. The following fluids are also considered potentially infectious: cerebrospinal fluid, synovial fluid, pleural fluid, peritoneal fluid, pericardial fluid, and amniotic fluid.The risk for transmission after exposure to fluids or tissues other than HIV-infected blood also has not been quantified but is probably considerably lower than for blood exposures. Feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are not considered potentially infectious unless they are visibly bloody. Rare cases of HIV transmission via human bites have been reported, but not after an occupational exposure. An increased risk for HIV infection after percutaneous exposures to HIV-infected blood is associated with exposures involving a relatively large quantity of blood, as in the case of a device visibly contaminated with the patient’s blood, a procedure that involves a needle placed directly in a vein or artery, or a deep injury. Factors that might be associated with mucocutaneous transmission of HIV include exposure to an unusually large volume of blood, prolonged contact, and a potential portal of entry. In addition, the risk increases for exposures to blood from patients with advanced-stage disease, owing to the higher titer of HIV in the blood as well as to other factors, such as the presence of more virulent strains of virus.The use of antiretroviral drugs as postexposure prophylaxis decreases the risk of infection compared with historic controls in occupationally exposed health care workers (see “HIV and the Health Care Worker” later in the chapter). The risk of hepatitis B virus (HBV) infection after a similar type of exposure is ~6–30% in nonimmune individuals; if a susceptible worker is exposed to HBV, postexposure prophylaxis with hepatitis B immune globulin and initiation of HBV vaccine is >90% effective in preventing HBV infection. The risk of hepatitis C virus (HCV) infection after percutaneous injury is ~1.8% (Chap. 92). Since the beginning of the HIV epidemic, there have been at least three reported instances in which transmission of infection from a health care worker to patients seemed highly probable. One cluster of infections involved an HIV-infected dentist in Florida who apparently infected as many as six of his patients, most likely

803


MATERNAL-FETAL/INFANT TRANSMISSION HIV infection can be transmitted from an infected mother to her fetus during pregnancy, during delivery, or by breast-feeding. This is an extremely important form of transmission of HIV infection in certain developing countries, where the proportion of infected women to infected men is ~1:1. Virologic analysis of aborted fetuses indicate that HIV can be transmitted to the fetus as early as the first and second trimester of pregnancy. However, maternal transmission to the fetus occurs most commonly in the perinatal period. Two studies performed in Rwanda and the former Zaire indicated that the relative proportions of mother-tochild transmissions were 23–30% before birth, 50–65% during birth, and 12–20% via breast-feeding.

In the absence of prophylactic antiretroviral therapy to the mother during pregnancy, labor, and delivery, and to the fetus after birth (see below), the probability of transmission of HIV from mother to infant/fetus ranges from 15–25% in industrialized countries and from 25–35% in developing countries. These differences may relate to the adequacy of prenatal care as well as to the stage of HIV disease and the general health of the mother during pregnancy. Higher rates of transmission have been reported to be associated with many factors, the best documented of which is the presence of high maternal levels of plasma viremia. In one study of 552 singleton pregnancies in the United States, the rate of mother-to-baby transmission was 0% among women with 100,000 copies/mL. However, there may not be a lower “threshold” below which transmission never occurs, since other studies have reported transmission by women with viral RNA levels 400 anophelines can transmit malaria, and those that do vary considerably in their efficiency as malaria vectors. More specifically, the transmission of malaria is directly proportional to the density of the vector, the square of the number of human bites per day per mosquito, and the tenth power of the probability of the mosquito’s surviving for 1 day. Mosquito longevity is particularly important, because the portion of the parasite’s life cycle that takes place within the mosquito— from gametocyte ingestion to subsequent inoculation (sporogony)—lasts 8–30 days, depending on ambient temperature; thus, to transmit malaria, the mosquito must survive for >7 days. In general, at temperatures below 16°–18°C, sporogony is not completed and transmission does not occur, although malaria outbreaks and transmission have recently occurred in the highlands of east Africa—areas (>1500 m) previously free of vectors. The most effective mosquito vectors of malaria are those, such as Anopheles gambiae in Africa, which are long-lived, occur in high densities in tropical climates, breed readily, and bite humans in preference to other animals.The entomologic inoculation rate (the number of sporozoite-positive mosquito bites per person per year) is the most common measure of malaria transmission and varies from 300 in parts of tropical Africa.

Protozoal and Helminthic Infections

ERYTHROCYTE CHANGES IN MALARIA After invading an erythrocyte, the growing malarial parasite progressively consumes and degrades intracellular proteins, principally hemoglobin. The potentially toxic heme is detoxified by polymerization to biologically inert hemozoin (malaria pigment).The parasite also alters the RBC membrane by changing its transport properties, exposing cryptic surface antigens, and inserting new parasitederived proteins. The RBC becomes more irregular in shape, more antigenic, and less deformable. In P. falciparum infections, membrane protuberances appear on the erythrocyte’s surface 12–15 h after the cell’s invasion.These “knobs” extrude a high-molecular-weight, antigenically variant, strain-specific erythrocyte membrane adhesive protein (PfEMP1) that mediates attachment to receptors on venular and capillary endothelium—an event termed cytoadherence. Several vascular receptors have been identified, of which intercellular adhesion molecule 1 (ICAM-1) is probably the most important in the brain, chondroitin sulfate B in the placenta, and CD36 in most other organs.Thus, the infected erythrocytes stick inside and eventually block capillaries and venules. At the same stage, these P. falciparum–infected RBCs may also adhere to uninfected RBCs (to form rosettes) and to other parasitized erythrocytes (agglutination). The processes of cytoadherence, rosetting, and agglutination are central to

the pathogenesis of falciparum malaria.They result in the sequestration of RBCs containing mature forms of the parasite in vital organs (particularly the brain), where they interfere with microcirculatory flow and metabolism. Sequestered parasites continue to develop out of reach of the principal host defense mechanism: splenic processing and filtration. As a consequence, only the younger ring forms of the asexual parasites are seen circulating in the peripheral blood in falciparum malaria, and the level of peripheral parasitemia underestimates the true number of parasites within the body. Severe malaria is also associated with reduced deformability of the uninfected erythrocytes, which compromises their passage through the partially obstructed capillaries and venules and shortens RBC survival. In the other three (“benign”) malarias, sequestration does not occur, and all stages of the parasite’s development are evident on peripheral blood smears. Whereas P. vivax, P. ovale, and P. malariae show a marked predilection for either young RBCs (P. vivax, P. ovale) or old cells (P. malariae) and produce a level of parasitemia that is seldom >2%, P. falciparum can invade erythrocytes of all ages and may be associated with very high levels of parasitemia.

HOST RESPONSE Initially, the host responds to plasmodial infection by activating nonspecific defense mechanisms. Splenic immunologic and filtrative clearance functions are augmented in malaria, and the removal of both parasitized and uninfected erythrocytes is accelerated. The parasitized cells escaping splenic removal are destroyed when the schizont ruptures. The material released induces the activation of macrophages and the release of proinflammatory mononuclear cell–derived cytokines, which cause fever and exert other pathologic effects. Temperatures of ≥40°C damage mature parasites; in untreated infections, the effect of such temperatures is to further synchronize the parasitic cycle, with eventual production of the regular fever spikes and rigors that originally served to characterize the different malarias.These regular fever patterns (tertian, every 2 days; quartan, every 3 days) are seldom seen today in patients who receive prompt and effective antimalarial treatment. The geographic distributions of sickle cell disease, ovalocytosis, thalassemia, and glucose-6-phosphate dehydrogenase (G6PD) deficiency closely resemble that of malaria before the introduction of control measures. This similarity suggests that these genetic disorders confer protection against death from falciparum malaria. For example, HbA/S heterozygotes (sickle cell trait) have a sixfold reduction in the risk of dying from severe falciparum malaria.This decrease in risk appears to be related to impaired parasite growth at low oxygen tensions. Parasite multiplication in HbA/E heterozygotes is reduced at high parasite densities. In Melanesia, children with α-thalassemia appear to have more frequent malaria (both vivax and falciparum) in the early years of life, and this pattern of infection appears to protect against severe disease. In Melanesian ovalocytosis, rigid erythrocytes

Malaria is a very common cause of fever in tropical countries. The first symptoms of malaria are nonspecific; the lack of a sense of well-being, headache, fatigue, abdominal discomfort, and muscle aches followed by fever are all similar to the symptoms of a minor viral illness. In some instances, a prominence of headache, chest pain, abdominal pain, arthralgia, myalgia, or diarrhea may suggest another diagnosis. Although headache may be severe in malaria, there is no neck stiffness or photophobia resembling that in meningitis. While myalgia may be prominent, it is not usually

SEVERE FALCIPARUM MALARIA Appropriately and promptly treated, uncomplicated falciparum malaria (i.e., the patient can swallow medicines and food) carries a mortality rate of ~0.1%. However, once vital-organ dysfunction occurs or the total proportion of erythrocytes infected increases to >2% (a level corresponding to >1012 parasites in an adult), mortality risk rises steeply. The major manifestations of severe falciparum malaria are shown in Table 116-2, and features indicating a poor prognosis are listed in Table 116-3. Cerebral Malaria Coma is a characteristic and ominous feature of falciparum malaria and, despite treatment, is associated with death rates of ~20% among adults and 15% among children.Any obtundation, delirium, or abnormal behavior should be taken very seriously.The onset may be gradual or sudden following a convulsion. Cerebral malaria manifests as diffuse symmetric encephalopathy; focal neurologic signs are unusual. Although some passive resistance to head flexion may be detected, signs of meningeal irritation are lacking. The eyes may be divergent and a pout reflex is common, but

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Malaria

CLINICAL FEATURES

as severe as in dengue fever, and the muscles are not tender as in leptospirosis or typhus. Nausea, vomiting, and orthostatic hypotension are common.The classic malarial paroxysms, in which fever spikes, chills, and rigors occur at regular intervals, are relatively unusual and suggest infection with P. vivax or P. ovale.The fever is irregular at first (that of falciparum malaria may never become regular); the temperature of nonimmune individuals and children often rises above 40°C in conjunction with tachycardia and sometimes delirium. Although childhood febrile convulsions may occur with any of the malarias, generalized seizures are specifically associated with falciparum malaria and may herald the development of cerebral disease. Many clinical abnormalities have been described in acute malaria, but most patients with uncomplicated infections have few abnormal physical findings other than fever, malaise, mild anemia, and (in some cases) a palpable spleen. Anemia is common among young children living in areas with stable transmission, particularly where resistance has compromised the efficacy of antimalarial drugs. In nonimmune individuals with acute malaria, the spleen takes several days to become palpable, but splenic enlargement is found in a high proportion of otherwise healthy individuals in malaria-endemic areas and reflects repeated infections. Slight enlargement of the liver is also common, particularly among young children. Mild jaundice is common among adults; it may develop in patients with otherwise uncomplicated falciparum malaria and usually resolves over 1–3 weeks. Malaria is not associated with a rash like those seen in meningococcal septicemia, typhus, enteric fever, viral exanthems, and drug reactions. Petechial hemorrhages in the skin or mucous membranes—features of viral hemorrhagic fevers and leptospirosis—develop only rarely in severe falciparum malaria.

CHAPTER 116

resist merozoite invasion, and the intraerythrocytic milieu is hostile. Nonspecific host defense mechanisms stop the infection’s expansion, and the subsequent specific immune response controls the infection. Eventually, exposure to sufficient strains confers protection from high-level parasitemia and disease but not from infection. As a result of this state of infection without illness (premunition), asymptomatic parasitemia is common among adults and older children living in regions with stable and intense transmission (i.e., holo- or hyperendemic areas). Immunity is mainly specific for both the species and the strain of infecting malarial parasite. Both humoral immunity and cellular immunity are necessary for protection, but the mechanisms of each are incompletely understood (Fig. 116-1). Immune individuals have a polyclonal increase in serum levels of IgM, IgG, and IgA, although much of this antibody is unrelated to protection. Antibodies to a variety of parasitic antigens presumably act in concert to limit in vivo replication of the parasite. In the case of falciparum malaria, the most important of these antigens is the surface adhesin—the variant protein Pf EMP1 mentioned above. Passively transferred IgG from immune adults has been shown to reduce levels of parasitemia in children; although parasitemia in very young infants can occur, passive transfer of maternal antibody contributes to the relative (but not complete) protection of infants from severe malaria in the first months of life. This complex immunity to disease declines when a person lives outside an endemic area for several months or longer. Several factors retard the development of cellular immunity to malaria. These factors include the absence of major histocompatibility antigens on the surface of infected RBCs, which precludes direct T cell recognition; malaria antigen–specific immune unresponsiveness; and the enormous strain diversity of malarial parasites, along with the ability of the parasites to express variant immunodominant antigens on the erythrocyte surface that change during the period of infection. Parasites may persist in the blood for months (or, in the case of P. malariae, for many years) if treatment is not given. The complexity of the immune response in malaria, the sophistication of the parasites’ evasion mechanisms, and the lack of a good in vitro correlate with clinical immunity have all slowed progress toward an effective vaccine.

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TABLE 116-2 MANIFESTATIONS OF SEVERE FALCIPARUM MALARIA SIGNS

Major Unarousable coma/cerebral malaria Acidemia/acidosis Severe normochromic, normocytic anemia Renal failure Pulmonary edema/adult respiratory distress syndrome Hypoglycemia Hypotension/shock Bleeding/disseminated intravascular coagulation Convulsions Hemoglobinuriaa

SECTION VIII

Other Impaired consciousness/ arousable Extreme weakness Hyperparasitemia Jaundice

MANIFESTATIONS

Failure to localize or respond appropriately to noxious stimuli; coma persisting for >30 min after generalized convulsion Arterial pH 20% of parasites identified as pigment-containing trophozoites and schizonts >5% of neutrophils with visible pigment

1084 and serum creatinine levels return to normal in a mean

of 17 days. Early dialysis or hemofiltration considerably enhances the likelihood of a patient’s survival, particularly in acute hypercatabolic renal failure.

TABLE 116-4 RELATIVE INCIDENCE OF SEVERE COMPLICATIONS OF FALCIPARUM MALARIA COMPLICATION

SECTION VIII

Hematologic Abnormalities Anemia results from accelerated RBC removal by the spleen, obligatory RBC destruction at parasite schizogony, and ineffective erythropoiesis. In severe malaria, both infected and uninfected RBCs show reduced deformability, which correlates with prognosis and development of anemia. Splenic clearance of all RBCs is increased. In nonimmune individuals and in areas with unstable transmission, anemia can develop rapidly and transfusion is often required. As a consequence of repeated malarial infections, children in many areas of Africa may develop severe anemia resulting from both shortened RBC survival and marked dyserythropoiesis.Anemia is a common consequence of antimalarial drug resistance, which results in repeated or continued infection. Slight coagulation abnormalities are common in falciparum malaria, and mild thrombocytopenia is usual. Of patients with severe malaria, 3 days. Aspiration pneumonia may follow generalized convulsions. The frequency of complications of severe falciparum malaria is summarized in Table 116-4.

MALARIA IN PREGNANCY In heavily endemic (hyper- and holoendemic) areas, falciparum malaria in primi- and secundigravid women is associated with low birth weight (average reduction, ~170 g) and consequently increased infant and childhood mortality. In general, infected mothers in areas of stable transmission remain asymptomatic despite intense accumulation of parasitized erythrocytes in the placental

Anemia Convulsions Hypoglycemia Jaundice Renal failure Pulmonary edema

NONPREGNANT ADULTS

PREGNANT WOMEN CHILDREN

+ + + +++ +++ ++

++ + +++ +++ +++ +++

+++ +++ +++ + − +

Key: −, rare; +, infrequent; ++, frequent; +++, very frequent.

microcirculation. Maternal HIV infection predisposes pregnant women to malaria, predisposes their newborns to congenital malarial infection, and exacerbates the reduction in birth weight associated with malaria. In areas with unstable transmission of malaria, pregnant women are prone to severe infections and are particularly vulnerable to high-level parasitemia with anemia, hypoglycemia, and acute pulmonary edema. Fetal distress, premature labor, and stillbirth or low birth weight are common results. Fetal death is usual in severe malaria. Congenital malaria occurs in 105 parasites/µL are at increased risk of dying, but nonimmune patients may die with much lower counts, and partially immune persons may tolerate parasitemia levels many times higher with only minor symptoms. In severe malaria, a poor prognosis

C

FIGURE 116-5 Thin blood films of Plasmodium vivax. A. Young trophozoites. B. Old trophozoites. C. Mature schizonts. D. Female gametocytes. E. Male gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)

B

A

FIGURE 116-6 Thick blood films of Plasmodium falciparum. A. Trophozoites. B. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)

is indicated by a predominance of more mature P. falciparum parasites (i.e., >20% of parasites with visible pigment) in the peripheral blood film or by the presence of phagocytosed malarial pigment in >5% of neutrophils. In P. falciparum infections, gametocytemia peaks 1 week after the peak of asexual parasites. Because the mature gametocytes of

A

B

B

LABORATORY FINDINGS Normochromic, normocytic anemia is usual.The leukocyte count is generally normal, although it may be raised in very severe infections.There is slight monocytosis, lymphopenia, and eosinopenia, with reactive lymphocytosis and eosinophilia in the weeks after the acute infection. The erythrocyte sedimentation rate, plasma viscosity, and levels of C-reactive protein and other acute-phase proteins are high.The platelet count is usually reduced to ~105/µL.

C

FIGURE 116-7 Thick blood films of Plasmodium vivax. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)

C

FIGURE 116-8 Thick blood films of Plasmodium ovale. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)

C

FIGURE 116-9 Thick blood films of Plasmodium malariae. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)

Malaria

A

B

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CHAPTER 116

A

P. falciparum are not affected by most antimalarial drugs, their persistence does not constitute evidence of drug resistance. Phagocytosed malarial pigment is sometimes seen inside peripheral-blood monocytes or polymorphonuclear leukocytes and may provide a clue to recent infection if malaria parasites are not detectable. After the clearance of the parasites, this intraphagocytic malarial pigment is often evident for several days in the peripheral blood or for longer in bone marrow aspirates or smears of fluid expressed after intradermal puncture. Staining of parasites with the fluorescent dye acridine orange allows more rapid diagnosis of malaria (but not speciation of the infection) in patients with low-level parasitemia.

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SECTION VIII

Protozoal and Helminthic Infections TABLE 116-5 METHODS FOR THE DIAGNOSIS OF MALARIAa METHOD

PROCEDURE

ADVANTAGES

DISADVANTAGES

Thick blood filmb

Blood should be uneven in thickness but sufficiently thin to read watch hands through part of the spot. Stain dried, unfixed blood spot with Giemsa, Field’s, or other Romanowsky stain. Count number of asexual parasites per 200 WBCs (or per 500 at low densities). Count gametocytes separately.c Stain fixed smear with Giemsa, Field’s, or other Romanowsky stain. Count number of RBCs containing asexual parasites per 1000 RBCs. In severe malaria, assess stage of parasite development and count neutrophils containing malaria pigment.e Count gametocytes separately.c A drop of blood is placed on the stick or card, which is then immersed in washing solutions. Monoclonal antibody captures the parasite antigen and reads out as a colored band. A drop of blood is placed on the stick or card, which is then immersed in washing solutions. Monoclonal antibodies capture the parasite antigens and read out as colored bands. One band is genus specific (all malarias), and the other is specific for P. falciparum.

Sensitive (0.001% parasitemia); species specific; inexpensive

Requires experience (artifacts may be misinterpreted as low-level parasitemia); underestimates true count

Rapid; species specific; inexpensive; in severe malaria, provides prognostic informatione

Insensitive (10,000 parasites/µL (~0.2% parasitemia) does indicate that malaria is the cause. Antibody and polymerase chain reaction tests have no role in the diagnosis of malaria. b Asexual parasites/200 WBCs × 40 = parasite count/µL (assumes a WBC count of 8000/µL). See Figs. 116-6 to 116-9. c Gametocytemia may persist for days or weeks after clearance of asexual parasites. Gametocytemia without asexual parasitemia does not indicate active infection. d Parasitized RBCs (%) × hematocrit × 1256 = parasite count/µL. See Figs. 116-3 and 116-4. e The presence of >100,000 parasites/µL (~2% parasitemia) is associated with an increased risk of severe malaria, but some patients have severe malaria with lower counts. At any level of parasitemia, the finding that >50% of parasites are tiny rings (cytoplasm width less than half of nucleus width) carries a relatively good prognosis. The presence of visible pigment in >20% of parasites or of phagocytosed pigment in >5% of polymorphonuclear leukocytes (indicating massive recent schizogony) carries a worse prognosis. f Persistence of PfHRP2 is a disadvantage in high-transmission settings, where many asymptomatic people have positive tests, but can be used to diagnostic advantage in low-transmission settings when a sick patient has received previous unknown treatment (which, in endemic areas, often consists of antimalarial drugs). A positive PfHRP2 test indicates that the illness is falciparum malaria, even if the blood smear is negative. Note: LDH, lactate dehydrogenase; PfHRP2, P. falciparum histidine-rich protein 2; RBCs, red blood cells; WBCs, white blood cells.

Severe infections may be accompanied by prolonged prothrombin and partial thromboplastin times and by more severe thrombocytopenia. Levels of antithrombin III are reduced even in mild infection. In uncomplicated malaria, plasma concentrations of electrolytes, blood urea nitrogen (BUN), and creatinine are usually normal. Findings in severe malaria may include metabolic acidosis, with low plasma concentrations of glucose, sodium, bicarbonate, calcium, phosphate, and albumin together with elevations in lactate, BUN, creatinine, urate, muscle and liver enzymes, and conjugated and unconjugated bilirubin. Hypergammaglobulinemia is usual in immune and semi-immune subjects. Urinalysis generally gives normal results. In adults and children with cerebral malaria, the mean opening pressure at lumbar puncture is ~160 mm of cerebrospinal fluid (CSF); usually the CSF is normal or has a slightly elevated total protein level [20% containing visible malaria pigment), and phagocytosed malaria pigment in >5% of neutrophils.

CHAPTER 118

Wright’s, Leishman’s). Thin film smears are shown in Figs. 118-1 to 118-4; thick film smears are shown in Figs. 118-5 to 118-8. The morphologic characteristics of the parasites are summarized in Table 118-1. In the thick film, lysis of red blood cells by water leaves the stained white cells and parasites, allowing detection of densities as low as 50 parasites/µL. This degree of sensitivity is up to 100 times greater than that of the thin

1102

SECTION VIII

FIGURE 118-3 Thin blood films of Plasmodium ovale. A. Old trophozoites. B. Mature schizonts. C. Male gametocytes. D. Female gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)

FIGURE 118-4 Thin blood films of Plasmodium malariae. A. Old trophozoites. B. Mature schizonts. C. Male gametocytes. D. Female gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)


TABLE 118-1 MORPHOLOGIC CHARACTERISTICS OF HUMAN MALARIA PARASITES P. FALCIPARUM

P. VIVAX

P. OVALE

P. MALARIAE

Asexual parasites

Usually only fine blue ring forms (some resembling stereo headsets) are seen. Parasitemia level may exceed 2%.

Schizonts

Rare in peripheral blood; 8–32 merozoites, dark brown-black pigment Banana-shaped; male: light blue; female: darker blue; a few scattered blue-black pigment granules in cytoplasm

Irregular, large, fairly thick rings become highly pleomorphic as the parasite grows. Parasitemia level is low. Common; 12–18 merozoites, orangebrown pigment Round or oval; male: round, pale blue; female: oval, dark blue; triangular nucleus, a few orange pigment granules RBCs are enlarged. Pale red Schüffner’s dots increase in number as the parasite matures.

Regular, dense ring enlarges to compact, blue, mature trophozoite (rectangular or bandform). Parasitemia level is low. 8–14 merozoites, brown or black pigment

Dense, thick rings mature to dense, round trophozoites. Parasitemia level is low. 8–10 merozoites, dark brown or black pigment Large, oval; male: pale blue; female: dense blue; large black pigment granules

Gametocytes

RBC changes

RBCs are normal in size. As the parasite matures, the RBC cytoplasm becomes pale, the cells become crenated, and a few small red dots may appear over the cytoplasm (Maurer’s clefts).

Note: RBC, red blood cell.

Large, round, dense, and blue (like P. malariae), but prominent James’s dots; brown pigment

RBCs become oval with tufted ends. Red James’s dots are prominent.

RBCs are normal in size and shape. No red dots are seen.

1103

FIGURE 118-5 Thick blood films of Plasmodium falciparum. A. Trophozoites. B. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)

FIGURE 118-8 Thick blood films of Plasmodium malariae. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)

CHAPTER 118 FIGURE 118-9 Thin blood film showing trophozoites of Babesia. ( Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization. )

Babesia microti appears as a small ring form resembling P. falciparum. Unlike Plasmodium, Babesia does not cause the production of pigment in parasites, nor are schizonts or gametocytes formed. Figure 118-9 shows a thin blood film of trophozoites of Babesia. FIGURE 118-7 Thick blood films of Plasmodium ovale. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)

FURTHER READINGS WARHURST C, WILLIAMS JE: Laboratory procedures for diagnosis of malaria, in Abdalla SH, Pasvol G (series eds): Malaria:A Hematological Perspective. G Pasvol, SL Hoffman (eds): Tropical Medicine: Science and Practice, vol 4. London, Imperial College Press, 2004

Atlas of Blood Smears of Malaria and Babesiosis

FIGURE 118-6 Thick blood films of Plasmodium vivax. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)

CHAPTER 119

LEISHMANIASIS Barbara L. Herwaldt The term leishmaniasis encompasses multiple clinical syndromes. Most notable are visceral, cutaneous, and mucosal leishmaniasis, which result from infection of macrophages throughout the reticuloendothelial system, in the dermis, and in the naso-oropharyngeal mucosa, respectively. Leishmaniasis, a vector-borne disease caused by obligate intracellular protozoa, is characterized by vast diversity and by specificity within that diversity. The disease is endemic in focal areas of ~90 countries in the tropics, subtropics, and southern Europe, in settings that range from deserts to rain forests and from rural to urban areas. Infection in humans is caused by ~20 Leishmania species (Leishmania and Viannia subgenera) (Table 119-1), which are transmitted by ~30 species of phlebotomine sandflies (Phlebotomus [Old World] and Lutzomyia [New World]). Amid this diversity, particular parasite, vector, and host species maintain the transmission cycle in a given setting. Both the diversity and the specificity of the disease confound attempts to generalize about any aspect of leishmaniasis, including control measures and clinical management. The multitudinous possible combinations of Leishmania species/strains, syndromes, and geographic areas—modified by host factors and immunoinflammatory responses—may be associated with clinically relevant differences, such as diverse manifestations of infection and diverse responses to particular therapies. It is essential that clinicians understand the dangers associated with extrapolating data from one setting to another and the importance of individualizing patient care, with expert consultation.

Leishmaniasis is viewed as a model system for exploring immunoregulatory responses to intracellular pathogens. Murine models of L. major infection exemplify the TH1/TH2 paradigm, in which polarized TH1 and TH2 responses govern resistance and susceptibility, respectively. Production of interferon γ (IFN-γ) by TH1 and natural killer cells confers resistance; interleukin (IL) 12 induces naïve T cells to differentiate into TH1 cells and induces T cells and natural killer cells to produce IFN-γ. In contrast, expansion of IL-4-producing TH2 cells and IL-10 mediate susceptibility. Although the immunoregulatory responses are more complex and less polarized in humans than in inbred mice, key principles are evident. The immunoinflammatory response is central to pathogenesis, healing is associated

LIFE CYCLE AND IMMUNOREGULATION Leishmania parasites, which target and persist in tissue macrophages, are transmitted by the bite of female phlebotomine sandflies.While probing for a blood meal, sandflies regurgitate the parasite’s flagellated promastigote stage into the host’s skin; sandfly salivary components with immunomodulating effects have been shown to promote experimental infection. Promastigotes bind to receptors on macrophages, are phagocytized, and transform within phagolysosomes into nonflagellated amastigotes (Fig. 119-1), which replicate and infect additional macrophages. Amastigotes ingested by sandflies transform back into infective promastigotes. Other modes of transmission include congenital and parenteral (e.g., by blood transfusion or needle sharing).

FIGURE 119-1 Amastigotes (the tissue stage of Leishmania parasites) in a Giemsa-stained impression smear of tissue from a patient with cutaneous leishmaniasis. Amastigotes are oval or egg shaped and ~2–4 µm in length. Their internal organelles include a nucleus (larger arrow) and rod-shaped kinetoplast (smaller arrow). In particular, the kinetoplast, a specialized mitochondrial structure that contains extranuclear DNA, should be visualized. The extracellular amastigotes probably were released from macrophages during manipulation of the specimen. Magnification: ×1000, obtained using a ×100 oil-immersion objective. (Photograph courtesy of H. Bishop; with permission.)

1104

TABLE 119-1

1105

LEISHMANIA SPECIES THAT CAUSE DISEASE IN HUMANS SPECIESa

CLINICAL SYNDROMEb

GEOGRAPHIC DISTRIBUTIONc

VL (PKDL, OWCL)

China, Indian subcontinent (southern Asia), southwestern Asia, Ethiopia,d Kenya, Somalia, Sudan, Uganda; possibly sporadic elsewhere in sub-Saharan Africa China, central and southwestern Asia, Middle East, southern Europe, northern Africa, Ethiopia,d Sudan; sporadic elsewhere in sub-Saharan Africa Central and South America

Subgenus Leishmania L. donovani complex L. donovani sensu stricto

L. infantum sensu strictoe

VL (OWCL)

VL (NWCL)

L. amazonensis L. tropica

NWCL (ML, DCL, VL) OWCL (VL)f

L. major

OWCL

L. aethiopica

OWCL (DCL)

Mexico, Central and South America; sporadic in Texas and Oklahoma Panama and South America Central Asia, India, Pakistan, southwestern Asia, Middle East, Turkey, Greece, northern Africa, Ethiopia,d Kenya, Namibia Central Asia, India, Pakistan, southwestern Asia, Middle East, Turkey, northern Africa, Sahel region of north-central Africa, Ethiopia,d Sudan, Kenya Ethiopia,d Kenya, Uganda

NWCL (ML) NWCL (ML) NWCL (ML) NWCLg

Central and South America South America Central America, Venezuela, Colombia, Ecuador, Peru Peru (western slopes of Andes)

NWCL (DCL)

Subgenus Viannia L. (V.) braziliensis L. (V.) guyanensis L. (V.) panamensis L. (V.) peruviana

CHAPTER 119

L. chagasie L. mexicana complex L. mexicana

a

with activation of macrophages to kill intracellular amastigotes, and persistent infection is characteristic. Although the correlates of immunity are not fully defined and may differ between treated and untreated persons, nonsterile cure is a mixed blessing: quiescent parasites may help the host maintain a protective T cell–mediated immune response but may also serve as a source for activation of latent or clinically cured infection if the protective mechanisms fail.

EPIDEMIOLOGY, PREVENTION, AND CONTROL Leishmaniasis is endemic or emerging in focal areas of ~90 countries in Asia, the Middle East, southern Europe, and Africa (Old World disease) and the Americas (New World disease) (Table 119-1).

Upwards of several hundred thousand cases of visceral leishmaniasis and 1–1.5 million cases of cutaneous leishmaniasis occur annually. Leishmaniasis is associated with the loss of ~2.4 million disability-adjusted life-years. More than 90% of the world’s cases of visceral leishmaniasis occur in three regions: (1) southern Asia or the Indian subcontinent, particularly in Bihar State in northeastern India and in foci in Bangladesh and Nepal; (2) eastern Africa (Sudan and neighboring countries); and (3) the Americas, particularly in periurban areas of northeastern Brazil.The predominant etiologic agents are L. donovani in southern Asia and eastern Africa and L. infantum/L. chagasi elsewhere in the Old and New Worlds. These organisms can also cause cutaneous leishmaniasis. More than 90% of the world’s cases of cutaneous leishmaniasis occur in Afghanistan (Fig. 119-2), Algeria, Iran, Iraq, Pakistan, Saudi Arabia, and Syria (Old World)

Leishmaniasis

Species other than those listed here have been reported to infect humans. DCL, diffuse cutaneous leishmaniasis; ML, mucosal leishmaniasis; NWCL, New World (American) cutaneous leishmaniasis; OWCL, Old World cutaneous leishmaniasis; PKDL, post–kala-azar dermal leishmaniasis; VL, visceral leishmaniasis. Clinical syndromes less frequently associated with the various species are shown in parentheses. c The geographic distribution is highly focal within countries/regions, and the order in which areas are listed does not reflect the level of endemicity. (See text for further information.) The geographic distribution of cases evaluated in countries such as the United States reflects travel and immigration patterns. d Cutaneous and visceral leishmaniasis also are endemic in parts of Eritrea, but the causative species have not been well established. e “L. infantum” and “L. chagasi” are considered synonymous. f L. tropica also causes leishmaniasis recidivans and viscerotropic leishmaniasis. g The cutaneous leishmaniasis syndrome caused by this species is called uta. b

sure, and suboptimal treatment can lead to dissemination of drug resistance. In southern Asia, which arguably carries ~70% of the global burden of visceral leishmaniasis, transmission of L. donovani is anthroponotic and largely intraor peridomiciliary. In 2005, India, Nepal, and Bangladesh resolved to collaborate to reduce the annual incidence of visceral leishmaniasis to 90%). In contrast, the parasites may be abundant in typical sites (e.g., bone marrow), in atypical sites (e.g., gastrointestinal tissue), and in circulating monocytes—a circumstance that facilitates parasitologic diagnosis. The sensitivities of peripheral-blood smear and buffy-coat culture are ~50% and ~70%, respectively. PCR may be even more sensitive. CUTANEOUS AND MUCOSAL LEISHMANIASIS Aspirates and biopsy specimens of skin lesions and lymph nodes are useful for parasitologic confirmation of cutaneous and mucosal leishmaniasis by traditional and molecular methods. Parasitologic confirmation of mucosal leishmaniasis—a pauciparasitic syndrome—by traditional methods can be difficult. Serologic testing usually is not helpful for patients with cutaneous leishmaniasis; except in patients with DCL and some patients with mucosal leishmaniasis, antibody is either undetectable or present at low levels. In contrast, skin-test reactivity usually develops during active infection except in patients with DCL.

Treatment: LEISHMANIASIS PRINCIPLES AND PERSPECTIVE (Table 119-2) Decisions about whether and how to treat leishmaniasis should be individualized. For cases in which systemic

treatment is indicated, the parenterally administered pentavalent antimonial (SbV) compounds sodium stibogluconate and meglumine antimonate have been the mainstays of therapy for more than half a century. Manifestations of toxicity (e.g., body aches, malaise, elevated aminotransferase levels, chemical pancreatitis, and electrocardiographic abnormalities) are commonly noted but usually do not limit therapy and are reversible. Conventional amphotericin B deoxycholate and pentamidine isethionate, the traditional parenteral alternatives to SbV, were previously relegated to second-line status, largely because of less experience with their use for the treatment of leishmaniasis and greater concern about their induction of potentially serious or irreversible toxicities (e.g., renal impairment). Amphotericin B, which has high-level, broad-spectrum antileishmanial activity, has been upgraded to first-line status in settings in which its benefits outweigh its risks (e.g., for SbV-resistant visceral leishmaniasis). Lipid formulations of amphotericin B passively target the agent to macrophage-rich organs, resulting in less renal and other toxicity and permitting the use of higher daily doses and shorter courses of therapy. Targeting of drug to the reticuloendothelial system is ideal for visceral leishmaniasis but may not be advantageous for other syndromes. For amphotericin B and other antileishmanial agents, various delivery/targeting mechanisms and formulations are being explored. Although some alternative therapies may have utility in particular settings, even data from well-conducted clinical trials cannot necessarily be generalized to other contexts. Of particular note, data from the many clinical trials of therapy for visceral leishmaniasis in foci in northeastern India are not necessarily directly applicable to visceral leishmaniasis caused by L. donovani in other foci in southern Asia or elsewhere (e.g., eastern Africa) or to visceral infection caused by L. infantum/chagasi—let alone to other leishmanial syndromes. Except for the development of resistance to SbV and pentamidine, Indian kala-azar typically is easier to treat than visceral leishmaniasis elsewhere:i.e.,it is more responsive to therapy, even with lower total doses. Counterintuitively, visceral leishmaniasis often is easier to treat than cutaneous or mucosal leishmaniasis. Achieving adequate drug levels in the phagolysosomes of dermal and mucosal macrophages can be challenging, and the difficulty can be compounded by the fact that some dermotropic species are intrinsically less sensitive than L. donovani to particular drugs. Some of these issues are exemplified by miltefosine, the first highly active oral agent for visceral leishmaniasis. Both experimental (in vitro) and clinical data indicate that L. donovani (the agent of Indian visceral leishmaniasis) is highly sensitive to miltefosine, whereas other species are variably responsive. In addition, the long half-life of the drug and suboptimal treatment predispose to the development of resistance. The most common side effects of therapy include gastrointestinal symptoms and reversible elevations in creatinine and aminotransferase levels. Miltefosine’s teratogenicity in animals has

TABLE 119-2

1109

PARENTERAL AND ORAL DRUG REGIMENS FOR TREATMENT OF LEISHMANIASISa CLINICAL SYNDROME, DRUG

ROUTE OF ADMINISTRATION

REGIMEN

IV, IM IV IV IV, IM IV, IM

20 mg SbV/kg qd for 28 days 2–5 mg/kg qd (total: usually ~15–21 mg/kg) 0.5–1 mg/kg qod or qd (total: usually ~15–20 mg/kg) 15–20 mg/kg qd for ~21 days 4 mg/kg qod or thrice weekly for ~15–30 doses

PO

2.5 mg/kg qd for 28 days

IV, IM IV, IM IV

20 mg SbV/kg qd for 10–20 days (standard recommendation: 20 days) 2 mg/kg qod for 7 doses 0.5–1 mg/kg qod or qd (total: up to ~20 mg/kg)

PO PO PO PO

200 mg qd for 6 weeksf 600 mg qd for 28 daysf 200 mg bid for 28 daysf 2.5 mg/kg qd for 28 days

IV, IM IV IV, IM

20 mg SbV/kg qd for 28 days 1 mg/kg qod or qd (total: usually ~20–40 mg/kg) 2–4 mg/kg qod or thrice weekly for ≥15 doses

Visceral Leishmaniasis Parenteral therapy Pentavalent antimonyb Amphotericin B, lipid formulationc Amphotericin B (deoxycholate) Paromomycin sulfated Pentamidine isethionate Oral therapy Miltefosined,e Cutaneous Leishmaniasis Parenteral therapy Pentavalent antimonyb

Mucosal Leishmaniasis Pentavalent antimonyb Amphotericin B (deoxycholate) Pentamidine isethionate

implications for its use in women of child-bearing age (Table 119-2). The primary goal of treatment for visceral leishmaniasis is to prevent death. Highly effective antileishmanial therapy is essential, as is supportive care (e.g., therapy for malnutrition,

VISCERAL LEISHMANIASIS

anemia, bleeding, and intercurrent infections). In most regions, SbV therapy remains highly effective. However, use of an alternative agent should be considered if high-level SbV resistance is prevalent or if non-SbV therapy is advantageous for other reasons (e.g., duration, cost, or tolerability). In general, most patients feel better and become afebrile during the first week of therapy;

Leishmaniasis

a See text for additional details and perspective about the drugs and regimens in this table and about treatment of leishmaniasis in general. Some of the listed drugs are effective only against certain Leishmania species/strains and only in certain areas of the world. Classification of drugs/regimens in such categories as first-line, alternative, (in)effective, investigational, (un)available, and cost-prohibitive is highly dependent on the setting. Ranges shown for doses and durations of therapy reflect variability both in dosage regimens among clinical trials and in responsiveness in different settings. To maximize effectiveness and minimize toxicity, the listed regimens should be individualized according to the particularities of the case and in consultation with an expert. Children may need different dosage regimens. Except for liposomal amphotericin B (see footnote c), as of this writing, none of the drugs listed is licensed by the U.S. Food and Drug Administration (FDA) for the treatment of leishmaniasis per se. b The Centers for Disease Control and Prevention (CDC) provides the pentavalent antimonial (SbV) compound sodium stibogluconate (Pentostam; Glaxo Operations UK Limited, Barnard Castle, United Kingdom; 100 mg SbV/mL) to U.S.-licensed physicians through the CDC Drug Service (404-639-3670) under an IND mechanism with the FDA. The other widely used SbV compound, meglumine antimonate (Glucantime; typically, ~85 mg SbV/mL), is available primarily in Spanish- and French-speaking areas of the world. Locally made (generic) SbV preparations may have different SbV concentrations and may vary in quality and safety. c The lipid formulations of amphotericin B include liposomal amphotericin B and amphotericin B lipid complex. In 1997, the FDA approved the following regimen of liposomal amphotericin B for immunocompetent patients with visceral leishmaniasis: 3 mg/kg qd on days 1–5, 14, and 21, for a total of 21 mg/kg. For immunosuppressed patients, the approved regimen is 4 mg/kg qd on days 1–5, 10, 17, 24, 31, and 38, for a total of 40 mg/kg. Many alternative regimens have been proposed for immunocompetent patients in various regions of the world; the regimens vary with respect to total and daily doses, number of doses, and intervals between doses. See text for perspective on the use of lipid formulations of amphotericin B for treatment of cutaneous and mucosal leishmaniasis. d Not commercially available in the United States as of this writing. e Miltefosine, which is teratogenic in animals, should not be used to treat pregnant women. Women of child-bearing age should use effective birth control during treatment and for 2 months thereafter. See text regarding the treatment of mucosal leishmaniasis. f Adult dosage.

CHAPTER 119

Pentamidine isethionate Amphotericin B (deoxycholate) Oral therapy Fluconazole Ketoconazole Itraconazole Miltefosined,e

1110

SECTION VIII Protozoal and Helminthic Infections

resolution of splenomegaly and hematologic abnormalities may require weeks or months. In northeastern India, districts of Bihar State north of the Ganges River constitute the epicenter of the epidemic of SbV resistance, which is spreading—to varying degrees—to contiguous areas of India and southern Nepal. Conventional amphotericin B has become firstline therapy where SbV and pentamidine are no longer effective. Lipid formulations of amphotericin B, which are cost-prohibitive where they are most needed, are increasingly being used in southern Europe. The anthroponotic transmission of L. donovani in southern Asia is both a blessing and a curse: a blessing because treatment can serve as a control measure, and a curse because suboptimal treatment can and does lead to the development and dissemination of drug resistance and thereby to the elimination of drugs from the limited armamentarium and to the demise of patients who cannot afford or access the few alternatives. In this context, the oral agent miltefosine, which is registered for commercial use in India and some other countries, has great potential but also is highly vulnerable. The advent of oral therapy translates into unsupervised outpatient treatment, in which patients buy the quantity of drug they can afford and prematurely stop therapy when their supply is depleted or their symptoms are alleviated. Unless protective measures are implemented (e.g., with directly observed or multidrug therapy), drug resistance almost assuredly will develop and spread. The oral agent sitamaquine, an 8-amino-quinoline, is being field-tested in various regions but appears to have a narrow therapeutic window and can cause nephrotoxicity. The aminoglycoside paromomycin (the chemical equivalent of aminosidine) is a candidate parenteral agent for use alone or in drug combinations.To date, the rates of response in field tests have been variable; response rates may be higher in India than in eastern Africa. Patients who are co-infected with HIV may initially respond well to standard therapy but typically experience more toxicity. Antiretroviral therapy delays but does not prevent relapses. Consensus approaches to treatment and secondary prophylaxis have not been established. CUTANEOUS LEISHMANIASIS Decisions about

clinical management of cutaneous leishmaniasis should be based on consideration of goals (e.g., accelerating the healing of skin lesions, decreasing morbidity, decreasing risks for local and mucosal dissemination and relapse), parasite factors (e.g., tissue tropisms and drug sensitivities), and the extent to which the lesions are of concern or are bothersome because of their location (e.g., on the face or near joints), number, size, persistence, or other features (e.g., nodular lymphangitis).When optimal effectiveness is important, parenteral SbV therapy is generally recommended. The first sign of a clinical response typically is decreasing induration, and relapses usually are noted first at the margins of healed lesions.

Although clinical trials of conventional amphotericin B for cutaneous leishmaniasis have not been conducted and standard dosage regimens have not been established, this agent almost assuredly is highly and broadly effective, albeit potentially toxic. Conflicting, limited data are available for lipid formulations. Pentamidine was effective in Colombia [predominantly against L. (V.) panamensis] but not in Peru [against L. (V.) braziliensis]. The effectiveness of the oral agent miltefosine is species and strain dependent. For example, this drug has been effective against L. (V.) panamensis in Colombia but ineffective against L. (V.) braziliensis in Guatemala. At best, azoles have shown modest activity against particular species in isolated studies—e.g., ketoconazole and itraconazole against L. mexicana in Guatemala, ketoconazole against L. (V.) panamensis in Panama, and fluconazole against L. major in Saudi Arabia. Itraconazole has been ineffective against L. (V.) panamensis in Colombia. Local therapy can be considered for some cases without demonstrable local dissemination or risk of mucosal dissemination (e.g., for relatively benign lesions caused by L. mexicana or L. major). Examples of approaches being used or evaluated in some settings include intralesional SbV, various formulations of paromomycin ointments, topical immunomodulators, thermotherapy, and cryotherapy. MUCOSAL LEISHMANIASIS The traditional treatment options for mucosal leishmaniasis include SbV and conventional amphotericin B; conflicting, limited data are available for lipid formulations of the latter drug. The response rates approach those for cutaneous leishmaniasis if mucosal disease is detected and treated at early stages, whereas advanced disease may be unresponsive or relapse repeatedly. Oral miltefosine therapy shows promise, on the basis of a clinical trial in Bolivia. Adjunctive immunotherapy is being evaluated. Concomitant glucocorticoid therapy is indicated if respiratory compromise develops after initiation of therapy.

FURTHER READINGS ALVAR J et al: Chemotherapy in the treatment and control of leishmaniasis.Adv Parasitol 61:223, 2006 AMATO VS et al: Treatment of mucosal leishmaniasis in Latin America: Systematic review.Am J Trop Med Hyg 77:266, 2007 COLER RN, REED SG: Second-generation vaccines against leishmaniasis.Trends Parasitol 21:244, 2005 CROFT SL et al: Drug resistance in leishmaniasis. Clin Microbiol Rev 19:111, 2006 CRUZ I et al: Leishmania/HIV co-infections in the second decade. Indian J Med Res 123:357, 2006 HERWALDT BL: Leishmaniasis. Lancet 354:1191, 1999 MURRAY HW et al: Advances in leishmaniasis. Lancet 366:1561, 2005 SMITH DF et al: Comparative genomics: From genotype to disease phenotype in the leishmaniases. Int J Parasitol 37:1173, 2007 SUNDAR S et al: Injectable paromomycin for visceral leishmaniasis in India. N Engl J Med 356:2571, 2007

CHAPTER 120

TRYPANOSOMIASIS Louis V. Kirchhoff The genus Trypanosoma contains many species of protozoans. Trypanosoma cruzi, the cause of Chagas’ disease in the Americas, and the two trypanosome subspecies that cause human African trypanosomiasis, Trypanosoma brucei gambiense and T. brucei rhodesiense, are the only members of the genus that cause disease in humans.

the bloodstream, muscles (including the myocardium) may become heavily parasitized (Fig. 120-1). The characteristic pseudocysts present in sections of infected tissues are intracellular aggregates of multiplying parasites. In the minority of persons with chronic T. cruzi infections who develop related clinical manifestations, the heart is the organ most commonly affected. Changes include thinning of the ventricular walls, biventricular enlargement, apical aneurysms, and mural thrombi. Widespread lymphocytic infiltration, diffuse interstitial fibrosis, and atrophy of myocardial cells are often apparent, but parasites are difficult to find in myocardial tissue. Conduction-system involvement often affects the right branch and the left anterior branch of the bundle of His. In chronic Chagas’ disease of the gastrointestinal tract (megadisease), the esophagus and colon may exhibit varying degrees of dilatation. On microscopic examination, focal inflammatory lesions with lymphocytic infiltration are seen, and the number of neurons in the myenteric plexus may be markedly reduced. Accumulating experimental evidence implicates the persistence of parasites and the accompanying chronic inflammation— rather than autoimmune mechanisms—as the basis for the pathology in patients with chronic T. cruzi infection.

CHAGAS’ DISEASE DEFINITION Chagas’ disease, or American trypanosomiasis, is a zoonosis caused by the protozoan parasite T. cruzi. Acute Chagas’ disease is usually a mild febrile illness that results from initial infection with the organism. After spontaneous resolution of the acute illness, most infected persons remain for life in the indeterminate phase of chronic Chagas’ disease, which is characterized by subpatent parasitemia, easily detectable antibodies to T. cruzi, and an absence of symptoms. In a minority of chronically infected patients, cardiac and gastrointestinal lesions develop that can result in serious morbidity and even death. LIFE CYCLE AND TRANSMISSION T. cruzi is transmitted among its mammalian hosts by hematophagous triatomine insects, often called reduviid bugs. The insects become infected by sucking blood from animals or humans who have circulating parasites. Ingested organisms multiply in the gut of the triatomines, and infective forms are discharged with the feces at the time of subsequent blood meals. Transmission to a second vertebrate host occurs when breaks in the skin, mucous membranes, or conjunctivae become contaminated with bug feces that contain infective parasites. T. cruzi can also be transmitted by the transfusion of blood donated by infected persons, by organ transplantation, from mother to fetus, and in laboratory accidents. PATHOLOGY An indurated inflammatory lesion called a chagoma often appears at the parasites’ portal of entry. Local histologic changes include the presence of parasites within leukocytes and cells of subcutaneous tissues and the development of interstitial edema, lymphocytic infiltration, and reactive hyperplasia of adjacent lymph nodes. After dissemination of the organisms through the lymphatics and

FIGURE 120-1 Trypanosoma cruzi in the heart muscle of a child who died of acute Chagas’ myocarditis. An infected myocyte containing several dozen T. cruzi amastigotes is in the center of the field (hematoxylin and eosin, ×900).

1111

1112 EPIDEMIOLOGY


T. cruzi is found only in the Americas. Wild and domestic mammals harboring T. cruzi and infected triatomines are found in spotty distributions from the southern United States to southern Argentina. Humans become involved in the cycle of transmission when infected vectors take up residence in the primitive wood, adobe, and stone houses common in much of Latin America.Thus human T. cruzi infection is a health problem primarily among the poor in rural areas of Mexico and Central and South America. Most new T. cruzi infections in rural settings occur in children, but the incidence is unknown because most cases go undiagnosed. Historically, transfusion-associated transmission of T. cruzi has been a serious public health problem in many endemic countries. However, with some notable exceptions, transmission by this route has been markedly reduced as effective programs for the screening of donated blood have been implemented. Several dozen patients with HIV and chronic T. cruzi infections who underwent acute recrudescence of the latter have been described.These patients generally presented with T. cruzi brain abscesses, a manifestation of the illness that does not occur in immunocompetent persons. Currently, it is estimated that 12 million people are chronically infected with T. cruzi and that 25,000 deaths due to the illness occur each year. Of chronically infected persons, 10–30% eventually develop symptomatic cardiac lesions or gastrointestinal disease. The resulting morbidity and mortality make Chagas’ disease the most important parasitic disease burden in Latin America. In recent years, the rate of T. cruzi transmission has decreased markedly in several endemic countries as a result of successful programs involving vector control, blood-bank screening, and education of at-risk populations. A major program begun in 1991 in the “southern cone” nations of South America (Uruguay, Paraguay, Bolivia, Brazil, Chile, and Argentina) has provided the framework for much of this progress. Uruguay and Chile were certified transmission-free in the late 1990s, and Brazil was declared free of transmission in 2006. Transmission has been reduced markedly in Argentina as well. Similar control programs have been initiated in the countries of northern South America and in the Central American nations. Acute Chagas’ disease is rare in the United States. Five cases of autochthonous transmission and five instances of transmission by blood transfusion have been reported. Moreover, T. cruzi was transmitted to five recipients of organs from three T. cruzi–infected donors. Two of these recipients became infected through cardiac transplants. Acute Chagas’ disease has not been reported in tourists returning to the United States from Latin America, although two such instances have been reported in Europe. In contrast, the prevalence of chronic T. cruzi infections in the United States has increased considerably in recent years. Data from the 2000 census indicate that >12 million immigrants from Chagas’-endemic countries currently live in the United States, ∼8 million of whom are Mexicans. The prevalence of T. cruzi infection in

Mexico is 0.5–1.0%, and most of the 4 million immigrants from Chagas’-endemic nations who are not Mexicans come from countries in which the prevalence of T. cruzi infection is greater than it is in Mexico.The total number of T. cruzi–infected persons living in the United States can be estimated reasonably to be 80,000–120,000.The number of instances of transfusionassociated transmission in this country is likely to be considerably greater than the number reported. Screening of the U.S. blood supply for evidence of T. cruzi infection has recently begun (see “Diagnosis” later in the chapter).

CLINICAL COURSE The first signs of acute Chagas’ disease develop at least 1 week after invasion by the parasites.When the organisms enter through a break in the skin, an indurated area of erythema and swelling (the chagoma), accompanied by local lymphadenopathy, may appear. Romaña’s sign—the classic finding in acute Chagas’ disease, which consists of unilateral painless edema of the palpebrae and periocular tissues—can result when the conjunctiva is the portal of entry (Fig. 120-2). These initial local signs may be followed by malaise, fever, anorexia, and edema of the face and lower extremities. A morbilliform rash may also appear. Generalized lymphadenopathy and hepatosplenomegaly may develop. Severe myocarditis develops rarely; most deaths in acute Chagas’ disease are due to heart failure. Neurologic signs are not common, but meningoencephalitis occurs occasionally. The acute symptoms resolve spontaneously in virtually all patients, who then enter the asymptomatic or indeterminate phase of chronic T. cruzi infection.

FIGURE 120-2 Romaña’s sign in an Argentinean patient with acute T. cruzi infection. (Courtesy of Dr. Humberto Lugones, Centro de Chagas, Santiago del Estero, Argentina; with permission.)

Symptomatic chronic Chagas’ disease becomes apparent years or even decades after the initial infection. The heart is commonly involved, and symptoms are caused by rhythm disturbances, dilated cardiomyopathy, and thromboembolism. Right bundle-branch block is a common electrocardiographic abnormality, but other types of atrioventricular block, premature ventricular contractions, and tachy- and bradyarrhythmias occur frequently. Cardiomyopathy often results in right-sided or biventricular heart failure. Embolization of mural thrombi to the brain or other areas may take place. Patients with megaesophagus suffer from dysphagia, odynophagia, chest pain, and regurgitation. Aspiration can occur (especially during sleep) in patients with severe esophageal dysfunction, and repeated episodes of aspiration pneumonitis are common. Weight loss, cachexia, and pulmonary infection can result in death. Patients with megacolon are plagued by abdominal pain and chronic constipation, and advanced megacolon can cause obstruction, volvulus, septicemia, and death.

1113

Treatment: CHAGAS’ DISEASE

Trypanosomiasis

Therapy for Chagas’ disease is unsatisfactory. For many years, only two drugs—nifurtimox and benznidazole— have been available for this purpose. Unfortunately, both drugs lack efficacy and often cause severe side effects. In acute Chagas’ disease, nifurtimox markedly reduces the duration of symptoms and parasitemia and decreases the mortality rate. Nevertheless, limited studies have shown that only ∼70% of acute infections are cured parasitologically by a full course of treatment. Despite its limitations, treatment with nifurtimox should be initiated as early as possible in acute Chagas’ disease. Common adverse effects of nifurtimox include abdominal pain, anorexia, nausea, vomiting, and weight loss. Neurologic reactions to the drug may include restlessness, disorientation, insomnia, twitching, paresthesia, polyneuritis, and seizures. These symptoms usually disappear when the dosage is reduced or treatment is discontinued. The recommended daily dosage is 8–10 mg/kg for adults, 12.5–15 mg/kg for adolescents, and 15–20 mg/kg for children 1–10 years of age. The drug should be given orally in four divided doses each day, and therapy should be continued for 90–120 days. Nifurtimox is available from the Drug Service of the Centers for Disease Control and Prevention (CDC) in Atlanta (telephone number, 770-639-3670). The efficacy of benznidazole is similar to that of nifurtimox; a cure rate of 90% among congenitally infected infants treated before their first birthday has been reported. Adverse effects include peripheral neuropathy, rash, and granulocytopenia. The recommended oral dosage is 5 mg/kg per day for 60 days. Benznidazole is generally considered the drug of choice in Latin America. The question of whether patients in the indeterminate or chronic symptomatic phase of Chagas’ disease should be treated with nifurtimox or benznidazole has been debated for years. The fact that parasitologic cure rates in chronically infected persons may be 100 such transplantations have been done in Brazil and the United States. The survival rate among Chagas’ disease cardiac transplant recipients is higher than that among persons receiving cardiac transplants for other reasons. This better outcome may be due to the fact that lesions are limited to the heart in most patients with symptomatic chronic Chagas’ disease.


PREVENTION Since drug therapy is unsatisfactory and vaccines are not available, the control of T. cruzi transmission in endemic countries must depend on reduction of domiciliary vector populations by spraying of insecticides, improvements in housing, and education of at-risk persons. As noted above, these measures, coupled with serologic screening of blood donors, have markedly reduced transmission of the parasite in many endemic countries. Tourists would be wise to avoid sleeping in dilapidated houses in rural areas of endemic countries. Mosquito nets and insect repellent provide additional protection. In view of the possibly serious consequences of chronic T. cruzi infection, it would be prudent for all immigrants from endemic regions living in the United States to be tested for evidence of infection. Identification of persons harboring the parasite would permit periodic electrocardiographic monitoring, which can be important because pacemakers benefit some patients who develop ominous rhythm disturbances. The possibility of congenital transmission is yet another justification for screening. Guidance for the evaluation and long-term monitoring of T. cruzi–infected persons is being developed by staff at the CDC. Laboratory personnel should wear gloves and eye protection when working with T. cruzi and infected vectors.

SLEEPING SICKNESS DEFINITION Sleeping sickness, or human African trypanosomiasis (HAT), is caused by flagellated protozoan parasites that belong to the T. brucei complex and are transmitted to

humans by tsetse flies. In untreated patients, the trypanosomes first cause a febrile illness that is followed months or years later by progressive neurologic impairment and death.

THE PARASITES AND THEIR TRANSMISSION The East African (rhodesiense) and the West African (gambiense) forms of sleeping sickness are caused, respectively, by two trypanosome subspecies: T. brucei rhodesiense and T. brucei gambiense. These subspecies are morphologically indistinguishable but cause illnesses that are epidemiologically and clinically distinct (Table 120-1). The parasites are transmitted by blood-sucking tsetse flies of the genus Glossina. The insects acquire the infection when they ingest blood from infected mammalian hosts. After many cycles of multiplication in the midgut of the vector, the parasites migrate to the salivary glands. Their transmission takes place when they are inoculated into a mammalian host during a subsequent blood meal. The injected trypanosomes multiply in the blood (Fig. 120-3) and other extracellular spaces and evade immune destruction for long periods by undergoing antigenic variation, a process driven by gene switching in which the antigenic structure of the organisms’ surface coat of glycoproteins changes periodically. PATHOGENESIS AND PATHOLOGY A self-limited inflammatory lesion (trypanosomal chancre) may appear a week or so after the bite of an infected TABLE 120-1 COMPARISON OF WEST AFRICAN AND EAST AFRICAN TRYPANOSOMIASES POINT OF COMPARISON

WEST AFRICAN (GAMBIENSE)

EAST AFRICAN (RHODESIENSE)

Organism Vectors

T. b. gambiense Tsetse flies (palpalis group) Humans Chronic (late CNS disease) Months to years

T. b. rhodesiense Tsetse flies (morsitans group) Antelope and cattle Acute (early CNS disease) 90% of 600 patients with stage II disease. The recommended treatment schedule is 400 mg/kg per day, given intravenously in four divided doses, for 2 weeks. Adverse reactions include diarrhea, anemia, thrombocytopenia, seizures, and hearing loss. The high dosage and duration

may be restarted cautiously at lower doses a few days after signs have resolved. Extravasation of the drug results in intense local reactions. Vomiting, abdominal pain, nephrotoxicity, and myocardial damage can occur.

1117

PREVENTION HAT poses complex public-health and epizootic problems in Africa. Considerable progress has been made in some areas through control programs that focus on eradication of vectors and drug treatment of infected humans; however, there is no consensus on the best approach to solving the overall problem, and major epidemics continue to occur. Individuals can reduce their risk of acquiring trypanosomiasis by avoiding areas known to harbor infected insects, by wearing protective clothing, and by using insect repellent. Chemoprophylaxis is not recommended, and no vaccine is available to prevent transmission of the parasites. FURTHER READINGS

Trypanosomiasis

BISSER S et al: Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei gambiense sleeping sickness. J Infect Dis 195:322, 2007 CHANG CD et al: Evaluation of a prototype Trypanosoma cruzi antibody assay with recombinant antigens on a fully automated chemiluminescence analyzer for blood donor screening.Transfusion 46:1737, 2006 FIORELLI AI et al: Later evolution after cardiac transplantation in Chagas’ disease.Transplant Proc 37:2793, 2005 KIRCHHOFF LV et al:Transfusion-associated Chagas’ disease (American trypanosomiasis) in Mexico: Implications for transfusion medicine in the United States.Transfusion 46:298, 2006 LAMBERT N et al: Chagasic encephalitis as the initial manifestation of AIDS.Ann Intern Med 144:941, 2006 MASCOLA L et al: Chagas disease after organ transplantation—Los Angeles, California, 2006. MMWR 55:798, 2006 RASSI A JR et al: Development and validation of a risk score for predicting death in Chagas’ heart disease. N Engl J Med 355:799, 2006 SARTORI AM et al: Exacerbation of HIV viral load simultaneous with asymptomatic reactivation of chronic Chagas’ disease. Am J Trop Med Hyg 67:521, 2002 SCHMUNIS GA, Cruz JR: Safety of the blood supply in Latin America. Clin Microbiol Rev 18:12, 2005 WELBURN SC et al: Crisis, what crisis? Control of Rhodesian sleeping sickness.Trends Parasitol 22:123, 2006

CHAPTER 120

of therapy required are disadvantages that make widespread use of eflornithine difficult. Pentamidine is the first-line drug for patients with stage I West African HAT. The dose for both adults and children is 4 mg/kg per day, given intramuscularly or intravenously, for 10 days. Frequent, immediate adverse reactions include nausea, vomiting, tachycardia, and hypotension.These reactions are usually transient and do not warrant cessation of therapy. Other adverse reactions include nephrotoxicity, abnormal liver function tests, neutropenia, rashes, hypoglycemia, and sterile abscesses. The arsenical melarsoprol is the drug of choice for the treatment of East African trypanosomiasis with CNS involvement and is an alternative agent for stage II West African disease. Melarsoprol cures both stages of the disease and therefore is also indicated for the treatment of stage I disease in patients who fail to respond to or cannot tolerate suramin or pentamidine. However, because of its relatively high toxicity, melarsoprol is never the first choice for the treatment of stage I disease. For East African disease, the drug should be given to adults in three courses of 3 days each. The dosage is 2–3.6 mg/kg per day, given intravenously in three divided doses for 3 days, followed 1 week later by 3.6 mg/kg per day, also in three divided doses and for 3 days.The latter course is repeated 7 days later. In debilitated patients, suramin is administered for 2–4 days before therapy with melarsoprol is initiated; an 18-mg initial dose of the latter drug, followed by progressive increases to the standard dose, has been recommended. For children, a total of 18–25 mg/kg should be given over 1 month. An IV starting dose of 0.36 mg/kg should be increased gradually to a maximum of 3.6 mg/kg at 1- to 5-day intervals, for a total of 9 or 10 doses. The regimen for West African disease is 2.2 mg/kg per day, given intravenously for 10 days. Melarsoprol is highly toxic and should be administered with great care. To reduce the likelihood of druginduced encephalopathy, all patients receiving melarsoprol should be given prednisolone at a dose of 1 mg/kg (up to 40 mg) per day, beginning 1–2 days before the first dose of melarsoprol and continuing through the last dose. Without prednisolone prophylaxis, the incidence of reactive encephalopathy has been reported to be as high as 18% in some series. Clinical manifestations of reactive encephalopathy include high fever, headache, tremor, impaired speech, seizures, and even coma and death. Treatment with melarsoprol should be discontinued at the first sign of encephalopathy but

CHAPTER 121

TOXOPLASMA INFECTIONS Lloyd H. Kasper DEFINITION Toxoplasmosis is caused by infection with the obligate intracellular parasite Toxoplasma gondii. Acute infection acquired after birth may be asymptomatic but frequently results in the chronic persistence of cysts in the host’s tissues. In both acute and chronic toxoplasmosis, the parasite is responsible for clinically evident disease, including lymphadenopathy, encephalitis, myocarditis, and pneumonitis. Congenital toxoplasmosis is an infection of newborns that results from the transplacental passage of parasites from an infected mother to the fetus. These infants usually are asymptomatic at birth but later manifest a wide range of signs and symptoms, including chorioretinitis, strabismus, epilepsy, and psychomotor retardation.

ETIOLOGY T. gondii is an intracellular coccidian that infects both birds and mammals. There are two distinct stages in the life cycle of T. gondii (Fig. 121-1). In the nonfeline stage, tissue cysts that contain bradyzoites or sporulated oocysts are ingested by an intermediate host (e.g., a human, mouse, sheep, pig, or bird).The cyst is rapidly digested by the acidic-pH gastric secretions. Bradyzoites or sporozoites are released, enter the small-intestinal epithelium, and transform into rapidly dividing tachyzoites. The tachyzoites can infect and replicate in all mammalian cells except red blood cells. Once attached to the host cell, the parasite penetrates the cell and forms a parasitophorous vacuole within which it divides. Parasite replication continues until the number of parasites

Intermediate host: birds, mammals, humans Bradyzoites encyst within the CNS and muscle of the infected host.

Tachyzoites infect all nucleated cells in the host, replicate, and cause tissue damage.

Oocysts are excreted in cat feces. Contaminated soil is ingested by birds, mammals, and humans.

Toxoplasmic encephalitis Definitive host

FIGURE 121-1 Life cycle of Toxoplasma gondii. The cat is the definitive host in which the sexual phase of the cycle is completed. Oocysts shed in cat feces can infect a wide range of animals, including birds, rodents, grazing domestic animals, and humans. The bradyzoites found in the muscle of food animals may infect humans who eat insufficiently cooked

meat products, particularly lamb and pork. Although human disease can take many forms, congenital infection and encephalitis from reactivation of latent infection in the brains of immunosuppressed persons are the most important manifestations. CNS, central nervous system. (Courtesy of Dominique Buzoni-Gatel, Institut Pasteur, Paris; with permission.)

1118

TRANSMISSION Oral Transmission The principal source of human Toxoplasma infection remains uncertain. Transmission usually takes place by the oral route and can be attributable to ingestion of either sporulated oocysts from contaminated soil or bradyzoites from undercooked meat. During acute feline infection, a cat may excrete as many as 100 million parasites per day. These very stable sporozoite-containing oocysts are highly infectious and may remain viable for many years in the soil. Humans infected during a well-documented outbreak of oocyst-transmitted infection develop stage-specific antibodies to the oocyst/sporozoite.

1119

Transmission via Blood or Organs In addition to oral transmission, direct transmission of the parasite by blood or organ products during transplantation takes place at a low rate. Viable parasites can be cultured from refrigerated anticoagulated blood, which may be a source of infection in individuals receiving blood transfusions. T. gondii infection also has been reported in kidney and heart transplant recipients who were uninfected before transplantation. Transplacental Transmission About one-third of all women who acquire infection with T. gondii during pregnancy transmit the parasite to the fetus; the remainder give birth to normal, uninfected babies. Of the various factors that influence fetal outcome, gestational age at the time of infection is the most critical (see below). Few data support a role for recrudescent maternal infection as the source of congenital disease. Thus, women who are seropositive before pregnancy usually are protected against acute infection and do not give birth to congenitally infected neonates. The following general guidelines can be used to evaluate congenital infection. There is essentially no risk if the mother becomes infected ≥6 months before conception. If infection is acquired 50 years old have serologic evidence of exposure; seroprevalence increases by ∼1% per year. In Central America, France, Turkey, and Brazil, the seroprevalence is higher. There may be as many as 2100 cases of toxoplasmic encephalitis (TE) each year in the United States.

Children and adults also can acquire infection from tissue cysts containing bradyzoites.The ingestion of a single cyst is all that is required for human infection. Undercooking or insufficient freezing of meat is an important source of infection in the developed world. In the United States, 10–20% of lamb products and 25–35% of pork products show evidence of cysts that contain bradyzoites. The incidence in beef is much lower—perhaps as low as 1%. Direct ingestion of bradyzoite cysts in these various meat products leads to acute infection.

CHAPTER 121

within the cell approaches a critical mass and the cell ruptures, releasing parasites that infect adjoining cells. As a result of this process, an infected organ soon shows evidence of cytopathology. Most tachyzoites are eliminated by the host’s humoral and cell-mediated immune responses. Tissue cysts containing many bradyzoites develop 7–10 days after systemic tachyzoite infection. These tissue cysts occur in various host organs but persist principally within the central nervous system (CNS) and muscle. The development of this chronic stage completes the nonfeline portion of the life cycle. Active infection in the immunocompromised host is most likely to be due to the spontaneous release of encysted parasites that undergo rapid transformation into tachyzoites within the CNS. The principal ( feline) stage in the life cycle takes place in the cat (the definitive host) and its prey. The parasite’s sexual phase is defined by the formation of oocysts within the feline host. This enteroepithelial cycle begins with the ingestion of the bradyzoite tissue cysts and culminates (after several intermediate stages) in the production of gametes. Gamete fusion produces a zygote, which envelops itself in a rigid wall and is secreted in the feces as an unsporulated oocyst. After 2–3 days of exposure to air at ambient temperature, the noninfectious oocyst sporulates to produce eight sporozoite progeny.The sporulated oocyst can be ingested by an intermediate host, such as a person emptying a cat’s litter box or a pig rummaging in a barnyard. It is in the intermediate host that T. gondii completes its life cycle.

1120 morphologic transformation, giving rise to invasive


tachyzoites. These tachyzoites induce a parasite-specific secretory IgA response. From the gastrointestinal tract, parasites are disseminated to a variety of organs, particularly lymphatic tissue, skeletal muscle, myocardium, retina, placenta, and the CNS. At these sites, the parasite infects host cells, replicates, and invades the adjoining cells. In this fashion, the hallmarks of the infection develop: cell death and focal necrosis surrounded by an acute inflammatory response. In the immunocompetent host, both the humoral and the cellular immune responses control infection; parasite virulence and tissue tropism may be strain specific.Tachyzoites are sequestered by a variety of immune mechanisms, including induction of parasiticidal antibody, activation of macrophages with radical intermediates, production of interferon γ (IFN-γ), and stimulation of cytotoxic T lymphocytes of the CD8+ phenotype. These antigen-specific lymphocytes are capable of killing both extracellular parasites and target cells infected with parasites. As tachyzoites are cleared from the acutely infected host, tissue cysts containing bradyzoites begin to appear, usually within the CNS and the retina. In the immunocompromised or fetal host, the immune factors necessary to control the spread of tachyzoite infection are lacking.This altered immune state allows the persistence of tachyzoites and gives rise to progressive focal destruction that results in organ failure (i.e., necrotizing encephalitis, pneumonia, and myocarditis). Persistence of infection with cysts containing bradyzoites is common in the immunocompetent host. This lifelong infection usually remains subclinical. Although bradyzoites are in a slow metabolic phase, cysts do degenerate and rupture within the CNS.This degenerative process, with the development of new bradyzoitecontaining cysts, is the most probable source of recrudescent infection in immunocompromised individuals and the most likely stimulus for the persistence of antibody titers in the immunocompetent host.

PATHOLOGY Cell death and focal necrosis due to replicating tachyzoites induce an intense mononuclear inflammatory response in any tissue or cell type infected. Tachyzoites rarely can be visualized by routine histopathologic staining of these inflammatory lesions. However, immunofluorescent staining with parasitic antigen–specific antibodies can reveal either the organism itself or evidence of antigen. In contrast to this inflammatory process caused by tachyzoites, bradyzoite-containing cysts cause inflammation only at the early stages of development, and even this inflammation may be a response to the presence of tachyzoite antigens. Once the cysts reach maturity, the inflammatory process can no longer be detected, and the cysts remain immunologically quiescent within the brain matrix until they rupture. Lymph Nodes During acute infection, lymph node biopsy demonstrates characteristic findings, including follicular hyperplasia and

irregular clusters of tissue macrophages with eosinophilic cytoplasm. Granulomas rarely are evident in these specimens. Although tachyzoites are not usually visible, they can be sought either by subinoculation of infected tissue into mice, with resultant disease, or by polymerase chain reaction (PCR). PCR amplification of DNA fragments representing either p30 (SAG-1) or p22 (SAG-2) surface antigen or B1 antigen is an effective and sensitive assay for establishing lymph node infection by tachyzoites. Eyes In the eye, infiltrates of monocytes, lymphocytes, and plasma cells may produce uni- or multifocal lesions. Granulomatous lesions and chorioretinitis can be observed in the posterior chamber after acute necrotizing retinitis. Other ocular complications include iridocyclitis, cataracts, and glaucoma. Central Nervous System During CNS involvement, both focal and diffuse meningoencephalitis can be documented, with evidence of necrosis and microglial nodules. Necrotizing encephalitis in patients without AIDS is characterized by small diffuse lesions with perivascular cuffing in contiguous areas. In the AIDS population, polymorphonuclear leukocytes may be present in addition to monocytes, lymphocytes, and plasma cells. Cysts containing bradyzoites frequently are found contiguous with the necrotic tissue border. As stated previously, it is estimated that there are as many as 2100 cases of TE in the United States each year. Lungs and Heart Among patients with AIDS who die of toxoplasmosis, 40–70% have involvement of the lungs and heart. Interstitial pneumonitis can develop in neonates and immunocompromised patients. Thickened and edematous alveolar septa infiltrated with mononuclear and plasma cells are apparent.This inflammation may extend to the endothelial walls.Tachyzoites and bradyzoite-containing cysts have been observed within the alveolar membrane. Superimposed bronchopneumonia can be caused by other microbial agents. Cysts and aggregates of parasites in cardiac muscle tissue are evident in patients with AIDS who die of toxoplasmosis. Focal necrosis surrounded by inflammatory cells is associated with hyaline necrosis and disrupted myocardial cells. Pericarditis is associated with toxoplasmosis in some patients. Gastrointestinal Tract Acute infection in certain strains of inbred mice (B6) results in lethal ileitis within 7–9 days. This inflammatory bowel disease has been recognized in several mammalian species, including pigs and nonhuman primates. The association between human inflammatory bowel disease and either acute or recurrent Toxoplasma infection has not been established.

Other Sites Pathologic changes during disseminated infection are similar to those described for the lymph nodes, eyes, and CNS. In patients with AIDS, the skeletal muscle, pancreas, stomach, and kidneys can be involved, with necrosis, invasion by inflammatory cells, and (rarely) tachyzoites detectable by routine staining. Large necrotic lesions may cause direct tissue destruction. In addition, secondary effects from acute infection of these various organs, including pancreatitis, myositis, and glomerulonephritis, have been reported.

Toxoplasmosis in Immunocompetent Patients The most common manifestation of acute toxoplasmosis is cervical lymphadenopathy. The nodes may be single or multiple, are usually nontender, are discrete, and vary in firmness. Lymphadenopathy also may be found in suboccipital, supraclavicular, inguinal, and mediastinal areas. Generalized lymphadenopathy occurs in 20–30% of symptomatic patients. Between 20 and 40% of patients with lymphadenopathy also have headache, malaise, fatigue, and fever [usually with a temperature of 1:10) can be detected as early as 2–3 weeks after infection. These titers usually peak at 6–8 weeks and decline slowly to a new baseline level that persists for life. It is necessary to measure the serum IgM titer in concert with the IgG titer to better establish the time of infection.The methods currently available for this determination are the double-sandwich IgM-ELISA and the IgMimmunosorbent assay (IgM-ISAGA). Both of these assays are specific and sensitive, and their use precludes the false-positive results associated with tests for rheumatoid factor and antinuclear antibody. The double-sandwich IgA-ELISA is more sensitive than the IgM-ELISA for detecting congenital infection in the fetus and newborn. Recently, the results obtained with PCR have suggested high sensitivity, specificity, and clinical utility in the diagnosis of TE in resource-poor settings. Molecular Diagnostics Molecular approaches can directly detect T. gondii in biologic samples independent of the serologic response. Specific molecular analysis for either the B1 gene or the 529-bp sequence is useful. Real-time PCR is a promising technique that can provide quantitative results. Isolates can be genotyped and polymorphic sequences can be obtained, with the consequent identification of the precise strain. Knowledge of the correct sequence is important in studies on the correlation of clinical signs and symptoms of disease with the T. gondii genotype. The Immunocompetent Adult or Child For the patient who presents with lymphadenopathy only, a positive IgM titer is an indication of acute infection—and an indication for therapy, if that is clinically warranted (see “Treatment” later in the chapter). The serum IgM titer should be determined again in 3 weeks. An elevation in the IgG titer without an increase in the IgM titer suggests that infection is present but is not

acute. If there is a borderline increase in either IgG or IgM, the titers should be reassessed in 3–4 weeks. The Immunocompromised Host A presumptive clinical diagnosis of TE in patients with AIDS is based on clinical presentation, history of exposure (as evidenced by positive serology), and radiologic evaluation.To detect latent infection with T. gondii, HIVinfected persons should be tested for IgG antibody to Toxoplasma soon after HIV infection is diagnosed. When these criteria are used, the predictive value is as high as 80%. More than 97% of patients with AIDS and toxoplasmosis have IgG antibody to T. gondii in serum. IgM serum antibody usually is not detectable. Attempts to evaluate rising IgG titers or to determine whether IgM is present are not productive. Serologic evidence of infection virtually always precedes the development of TE. It is therefore important to determine the Toxoplasma antibody status of all patients infected with HIV. Antibody titers may range from negative to 1:1024 in patients with AIDS and TE. Fewer than 3% of patients have no demonstrable antibody to Toxoplasma at diagnosis. Intrathecal antibody to T. gondii may be present; determination of the titer may help identify prior infection. Patients with TE have focal or multifocal abnormalities demonstrable by CT or MRI. Neuroradiologic evaluation should include double-dose contrast CT of the head. By this test, single and frequently multiple contrast-enhancing lesions (50% of patients by day 3. By day 7, >90% of treated patients show evidence of improvement. In contrast, if patients fail to respond or have lymphoma, clinical signs and symptoms worsen by day 7. Patients in this category require brain biopsy with or without a change in therapy.This procedure can now be performed by a stereotactic CT-guided method that reduces the potential for complications. Brain biopsy for T. gondii identifies organisms in 50–75% of cases. PCR amplification of genetic material of the parasite found in the CSF may prove diagnostically beneficial in the future. Now used in some centers, single-photon emission CT (SPECT) has been touted as a definitive means of detecting or ruling out Toxoplasma infection when a

CNS lesion is suspected. In the future, SPECT may well be widely used for this purpose. As in other conditions, the radiologic response may lag behind the clinical response. Resolution of lesions may take from 3 weeks to 6 months. Some patients show clinical improvement despite worsening radiographic findings. Congenital Infection The issue of concern when a pregnant woman has evidence of recent T. gondii infection is obviously whether the fetus is infected. PCR analysis of the amniotic fluid for the B1 gene of T. gondii has replaced fetal blood sampling. Serologic diagnosis is based on the persistence of IgG antibody or a positive IgM titer after the first week of life (a time frame that excludes placental leak).The IgG determination should be repeated every 2 months. An increase in IgM beyond the first week of life is indicative of acute infection. However, up to 25% of infected newborns may be seronegative and have normal routine physical examinations. Thus assessment of the eye and the brain, with ophthalmologic testing, CSF evaluation, and radiologic studies, is important in establishing the diagnosis.

Congenitally infected neonates are treated with daily oral pyrimethamine CONGENITAL INFECTION

INFECTION IN IMMUNOCOMPETENT PATIENTS Immunologically competent adults and older

children who have only lymphadenopathy do not require specific therapy unless they have persistent, severe symptoms. Patients with ocular toxoplasmosis should be treated for 1 month with pyrimethamine plus either sulfadiazine or clindamycin. Prenatal antibiotic therapy can reduce the number of infants severely affected by Toxoplasma infection. INFECTION IN IMMUNOCOMPROMISED PATIENTS Primary Prophylaxis Patients with AIDS should

be treated for acute toxoplasmosis; in immunocompromised patients, toxoplasmosis is rapidly fatal if untreated. Before the introduction of antiretroviral therapy (ART), the median survival time was >1 year for patients who could tolerate treatment for TE. Despite their toxicity, the drugs used to treat TE were required for survival prior to ART. The incidence of TE has declined as survival of patients with HIV infection has increased as a result of ART. In Africa, many patients are diagnosed with HIV infection only after developing opportunistic infections such as TE. Hence, the optimal management of these opportunistic infections is important if the benefits of subsequent ART are to be realized. AIDS patients who are seropositive for T. gondii and who have a CD4+ T-lymphocyte count of 200/µL has only a limited preventive effect against TE. Discontinuation of therapy reduces the pill burden; the potential for drug toxicity, drug interaction, or selection of drug-resistant pathogens; and cost. Prophylaxis should be recommenced if the CD4+ T-lymphocyte count again decreases to 200/µL, occurs as a consequence of ART. Combination therapy with pyrimethamine plus sulfadiazine plus leucovorin is effective for this purpose. An alternative to sulfadiazine in this regimen is clindamycin. Unfortunately, only the combination of pyrimethamine plus sulfadiazine provides protection against PcP as well. Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy) Patients


receiving secondary prophylaxis for TE are at low risk for recurrence when they have completed initial therapy for TE, remain asymptomatic, and have a CD4+ T-lymphocyte count of >200/µL for at least 6 months after ART. This recommendation is based on recent observations in a large cohort (381 patients) and is consistent with more extensive data indicating the safety of discontinuing secondary prophylaxis for other opportunistic infections during advanced HIV disease. Discontinuation of chronic maintenance therapy among these patients appears reasonable. A repeat MRI brain scan is recommended. Secondary prophylaxis should be reintroduced if the CD4+ T-lymphocyte count decreases to 1 week, although diarrhea often subsides. Individuals with chronic giardiasis may present with or without having experienced an antecedent acute symptomatic episode. Diarrhea is not necessarily prominent, but increased flatus, loose stools, sulfurous belching, and (in some instances) weight loss occur. Symptoms may be continual or episodic and can persist for years. Some persons who have relatively mild symptoms for long periods recognize the extent of their discomfort only in retrospect. Fever, the presence of blood and/or mucus in the stools, and other signs and symptoms of colitis are uncommon and suggest a different diagnosis or a concomitant illness. Symptoms tend to be intermittent yet recurring and gradually debilitating, in contrast with the acute disabling symptoms associated with many enteric bacterial infections. Because of the less severe illness and the propensity for chronic infections, patients may seek medical advice late in the course of the illness; however, disease can be severe, resulting in malabsorption, weight loss, growth retardation, and dehydration. A number of extraintestinal manifestations have been described, such as urticaria, anterior uveitis, and arthritis; whether these are caused by giardiasis or concomitant processes is unclear. Giardiasis can be severe in patients with hypogammaglobulinemia and can complicate other preexisting intestinal diseases, such as that occurring in cystic fibrosis. In patients with AIDS, Giardia can cause enteric illness that is refractory to treatment. Diagnosis (Table 122-1) Giardiasis is diagnosed by detection of parasite antigens in the feces or by identification of cysts in the feces or of trophozoites in the feces or small intestines. Cysts are oval, measure 8–12 µm × 7–10 µm, and characteristically contain four nuclei. Trophozoites are pear-shaped, dorsally convex, flattened parasites with

Prevention Although Giardia is extremely infectious, disease can be prevented by consumption of noncontaminated food and water and by personal hygiene when caring for infected children. Boiling or filtering potentially contaminated water prevents infection.

TABLE 122-1 DIAGNOSIS OF INTESTINAL PROTOZOAL INFECTIONS

PARASITE

STOOL O+Pa

Giardia Cryptosporidium Isospora Cyclospora Microsporidia

+ – – – –

FECAL ACIDFAST STAIN

+ + +

STOOL ANTIGEN IMMUNOASSAYS

1129

OTHER

+ +

Special fecal stains, tissue biopsies

a

O+P, ova and parasites.

Cure rates with metronidazole (250 mg thrice daily for 5 days) are usually >90%. Tinidazole (2 g once by mouth) is reportedly more effective than metronidazole. Nitazoxanide (500 mg twice daily for 3 days) is an alternative agent for treatment of giardiasis. Paromomycin, an oral aminoglycoside that is not well absorbed, can be given to symptomatic pregnant patients, although information is limited on how effectively this agent eradicates infection. Almost all patients respond to therapy and are cured, although some with chronic giardiasis experience delayed resolution of symptoms after eradication of Giardia. For many of the latter patients, residual symptoms probably reflect delayed regeneration of intestinal brush-border enzymes. Continued infection should be documented by stool examinations before treatment is repeated. Patients who remain infected after repeated treatments should be evaluated for reinfection through family members, close personal contacts, and environmental sources as well as for hypogammaglobulinemia. In cases refractory to multiple treatment courses, prolonged therapy with metronidazole (750 mg thrice daily for 21 days) has been successful.

Pathophysiology Although intestinal epithelial cells harbor cryptosporidia in an intracellular vacuole, the means by which secretory diarrhea is elicited remain uncertain. No characteristic pathologic changes are found by biopsy. The distribution of infection can be spotty within the principal site of infection, the small bowel. Cryptosporidia are found in the pharynx, stomach, and large bowel of some patients and at times in the respiratory tract. Especially in patients with AIDS, involvement of the biliary tract can cause papillary stenosis, sclerosing cholangitis, or cholecystitis. Clinical Manifestations Asymptomatic infections can occur in both immunocompetent and immunocompromised hosts. In immunocompetent persons, symptoms develop after an incubation period of ∼1 week and consist principally of watery nonbloody diarrhea, sometimes in conjunction with abdominal pain, nausea, anorexia, fever, and/or weight loss. In these hosts, the illness usually subsides after 1–2 weeks. In contrast, in immunocompromised hosts (especially those

Protozoal Intestinal Infections and Trichomoniasis

Treatment: GIARDIASIS

Life Cycle and Epidemiology Cryptosporidium species are widely distributed in the world. Cryptosporidiosis is acquired by the consumption of oocysts (50% infectious dose: ∼132 oocysts in nonimmune individuals), which excyst to liberate sporozoites that in turn enter and infect intestinal epithelial cells. The parasite’s further development involves both asexual and sexual cycles, which produce forms capable of infecting other epithelial cells and of generating oocysts that are passed in the feces. Cryptosporidium species infect a number of animals, and C. parvum can spread from infected animals to humans. Since oocysts are immediately infectious when passed in feces, person-to-person transmission takes place in day-care centers and among household contacts and medical providers. Waterborne transmission (especially that of C. hominis) accounts for infections in travelers and for commonsource epidemics. Oocysts are quite hardy and resist killing by routine chlorination. Both drinking water and recreational water (e.g., pools, waterslides) have been increasingly recognized as sources of infection.

CHAPTER 122

two nuclei and four pairs of flagella (Fig. 122-2). The diagnosis is sometimes difficult to establish. Direct examination of fresh or properly preserved stools as well as concentration methods should be used. Because cyst excretion is variable and may be undetectable at times, repeated examination of stool, sampling of duodenal fluid, and biopsy of the small intestine may be required to detect the parasite. Tests for parasitic antigens in stool are at least as sensitive and specific as good microscopic examinations and are easier to perform. All of these methods occasionally yield false-negative results.

CRYPTOSPORIDIOSIS The coccidian parasite Cryptosporidium causes diarrheal disease that is self-limited in immunocompetent human hosts but can be severe in persons with AIDS or other forms of immunodeficiency. Two species of Cryptosporidium, C. hominis and C. parvum, cause most human infections.

1130 with AIDS and CD4+ T cell counts 1 month. Cyclospora can cause enteric illness in patients infected with HIV. The parasite is detectable in epithelial cells of smallbowel biopsy samples and elicits secretory diarrhea by unknown means.The absence of fecal blood and leukocytes indicates that disease due to Cyclospora is not caused by destruction of the small-bowel mucosa. The diagnosis (Table 122-1) can be made by detection of spherical 8- to 10-µm oocysts in the stool, although routine stool O and P examinations are not sufficient. Specific fecal examinations must be requested to detect the oocysts, which are variably acid-fast and are fluorescent when viewed with ultraviolet light microscopy. Cyclosporiasis should be considered in the differential diagnosis of prolonged diarrhea, with or without a history of travel by the patient to other countries. Treatment: CYCLOSPORIASIS

Cyclosporiasis is treated with TMP-SMX (160/800 mg twice daily for 7 days). HIV-infected patients may experience relapses after such treatment and thus may require longer-term suppressive maintenance therapy.

hosts. In patients with AIDS, intestinal infections with Enterocytozoon bieneusi and Encephalitozoon (formerly Septata) intestinalis are recognized to contribute to chronic diarrhea and wasting; these infections are found in 10–40% of patients with chronic diarrhea. Both organisms have been found in the biliary tracts of patients with cholecystitis. E. intestinalis may also disseminate to cause fever, diarrhea, sinusitis, cholangitis, and bronchiolitis. In patients with AIDS, Encephalitozoon hellem has caused superficial keratoconjunctivitis as well as sinusitis, respiratory tract disease, and disseminated infection. Myositis due to Pleistophora has been documented. Nosema, Vittaforma, and Microsporidium have caused stromal keratitis associated with trauma in immunocompetent patients. Microsporidia are small gram-positive organisms with mature spores measuring 0.5–2 µm × 1–4 µm. Diagnosis of microsporidial infections in tissue often requires electron microscopy, although intracellular spores can be visualized by light microscopy with hematoxylin and eosin, Giemsa, or tissue Gram’s stain. For the diagnosis of intestinal microsporidiosis, modified trichrome or chromotrope

MICROSPORIDIOSIS Microsporidia are obligate intracellular spore-forming protozoa that infect many animals and cause disease in humans, especially as opportunistic pathogens in AIDS. Microsporidia are members of a distinct phylum, Microspora, which contains dozens of genera and hundreds of species. The various microsporidia are differentiated by their developmental life cycles, ultrastructural features, and molecular taxonomy based on ribosomal RNA. The complex life cycles of the organisms result in the production of infectious spores (Fig. 122-3). Currently, eight genera of microsporidia—Encephalitozoon, Pleistophora, Nosema, Vittaforma, Trachipleistophora, Brachiola, Microsporidium, and Enterocytozoon—are recognized as causes of human disease. Although some microsporidia are probably prevalent causes of self-limited or asymptomatic infections in immunocompetent patients, little is known about how microsporidiosis is acquired. Microsporidiosis is most common among patients with AIDS, less common among patients with other types of immunocompromise, and rare among immunocompetent

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Microsporidia Enterocytozoon bieneusi, Encephalitozoon spp., et al.

Presumed ingestion or respiratory aquisition of spores

Encephalitozoon intestinalis in epithelial cells, endothelial cells, or macrophages

Protozoal Intestinal Infections and Trichomoniasis

Polar tubule pierces host epithelial cell, injects sporoplasm

CHAPTER 122

Intracellular multiplication via merogony and sporogony

E. bieneusi in epithelial cell

While E. bieneusi is primarily in the gastrointestinal tract, other species may invade the lung or eye or disseminate to cause: Chronic diarrhea Cholangitis Sinusitis Bronchitis Nephritis Cystitis/prostatitis Keratoconjunctivitis Encephalitis

Person-to-person, zoonotic, water-borne, or food-borne transmission?

Spore-laden host epithelial cells sloughed into lumina of gastrointestinal, respiratory, or genitourinary tract

Sloughed cells degenerate; spores shed in bodily fluids Diagnostic spores present in stool, urine, respiratory fluids, cerebrospinal fluid, or various tissue specimens

FIGURE 122-3 Life cycle of microsporidia. (Reprinted from RL Guerrant et al: Tropical Infectious Disease: Principles, Pathogens and Practice, 2d ed, 2006, p 1128, with permission from Elsevier Science.)

1132 2R-based staining and Uvitex 2B or calcofluor fluores-

cent staining reveal spores in smears of feces or duodenal aspirates. Definitive therapies for microsporidial infections remain to be established. For superficial keratoconjunctivitis due to E. hellem, topical therapy with fumagillin suspension has shown promise (Chap. 113). For enteric infections with E. bieneusi and E. intestinalis in HIV-infected patients, therapy with albendazole may be efficacious (Chap. 113).


OTHER INTESTINAL PROTOZOA Balantidiasis Balantidium coli is a large ciliated protozoal parasite that can produce a spectrum of large-intestinal disease analogous to amebiasis. The parasite is widely distributed in the world. Since it infects pigs, cases in humans are more common where pigs are raised. Infective cysts can be transmitted from person to person and through water, but many cases are due to the ingestion of cysts derived from porcine feces in association with slaughtering, with use of pig feces for fertilizer, or with contamination of water supplies by pig feces. Ingested cysts liberate trophozoites, which reside and replicate in the large bowel. Many patients remain asymptomatic, but some have persisting intermittent diarrhea, and a few develop more fulminant dysentery. In symptomatic individuals, the pathology in the bowel— both gross and microscopic—is similar to that seen in amebiasis, with varying degrees of mucosal invasion, focal necrosis, and ulceration. Balantidiasis, unlike amebiasis, does not spread hematogenously to other organs. The diagnosis is made by detection of the trophozoite stage in stool or sampled colonic tissue.Tetracycline (500 mg four times daily for 10 days) is an effective therapeutic agent. Blastocystis Hominis Infection B. hominis, while believed by some to be a protozoan capable of causing intestinal disease, remains an organism of uncertain pathogenicity. Some patients who pass B. hominis in their stools are asymptomatic, whereas others have diarrhea and associated intestinal symptoms. Diligent evaluation reveals other potential bacterial, viral, or protozoal causes of diarrhea in some but not all patients with symptoms. Because the pathogenicity of B. hominis is uncertain and because therapy for Blastocystis infection is neither specific nor uniformly effective, patients with prominent intestinal symptoms should be fully evaluated for other infectious causes of diarrhea. If diarrheal symptoms associated with Blastocystis are prominent, either metronidazole (750 mg thrice daily for 10 days) or TMP-SMX (160 mg/800 mg twice daily for 7 days) can be used. Dientamoeba Fragilis Infection D. fragilis is unique among intestinal protozoa in that it has a trophozoite stage but not a cyst stage. How trophozoites survive to transmit infection is not known. When symptoms develop in patients with D. fragilis

infection, they are generally mild and include intermittent diarrhea, abdominal pain, and anorexia.The diagnosis is made by the detection of trophozoites in stool; the lability of these forms accounts for the greater yield when fecal samples are preserved immediately after collection. Since fecal excretion rates vary, examination of several samples obtained on alternate days increases the rate of detection. Iodoquinol (650 mg three times daily for 20 days), paromomycin (25–35 mg/kg per day in three doses for 7 days), metronidazole (500–750 mg three times daily for 10 days), or tetracycline (500 mg four times daily for 10 days) is appropriate for treatment.

TRICHOMONIASIS Various species of trichomonads can be found in the mouth (in association with periodontitis) and occasionally in the gastrointestinal tract. Trichomonas vaginalis— one of the most prevalent protozoal parasites in the United States—is a pathogen of the genitourinary tract and a major cause of symptomatic vaginitis.

LIFE CYCLE AND EPIDEMIOLOGY T. vaginalis is a pear-shaped, actively motile organism that measures about 10 × 7 µm, replicates by binary fission, and inhabits the lower genital tract of females and the urethra and prostate of males. In the United States, it accounts for ∼3 million infections per year in women. While the organism can survive for a few hours in moist environments and could be acquired by direct contact, person-to-person venereal transmission accounts for virtually all cases of trichomoniasis. Its prevalence is greatest among persons with multiple sexual partners and among those with other sexually transmitted diseases (Chap. 28). CLINICAL MANIFESTATIONS Many men infected with T. vaginalis are asymptomatic, although some develop urethritis and a few have epididymitis or prostatitis. In contrast, infection in women, which has an incubation period of 5–28 days, is usually symptomatic and manifests with malodorous vaginal discharge (often yellow), vulvar erythema and itching, dysuria or urinary frequency (in 30–50% of patients), and dyspareunia. These manifestations, however, do not clearly distinguish trichomoniasis from other types of infectious vaginitis. DIAGNOSIS Detection of motile trichomonads by microscopic examination of wet mounts of vaginal or prostatic secretions has been the conventional means of diagnosis. Although this approach provides an immediate diagnosis, its sensitivity for the detection of T. vaginalis is only ∼50–60% in routine evaluations of vaginal secretions. Direct immunofluorescent antibody staining is more sensitive (70–90%) than wet-mount examinations. T. vaginalis can be recovered from the urethra of both males and females and is

detectable in males after prostatic massage. Culture of the parasite is the most sensitive means of detection; however, the facilities for culture are not generally available, and detection of the organism takes 3–7 days. Treatment: TRICHOMONIASIS

Metronidazole, given either as a single 2-g dose or in 500-mg doses twice daily for 7 days, is usually effective. Tinidazole (a single 2-g dose) is also effective. All sexual partners must be treated concurrently to prevent reinfection, especially from asymptomatic males. In males with persistent symptomatic urethritis after therapy for nongonococcal urethritis, metronidazole therapy should be considered for possible trichomoniasis. Alternatives to metronidazole for treatment during pregnancy are not readily available, although use of 100-mg clotrimazole vaginal suppositories nightly for 2 weeks may cure some infections in pregnant women. Reinfection often accounts for apparent treatment failures, but strains of T. vaginalis exhibiting high-level resistance to metronidazole have been encountered. Treatment of these resistant infections with higher oral doses, parenteral doses, or concurrent oral and vaginal doses of metronidazole or with tinidazole has been successful.

PART 3

HELMINTHIC INFECTIONS

CHAPTER 123

TRICHINELLA AND OTHER TISSUE NEMATODES Peter F. Weller Nematodes are elongated, symmetric roundworms. Parasitic nematodes of medical significance may be broadly classified as either predominantly intestinal or tissue nematodes.This chapter covers trichinellosis, visceral and ocular larva migrans, cutaneous larva migrans, cerebral

angiostrongyliasis, and gnathostomiasis. All are zoonotic infections caused by incidental exposure to infectious nematodes.The clinical symptoms of these infections are due largely to invasive larval stages that (except in the case of Trichinella) do not reach maturity in humans.

Trichinella and Other Tissue Nematodes

CENTERS FOR DISEASE CONTROL AND PREVENTION, DIVISION OF PARASITIC DISEASES: http://www.cdc.gov/ncidod/dpd/default.htm CHEX XM et al: Cryptosporidiosis. N Engl J Med 346:1723, 2002 DIDIER ES: Microsporidiosis: An emerging and opportunistic infection in humans and animals.Acta Trop 94:61, 2005

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FURTHER READINGS

HLAVSA MC et al: Giardiasis surveillance—United States, 1998–2002. MMWR Surveill Summ 54:9, 2005 ——— et al: Cryptosporidiosis surveillance—United States, 1999–2002. MMWR Surveill Summ 54:1, 2005 LEDER K et al: No correlation between clinical symptoms and Blastocystis hominis in immunocompetent individuals. J Gastroenterol Hepatol 20:1390, 2005 PATTULLO L et al: Stepwise diagnosis of Trichomonas vaginalis infection in adolescent women. J Clin Microbiol 47:59, 2009 PIERCE KK, KIRKPATRICK BD: Update on human infections caused by intestinal protozoa. Curr Opin Gastroenterol 25:12, 2009 ROXSTROM-LINDQUIST K et al: Giardia immunity—an update. Trends Parasitol 22:26, 2006 SHAFIR SC et al: Current issues and considerations regarding trichomoniasis and human immunodeficiency virus in African-Americans. Clin Microbiol Rev 22:37, 2009 SUTTON M et al: The prevalence of Trichomonas vaginalis infection among reproductive-age women in the United States, 2001–2004. Clin Infect Dis 45:1319, 2007 VANDENBERG O et al: Clinical and microbiological features of dientamoebiasis in patients suspected of suffering from a parasitic gastrointestinal illness: A comparison of Dientamoeba fragilis and Giardia lamblia infections. Int J Infect Dis 10:255, 2006 VAN DER POL B et al: Prevalence, incidence, natural history, and response to treatment of Trichomonas vaginalis infection among adolescent women. J Infect Dis 192:2039, 2005 WEISS LM, SCHWARTZ DA: Microsporidiosis, in Tropical Infectious Diseases: Principles, Pathogens and Practice, 2d ed, RL Guerrant et al (eds). Elsevier, Philadelphia, 2006, pp 1126–1140 WEITZEL T et al: Epidemiological and clinical features of travel-associated cryptosporidiosis. Clin Microbiol Infect 12:921, 2006 YODER JS, BEACH MJ: Cryptosporidiosis surveillance—United States, 2003–2005. MMWR Surveill Summ 56:1, 2007 ——— et al: Giardiasis surveillance—United States, 2003–2005. MMWR Surveill Summ 56:11, 2007

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TRICHINELLOSIS Trichinellosis develops after the ingestion of meat containing cysts of Trichinella—for example, pork or other meat from a carnivore. Although most infections are mild and asymptomatic, heavy infections can cause severe enteritis, periorbital edema, myositis, and (infrequently) death.

SECTION VIII

Life Cycle and Epidemiology Eight species of Trichinella are recognized as causes of infection in humans. Two species are distributed worldwide: T. spiralis, which is found in a great variety of carnivorous and omnivorous animals, and T. pseudospiralis, which is found in mammals and birds. T. nativa is present in Arctic regions and infects bears; T. nelsoni is found in equatorial eastern Africa, where it is common among felid predators and scavengers such as hyenas and bush pigs; and T. britovi is found in Europe, western Africa, and western Asia among carnivores but not among domestic swine. T. murrelli is present in North American game animals. After human consumption of trichinous meat, encysted larvae are liberated by digestive acid and pepsin (Fig. 123-1).The larvae invade the small-bowel mucosa and mature into adult worms. After ∼1 week, female worms release newborn larvae that migrate via the circulation to striated muscle. The larvae of all species except T. pseudospiralis, T. papuae, and T. zimbabwensis then encyst by inducing a radical transformation in the muscle cell architecture. Although host immune responses may help to expel intestinal adult worms, they have little effect on muscle-dwelling larvae.

Human trichinellosis is often caused by the ingestion of infected pork products and thus can occur in almost any location where the meat of domestic or wild swine is eaten. Human trichinellosis also may be acquired from the meat of other animals, including dogs (in parts of Asia and Africa), horses (in Italy and France), and bears and walruses (in northern regions). Although cattle (being herbivores) are not natural hosts of Trichinella, beef has been implicated in outbreaks when contaminated or adulterated with trichinous pork. Laws that prohibit the feeding of uncooked garbage to pigs have greatly reduced the transmission of trichinellosis in the United States. About 12 cases of trichinellosis are reported annually in this country, but most mild cases probably remain undiagnosed. Recent U.S. and Canadian outbreaks have been attributable to consumption of wild game (especially bear meat) and, less frequently, of pork.

Pathogenesis and Clinical Features Clinical symptoms of trichinellosis arise from the successive phases of parasite enteric invasion, larval migration, and muscle encystment (Fig. 123-1). Most light infections (those with 50 larvae per gram of muscle) can be lifethreatening. Invasion of the gut by large numbers of parasites occasionally provokes diarrhea during the first week after infection. Abdominal pain, constipation, nausea, or vomiting also may be prominent. Symptoms due to larval migration and muscle invasion begin to appear in the second week after infection. The


Larvae migrate, penetrate striated muscle, reside in "nurse-cells," and encyst,* causing:

Larvae are released in the stomach and mature into adults over 1–2 wks in the small bowel, causing:

Muscle pain, fever, periorbital edema, eosinophilia, occasional CNS or cardiac damage

Irritation and mild abdominal cramping or even diarrhea

Encysted larvae ingested in undercooked pork, boar, horse, or bear

Similar cycle (as humans) in swine or other carnivores (rats, bears, foxes, dogs, or horses)

*T. papuae, T. zimbabwensis, and T. pseudospiralis do not encyst.

FIGURE 123-1 Life cycle of Trichinella spiralis (cosmopolitan); nelsoni (equatorial Africa); britovi (Europe, western Africa, western Asia); nativa (Arctic); murrelli (North America); papuae (Papua New Guinea); zimbabwensis (Tanzania); and pseudospiralis (cosmopolitan). [Reprinted from Guerrant RL et al (eds): Tropical Infectious Diseases: Principles, Pathogens and Practice, 2d ed, p 1218. © 2006, with permission from Elsevier Science.]

migrating Trichinella larvae provoke a marked local and systemic hypersensitivity reaction, with fever and hypereosinophilia. Periorbital and facial edema is common, as are hemorrhages in the subconjunctivae, retina, and nail beds (“splinter” hemorrhages). A maculopapular rash, headache, cough, dyspnea, or dysphagia sometimes develops. Myocarditis with tachyarrhythmias or heart failure— and, less commonly, encephalitis or pneumonitis—may develop and accounts for most deaths of patients with trichinellosis. Upon onset of larval encystment in muscle 2–3 weeks after infection, symptoms of myositis with myalgias, muscle edema, and weakness develop, usually overlapping with the inflammatory reactions to migrating larvae. The most commonly involved muscle groups include the extraocular muscles; the biceps; and the muscles of the jaw, neck, lower back, and diaphragm. Peaking ∼3 weeks after infection, symptoms subside only gradually during a prolonged convalescence. Uncommon infections with T. pseudospiralis, whose larvae do not encapsulate in muscles, elicit prolonged polymyositis-like illness.

Most lightly infected patients recover uneventfully with bed rest, antipyretics, and analgesics. Glucocorticoids like prednisone (Table 123-1) are beneficial for severe myositis and myocarditis. Mebendazole and albendazole are active against enteric stages of the parasite, but their efficacy against encysted larvae has not been conclusively demonstrated.

Prevention Larvae may be killed by cooking pork until it is no longer pink or by freezing it at –15°C for 3 weeks. However,Arctic T. nativa larvae in walrus or bear meat are relatively resistant and may remain viable despite freezing.

VISCERAL AND OCULAR LARVA MIGRANS Visceral larva migrans is a syndrome caused by nematodes that are normally parasitic for nonhuman host species. In humans, the nematode larvae do not develop into adult worms but instead migrate through host tissues and elicit eosinophilic inflammation. The more common form of visceral larva migrans is toxocariasis due to larvae of the canine ascarid Toxocara canis, less commonly to the feline ascarid T. cati, and even less commonly to the pig ascarid Ascaris suum. Rare cases with eosinophilic meningoencephalitis have been caused by the raccoon ascarid Baylisascaris procyonis. Life Cycle and Epidemiology The canine roundworm T. canis is distributed among dogs worldwide. Ingestion of infective eggs by dogs is followed by liberation of Toxocara larvae, which penetrate the gut wall and migrate intravascularly into canine tissues, where most remain in a developmentally arrested state. During pregnancy, some larvae resume migration in bitches and infect puppies prenatally (through transplacental transmission) or after birth (through suckling). Thus, in lactating bitches and puppies, larvae return to the intestinal tract and develop into adult worms, which produce eggs that are released in the feces. Humans acquire toxocariasis mainly by eating soil contaminated by puppy feces that contains infective T. canis eggs. Visceral larva migrans is most common among children who habitually eat dirt. Pathogenesis and Clinical Features Clinical disease most commonly afflicts preschool children. After humans ingest Toxocara eggs, the larvae hatch


Treatment: TRICHINELLOSIS

FIGURE 123-2 Trichinella larva encysted in a characteristic hyalinized capsule in striated muscle tissue. (Photo/Wadsworth Center, New York State Department of Health. Reprinted from CDC MMWR 53:606, 2004; public domain.)

CHAPTER 123

Laboratory Findings and Diagnosis Blood eosinophilia develops in >90% of patients with symptomatic trichinellosis and may peak at a level of >50% between 2 and 4 weeks after infection. Serum levels of muscle enzymes, including creatine phosphokinase, are elevated in most symptomatic patients. Patients should be questioned thoroughly about their consumption of pork or wild-animal meat and about illness in other individuals who ate the same meat. A presumptive clinical diagnosis can be based on fevers, eosinophilia, periorbital edema, and myalgias after a suspect meal. A rise in the titer of parasite-specific antibody, which usually does not occur until after the third week of infection, confirms the diagnosis. Alternatively, a definitive diagnosis requires surgical biopsy of at least 1 g of involved muscle; the yields are highest near tendon insertions.The fresh muscle tissue should be compressed between glass slides and examined microscopically (Fig. 123-2), because larvae may be overlooked by examination of routine histopathologic sections alone.

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TABLE 123-1 THERAPY FOR TISSUE NEMATODE INFECTIONS INFECTION

SEVERITY

TREATMENT

Trichinellosis

Mild Moderate

Supportive Albendazole (400 mg bid × 8–14 days) or Mebendazole (200–400 mg tid × 3 days, then 400 mg tid × 8–14 days) Add glucocorticoids (e.g., prednisone, 1 mg/kg qd × 5 days) Supportive Glucocorticoids (as above) Not fully defined; albendazole (800 mg bid for adults, 400 mg bid for children) with glucocorticoids × 5–20 days has been effective Ivermectin (single dose, 200 µg/kg) or Albendazole (200 mg bid × 3 days) Supportive Glucocorticoids (as above) Ivermectin (200 µg/kg per day × 2 days) or Albendazole (400 mg bid × 21 days)

Severe Visceral larva migrans

Mild to moderate Severe Ocular

Cutaneous larva migrans

Angiostrongyliasis

Mild to moderate Severe

Gnathostomiasis


and penetrate the intestinal mucosa, from which they are carried by the circulation to a wide variety of organs and tissues. The larvae invade the liver, lungs, central nervous system (CNS), and other sites, provoking intense local eosinophilic granulomatous responses.The degree of clinical illness depends on larval number and tissue distribution, reinfection, and host immune responses. Most light infections are asymptomatic and may be manifest only by blood eosinophilia. Characteristic symptoms of visceral larva migrans include fever, malaise, anorexia and weight loss, cough, wheezing, and rashes. Hepatosplenomegaly is common.These features are often accompanied by extraordinary peripheral eosinophilia, which may approach 90%. Uncommonly, seizures or behavioral disorders develop. Rare deaths are due to severe neurologic, pneumonic, or myocardial involvement. The ocular form of the larva migrans syndrome occurs when Toxocara larvae invade the eye. An eosinophilic granulomatous mass, most commonly in the posterior pole of the retina, develops around the entrapped larva. The retinal lesion can mimic retinoblastoma in appearance, and mistaken diagnosis of the latter condition can lead to unnecessary enucleation. The spectrum of eye involvement also includes endophthalmitis, uveitis, and chorioretinitis. Unilateral visual disturbances, strabismus, and eye pain are the most common presenting symptoms. In contrast to visceral larva migrans, ocular toxocariasis usually develops in older children or young adults with no history of pica; these patients seldom have eosinophilia or visceral manifestations. Diagnosis In addition to eosinophilia, leukocytosis and hypergammaglobulinemia may be evident. Transient pulmonary

infiltrates are apparent on chest x-rays of about half of patients with symptoms of pneumonitis.The clinical diagnosis can be confirmed by an enzyme-linked immunosorbent assay for toxocaral antibodies. Stool examination for parasite eggs, while important in the evaluation of unexplained eosinophilia, is worthless for toxocariasis, since the larvae do not develop into egg-producing adults in humans. Treatment: VISCERAL AND OCULAR LARVA MIGRANS

The vast majority of Toxocara infections are self-limited and resolve without specific therapy. In patients with severe myocardial, CNS, or pulmonary involvement, glucocorticoids may be employed to reduce inflammatory complications. Available anthelmintic drugs, including mebendazole and albendazole, have not been shown conclusively to alter the course of larva migrans. Control measures include prohibiting dog excreta in public parks and playgrounds, deworming dogs, and preventing pica in children. Treatment of ocular disease is not fully defined, but the administration of albendazole in conjunction with glucocorticoids has been effective (Table 123-1).

CUTANEOUS LARVA MIGRANS Cutaneous larva migrans (“creeping eruption”) is a serpiginous skin eruption caused by burrowing larvae of animal hookworms, usually the dog and cat hookworm Ancylostoma braziliense.The larvae hatch from eggs passed in dog and cat feces and mature in the soil. Humans

become infected after skin contact with soil in areas frequented by dogs and cats, such as areas underneath house porches. Cutaneous larva migrans is prevalent among children and travelers in regions with warm humid climates, including the southeastern United States. After larvae penetrate the skin, erythematous lesions form along the tortuous tracks of their migration through the dermal-epidermal junction; the larvae advance several centimeters in a day. The intensely pruritic lesions may occur anywhere on the body and can be numerous if the patient has lain on the ground.Vesicles and bullae may form later. The animal hookworm larvae do not mature in humans and, without treatment, will die after an interval ranging from weeks to a couple of months, with resolution of skin lesions.The diagnosis is made on clinical grounds. Skin biopsies only rarely detect diagnostic larvae. Symptoms can be alleviated by ivermectin or albendazole (Table 123-1).

ANGIOSTRONGYLIASIS Angiostrongylus cantonensis, the rat lungworm, is the most common cause of human eosinophilic meningitis (Fig. 123-3).

Laboratory Findings Examination of cerebrospinal fluid (CSF) is mandatory in suspected cases and usually reveals an elevated opening pressure, a white blood cell count of 150–2000/µL, and an eosinophilic pleocytosis of >20%. The protein concentration is usually elevated and the glucose level normal. The larvae of A. cantonensis are only rarely seen in CSF. Peripheral-blood eosinophilia may be mild. The diagnosis is generally based on the clinical presentation of eosinophilic meningitis together with a compatible epidemiologic history.

Treatment: ANGIOSTRONGYLIASIS

Eosinophilic meningitis

Adult in pulmonary artery produces fertile eggs; larvae hatch, penetrate arterioles, migrate up bronchi, and are coughed up, swallowed, and passed in feces

3rd-stage larvae (consumed in snail or slime) penetrate gut, go to CNS (then lung in rat)

Larvae consumed by land snail/slug (Achatina fulica)

FIGURE 123-3 Life cycle of Angiostrongylus cantonensis (rat lung worm). Also found in Southeast Asia, Pacific Islands, Cuba, Australia, Japan, China, Mauritius, and U.S. ports. [Reprinted from Guerrant RL et al (eds): Tropical Infectious Diseases: Principles, Pathogens and Practice, 2d ed, p 1225. (c) 2006, with permission from Elsevier Science.]


Specific chemotherapy is not of benefit in angiostrongyliasis; larvicidal agents may exacerbate inflammatory brain lesions. Management consists of supportive measures, including the administration of analgesics, sedatives, and—in severe cases—glucocorticoids (Table 123-1). Repeated lumbar punctures with removal of CSF can relieve symptoms. In most patients,

2 weeks

viable in fresh water

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CHAPTER 123

Life Cycle and Epidemiology This infection occurs principally in Southeast Asia and the Pacific Basin but has spread to other areas of the world. A. cantonensis larvae produced by adult worms in the rat lung migrate to the gastrointestinal tract and are expelled with the feces. They develop into infective larvae in land snails and slugs. Humans acquire the infection by ingesting raw infected mollusks; vegetables contaminated by mollusk slime; or crabs, freshwater shrimp, and certain marine fish that have themselves eaten infected mollusks.The larvae then migrate to the brain.

Pathogenesis and Clinical Features The parasites eventually die in the CNS, but not before initiating pathologic consequences that, in heavy infections, can result in permanent neurologic sequelae or death. Migrating larvae cause marked local eosinophilic inflammation and hemorrhage, with subsequent necrosis and granuloma formation around dying worms. Clinical symptoms develop 2–35 days after the ingestion of larvae. Patients usually present with an insidious or abrupt excruciating frontal, occipital, or bitemporal headache. Neck stiffness, nausea and vomiting, and paresthesias are also common. Fever, cranial and extraocular nerve palsies, seizures, paralysis, and lethargy are uncommon.

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cerebral angiostrongyliasis has a self-limited course, and recovery is complete.The infection may be prevented by adequately cooking snails, crabs, and prawns and inspecting vegetables for mollusk infestation. Other parasitic or fungal causes of eosinophilic meningitis in endemic areas may include gnathostomiasis (see below), paragonimiasis (Chap. 126), schistosomiasis (Chap. 126), neurocysticercosis (Chap. 127), and coccidioidomycosis (Chap. 104).

GNATHOSTOMIASIS Infection of human tissues with larvae of Gnathostoma spinigerum can cause eosinophilic meningoencephalitis, migratory cutaneous swellings, or invasive masses of the eye and visceral organs.


Life Cycle and Epidemiology Human gnathostomiasis occurs in many countries and is notably endemic in Southeast Asia and parts of China and Japan. In nature, the mature adult worms parasitize the gastrointestinal tract of dogs and cats. First-stage larvae hatch from eggs passed into water and are ingested by Cyclops species (water fleas). Infective third-stage larvae develop in the flesh of many animal species (including fish, frogs, eels, snakes, chickens, and ducks) that have eaten either infected Cyclops or another infected second intermediate host. Humans typically acquire the infection by eating raw or undercooked fish or poultry. Raw fish dishes, such as som fak in Thailand and sashimi in Japan, account for many cases of human gnathostomiasis. Some cases in Thailand result from the local practice of applying frog or snake flesh as a poultice. Pathogenesis and Clinical Features Clinical symptoms are due to the aberrant migration of a single larva into cutaneous, visceral, neural, or ocular tissues. After invasion, larval migration may cause local inflammation, with pain, cough, or hematuria accompanied by fever and eosinophilia. Painful, itchy, migratory swellings may develop in the skin, particularly in the distal extremities or periorbital area. Cutaneous swellings usually last ∼1 week but often recur intermittently over many years. Larval invasion of the eye can provoke a sight-threatening inflammatory response. Invasion of the CNS results in eosinophilic meningitis with myeloencephalitis, a serious complication due to ascending larval migration along a large nerve track. Patients characteristically present with agonizing radicular pain and paresthesias in the trunk or a limb, which are followed

shortly by paraplegia. Cerebral involvement, with focal hemorrhages and tissue destruction, is often fatal. Diagnosis and Treatment Cutaneous migratory swellings with marked peripheral eosinophilia, supported by an appropriate geographic and dietary history, generally constitute an adequate basis for a clinical diagnosis of gnathostomiasis. However, patients may present with ocular or cerebrospinal involvement without antecedent cutaneous swellings. In the latter case, eosinophilic pleocytosis is demonstrable (usually along with hemorrhagic or xanthochromic CSF), but worms are almost never recovered from CSF. Surgical removal of the parasite from subcutaneous or ocular tissue, though rarely feasible, is both diagnostic and therapeutic. Albendazole or ivermectin may be helpful (Table 123-1). At present, cerebrospinal involvement is managed with supportive measures and generally with a course of glucocorticoids. Gnathostomiasis can be prevented by adequate cooking of fish and poultry in endemic areas. FURTHER READINGS BARISANI-ASENBAUER T et al: Treatment of ocular toxocariasis with albendazole. J Ocul Pharmacol Ther 17:287, 2001 BOUCHARD O et al: Cutaneous larva migrans in travelers: A prospective study, with assessment of therapy with ivermectin. Clin Infect Dis 31:493, 2000 CDC DIVISION OF PARASITIC DISEASES. www.cdc.gov/ncidod/dpd/ default.htm CIANFERONI A et al: Visceral larva migrans associated with earthworm ingestion: Clinical evolution in an adolescent patient. Pediatrics 117:e336, 2006 GOTTSTEIN B et al: Epidemiology, diagnosis, treatment, and control of trichinellosis. Clin Microbiol Rev 22:127, 2009 LIGON BL: Gnathostomiasis: A review of a previously localized zoonosis now crossing numerous geographical boundaries. Semin Pediatr Infect Dis 16:137, 2005 MADARIAGA MG et al: A probable case of human neurotrichinellosis in the United States.Am J Trop Med Hyg 77:347, 2007 MAGANA M et al: Gnathostomiasis: Clinicopathologic study. Am J Dermatopathol 26:91, 2004 MENARD A et al: Imported cutaneous gnathostomiasis: Report of five cases.Trans R Soc Trop Med Hyg 97:200, 2003 PULJIZ I et al: Electrocardiographic changes in trichinellosis: A retrospective study of 154 patients. Ann Trop Med Parasitol 99:403, 2005 SAKAI S et al: Pulmonary lesions associated with visceral larva migrans due to Ascaris suum or Toxocara canis: Imaging of six cases. AJR Am J Roentgenol 186:1697, 2006 SLOM TJ et al: An outbreak of eosinophilic meningitis caused by Angiostrongylus cantonensis in travelers returning from the Caribbean. N Engl J Med 346:668, 2002 TSAI HC et al: Outbreak of eosinophilic meningitis associated with drinking raw vegetable juice in southern Taiwan. Am J Trop Med Hyg 71:222, 2004

CHAPTER 124

INTESTINAL NEMATODES Peter F. Weller Thomas B. Nutman More than a billion persons worldwide are infected with one or more species of intestinal nematodes. Table 124-1 summarizes biologic and clinical features of infections due to the major intestinal parasitic nematodes. These parasites are most common in regions with poor fecal sanitation, particularly in resource-poor countries in the tropics and subtropics, but they have also been seen with increasing frequency among immigrants and refugees to resource-rich countries. Although nematode infections are not usually fatal, they contribute to malnutrition and diminished work capacity. It is interesting that these helminth infections may protect some individuals from allergic disease. Humans may on occasion be infected with nematode parasites that ordinarily infect animals; these zoonotic infections produce diseases such as trichostrongyliasis, anisakiasis, capillariasis, and abdominal angiostrongyliasis. Intestinal nematodes are roundworms; they range in length from 1 mm to many centimeters when mature (Table 124-1). Their life cycles are complex and highly varied; some species, including Strongyloides stercoralis and Enterobius vermicularis, can be transmitted directly from person to person, while others, such as Ascaris lumbricoides, Necator americanus, and Ancylostoma duodenale, require a soil phase for development. Because most helminth parasites do not self-replicate, the acquisition of a heavy burden of adult worms requires repeated exposure to the parasite in its infectious stage, whether larva or egg. Hence, clinical disease, as opposed to asymptomatic infection, generally develops only with prolonged residence in an endemic area. In persons with marginal nutrition, intestinal helminth infections may impair growth and development. Eosinophilia and elevated serum IgE levels are features of many helminthic infections and, when unexplained, should always prompt a search for occult helminthiasis. Significant protective immunity to intestinal nematodes appears not to develop in humans, although mechanisms of parasite immune evasion and host immune responses to these infections have not been elucidated in detail.

migration in the lungs or effects of the adult worms in the intestines. Life Cycle Adult worms live in the lumen of the small intestine. Mature female Ascaris worms are extraordinarily fecund, each producing up to 240,000 eggs a day, which pass with the feces. Ascarid eggs, which are remarkably resistant to environmental stresses, become infective after several weeks of maturation in the soil and can remain infective for years.After infective eggs are swallowed, larvae hatched in the intestine invade the mucosa, migrate through the circulation to the lungs, break into the alveoli, ascend the bronchial tree, and return via swallowing to the small intestine, where they develop into adult worms. Between 2 and 3 months elapse between initial infection and egg production.Adult worms live for 1–2 years. Epidemiology Ascaris is widely distributed in tropical and subtropical regions as well as in other humid areas, including the rural southeastern United States. Transmission typically occurs through fecally contaminated soil and is due either to a lack of sanitary facilities or to the use of human feces as fertilizer. With their propensity for hand-to-mouth fecal carriage, younger children are most affected. Infection outside endemic areas, though uncommon, can occur when eggs on transported vegetables are ingested. Clinical Features During the lung phase of larval migration, ∼9–12 days after egg ingestion, patients may develop an irritating nonproductive cough and burning substernal discomfort that is aggravated by coughing or deep inspiration. Dyspnea and blood-tinged sputum are less common. Fever is usually reported. Eosinophilia develops during this symptomatic phase and subsides slowly over weeks. Chest x-rays may reveal evidence of eosinophilic pneumonitis (Löffler’s syndrome), with rounded infiltrates a few millimeters to several centimeters in size. These infiltrates may be transient and intermittent, clearing after several weeks. Where there is seasonal transmission of the parasite, seasonal pneumonitis with eosinophilia may develop in previously infected and sensitized hosts.

ASCARIASIS A. lumbricoides is the largest intestinal nematode parasite of humans, reaching up to 40 cm in length. Most infected individuals have low worm burdens and are asymptomatic. Clinical disease arises from larval

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1140

TABLE 124-1 MAJOR HUMAN INTESTINAL PARASITIC NEMATODES PARASITIC NEMATODE

FEATURE

Global prevalence in humans (millions) Endemic areas Infective stage Route of infection Gastrointestinal location of worms Adult worm size Pulmonary passage of larvae Incubation perioda (days) Longevity


ASCARIS LUMBRICOIDES (ROUNDWORM)

NECATOR AMERICANUS, ANCYLOSTOMA DUODENALE (HOOKWORM)

STRONGYLOIDES STERCORALIS

TRICHURIS TRICHIURA (WHIPWORM)

ENTEROBIUS VERMICULARIS (PINWORM)

1221

740

50

795

300

Worldwide Egg Oral

Hot, humid regions Filariform larva Percutaneous

Worldwide Egg Oral

Worldwide Egg Oral

Jejunal lumen

Jejunal mucosa

15–40 cm Yes

7–12 mm Yes

Hot, humid regions Filariform larva Percutaneous or autoinfection Small-bowel mucosa 2 mm Yes

Cecum, colonic mucosa 30–50 mm No

Cecum, appendix 8–13 mm (female) No

60–75

40–100

17–28

70–90

35–45

1y

N. americanus: 2–5 y A. duodenale: 6–8 y N. americanus: 4000–10,000 A. duodenale: 10,000–25,000 Iron-deficiency anemia in heavy infection

Decades (owing to autoinfection) 5000–10,000

5y

2 months

3000–7000

2000

Gastrointestinal symptoms, anemia

Perianal pruritus

Eggs in stool

Eggs from perianal skin on cellulose acetate tape Mebendazole Pyrantel pamoate Albendazole

Fecundity (eggs/ day/worm)

240,000

Principal symptoms

Rarely gastrointestinal or biliary obstruction

Diagnostic stage

Eggs in stool

Eggs in fresh stool, larvae in old stool

Treatment

Mebendazole Albendazole Pyrantel pamoate Ivermectin

Mebendazole Pyrantel pamoate Albendazole

Gastrointestinal symptoms; malabsorption or sepsis in hyperinfection Larvae in stool or duodenal aspirate; sputum in hyperinfection 1. Ivermectin 2. Albendazole

Mebendazole Albendazole Ivermectin

a

Time from infection to egg production by mature female worm.

In established infections, adult worms in the small intestine usually cause no symptoms. In heavy infections, particularly in children, a large bolus of entangled worms can cause pain and small-bowel obstruction, sometimes complicated by perforation, intussusception, or volvulus. Single worms may cause disease when they migrate into aberrant sites. A large worm can enter and occlude the biliary tree, causing biliary colic, cholecystitis, cholangitis, pancreatitis, or (rarely) intrahepatic abscesses. Migration of an adult worm up the esophagus can provoke coughing and oral expulsion of the worm. In highly endemic areas, intestinal and biliary ascariasis can rival acute appendicitis and gallstones as causes of surgical acute abdomen.

Laboratory Findings Most cases of ascariasis can be diagnosed by microscopic detection of characteristic Ascaris eggs (65 by 45 µm) in fecal samples. Occasionally, patients present after passing an adult worm—identifiable by its large size and smooth cream-colored surface—in the stool or through the mouth or nose. During the early transpulmonary migratory phase, when eosinophilic pneumonitis occurs, larvae can be found in sputum or gastric aspirates before diagnostic eggs appear in the stool.The eosinophilia that is prominent during this early stage usually decreases to minimal levels in established infection. Adult worms may be visualized, occasionally serendipitously, on contrast studies of the gastrointestinal tract.A plain abdominal

film may reveal masses of worms in gas-filled loops of bowel in patients with intestinal obstruction. Pancreaticobiliary worms can be detected by ultrasound and endoscopic retrograde cholangiopancreatography; the latter method also has been used to extract biliary Ascaris worms. Treatment: ASCARIASIS

Ascariasis should always be treated to prevent potentially serious complications. Albendazole (400 mg once), mebendazole (500 mg once), or ivermectin (150–200 µg/kg once) is effective. These medications are contraindicated in pregnancy, however. Pyrantel pamoate (11 mg/kg once; maximum, 1 g) is safe in pregnancy. Mild diarrhea and abdominal pain are uncommon side effects of these agents. Partial intestinal obstruction should be managed with nasogastric suction, IV fluid administration, and instillation of piperazine through the nasogastric tube, but complete obstruction and its severe complications require immediate surgical intervention.

in many tropical regions, particularly Southeast Asia. In most areas, older children have the highest incidence and greatest intensity of hookworm infection. In rural areas where fields are fertilized with human feces, older working adults also may be heavily affected. Clinical Features Most hookworm infections are asymptomatic. Infective larvae may provoke pruritic maculopapular dermatitis (“ground itch”) at the site of skin penetration as well as serpiginous tracks of subcutaneous migration (similar to those of cutaneous larva migrans; Chap. 123) in previously sensitized hosts. Larvae migrating through the lungs occasionally cause mild transient pneumonitis, but this condition develops less frequently in hookworm infection than in ascariasis. In the early intestinal phase, infected persons may develop epigastric pain (often with postprandial accentuation), inflammatory diarrhea, or other abdominal symptoms accompanied by eosinophilia. The major consequence of chronic hookworm infection is iron deficiency. Symptoms are minimal if iron intake is adequate, but marginally nourished individuals develop symptoms of progressive iron-deficiency anemia and hypoproteinemia, including weakness and shortness of breath.

Epidemiology A. duodenale is prevalent in southern Europe, North Africa, and northern Asia, and N. americanus is the predominant species in the western hemisphere and equatorial Africa.The two species overlap

Treatment: HOOKWORM INFECTION

Hookworm infection can be eradicated with several safe and highly effective anthelmintic drugs, including albendazole (400 mg once), mebendazole (500 mg once), and pyrantel pamoate (11 mg/kg for 3 days). Mild iron-deficiency anemia can often be treated with oral iron alone. Severe hookworm disease with protein loss and malabsorption necessitates nutritional support and oral iron replacement along with deworming.

Ancylostoma Caninum and Ancylostoma Braziliense A. caninum, the canine hookworm, has been identified as a cause of human eosinophilic enteritis, especially in northeastern Australia. In this zoonotic infection, adult hookworms attach to the small intestine (where they may be visualized by endoscopy) and elicit abdominal pain and intense local eosinophilia. Treatment with

Intestinal Nematodes

Life Cycle Adult hookworms, which are ∼1 cm long, use buccal teeth (Ancylostoma) or cutting plates (Necator) to attach to the small-bowel mucosa and suck blood (0.2 mL/d per Ancylostoma adult) and interstitial fluid. The adult hookworms produce thousands of eggs daily. The eggs are deposited with feces in soil, where rhabditiform larvae hatch and develop over a 1-week period into infectious filariform larvae. Infective larvae penetrate the skin and reach the lungs by way of the bloodstream. There they invade alveoli and ascend the airways before being swallowed and reaching the small intestine.The prepatent period from skin invasion to appearance of eggs in the feces is ∼6–8 weeks, but it may be longer with A. duodenale. Larvae of A. duodenale, if swallowed, can survive and develop directly in the intestinal mucosa.Adult hookworms may survive over a decade but usually live ∼6–8 years for A. duodenale and 2–5 years for N. americanus.

Laboratory Findings The diagnosis is established by the finding of characteristic 40- by 60-µm oval hookworm eggs in the feces. Stool-concentration procedures may be required to detect light infections. Eggs of the two species are indistinguishable by light microscopy. In a stool sample that is not fresh, the eggs may have hatched to release rhabditiform larvae, which need to be differentiated from those of S. stercoralis. Hypochromic microcytic anemia, occasionally with eosinophilia or hypoalbuminemia, is characteristic of hookworm disease.

CHAPTER 124

HOOKWORM Two hookworm species (A. duodenale and N. americanus) are responsible for human infections. Most infected individuals are asymptomatic. Hookworm disease develops from a combination of factors—a heavy worm burden, a prolonged duration of infection, and an inadequate iron intake—and results in iron-deficiency anemia and, on occasion, hypoproteinemia.

1141

1142 mebendazole (100 mg twice daily for 3 days) or albenda-

zole (400 mg once) or endoscopic removal is effective. Both of these animal hookworm species can cause cutaneous larva migrans (“creeping eruption”; Chap. 123).

STRONGYLOIDIASIS S. stercoralis is distinguished by its ability—unusual among helminths—to replicate in the human host. This capacity permits ongoing cycles of autoinfection as infective larvae are internally produced. Strongyloidiasis can thus persist for decades without further exposure of the host to exogenous infective larvae. In immunocompromised hosts, large numbers of invasive Strongyloides larvae can disseminate widely and can be fatal. Life Cycle In addition to a parasitic cycle of development, Strongyloides can undergo a free-living cycle of development in the soil (Fig. 124-1).This adaptability facilitates the parasite’s survival in the absence of mammalian hosts. Rhabditiform larvae passed in feces can transform into infectious filariform larvae either directly or after a free-living

phase of development. Humans acquire strongyloidiasis when filariform larvae in fecally contaminated soil penetrate the skin or mucous membranes. The larvae then travel through the bloodstream to the lungs, where they break into the alveolar spaces, ascend the bronchial tree, are swallowed, and thereby reach the small intestine. There the larvae mature into adult worms that penetrate the mucosa of the proximal small bowel.The minute (2mm-long) parasitic adult female worms reproduce by parthenogenesis; adult males do not exist. Eggs hatch in the intestinal mucosa, releasing rhabditiform larvae that migrate to the lumen and pass with the feces into soil. Alternatively, rhabditiform larvae in the bowel can develop directly into filariform larvae that penetrate the colonic wall or perianal skin and enter the circulation to repeat the migration that establishes ongoing internal reinfection.This autoinfection cycle allows strongyloidiasis to persist for decades. Epidemiology S. stercoralis is spottily distributed in tropical areas and other hot, humid regions and is particularly common in Southeast Asia, sub-Saharan Africa,


2-mm hermaphroditic adult s penetrate small-bowel mucosa and release eggs, which hatch to rhabditiform larvae. Lung or intestinal stage may cause: Larvae migrate via bloodstream or lymphatics to lungs, ascend airway to trachea and pharynx, and are swallowed.

Eosinophilia and intermittent epigastric pain

Autoinfection: Transform within the intestine into filariform larvae, which penetrate perianal skin or bowel mucosa, causing: Pruritic larva currens Eosinophilia Hyperinfection: With immunosuppression, larger numbers of filariform larvae develop, penetrate bowel, and disseminate, causing: Colitis, polymicrobial sepsis, pneumonitis, or meningitis

Larvae shed in stool

Free-living 1-mm adults in soil

Direct development Rhabditiform larvae in soil

Eggs in soil Indirect development (heterogonic) (can multiply outside host for several generations) in soil

FIGURE 124-1 Life cycle of Strongyloides stercoralis. [Adapted from Guerrant RL et al (eds): Tropical Infectious Diseases: Principles,

Pathogens and Practice, 2d ed, p 1276. © 2006, with permission from Elsevier Science.]

and Brazil. In the United States, the parasite is endemic in parts of the South and is found in immigrants and military veterans who have lived in endemic areas abroad.

Treatment: STRONGYLOIDIASIS

Even in the asymptomatic state, strongyloidiasis must be treated because of the potential for subsequent fatal hyperinfection. Ivermectin (200 µg/kg daily for 2 days) is more effective than albendazole (400 mg daily for 3 days). For disseminated strongyloidiasis, treatment with ivermectin should be extended for at least 5–7 days or until the parasites are eradicated.

TRICHURIASIS Most infections with the Trichuris trichiura are asymptomatic, but heavy infections may cause gastrointestinal symptoms. Like the other soiltransmitted helminths, whipworm is distributed globally in the tropics and subtropics and is most common among poor children from resource-poor regions of the world. Life Cycle Adult Trichuris worms reside in the colon and cecum, the anterior portions threaded into the superficial mucosa. Thousands of eggs laid daily by adult female worms pass with the feces and mature in the soil. After ingestion, infective eggs hatch in the duodenum, releasing larvae that mature before migrating to the large bowel. The entire cycle takes ∼3 months, and adult worms may live for several years.

Intestinal Nematodes

Diagnosis In uncomplicated strongyloidiasis, the finding of rhabditiform larvae in feces is diagnostic. Rhabditiform larvae are ∼250 µm long, with a short buccal cavity that distinguishes them from hookworm larvae. In uncomplicated infections, few larvae are passed and single stool examinations detect only about one-third of cases. Serial examinations and the use of the agar plate detection method improve the sensitivity of stool diagnosis. In uncomplicated strongyloidiasis (but not in hyperinfection), stool examinations may be repeatedly negative. Strongyloides larvae may also be found by sampling of the duodenojejunal contents by aspiration or biopsy. An enzyme-linked immunosorbent assay for serum antibodies to antigens of Strongyloides is a sensitive method of

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CHAPTER 124

Clinical Features In uncomplicated strongyloidiasis, many patients are asymptomatic or have mild cutaneous and/or abdominal symptoms. Recurrent urticaria, often involving the buttocks and wrists, is the most common cutaneous manifestation. Migrating larvae can elicit a pathognomonic serpiginous eruption, larva currens (“running larva”).This pruritic, raised, erythematous lesion advances as rapidly as 10 cm/h along the course of larval migration. Adult parasites burrow into the duodenojejunal mucosa and can cause abdominal (usually midepigastric) pain, which resembles peptic ulcer pain except that it is aggravated by food ingestion. Nausea, diarrhea, gastrointestinal bleeding, mild chronic colitis, and weight loss can occur. Small-bowel obstruction may develop with early, heavy infection. Pulmonary symptoms are rare in uncomplicated strongyloidiasis. Eosinophilia is common, with levels fluctuating over time. The ongoing autoinfection cycle of strongyloidiasis is normally contained by unknown factors of the host’s immune system. Abrogation of host immunity, especially with glucocorticoid therapy and much less commonly with other immunosuppressive medications, leads to hyperinfection, with the generation of large numbers of filariform larvae. Colitis, enteritis, or malabsorption may develop. In disseminated strongyloidiasis, larvae may invade not only gastrointestinal tissues and the lungs but also the central nervous system, peritoneum, liver, and kidneys. Moreover, bacteremia may develop because of the passage of enteric flora through disrupted mucosal barriers. Gram-negative sepsis, pneumonia, or meningitis may complicate or dominate the clinical course. Eosinophilia is often absent in severely infected patients. Disseminated strongyloidiasis, particularly in patients with unsuspected infection who are given glucocorticoids, can be fatal. Strongyloidiasis is a frequent complication of infection with human T-cell lymphotropic virus type I, but disseminated strongyloidiasis is not common among patients infected with HIV.

diagnosing uncomplicated infections. Such serologic testing should be performed for patients whose geographic histories indicate potential exposure, especially those who exhibit eosinophilia and/or are candidates for glucocorticoid treatment of other conditions. In disseminated strongyloidiasis, filariform larvae should be sought in stool as well as in samples obtained from sites of potential larval migration, including sputum, bronchoalveolar lavage fluid, or surgical drainage fluid.

Clinical Features Tissue reactions to Trichuris are mild. Most infected individuals have no symptoms or eosinophilia. Heavy infections may result in abdominal pain, anorexia, and bloody or mucoid diarrhea resembling inflammatory bowel disease. Rectal prolapse can result from massive infections in children, who often suffer from malnourishment and other diarrheal illnesses. Moderately heavy Trichuris burdens also contribute to growth retardation. Diagnosis and Treatment The characteristic 50- by 20-µm lemon-shaped Trichuris eggs are readily detected on stool examination. Adult worms, which are 3–5 cm long, are occasionally seen on proctoscopy. Mebendazole (500 mg once) or albendazole (400 mg daily for 3 doses) is safe and effective

1144 for treatment. Ivermectin (200 µg/kg daily for 3 doses) is also safe but is not quite as efficacious as the benzimidazoles.

ENTEROBIASIS (PINWORM) E. vermicularis is more common in temperate countries than in the tropics. In the United States, ∼40 million persons are infected with pinworms, with a disproportionate number of cases among children.

SECTION VIII

Life Cycle and Epidemiology Enterobius adult worms are ∼1 cm long and dwell in the cecum. Gravid female worms migrate nocturnally into the perianal region and release up to 10,000 immature eggs each. The eggs become infective within hours and are transmitted by hand-to-mouth passage. From ingested eggs, larvae hatch and mature into adults. This life cycle takes ∼1 month, and adult worms survive for ∼2 months. Self-infection results from perianal scratching and transport of infective eggs on the hands or under the nails to the mouth. Because of the ease of person-to-person spread, pinworm infections are common among family members.


Clinical Features Most pinworm infections are asymptomatic. Perianal pruritus is the cardinal symptom. The itching, which is often worse at night as a result of the nocturnal migration of the female worms, may lead to excoriation and bacterial superinfection. Heavy infections have been claimed to cause abdominal pain and weight loss. On rare occasions, pinworms invade the female genital tract, causing vulvovaginitis and pelvic or peritoneal granulomas. Eosinophilia is uncommon. Diagnosis Since pinworm eggs are not released in feces, the diagnosis cannot be made by conventional fecal ova and parasites tests. Instead, eggs are detected by the application of clear cellulose acetate tape to the perianal region in the morning.After the tape is transferred to a slide, microscopic examination will detect pinworm eggs, which are oval, measure 55 by 25 µm, and are flattened along one side.

Treatment: ENTEROBIASIS

Infected children and adults should be treated with mebendazole (100 mg once), albendazole (400 mg once), or pyrantel pamoate (11 mg/kg once; maximum, 1 g), with the same treatment repeated after 2 weeks. Treatment of household members is advocated to eliminate asymptomatic reservoirs of potential reinfection.

TRICHOSTRONGYLIASIS Trichostrongylus species, which are normally parasites of herbivorous animals, occasionally infect humans, particularly in Asia and Africa. Humans acquire the infection by accidentally ingesting Trichostrongylus larvae on contaminated leafy vegetables. The larvae do not migrate in humans but mature directly into adult worms in the small bowel. These worms ingest far less blood than hookworms; most infected persons are asymptomatic, but heavy infections may give rise to mild anemia and eosinophilia. Trichostrongylus eggs in stool examinations resemble those of hookworms but are larger (85 by 115 µm). Treatment consists of mebendazole or albendazole (Chap. 113).

ANISAKIASIS Anisakiasis is a gastrointestinal infection caused by the accidental ingestion in uncooked saltwater fish of nematode larvae belonging to the family Anisakidae. The incidence of anisakiasis in the United States has increased as a result of the growing popularity of raw fish dishes. Most cases occur in Japan, the Netherlands, and Chile, where raw fish—sashimi, pickled green herring, and ceviche, respectively—are national culinary staples. Anisakid nematodes parasitize large sea mammals such as whales, dolphins, and seals. As part of a complex parasitic life cycle involving marine food chains, infectious larvae migrate to the musculature of a variety of fish. Both Anisakis simplex and Pseudoterranova decipiens have been implicated in human anisakiasis, but an identical gastric syndrome may be caused by the red larvae of eustrongylid parasites of fish-eating birds. When humans consume infected raw fish, live larvae may be coughed up within 48 h. Alternatively, larvae may immediately penetrate the mucosa of the stomach.Within hours, violent upper abdominal pain accompanied by nausea and occasionally vomiting ensues, mimicking an acute abdomen.The diagnosis can be established by direct visualization on upper endoscopy, outlining of the worm by contrast radiographic studies, or histopathologic examination of extracted tissue. Extraction of the burrowing larvae during endoscopy is curative. In addition, larvae may pass to the small bowel, where they penetrate the mucosa and provoke a vigorous eosinophilic granulomatous response. Symptoms may appear 1–2 weeks after the infective meal, with intermittent abdominal pain, diarrhea, nausea, and fever resembling the manifestations of Crohn’s disease. The diagnosis may be suggested by barium studies and confirmed by curative surgical resection of a granuloma in which the worm is embedded.Anisakid eggs are not found in the stool, since the larvae do not mature in humans. Anisakid larvae in saltwater fish are killed by cooking to 60°C, freezing at –20°C for 3 days, or commercial blast freezing, but not usually by salting, marinating, or cold smoking. No medical treatment is available; surgical or endoscopic removal should be undertaken.

CAPILLARIASIS Intestinal capillariasis is caused by ingestion of raw fish infected with Capillaria philippinensis. Subsequent autoinfection can lead to a severe wasting syndrome.The disease occurs in the Philippines and Thailand and, on occasion, elsewhere in Asia. The natural cycle of C. philippinensis involves fish from fresh and brackish water.When humans eat infected raw fish, the larvae mature in the intestine into adult worms, which produce invasive larvae that cause intestinal inflammation and villus loss. Capillariasis has an insidious onset with nonspecific abdominal pain and watery diarrhea. If untreated, progressive autoinfection can lead to protein-losing enteropathy and severe malabsorption and ultimately to death from cachexia, cardiac failure, or superinfection. The diagnosis is established by identification of the characteristic peanut-shaped (20- by 40-µm) eggs on stool examination. Severely ill patients require hospitalization and supportive therapy in addition to prolonged anthelmintic treatment with mebendazole or albendazole (Chap. 113).

ABDOMINAL ANGIOSTRONGYLIASIS

FURTHER READINGS

FILARIAL AND RELATED INFECTIONS

Filarial worms are nematodes that dwell in the subcutaneous tissues and the lymphatics. Eight filarial species infect humans (Table 125-1); of these, four—Wuchereria bancrofti, Brugia malayi, Onchocerca volvulus, and Loa loa—are responsible for most serious filarial infections. Filarial parasites, which infect an estimated 170 million persons worldwide, are transmitted by specific species of

Peter F. Weller

mosquitoes or other arthropods and have a complex life cycle including infective larval stages carried by insects and adult worms that reside in either lymphatic or subcutaneous tissues of humans. The offspring of adults are microfilariae, which, depending on their species, are 200– 250 µm long and 5–7 µm wide, may or may not be enveloped in a loose sheath, and either circulate in the

Filarial and Related Infections

BETHONY J et al: Soil-transmitted helminth infections: Ascariasis, trichuriasis, and hookworm. Lancet 367:1521, 2006 BIGGS BA et al: Management of chronic strongyloidiasis in immigrants and refugees: Is serologic testing useful? Am J Trop Med Hyg 80:788, 2009 HOTEZ PJ et al: Hookworm infection. N Engl J Med 351:799, 2004 KEISER PB et al: Strongyloides stercoralis in the immunocompromised population. Clin Microbiol Rev 17:208, 2004 LAM CS et al: Disseminated strongyloidiasis: A retrospective study of clinical course and outcome. Eur J Clin Microbiol Infect Dis 25:14, 2006 LIM S et al: Complicated and fatal Strongyloides infection in Canadians: Risk factors, diagnosis and management. CMAJ 171:479, 2004 LU LH et al: Human intestinal capillariasis (Capillaria philippinensis) in Taiwan.Am J Trop Med Hyg 74:810, 2006 MARCOS LA et al: Strongyloides hyperinfection syndrome: an emerging global infectious disease. Trans R Soc Trop Med Hyg 102:314, 2008 SHAH OJ et al: Biliary ascariasis: A review. World J Surg 30:1500, 2006

CHAPTER 125

Thomas B. Nutman

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CHAPTER 125

Abdominal angiostrongyliasis is found in Latin America and Africa. The zoonotic parasite Angiostrongylus costaricensis causes eosinophilic ileocolitis after the ingestion of contaminated vegetation. A. costaricensis normally parasitizes the cotton rat and other rodents, with slugs and snails serving as intermediate hosts. Humans become infected by accidentally ingesting infective larvae in mollusk slime deposited on fruits and vegetables; children are at highest risk. The larvae penetrate the gut wall and migrate to the mesenteric artery, where they develop into adult worms. Eggs deposited in the gut wall provoke an intense eosinophilic granulomatous reaction, and adult worms may cause mesenteric arteritis, thrombosis,

or frank bowel infarction. Symptoms may mimic those of appendicitis, including abdominal pain and tenderness, fever, vomiting, and a palpable mass in the right iliac fossa. Leukocytosis and eosinophilia are prominent. A barium enema may reveal ileocecal-filling defects, but a definitive diagnosis is usually made surgically with partial bowel resection. Pathologic study reveals a thickened bowel wall with eosinophilic granulomas surrounding the Angiostrongylus eggs. In nonsurgical cases, the diagnosis rests solely on clinical grounds because larvae and eggs cannot be detected in the stool. Medical therapy for abdominal angiostrongyliasis (mebendazole, thiabendazole; Chap. 113) is of uncertain efficacy. Careful observation and surgical resection for severe symptoms are the mainstays of treatment.

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TABLE 125-1 CHARACTERISTICS OF THE FILARIAE ORGANISM

PERIODICITY

DISTRIBUTION

Wuchereria bancrofti

Nocturnal

Culex Cosmopolitan areas worldwide, including (mosquitoes) South America and Africa Anopheles Mainly India (mosquitoes) Aedes China, Indonesia (mosquitoes) Aedes Eastern Pacific (mosquitoes) Mansonia, Southeast Asia, Anopheles Indonesia, India (mosquitoes) Indonesia, Southeast Coquillettidia, Mansonia Asia (mosquitoes) Anopheles Indonesia (mosquitoes) Chrysops West and Central (deerflies) Africa Simulium South and Central (blackflies) America, Africa Culicoides South and Central (midges) America Simulium Caribbean (blackflies) Culicoides South and Central (midges) America, Africa

Subperiodic Brugia malayi Nocturnal

Subperiodic

SECTION VIII

B. timori

Nocturnal

Loa loa

Diurnal

Onchocerca volvulus Mansonella ozzardi

None

M. perstans

None

None


None M. streptocerca

West and Central Africa

VECTOR

Culicoides (midges)

blood or migrate through the skin (Table 125-1). To complete the life cycle, microfilariae are ingested by the arthropod vector and develop over 1–2 weeks into new infective larvae. Adult worms live for many years, whereas microfilariae survive for 3–36 months. The Rickettsia-like endosymbiont Wolbachia has been found intracellularly in all stages of Brugia, Wuchereria, Mansonella, and Onchocerca and is viewed as a possible target for antifilarial chemotherapy. Usually, infection is established only with repeated, prolonged exposures to infective larvae. Since the clinical manifestations of filarial diseases develop relatively slowly, these infections should be considered to induce chronic diseases with possible long-term debilitating effects. In terms of the nature, severity, and timing of clinical manifestations, patients with filarial infections who are native to endemic areas and undergo lifelong exposure may differ significantly from those who are travelers or who have recently moved to these areas. Characteristically, filarial disease is more acute and intense in newly exposed individuals than in natives of endemic areas.

LOCATION OF ADULT

MICROFILARIAL LOCATION

SHEATH

Lymphatic tissue

Blood

+

Lymphatic tissue

Blood

+

Lymphatic tissue

Blood

+

Lymphatic tissue

Blood

+

Lymphatic tissue

Blood

+

Subcutaneous tissue Subcutaneous tissue Undetermined site

Blood

+

Skin, eye

−

Blood

−

Body cavities, mesentery, perirenal tissue Subcutaneous tissue

Blood

−

Skin

−

LYMPHATIC FILARIASIS Lymphatic filariasis is caused by W. bancrofti, B. malayi, or B. timori. The threadlike adult parasites reside in lymphatic channels or lymph nodes, where they may remain viable for more than two decades.

EPIDEMIOLOGY W. bancrofti, the most widely distributed human filarial parasite, affects an estimated 115 million people and is found throughout the tropics and subtropics, including Asia and the Pacific Islands, Africa, areas of South America, and the Caribbean basin. Humans are the only definitive host for the parasite. Generally, the subperiodic form is found only in the Pacific Islands; elsewhere, W. bancrofti is nocturnally periodic. (Nocturnally periodic forms of microfilariae are scarce in peripheral blood by day and increase at night, whereas subperiodic forms are present in peripheral blood at all times and reach maximal levels in the afternoon.) Natural vectors for W. bancrofti are Culex fatigans

mosquitoes in urban settings and anopheline or aedean mosquitoes in rural areas. Brugian filariasis due to B. malayi occurs primarily in China, India, Indonesia, Korea, Japan, Malaysia, and the Philippines. B. malayi also has two forms distinguished by the periodicity of microfilaremia.The more common nocturnal form is transmitted in areas of coastal rice fields, while the subperiodic form is found in forests. B. malayi naturally infects cats as well as humans. B. timori exists only on islands of the Indonesian archipelago.

become indurated and inflamed. Concomitant local thrombophlebitis can occur as well. In brugian filariasis, a single local abscess may form along the involved lymphatic tract and subsequently rupture to the surface.The lymphadenitis and lymphangitis can involve both the upper and lower extremities in both bancroftian and brugian filariasis, but involvement of the genital lymphatics occurs almost exclusively with W. bancrofti infection. This genital involvement can be manifested by funiculitis, epididymitis, and scrotal pain and tenderness. In endemic areas, another type of acute disease—dermatolymphangioadenitis (DLA)—is recognized as a syndrome that includes high fever, chills, myalgias, and headache. Edematous inflammatory plaques clearly demarcated from normal skin are seen. Vesicles, ulcers, and hyperpigmentation may also be noted. There is often a history of trauma, burns, radiation, insect bites, punctiform lesions, or chemical injury. Entry lesions, especially in the interdigital area, are common. DLA is often diagnosed as cellulitis. If lymphatic damage progresses, transient lymphedema can develop into lymphatic obstruction and the permanent changes associated with elephantiasis (Fig. 125-2). Brawny edema follows early pitting edema, and thickening of the subcutaneous tissues and hyperkeratosis occur. Fissuring of the skin develops, as do hyperplastic changes. Superinfection of these poorly vascularized tissues becomes a problem. In bancroftian filariasis, in which genital involvement is common, hydroceles may develop (Fig. 125-1); in advanced stages, this condition may evolve into scrotal lymphedema and scrotal elephantiasis. Furthermore, if there is obstruction of the retroperitoneal lymphatics, the increased renal lymphatic pressure leads to rupture of the renal lymphatics and the development of


CLINICAL FEATURES The most common presentations of the lymphatic filariases are asymptomatic (or subclinical) microfilaremia, hydrocele (Fig. 125-1), acute adenolymphangitis (ADL), and chronic lymphatic disease. In areas where W. bancrofti or B. malayi is endemic, the overwhelming majority of infected individuals have few overt clinical manifestations of filarial infection despite large numbers of circulating microfilariae in the peripheral blood. Although they may be clinically asymptomatic, virtually all persons with W. bancrofti or B. malayi microfilaremia have some degree of subclinical disease that includes microscopic hematuria and/or proteinuria, dilated (and tortuous) lymphatics (visualized by imaging), and—in men—scrotal lymphangiectasia (detectable by ultrasound). In spite of these findings, the majority of individuals appear to remain clinically asymptomatic for years; relatively few progress to either acute or chronic disease. ADL is characterized by high fever, lymphatic inflammation (lymphangitis and lymphadenitis), and transient local edema. The lymphangitis is retrograde, extending peripherally from the lymph node draining the area where the adult parasites reside. Regional lymph nodes are often enlarged, and the entire lymphatic channel can

FIGURE 125-1 Hydrocele associated with Wuchereria bancrofti infection.

CHAPTER 125

PATHOLOGY The principal pathologic changes result from inflammatory damage to the lymphatics, which is typically caused by adult worms and not by microfilariae. Adult worms live in afferent lymphatics or sinuses of lymph nodes and cause lymphatic dilatation and thickening of the vessel walls. The infiltration of plasma cells, eosinophils, and macrophages in and around the infected vessels, along with endothelial and connective tissue proliferation, leads to tortuosity of the lymphatics and damaged or incompetent lymph valves. Lymphedema and chronicstasis changes with hard or brawny edema develop in the overlying skin. These consequences of filariasis are due both to direct effects of the worms and to the inflammatory response of the host to the parasite. Inflammatory responses are believed to cause the granulomatous and proliferative processes that precede total lymphatic obstruction. It is thought that the lymphatic vessel remains patent as long as the worm remains viable and that the death of the worm leads to enhanced granulomatous reaction and fibrosis. Lymphatic obstruction results, and, despite collateralization of the lymphatics, lymphatic function is compromised.

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FIGURE 125-2 Elephantiasis of the lower extremity associated with Wuchereria bancrofti infection.


chyluria, which is usually intermittent and most prominent in the morning. The clinical manifestations of filarial infections in travelers or transmigrants who have recently entered an endemic region are distinctive. Given a sufficient number of bites by infected vectors, usually over a 3- to 6-month period, recently exposed patients can develop acute lymphatic or scrotal inflammation with or without urticaria and localized angioedema. Lymphadenitis of epitrochlear, axillary, femoral, or inguinal lymph nodes is often followed by retrogradely evolving lymphangitis. Acute attacks are short-lived and are not usually accompanied by fever. With prolonged exposure to infected mosquitoes, these attacks, if untreated, become more severe and lead to permanent lymphatic inflammation and obstruction.

DIAGNOSIS A definitive diagnosis can be made only by detection of the parasites and hence can be difficult. Adult worms localized in lymphatic vessels or nodes are largely inaccessible. Microfilariae can be found in blood, in hydrocele fluid, or (occasionally) in other body fluids. Such fluids can be examined microscopically, either directly or—for greater sensitivity—after concentration of the parasites by the passage of fluid through a polycarbonate cylindrical pore filter (pore size, 3 µm) or by the centrifugation of fluid fixed in 2% formalin (Knott’s concentration technique). The timing of blood collection is critical and should be based on the periodicity of the microfilariae in the endemic region involved. Many infected individuals do not have microfilaremia, and definitive diagnosis in such cases can be difficult. Assays

for circulating antigens of W. bancrofti permit the diagnosis of microfilaremic and cryptic (amicrofilaremic) infection. Two tests are commercially available: an enzymelinked immunosorbent assay (ELISA) and a rapid-format immunochromatographic card test. Both assays have sensitivities of 96–100% and specificities approaching 100%. There are currently no tests for circulating antigens in brugian filariasis. Polymerase chain reaction (PCR)–based assays for DNA of W. bancrofti and B. malayi in blood have been developed. A number of studies indicate that this diagnostic method is of equivalent or greater sensitivity compared with parasitologic methods, detecting patent infection in almost all infected individuals. In cases of suspected lymphatic filariasis, examination of the scrotum or the female breast by means of highfrequency ultrasound in conjunction with Doppler techniques may result in the identification of motile adult worms within dilated lymphatics. Worms may be visualized in the lymphatics of the spermatic cord in up to 80% of infected men. Live adult worms have a distinctive pattern of movement within the lymphatic vessels (termed the filaria dance sign). Radionuclide lymphoscintigraphic imaging of the limbs reliably demonstrates widespread lymphatic abnormalities in both asymptomatic microfilaremic persons and those with clinical manifestations of lymphatic pathology. While of potential utility in the delineation of anatomic changes associated with infection, lymphoscintigraphy is unlikely to assume primacy in the diagnostic evaluation of individuals with suspected infection; it is principally a research tool, although it has been used more widely for assessment of lymphedema of any cause. Eosinophilia and elevated serum concentrations of IgE and antifilarial antibody support the diagnosis of lymphatic filariasis. There is, however, extensive crossreactivity between filarial antigens and antigens of other helminths, including the common intestinal roundworms; thus, interpretations of serologic findings can be difficult. In addition, residents of endemic areas can become sensitized to filarial antigens (and thus be serologically positive) through exposure to infected mosquitoes without having patent filarial infections. The ADL associated with lymphatic filariasis must be distinguished from thrombophlebitis, infection, and trauma. Retrogradely evolving lymphangitis is a characteristic feature that helps distinguish filarial lymphangitis from ascending bacterial lymphangitis. Chronic filarial lymphedema must also be distinguished from the lymphedema of malignancy, postoperative scarring, trauma, chronic edematous states, and congenital lymphatic system abnormalities.

Treatment: LYMPHATIC FILARIASIS

With newer definitions of clinical syndromes in lymphatic filariasis and new tools to assess clinical status (e.g., ultrasound, lymphoscintigraphy, circulating filarial antigen assays, PCR), approaches to treatment based on infection

the intracellular Wolbachia endosymbionts freed from their intracellular niche. Ivermectin has a side effect profile similar to that of DEC when used in lymphatic filariasis. In patients infected with L. loa, who have high levels of Loa microfilaremia, DEC—like ivermectin (see “Loiasis” later in the chapter)—can elicit severe encephalopathic complications. When used in single-dose regimens for the treatment of lymphatic filariasis, albendazole is associated with relatively few side effects.

TROPICAL PULMONARY EOSINOPHILIA Tropical pulmonary eosinophilia (TPE) is a distinct syndrome that develops in some individuals infected with lymphatic filarial species.This syndrome affects males and females in a ratio of 4:1, often during the third decade of life. The majority of cases have been reported from India, Pakistan, Sri Lanka, Brazil, Guyana, and Southeast Asia.

CLINICAL FEATURES The main features include a history of residence in filarialendemic regions, paroxysmal cough and wheezing (usually nocturnal and probably related to the nocturnal periodicity of microfilariae), weight loss, low-grade fever, adenopathy, and pronounced blood eosinophilia (>3000 eosinophils/µL). Chest x-rays or CT scans may be normal but generally show increased bronchovascular markings. Diffuse miliary lesions or mottled opacities may be present in the middle and lower lung fields.Tests of pulmonary function show restrictive abnormalities in


PREVENTION AND CONTROL Avoidance of mosquito bites usually is not feasible for residents of endemic areas, but visitors should make use of insect repellent and mosquito nets. Impregnated bednets have a salutary effect. DEC can kill developing forms of filarial parasites and is useful as a prophylactic agent in humans. Community-based intervention is the current approach to elimination of lymphatic filariasis as a public health problem. The underlying tenet of this approach is that mass annual distribution of antimicrofilarial chemotherapy—albendazole with either DEC (for all areas except those where onchocerciasis is coendemic) or ivermectin—will profoundly suppress microfilaremia. If the suppression is sustained, then transmission can be interrupted. As an added benefit, these combinations have secondary effects on gastrointestinal helminths. An alternative approach to the control of lymphatic filariasis is the use of salt fortified with DEC. Community use of DEC-fortified salt dramatically reduces microfilarial density with no apparent adverse reactions. Community education and clinical care for persons already suffering from the chronic sequelae of lymphatic filariasis are important components of filariasis control and elimination programs.

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CHAPTER 125

status can be considered. Diethylcarbamazine (DEC, 6 mg/kg daily for 12 days), which has both macro- and microfilaricidal properties, remains the treatment of choice for the individual with active lymphatic filariasis (microfilaremia, antigen positivity, or adult worms on ultrasound). An alternative treatment is albendazole (400 mg bid for 21 days), although this drug’s macrofilaricidal efficacy may be less than that of DEC. An 8-week course of daily doxycycline (targeting the intracellular Wolbachia endosymbiont) has significant macrofilaricidal activity, as does a 7-day course of daily DEC/albendazole. As has already been mentioned, a growing body of evidence indicates that, although they may be asymptomatic, virtually all persons with W. bancrofti or B. malayi microfilaremia have some degree of subclinical disease (hematuria, proteinuria, abnormalities on lymphoscintigraphy). Thus, early treatment of asymptomatic persons is recommended to prevent further lymphatic damage. For ADL, supportive treatment (including the administration of antipyretics and analgesics) is recommended, as is antibiotic therapy if secondary bacterial infection is likely. Similarly, because lymphatic disease is associated with the presence of adult worms, treatment with DEC is recommended for microfilaria-negative adult-worm carriers. In persons with chronic manifestations of lymphatic filariasis, treatment regimens that emphasize hygiene, prevention of secondary bacterial infections, and physiotherapy have gained wide acceptance for morbidity control. These regimens are similar to those recommended for lymphedema of most nonfilarial causes and known by a variety of names, including complex decongestive physiotherapy and complex lymphedema therapy. Hydroceles (Fig. 125-1) can be drained repeatedly or managed surgically. With chronic manifestations of lymphatic filariasis, drug treatment should be reserved for individuals with evidence of active infection; therapy has been associated with clinical improvement and, in some cases, reversal of lymphedema. The recommended course of DEC treatment (12 days; total dose, 72 mg/kg) has remained standard for many years. However, data indicate that single-dose DEC treatment with 6 mg/kg may be equally efficacious. The 12-day course provides more rapid short-term microfilarial suppression. Regimens that use combinations of single doses of albendazole and either DEC or ivermectin all have a sustained microfilaricidal effect. As mentioned above, an 8-week course of daily doxycycline (200 mg/d) or a 7-day course of daily DEC/albendazole has both significant macrofilaricidal activity and sustained microfilaricidal activity. Side effects of DEC treatment include fever, chills, arthralgias, headaches, nausea, and vomiting. Both the development and the severity of these reactions are directly related to the number of microfilariae circulating in the bloodstream. The adverse reactions may represent either an acute hypersensitivity reaction to the antigens being released by dead and dying parasites or an inflammatory reaction induced by lipopolysaccharides from

1150 most cases and obstructive defects in half. Characteristically, total serum IgE levels (10,000–100,000 ng/mL) and antifilarial antibody titers are markedly elevated.

PATHOLOGY In TPE, microfilariae and parasite antigens are rapidly cleared from the bloodstream by the lungs. The clinical symptoms result from allergic and inflammatory reactions elicited by the cleared parasites. In some patients, trapping of microfilariae in other reticuloendothelial organs can cause hepatomegaly, splenomegaly, or lymphadenopathy. A prominent, eosinophil-enriched, intraalveolar infiltrate is often reported, and with it comes the release of cytotoxic proinflammatory granular proteins that may mediate some of the pathology seen in TPE. In the absence of successful treatment, interstitial fibrosis can lead to progressive pulmonary damage.

SECTION VIII

DIFFERENTIAL DIAGNOSIS TPE must be distinguished from asthma, Löffler’s syndrome, allergic bronchopulmonary aspergillosis, allergic granulomatosis with angiitis (Churg-Strauss syndrome), the systemic vasculitides (most notably periarteritis nodosa and Wegener’s granulomatosis), chronic eosinophilic pneumonia, and the idiopathic hypereosinophilic syndrome. In addition to a geographic history of filarial exposure, useful features for distinguishing TPE include wheezing that is solely nocturnal, very high levels of antifilarial antibodies, and a rapid initial response to treatment with DEC.


Treatment: TROPICAL PULMONARY EOSINOPHILIA

DEC is used at a daily dosage of 4–6 mg/kg for 14 days. Symptoms usually resolve within 3–7 days after the initiation of therapy. Relapse, which occurs in ∼12–25% of cases (sometimes after an interval of years), requires retreatment.

ONCHOCERCIASIS Onchocerciasis (“river blindness”) is caused by the filarial nematode O. volvulus, which infects an estimated 13 million individuals. The majority of individuals infected with O. volvulus live in the equatorial region of Africa extending from the Atlantic coast to the Red Sea. About 70,000 persons are infected in Guatemala and Mexico, with smaller foci in Venezuela, Colombia, Brazil, Ecuador, Yemen, and Saudi Arabia. Onchocerciasis is the second leading cause of infectious blindness worldwide.

ETIOLOGY AND EPIDEMIOLOGY Infection in humans begins with the deposition of infective larvae on the skin by the bite of an infected blackfly. The larvae develop into adults, which are typically found in subcutaneous nodules. About 7 months to

3 years after infection, the gravid female releases microfilariae that migrate out of the nodule and throughout the tissues, concentrating in the dermis. Infection is transmitted to other persons when a female fly ingests microfilariae from the host’s skin and these microfilariae then develop into infective larvae.Adult O. volvulus females and males are ∼40–60 cm and ∼3–6 cm in length, respectively. The life span of adults can be as long as 18 years, with an average of ∼9 years. Because the blackfly vector breeds along free-flowing rivers and streams (particularly in rapids) and generally restricts its flight to an area within several kilometers of these breeding sites, both biting and disease transmission are most intense in these locations.

PATHOLOGY Onchocerciasis primarily affects the skin, eyes, and lymph nodes. In contrast to the pathology in lymphatic filariasis, the damage in onchocerciasis is elicited by microfilariae and not by adult parasites. In the skin, there are mild but chronic inflammatory changes that can result in loss of elastic fibers, atrophy, and fibrosis. The subcutaneous nodules, or onchocercomata, consist primarily of fibrous tissues surrounding the adult worm, often with a peripheral ring of inflammatory cells. In the eye, neovascularization and corneal scarring lead to corneal opacities and blindness. Inflammation in the anterior and posterior chambers frequently results in anterior uveitis, chorioretinitis, and optic atrophy. Although punctate opacities are due to an inflammatory reaction surrounding dead or dying microfilariae, the pathogenesis of most manifestations of onchocerciasis is still unclear. CLINICAL FEATURES Skin Pruritus and rash are the most frequent manifestations of onchocerciasis. The pruritus can be incapacitating; the rash is typically a papular eruption (Fig. 125-3) that is generalized rather than localized to a particular region of the body. Long-term infection results in exaggerated and premature wrinkling of the skin, loss of elastic fibers, and epidermal atrophy that can lead to loose, redundant skin and hypo- or hyperpigmentation. Localized eczematoid dermatitis can cause hyperkeratosis, scaling, and pigmentary changes. In an immunologically hyperreactive form of onchodermatitis (commonly termed sowdah, from the Yemeni word meaning “black”), the affected skin darkens as a consequence of the profound inflammation that occurs as microfilariae in the skin are cleared. Onchocercomata These subcutaneous nodules, which can be palpable and/or visible, contain the adult worm. In African patients, they are common over the coccyx and sacrum, the trochanter of the femur, the lateral anterior crest, and other bony prominences; in patients from South and Central America, nodules tend to

Systemic Manifestations Some heavily infected individuals develop cachexia with loss of adipose tissue and muscle mass. Among adults who become blind, there is a three- to fourfold increase in the mortality rate.

FIGURE 125-3 Papular eruption as a consequence of onchocerciasis.

Lymph Nodes Mild to moderate lymphadenopathy is common, particularly in the inguinal and femoral areas, where the enlarged nodes may hang down in response to gravity (“hanging groin”), sometimes predisposing to inguinal and femoral hernias.

Treatment: ONCHOCERCIASIS

The main goals of therapy are to prevent the development of irreversible lesions and to alleviate symptoms. Surgical excision is recommended when nodules are located on the head (because of the proximity of microfilaria-producing adult worms to the eye), but chemotherapy is the mainstay of management. Ivermectin, a semisynthetic macrocyclic lactone active against microfilariae, is the first-line agent for the treatment of onchocerciasis. It is given orally in a single dose of 150 µg/kg, either yearly or semiannually. Recently, more frequent ivermectin administration (every 3 months) has been suggested to ameliorate pruritus and skin disease. Moreover, quadrennial administration of ivermectin has some macrofilaricidal activity. After treatment, most individuals have few or no reactions. Pruritus, cutaneous edema, and/or maculopapular rash occurs in ∼1–10% of treated individuals. In areas of Africa co-endemic for O. volvulus and L. loa, however, ivermectin is contraindicated (as it is for pregnant or breast-feeding women) because of severe posttreatment encephalopathy seen in patients,


Ocular Tissue Visual impairment is the most serious complication of onchocerciasis and usually affects only those persons with moderate or heavy infections. Lesions may develop in all parts of the eye.The most common early finding is conjunctivitis with photophobia. Punctate keratitis— acute inflammatory reactions surrounding dying microfilariae and manifested as “snowflake” opacities—is common among younger patients and resolves without apparent complications. Sclerosing keratitis occurs in 1–5% of infected persons and is the leading cause of onchocercal blindness in Africa. Anterior uveitis and iridocyclitis develop in ∼5% of infected persons in Africa. In Latin America, complications of the anterior uveal tract (pupillary deformity) may cause secondary glaucoma. Characteristic chorioretinal lesions develop as a result of atrophy and hyperpigmentation of the retinal pigment epithelium. Constriction of the visual fields and frank optic atrophy may occur.

CHAPTER 125

develop preferentially in the upper part of the body, particularly on the head, neck, and shoulders. Nodules vary in size and characteristically are firm and not tender. It has been estimated that, for every palpable nodule, there are four deeper nonpalpable ones.

DIAGNOSIS Definitive diagnosis depends on the detection of an adult worm in an excised nodule or, more commonly, of microfilariae in a skin snip. Skin snips are obtained with a corneal-scleral punch, which collects a blood-free skin biopsy sample extending to just below the epidermis, or by lifting of the skin with the tip of a needle and excision of a small (1- to 3-mm) piece with a sterile scalpel blade. The biopsy tissue is incubated in tissue culture medium or in saline on a glass slide or flat-bottomed microtiter plate. After incubation for 2–4 h (or occasionally overnight in light infections), microfilariae emergent from the skin can be seen by low-power microscopy. Eosinophilia and elevated serum IgE levels are common but, because they occur in many parasitic infections, are not diagnostic in themselves. Assays to detect specific antibodies to Onchocerca and PCR to detect onchocercal DNA in skin snips are used in specialized laboratories and are highly sensitive and specific. The Mazzotti test is a provocative technique that can be used in cases where the diagnosis of onchocerciasis is still in doubt (i.e., when skin snips and ocular examination reveal no microfilariae). A small dose of DEC (0.5–1.0 mg/kg) is given orally; the ensuing death of any dermal microfilariae elicits the development or exacerbation of pruritus or dermatitis within hours—an event that strongly suggests onchocerciasis.

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especially children, who are heavily microfilaremic for L. loa (2000–5000 microfilariae/mL). Although ivermectin treatment results in a marked drop in microfilarial density, its effect can be short-lived (40 years). Intensity of infection (as measured by fecal or urinary egg counts, which correlate with adult worm burdens in most circumstances) follows the increase in prevalence up to the age of 15–20 years and then declines markedly in older age groups. This decline may reflect acquisition of resistance or may be due to changes in water contact patterns, since older people have less exposure. Furthermore, the overdispersed distribution of schistosomes in human populations may be due to the heterogeneity of worm populations, with some more invasive than others; alternatively, it may be due to the demonstrated differences in genetic susceptibility of host populations. Disease due to schistosome infection is the outcome of parasitologic, host, and additional infectious, nutritional, and environmental factors. Most disease syndromes relate to the presence of one or more of the parasite stages in humans. Disease manifestations in the populations of endemic areas correlate, in general, with the intensity and

Schistosomiasis and Other Trematode Infections

A

FIGURE 126-2 Global distribution of schistosomiasis. A. S. mansoni infection (dark blue) is endemic in Africa, the Middle East, South America, and a few Caribbean countries. S. intercalatum infection (green) is endemic in sporadic foci in West and Central Africa. B. S. haematobium infection (purple) is

B

endemic in Africa and the Middle East. The major endemic countries for S. japonicum infection (green) are China, the Philippines, and Indonesia. S. mekongi infection (red) is endemic in sporadic foci in Southeast Asia.

1158 duration of infection as well as with the age and genetic

susceptibility of the host. Overall, disease manifestations are clinically relevant in only a small proportion of persons infected with any of the intestinal schistosomes. In contrast, urinary schistosomiasis manifests clinically in most infected individuals. Recent estimates of total morbidity due to chronic schistosomiasis indicate a significantly greater burden than was previously appreciated. Patients with both HIV infection and schistosomiasis excrete far fewer eggs in their stools than those infected with S. mansoni alone; the mechanism underlying this difference is unknown.Treatment with praziquantel may result in reduced HIV replication and increased CD4+ T lymphocyte counts.


PATHOGENESIS AND IMMUNITY Cercarial invasion is associated with dermatitis arising from dermal and subdermal inflammatory responses, both humoral and cell-mediated. As the parasites approach sexual maturity and with the commencement of oviposition, acute schistosomiasis or Katayama fever (a serum sickness–like illness; see “Clinical Features” next in the chapter) may occur.The associated antigen excess results in formation of soluble immune complexes, which may be deposited in several tissues, initiating multiple pathologic events. In chronic schistosomiasis, most disease manifestations are due to eggs retained in host tissues. The granulomatous response around these ova is cell-mediated and is regulated both positively and negatively by a cascade of cytokine, cellular, and humoral responses. Granuloma formation begins with recruitment of a host of inflammatory cells in response to antigens secreted by the living organism within the ova. Cells recruited initially include phagocytes, antigen-specific T cells, and eosinophils. Fibroblasts, giant cells, and B lymphocytes predominate later. These lesions reach a size many times that of parasite eggs, thus inducing organomegaly and obstruction. Immunomodulation or downregulation of host responses to schistosome eggs plays a significant role in limiting the extent of the granulomatous lesions—and consequently disease—in chronically infected experimental animals or humans. The underlying mechanisms involve another cascade of regulatory cytokines and idiotypic antibodies. Subsequent to the granulomatous response, fibrosis sets in, resulting in more permanent disease sequelae. Because schistosomiasis is also a chronic infection, the accumulation of antigen-antibody complexes results in deposits in renal glomeruli and may cause significant kidney disease. The better-studied pathologic sequelae in schistosomiasis are those observed in liver disease. Ova that are carried by portal blood embolize to the liver. Because of their size (∼150 × 60 µm in the case of S. mansoni), they lodge at presinusoidal sites, where granulomas are formed. These granulomas contribute to the hepatomegaly observed in infected individuals. Schistosomal liver enlargement is also associated with certain class I and class II human leukocyte antigen (HLA) haplotypes and markers; its genetic basis appears to be multigenic. Presinusoidal

portal blockage causes several hemodynamic changes, including portal hypertension and associated development of portosystemic collaterals at the esophagogastric junction and other sites. Esophageal varices are most likely to break and cause repeated episodes of hematemesis. Because changes in hepatic portal blood flow occur slowly, compensatory arterialization of the blood flow through the liver is established. While this compensatory mechanism may be associated with certain metabolic side effects, retention of hepatocyte perfusion permits maintenance of normal liver function for several years. The second most significant pathologic change in the liver relates to fibrosis. It is characteristically periportal (Symmers’ clay pipe–stem fibrosis) but may be diffuse. Fibrosis, when diffuse, may be seen in areas of egg deposition and granuloma formation but is also seen in distant locations such as portal tracts. Schistosomiasis results in pure fibrotic lesions in the liver; cirrhosis occurs when other nutritional factors or infectious agents (e.g., hepatitis B or C virus) are involved. In recent years, it has been recognized that deposition of fibrotic tissue in the extracellular matrix results from the interaction of T lymphocytes with cells of the fibroblast series; several cytokines, such as interleukin (IL) 2, IL-4, IL-1, and transforming growth factor β (TGF-β), are known to stimulate fibrogenesis.The process may be dependent on the genetic constitution of the host. Furthermore, regulatory cytokines that can suppress fibrogenesis, such as interferon γ (IFN-γ) or IL-12, may play a role in modulating the response. While the above description focuses on granuloma formation and fibrosis of the liver, similar processes occur in urinary schistosomiasis. Granuloma formation at the lower end of the ureters obstructs urinary flow, with subsequent development of hydroureter and hydronephrosis. Similar lesions in the urinary bladder cause the protrusion of papillomatous structures into its cavity; these may ulcerate and/or bleed. The chronic stage of infection is associated with scarring and deposition of calcium in bladder wall. Studies on immunity to schistosomiasis, whether innate or adaptive, have expanded our knowledge of the components of these responses and target antigens. The critical question, however, is whether humans acquire immunity to schistosomes. Epidemiologic data suggest the onset of acquired immunity during the course of infection in young adults. Curative treatment of infection divides populations in endemic areas into those who acquire reinfection rapidly (susceptible) and those who follow a protracted course (resistant). This difference may be explained by differences in transmission, immunologic response, or genetic susceptibility. The mechanism of acquired immunity involves antibodies, complement, and several effector cells, particularly eosinophils. Furthermore, the intensity of schistosome infection has been correlated with a region in chromosome 5. In several studies, a few protective schistosome antigens have been identified as vaccine candidates, but none has been evaluated in human populations to date.

1159


gresses. Bleeding from esophageal varices may, however, be the first clinical manifestation of this phase. Patients may experience repeated bleeding but seem to tolerate its impact, since an adequate total hepatic blood flow permits normal liver function for a considerable duration. In late-stage disease, typical fibrotic changes occur along with liver function deterioration and the onset of ascites, hypoalbuminemia, and defects in coagulation. Intercurrent viral infections of the liver (especially hepatitis B and C) or nutritional deficiencies may well accelerate or exacerbate the deterioration of hepatic function. The extent and severity of intestinal and hepatic disease in schistosomiasis mansoni and japonica have been well described. While it was originally thought that S. japonicum might induce more severe disease manifestations because the adult worms can produce 10 times more eggs than S. mansoni, subsequent field studies have not supported this claim. Clinical observations of individuals infected with S. mekongi or S. intercalatum have been less detailed, partly because of the limited geographic distribution of these organisms. The clinical manifestations of S. haematobium infection occur relatively early and involve a high percentage of infected individuals. Up to 80% of children infected with S. haematobium have dysuria, frequency, and hematuria, which may be terminal. Urine examination reveals blood and albumin as well as an unusually high frequency of bacterial urinary tract infection and urinary sediment cellular metaplasia.These manifestations correlate with intensity of infection, the presence of urinary bladder granulomas, and subsequent ulceration. Along with local effects of granuloma formation in the urinary bladder, obstruction of the lower end of the ureters results in hydroureter and hydronephrosis, which may be seen in 25–50% of infected children. As infection progresses, bladder granulomas undergo fibrosis, which results in typical sandy patches visible on cystoscopy. In many endemic areas, an association between squamous cell carcinoma of the bladder and S. haematobium infection has been observed. Such malignancy is detected in a younger age group than is transitional cell carcinoma. In fact, S. haematobium has now been classified as a human carcinogen. Significant disease may occur in other organs during chronic schistosomiasis. Most important are the lungs and central nervous system (CNS); other locations, such as the skin and the genital organs, are far less frequently affected. In pulmonary schistosomiasis, embolized eggs lodge in small arterioles, producing acute necrotizing arteriolitis and granuloma formation. During S. mansoni and S. japonicum infection, schistosome eggs reach the lungs after the development of portosystemic collateral circulation; in S. haematobium infection, ova may reach the lungs directly via connections between the vesical and systemic circulation. Subsequent fibrous tissue deposition leads to endarteritis obliterans, pulmonary hypertension, and cor pulmonale. The most common symptoms are cough, fever, and dyspnea. Cor pulmonale may be diagnosed radiologically on the basis of prominent right side of the heart and dilation of the pulmonary artery. Frank evidence of right-sided heart failure may be seen in late cases.

CHAPTER 126

CLINICAL FEATURES In general, disease manifestations of schistosomiasis occur in three stages, which vary not only by species but also by intensity of infection and other host factors, such as age and genetics. During the phase of cercarial invasion, a form of dermatitis may be observed.This so-called swimmers’ itch occurs most often with S. mansoni and S. japonicum infections, manifesting 2 or 3 days after invasion as an itchy maculopapular rash on the affected areas of the skin. The condition is particularly severe when humans are exposed to avian schistosomes.This form of cercarial dermatitis is also seen around freshwater lakes in the northern United States, particularly in the spring. Cercarial dermatitis is a self-limiting clinical entity. During worm maturation and at the beginning of oviposition (i.e., 4–8 weeks after skin invasion), acute schistosomiasis or Katayama fever—a serum sickness–like syndrome with fever, generalized lymphadenopathy, and hepatosplenomegaly—may develop. Individuals with acute schistosomiasis show a high degree of peripheral blood eosinophilia. Parasite-specific antibodies may be detected before schistosome eggs are identified in excreta. Acute schistosomiasis has become an important clinical entity worldwide because of increased travel to endemic areas.Travelers are exposed to parasites while swimming or wading in freshwater bodies and upon their return present with the acute manifestations. The course of acute schistosomiasis is generally benign, but deaths are occasionally reported in association with heavy exposure to schistosomes. The main clinical manifestations of chronic schistosomiasis are species-dependent. Intestinal species (S. mansoni, S. japonicum, S. mekongi, and S. intercalatum) cause intestinal and hepatosplenic disease as well as several manifestations associated with portal hypertension. During the intestinal phase, which may begin a few months after infection and may last for years, symptomatic patients characteristically have colicky abdominal pain, bloody diarrhea, and anemia. Patients may also report fatigue and an inability to perform daily routine functions and may show evidence of growth retardation. It has been demonstrated that schistosomiasis morbidity is generally underappreciated. The severity of intestinal schistosomiasis is often related to the intensity of the worm burden. The disease runs a chronic course and may result in colonic polyposis, which has been reported from some endemic areas, such as Egypt. The hepatosplenic phase of disease manifests early (during the first year of infection, particularly in children) with liver enlargement due to parasite-induced granulomatous lesions. Hepatomegaly is seen in ∼15–20% of infected individuals; it correlates roughly with intensity of infection, occurs more often in children, and may be related to specific HLA haplotypes. In subsequent phases of infection, presinusoidal blockage of blood flow leads to portal hypertension and splenomegaly. Moreover, portal hypertension may lead to varices at the lower end of the esophagus and at other sites. Patients with schistosomal liver disease may have right-upper-quadrant “dragging” pain during the hepatomegaly phase, and this pain may move to the left upper quadrant as splenomegaly pro-

1160

SECTION VIII

CNS schistosomiasis is important but less common than pulmonary schistosomiasis. It characteristically occurs as cerebral disease due to S. japonicum infection. Migratory worms deposit eggs in the brain and induce a granulomatous response. The frequency of this manifestation among infected individuals in some endemic areas (e.g., the Philippines) is calculated at 2–4%. Jacksonian epilepsy due to S. japonicum infection is the second most common cause of epilepsy in these areas. S. mansoni and S. haematobium infections have been associated with transverse myelitis. This syndrome is thought to be due to eggs traveling to the venous plexus around the spinal cord. In schistosomiasis mansoni, transverse myelitis is usually seen in the chronic stage after the development of portal hypertension and portosystemic shunts, which allow ova to travel to the spinal cord veins. This proposed sequence of events has been challenged because of a few reports of transverse myelitis occurring early in the course of S. mansoni infection. More information is needed to confirm these observations. During schistosomiasis haematobia, ova may travel through communication between vesical and systemic veins, resulting in spinal cord disease that may be detected at any stage of infection. Pathologic study of lesions in schistosomal transverse myelitis may reveal eggs along with necrotic or granulomatous lesions. Patients usually present with acute or rapidly progressing lower-leg weakness accompanied by sphincter dysfunction.


DIAGNOSIS Physicians in areas not endemic for schistosomiasis face considerable diagnostic challenges. In the most common clinical presentation, a traveler returns with symptoms and signs of acute syndromes of schistosomiasis—namely, cercarial dermatitis or Katayama fever. Central to correct diagnosis is a thorough inquiry into travel history and exposure to freshwater bodies, whether slow or fast running. Differential diagnosis of fever in returned travelers includes a spectrum of infections whose etiologies are viral (e.g., Dengue fever), bacterial (e.g., enteric fever, leptospirosis), rickettsial, or protozoal (e.g., malaria). In cases of Katayama fever, prompt diagnosis is essential and is based on clinical presentation, high-level peripheral blood eosinophilia, and a positive serologic assay for schistosomal antibodies. Two tests are available at the CDC: the Falcon assay screening test/enzyme-linked immunosorbent assay (FAST-ELISA) and the confirmatory enzyme-linked immunoelectrotransfer blot (EITB). Both tests are highly sensitive and ∼96% specific. In some instances, examination of stool or urine for ova may yield positive results. Individuals with established infection are diagnosed by a combination of geographic history, characteristic clinical presentation, and presence of schistosome ova in excreta. The diagnosis may also be established with the serologic assays mentioned above or with those that detect circulating schistosome antigens. These assays can be applied either to blood or to other body fluids (e.g., cerebrospinal fluid). For suspected schistosome infection, stool examination by the Kato thick smear or any other concentration method generally identifies all but the most lightly infected individuals. For S. haematobium, urine may be

examined by microscopy of sediment or by filtration of a known volume through Nuclepore filters. Kato thick smear and Nuclepore filtration provide quantitative data on the intensity of infection, which is of value in assessing the degree of tissue damage and in monitoring the effect of chemotherapy. Schistosome infection may also be diagnosed by examination of tissue samples, typically rectal biopsies; other biopsy procedures (e.g., liver biopsy) are not needed, except in rare circumstances. Differential diagnosis of schistosomal hepatomegaly must include viral hepatitis of all etiologies, miliary tuberculosis, malaria, visceral leishmaniasis, ethanol abuse, and causes of hepatic and portal vein obstruction. Differential diagnosis of hematuria in S. haematobium infection includes bacterial cystitis, tuberculosis, urinary stones, and malignancy.

Treatment: SCHISTOSOMIASIS

Treatment of schistosomiasis depends on stage of infection and clinical presentation. Other than topical dermatologic applications for relief of itching, no specific treatment is indicated for cercarial dermatitis caused by avian schistosomes. Therapy for acute schistosomiasis or Katayama fever needs to be adjusted appropriately for each case. While antischistosomal chemotherapy may be used, it does not have a significant impact on maturing worms. In severe acute schistosomiasis, management in an acute-care setting is necessary, with supportive measures and consideration of glucocorticoid treatment. Once the acute critical phase is over, specific chemotherapy is indicated for parasite elimination. For all individuals with established infection, treatment to eradicate the parasite should be administered. The drug of choice is praziquantel, which—depending on the infecting species (Table 126-2)—is administered PO as a total of 40 or 60 mg/kg in two or three doses over a single day. Praziquantel treatment results in parasitologic cure in ∼85% of cases and reduces egg counts by >90%. Few side effects have been encountered, and those that do develop usually do not interfere with completion of treatment. Dependence on a single chemotherapeutic agent has raised the possibility of development of resistance in schistosomes; to date, such resistance does not seem to be clinically significant. The effect of antischistosomal treatment on disease manifestations varies by stage. Early hepatomegaly and bladder lesions are known to resolve after chemotherapy, but the late established manifestations, such as fibrosis, do not recede. Additional management modalities are needed for individuals with other manifestations, such as hepatocellular failure or recurrent hematemesis. The use of these interventions is guided by general medical and surgical principles.

PREVENTION AND CONTROL Transmission of schistosomiasis is dependent on human behavior. Since the geographic distribution of infections in endemic regions of the world

TABLE 126-2 DRUG THERAPY FOR HUMAN TREMATODE INFECTIONS INFECTION

DRUG OF CHOICE

ADULT DOSE AND DURATION

Praziquantel

20 mg/kg, 2 doses in 1 day

Praziquantel


Blood Flukes S. mansoni, S. intercalatum, S. haematobium S. japonicum, S. mekongi

Biliary (Hepatic) Flukes C. sinensis, O. viverrini, O. felineus F. hepatica, F. gigantica


Triclabendazole

10 mg/kg once

Praziquantel


Praziquantel

25 mg/kg, 3 doses per day for 2 days

Intestinal Flukes F. buski, H. heterophyes Lung Flukes P. westermani

LIVER (BILIARY) FLUKES Several species of biliary fluke infecting humans are particularly common in Southeast Asia and Russia. Other species are transmitted in Europe, Africa, and the Americas. On the basis of their migratory

FASCIOLIASIS Infections with Fasciola hepatica and F. gigantica are worldwide zoonoses that are particularly endemic in sheep-raising countries. Human cases have been reported in South America, Europe,Africa,Australia, and the Far East. Recent estimates indicate a worldwide prevalence of 17 million cases. High endemicity has been reported in certain areas of Peru and Bolivia. In most endemic areas the predominant species is F. hepatica, but in Asia and Africa a varying degree of overlap with F. gigantica has been observed. Humans acquire fascioliasis by ingestion of metacercariae attached to certain aquatic plants, such as watercress. Infection may also be acquired by consumption of contaminated water or ingestion of food items washed with such water. Acquisition of human infection through consumption of freshly prepared raw liver containing immature flukes has been reported. Infection is initiated when metacercariae excyst, penetrate the gut wall, and travel through the peritoneal cavity to invade the liver capsule. Adult worms finally reach bile ducts,


is not clearly demarcated, it is prudent for travelers to avoid contact with all freshwater bodies, irrespective of the speed of water flow or unsubstantiated claims of safety. Some topical agents, when applied to skin, may inhibit cercarial penetration, but none is currently available. If exposure occurs, a follow-up visit with a health care provider is strongly recommended. Prevention of infection in inhabitants of endemic areas is a significant challenge. Residents of these regions use freshwater bodies for sanitary, domestic, recreational, and agricultural purposes. Several control measures have been used, including application of molluscicides, provision of sanitary water and sewage disposal, chemotherapy, and health education. Current recommendations to countries endemic for schistosomiasis emphasize the use of multiple approaches. With the advent of an oral, safe, and effective antischistosomal agent, chemotherapy has been most successful in reducing intensity of infection and reversing disease. The duration of this positive impact depends on transmission dynamics of the parasite in any specific endemic region.The ultimate goal of research on prevention and control is development of a vaccine. Although there are a few promising leads, this goal is probably not within reach during the next decade or so.

CLONORCHIASIS AND OPISTHORCHIASIS Infection with Clonorchis sinensis, the Chinese or oriental fluke, is endemic among fish-eating mammals in Southeast Asia. Humans are an incidental host; the prevalence of human infection is highest in China, Vietnam, and Korea. Infection with Opisthorchis viverrini and O. felineus is zoonotic in cats and dogs. Transmission to humans occurs occasionally, particularly in Thailand (O. viverrini) and in Southeast Asia and eastern Europe (O. felineus). Data on the exact geographic distribution of these infectious agents in human populations are rudimentary. Infection with any of these three species is established by ingestion of raw or inadequately cooked freshwater fish harboring metacercariae. These organisms excyst in the duodenum, releasing larvae that travel through the ampulla of Vater and mature into adult worms in bile canaliculi. Mature flukes are flat and elongated, measuring 1–2 cm in length. The hermaphroditic worms reproduce by releasing small operculated eggs, which pass with bile into the intestines and are voided with stools. The life cycle is completed in the environment in specific freshwater snails (the first intermediate host) and encystment of metacercariae in freshwater fish. Except for late sequelae, the exact clinical syndromes caused by clonorchiasis and opisthorchiasis are not well defined. Since most infected individuals harbor a low worm burden, many are asymptomatic. Moderate to heavy infection may be associated with vague right-upper-quadrant pain. In contrast, chronic or repeated infection is associated with manifestations such as cholangitis, cholangiohepatitis, and biliary obstruction. Cholangiocarcinoma is epidemiologically related to C. sinensis infection in China and to O. viverrini infection in northeastern Thailand.This association has resulted in classification of these infectious agents as human carcinogens.

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CHAPTER 126

Praziquantel

pathway in humans, these infections may be divided into the Clonorchis and Fasciola groups (Table 126-1).

1162 where they produce large operculated eggs, which are

voided in bile through the gastrointestinal tract to the outside environment. The flukes’ life cycle is completed in specific snails (the first intermediate host) and encystment on aquatic plants. Clinical features of fascioliasis relate to the stage and intensity of infection. Acute disease develops during parasite migration (1–2 weeks after infection) and includes fever, right-upper-quadrant pain, hepatomegaly, and eosinophilia. CT of the liver may show migratory tracks. Symptoms and signs usually subside as the parasites reach their final habitat. In individuals with chronic infection, bile duct obstruction and biliary cirrhosis are infrequently demonstrated. No relation to hepatic malignancy has been ascribed to fascioliasis.

DIAGNOSIS Diagnosis of infection with any of the biliary flukes depends on a high degree of suspicion, elicitation of an appropriate geographic history, and stool examination for characteristically shaped parasite ova. Additional evidence may be obtained by documenting peripheral blood eosinophilia or imaging the liver. Serologic testing is helpful, particularly in lightly infected individuals.

SECTION VIII

Treatment: BILIARY FLUKES

Drug therapy (praziquantel or triclabendazole) is summarized in Table 126-2. Patients with anatomic lesions in the biliary tract or malignancy are managed according to general medical guidelines.


INTESTINAL FLUKES Two species of intestinal flukes cause human infection in defined geographic areas worldwide (Table 126-1). The large Fasciolopsis buski (adults measure 2 × 7 cm) is endemic in Southeast Asia, while the smaller Heterophyes heterophyes is found in the Nile Delta of Egypt and in the Far East. Infection is initiated by ingestion of metacercariae attached to aquatic plants (F. buski) or encysted in freshwater or brackish-water fish (H. heterophyes). Flukes mature in human intestines, and eggs are passed with stools. Most individuals infected with intestinal flukes are asymptomatic. In heavy F. buski infection, diarrhea, abdominal pain, and malabsorption may be encountered. Heavy infection with H. heterophyes may be associated with abdominal pain and mucous diarrhea. Diagnosis is established by detection of characteristically shaped ova in stool samples. The drug of choice for treatment is praziquantel (Table 126-2).

LUNG FLUKES Infection with the lung fluke Paragonimus westermani (Table 126-1) and related species (e.g., P. africanus) is endemic in many parts of the

world, excluding North America and Europe. Endemicity is particularly noticeable in West Africa, Central and South America, and Asia. In nature, the reservoir hosts of P. westermani are wild and domestic felines. In Africa, P. africanus has been found in other species, such as dogs. Adult lung flukes, which are 7–12 mm in length, are found encapsulated in the lungs of infected persons. In rare circumstances, flukes are found encysted in the CNS (cerebral paragonimiasis) or abdominal cavity. Humans acquire lung fluke infection by ingesting infective metacercariae encysted in the muscles and viscera of crayfish and freshwater crabs. In endemic areas, these crustaceans are consumed either raw or pickled. Once the organisms reach the duodenum, they excyst, penetrate the gut wall, and travel through the peritoneal cavity, diaphragm, and pleural space to reach the lungs. Mature flukes are found in the bronchioles surrounded by cystic lesions. Parasite eggs are either expectorated with sputum or swallowed and passed to the outside environment with feces. The life cycle is completed in snails and freshwater crustacea. When maturing flukes lodge in lung tissues, they cause hemorrhage and necrosis, resulting in cyst formation. The adjacent lung parenchyma shows evidence of inflammatory infiltration, predominantly by eosinophils. Cysts usually measure 1–2 cm in diameter and may contain one or two worms each. With the onset of oviposition, cysts usually rupture in adjacent bronchioles—an event allowing ova to exit the human host. Older cysts develop thickened walls, which may undergo calcification. During the active phase of paragonimiasis, lung tissues surrounding parasite cysts may contain evidence of pneumonia, bronchitis, bronchiectasis, and fibrosis. Pulmonary paragonimiasis is particularly symptomatic in persons with moderate to heavy infection. Productive cough with brownish sputum or frank hemoptysis associated with peripheral blood eosinophilia is usually the presenting feature. Chest examination may reveal signs of pleurisy. In chronic cases, bronchitis or bronchiectasis may predominate, but these conditions rarely proceed to lung abscess. Imaging of the lungs demonstrates characteristic features, including patchy densities, cavities, pleural effusion, and ring shadows. Cerebral paragonimiasis presents as either space-occupying lesions or epilepsy.

DIAGNOSIS Pulmonary paragonimiasis is diagnosed by detection of parasite ova in sputum and/or stools. Serology is of considerable help in egg-negative cases and in cerebral paragonimiasis. Treatment: LUNG FLUKES

The drug of choice for treatment is praziquantel (Table 126-2). Other medical or surgical management may be needed for pulmonary or cerebral lesions.

CONTROL AND PREVENTION OF TISSUE FLUKES

FURTHER READINGS

CHAPTER 127

CESTODES A. Clinton White, Jr. Cestodes, or tapeworms, are segmented worms.The adults reside in the gastrointestinal tract, but the larvae can be found in almost any organ. Human tapeworm infections can be divided into two major clinical groups. In one group, humans are the definitive hosts, with the adult tapeworms living in the gastrointestinal tract (Taenia saginata, Diphyllobothrium, Hymenolepis, and Dipylidium caninum). In the other, humans are intermediate hosts, with larval-stage parasites present in the tissues; diseases in this category include echinococcosis, sparganosis, and

Peter F. Weller

coenurosis. For Taenia solium, the human may be either the definitive or the intermediate host. The ribbon-shaped tapeworm attaches to the intestinal mucosa by means of sucking cups or hooks located on the scolex. Behind the scolex is a short, narrow neck from which proglottids (segments) form. As each proglottid matures, it is displaced further back from the neck by the formation of new, less mature segments.The progressively elongating chain of attached proglottids, called the strobila, constitutes the bulk of the tapeworm.

Cestodes

ALVES OLIVEIRA LF et al: Cytokine production associated with peripheral fibrosis during chronic schistosomiasis mansoni in humans. Infect Immun 74:1215, 2006 CAFFREY CR: Chemotherapy of schistosomiasis: Present and future. Curr Opin Chem Biol 11:433, 2007

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For residents of nonendemic areas who are visiting an endemic region, the only effective preventive measure is to avoid ingestion of local plants, fish, or crustaceans; if their ingestion is necessary, these items should be washed or cooked thoroughly. Instruction on water and food preparation and consumption should be included in physicians’ advice to travelers (Chap. 4). Interruption of transmission among residents of endemic areas depends on avoiding ingestion of infective stages and disposing of feces and sputum appropriately to prevent hatching of eggs in the environment. These two approaches rely greatly on socioeconomic development and health education. In countries where economic progress has resulted in financial and social improvements, transmission has decreased.The third approach to control in endemic communities entails selective use of chemotherapy for individuals posing the highest risk of transmission—i.e., those with heavy infections.The availability of praziquantel—a broad-spectrum, safe, and effective anthelmintic agent—provides a means for reducing the reservoirs of infection in human populations. However, the existence of most of these helminths as zoonoses in several animal species complicates control efforts.

CENTERS FOR DISEASE CONTROL AND PREVENTION: http://www. cdc.gov/ncidod/dpd DOENHOFF MJ et al: Praziquantel: Mechanisms of action, resistance and new derivatives for schistosomiasis. Curr Opin Infect Dis 21:659, 2008 Drugs for Parasitic Infections. Med Lett Drugs Ther, August 1, 2004 JIA TW et al:Assessment of the age-specific disability weight of chronic schistosomiasis japonica. Bull World Health Organ 85:458, 2007 KALLESTRUP P et al: Schistosomiasis and HIV-1 infection in rural Zimbabwe: Effect of treatment of schistosomiasis on CD4 cell count and plasma HIV-1 RNA load. J Infect Dis 192:1956, 2005 KING CH: Lifting the burden of schistosomiasis—defining elements of infection-associated disease and the benefits of antiparasite treatment. J Infect Dis 196:653, 2007 LAPA M et al: Cardiopulmonary manifestations of hepatosplenic schistosomiasis. Circulation 119:1518, 2009 LESHEM E et al: Acute schistosomiasis outbreak: Clinical features and economic impact. Clin Infect Dis 47:1499, 2008 LIM JH et al: Parasitic diseases of the biliary tract. AJR Am J Roentgenol 188:1596, 2007 LUN ZR et al: Clonorchiasis: A key foodborne zoonosis in China. Lancet Infect Dis 5:31, 2005 MAHMOUD AAFM (ed): Schistosomiasis, in Tropical Medicine: Science and Practice, G Pasvol, S Hoffman (eds). London, Imperial College Press, 2001, pp 1–510 NICOLLS DJ et al: Characteristics of schistosomiasis in travelers reported to the GeoSentinel Surveillance Network 1997–2008. Am J Trop Med Hyg 79:729, 2008 STAUFFER WM et al: Biliary liver flukes (opisthorchiasis and clonorchiasis) in immigrants in the United States: Often subtle and diagnosed years after arrival. J Travel Med 11:157, 2004 Toward the elimination of schistosomiasis. N Engl J Med 360:106, 2009 WANG LD et al: A strategy to control transmission of Schistosoma japonicum in China. N Engl J Med 360:121, 2009

1164 The length varies among species. In some, the tape-

worm may consist of more than 1000 proglottids and may be several meters long. The mature proglottids are hermaphroditic and produce eggs, which are subsequently released. Since eggs of the different Taenia species are morphologically identical, differences in the morphology of the scolex or proglottids provide the basis for diagnostic identification to the species level. Most human tapeworms require at least one intermediate host for complete larval development. After ingestion of the eggs or proglottids by an intermediate host, the larval oncospheres are activated, escape the egg, and penetrate the intestinal mucosa. The oncosphere migrates to tissues and develops into an encysted form known as a cysticercus (single scolex), a coenurus (multiple scolices), or a hydatid (cyst with daughter cysts, each containing several protoscolices). Ingestion by the definitive host of tissues containing a cyst enables a scolex to develop into a tapeworm.

SECTION VIII

TAENIASIS SAGINATA The beef tapeworm T. saginata occurs in all countries where raw or undercooked beef is eaten. It is most prevalent in sub-Saharan African and Middle Eastern countries. T. saginata asiatica is a variant of T. saginata that is found in Asia and for which pigs are the intermediate host.


Etiology and Pathogenesis Humans are the only definitive host for the adult stage of T. saginata. This tapeworm, which can reach 8 m in length, inhabits the upper jejunum and has a scolex with four prominent suckers and 1000–2000 proglottids. Each gravid segment has 15–30 uterine branches (in contrast to 8–12 for T. solium). The eggs are indistinguishable from those of T. solium; they measure 30–40 µm, contain the oncosphere, and have a thick brown striated shell. Eggs deposited on vegetation can live for months or years until they are ingested by cattle or other herbivores. The embryo released after ingestion invades the intestinal wall and is carried to striated muscle, where it transforms into a cysticercus. When ingested in raw or undercooked beef, this form can infect humans. After the cysticercus is ingested, it takes ∼2 months for the mature adult worm to develop. Clinical Manifestations Patients become aware of the infection most commonly by noting passage of proglottids in their feces.The proglottids are often motile, and patients may experience perianal discomfort when proglottids are discharged. Mild abdominal pain or discomfort,nausea,change in appetite,weakness,and weight loss can occur with T.saginata infection. Diagnosis The diagnosis is made by the detection of eggs or proglottids in the stool. Eggs may also be present in the perianal area; thus, if proglottids or eggs are not found in the stool, the perianal region should be examined with

use of a cellophane-tape swab (as in pinworm infection; Chap. 124). Distinguishing T. saginata from T. solium requires examination of mature proglottids or the scolex. Serologic tests are not helpful diagnostically. Eosinophilia and elevated levels of serum IgE may be detected.

Treatment: TAENIASIS SAGINATA

A single dose of praziquantel (10 mg/kg) is highly effective.

Prevention The major method of preventing infection is the adequate cooking of beef; exposure to temperatures as low as 56°C for 5 min will destroy cysticerci. Refrigeration or salting for long periods or freezing at –10°C for 9 days also kills cysticerci in beef. General preventive measures include inspection of beef and proper disposal of human feces.

TAENIASIS SOLIUM AND CYSTICERCOSIS The pork tapeworm T. solium can cause two distinct forms of infection in humans: adult tapeworms in the intestine or larval forms in the tissues (cysticercosis). Humans are the only definitive hosts for T. solium; pigs are the usual intermediate hosts, although other animals may harbor the larval forms. T. solium exists worldwide but is most prevalent in Latin America, sub-Saharan Africa, China, southern and Southeast Asia, and eastern Europe. Cysticercosis occurs in industrialized nations largely as a result of the immigration of infected persons from endemic areas. Etiology and Pathogenesis The adult tapeworm generally resides in the upper jejunum. The scolex attaches by both sucking disks and two rows of hooklets. Often only one adult worm is present, but that worm may live for years. The tapeworm, usually ∼3 m in length, may have as many as 1000 proglottids, each of which produces up to 50,000 eggs. Groups of 3–5 proglottids are generally released and excreted into the feces, and the eggs in these proglottids are infective for both humans and animals. The eggs may survive in the environment for several months. After ingestion of eggs by the pig intermediate host, the larvae are activated, escape the egg, penetrate the intestinal wall, and are carried to many tissues, with a predilection for striated muscle of the neck, tongue, and trunk. Within 60–90 days, the encysted larval stage develops. These cysticerci can survive for months to years. By ingesting undercooked pork containing cysticerci, humans acquire infections that lead to intestinal tapeworms. Infections that cause human cysticercosis follow the ingestion of T. solium eggs, usually from close contact with a tapeworm carrier. Autoinfection may

1165

A

B

FIGURE 127-1 Neurocysticercosis is caused by Taenia solium. Neurologic infection can be classified on the basis of the location and viability of the parasites. When the parasites are in the ventricles, they often cause obstructive hydrocephalus. A. MRI showing a cysticercus in the lateral ventricle, with resultant hydrocephalus. The arrow points to the scolex within the cystic parasite. B. CT showing a parenchymal cysticercus,

occur if an individual with an egg-producing tapeworm ingests eggs derived from his or her own feces.

demonstration of the parasite (absolute criteria).This task can be accomplished by histologic observation of the parasite in excised tissue, by funduscopic visualization of the parasite in the eye (in the anterior chamber, vitreous, or subretinal spaces), or by neuroimaging studies demonstrating cystic lesions containing a characteristic scolex. In most cases, diagnostic certainty is not possible. Instead, a clinical diagnosis is made on the basis of a combination of clinical presentation, radiographic studies, serologic tests, and exposure history. Neuroimaging findings suggestive of neurocysticercosis constitute the primary major diagnostic criterion. These findings include cystic lesions with or without enhancement (e.g., ring enhancement), one or more nodular calcifications (which may also have associated enhancement), or focal enhancing lesions. Cysticerci in the brain parenchyma are usually 5–20 mm in diameter and rounded. Cystic lesions in the subarachnoid space or fissures may enlarge up to 6 cm in diameter and may be lobulated. For cysticerci within the subarachnoid space or ventricles, the walls may be very thin and the cyst fluid is often isodense with CSF. Thus, obstructive hydrocephalus or enhancement of the basilar meninges may be the only finding on CT in extraparenchymal neurocysticercosis. Cysticerci in the ventricles or subarachnoid space are usually visible to an experienced neuroradiologist on MRI or on CT with intraventricular contrast injection. CT is more sensitive than MRI in identifying calcified lesions, whereas MRI is better for identifying cystic lesions and enhancement. The second major diagnostic criterion is detection of specific antibodies to cysticerci. While most tests employing unfractionated antigen have high rates of false-positive and false-negative results, this problem can be overcome by using the more specific immunoblot assay. An immunoblot assay using lentil-lectin purified glycoproteins has >99% specificity and is highly sensitive. However,

Cestodes

Diagnosis The diagnosis of intestinal T. solium infection is made by the detection of eggs or proglottids, as described for T. saginata. In cysticercosis, diagnosis can be difficult. A consensus conference has delineated absolute, major, minor, and epidemiologic criteria for diagnosis (Table 127-1). Diagnostic certainty is possible only with definite

with enhancement of the cyst wall and an internal scolex (arrow). C. Multiple cysticerci, including calcified lesions from prior infection (arrowheads), viable cysticerci in the basilar cisterns (white arrow), and a large degenerating cysticercus in the Sylvian fissure (black arrow). (Modified with permission from JC Bandres et al: Clin Infect Dis 15:799, 1992. © The University of Chicago Press.)

CHAPTER 127

Clinical Manifestations Intestinal infections with T. solium may be asymptomatic. Fecal passage of proglottids may be noted by patients. Other symptoms are infrequent. In cysticercosis, the clinical manifestations are variable. Cysticerci can be found anywhere in the body but are most commonly detected in the brain, cerebrospinal fluid (CSF), skeletal muscle, subcutaneous tissue, or eye. The clinical presentation of cysticercosis depends on the number and location of cysticerci as well as the extent of associated inflammatory responses or scarring. Neurologic manifestations are the most common (Fig. 127-1). Seizures are associated with inflammation surrounding cysticerci in the brain parenchyma.These seizures may be generalized, focal, or Jacksonian. Hydrocephalus results from obstruction of CSF flow by cysticerci and accompanying inflammation or by CSF outflow obstruction from arachnoiditis. Signs of increased intracranial pressure, including headache, nausea, vomiting, changes in vision, dizziness, ataxia, or confusion, are often evident. Patients with hydrocephalus may develop papilledema or display altered mental status. When cysticerci develop at the base of the brain or in the subarachnoid space, they may cause chronic meningitis or arachnoiditis, communicating hydrocephalus, or strokes.

C

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TABLE 127-1 DIAGNOSTIC CRITERIA FOR HUMAN CYSTICERCOSISa

SECTION VIII

1. Absolute criteria a. Demonstration of cysticerci by histologic or microscopic examination of biopsy material b. Visualization of the parasite in the eye by funduscopy c. Neuroradiologic demonstration of cystic lesions containing a characteristic scolex 2. Major criteria a. Neuroradiologic lesions suggestive of neurocysticercosis b. Demonstration of antibodies to cysticerci in serum by enzyme-linked immunoelectrotransfer blot c. Resolution of intracranial cystic lesions spontaneously or after therapy with albendazole or praziquantel alone 3. Minor criteria a. Lesions compatible with neurocysticercosis detected by neuroimaging studies b. Clinical manifestations suggestive of neurocysticercosis c. Demonstration of antibodies to cysticerci or cysticercal antigen in cerebrospinal fluid by ELISA d. Evidence of cysticercosis outside the central nervous system (e.g., cigar-shaped soft tissue calcifications) 4. Epidemiologic criteria a. Residence in a cysticercosis-endemic area b. Frequent travel to a cysticercosis-endemic area c. Household contact with an individual infected with Taenia solium a


Diagnosis is confirmed by either one absolute criterion or a combination of two major criteria, one minor criterion, and one epidemiologic criterion. A probable diagnosis is supported by the fulfillment of (1) one major criterion plus two minor criteria; (2) one major criterion plus one minor criterion and one epidemiologic criterion; or (3) three minor criteria plus one epidemiologic criterion. Note: ELISA, enzyme-linked immunosorbent assay. Source: Modified from Del Brutto et al.

patients with single intracranial lesions or with calcifications may be seronegative. With this assay, serum samples provide greater diagnostic sensitivity than CSF. All of the diagnostic antigens have been cloned, and enzyme-linked immunosorbent assays (ELISAs) using recombinant antigens are being developed. Antigen detection assays employing monoclonal antibodies to detect parasite antigen in the blood or spinal fluid may also facilitate diagnosis. However, these assays are not widely available. Studies have demonstrated that clinical criteria can aid in the diagnosis in selected cases. In patients from endemic areas who had single enhancing lesions presenting with seizures, a normal physical examination, and no evidence of systemic disease (e.g., no fever, adenopathy, or abnormal chest radiograph), the constellation of rounded CT lesions 5–20 mm in diameter with no midline shift was almost always caused by neurocysticercosis. Finally, spontaneous resolution or resolution after therapy with albendazole alone is consistent with neurocysticercosis.

Minor diagnostic criteria include neuroimaging findings consistent with but less characteristic of cysticercosis, clinical manifestations suggestive of neurocysticercosis (e.g., seizures, hydrocephalus, or altered mental status), evidence of cysticercosis outside the central nervous system (CNS; e.g., cigar-shaped soft tissue calcifications), or detection of antibody in CSF by ELISA. Epidemiologic criteria include exposure to a tapeworm carrier or household member infected with T. solium, current or prior residence in an endemic area, and frequent travel to an endemic area. Diagnosis is confirmed in patients with either one absolute criterion or a combination of two major criteria, one minor criterion, and one epidemiologic criterion (Table 127-1). A probable diagnosis is supported by the fulfillment of (1) one major criterion plus two minor criteria; (2) one major criterion plus one minor criterion and one epidemiologic criterion; or (3) three minor criteria plus one epidemiologic criterion. While the CSF is usually abnormal in neurocysticercosis, CSF abnormalities are not pathognomonic. Patients may have CSF pleocytosis with a predominance of lymphocytes, neutrophils, or eosinophils. The protein level in CSF may be elevated; the glucose concentration is usually normal but may be depressed. Treatment: TAENIASIS SOLIUM AND CYSTICERCOSIS

Intestinal T. solium infection is treated with a single dose of praziquantel (10 mg/kg). However, praziquantel occasionally evokes an inflammatory response in the CNS if concomitant cryptic cysticercosis is present. Niclosamide (2 g) is also effective but is not widely available. The initial management of neurocysticercosis should focus on symptom-based treatment of seizures or hydrocephalus. Seizures can usually be controlled with antiepileptic treatment. If parenchymal lesions resolve without development of calcifications and patients remain free of seizures, antiepileptic therapy can usually be discontinued after 1–2 years. Placebo-controlled trials are beginning to clarify the clinical advantage of antiparasitic drugs for parenchymal neurocysticercosis. Trends toward faster resolution of neuroradiologic abnormalities have been observed in most studies. The clinical benefits are less dramatic and consist mainly of shortening the period during which recurrent seizures occur and decreasing the number of patients who have many recurrent seizures. For the treatment of patients with brain parenchymal cysticerci, most authorities favor antiparasitic drugs, including praziquantel (50–60 mg/kg daily in three divided doses for 15–30 days) or albendazole (15 mg/kg per day for 8–28 days). Both agents may exacerbate the inflammatory response around the dying parasite, thereby exacerbating seizures or hydrocephalus as well. Thus, patients receiving these drugs should be carefully monitored, and high-dose glucocorticoids should be used during treatment. Since glucocorticoids induce first-pass metabolism of praziquantel

ECHINOCOCCOSIS Echinococcosis is an infection caused in humans by the larval stage of the Echinococcus granulosus complex, E. multilocularis, or E. vogeli. E. granulosus complex parasites, which produce unilocular cystic lesions, are prevalent in areas where livestock is raised in association with dogs. These parasites are found on all continents, with areas of high prevalence in China, central Asia, the Middle East, the Mediterranean region, eastern Africa, and parts of South America. Molecular evidence suggests that E. granulosus strains may actually belong to more than one species; specifically, strains from sheep, cattle, pigs, horses, and camels probably represent separate species. E. multilocularis, which causes multilocular alveolar lesions that are locally invasive, is found in Alpine, sub-Arctic, or Arctic regions, including Canada, the United States, and central and northern Europe; China; and central Asia.

Etiology The small (5-mm-long) adult E. granulosus worm, which lives for 5–20 months in the jejunum of dogs, has only three proglottids: one immature, one mature, and one gravid. The gravid segment splits to release eggs that are morphologically similar to Taenia eggs and are extremely hardy. After humans ingest the eggs, embryos escape from the eggs, penetrate the intestinal mucosa, enter the portal circulation, and are carried to various organs, most commonly the liver and lungs. Larvae develop into fluid-filled unilocular hydatid cysts that consist of an external membrane and an inner germinal layer. Daughter cysts develop from the inner aspect of the germinal layer, as do germinating cystic structures called brood capsules. New larvae, called protoscolices, develop in large numbers within the brood capsule.The cysts expand slowly over a period of years. The life cycle of E. multilocularis is similar except that wild canines, such as foxes, serve as the definitive hosts and small rodents serve as the intermediate hosts.The larval form of E. multilocularis, however, is quite different in that it remains in the proliferative phase, the parasite is always multilocular, and vesicles without brood capsule or protoscolices progressively invade the host tissue by peripheral extension of processes from the germinal layer. Clinical Manifestations Slowly enlarging echinococcal cysts generally remain asymptomatic until their expanding size or their spaceoccupying effect in an involved organ elicits symptoms. The liver and the lungs are the most common sites of these cysts. The liver is involved in about two-thirds of E. granulosus infections and in nearly all E. multilocularis infections. Since a period of years elapses before cysts enlarge sufficiently to cause symptoms, they may be discovered incidentally on a routine x-ray or ultrasound study. Patients with hepatic echinococcosis who are symptomatic most often present with abdominal pain or a palpable mass in the right upper quadrant. Compression of a bile duct or leakage of cyst fluid into the biliary tree may mimic recurrent cholelithiasis, and biliary obstruction can result in jaundice. Rupture of or episodic leakage from a hydatid cyst may produce fever, pruritus, urticaria, eosinophilia, or anaphylaxis. Pulmonary hydatid cysts may rupture into the bronchial tree or peritoneal cavity and produce cough, dyspnea, chest pain, or hemoptysis. Rupture of hydatid cysts, which can occur spontaneously

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Cestodes

Prevention Measures for the prevention of intestinal T. solium infection consist of the application to pork of precautions similar to those described above for beef with regard to T. saginata infection. The prevention of cysticercosis involves minimizing the opportunities for ingestion of fecally derived eggs by means of good personal hygiene, effective fecal disposal, and treatment and prevention of human intestinal infections. Mass chemotherapy has been administered to human and porcine populations in efforts at disease eradication.

E. vogeli causes polycystic hydatid disease and is found only in Central and South America. Like other cestodes, echinococcal species have both intermediate and definitive hosts. The definitive hosts are canines that pass eggs in their feces. After the ingestion of eggs, cysts develop in the intermediate hosts— sheep, cattle, humans, goats, camels, and horses for the E. granulosus complex and mice and other rodents for E. multilocularis. When a dog (E. granulosus) or fox (E. multilocularis) ingests infected meat containing cysts, the life cycle is completed.

CHAPTER 127

and may decrease its antiparasitic effect, cimetidine should be coadministered to inhibit praziquantel metabolism. For patients with hydrocephalus, the emergent reduction of intracranial pressure is the mainstay of therapy. In the case of obstructive hydrocephalus, the preferred approach is removal of the cysticercus via endoscopic surgery. However, this intervention is not always possible. An alternative approach is initially to perform a diverting procedure, such as ventriculoperitoneal shunting. Historically, shunts have usually failed, but low failure rates have been attained with administration of antiparasitic drugs and glucocorticoids. Open craniotomy to remove cysticerci is now required only infrequently. For patients with subarachnoid cysts or giant cysticerci, glucocorticoids are needed to reduce arachnoiditis and accompanying vasculitis. Most authorities recommend prolonged courses of antiparasitic drugs and shunting when hydrocephalus is present. In patients with diffuse cerebral edema and elevated intracranial pressure due to multiple inflamed lesions, glucocorticoids are the mainstay of therapy, and antiparasitic drugs should be avoided. For ocular and spinal medullary lesions, drug-induced inflammation may cause irreversible damage. Most patients should be managed surgically, although case reports have described cures with medical therapy.

1168 or at surgery, may lead to multifocal dissemination of

protoscolices, which can form additional cysts. Other presentations are due to the involvement of bone (invasion of the medullary cavity with slow bone erosion producing pathologic fractures), the CNS (space-occupying lesions), the heart (conduction defects, pericarditis), and the pelvis (pelvic mass). The larval forms of E. multilocularis characteristically present as a slowly growing hepatic tumor, with progressive destruction of the liver and extension into vital structures. Patients commonly report upper quadrant and epigastric pain. Liver enlargement and obstructive jaundice may be apparent. The lesions may infiltrate adjoining organs (e.g., diaphragm, kidneys, or lungs) or may metastasize to the spleen, lungs, or brain.

SECTION VIII

Diagnosis Radiographic and related imaging studies are important in detecting and evaluating echinococcal cysts. Plain films will define pulmonary cysts of E. granulosus—usually as rounded masses of uniform density—but may miss cysts in other organs unless there is cyst wall calcification (as occurs in the liver). MRI, CT, and ultrasound reveal well-defined cysts with thick or thin walls. When older cysts contain a layer of hydatid sand that is rich in accumulated protoscolices, these imaging methods may detect this fluid layer of different density. However, the most pathognomonic finding, if demonstrable, is that of daughter cysts within the larger cyst. This finding, like eggshell or mural calcification on CT, is indicative of

E. granulosus infection and helps to distinguish the cyst from carcinomas, bacterial or amebic liver abscesses, or hemangiomas. In contrast, ultrasound or CT of alveolar hydatid cysts reveals indistinct solid masses with central necrosis and plaquelike calcifications. A specific diagnosis of E. granulosus infection can be made by the examination of aspirated fluids for protoscolices or hooklets, but diagnostic aspiration is not usually recommended because of the risk of fluid leakage resulting in either dissemination of infection or anaphylactic reactions. Serodiagnostic assays can be useful, although a negative test does not exclude the diagnosis of echinococcosis. Cysts in the liver elicit positive antibody responses in ∼90% of cases, whereas up to 50% of individuals with cysts in the lungs are seronegative. Detection of antibody to specific echinococcal antigens by immunoblotting has the highest degree of specificity.

Treatment: ECHINOCOCCOSIS

Therapy for cystic echinococcosis is based on considerations of the size, location, and manifestations of cysts and the overall health of the patient. Surgery has traditionally been the principal definitive method of treatment. Currently, ultrasound staging is recommended for E. granulosus infections (Fig. 127-2). For CE1 lesions, uncomplicated CE3 lesions, and some CE2 lesions, PAIR (percutaneous aspiration, infusion of scolicidal agents,

Protozoal and Helminthic Infections FIGURE 127-2 Management of cystic hydatid disease caused by Echinococcus granulosus should be based on viability of the parasite, which can be estimated from radiographic appearance. The ultrasound appearance includes lesions classified as active, transitional, and inactive. Active cysts include types CL (with a cystic lesion and no visible cyst wall), CE1 [with a visible cyst wall and internal echoes (snowflake sign)], and CE2 (with a

visible cyst wall and internal septation). Transitional cysts (CE3) may have detached laminar membranes or may be partially collapsed. Inactive cysts include types CE4 (a nonhomogeneous mass) and CE5 (a cyst with a thick calcified wall). [Adapted from RL Guerrant et al (eds): Tropical Infectious Diseases: Principles, Pathogens and Practice, 2d ed, p 1312. © 2005, with permission from Elsevier Science.]

resection is not possible; in these cases, albendazole treatment should be continued indefinitely, with careful monitoring. In some cases, liver transplantation has been used because of the size of the necessary liver resection. However, continuous immunosuppression favors the proliferation of E. multilocularis larvae and reinfection of the transplant. Thus, indefinite treatment with albendazole is required.

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Prevention In endemic areas, echinococcosis can be prevented by administering praziquantel to infected dogs, by denying dogs access to infected animals, or by vaccinating sheep. Limitation of the number of stray dogs is helpful in reducing the prevalence of infection among humans.

HYMENOLEPIASIS NANA Infection with Hymenolepis nana, the dwarf tapeworm, is the most common of all the cestode infections. H. nana is endemic in both temperate and tropical regions of the world. Infection is spread by fecal/oral contamination and is common among institutionalized children.

Clinical Manifestations H. nana infection, even with many intestinal worms, is usually asymptomatic.When infection is intense, anorexia, abdominal pain, and diarrhea develop. Diagnosis Infection is diagnosed by the finding of eggs in the stool.

Cestodes

Etiology and Pathogenesis H. nana is the only cestode of humans that does not require an intermediate host. Both the larval and adult phases of the life cycle take place in the human. The adult—the smallest tapeworm parasitizing humans—is ∼2 cm long and dwells in the proximal ileum. Proglottids, which are quite small and are rarely seen in the stool, release spherical eggs 30–44 µm in diameter, each of which contains an oncosphere with six hooklets. The eggs are immediately infective and are unable to survive for >10 days in the external environment. H. nana can also be acquired by the ingestion of infected insects (especially larval meal-worms and larval fleas). When the egg is ingested by a new host, the oncosphere is freed and penetrates the intestinal villi, becoming a cysticercoid larva. Larvae migrate back into the intestinal lumen, attach to the mucosa, and mature into adult worms over 10–12 days. Eggs may also hatch before passing into the stool, causing internal autoinfection with increasing numbers of intestinal worms. Although the life span of adult H. nana worms is only ∼4–10 weeks, the autoinfection cycle perpetuates the infection.

CHAPTER 127

and reaspiration) is now recommended instead of surgery. PAIR is contraindicated for superficially located cysts (because of the risk of rupture), for cysts with multiple thick internal septal divisions (honeycombing pattern), and for cysts communicating with the biliary tree. For prophylaxis of secondary peritoneal echinococcosis due to inadvertent spillage of fluid during PAIR, the administration of albendazole (15 mg/kg daily in two divided doses) should be initiated at least 4 days before the procedure and continued for at least 4 weeks afterward. Ultrasound- or CT-guided aspiration allows confirmation of the diagnosis by demonstration of protoscolices in the aspirate. After aspiration, contrast material should be injected to detect occult communications with the biliary tract. Alternatively, the fluid should be checked for bile staining by dipstick. If no bile is found and no communication visualized, the contrast material is reaspirated, with subsequent infusion of scolicidal agents (usually 95% ethanol; alternatively, hypertonic saline). Daughter cysts within the primary cyst may need to be punctured separately. In experienced hands, this approach yields rates of cure and relapse equivalent to those following surgery, with less perioperative morbidity and shorter hospitalization. Surgery remains the treatment of choice for complicated E. granulosus cysts (e.g., those communicating with the biliary tract) or for areas where PAIR is not possible. For E. granulosus, the preferred surgical approach is pericystectomy, in which the entire cyst and the surrounding fibrous tissue are removed. The risks posed by leakage of fluid during surgery or PAIR include anaphylaxis and dissemination of infectious protoscolices. The latter complication has been minimized by careful attention to the prevention of spillage of the cyst and by soaking of the drapes with hypertonic saline. Infusion of scolicidal agents is no longer recommended because of problems with hypernatremia, intoxication, or sclerosing cholangitis. Albendazole, which is active against Echinococcus, should be administered adjunctively, beginning several days before resection and continuing for several weeks for E. granulosus. Praziquantel (50 mg/kg daily for 2 weeks) may hasten the death of the protoscolices. Medical therapy with albendazole alone for 12 weeks to 6 months results in cure in ∼30% of cases and in improvement in another 50%. In many instances of treatment failure, E. granulosus infections are subsequently treated successfully with PAIR or additional courses of medical therapy. Response to treatment is best assessed by serial imaging studies, with attention to cyst size and consistency. Some cysts may not demonstrate complete radiologic resolution even though no viable protoscolices are present. Some of these cysts with partial radiologic resolution (e.g., CE4) can be managed with observation only. Surgical resection remains the treatment of choice for E. multilocularis infection. Complete removal of the parasite continues to offer the best chance for cure. Ongoing therapy with albendazole for at least 2 years after presumptively curative surgery is recommended. Most cases are diagnosed at a stage at which complete

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Treatment: HYMENOLEPIASIS NANA

Praziquantel (25 mg/kg once) is the treatment of choice, since it acts against both the adult worms and the cysticercoids in the intestinal villi. Nitazoxanide (500 mg bid for 3 days) may be used as an alternative.

Diagnosis The diagnosis is made readily by the detection of the characteristic eggs in the stool. The eggs possess a single shell with an operculum at one end and a knob at the other. Mild to moderate eosinophilia may be detected. Treatment: DIPHYLLOBOTHRIASIS

Prevention Good personal hygiene and improved sanitation can eradicate the disease. Epidemics have been controlled by mass chemotherapy coupled with improved hygiene.

Praziquantel (5–10 mg/kg once) is highly effective. Parenteral vitamin B12 should be given if B12 deficiency is manifest.

HYMENOLEPIASIS DIMINUTA Hymenolepis diminuta, a cestode of rodents, occasionally infects small children, who ingest the larvae in uncooked cereal foods contaminated by fleas and other insects in which larvae develop. Infection is usually asymptomatic and is diagnosed by the detection of eggs in the stool. Treatment with praziquantel results in cure in most cases.

Prevention Infection can be prevented by heating fish to 54°C for 5 min or by freezing it at –18°C for 24 h. Placing fish in brine with a high salt concentration for long periods kills the eggs.

SECTION VIII

DIPHYLLOBOTHRIASIS Diphyllobothrium latum and other Diphyllobothrium species are found in the lakes, rivers, and deltas of the northern hemisphere, Central Africa, and Chile.


Etiology and Pathogenesis The adult worm—the longest tapeworm (up to 25 m)— attaches to the ileal and occasionally to the jejunal mucosa by its suckers, which are located on its elongated scolex.The adult worm has 3000–4000 proglottids, which release ∼1 million eggs daily into the feces. If an egg reaches water, it hatches and releases a free-swimming embryo that can be eaten by small freshwater crustaceans (Cyclops or Diaptomus species). After an infected crustacean containing a developed procercoid is swallowed by a fish, the larva migrates into the fish’s flesh and grows into a plerocercoid, or sparganum larva. Humans acquire the infection by ingesting infected raw or smoked fish. Within 3–5 weeks, the tapeworm matures into an adult in the human intestine. Clinical Manifestations Most D. latum infections are asymptomatic, although manifestations may include transient abdominal discomfort, diarrhea, vomiting, weakness, and weight loss. Occasionally, infection can cause acute abdominal pain and intestinal obstruction; in rare cases, cholangitis or cholecystitis may be produced by migrating proglottids. Because the tapeworm absorbs large quantities of vitamin B12 and interferes with ileal B12 absorption, vitamin B12 deficiency can develop. Up to 2% of infected patients, especially the elderly, have megaloblastic anemia resembling pernicious anemia and may exhibit neurologic sequelae of B12 deficiency.

DIPYLIDIASIS Dipylidium caninum, a common tapeworm of dogs and cats, may accidentally infect humans. Dogs, cats, and occasionally humans become infected by ingesting fleas harboring cysticercoids. Children are more likely to become infected than adults. Most infections are asymptomatic, but abdominal pain, diarrhea, anal pruritus, urticaria, eosinophilia, or passage of segments in the stool may occur.The diagnosis is made by the detection of proglottids or ova in the stool.As in D. latum infection, therapy consists of praziquantel. Prevention requires anthelmintic treatment and flea control for pet dogs or cats. SPARGANOSIS Humans can be infected by the sparganum, or plerocercoid larva, of a diphyllobothrid tapeworm of the genus Spirometra. Infection can be acquired by the consumption of water containing infected Cyclops; by the ingestion of infected snakes, birds, or mammals; or by the application of infected flesh as poultices. The worm migrates slowly in tissues, and infection commonly presents as a subcutaneous swelling. Periorbital tissues can be involved, and ocular sparganosis may destroy the eye. Surgical excision is used to treat localized sparganosis. COENUROSIS This rare infection of humans by the larval stage (coenurus) of the dog tapeworm Taenia multiceps or T. serialis results in a space-occupying cystic lesion. As in cysticercosis, involvement of the CNS and subcutaneous tissue is most common. Both definitive diagnosis and treatment require surgical excision of the lesion. Chemotherapeutic agents generally are not effective. FURTHER READINGS CENTERS FOR DISEASE CONTROL AND PREVENTION, DIVISION PARASITIC DISEASES: www.cdc.gov/ncidod/dpd/default.htm

OF

DEL BRUTTO OH et al: Proposed diagnostic criteria for neurocysticercosis. Neurology 57:177, 2001 ECKERT J, DEPLAZES P: Biological, epidemiological, and clinical aspects of echinococcosis, a zoonosis of increasing concern. Clin Microbiol Rev 17:107, 2004 GARCIA HH et al: Current consensus guidelines for treatment of neurocysticercosis. Clin Microbiol Rev 15:747, 2002 ——— et al: A trial of antiparasitic treatment to reduce the rate of seizures due to cerebral cysticercosis. N Engl J Med 350:249, 2004 NASH TE et al: Treatment of neurocysticercosis: Current status and future research needs. Neurology 67:1120, 2006 PAWLOWSKI ZS et al: Echinococcosis in humans: Clinical aspects, diagnosis, and treatment, in WHO/OIE Manual on Echinococcosis in Humans and Animals:A Public Health Problem of Global Concern, J Eckert et al (eds). Paris,World Organization for Animal Health, 2001

SCHANTZ PM et al: Echinococcosis, in Tropical Infectious Diseases: Principles, Pathogens and Practice, 2d ed, RL Guerrant et al (eds). Philadelphia, Churchill Livingstone, 2005, p 1304 SCHOLZ T et al: Update on the human broad tapeworm (genus diphyllobothrium), including clinical relevance. Clin Microbiol Rev 22:146, 2009 SINGH G, PRABHAKAR S: Taenia solium Cysticercosis: From Basic Science to Clinical Science. Wallingford, UK, CABI Publishing, 2002 WORLD HEALTH ORGANIZATION INFORMAL WORKING GROUP ON ECHINOCOCCOSIS: PAIR: puncture, aspiration, injection, re-aspiration: An option for the treatment of cystic echinococcosis. WHO/CDS/CSR/APH/2001.6. Geneva,WHO, 2001 ———: International classification of ultrasound images in cystic echinococcosis for application in clinical and field epidemiological settings.Acta Tropica 85:253, 2003

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APPENDIX

LABORATORY VALUES OF CLINICAL IMPORTANCE Alexander Kratz

Michael A. Pesce

Daniel J. Fink†

In preparing the Appendix, the authors have taken into account the fact that the system of international units (SI, système international d’unités) is used in most countries and in some medical journals. However, clinical laboratories may continue to report values in “conventional” units.Therefore, both systems are provided in the Appendix. The dual system is also used in the text except for (1) those instances in which the numbers remain the same but only the terminology is changed (mmol/L for meq/L or IU/L for mIU/mL), when only the SI units are given; and (2) most pressure measurements (e.g., blood and cerebrospinal fluid pressures), when the conventional units (mmHg, mmH2O) are used. In all other instances in the text the SI unit is followed by the traditional unit in parentheses.

INTRODUCTORY COMMENTS The following are tables of reference values for laboratory tests, special analytes, and special function tests. A variety of factors can influence reference values. Such variables include the population studied, the duration and means of specimen transport, laboratory methods and instrumentation, and even the type of container used for the collection of the specimen. The reference or “normal” ranges given in this Appendix may therefore not be appropriate for all laboratories, and these values should only be used as general guidelines. Whenever possible, reference values provided by the laboratory performing the testing should be utilized in the interpretation of laboratory data.Values supplied in this Appendix reflect typical reference ranges in adults. Pediatric reference ranges may vary significantly from adult values.

†

Deceased.

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1174 REFERENCE VALUES FOR LABORATORY TESTS TABLE A-1 HEMATOLOGY AND COAGULATION

APPENDIX Laboratory Values of Clinical Importance

ANALYTE

SPECIMENa

SI UNITS

CONVENTIONAL UNITS

Activated clotting time Activated protein C resistance (Factor V Leiden) Alpha2 antiplasmin Antiphospholipid antibody panel PTT-LA (Lupus anticoagulant screen) Platelet neutralization procedure Dilute viper venom screen Anticardiolipin antibody IgG IgM Antithrombin III Antigenic Functional Anti-Xa assay (heparin assay) Unfractionated heparin Low-molecular-weight heparin Danaparoid (Orgaran) Autohemolysis test Autohemolysis test with glucose Bleeding time (adult) Bone marrow: see Table A-8 Clot retraction Cryofibrinogen D-Dimer Differential blood count Neutrophils Bands Lymphocytes Monocytes Eosinophils Basophils Eosinophil count Erythrocyte count Adult males Adult females Erythrocyte life span Normal survival Chromium labeled, half life (t1/2) Erythrocyte sedimentation rate Females Males Euglobulin lysis time Factor II, prothrombin Factor V Factor VII Factor VIII Factor IX Factor X Factor XI Factor XII Factor XIII screen Factor inhibitor assay

WB P P

70–180 s Not applicable 0.87–1.55

70–180 s Ratio > 2.1 87–155%

P P P S

Negative Negative Negative

Negative Negative Negative

0–15 arbitrary units 0–15 arbitrary units

0–15 GPL 0–15 MPL

220–390 mg/L 0.7–1.30 U/L

22–39 mg/dL 70–130%

0.3–0.7 kIU/L 0.5–1.0 kIU/L 0.5–0.8 kIU/L 0.004–0.045 0.003–0.007 400 ng/mL >350 ng/mL >300 ng/mL >250 ng/mL >200 ng/mL >500 ng/mL

0.7–3.5 µmol/L 0.4–6.6 µmol/L 0.64–2.6 nmol/L >7.4 µmol/L

0.2–1.0 µg/mL 0.1–1.8 µg/mL 0.5–2.0 ng/mL 2.5 µg/mL

>7.0 µmol/L >9.2 µmol/L >3.1 nmol/L 20.6 µmol/L

>2.0 µg/mL >2.5 µg/mL >2.4 ng/mL >7 µg/mL

0.36–0.98 µmol/L 0.38–1.04 µmol/L

101–274 ng/mL 106–291 ng/mL

>1.8 µmol/L >1.9 µmol/L

>503 ng/mL >531 ng/mL

>4.3 mmol/L ≥17 mmol/L >54 mmol/L

>20 mg/dL ≥80 mg/dL >250 mg/dL

Laboratory Values of Clinical Importance

Carbamazepine Chloramphenicol Peak Trough Chlordiazepoxide Clonazepam Clozapine Cocaine Codeine Cyclosporine Renal transplant 0–6 months 6–12 months after transplant >12 months Cardiac transplant 0–6 months 6–12 months after transplant >12 months Lung transplant 0–6 months Liver transplant 0–7 days 2–4 weeks 5–8 weeks 9–52 weeks >1 year Desipramine Diazepam (and metabolite) Diazepam Nordiazepam Digoxin Disopyramide Doxepin and nordoxepin Doxepin Nordoxepin Ethanol Behavioral changes Legal limit Critical with acute exposure

APPENDIX

DRUG

(Continued)

1184

TABLE A-3 (CONTINUED) TOXICOLOGY AND THERAPEUTIC DRUG MONITORING THERAPEUTIC RANGE DRUG

Ethylene glycol Toxic Lethal Ethosuximide Flecainide Gentamicin Peak Trough Heroin (diacetyl morphine) Ibuprofen Imipramine (and metabolite) Desimipramine Total imipramine + desimipramine Lidocaine Lithium Methadone Methamphetamine Methanol

APPENDIX Laboratory Values of Clinical Importance

Methotrexate Low-dose High-dose (24 h) High-dose (48 h) High-dose (72 h) Morphine Nitroprusside (as thiocyanate) Nortriptyline Phenobarbital Phenytoin Phenytoin, free % Free Primidone and metabolite Primidone Phenobarbital Procainamide Procainamide NAPA (N-acetylprocainamide) Quinidine Salicylates Sirolimus (trough level) Kidney transplant Tacrolimus (FK506) (trough) Kidney and liver 0–2 months posttransplant >2 months posttransplant Heart 0–2 months posttransplant 3–6 months posttransplant >6 months posttransplant Theophylline

SI UNITS

TOXIC LEVEL

CONVENTIONAL UNITS

SI UNITS

CONVENTIONAL UNITS

280–700 µmol/L 0.5–2.4 µmol/L

40–100 µg/mL 0.2–1.0 µg/mL

>2 mmol/L >20 mmol/L >700 µmol/L >3.6 µmol/L

>12 mg/dL >120 mg/dL >100 µg/mL >1.5 µg/mL

10–21 µmol/mL 0–4.2 µmol/mL

5–10 µg/mL 0–2 µg/mL

>25 µmol/mL >4.2 µmol/mL >700 µmol/L

49–243 µmol/L

10–50 µg/mL

>97 µmol/L

>12 µg/mL >2 µg/mL >200 ng/mL (as morphine) >200 µg/mL

375–1130 nmol/L 563–1130 nmol/L

100–300 ng/mL 150–300 ng/mL

>1880 nmol/L >1880 nmol/L

>500 ng/mL >500 ng/mL

5.1–21.3 µmol/L 0.5–1.3 meq/L 1.3–3.2 µmol/L

1.2–5.0 µg/mL 0.5–1.3 meq/L 0.4–1.0 µg/mL 20–30 ng/mL

>38.4 µmol/L >2 mmol/L >6.5 µmol/L

>28 mmol/L

>9.0 µg/mL >2 meq/L >2 µg/mL 0.1–1.0 µg/mL >20 mg/dL >50 mg/dL, severe toxicity >89 mg/dL, lethal

>6 mmol/L >16 mmol/L

0.01–0.1 µmol/L 215 µmol/L >118 µmol/L >13.9 µg/mL

>0.1 mmol/L >5.0 µmol/L >0.5 µmol/L >0.1 µmol/L 50–4000 ng/mL >50 µg/mL >500 ng/mL >50 µg/mL >30 µg/mL >3.5 µg/mL

23–55 µmol/L 65–172 µmol/L

5–12 µg/mL 15–40 µg/mL

>69 µmol/L >215 µmol/L

>15 µg/mL >50 µg/mL

17–42 µmol/L 22–72 µmol/L >6.2–15.4 µmol/L 145–2100 µmol/L

4–10 µg/mL 6-20 µg/mL 2.0 –5.0 µg/mL 2–29 mg/dL

>51 µmol/L >126 µmol/L >31 µmol/L >2172 µmol/L

>12 µg/mL >35 µg/mL >10 µg/mL >30 mg/dL

4.4–13.1 nmol/L

4–12 ng/mL

>16 nmol/L

>15 ng/mL

12–19 nmol/L 6–12 nmol/L

10–15 ng/mL 5–10 ng/mL

>25 nmol/L

>20 ng/mL

19–25 nmol/L 12–19 nmol/L 10–12 nmol/L 56–111 µg/mL

15–20 ng/mL 10–15 ng/mL 8–10 ng/mL 10–20 µg/mL

>25 nmol/L

>20 ng/mL

>140 µg/mL

>25 µg/mL (Continued)

TABLE A-3 (CONTINUED)

1185

TOXICOLOGY AND THERAPEUTIC DRUG MONITORING THERAPEUTIC RANGE DRUG

Thiocyanate After nitroprusside infusion Nonsmoker Smoker Tobramycin Peak Trough Valproic acid Vancomycin Peak Trough

TOXIC LEVEL

SI UNITS

CONVENTIONAL UNITS

SI UNITS

CONVENTIONAL UNITS

103–499 µmol/L 17–69 µmol/L 52–206 µmol/L

6–29 µg/mL 1–4 µg/mL 3–12 µg/mL

860 µmol/L

>50 µg/mL

11–22 µg/L 0–4.3 µg/L 350–700 µmol/L

5–10 µg/mL 0–2 µg/mL 50–100 µg/mL

>26 µg/L >4.3 µg/L >1000 µmol/L

>12 µg/mL >2 µg/mL >150 µg/mL

14–28 µmol/L 3.5–10.4 µmol/L

20–40 µg/mL 5–15 µg/mL

>55 µmol/L >14 µmol/L

>80 µg/mL >20 µg/mL

TABLE A-4 VITAMINS AND SELECTED TRACE MINERALS REFERENCE RANGE SI UNITS

CONVENTIONAL UNITS

Aluminum

S U, random WB U, 24 h WB P S

Harrison's Infectious Diseases

Equine Infectious Diseases

Encyclopedia of Infectious Diseases

Pediatric Practice Infectious Diseases