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Mandell, Douglas, and Bennett’s

Principles and Practice of

INFECTIOUS DISEASES


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Mandell, Douglas, and Bennett’s

Principles and Practice of

INFECTIOUS DISEASES

Eighth Edition Volume 1 JOHN E. BENNETT, MD, MACP Adjunct Professor of Medicine Uniformed Services University of the Health Sciences F. Edward Hebert School of Medicine Bethesda, Maryland

RAPHAEL DOLIN, MD

Maxwell Finland Professor of Medicine (Microbiology and Molecular Genetics) Harvard Medical School; Attending Physician Beth Israel Deaconess Medical Center; Brigham and Women’s Hospital Boston, Massachusetts

MARTIN J. BLASER, MD

Muriel G. and George W. Singer Professor of Translational Medicine Professor of Microbiology Director, Human Microbiome Program Departments of Medicine and Microbiology New York University School of Medicine Langone Medical Center New York, New York


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

MANDELL, DOUGLAS, AND BENNETT’S PRINCIPLES AND PRACTICE OF INFECTIOUS DISEASES, EIGHTH EDITION ISBN: 978-1-4557-4801-3 Copyright © 2015 by Saunders, an imprint of Elsevier Inc. Copyright © 2010, 2005, 2000, 1995, 1990, 1985, 1979 Elsevier Inc. All rights reserved. The chapters listed below are in the public domain: • Foodborne Disease by Rajal K. Mody and Patricia M. Griffin • The Immunology of Human Immunodeficiency Virus Infection by Susan Moir, Mark Connors, and Anthony S. Fauci • Introduction to Herpesviridae by Jeffrey I. Cohen • Human Herpesvirus Types 6 and 7 (Exanthem Subitum) by Jeffrey I. Cohen • Herpes B Virus by Jeffrey I. Cohen • Yersinia Species (Including Plague) by Paul S. Mead • Trypanosoma Species (American Trypanosomiasis, Chagas’ Disease): Biology of Trypanosomes by Louis V. Kirchhoff • Agents of African Trypanosomiasis (Sleeping Sickness) by Louis V. Kirchhoff • Visceral Larva Migrans and Other Uncommon Helminth Infections by Theodore E. Nash • Infections Caused by Percutaneous Intravascular Devices by Susan E. Beekmann and David K. Henderson • Transfusion- and Transplantation-Transmitted Infections by Matthew J. Kuehnert and Sridhar V. Basavaraju • Human Immunodeficiency Virus in Health Care Settings by David K. Henderson All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

Library of Congress Cataloging-in-Publication Data Mandell, Douglas, and Bennett’s principles and practice of infectious diseases / [edited by] John E. Bennett, Raphael Dolin, Martin J. Blaser. – Eighth edition.    p. ; cm.   Principles and practice of infectious diseases   Includes bibliographical references and index.   ISBN 978-1-4557-4801-3 (2 v. set : hardcover : alk. paper) – ISBN 978-9996096686 (v. 1 : hardcover : alk. paper) – ISBN 9996096688 (v. 1 : hardcover : alk. paper) – ISBN 978-9996096747 (v. 2 : hardcover : alk. paper) – ISBN 9996096742 (v. 2 : hardcover : alk. paper)   I. Bennett, John E. (John Eugene), 1933- editor. II. Dolin, Raphael., editor. III. Blaser, Martin J., editor. IV. Title: Principles and practice of infectious diseases.   [DNLM: 1.  Communicable Diseases.  WC 100]   RC111   616.9–dc23 2014020246 Content Strategy Director: Mary Gatsch Content Development Manager: Taylor Ball Publishing Services Manager: Patricia Tannian Senior Project Manager: Kristine Feeherty Design Direction: Steve Stave Chapter Opener Art: Andrew McAfee Main cover image: Scanning electron micrograph of Staphylococcus aureus bound to the surface of a human neutrophil. (Figure 8-5 from “Granulocytic Phagocytes,” by Frank R. DeLeo and William M. Nauseef.) Printed in Canada Last digit is the print number:  9  8  7  6  5  4  3  2  1 


Contributors Kjersti Aagaard, MD, PhD

Associate Professor, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, Houston, Texas The Human Microbiome of Local Body Sites and Their Unique Biology

Fredrick M. Abrahamian, DO

Professor of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; Director of Education, Department of Emergency Medicine, Olive View–UCLA Medical Center, Sylmar, California Bites

Ban Mishu Allos, MD

Michael H. Augenbraun, MD

Professor of Medicine, Chief, Division of Infectious Diseases, Department of Medicine, SUNY Downstate Medical Center, Brooklyn, New York Genital Skin and Mucous Membrane Lesions; Urethritis; Vulvovaginitis and Cervicitis

Francisco Averhoff, MD, MPH

Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia Hepatitis A Virus

Dimitri T. Azar, MD, MBA

Associate Professor, Departments of Medicine and Preventive Medicine, Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, Tennessee

Dean and B.A. Field Chair of Ophthalmologic Research, Distinguished Professor of Ophthalmology, Pharmacology, and Bioengineering, College of Medicine, University of Illinois at Chicago, Chicago, Illinois

David R. Andes, MD

Larry M. Baddour, MD

Campylobacter jejuni and Related Species

Associate Professor of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin Cephalosporins

Fred Y. Aoki, MD

Professor, Departments of Medicine, Medical Microbiology, and Pharmacology & Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada Antiviral Drugs for Influenza and Other Respiratory Virus Infections; Antivirals against Herpes Viruses

Michael A. Apicella, MD

Professor and Head, Department of Microbiology, University of Iowa Carver College of Medicine, Iowa City, Iowa Neisseria meningitidis; Neisseria gonorrhoeae (Gonorrhea)

Kevin L. Ard, MD, MPH

Instructor in Medicine, Harvard Medical School; Associate Physician, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts Pulmonary Manifestations of Human Immunodeficiency Virus Infection

Cesar A. Arias, MD, MSc, PhD

Associate Professor of Medicine, Department of Internal Medicine, Division of Infectious Diseases and Department of Microbiology and Molecular Genetics, University of Texas Medical School at Houston, Houston, Texas; Director, Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Bogota, Colombia

Glycopeptides (Vancomycin and Teicoplanin), Streptogramins (Quinupristin-Dalfopristin), Lipopeptides (Daptomycin), and Lipoglycopeptides (Telavancin); Enterococcus Species, Streptococcus gallolyticus Group, and Leuconostoc Species

David M. Aronoff, MD

Director, Division of Infectious Diseases; Addison Scoville Professor of Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee

Microbial Conjunctivitis; Microbial Keratitis

Professor of Medicine, Mayo Clinic College of Medicine; Consultant, Infectious Diseases, Mayo Clinic, Rochester, Minnesota

Prosthetic Valve Endocarditis; Infections of Nonvalvular Cardiovascular Devices

Lindsey R. Baden, MD

Associate Professor of Medicine, Harvard Medical School; Associate Physician, Director of Clinical Research (Division of Infectious Diseases), Director of Transplant Infectious Diseases, Brigham and Women’s Hospital; Director of Infectious Diseases, Dana-Farber Cancer Institute, Boston, Massachusetts Vaccines for Human Immunodeficiency Virus Type 1 Infection

Carol J. Baker, MD

Professor of Pediatrics, Molecular Virology, and Microbiology, Department of Pediatrics, Infectious Diseases Section, Baylor College of Medicine; Attending Physician, Texas Children’s Hospital, Houston, Texas Streptococcus agalactiae (Group B Streptococcus)

Ronald C. Ballard, MSB, PhD

Associate Director for Laboratory Science, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia Klebsiella granulomatis (Donovanosis, Granuloma Inguinale)

Gerard R. Barber, RPh, MPH

Department of Pharmacy Services, University of Colorado Hospital, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado Unique Antibacterial Agents

Scott D. Barnes, MD

Chief, Warfighter Refractive Eye Surgery Clinic, Womack Army Medical Center, Fort Bragg, North Carolina Microbial Conjunctivitis; Microbial Keratitis

Metronidazole

v


vi

Contributors

Dan H. Barouch, MD, PhD

Professor of Medicine, Harvard Medical School; Director, Center for Virology and Vaccine Research, Staff Physician, Beth Israel Deaconess Medical Center; Associate Physician, Brigham and Women’s Hospital, Boston, Massachusetts Vaccines for Human Immunodeficiency Virus Type 1 Infection; Adenoviruses

Alan D. Barrett, PhD

Director, Sealy Center for Vaccine Development, Professor, Departments of Pathology and Microbiology & Immunology, University of Texas Medical Branch, Galveston, Texas

Flaviviruses (Dengue, Yellow Fever, Japanese Encephalitis, West Nile Encephalitis, St. Louis Encephalitis, Tick-Borne Encephalitis, Kyasanur Forest Disease, Alkhurma Hemorrhagic Fever, Zika)

Miriam Baron Barshak, MD

Assistant Professor of Medicine, Harvard Medical School; Associate Physician, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts Pancreatic Infection

Sridhar V. Basavaraju, MD

Centers for Disease Control and Prevention, Atlanta, Georgia Transfusion- and Transplantation-Transmitted Infections

Byron E. Batteiger, MD

Professor of Medicine, Microbiology, and Immunology, Division of Infectious Diseases, Indiana University School of Medicine, Indianapolis, Indiana Chlamydia trachomatis (Trachoma, Genital Infections, Perinatal Infections, and Lymphogranuloma Venereum)

Stephen G. Baum, MD

Professor of Medicine, Microbiology, and Immunology, Albert Einstein College of Medicine, Bronx, New York Mumps Virus

Arnold S. Bayer, MD

Professor of Medicine, Department of Internal Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California; Associate Chief, Adult Infectious Diseases, Department of Internal Medicine, Harbor-UCLA Medical Center; Senior Investigator, St. John’s Cardiovascular Research Center, Los Angeles Biomedical Research Institute, Torrance, California Endocarditis and Intravascular Infections

J. David Beckham, MD

Assistant Professor, Departments of Medicine, Neurology, and Microbiology, Division of Infectious Diseases, Director, Infectious Disease Fellowship Training Program, Medical Director, Occupational Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado Encephalitis

Susan E. Beekmann, RN, MPH

University of Iowa Carver College of Medicine, Iowa City, Iowa Infections Caused by Percutaneous Intravascular Devices

Beth P. Bell, MD, MPH

Director, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia Emerging and Reemerging Infectious Disease Threats; Hepatitis A Virus

John E. Bennett, MD, MACP

Adjunct Professor of Medicine, Uniformed Services University of the Health Sciences, F. Edward Hebert School of Medicine, Bethesda, Maryland Chronic Meningitis; Introduction to Mycoses

Dennis A. Bente, DVM, PhD

Assistant Professor, Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas

California Encephalitis, Hantavirus Pulmonary Syndrome, and Bunyavirus Hemorrhagic Fevers

Elie F. Berbari, MD

Professor of Medicine, Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota Osteomyelitis

Jonathan Berman, MD, PhD

Vice President, Clinical Affairs, Fast-Track Drugs and Biologics, North Potomac, Maryland Complementary Diseases

and

Alternative

Medicines

for

Infectious

Joseph S. Bertino, Jr., PharmD

Associate Professor of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York; Principal, Bertino Consulting, Schenectady, New York Pharmacokinetics and Pharmacodynamics of Anti-infective Agents; Tables of Anti-infective Agent Pharmacology

Adarsh Bhimraj, MD

Head, Section of Neurologic Infectious Diseases, Associate Program Director, Internal Medicine Residency Program, Cleveland Clinic, Cleveland, Ohio Cerebrospinal Fluid Shunt and Drain Infections

Holly H. Birdsall, MD, PhD

Deputy Chief Research and Development Officer, Office of Research and Development, Department of Veterans Affairs, Washington, DC; Professor, Departments of Otolaryngology, Immunology, and Psychiatry, Baylor College of Medicine, Houston, Texas Adaptive Immunity: Antibodies and Immunodeficiencies

Alan L. Bisno, MD

Professor Emeritus, Department of Medicine, University of Miami Miller School of Medicine; Staff Physician, Miami Veterans Affairs Medical Center, Miami, Florida Classification of Streptococci; Nonsuppurative Poststreptococcal Sequelae: Rheumatic Fever and Glomerulonephritis

Brian G. Blackburn, MD

Clinical Associate Profesor, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine; Attending Physician, Department of Internal Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford Hospital and Clinics, Stanford, California Free-Living Amebae

Lucas S. Blanton, MD

Assistant Professor, Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, Texas Rickettsia rickettsii and Other Spotted Fever Group Rickettsiae (Rocky Mountain Spotted Fever and Other Spotted Fevers); Rickettsia prowazekii (Epidemic or Louse-Borne Typhus); Rickettsia typhi (Murine Typhus)


vii

Martin J. Blaser, MD

Introduction to Bacteria and Bacterial Diseases; Campylobacter jejuni and Related Species; Helicobacter pylori and Other Gastric Helicobacter Species

Thomas P. Bleck, MD

Professor of Neurological Sciences, Neurosurgery, Medicine, and Anesthesiology, Rush Medical College; Associate Chief Medical Officer (Critical Care), Associate Vice President, Director, Laboratory of Electroencephalography and Evoked Potentials, Rush University Medical Center, Chicago, Illinois Rabies (Rhabdoviruses); Tetanus (Clostridium tetani); Botulism (Clostridium botulinum)

Nicole M. A. Blijlevens, MD, PhD

Consultant and Lecturer, Department of Haematology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Infections in the Immunocompromised Host: General Principles

David A. Bobak, MD

Associate Professor of Medicine, Associate Chair for Clinical Affairs, Division of Infectious Diseases and HIV Medicine, Case Western Reserve University School of Medicine; Director, Traveler’s Healthcare Center, Chair, Health System Medication Safety and Therapeutics Committee, Staff Physician, Transplant Infectious Diseases Clinic, University Hospitals Case Medical Center, Cleveland, Ohio Nausea, Vomiting, and Noninflammatory Diarrhea

William Bonnez, MD

Professor of Medicine, Department of Medicine, Division of Infectious Diseases, University of Rochester School of Medicine and Dentistry, Rochester, New York Papillomaviruses

John C. Boothroyd, MD

Professor of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California Toxoplasma gondii

Kevin E. Brown, MD, MRCP

Consultant Medical Virologist, Virus Reference Department, Public Health England, Microbiology Services, London, United Kingdom Human Parvoviruses, Including Parvovirus B19V and Human Bocaparvoviruses

Patricia D. Brown, MD

Professor of Medicine, Department of Internal Medicine, Division of Infectious Diseases, Wayne State University School of Medicine; Corporate Vice President of Quality and Patient Safety, Detroit Medical Center, Detroit, Michigan Infections in Injection Drug Users

Barbara A. Brown-Elliott, MS, MT(ASCP)SM

Research Assistant Professor, Microbiology, Supervisor, Mycobacteria/ Nocardia Laboratory, University of Texas Health Science Center, Tyler, Texas Infections Caused by Nontuberculous Mycobacteria Other than Mycobacterium avium Complex

Roberta L. Bruhn, MS, PhD

Staff Scientist, Department of Epidemiology, Blood Systems Research Institute, San Francisco, California Human T-Lymphotropic Virus (HTLV)

Amy E. Bryant, PhD

Research Career Scientist, Infectious Diseases Section, Veterans Affairs Medical Center, Boise, Idaho Streptococcus pyogenes

Eileen M. Burd, PhD

Associate Professor, Department of Pathology and Laboratory Medicine, Emory University School of Medicine; Director, Clinical Microbiology, Emory University Hospital, Atlanta, Georgia Other Gram-Negative and Gram-Variable Bacilli

Jane C. Burns, MD

Professor of Pediatrics, University of California San Diego School of Medicine, La Jolla, California Kawasaki Disease

Larry M. Bush, MD

Assistant Commissioner for Counterterrorism Policy, United States Food and Drug Administration, Silver Spring, Maryland

Affiliated Associate Professor of Medicine, University of Miami Miller School of Medicine, JFK Medical Center, Palm Beach County, Florida; Affiliated Professor of Medicine, Charles E. Schmidt School of Medicine, Florida Atlantic University, Boca Raton, Florida

Patrick J. Bosque, MD

Stephen B. Calderwood, MD

Luciana L. Borio, MD

Bioterrorism: An Overview

Associate Professor, Department of Neurology, University of Colorado Denver School of Medicine; Neurologist, Department of Medicine, Denver Health Medical Center, Denver, Colorado Prions and Prion Diseases of the Central Nervous System (Transmissible Neurodegenerative Diseases)

John Bower, MD

Associate Professor of Pediatrics, Northeast Ohio Medical University, Rootstown, Ohio Croup in Children (Acute Laryngotracheobronchitis); Bronchiolitis

Robert W. Bradsher, Jr., MD

Peritonitis and Intraperitoneal Abscesses

Morton N. Swartz, MD, Academy Professor of Medicine (Microbiology and Immunobiology), Department of Medicine, Harvard Medical School; Chief, Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts Syndromes of Enteric Infection

Luz Elena Cano, PhD

Head of Medical and Experimental Mycology Group, Corporación para Investigaciones Biológicas; Titular Professor, Microbiology School, Universidad de Antioquia, Medellín, Colombia Paracoccidioidomycosis

Ebert Professor of Medicine, Department of Medicine, Division of Infectious Diseases, University of Arkansas for Medical Sciences, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas

Charles C. J. Carpenter, MD

Itzhak Brook, MD

Mary T. Caserta, MD

Blastomycosis

Professor of Pediatrics, Georgetown University School of Medicine, Washington, DC Tetracyclines, Glycylcyclines, and Chloramphenicol

Professor of Medicine, Warren Alpert Medical School of Brown University; Attending Physician, Division of Infectious Diseases, Miriam Hospital, Providence, Rhode Island Other Pathogenic Vibrios

Professor of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York Pharyngitis; Acute Laryngitis

Contributors

Muriel G. and George W. Singer Professor of Translational Medicine, Professor of Microbiology, Director, Human Microbiome Program, Departments of Medicine and Microbiology, New York University School of Medicine, Langone Medical Center, New York, New York


viii

Elio Castagnola, MD Contributors

Infectious Diseases Unit, Istituto Giannina Gaslini, Genova, Italy

Prophylaxis and Empirical Therapy of Infection in Cancer Patients

Richard E. Chaisson, MD

Professor of Medicine, Epidemiology, and International Health, Johns Hopkins University School of Medicine, Baltimore, Maryland

General Clinical Manifestations of Human Immunodeficiency Virus Infection (Including Acute Retroviral Syndrome and Oral, Cutaneous, Renal, Ocular, Metabolic, and Cardiac Diseases)

Henry F. Chambers, MD

Professor of Medicine, Director, UCSF Infectious Diseases Fellowship Training Program, University of California San Francisco; Chief, Division of Infectious Diseases, San Francisco General Hospital, San Francisco, California Penicillins and β-Lactamase Inhibitors; Other β-Lactam Antibiotics

Stephen J. Chapman, DM

Consultant Physician and Senior Lecturer in Respiratory Medicine, Oxford University Hospitals, Oxford, United Kingdom Human Genetics and Infection

James D. Chappell, MD, PhD

Associate Professor of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee Biology of Viruses and Viral Diseases

Lea Ann Chen, MD

Instructor, Division of Gastroenterology, NYU Langone School of Medicine, New York, New York Prebiotics, Probiotics, and Synbiotics

Sharon C-A. Chen, MBBS, PhD

Clinical Associate Professor, University of Sydney Faculty of Medicine, Sydney, New South Wales, Australia; Senior Staff Specialist, Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, New South Wales, Australia Nocardia Species

Anthony W. Chow, MD

Professor Emeritus, Department of Internal Medicine, Division of Infectious Diseases, University of British Columbia; Honorary Consultant, Department of Internal Medicine, Division of Infectious Diseases, Vancouver Hospital, Vancouver, British Columbia, Canada Infections of the Oral Cavity, Neck, and Head

Rebecca A. Clark, MD, PhD

Professor of Medicine, Louisiana State University Health Science Center; Lead Physician, HIV Outpatient Program, Interim LSU Public Hospital, New Orleans, Louisiana Human Immunodeficiency Virus Infection in Women

Jeffrey I. Cohen, MD

Chief, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

Introduction to Herpesviridae; Human Herpesvirus Types 6 and 7 (Exanthem Subitum); Herpes B Virus

Myron S. Cohen, MD

Yergin-Bates Eminent Professor of Medicine, Microbiology, and Epidemiology, Director, Institute of Global Health and Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina The Acutely Ill Patient with Fever and Rash

Ronit Cohen-Poradosu, MD

Infectious Diseases Unit, Tel-Aviv Sourasky Medical Center, Tel-Aviv University Sackler School of Medicine, Tel Aviv, Israel Anaerobic Infections: General Concepts

Susan E. Cohn, MD, MPH

Professor of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois Human Immunodeficiency Virus Infection in Women

Mark Connors, MD

Chief, HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland The Immunology of Human Immunodeficiency Virus Infection

Lawrence Corey, MD

Professor of Medicine and Laboratory Medicine, University of Washington School of Medicine; President and Director, Fred Hutchinson Cancer Research Center, Seattle, Washington Herpes Simplex Virus

Mackenzie L. Cottrell, PharmD, MS

Postdoctoral Fellow, Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina Pharmacokinetics Agents

and

Pharmacodynamics

of

Anti-infective

Timothy L. Cover, MD

Professor of Medicine, Professor of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center; Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee Helicobacter pylori and Other Gastric Helicobacter Species

Heather L. Cox, PharmD

Assistant Professor of Medicine and Infectious Diseases, Department of Medicine, University of Virginia School of Medicine; Clinical Coordinator, Infectious Diseases, Department of Pharmacy Services, University of Virginia Health System, Charlottesville, Virginia Linezolid and Other Oxazolidinones

William A. Craig, MD

Emeritus Professor of Medicine, Infectious Disease Section, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin Cephalosporins

Kent B. Crossley, MD, MHA

Professor, Department of Medicine, University of Minnesota Medical School; Chief of Staff, Minneapolis Veterans Administration Healthcare System, Minneapolis, Minnesota Infections in the Elderly

Clyde S. Crumpacker II, MD

Professor of Medicine, Harvard Medical School; Attending Physician, Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts Cytomegalovirus (CMV)

James W. Curran, MD, MPH

Dean and Professor of Epidemiology, Rollins School of Public Health, Emory University; Co-Director, Emory Center for AIDS Research, Atlanta, Georgia Epidemiology and Prevention of Acquired Immunodeficiency Syndrome and Human Immunodeficiency Virus Infection


ix

Bart J. Currie, MBBS, DTM&H

Burkholderia pseudomallei and Burkholderia mallei: Melioidosis and Glanders

Erika D’Agata, MD, MPH

Associate Professor of Medicine, Brown University; Department of Medicine, Division of Infectious Diseases, Rhode Island Hospital, Providence, Rhode Island Pseudomonas aeruginosa and Other Pseudomonas Species

Adjunct Clinical Faculty, Department of Medicine, Emory University School of Medicine; Director, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia Orthopoxviruses: Vaccinia (Smallpox Vaccine), Variola (Smallpox), Monkeypox, and Cowpox; Other Poxviruses That Infect Humans: Parapoxviruses (Including Orf Virus), Molluscum Contagiosum, and Yatapoxviruses

Rabih O. Darouiche, MD

VA Distinguished Service Professor, Departments of Medicine, Surgery, and Physical Medicine and Rehabilitation, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas Infections in Patients with Spinal Cord Injury

Acting Chief, Division of Pediatric Infectious Diseases, Children’s National Medical Center; Professor of Pediatrics and Microbiology, Immunology and Tropical Medicine, George Washington University School of Medicine; Principal Investigator, Center for Clinical and Translational Science, Children’s Research Institute, Washington, DC Orbiviruses;

Coltiviruses

and

George S. Deepe, Jr., MD

Professor, Department of Internal Medicine, Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio Histoplasma capsulatum (Histoplasmosis)

Carlos del Rio, MD

Professor and Chair, Hubert Department of Global Health, Rollins School of Public Health, Emory University; Co-Director, Emory Center for AIDS Research, Atlanta, Georgia Epidemiology and Prevention of Acquired Immunodeficiency Syndrome and Human Immunodeficiency Virus Infection

Andrew S. Delemos, MD

Transplant Hepatologist, Carolinas Healthcare System, Charlotte, North Carolina Viral Hepatitis

Frank R. DeLeo, PhD

Chief, Pathogen-Host Cell Biology Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland Granulocytic Phagocytes

Associate Professor, University of Wisconsin School of Medicine and Public Health; Attending Physician, American Family Children’s Hospital, Madison, Wisconsin Sinusitis

Complement and Deficiencies

Terence S. Dermody, MD

Dorothy Overall Wells Professor of Pediatrics, Director, Division of Infectious Diseases, Director, Elizabeth B. Lamb Center for Pediatric Research, Director, Vanderbilt Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, Tennessee Biology of Viruses and Viral Diseases

Principal Scientist, Leidos Biomedical Research—Frederick, National Cancer Institute—Frederick, Frederick, Maryland Diagnosis of Human Immunodeficiency Virus Infection

James H. Diaz, MD, MPHTM, DrPH

Professor of Public Health and Preventive Medicine, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, Louisiana Introduction to Ectoparasitic Diseases; Lice (Pediculosis); Scabies; Myiasis and Tungiasis; Mites, Including Chiggers; Ticks, Including Tick Paralysis

Carl W. Dieffenbach, PhD

Director, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland Innate (General or Nonspecific) Host Defense Mechanisms

Roberta L. DeBiasi, MD

Gregory P. DeMuri, MD

Professor of Internal Medicine, Division of Infectious Diseases, University of Iowa Hospitals and Clinics, Iowa City, Iowa

Robin Dewar, PhD

Inger K. Damon, MD, PhD

Orthoreoviruses and Seadornaviruses

Peter Densen, MD

Jules L. Dienstag, MD

Dean for Medical Education, Carl W. Walter Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital, Boston, Massachusetts Antiviral Drugs against Hepatitis Viruses; Viral Hepatitis

Yohei Doi, MD, PhD

Assistant Professor of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Penicillins and β-Lactamase Inhibitors; Other β-Lactam Antibiotics

Raphael Dolin, MD

Maxwell Finland Professor of Medicine (Microbiology and Molecular Genetics), Harvard Medical School; Attending Physician, Beth Israel Deaconess Medical Center; Brigham and Women’s Hospital, Boston, Massachusetts Antiviral Agents: General Principles; Miscellaneous Antiviral Agents (Interferons, Imiquimod, Pleconaril); Vaccines for Human Immunodeficiency Virus Type 1 Infection; Zoonotic Paramyxoviruses: Nipah, Hendra, and Menangle; Noroviruses and Sapoviruses (Caliciviruses); Astroviruses and Picobirnaviruses

J. Peter Donnelly, PhD

Coordinator of Studies in Supportive Care, Department of Hae­ matology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Infections in the Immunocompromised Host: General Principles

Michael S. Donnenberg, MD

Professor of Medicine, Microbiology, and Immunology, University of Maryland School of Medicine, Baltimore, Maryland Enterobacteriaceae

Gerald R. Donowitz, MD

Professor of Medicine and Infectious Diseases/International Health, Department of Medicine, University of Virginia, Charlottesville, Virginia Linezolid and Other Oxazolidinones; Acute Pneumonia

Contributors

Professor in Medicine, Department of Infectious Diseases, Royal Darwin Hospital; Global and Tropical Health Division, Menzies School of Health Research, Darwin, Australia


x

Contributors

Philip R. Dormitzer, MD, PhD

Head of U.S. Research, Global Head of Virology, Vice President, Novartis Vaccines, Cambridge, Massachusetts Rotaviruses

James M. Drake, MB BCh, MSc

Morven S. Edwards, MD

Professor of Pediatrics, Baylor College of Medicine; Attending Physician, Department of Pediatrics, Infectious Diseases Section, Texas Children’s Hospital, Houston, Texas Streptococcus agalactiae (Group B Streptococcus)

Professor of Surgery, University of Toronto Faculty of Medicine; Neurosurgeon-in-Chief and Harold Hoffman Shopper’s Drug Mart Chair in Pediatric Neurosurgery, Division of Neurosurgery, Hospital for Sick Children, Toronto, Ontario, Canada

George M. Eliopoulos, MD

J. Stephen Dumler, MD

Richard T. Ellison III, MD

Cerebrospinal Fluid Shunt and Drain Infections

Professor, Departments of Pathology and Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland

Rickettsia typhi (Murine Typhus); Ehrlichia chaffeensis (Human Monocytotropic Ehrlichiosis), Anaplasma phagocytophilum (Human Granulocytotropic Anaplasmosis), and Other Anaplasmataceae

J. Stephen Dummer, MD

Professor, Departments of Medicine and Surgery, Chief, Transplant Infectious Diseases, Vanderbilt University School of Medicine, Nashville, Tennessee Risk Factors and Approaches to Infections in Transplant Recipients

Herbert L. DuPont, MD

Professor and Director, Center for Infectious Diseases, University of Texas School of Public Health; Chief, Internal Medicine Service, Baylor St. Luke’s Medical Center; Professor and Vice Chairman, Department of Medicine, Baylor College of Medicine, Houston, Texas Bacillary Dysentery: Shigella and Enteroinvasive Escherichia coli

David T. Durack, MB, DPhil

Consulting Professor of Medicine, Duke University School of Medicine, Durham, North Carolina Prophylaxis of Infective Endocarditis

Marlene L. Durand, MD

Associate Professor of Medicine, Harvard Medical School; Physician, Infectious Disease Unit, Massachusetts General Hospital; Director, Infectious Disease Service, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts Introduction to Eye Infections; Endophthalmitis; Infectious Causes of Uveitis; Periocular Infections

Paul H. Edelstein, MD

Professor of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine; Director of Clinical Microbiology, Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Legionnaires’ Disease and Pontiac Fever

Michael B. Edmond, MD, MPH, MPA

Richard P. Wenzel Professor of Internal Medicine, Division of Infectious Diseases, Virginia Commonwealth University School of Medicine; Hospital Epidemiologist, VCU Medical Center, Richmond, Virginia Infection Prevention in the Health Care Setting

John E. Edwards, Jr., MD

Chief, Division of Infectious Diseases, Department of Medicine, Harbor/UCLA Medical Center, Torrance, California; Professor of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California Candida Species

Professor of Medicine, Harvard Medical School; Physician, Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts Principles of Anti-infective Therapy

Professor, Departments of Medicine and Microbiology & Physiological Systems, Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, Massachusetts Acute Pneumonia

Timothy P. Endy, MD, MPH

Professor of Medicine, Division Chief of Infectious Diseases, Upstate Medical University, State University of New York, Syracuse, New York Flaviviruses (Dengue, Yellow Fever, Japanese Encephalitis, West Nile Encephalitis, St. Louis Encephalitis, Tick-Borne Encephalitis, Kyasanur Forest Disease, Alkhurma Hemorrhagic Fever, Zika)

N. Cary Engleberg, MD

Professor, Departments of Infectious Diseases and Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan Chronic Fatigue Syndrome

Hakan Erdem, MD

Department of Infectious Diseases and Clinical Microbiology, GATA Haydarpasa Training Hospital, Istanbul, Turkey Brucellosis (Brucella Species)

Joel D. Ernst, MD

Professor, Departments of Medicine, Pathology, and Microbiology, New York University School of Medicine, New York, New York Mycobacterium leprae (Leprosy)

Peter B. Ernst, DVM, PhD

Professor of Pathology and Director, Comparative Pathology and Medicine, University of California San Diego School of Medicine, La Jolla, California Mucosal Immunity

Rick M. Fairhurst, MD, PhD

Chief, Malaria Pathogenesis and Human Immunity Unit, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Rockville, Maryland Malaria (Plasmodium Species)

Jessica K. Fairley, MD

Assistant Professor of Medicine, Emory University School of Medicine, The Emory Clinic, Atlanta, Georgia Tapeworms (Cestodes)

Stanley Falkow, PhD

Robert W. and Vivian K. Cahill Professor, Emeritus, Departments of Microbiology & Immunology and Medicine, Stanford University School of Medicine, Stanford, California A Molecular Perspective of Microbial Pathogenicity

Ann R. Falsey, MD

Professor of Medicine, Infectious Diseases Unit, University of Rochester School of Medicine, Rochester, New York Human Metapneumovirus


xi

Anthony S. Fauci, MD

The Immunology of Human Immunodeficiency Virus Infection

Thomas Fekete, MD

Professor of Medicine and Chief, Section of Infectious Diseases, Temple University School of Medicine, Philadelphia, Pennsylvania

Bacillus Species and Related Genera Other Than Bacillus anthracis

Paul D. Fey, PhD

Professor, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska Staphylococcus epidermidis Staphylococci

and

Other

Coagulase-Negative

Steven M. Fine, MD, PhD

Associate Professor of Medicine, Division of Infectious Diseases, University of Rochester Medical Center, Rochester, New York Vesicular Stomatitis Virus and Related Vesiculoviruses

Daniel W. Fitzgerald, MD

Associate Professor of Medicine, Microbiology, and Immunology, Weill Cornell Medical College, New York, New York Mycobacterium tuberculosis

Anthony R. Flores, MD, MPH, PhD

Assistant Professor, Department of Pediatrics, Section of Infectious Diseases, Baylor College of Medicine, Houston, Texas Pharyngitis

Derek Forster, MD

Section on Infectious Diseases, Wake Forest School of Medicine, Winston-Salem, North Carolina Infectious Arthritis of Native Joints

Vance G. Fowler, Jr., MD, MHS

Professor of Medicine, Division of Infectious Diseases, Duke University School of Medicine, Durham, North Carolina Endocarditis and Intravascular Infections

David O. Freedman, MD

Professor of Medicine and Epidemiology, Gorgas Center for Geographic Medicine, Division of Infectious Diseases, University of Alabama at Birmingham School of Medicine; Director, University of Alabama at Birmingham Travelers Health Clinic, University of Alabama at Birmingham Health System, Birmingham, Alabama Protection of Travelers; Infections in Returning Travelers

Arthur M. Friedlander, MD

Adjunct Professor of Medicine, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Senior Scientist, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland Bacillus anthracis (Anthrax)

John N. Galgiani, MD

Professor of Internal Medicine, Director, Valley Fever Center for Excellence, University of Arizona College of Medicine; Chief Medical Officer, Valley Fever Solutions, Tucson, Arizona Coccidioidomycosis (Coccidioides Species)

John I. Gallin, MD

Director, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, Maryland Evaluation of the Patient with Suspected Immunodeficiency

Robert C. Gallo, MD

Director, Institute of Human Virology, Professor, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland Human Immunodeficiency Viruses

Tejal N. Gandhi, MD

Clinical Assistant Professor of Medicine, Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan Bartonella, Including Cat-Scratch Disease

Wendy S. Garrett, MD, PhD

Assistant Professor, Immunology & Infectious Diseases and Genetic & Complex Diseases, Department of Medicine, Harvard School of Public Health; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts

Gas Gangrene and Other Clostridium-Associated Diseases; Bacteroides, Prevotella, Porphyromonas, and Fusobacterium Species (and Other Medically Important Anaerobic Gram-Negative Bacilli)

Charlotte A. Gaydos, DrPH, MPH, MS

Professor of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine; Emergency Medicine Department and Epidemiology, Population, Family and Reproductive Health, Bloomberg Johns Hopkins School of Public Health; Director, International Sexually Transmitted Diseases Research Laboratory, Baltimore, Maryland Chlamydia pneumoniae

Thomas W. Geisbert, PhD

Professor, Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas Marburg and Ebola Hemorrhagic Fevers (Filoviruses)

Jeffrey A. Gelfand, MD

Clinical Professor of Medicine, Harvard Medical School; Attending Physician, Infectious Diseases Division, Massachusetts General Hospital, Boston, Massachusetts Babesia Species

Steven P. Gelone, PharmD

Vice President of Clinical Development, ViroPharma, Inc., Exton, Pennsylvania Topical Antibacterials

Dale N. Gerding, MD

Professor of Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Research Physician, Department of Medicine, Edward Hines, Jr., Veterans Affairs Hospital, Hines, Illinois Clostridium difficile Infection

Anne A. Gershon, MD

Professor of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York Rubella Virus (German Measles); Measles Virus (Rubeola)

Janet R. Gilsdorf, MD

Robert P. Kelch Research Professor of Pediatrics and Communicable Diseases, University of Michigan Medical School and C.S. Mott Children’s Hospital, Ann Arbor, Michigan Infections in Asplenic Patients

Ellie J. C. Goldstein, MD

Clinical Professor of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California; Director, R.M. Alden Research Laboratory, Santa Monica, California Bites

Contributors

Chief, Laboratory of Immunoregulation, Chief, Immunopathogenesis Section, Laboratory of Immunoregulation, Director, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland


xii

Contributors

Fred M. Gordin, MD

Professor of Medicine, George Washington University School of Medicine; Chief, Infectious Diseases, Veterans Affairs Medical Center, Washington, DC Mycobacterium avium Complex

Paul S. Graman, MD

Professor of Medicine, University of Rochester School of Medicine and Dentistry; Attending Physician and Clinical Director, Infectious Diseases Division, Strong Memorial Hospital, Rochester, New York Esophagitis

M. Lindsay Grayson, MD

Infectious Diseases Department, Austin Health, Department of Epidemiology and Preventive Medicine, Monash University; Department of Medicine, University of Melbourne, Melbourne, Australia Fusidic Acid

Caroline Breese Hall, MDâ€

Professor of Pediatrics and Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York Respiratory Syncytial Virus (RSV)

Joelle Hallak, BS, MS

Research Assistant, Department of Ophthalmology and Visual Science, University of Illinois at Chicago, Chicago, Illinois Microbial Keratitis

Scott A. Halperin, MD

Professor, Departments of Pediatrics and Microbiology & Immunology, Director, Canadian Center for Vaccinology, Dalhousie University; Head, Pediatric Infectious Diseases, IWK Health Centre, Halifax, Nova Scotia, Canada Bordetella pertussis

Margaret R. Hammerschlag, MD

Section Chief, Infectious Diseases, NYU Langone Medical Center, New York City, New York

Professor of Pediatrics and Medicine, State University of New York Downstate College of Medicine; Director, Division of Pediatric Infectious Diseases, State University of New York Downstate Medical Center, Brooklyn, New York

Patricia M. Griffin, MD

Rashidul Haque, MD

Jeffrey Bruce Greene, MD

Outpatient Parenteral Antimicrobial Therapy

Chief, Enteric Diseases Epidemiology Branch, Division of Foodborne, Waterborne, and Environmental Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia Foodborne Disease

David E. Griffith, MD

Professor of Medicine and William A. and Elizabeth B. Moncrief Distinguished Professor, University of Texas Health Science Center at Tyler, Tyler, Texas

Chlamydia pneumoniae

Scientist and Head of Parasitology Laboratory, Laboratory Sciences Division, International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka, Bangladesh Entamoeba Species, Including Amebic Colitis and Liver Abscess

Jason B. Harris, MD, MPH

Assistant Professor of Pediatrics, Harvard Medical School; Division of Infectious Diseases, MassGeneral Hospital for Children, Boston, Massachusetts Enteric Fever and Other Causes of Fever and Abdominal Symptoms

Antimycobacterial Agents

Richard L. Guerrant, MD

Professor of Medicine, Infectious Diseases, and International Health, University of Virginia School of Medicine, Charlottesville, Virginia Nausea, Vomiting, and Noninflammatory Diarrhea; Bacterial Inflammatory Enteritides

H. Cem Gul, MD

Department of Infectious Diseases and Microbiology, Gulhane Military Medical Academy, Ankara, Turkey Brucellosis (Brucella Species)

David A. Haake, MD

Professor, Departments of Medicine, Urology, and Microbiology, Immunology, & Molecular Genetics, The David Geffen School of Medicine at UCLA; Staff Physician, Department of Medicine, Division of Infectious Diseases, The Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California Leptospira Species (Leptospirosis)

David W. Haas, MD

Professor of Medicine, Pharmacology, Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee Mycobacterium tuberculosis

Charles Haines, MD, PhD

Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland

Claudia Hawkins, MD, MPH

Assistant Professor, Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois Hepatitis B Virus and Hepatitis Delta Virus

Roderick J. Hay, DM

Professor of Cutaneous Infection, Department of Dermatology (KCH Campus), Kings College London, London, United Kingdom Dermatophytosis (Ringworm) and Other Superficial Mycoses

Craig W. Hedberg, PhD

Professor, Division of Environmental Health Sciences, University of Minnesota School of Public Health, Minneapolis, Minnesota Epidemiologic Principles

David K. Henderson, MD

Deputy Director for Clinical Care, Clinical Center, National Institutes of Health, Bethesda, Maryland Infections Caused by Percutaneous Intravascular Devices; Human Immunodeficiency Virus in Health Care Settings; Nosocomial Herpesvirus Infections

Donald A. Henderson, MD, MPH

Professor of Medicine and Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania; Distinguished Scholar, UPMC Center for Biosecurity, Baltimore, Maryland Bioterrorism: An Overview

Gastrointestinal, Hepatobiliary, and Pancreatic Manifestations of Human Immunodeficiency Virus Infection

â€

Deceased.


xiii

Kevin P. High, MD, MS

Nutrition, Immunity, and Infection

Adrian V. S. Hill, DPhil, DM

Professor of Human Genetics, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom Human Genetics and Infection

David R. Hill, MD, DTM&H

Professor, Department of Medical Sciences, Director, Global Public Health, Frank H. Netter MD School of Medicine, Quinnipiac University, Hamden, Connecticut Giardia lamblia

Alan R. Hinman, MD, MPH

Center for Vaccine Equity, Task Force for Global Health, Decatur, Georgia Immunization

Martin S. Hirsch, MD

Professor of Medicine, Harvard Medical School; Professor of Infectious Diseases and Immunology, Harvard School of Public Health; Senior Physician, Infectious Diseases Service, Massachusetts General Hospital, Boston, Massachusetts Antiretroviral Therapy for Human Immunodeficiency Virus Infection

Aimee Hodowanec, MD

Assistant Professor, Department of Medicine, Division of Infectious Diseases, Rush University Medical Center, Chicago, Illinois Tetanus (Clostridium tetani); Botulism (Clostridium botulinum)

Tobias M. Hohl, MD, PhD

Harold W. Horowitz, MD

Professor of Medicine, Infectious Diseases and Immunology, Department of Medicine, New York University School of Medicine; Chief of Service Infectious Diseases, Bellevue Hospital Center, New York, New York Acute Exacerbations of Chronic Obstructive Pulmonary Disease

C. Robert Horsburgh, Jr., MD, MUS

Professor of Epidemiology, Biostatistics, and Medicine, Boston University Schools of Public Health and Medicine, Boston, Massachusetts Mycobacterium avium Complex

James M. Horton, MD

Chief, Division of Infectious Diseases, Department of Internal Medicine, Carolinas Medical Center, Charlotte, North Carolina Urinary Tract Agents: Nitrofurantoin, Fosfomycin, and Methenamine; Relapsing Fever Caused by Borrelia Species

Duane R. Hospenthal, MD, PhD

Adjunct Professor of Medicine, Department of Medicine, Infectious Disease Division, University of Texas Health Science Center at San Antonio, San Antonio, Texas Agents of Chromoblastomycosis; Agents of Mycetoma; Uncommon Fungi and Related Species

Kevin Hsueh, MD

Infectious Diseases Fellow, NYU Langone Medical Center, New York, New York Outpatient Parenteral Antimicrobial Therapy

James M. Hughes, MD

Professor of Medicine (Infectious Diseases) and Public Health (Global Health), School of Medicine and Rollins School of Public Health, Emory University, Atlanta, Georgia Emerging and Reemerging Infectious Disease Threats

Assistant Member, Department of Medicine, Infectious Disease Service, Memorial Sloan Kettering Cancer Center; Head, Laboratory of Antifungal Immunity, Assistant Member (Joint), Immunology Program, Sloan Kettering Institute; Assistant Professor, Department of Medicine, Weill Cornell Medical College, New York, New York

Noreen A. Hynes, MD, MPH

Steven M. Holland, MD

Nicole M. Iovine, MD, PhD

Cell-Mediated Defense against Infection

Chief, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland Evaluation of the Patient with Suspected Immunodeficiency

Robert S. Holzman, MD

Professor Emeritus of Medicine, Department of Medicine, Division of Infectious Diseases and Immunology, New York University School of Medicine, New York, New York Mycoplasma pneumoniae and Atypical Pneumonia

Edward W. Hook III, MD

Professor and Director, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama Endemic Treponematoses

David C. Hooper, MD

Associate Chief, Division of Infectious Diseases, Chief, Infection Control Unit, Massachusetts General Hospital, Boston, Massachusetts Quinolones

Thomas M. Hooton, MD

Professor of Clinical Medicine, Department of Medicine, Clinical Director, Division of Infectious Diseases, University of Miami Miller School of Medicine; Chief of Medicine, Miami Veterans Affairs Healthcare System, Miami, Florida Nosocomial Urinary Tract Infections

Associate Professor, Johns Hopkins University Schools of Medicine and Public Health; Director, Geographic Medicine Center of the Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland Bioterrorism: An Overview

Assistant Professor of Medicine, Director, Antimicrobial Stewardship Program, Department of Medicine, Division of Infectious Diseases and Global Medicine, University of Florida School of Medicine, Gainesville, Florida Campylobacter jejuni and Related Species

Jonathan R. Iredell, MBBS, PhD

Associate Professor, University of Sydney Faculty of Medicine, Sydney, New South Wales, Australia; Director, Department of Infectious Diseases, Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, New South Wales, Australia Nocardia Species

Michael G. Ison, MD, MS

Associate Professor, Divisions of Infectious Diseases and Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, Illinois Parainfluenza Viruses

J. Michael Janda, PhD, D(ABMM)

Laboratory Director, Public Health Laboratory, Department of Public Health, County of Los Angeles, Downey, California Capnocytophaga

Contributors

Professor of Medicine and Chief, Section on Infectious Diseases, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina


xiv

Contributors

Edward N. Janoff, MD

Professor of Medicine, Microbiology, and Immunology, Departments of Medicine and Infectious Diseases, University of Colorado Denver, Aurora, Colorado; Director, Mucosal and Vaccine Research Center, Denver Veterans Affairs Medical Center, Denver, Colorado Streptococcus pneumoniae

Eric C. Johannsen, MD

Assistant Professor of Medicine, University of Wisconsin School of Medicine and Public Health; Physician, Division of Infectious Diseases, University of Wisconsin Hospitals and Clinics, Madison, Wisconsin Epstein-Barr Virus (Infectious Mononucleosis, Epstein-Barr Virus– Associated Malignant Diseases, and Other Diseases)

Angela D. M. Kashuba, PharmD

John A. and Deborah S. McNeill Jr. Distinguished Professor and Vice Chair for Research and Graduate Education, Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy; Director, UNC Center for AIDS Research Clinical Pharmacology and Analytical Chemistry Core; Adjunct Professor, University of North Carolina School of Medicine, Chapel Hill, North Carolina Pharmacokinetics Agents

and

Pharmacodynamics

of

Anti-infective

Dennis L. Kasper, MD

William Ellery Channing Professor of Medicine, Professor of Microbiology and Immunology, Department of Microbiology and Immunology, Harvard Medical School, Boston, Massachusetts Anaerobic Infections: General Concepts

Donald Kaye, MD

Professor of Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania Polymyxins (Polymyxin B and Colistin); Urinary Tract Infections

Keith S. Kaye, MD, MPH

Professor of Medicine, Wayne State University; Corporate Vice President, Quality and Patient Safety, Corporate Medical Director, Infection Prevention, Hospital Epidemiology and Antimicrobial Stewardship, Detroit Medical Center, Detroit, Michigan Polymyxins (Polymyxin B and Colistin)

Kenneth M. Kaye, MD

Associate Professor, Department of Medicine, Harvard Medical School; Attending Physician, Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, Massachusetts Epstein-Barr Virus (Infectious Mononucleosis, Epstein-Barr Virus– Associated Malignant Diseases, and Other Diseases); Kaposi’s Sarcoma–Associated Herpesvirus (Human Herpesvirus 8)

James W. Kazura, MD

Professor of International Health, Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio

Tissue Nematodes (Trichinellosis, Dracunculiasis, Filariasis, Loiasis, and Onchocerciasis)

Jay S. Keystone, MD, MSc (CTM)

Professor of Medicine, University of Toronto; Senior Staff Physician, Tropical Disease Unit, Toronto General Hospital, Toronto, Canada Cyclospora cayetanensis, Cystoisospora (Isospora) belli, Sarcocystis Species, Balantidium coli, and Blastocystis Species

Rima Khabbaz, MD

Deputy Director for Infectious Diseases, Director, Office of Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia Emerging and Reemerging Infectious Disease Threats

David A. Khan, MD

Professor of Medicine and Pediatrics, Program Director, Allergy and Immunology Fellowship Program, Departments of Internal Medicine and Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas Antibiotic Allergy

Yury Khudyakov, PhD

Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia Hepatitis A Virus

Rose Kim, MD

Associate Professor of Medicine, Division of Infectious Diseases, Cooper Medical School of Rowan University, Cooper University Hospital, Camden, New Jersey Other Coryneform Bacteria and Rhodococci

Charles H. King, MD

Professor of International Health, Center for Global Health and Diseases, Case Western Reserve University, Cleveland, Ohio Tapeworms (Cestodes)

Louis V. Kirchhoff, MD, MPH

Professor of Internal Medicine, University of Iowa; Staff Physician, Medical Service, Department of Veterans Affairs Medical Center, Iowa City, Iowa; Professor of Medicine, State University of New York Upstate Medical University, Syracuse, New York

Drugs for Protozoal Infections Other Than Malaria; Trypanosoma Species (American Trypanosomiasis, Chagas’ Disease): Biology of Trypanosomes; Agents of African Trypanosomiasis (Sleeping Sickness)

Jerome O. Klein, MD

Professor, Department of Pediatrics, Boston University School of Medicine; Former Director, Division of Pediatric Infectious Diseases, Boston Medical Center, Boston, Massachusetts Otitis Externa, Otitis Media, and Mastoiditis

Michael Klompas, MD, MPH

Associate Professor of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute; Associate Hospital Epidemiologist, Brigham and Women’s Hospital, Boston, Massachusetts Nosocomial Pneumonia

Bettina M. Knoll, MD, PhD

Assistant Professor of Medicine, Warren Alpert Medical School of Brown University; Physician, Miriam Hospital and Rhode Island Hospital, Providence, Rhode Island Prosthetic Valve Endocarditis

Kirk U. Knowlton, MD

Professor of Medicine, Chief of Cardiology, University of California San Diego School of Medicine, La Jolla, California Myocarditis and Pericarditis

Jane E. Koehler, MA, MD

Professor of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, California Bartonella, Including Cat-Scratch Disease

Stephan A. Kohlhoff, MD

Assistant Professor of Pediatrics and Medicine, State University of New York Downstate College of Medicine; Co-Director, Division of Pediatric Infectious Diseases, State University of New York Downstate Medical Center, Brooklyn, New York Chlamydia pneumoniae


xv

Eija Kรถnรถnen, DDS, PhD

Professor, Institute of Dentistry, University of Turku, Turku, Finland

Dimitrios P. Kontoyiannis, MD

Frances King Black Endowed Professor, Department of Infectious Diseases, Deputy Head, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas Agents of Mucormycosis and Entomophthoramycosis

Igor J. Koralnik, MD

Professor of Neurology, Harvard Medical School; Chief, Division of Neuro-Virology, Director, HIV/Neurology Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts

Neurologic Diseases Caused by Human Immunodeficiency Virus Type 1 and Opportunistic Infections; JC, BK, and Other Polyomaviruses: Progressive Multifocal Leukoencephalopathy (PML)

Poonum S. Korpe, MD

Infectious Diseases Fellow, University of Virginia School of Medicine, Charlottesville, Virginia Introduction to Protozoal Diseases

Anita A. Koshy, MD

Assistant Professor, Department of Medicine, Harvard Medical School; Assistant Physician, Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts Syndromes of Enteric Infection

James E. Leggett, MD

Associate Professor of Medicine, Oregon Health and Science University; Infectious Diseases Consultant, Medical Education, Providence Portland Medical Center, Portland, Oregon Aminoglycosides

Helena Legido-Quigley, MSc, PhD

Lecturer in Global Health, London School of Hygiene and Tropical Medicine, London, United Kingdom

Global Perspectives on Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome

Paul N. Levett, PhD, DSc

Assistant Clinical Director, Saskatchewan Disease Control Laboratory, Regina, Saskatchewan, Canada Leptospira Species (Leptospirosis)

Donald P. Levine, MD

Assistant Professor, Departments of Neurology and Immunobiology, University of Arizona, Tucson, Arizona

Professor of Medicine, Associate Vice Chair for Continuing Medical Education and Community Affairs, Department of Medicine, Wayne State University, Detroit, Michigan

Joseph A. Kovacs, MD

Matthew E. Levison, MD

Free-Living Amebae

Senior Investigator, Head, AIDS Section, Critical Care Medicine Department, National Institute of Health Clinical Center, Bethesda, Maryland Toxoplasma gondii

Phyllis Kozarsky, MD

Professor of Medicine, Division of Infectious Diseases, Emory University School of Medicine; Medical Director, TravelWell, Emory University Hospital, Atlanta, Georgia Cyclospora cayetanensis, Cystoisospora (Isospora) belli, Sarcocystis Species, Balantidium coli, and Blastocystis Species

John Krieger, MD

Professor, Department of Urology, University of Washington; Chief, Urology Section, Veterans Affairs Puget Sound Health Care System, Seattle, Washington Prostatitis, Epididymitis, and Orchitis

Andrew T. Kroger, MD, MPH

Medical Officer, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia Immunization

Matthew J. Kuehnert, MD

Director, Office of Blood, Organ, and Other Tissue Safety, Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia Transfusion- and Transplantation-Transmitted Infections

Nalin M. Kumar, DPhil

Professor, Department of Ophthalmology and Visual Sciences, College of Medicine, University of Illinois at Chicago, Chicago, Illinois Microbial Conjunctivitis

Merin Elizabeth Kuruvilla, MD

Department of Internal Medicine, Division of Allergy/Immunology, University of Texas Southwestern Medical Center, Dallas, Texas Antibiotic Allergy

Infections in Injection Drug Users

Professor of Public Health, Drexel University School of Public Health; Adjunct Professor of Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania Peritonitis and Intraperitoneal Abscesses

Alexandra Levitt, PhD

Health Scientist, Office of Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia Emerging and Reemerging Infectious Disease Threats

Russell E. Lewis, PharmD

Associate Professor, Department of Medical Sciences and Surgery, University of Bologna Infectious Diseases Unit, S. Orsola Malpighi Hospital, Bologna, Italy Agents of Mucormycosis and Entomophthoramycosis

W. Conrad Liles, MD, PhD

Associate Chair and Professor of Medicine, University of Washington School of Medicine, Seattle, Washington Immunomodulators

Aldo A. M. Lima, MD, PhD

Professor, Institute of Biomedicine, Federal University of Ceara, Fortaleza, Cearรก, Brazil Bacterial Inflammatory Enteritides

Ajit P. Limaye, MD

Professor, Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle, Washington Infections in Solid-Organ Transplant Recipients

W. Ian Lipkin, MD

Director, Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York Zoonoses

Contributors

Anaerobic Cocci and Anaerobic Gram-Positive Nonsporulating Bacilli

Regina C. LaRocque, MD


xvi

Contributors

Nathan Litman, MD

Professor of Pediatrics, Albert Einstein College of Medicine; Vice Chair, Clinical Affairs, Department of Pediatrics, Chief, Division of Pediatric Infectious Diseases, Children’s Hospital at Montefiore, Bronx, New York Mumps Virus

Bennett Lorber, MD, DSc (Hon)

Thomas M. Durant Professor of Medicine, Professor of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania Bacterial Lung Abscess; Listeria monocytogenes

Ruth Ann Luna, PhD

Assistant Professor, Texas Children’s Microbiome Center, Department of Pathology and Immunology, Baylor College of Medicine; Department of Pathology, Texas Children’s Hospital, Houston, Texas The Human Microbiome of Local Body Sites and Their Unique Biology

Conan MacDougall, PharmD, MAS

Associate Professor of Clinical Pharmacy, Department of Clinical Pharmacy, University of California San Francisco School of Pharmacy, San Francisco, California Antimicrobial Stewardship

Rob Roy MacGregor, MD

Professor, Department of Medicine, Division of Infectious Diseases, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Corynebacterium diphtheriae (Diphtheria)

Philip A. Mackowiak, MD, MBA

Professor and Vice Chairman, Department of Medicine, University of Maryland School of Medicine; Chief, Medical Care Clinical Center, Veterans Affairs Maryland Health Care System, Baltimore, Maryland Temperature Regulation and the Pathogenesis of Fever; Fever of Unknown Origin

Lawrence C. Madoff, MD

Professor of Medicine, University of Massachusetts Medical School; Director, Division of Epidemiology and Immunization, Massachusetts Department of Public Health; Division of Infectious Disease and Immunology, University of Massachusetts Memorial Medical Center, Worcester, Massachusetts Infections of the Liver and Biliary System (Liver Abscess, Cholangitis, Cholecystitis); Splenic Abscess; Appendicitis; Diverticulitis and Typhlitis

Alan J. Magill, MD

Director, Malaria, Bill and Melinda Gates Foundation, Seattle, Washington

Leishmania Species: Visceral (Kala-Azar), Cutaneous, and Mucosal Leishmaniasis

James H. Maguire, MD, MPH

Professor of Medicine, Harvard Medical School; Senior Physician, Division of Infectious Disease, Brigham and Women’s Hospital, Boston, Massachusetts Introduction to Helminth Infections; Intestinal Nematodes (Roundworms); Trematodes (Schistosomes and Liver, Intestinal, and Lung Flukes)

Frank Maldarelli, MD, PhD

Head, Clinical Retrovirology Section, HIV Drug Resistance Program, National Cancer Institute—Frederick, National Institutes of Health, Frederick, Maryland Diagnosis of Human Immunodeficiency Virus Infection

Lewis Markoff, MD

Chief, Laboratory of Vector-Borne Virus Diseases, Office of Vaccines, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland Alphaviruses

Jeanne M. Marrazzo, MD, MPH

Associate Professor of Medicine, Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle, Washington Neisseria gonorrhoeae (Gonorrhea)

Thomas J. Marrie, MD

Dean, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada Coxiella burnetii (Q Fever)

Thomas Marth, MD

Professor of Internal Medicine, Chief, Division of Internal Medicine, Krankenhaus Maria Hilf, Daun, Germany Whipple’s Disease

David H. Martin, MD

Harry E. Dascomb, M.D., Professor of Medicine, Department of Internal Medicine, Professor of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana Genital Mycoplasmas: Mycoplasma genitalium, Mycoplasma hominis, and Ureaplasma Species

Gregory J. Martin, MD

Chief, Infectious Diseases—Tropical Medicine, Office of Medical Services, U.S. Department of State, Washington, DC; Associate Professor of Medicine and Preventive Medicine and Biometrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland Bacillus anthracis (Anthrax)

Francisco M. Marty, MD

Associate Professor of Medicine, Department of Medicine, Harvard Medical School; Brigham and Women’s Hospital, Boston, Massachusetts Cystic Fibrosis

Melanie Jane Maslow, MD

Professor of Medicine, Department of Internal Medicine, New York University School of Medicine; Chief, Infectious Diseases, Veterans Affairs New York Harbor Healthcare System, New York, New York Rifamycins

Henry Masur, MD

Chief, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland

Management of Opportunistic Infections Associated with Human Immunodeficiency Virus Infection

Alison Mawle, MD

Associate Director for Laboratory Science, Centers for Disease Control and Prevention, Atlanta, Georgia Immunization

Kenneth H. Mayer, MD

Professor of Medicine, Harvard Medical School; Professor, Department of Global Health and Population, Harvard School of Public Health; Infectious Disease Attending and Director of HIV Prevention Research, Beth Israel Deaconess Medical Center; Medical Research Director, The Fenway Institute, Fenway Health, Boston, Massachusetts Sulfonamides and Trimethoprim


xvii

John T. McBride, MD

Croup in Children (Acute Laryngotracheobronchitis); Bronchiolitis

John F. Modlin, MD

Professor of Pediatrics and Medicine, Chair, Department of Pediatrics, Senior Advising Dean, Geisel School of Medicine at Dartmouth; Interim Director, Children’s Hospital at Dartmouth, Lebanon, New Hampshire Introduction to the Human Enteroviruses and Parechoviruses; Poliovirus; Coxsackieviruses, Echoviruses, and Numbered Enteroviruses; Human Parechoviruses

James S. McCarthy, MD

Professor of Medicine, Division of Infectious Diseases, Royal Brisbane and Women’s Hospital; Professor of Medicine, Department of Infectious Diseases, Queensland Institute of Medical Research, University of Queensland, Brisbane, Australia Antimalarial Drugs; Drugs for Protozoal Infections Other Than Malaria; Drugs for Helminths

William M. McCormack, MD

Distinguished Teaching Professor of Medicine and of Obstetrics and Gynecology, Emeritus, Division of Infectious Diseases, Department of Medicine, SUNY Downstate Medical Center, Brooklyn, New York Urethritis; Vulvovaginitis and Cervicitis

Catherine C. McGowan, MD

Associate Professor, Department of Medicine, Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, Tennessee Prostatitis, Epididymitis, and Orchitis

Kenneth McIntosh, MD

Professor of Pediatrics, Harvard Medical School; Senior Physician, Department of Medicine, Children’s Hospital, Boston, Massachusetts

Coronaviruses, Including Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS)

Paul S. Mead, MD, MPH

Chief, Epidemiology and Surveillance Activity, Bacterial Disease Branch, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado Yersinia Species (Including Plague)

Malgorzata Mikulska, MD

Division of Infectious Diseases, IRCCS AOU San Martino-IST; Department of Health Sciences, University of Genova, Genova, Italy Prophylaxis and Empirical Therapy of Infection in Cancer Patients

Robert F. Miller, MBBS

Reader in Clinical Infection, Honorary Professor, London School of Hygiene and Tropical Medicine; Honorary Consultant Physician, Camden Provider Services, Central and North West London NHS Foundation Trust, and at University College London Hospitals, University College London, London, United Kingdom Pneumocystis Species

Samuel I. Miller, MD

Professor of Medicine, Microbiology, Genome Sciences, and Immunology, Department of Immunology, University of Washington School of Medicine, Seattle, Washington Salmonella Species

David H. Mitchell, MBBS

Clinical Senior Lecturer, University of Sydney Faculty of Medicine, Sydney, New South Wales, Australia; Senior Staff Specialist, Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, New South Wales, Australia Nocardia Species

Rajal K. Mody, MD, MPH

Lead, National Surveillance Team, Enteric Diseases Epidemiology Branch, Division of Foodborne, Waterborne, and Environmental Diseases, National Center for Emerging and Zoonotic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia Foodborne Disease

Robert C. Moellering, Jr., MD†

Shields Warren-Mallinckrodt Professor of Medical Research, Harvard Medical School; Physician, Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts Principles of Anti-infective Therapy

Matthew Moffa, DO

Physician, Infectious Diseases and Travel Medicine, Georgetown University Hospital, Washington, DC Tetracyclines, Glycylcyclines, and Chloramphenicol

Susan Moir, PhD

Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland The Immunology of Human Immunodeficiency Virus Infection

José G. Montoya, MD

Professor of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, California Toxoplasma gondii

Thomas A. Moore, MD

Clinical Professor of Medicine, University of Kansas School of Medicine at Wichita, Wichita, Kansas Drugs for Helminths

Philippe Moreillon, MD, PhD

Professor and Vice Rector for Research, Department of Fundamental Microbiology, University of Lausanne, Lausanne, Switzerland Staphylococcus aureus (Including Staphylococcal Toxic Shock Syndrome)

J. Glenn Morris, Jr., MD, MPH&TM

Director, Emerging Pathogens Institute, University of Florida; Professor of Medicine, Division of Infectious Diseases. University of Florida College of Medicine, Gainesville, Florida Human Illness Associated with Harmful Algal Blooms

Caryn Gee Morse, MD, MPH

Assistant Clinical Investigator, Critical Care Medicine Department, HIV/AIDS Section, National Institutes of Health Clinical Center, Bethesda, Maryland Nutrition, Immunity, and Infection

Robin Moseley, MAT

Public Health Advisor, Office of Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia Emerging and Reemerging Infectious Disease Threats

Deceased.

Contributors

Professor of Pediatrics, Northeast Ohio Medical University, Roots­ town, Ohio; Vice Chair, Department of Pediatrics, Akron Children’s Hospital, Akron, Ohio


xviii

Contributors

Robert S. Munford, MD

Senior Clinician, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland Sepsis, Severe Sepsis, and Septic Shock

Edward L. Murphy, MD, MPH

Professor, Departments of Laboratory Medicine and Epidemiology/ Biostatistics, University of California School of Medicine; Senior Investigator, Blood Systems Research Institute, San Francisco, California Human T-Lymphotropic Virus (HTLV)

Timothy F. Murphy, MD

SUNY Distinguished Professor, Clinical and Translational Research Center, University at Buffalo, State University of New York, Buffalo, New York

Moraxella catarrhalis, Kingella, and Other Gram-Negative Cocci; Haemophilus Species, including H. influenzae and H. ducreyi (Chancroid)

Barbara E. Murray, MD

J. Ralph Meadows Professor and Director, Division of Infectious Diseases, Department of Internal Medicine and Department of Microbiology and Molecular Genetics, University of Texas Medical School at Houston, Houston, Texas

Glycopeptides (Vancomycin and Teicoplanin), Streptogramins (Quinupristin-Dalfopristin), Lipopeptides (Daptomycin), and Lipoglycopeptides (Telavancin); Enterococcus Species, Streptococcus gallolyticus Group, and Leuconostoc Species

Clinton K. Murray, MD

Chief, Infectious Disease, Brooke Army Medical Center, Fort Sam Houston, Houston, Texas; Professor of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland; Clinical Professor of Medicine and Infectious Diseases, University of Texas Health Sciences Center, San Antonio, Texas Burns

Patrick R. Murray, PhD

Worldwide Director, Scientific Affairs, Becton Dickinson, Sparks, Maryland The Clinician and the Microbiology Laboratory

Daniel M. Musher, MD

Professor of Medicine and of Molecular Virology and Microbiology, Distinguished Service Professor, Baylor College of Medicine; Infectious Disease Section, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas Streptococcus pneumoniae

Jerod L. Nagel, PharmD

Adjunct Clinical Instructor, University of Michigan, College of Pharmacy; Clinical Pharmacist, Infectious Diseases, University of Michigan Hospitals and Health Systems, Ann Arbor, Michigan Metronidazole

Esteban C. Nannini, MD

Assistant Professor, Division of Infectious Diseases, School of Medicine, Universidad Nacional de Rosario; Director, Division of Infectious Diseases and Clinical Research Unit, Sanatorio Británico, Rosario, Argentina Glycopeptides (Vancomycin and Teicoplanin), Streptogramins (Quinupristin-Dalfopristin), Lipopeptides (Daptomycin), and Lipoglycopeptides (Telavancin)

Anna Narezkina, MD

Fellow, Division of Cardiology, University of California San Diego School of Medicine, La Jolla, California Myocarditis and Pericarditis

Theodore E. Nash, MD

Head, Gastrointestinal Parasites Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

Giardia lamblia; Visceral Larva Migrans and Other Uncommon Helminth Infections

William M. Nauseef, MD

Professor of Medicine and Microbiology, Inflammation Program and Department of Medicine, University of Iowa Carver College of Medicine; Attending Physician, Iowa City Veterans Affairs Medical Center, Iowa City, Iowa Granulocytic Phagocytes

Jennifer L. Nayak, MD

Assistant Professor, Department of Pediatrics, University of Rochester School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York Epiglottitis

Marguerite A. Neill, MD

Associate Professor of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island; Attending Physician, Division of Infectious Diseases, Memorial Hospital of Rhode Island, Pawtucket, Rhode Island Other Pathogenic Vibrios

Judith A. O’Donnell, MD

Associate Professor of Clinical Medicine, Division of Infectious Diseases, Perelman School of Medicine at the University of Pennsylvania; Chief, Division of Infectious Diseases, Hospital Epidemiologist and Director, Department of Infection Prevention & Control and Healthcare Epidemiology, Penn Presbyterian Medical Center, Philadelphia, Pennsylvania Topical Antibacterials

Christopher A. Ohl, MD

Professor of Medicine, Section on Infectious Diseases, Wake Forest School of Medicine; Medical Director, Center for Antimicrobial Utilization, Stewardship, and Epidemiology, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina Infectious Arthritis of Native Joints

Pablo C. Okhuysen, MD

Professor, Department of Infectious Diseases, Infection Control and Employee Health, MD Anderson Cancer Center, Houston, Texas Sporothrix schenckii

Andrew B. Onderdonk, PhD

Professor of Pathology, Harvard Medical School; Microbiology Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts

Gas Gangrene and Other Clostridium-Associated Diseases; Bacteroides, Prevotella, Porphyromonas, and Fusobacterium Species (and Other Medically Important Anaerobic Gram-Negative Bacilli)

Steven M. Opal, MD

Professor of Medicine, Infectious Disease Division, Warren Alpert Medical School of Brown University, Providence, Rhode Island; Chief, Infectious Disease Division, Memorial Hospital of Rhode Island, Pawtucket, Rhode Island Molecular Mechanisms of Antibiotic Resistance in Bacteria

Walter A. Orenstein, MD

Professor of Infectious Diseases, Department of Medicine, Emory University School of Medicine; Director, Strategic Planning, The Hope Clinic; Director, Emory Program for Vaccine Policy and Development, Atlanta, Georgia Immunization


xix

Douglas R. Osmon, MD Osteomyelitis

Michael T. Osterholm, PhD, MPH

Professor, Division of Environmental Health Sciences, University of Minnesota School of Public Health; Adjunct Professor, University of Minnesota Medical School, Minneapolis, Minnesota Epidemiologic Principles

Stephen M. Ostroff, MD

Chief Science Officer (Acting), Office of the Chief Scientist, U.S. Food and Drug Administration, Silver Spring, Maryland Emerging and Reemerging Infectious Disease Threats

Michael N. Oxman, MD

Professor of Medicine and Pathology, University of California San Diego School of Medicine, La Jolla, California; Staff Physician, Infectious Diseases, Veterans Affairs San Diego Healthcare System, San Diego, California Myocarditis and Pericarditis

Slobodan Paessler, DVM, PhD

Professor, Department of Pathology, Director, Preclinical Studies Core, Director, Animal Biosafety Level 3, Galveston National Laboratory, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas

Lymphocytic Choriomeningitis, Lassa Fever, and the South American Hemorrhagic Fevers (Arenaviruses)

Andrea V. Page, MD, MSc

Assistant Professor, Department of Medicine, University of Toronto; Staff Physician, Division of Infectious Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada Immunomodulators

Manjunath P. Pai, PharmD

Associate Professor, Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, New York

Pharmacokinetics and Pharmacodynamics of Anti-infective Agents; Tables of Anti-infective Agent Pharmacology

Tara N. Palmore, MD

Epidemiologist, National Institutes of Health Clinical Center; Attending Physician, Infectious Diseases Consultation Service, Program Director, Infectious Diseases Training Program, National Institute of Allergy and Infectious Diseases/National Institutes of Health, Bethesda, Maryland Nosocomial Herpesvirus Infections

Raj Palraj, MBBS

Instructor of Medicine, Mayo Clinic College of Medicine; Senior Associate Consultant, Infectious Diseases, Mayo Clinic, Rochester, Minnesota Prosthetic Valve Endocarditis

Peter G. Pappas, MD

Professor of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama Chronic Pneumonia

Mark S. Pasternack, MD

Chief, Pediatric Infectious Disease Unit, Massachusetts General Hospital, Boston, Massachusetts

Cellulitis, Necrotizing Fasciitis, and Subcutaneous Tissue Infections; Myositis and Myonecrosis; Lymphadenitis and Lymphangitis

Thomas F. Patterson, MD

Professor, Department of Medicine, Division of Infectious Diseases, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, Texas Aspergillus Species

Deborah Pavan-Langston, MD

Professor, Department of Ophthalmology, Harvard Medical School; Attending Physician, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts Microbial Conjunctivitis; Microbial Keratitis

David A. Pegues, MD

Professor of Medicine, Division of Infectious Diseases, Perelman School of Medicine at the University of Pennsylvania; Medical Director, Healthcare Epidemiology, Infection Prevention and Control; Antimicrobial Management Program, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Salmonella Species

Robert L. Penn, MD

Professor of Medicine, Infectious Diseases Section, Louisiana State University School of Medicine in Shreveport; Physician, Infectious Diseases Section, Overton Brooks Veterans Affairs Medical Center, Shreveport, Louisiana Francisella tularensis (Tularemia)

John R. Perfect, MD

James B. Duke Professor of Medicine, Chief, Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, North Carolina

Cryptococcosis (Cryptococcus neoformans and Cryptococcus gattii)

Stanley Perlman, MD, PhD

Professor, Department of Microbiology and Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa

Coronaviruses, Including Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS)

Brett W. Petersen, MD, MPH

Medical Officer, Poxvirus and Rabies Branch, Division of HighConsequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia Orthopoxviruses: Vaccinia (Smallpox Vaccine), Variola (Smallpox), Monkeypox, and Cowpox; Other Poxviruses That Infect Humans: Parapoxviruses (Including Orf Virus), Molluscum Contagiosum, and Yatapoxviruses

Phillip K. Peterson, MD

Professor of Medicine, Director, International Medical Education and Research, University of Minnesota Medical School, Minneapolis, Minnesota Infections in the Elderly

William A. Petri, Jr., MD, PhD

Wade Hampton Frost Professor of Epidemiology, University of Virginia; Chief, Division of Infectious Disease and International Health, University of Virginia Health System, Charlottesville, Virginia

Introduction to Protozoal Diseases; Entamoeba Species, Including Amebic Colitis and Liver Abscess

Cathy A. Petti, MD

CEO, HealthSpring Global, Inc., Bradenton, Florida Streptococcus anginosus Group

Jennifer A. Philips, MD, PhD

Assistant Professor, Department of Infectious Diseases, New York University School of Medicine, New York, New York Introduction to Bacteria and Bacterial Diseases

Contributors

Professor of Medicine, Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota


xx

Julie V. Philley, MD Contributors

University of Texas Health Science Center at Tyler, Tyler, Texas Antimycobacterial Agents

Michael Phillips, MD

Associate Professor (Clinical), Associate Director for Clinical Affairs, Division of Infectious Disease and Immunology, New York University School of Medicine; Hospital Epidemiologist and Director of Infection Prevention and Control, NYU Langone Medical Center, New York, New York Acinetobacter Species

Larry K. Pickering, MD

Senior Advisor to the Director, National Center for Immunization and Respiratory Diseases; Executive Secretary, Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention, Atlanta, Georgia Immunization

Peter Piot, MD, PhD

Director and Professor of Global Health, London School of Hygiene and Tropical Medicine, London, United Kingdom

Global Perspectives on Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome

Jason M. Pogue, PharmD

Clinical Pharmacist, Infectious Diseases, Sinai Grace Hospital; Detroit Medical Center; Clinical Assistant Professor of Medicine, Wayne State University School of Medicine, Detroit, Michigan Polymyxins (Polymyxin B and Colistin)

Aurora Pop-Vicas, MD, MPH

Assistant Professor of Medicine, Infectious Disease Division, Warren Alpert Medical School of Brown University, Providence, Rhode Island; Infection Control Officer, Memorial Hospital of Rhode Island, Pawtucket, Rhode Island Molecular Mechanisms of Antibiotic Resistance in Bacteria

Cynthia Portal-Celhay, MD, PhD

Instructor, Department of Medicine/Infectious Diseases, New York University School of Medicine, New York, New York Rifamycins

John H. Powers III, MD

Associate Clinical Professor, Department of Medicine, George Washington University School of Medicine, Washington, DC; Senior Medical Scientist, Division of Clinical Research, Leidos Biomedical Research in support of National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland Designing and Diseases

Interpreting

Clinical

Studies

in

Infectious

Richard N. Price, MD

Professor, Global Health Division, Menzies School of Health Research, Darwin, Australia; Professor, Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom Antimalarial Drugs

Yok-Ai Que, MD, PhD

Instructor and Researcher, University of Lausanne School of Medicine; Attending Physician, Department of Critical Care Medicine, Centre Hospitalier Universitaire Vaudois Lausanne, Lausanne, Switzerland Staphylococcus aureus (Including Staphylococcal Toxic Shock Syndrome)

Justin D. Radolf, MD

Professor, Departments of Medicine, Pediatrics, Immunology, Genetics & Developmental Biology, and Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, Connecticut; Senior Scientific Advisor, Connecticut Children’s Medical Center, Hartford, Connecticut Syphilis (Treponema pallidum)

Sanjay Ram, MBBS

Associate Professor of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical Center, Worcester, Massachusetts Complement and Deficiencies

Didier Raoult, MD, PhD

Professor and President, Aix Marseille Université; Director, Clinical Microbiology Laboratory for the University Hospitals; Founder, WHO Collaborative Center; President, Universite de la Mediteranee in Marseille, Marseille, France Introduction to Rickettsioses, Ehrlichioses, and Anaplasmosis; Rickettsia akari (Rickettsialpox); Coxiella burnetii (Q Fever); Orientia tsutsugamushi (Scrub Typhus)

Jonathan I. Ravdin, MD Milwaukee, Wisconsin

Introduction to Protozoal Diseases

Stuart C. Ray, MD

Professor of Medicine, Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland Hepatitis C

Annette C. Reboli, MD

Founding Vice Dean, Professor of Medicine, Division of Infectious Diseases, Cooper Medical School of Rowan University, Cooper University Hospital, Camden, New Jersey Other Coryneform Bacteria and Rhodococci; Erysipelothrix rhusiopathiae

Marvin S. Reitz, Jr., PhD

Professor, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland Human Immunodeficiency Viruses

David A. Relman, MD

Thomas C. and Joan M. Merigan Professor, Departments of Medicine and Microbiology & Immunology, Stanford University School of Medicine, Stanford, California; Chief of Infectious Diseases, Veterans Affairs Palo Alto Health Care System, Palo Alto, California A Molecular Perspective of Microbial Pathogenicity

Cybèle A. Renault, MD, DTM&H

Clinical Assistant Professor, Department of Internal Medicine, Division of Infectious Diseases, Stanford University School of Medicine, Stanford, California; Attending Physician, Veterans Affairs Palo Alto Health Care, Palo Alto, California Mycobacterium leprae (Leprosy)

Angela Restrepo, MSc, PhD

Senior Researcher, Medical and Experimental Mycology Unit, Corporación para Investigaciones Biológicas, Medellín, Antioquia, Colombia Paracoccidioidomycosis


xxi

John H. Rex, MD

Drugs Active against Fungi, Pneumocystis, and Microsporidia; Sporothrix schenckii

Elizabeth G. Rhee, MD

Director, Clinical Research, Department of Clinical Pharmacology, Merck Research Laboratories, Kenilworth, New Jersey Adenoviruses

Norbert J. Roberts, Jr., MD

Professor Emeritus, Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, Texas; Adjunct Professor, Department of Medicine, Division of Infectious Diseases and Immunology, New York University School of Medicine, New York, New York Hyperbaric Oxygen

José R. Romero, MD

Horace C. Cabe Professor of Infectious Diseases, Department of Pediatrics, University of Arkansas for Medical Sciences; Director, Pediatric Infectious Diseases Section, Department of Pediatrics, Arkansas Children’s Hospital; Director, Clinical Trials Research, Arkansas Children’s Hospital Research Institute, Little Rock, Arkansas Introduction to the Human Enteroviruses and Parechoviruses; Poliovirus; Coxsackieviruses, Echoviruses, and Numbered Enteroviruses; Human Parechoviruses

Alan L. Rothman, MD

Research Professor, Institute for Immunology and Informatics and Department of Cell and Molecular Biology, University of Rhode Island, Providence, Rhode Island

Flaviviruses (Dengue, Yellow Fever, Japanese Encephalitis, West Nile Encephalitis, St. Louis Encephalitis, Tick-Borne Encephalitis, Kyasanur Forest Disease, Alkhurma Hemorrhagic Fever, Zika)

Craig R. Roy, PhD

Professor, Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut Legionnaires’ Disease and Pontiac Fever

Kathryn L. Ruoff, PhD

Associate Professor of Pathology, Geisel School of Medicine, Hanover, New Hampshire; Associate Director, Clinical Microbiology Laboratory, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire Classification of Streptococci

Mark E. Rupp, MD

William A. Rutala, MS, PhD, MPH

Professor of Medicine, Director, Statewide Program for Infection Control and Epidemiology, University of North Carolina at Chapel Hill School of Medicine; Director, Hospital Epidemiology, Occupational Health and Safety, University of North Carolina Health Care, Chapel Hill, North Carolina The Acutely Ill Patient with Fever and Rash; Disinfection, Sterilization, and Control of Hospital Waste

Edward T. Ryan, MD

Professor of Medicine, Harvard Medical School; Professor of Immunology and Infectious Diseases, Harvard School of Public Health; Director, Tropical Medicine, Massachusetts General Hospital, Boston, Massachusetts Enteric Fever and Other Causes of Fever and Abdominal Symptoms; Vibrio cholerae

Amar Safdar, MD, MBBS

Associate Professor of Medicine, Division of Infectious Diseases and Immunology, New York University School of Medicine; Director, Transplant Infectious Diseases, Department of Medicine, NYU Langone Medical Center, New York, New York Unique Antibacterial Agents; Topical Antibacterials; Stenotrophomonas maltophilia and Burkholderia cepacia

Mohammad M. Sajadi, MD

Assistant Professor of Medicine, Institute of Human Virology, University of Maryland School of Medicine; Staff Physician, Department of Medicine, Baltimore Veterans Affairs Medical Center, Baltimore, Maryland Temperature Regulation and the Pathogenesis of Fever

Juan C. Salazar, MD, MPH

Professor and Chairman, Department of Pediatrics, University of Connecticut School of Medicine, Farmington, Connecticut; Physicianin-Chief, Head of Division of Pediatric Infectious Diseases and Immunology, Connecticut Children’s Medical Center, Hartford, Connecticut Syphilis (Treponema pallidum)

Juan Carlos Sarria, MD

Professor of Medicine, Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, Texas Hyperbaric Oxygen

Maria C. Savoia, MD

Dean for Medical Education, Professor of Medicine, University of California San Diego School of Medicine, La Jolla, California Myocarditis and Pericarditis

Paul E. Sax, MD

Professor and Chief, Infectious Diseases, University of Nebraska Medical Center; Medical Director, Infection Control and Epidemiology, The Nebraska Medical Center, Omaha, Nebraska

Professor of Medicine, Harvard Medical School; Clinical Director, Division of Infectious Diseases and Human Immunodeficiency Virus Program, Brigham and Women’s Hospital, Boston, Massachusetts

Charles E. Rupprecht, VMD, PhD

W. Michael Scheld, MD

Mediastinitis; Staphylococcus epidermidis and Other CoagulaseNegative Staphylococci

Research Coordinator at Global Alliance for Rabies Control, Atlanta, Georgia; Professor, Ross University School of Veterinary Medicine, Basseterre St. Kitts, West Indies Rabies (Rhabdoviruses)

Thomas A. Russo, MD, CM

Professor of Medicine and Microbiology, Division of Infectious Diseases, State University of New York at Buffalo School of Medicine and Biomedical Sciences; Staff Physician, Veterans Affairs Western New York Health Care System, Buffalo, New York Agents of Actinomycosis

Pulmonary Manifestations of Human Immunodeficiency Virus Infection

Gerald L. Mandell–Bayer Professor of Infectious Diseases, Professor of Medicine, University of Virginia School of Medicine; Clinical Professor of Neurosurgery, Director, Pfizer Initiative in International Health, University of Virginia Health System, Charlottesville, Virginia Endocarditis and Intravascular Infections; Acute Meningitis

Contributors

Adjunct Professor of Medicine, Department of Internal Medicine, Division of Infectious Diseases, Center for the Study of Emerging and Reemerging Pathogens, University of Texas Medical School, Houston, Texas; Head of Infection, Global Medicines Development, AstraZeneca Pharmaceuticals, Waltham, Massachusetts


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Contributors

Joshua T. Schiffer, MD, MSc

Assistant Professor, Department of Medicine, University of Washington; Assistant Member, Vaccine and Infectious Diseases Division, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Herpes Simplex Virus

David Schlossberg, MD

Professor, Department of Medicine, Temple University School of Medicine; Medical Director, Tuberculosis Control Program, Philadelphia Department of Public Health, Philadelphia, Pennsylvania Psittacosis (Due to Chlamydia psittaci)

Thomas Schneider, MD, PhD

Professor of Infectious Diseases, Charité University Hospital, Benjamin Franklin Campus, Berlin, Germany Whipple’s Disease

Anne Schuchat, MD (RADM USPHS)

Assistant Surgeon General, United States Public Health Service; Director, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia Emerging and Reemerging Infectious Disease Threats

Jane R. Schwebke, MD

Professor of Medicine, Medicine/Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama Trichomonas vaginalis

Cynthia L. Sears, MD

Professor of Medicine, Divisions of Infectious Diseases and Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland Prebiotics, Probiotics, and Synbiotics

Leopoldo N. Segal, MD

Assistant Professor, Department of Medicine, New York University School of Medicine, New York, New York Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Parham Sendi, MD

Consultant and Lecturer, Basel University Medical Clinic, Liestal, Switzerland; Department of Infectious Diseases, University Hospital and Institute for Infectious Diseases, University of Bern, Bern, Switzerland Orthopedic Implant–Associated Infections

Kent A. Sepkowitz, MD

Deputy Physician-in-Chief, Quality and Safety, Memorial Sloan Kettering Cancer Center; Professor of Medicine, Weill Cornell Medical College, New York, New York Health Care–Acquired Hepatitis

Edward J. Septimus, MD

Stanford T. Shulman, MD

Virginia H. Rogers Professor of Pediatric Infectious Diseases, Northwestern University Feinberg School of Medicine; Chief, Division of Infectious Diseases, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois Nonsuppurative Poststreptococcal Sequelae: Rheumatic Fever and Glomerulonephritis

George K. Siberry, MD, MPH

Medical Officer, Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland Pediatric Human Immunodeficiency Virus Infection

Omar K. Siddiqi, MD

Clinical Instructor, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Honorary Lecturer, Department Medicine, University of Zambia School of Medicine, Lusaka, Zambia

Neurologic Diseases Caused by Human Immunodeficiency Virus Type 1 and Opportunistic Infections

Costi D. Sifri, MD

Associate Professor of Medicine, Division of Infectious Diseases and International Health, University of Virginia School of Medicine; Attending Physician, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia

Infections of the Liver and Biliary System (Liver Abscess, Cholangitis, Cholecystitis); Appendicitis; Diverticulitis and Typhlitis

Michael S. Simberkoff, MD

Professor of Medicine, Department of Medicine, Division of Infectious Diseases and Immunology, New York University School of Medicine, New York, New York Mycoplasma pneumoniae and Atypical Pneumonia

Francesco R. Simonetti, MD

Guest Researcher, HIV Drug Resistance Program, National Cancer Institute—Frederick, National Institutes of Health, Frederick, Maryland Diagnosis of Human Immunodeficiency Virus Infection

Kamaljit Singh, MD, D(ABMM)

Associate Professor, Departments of Medicine and Pathology, Rush University Medical Center, Chicago, Illinois Rabies (Rhabdoviruses)

Nina Singh, MD

Professor of Medicine, Department of Medicine, Division of Infectious Diseases, University of Pittsburgh and VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania Infections in Solid-Organ Transplant Recipients

Clinical Professor, Department of Internal Medicine, Texas A&M Health Science Center, Houston, Texas; Medical Director, Infection Prevention and Epidemiology, Clinical Services Group, HCA, Inc., Nashville, Tennessee

Upinder Singh, MD

Alexey Seregin, PhD

Scott W. Sinner, MD

Pleural Effusion and Empyema

Research Scientist, Department of Pathology, University of Texas Medical Branch, Galveston, Texas Lymphocytic Choriomeningitis, Lassa Fever, and the South American Hemorrhagic Fevers (Arenaviruses)

Associate Professor of Medicine, Departments of Infectious Diseases and Microbiology & Immunology, Stanford School of Medicine, Stanford, California Free-Living Amebae

Hyperbaric Medical Director, Mercy-Clermont Hospital, Batavia, Ohio Viridans Streptococci, Nutritionally Variant Streptococci, Groups C and G Streptococci, and Other Related Organisms

Sumathi Sivapalasingam, MD

Assistant Professor, Department of Medicine, Division of Infectious Diseases and Immunology, New York University School of Medicine, New York, New York Macrolides, Clindamycin, and Ketolides


xxiii

Leonard N. Slater, MD

Timothy R. Sterling, MD

Professor of Medicine, Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, Tennessee

General Clinical Manifestations of Human Immunodeficiency Virus Infection (Including Acute Retroviral Syndrome and Oral, Cutaneous, Renal, Ocular, Metabolic, and Cardiac Diseases); Mycobacterium tuberculosis

Bartonella, Including Cat-Scratch Disease

A. George Smulian, MB BCh, MSc

Associate Professor, University of Cincinnati College of Medicine; Chief, Infectious Disease Section, Veterans Affairs Cincinnati Medical Center, Cincinnati, Ohio Pneumocystis Species

Jack D. Sobel, MD

Professor of Medicine, Division of Infectious Diseases, Wayne State University School of Medicine, Detroit, Michigan Urinary Tract Infections

M. Rizwan Sohail, MD

Associate Professor of Medicine, Divisions of Infectious Diseases and Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota Infections of Nonvalvular Cardiovascular Devices

David E. Soper, MD

Professor and Vice Chairman, Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, South Carolina Infections of the Female Pelvis

Tania C. Sorrell, AM, MD, MBBS

Professor and Director, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Sydney, New South Wales, Australia; Director, Centre for Infectious Diseases and Microbiology and Service Director, Infectious Diseases and Sexual Health, Westmead, New South Wales, Australia Nocardia Species

James M. Steckelberg, MD

Professor of Medicine, Consultant, Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota Osteomyelitis

Allen C. Steere, MD

Professor of Medicine, Harvard Medical School, Harvard University; Director, Translational Research in Rheumatology, Massachusetts General Hospital, Boston, Massachusetts Lyme Disease (Lyme Borreliosis) Due to Borrelia burgdorferi

Neal H. Steigbigel, MD

Professor of Medicine, Division of Infectious Diseases and Immunology, New York University School of Medicine; Staff Physician, Medical Service, Infectious Diseases Section, New York Veterans Affairs Medical Center, New York, New York Macrolides, Clindamycin, and Ketolides

James P. Steinberg, MD

Professor of Medicine, Division of Infectious Diseases, Emory University School of Medicine; Chief Medical Officer, Emory University Hospital Midtown, Atlanta, Georgia Other Gram-Negative and Gram-Variable Bacilli

David S. Stephens, MD

Stephen W. Schwarzmann Distinguished Professor of Medicine, Chair, Department of Medicine, Emory University School of Medicine; Vice President for Research, Robert W. Woodruff Health Sciences Center, Emory University, Atlanta, Georgia

David A. Stevens, MD

Professor of Medicine, Stanford University, Stanford, California; Hospital Epidemiologist, Santa Clara Valley Medical Center; President, California Institute for Medical Research; Principal Investigator, Infectious Diseases Research Laboratory, California Institute for Medical Research, San Jose, California Drugs Active against Fungi, Pneumocystis, and Microsporidia

Dennis L. Stevens, MD, PhD

Associate Chief of Staff, Research and Development Service, Veterans Affairs Medical Center, Boise, Idaho; Professor of Medicine Department of Medicine, University of Washington, Seattle, Washington Streptococcus pyogenes

Jacob Strahilevitz, MD

Senior Lecturer in Clinical Microbiology, Hebrew University; Attending Physician, Clinical Microbiology and Infectious Diseases, Hadassah Medical Center, Jerusalem, Israel Quinolones

Charles W. Stratton IV, MD

Associate Professor of Pathology and Medicine, Vanderbilt University School of Medicine; Director, Clinical Microbiology Laboratory, Vanderbilt University Medical Center, Nashville, Tennessee Streptococcus anginosus Group

Anthony F. Suffredini, MD

Senior Investigator, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland Sepsis, Severe Sepsis, and Septic Shock

Kathryn N. Suh, MD, MSc

Associate Professor of Medicine, University of Ottawa; Division of Infectious Diseases, The Ottawa Hospital, Ottawa, Canada

Cyclospora cayetanensis, Cystoisospora (Isospora) belli, Sarcocystis Species, Balantidium coli, and Blastocystis Species

Mark S. Sulkowski, MD

Professor of Medicine, Medical Director, Viral Hepatitis Center Divisions of Infectious Diseases and Gastroenterology/Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Gastrointestinal, Hepatobiliary, and Pancreatic Manifestations of Human Immunodeficiency Virus Infection

Morton N. Swartz, MDâ€

Associate Firm Chief, Infectious Diseases Unit, Massachusetts General Hospital, Boston, Massachusetts

Cellulitis, Necrotizing Fasciitis, and Subcutaneous Tissue Infections; Myositis and Myonecrosis; Lymphadenitis and Lymphangitis

Thomas R. Talbot, MD, MPH

Associate Professor of Medicine and Health Policy, Vanderbilt University School of Medicine; Chief Hospital Epidemiologist, Vanderbilt University Medical Center, Nashville, Tennessee Surgical Site Infections and Antimicrobial Prophylaxis

Neisseria meningitidis

â€

Deceased.

Contributors

Professor of Infectious Diseases, Department of Internal Medicine, College of Medicine, University of Oklahoma, Oklahoma City, Oklahoma


xxiv

Contributors

C. Sabrina Tan, MD

Assistant Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts JC, BK, and Other Polyomaviruses: Progressive Multifocal Leukoencephalopathy (PML)

Ming Tan, MD

Professor of Medicine, Microbiology and Molecular Genetics, University of California at Irvine School of Medicine, Irvine, California Chlamydia trachomatis (Trachoma, Genital Infections, Perinatal Infections, and Lymphogranuloma Venereum)

Chloe Lynne Thio, MD

Associate Professor of Medicine, Department of Internal Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland Hepatitis B Virus and Hepatitis Delta Virus

David L. Thomas, MD, MPH

Professor of Medicine, Director, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland Hepatitis C

Lora D. Thomas, MD, MPH

Assistant Professor of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee

Risk Factors and Approaches to Infections in Transplant Recipients

Stephen J. Thomas, MD

Director, Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland

Flaviviruses (Dengue, Yellow Fever, Japanese Encephalitis, West Nile Encephalitis, St. Louis Encephalitis, Tick-Borne Encephalitis, Kyasanur Forest Disease, Alkhurma Hemorrhagic Fever, Zika)

Athe M. N. Tsibris, MD, MS

Assistant Professor in Medicine, Division of Infectious Diseases, Harvard Medical School; Brigham and Women’s Hospital, Boston, Massachusetts Antiretroviral Therapy for Human Immunodeficiency Virus Infection

Allan R. Tunkel, MD, PhD, MACP

Professor of Medicine, Associate Dean for Medical Education, Warren Alpert Medical School of Brown University, Providence, Rhode Island

Approach to the Patient with Central Nervous System Infection; Acute Meningitis; Brain Abscess; Subdural Empyema, Epidural Abscess, and Suppurative Intracranial Thrombophlebitis; Cerebrospinal Fluid Shunt and Drain Infections; Viridans Streptococci, Nutritionally Variant Streptococci, Groups C and G Streptococci, and Other Related Organisms

Ronald B. Turner, MD

Professor of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia The Common Cold; Rhinovirus

Kenneth L. Tyler, MD

Reuler-Lewin Family Professor of Neurology and Professor of Medicine and Microbiology, University of Colorado Denver School of Medicine, Aurora, Colorado; Chief, Neurology Service, Denver Veterans Affairs Medical Center, Denver, Colorado Encephalitis; Orthoreoviruses and Orbiviruses; Coltiviruses and Seadornaviruses; Prions and Prion Diseases of the Central Nervous System (Transmissible Neurodegenerative Diseases)

Ahmet Uluer, DO, MS

Assistant Professor of Pediatrics, Department of Medicine, Harvard Medical School; Boston Children’s Hospital, Boston, Massachusetts Cystic Fibrosis

Anna R. Thorner, MD

Assistant Clinical Professor of Medicine, Department of Medicine, Harvard Medical School; Associate Physician, Division of Infectious Disease, Brigham and Women’s Hospital, Boston, Massachusetts Zoonotic Paramyxoviruses: Nipah, Hendra, and Menangle

Diederik van de Beek, MD, PhD

Professor, Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Acute Meningitis

Angela María Tobón, MD

Director, Chronic Infectious Diseases Unit, Department of Internal Medicine, Corporación para Investigaciones Biológicas, Medellín, Colombia

Walter J. F. M. van der Velden, MD, PhD

Edmund C. Tramont, MD

Edouard G. Vannier, PharmD, PhD

Paracoccidioidomycosis

Associate Director, Special Projects, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland Innate (General or Nonspecific) Host Defense Mechanisms; Syphilis (Treponema pallidum)

John J. Treanor, MD

Chief, Division of Infectious Diseases, Department of Medicine, University of Rochester Medical Center, Rochester, New York Influenza (Including Avian Influenza and Swine Influenza); Noroviruses and Sapoviruses (Caliciviruses); Astroviruses and Picobirnaviruses

Jason Trubiano, MD Infectious Diseases Australia Fusidic Acid

Department,

Austin

Health,

Melbourne,

Department of Haematology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Infections in the Immunocompromised Host: General Principles

Assistant Professor of Medicine, Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center and Tufts University School of Medicine, Boston, Massachusetts Babesia Species

Trevor C. Van Schooneveld, MD

Assistant Professor of Infectious Diseases, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska Mediastinitis

James Versalovic, MD, PhD

Milton J. Finegold Professor, Texas Children’s Microbiome Center, Department of Pathology and Immunology, Baylor College of Medicine; Department of Pathology, Texas Children’s Hospital, Houston, Texas The Human Microbiome of Local Body Sites and Their Unique Biology

Claudio Viscoli, MD

Division of Infectious Diseases, IRCCS AOU San Martino-IST; Department of Health Sciences, University of Genova, Genova, Italy Prophylaxis and Empirical Therapy of Infection in Cancer Patients


xxv

Ellen R. Wald, MD

Sinusitis

Matthew K. Waldor, MD, PhD

Edward H. Kass Professor of Medicine, Harvard Medical School; Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, Massachusetts Vibrio cholerae

David H. Walker, MD

Professor, Department of Pathology, University of Texas Medical Branch; Executive Director, Center for Biodefense and Emerging Infectious Diseases, Galveston, Texas

Rickettsia rickettsii and Other Spotted Fever Group Rickettsiae (Rocky Mountain Spotted Fever and Other Spotted Fevers); Rickettsia prowazekii (Epidemic or Louse-Borne Typhus); Rickettsia typhi (Murine Typhus); Ehrlichia chaffeensis (Human Monocytotropic Ehrlichiosis), Anaplasma phagocytophilum (Human Granulocytotropic Anaplasmosis), and Other Anaplasmataceae

Richard J. Wallace, Jr., MD

Chairman, Department of Microbiology, University of Texas Health Northeast, Tyler, Texas Antimycobacterial Agents; Infections Caused by Nontuberculous Mycobacteria Other than Mycobacterium avium Complex

Edward E. Walsh, MD

Professor of Medicine, Department of Infectious Diseases, University of Rochester School of Medicine and Dentistry, Rochester, New York Acute Bronchitis; Respiratory Syncytial Virus (RSV)

Stephen R. Walsh, MD

Assistant Professor of Medicine, Harvard Medical School; Beth Israel Deaconess Medical Center, Boston, Massachusetts Hepatitis E Virus

Peter D. Walzer, MD, MSc

David J. Weber, MD, MPH

Professor of Medicine, Pediatrics, and Epidemiology, University of North Carolina at Chapel Hill School of Medicine; Associate Chief of Staff and Medical Director, Hospital Epidemiology and Occupational Health, University of North Carolina Health Care, Chapel Hill, North Carolina The Acutely Ill Patient with Fever and Rash; Disinfection, Sterilization, and Control of Hospital Waste

Michael D. Weiden, MD

Associate Professor, Departments of Medicine and Environmental Medicine, New York University School of Medicine, Langone Medical Center, New York, New York Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Geoffrey A. Weinberg, MD

Professor of Pediatrics, Department of Pediatrics, University of Rochester School of Medicine and Dentistry; Director, Pediatric HIV Program, Golisano Children’s Hospital, University of Rochester Medical Center, Rochester, New York Epiglottitis; Pediatric Human Immunodeficiency Virus Infection

Daniel J. Weisdorf, MD

Professor of Medicine, Division of Hematology, Oncology, and Transplantation, Director, Adult Blood and Marrow Transplant Program, University of Minnesota Medical School, Minneapolis, Minnesota Infections in Recipients of Hematopoietic Stem Cell Transplants

Louis M. Weiss, MD, MPH

Professor, Departments of Pathology and Medicine, Albert Einstein College of Medicine, Bronx, New York Microsporidiosis

David F. Welch, PhD

Clinical Consultant, Medical Microbiology Consulting, LLC, Dallas, Texas Bartonella, Including Cat-Scratch Disease

Thomas E. Wellems, MD, PhD

Emeritus Professor of Medicine, University of Cincinnati; Retired Associate Chief of Staff for Research, Cincinnati VA Medical Center, Cincinnati, Ohio

Chief, Laboratory of Malaria and Vector Research, Chief, Malaria Genetics Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Rockville, Maryland

Christine A. Wanke, MD

Richard P. Wenzel, MD, MSc

Pneumocystis Species

Professor, Department of Medicine, Associate Chair, Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, Massachusetts Tropical Sprue: Enteropathy

Cirle A. Warren, MD

Assistant Professor, Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, Virginia Bacterial Inflammatory Enteritides

Ronald G. Washburn, MD

Associate Chief of Staff for Research and Development, Medical Research, Chief of Infectious Diseases, Medical Service, Shreveport Veterans Affairs Medical Center; Professor of Medicine, Infectious Diseases Section, Louisiana State University Health Sciences Center, Shreveport, Louisiana Rat-Bite Fever: Streptobacillus moniliformis and Spirillum minus

Valerie Waters, MD, MSc

Associate Professor, Department of Pediatric Infectious Diseases, Hospital for Sick Children, Toronto, Ontario, Canada Bordetella pertussis

Malaria (Plasmodium Species)

Chair Emeritus, Department of Internal Medicine; Professor of Internal Medicine, Division of Infectious Diseases, Virginia Commonwealth University School of Medicine, Richmond, Virginia Infection Prevention in the Health Care Setting

Melinda Wharton, MD, MPH

Acting Director, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia Immunization

A. Clinton White, Jr., MD

Paul R. Stalnaker Distinguished Professor, Director, Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas Cryptosporidiosis (Cryptosporidium Species)

Richard J. Whitley, MD

Distinguished Professor of Pediatrics, Loeb Eminent Scholar Chair in Pediatrics, Professor of Microbiology, Medicine, and Neurosurgery, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama Chickenpox and Herpes Zoster (Varicella-Zoster Virus)

Contributors

Alfred Dorrance Daniels Professor on Diseases of Children, University of Wisconsin School of Medicine and Public Health; Pediatrician-inChief, American Family Children’s Hospital, Madison, Wisconsin


xxvi

Contributors

Walter R. Wilson, MD

Professor of Medicine and Assistant Professor of Microbiology, Mayo Clinic College of Medicine; Consultant, Infectious Diseases, Mayo Clinic, Rochester, Minnesota Prosthetic Valve Endocarditis; Infections of Nonvalvular Cardiovascular Devices

Glenn W. Wortmann, MD

Chief, Infectious Diseases Section, MedStar Washington Hospital Center, Washington, DC; Professor of Medicine, Infectious Diseases, Uniformed Services University of the Health Sciences, F. Edward Hebert School of Medicine, Bethesda, Maryland Drugs for Protozoal Infections Other Than Malaria

William F. Wright, DO, MPH

Assistant Professor of Medicine and Microbiology, Division of Infectious Diseases and Travel Medicine, Georgetown University School of Medicine, Washington, DC Fever of Unknown Origin

Jo-Anne H. Young, MD

Professor of Medicine, Division of Infectious Disease and International Medicine, Medical Director of the Program in Adult Transplant Infectious Disease University of Minnesota, Minneapolis, Minnesota; Editor-in-Chief, Clinical Microbiology Reviews, American Society of Microbiology, Washington, DC Infections in Recipients of Hematopoietic Stem Cell Transplants

Vincent B. Young, MD, PhD

Associate Professor, Department of Internal Medicine, Division of Infectious Diseases, Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan Clostridium difficile Infection

Nadezhda Yun, MD

Assistant Professor, Department of Pathology, Assistant Director, Preclinical Studies Core, Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas Lymphocytic Choriomeningitis, Lassa Fever, and the South American Hemorrhagic Fevers (Arenaviruses)

Werner Zimmerli, MD

Professor, Basel University Medical Clinic, Liestal, Switzerland Orthopedic Implant–Associated Infections

Stephen H. Zinner, MD

Charles S. Davidson Professor of Medicine, Harvard Medical School, Boston, Massachusetts; Chair, Department of Medicine, Mount Auburn Hospital, Cambridge, Massachusetts Sulfonamides and Trimethoprim

John J. Zurlo, MD

Professor of Medicine, Department of Medicine/Infectious Diseases, Penn State Hershey Medical Center, Hershey, Pennsylvania Pasteurella Species


Preface to the Eighth Edition The field of infectious diseases is undergoing an extraordinary expansion of knowledge. Now in its eighth edition, Principles and Practice of Infectious Diseases remains dedicated to a clear, complete, up-to-date, and—most important—authoritative presentation of the current information. Frequent online updates will keep the text current. Since the previous edition there have been newly recognized infectious diseases, descriptions of new pathogens, development of novel antimicrobial agents, and advances in diagnosis. New infectious diseases include the Middle East respiratory syndrome (MERS) caused by a new coronavirus, the Heartland virus carried by ticks in Missouri, and Exserohilum meningitis from contaminated corticosteroid injections. Details and rationales are provided for new treatments for a panoply of infections, including hepatitis C, human immunodeficiency virus (HIV), tuberculosis, anthrax, genital herpes, methicillin-resistant Staphylococcus aureus (MRSA), and Clostridium difficile, as well as treatment options for increasingly antibiotic-resistant bacteria. Awareness of diseases imported from overseas on food, travelers, exotic pets, and immigrants has become even more imperative. The complexities of managing infections in patients immunosuppressed by new drugs and by stem cell or organ transplantation requires extensive updating, as well as issues arising in patients with implanted mechanical hearts or prosthetic joints. Improved diagnostic tests for C. difficile, norovirus, human herpesvirus 6, JC virus, respiratory pathogens, Tropheryma whipplei, and many other organisms are now broadly available. In addition, there have been major advances in understanding of the human microbiome and of molecular microbiology, pathogenesis, and host responses; all of these are addressed as well. As before, Principles and Practice of Infectious Diseases is divided into relevant sections that cover all of these areas and that are presented in an interrelated manner. For this edition, Principles and Practice of Infectious Diseases is proud to have Martin Blaser, MD, as a new editor. He replaces Gerald Mandell, MD, one of the three founding editors of the book, who is stepping down from his duties after seven highly successful editions. Dr. Blaser is the Muriel G. and George W. Singer Professor of Translational Medicine and Professor of Microbiology at New York Langone Medical Center, and is a distinguished infectious disease researcher, clinician, and educator.

The authors who have been selected to write each of the individual chapters in the book are recognized experts in their fields, and, in turn, every chapter is carefully reviewed by all three editors to be placed into appropriate context and perspective. Thus, we believe that Principles and Practices of Infectious Diseases will be of interest and use to a wide audience of physicians, including infectious disease clinicians, internists, family practitioners, and HIV/AIDS specialists, as well as to other health care providers, public health experts, microbiologists, immunologists, and other medical scientists. The editors and publisher of Principles and Practice of Infectious Diseases have gone to great effort to ensure that its content is highly accessible and current. The text, figures, and tables are readily available through Expert Consult, which is accessible through a powerful and easy-to-use search engine and is compatible with PC, Mac, most mobile devices, and eReaders. In addition, chapters have an introductory short summary, which is linked to individual content in each chapter. Individual chapters will also be updated on a regular basis, twice a year, to ensure that their content remains current. The appropriateness and significance of the updates will be emphasized by the authors and editors. The eighth edition of Principles and Practice and Infectious Diseases represents the extraordinary efforts of many individuals. Foremost are the contributions of authors of the 324 chapters, who are dedicated to maintaining the tradition of an authoritative text that meets the highest standards of accuracy and integrity. We are very grateful to Janet Morgan and Joyce Ying for the invaluable assistance that they have provided to us. We would also like to thank Mary Gatsch, Taylor Ball, and Kristine Feeherty of Elsevier for their overall support and efforts. And as always, this work would not have been possible without the encouragement, understanding, and—as needed—forbearance of our wives, Shirley Bennett, Kelly Dolin, and Maria Gloria Dominguez Bello. JOHN E. BENNETT, MD RAPHAEL DOLIN, MD MARTIN J. BLASER, MD

xxvii


Contents VOLUME 1 I 

Basic Principles in the Diagnosis and Management of Infectious Diseases

A Microbial Pathogenesis    1  A Molecular Perspective of Microbial

Pathogenicity  1

David A. Relman and Stanley Falkow    2  The Human Microbiome of Local Body Sites and

Their Unique Biology  11

Kjersti Aagaard, Ruth Ann Luna, and James Versalovic    3  Prebiotics, Probiotics, and Synbiotics  19 Lea Ann Chen and Cynthia L. Sears

B Host Defense Mechanisms    4  Innate (General or Nonspecific) Host Defense

Mechanisms  26

Carl W. Dieffenbach and Edmund C. Tramont    5  Adaptive Immunity: Antibodies and

Immunodeficiencies  34 Holly H. Birdsall

   6  Cell-Mediated Defense against

Infection  50 Tobias M. Hohl

   7  Mucosal Immunity  70 Peter B. Ernst    8  Granulocytic Phagocytes  78 Frank R. DeLeo and William M. Nauseef    9  Complement and Deficiencies  93 Peter Densen and Sanjay Ram   10  Human Genetics and Infection  116 Stephen J. Chapman and Adrian V. S. Hill   11  Nutrition, Immunity, and Infection  125 Caryn Gee Morse and Kevin P. High   12  Evaluation of the Patient with Suspected

Immunodeficiency  134

Steven M. Holland and John I. Gallin

C Epidemiology of Infectious Disease   13  Epidemiologic Principles  146 Michael T. Osterholm and Craig W. Hedberg   14  Emerging and Reemerging Infectious Disease

Threats  158

Rima Khabbaz, Beth P. Bell, Anne Schuchat, Stephen M. Ostroff, Robin Moseley, Alexandra Levitt, and James M. Hughes xxviii

  15  Bioterrorism: An Overview  178 Luciana L. Borio, Donald A. Henderson, and Noreen A. Hynes

D Clinical Microbiology   16  The Clinician and the Microbiology

Laboratory  191 Patrick R. Murray

E Anti-infective Therapy   17  Principles of Anti-infective Therapy  224 George M. Eliopoulos and Robert C. Moellering, Jr.   18  Molecular Mechanisms of Antibiotic Resistance

in Bacteria  235

Steven M. Opal and Aurora Pop-Vicas   19  Pharmacokinetics and Pharmacodynamics of

Anti-infective Agents  252

Manjunath P. Pai, Mackenzie L. Cottrell, Angela D. M. Kashuba, and Joseph S. Bertino, Jr.   20  Penicillins and β-Lactamase Inhibitors  263 Yohei Doi and Henry F. Chambers   21  Cephalosporins  278 William A. Craig and David R. Andes   22  Other β-Lactam Antibiotics  293 Yohei Doi and Henry F. Chambers   23  Antibiotic Allergy  298 Merin Elizabeth Kuruvilla and David A. Khan   24  Fusidic Acid  304 Jason Trubiano and M. Lindsay Grayson   25  Aminoglycosides  310 James E. Leggett   26  Tetracyclines, Glycylcyclines, and

Chloramphenicol  322

Matthew Moffa and Itzhak Brook   27  Rifamycins  339 Melanie Jane Maslow and Cynthia Portal-Celhay   28  Metronidazole  350 Jerod L. Nagel and David M. Aronoff   29  Macrolides, Clindamycin, and Ketolides  358 Sumathi Sivapalasingam and Neal H. Steigbigel   30  Glycopeptides (Vancomycin and Teicoplanin),

Streptogramins (Quinupristin-Dalfopristin), Lipopeptides (Daptomycin), and Lipoglycopeptides (Telavancin)  377

Barbara E. Murray, Cesar A. Arias, and Esteban C. Nannini   31  Polymyxins (Polymyxin B and Colistin)  401 Keith S. Kaye, Jason M. Pogue, and Donald Kaye


xxix   32  Linezolid and Other Oxazolidinones  406 Heather L. Cox and Gerald R. Donowitz

Therapy  625

Kevin Hsueh and Jeffrey Bruce Greene   54  Tables of Anti-infective Agent

Pharmacology  631

  34  Quinolones  419 David C. Hooper and Jacob Strahilevitz   35  Unique Antibacterial Agents  440 Gerard R. Barber and Amar Safdar   36  Urinary Tract Agents: Nitrofurantoin,

Fosfomycin, and Methenamine  447 James M. Horton

  37  Topical Antibacterials  452 Judith A. O’Donnell, Steven P. Gelone, and Amar Safdar   38  Antimycobacterial Agents  463 Richard J. Wallace, Jr., Julie V. Philley, and David E. Griffith   39  Drugs Active against Fungi, Pneumocystis,

and Microsporidia  479

John H. Rex and David A. Stevens   40  Antimalarial Drugs  495 James S. McCarthy and Richard N. Price   41  Drugs for Protozoal Infections Other Than

Malaria  510

James S. McCarthy, Glenn W. Wortmann, and Louis V. Kirchhoff   42  Drugs for Helminths  519 James S. McCarthy and Thomas A. Moore   43  Antiviral Agents: General Principles  528 Raphael Dolin   44  Antiviral Drugs for Influenza and Other

Respiratory Virus Infections  531 Fred Y. Aoki

  45  Antivirals against Herpes Viruses  546 Fred Y. Aoki   46  Antiviral Drugs against Hepatitis Viruses  563 Jules L. Dienstag   47  Miscellaneous Antiviral Agents (Interferons,

Imiquimod, Pleconaril)  576 Raphael Dolin

Manjunath P. Pai and Joseph S. Bertino, Jr.

II 

Major Clinical Syndromes

A Fever   55  Temperature Regulation and the Pathogenesis

of Fever  708

Mohammad M. Sajadi and Philip A. Mackowiak   56  Fever of Unknown Origin  721 William F. Wright and Philip A. Mackowiak   57  The Acutely Ill Patient with Fever and

Rash  732

David J. Weber, Myron S. Cohen, and William A. Rutala

B Upper Respiratory Tract Infections   58  The Common Cold  748 Ronald B. Turner   59  Pharyngitis  753 Anthony R. Flores and Mary T. Caserta   60  Acute Laryngitis  760 Mary T. Caserta   61  Croup in Children (Acute

Laryngotracheobronchitis)  762 John Bower and John T. McBride

  62  Otitis Externa, Otitis Media, and

Mastoiditis  767 Jerome O. Klein

  63  Sinusitis  774 Gregory P. DeMuri and Ellen R. Wald   64  Epiglottitis  785 Jennifer L. Nayak and Geoffrey A. Weinberg   65  Infections of the Oral Cavity, Neck, and

Head  789

Anthony W. Chow

C Pleuropulmonary and Bronchial Infections

  48  Immunomodulators  581 Andrea V. Page and W. Conrad Liles

  66  Acute Bronchitis  806 Edward E. Walsh

  49  Hyperbaric Oxygen  591 Juan Carlos Sarria and Norbert J. Roberts, Jr.

  67  Acute Exacerbations of Chronic Obstructive

  50  Complementary and Alternative Medicines for

Infectious Diseases  597 Jonathan Berman

  51  Antimicrobial Stewardship  605 Conan MacDougall   52  Designing and Interpreting Clinical Studies in

Infectious Diseases  612 John H. Powers III

Pulmonary Disease  810

Leopoldo N. Segal, Michael D. Weiden, and Harold W. Horowitz   68  Bronchiolitis  818 John Bower and John T. McBride   69  Acute Pneumonia  823 Richard T. Ellison III and Gerald R. Donowitz   70  Pleural Effusion and Empyema  847 Edward J. Septimus

Contents

  33  Sulfonamides and Trimethoprim  410 Stephen H. Zinner and Kenneth H. Mayer

  53  Outpatient Parenteral Antimicrobial


xxx

Contents

  71  Bacterial Lung Abscess  855 Bennett Lorber   72  Chronic Pneumonia  860 Peter G. Pappas   73  Cystic Fibrosis  874 Ahmet Uluer and Francisco M. Marty

D Urinary Tract Infections   74  Urinary Tract Infections  886 Jack D. Sobel and Donald Kaye

  89  Acute Meningitis  1097 Allan R. Tunkel, Diederik van de Beek, and W. Michael Scheld   90  Chronic Meningitis  1138 John E. Bennett   91  Encephalitis  1144 J. David Beckham and Kenneth L. Tyler   92  Brain Abscess  1164 Allan R. Tunkel   93  Subdural Empyema, Epidural Abscess, and

Suppurative Intracranial Thrombophlebitis  1177

E Sepsis   75  Sepsis, Severe Sepsis, and Septic Shock  914 Robert S. Munford and Anthony F. Suffredini

Allan R. Tunkel

  94  Cerebrospinal Fluid Shunt and Drain

Infections  1186

F Intra-abdominal Infections   76  Peritonitis and Intraperitoneal Abscesses  935 Matthew E. Levison and Larry M. Bush   77  Infections of the Liver and Biliary

System (Liver Abscess, Cholangitis, Cholecystitis)  960

Adarsh Bhimraj, James M. Drake, and Allan R. Tunkel

I

  95  Cellulitis, Necrotizing Fasciitis, and

Subcutaneous Tissue Infections  1194 Mark S. Pasternack and Morton N. Swartz

Costi D. Sifri and Lawrence C. Madoff   78  Pancreatic Infection  969 Miriam Baron Barshak   79  Splenic Abscess  979 Lawrence C. Madoff   80  Appendicitis  982 Costi D. Sifri and Lawrence C. Madoff

  81  Diverticulitis and Typhlitis  986 Costi D. Sifri and Lawrence C. Madoff

G Cardiovascular Infections   82  Endocarditis and Intravascular Infections  990 Vance G. Fowler, Jr., W. Michael Scheld, and Arnold S. Bayer   83  Prosthetic Valve Endocarditis  1029 Raj Palraj, Bettina M. Knoll, Larry M. Baddour, and Walter R. Wilson   84  Infections of Nonvalvular Cardiovascular

Devices  1041

M. Rizwan Sohail, Walter R. Wilson, and Larry M. Baddour

Skin and Soft Tissue Infections

  96  Myositis and Myonecrosis  1216 Mark S. Pasternack and Morton N. Swartz   97  Lymphadenitis and Lymphangitis  1226 Mark S. Pasternack and Morton N. Swartz

J

Gastrointestinal Infections and Food Poisoning

  98  Syndromes of Enteric Infection  1238 Regina C. LaRocque and Stephen B. Calderwood   99  Esophagitis  1248 Paul S. Graman 100  Nausea, Vomiting, and Noninflammatory

Diarrhea  1253

David A. Bobak and Richard L. Guerrant 101  Bacterial Inflammatory Enteritides  1263 Aldo A. M. Lima, Cirle A. Warren, and Richard L. Guerrant 102  Enteric Fever and Other Causes of Fever and

Abdominal Symptoms  1270

Jason B. Harris and Edward T. Ryan

  85  Prophylaxis of Infective Endocarditis  1057 David T. Durack

103  Foodborne Disease  1283 Rajal K. Mody and Patricia M. Griffin

  86  Myocarditis and Pericarditis  1066 Kirk U. Knowlton, Anna Narezkina, Maria C. Savoia, and Michael N. Oxman

104  Tropical Sprue: Enteropathy  1297 Christine A. Wanke

  87  Mediastinitis  1080 Trevor C. Van Schooneveld and Mark E. Rupp

H Central Nervous System Infections   88  Approach to the Patient with Central Nervous

System Infection  1091 Allan R. Tunkel

K Bone and Joint Infections 105  Infectious Arthritis of Native

Joints  1302

Christopher A. Ohl and Derek Forster 106  Osteomyelitis  1318 Elie F. Berbari, James M. Steckelberg, and Douglas R. Osmon


xxxi 107  Orthopedic Implant–Associated

Infections  1328

124  General Clinical Manifestations of

L Diseases of the Reproductive Organs and

Sexually Transmitted Diseases

108  Genital Skin and Mucous Membrane

Lesions  1341

Timothy R. Sterling and Richard E. Chaisson

125  Pulmonary Manifestations of Human

Immunodeficiency Virus Infection  1558

Michael H. Augenbraun 109  Urethritis  1349 Michael H. Augenbraun and William M. McCormack

Paul E. Sax and Kevin L. Ard

126  Gastrointestinal, Hepatobiliary, and Pancreatic

Manifestations of Human Immunodeficiency Virus Infection  1567

110  Vulvovaginitis and Cervicitis  1358 William M. McCormack and Michael H. Augenbraun 111  Infections of the Female Pelvis  1372 David E. Soper

Charles Haines and Mark S. Sulkowski

127  Neurologic Diseases Caused by Human

Immunodeficiency Virus Type 1 and Opportunistic Infections  1574

112  Prostatitis, Epididymitis, and Orchitis  1381 Catherine C. McGowan and John Krieger

M Eye Infections 113  Introduction to Eye Infections  1388 Marlene L. Durand 114  Microbial Conjunctivitis  1392 Scott D. Barnes, Nalin M. Kumar, Deborah Pavan-Langston, and Dimitri T. Azar 115  Microbial Keratitis  1402 Scott D. Barnes, Joelle Hallak, Deborah Pavan-Langston, and Dimitri T. Azar

Omar K. Siddiqi and Igor J. Koralnik

128  Human Immunodeficiency Virus Infection in

Women  1590

Susan E. Cohn and Rebecca A. Clark 129  Pediatric Human Immunodeficiency Virus

Infection  1616

Geoffrey A. Weinberg and George K. Siberry 130  Antiretroviral Therapy for Human

Immunodeficiency Virus Infection  1622 Athe M. N. Tsibris and Martin S. Hirsch

131  Management of Opportunistic Infections

Associated with Human Immunodeficiency Virus Infection  1642

116  Endophthalmitis  1415 Marlene L. Durand 117  Infectious Causes of Uveitis  1423 Marlene L. Durand

Henry Masur

132  Vaccines for Human Immunodeficiency

Virus Type 1 Infection  1666

Dan H. Barouch, Lindsey R. Baden, and Raphael Dolin

118  Periocular Infections  1432 Marlene L. Durand

N Hepatitis 119  Viral Hepatitis  1439 Jules L. Dienstag and Andrew S. Delemos

P Miscellaneous Syndromes 133  Chronic Fatigue Syndrome  1674 N. Cary Engleberg

O Acquired Immunodeficiency Syndrome 120  Global Perspectives on Human

Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome  1469 Peter Piot and Helena Legido-Quigley

121  Epidemiology and Prevention of Acquired

Immunodeficiency Syndrome and Human Immunodeficiency Virus Infection  1483 Carlos del Rio and James W. Curran

122  Diagnosis of Human Immunodeficiency Virus

Infection  1503

Francesco R. Simonetti, Robin Dewar, and Frank Maldarelli 123  The Immunology of Human Immunodeficiency

Virus Infection  1526

Susan Moir, Mark Connors, and Anthony S. Fauci

VOLUME 2 III 

Infectious Diseases and Their Etiologic Agents

A Viral Diseases 134  Biology of Viruses and Viral Diseases  1681 James D. Chappell and Terence S. Dermody

i.  DNA Viruses  •  a.  Poxviridae 135  Orthopoxviruses: Vaccinia (Smallpox Vaccine),

Variola (Smallpox), Monkeypox, and Cowpox  1694 Brett W. Petersen and Inger K. Damon

Contents

Human Immunodeficiency Virus Infection (Including Acute Retroviral Syndrome and Oral, Cutaneous, Renal, Ocular, Metabolic, and Cardiac Diseases)  1541

Werner Zimmerli and Parham Sendi


xxxii

Contents

136  Other Poxviruses That Infect Humans:

Parapoxviruses (Including Orf Virus), Molluscum Contagiosum, and Yatapoxviruses  1703 Brett W. Petersen and Inger K. Damon

b.  Herpesviridae

151  Coltiviruses and Seadornaviruses  1851 Roberta L. DeBiasi and Kenneth L. Tyler 152  Rotaviruses  1854 Philip R. Dormitzer

b.  Togaviridae

137  Introduction to Herpesviridae  1707 Jeffrey I. Cohen

153  Alphaviruses  1865 Lewis Markoff

138  Herpes Simplex Virus  1713 Joshua T. Schiffer and Lawrence Corey

154  Rubella Virus (German Measles)  1875 Anne A. Gershon

139  Chickenpox and Herpes Zoster (Varicella-Zoster

Virus)  1731

Richard J. Whitley 140  Cytomegalovirus (CMV)  1738 Clyde S. Crumpacker II 141  Epstein-Barr Virus (Infectious Mononucleosis,

Epstein-Barr Virus–Associated Malignant Diseases, and Other Diseases)  1754 Eric C. Johannsen and Kenneth M. Kaye

142  Human Herpesvirus Types 6 and 7 (Exanthem

Subitum)  1772 Jeffrey I. Cohen

143  Kaposi’s Sarcoma–Associated Herpesvirus

(Human Herpesvirus 8)  1777 Kenneth M. Kaye

144  Herpes B Virus  1783 Jeffrey I. Cohen

c.  Adenoviridae 145  Adenoviruses  1787 Elizabeth G. Rhee and Dan H. Barouch

d.  Papillomaviridae 146  Papillomaviruses  1794 William Bonnez

147  JC, BK, and Other Polyomaviruses:

Progressive Multifocal Leukoencephalopathy (PML)  1807 C. Sabrina Tan and Igor J. Koralnik

e.  Hepadnaviridae 148  Hepatitis B Virus and Hepatitis Delta

Virus  1815

Chloe Lynne Thio and Claudia Hawkins

f.  Parvoviridae 149  Human Parvoviruses, Including

Parvovirus B19V and Human Bocaparvoviruses  1840 Kevin E. Brown

ii.  RNA Viruses  •  a.  Reoviridae 150  Orthoreoviruses and Orbiviruses  1848 Roberta L. DeBiasi and Kenneth L. Tyler

c.  Flaviviridae 155  Flaviviruses (Dengue, Yellow Fever, Japanese

Encephalitis, West Nile Encephalitis, St. Louis Encephalitis, Tick-Borne Encephalitis, Kyasanur Forest Disease, Alkhurma Hemorrhagic Fever, Zika)  1881 Stephen J. Thomas, Timothy P. Endy, Alan L. Rothman, and Alan D. Barrett

156  Hepatitis C  1904 Stuart C. Ray and David L. Thomas

d.  Coronaviridae 157  Coronaviruses, Including Severe Acute

Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS)  1928 Kenneth McIntosh and Stanley Perlman

e.  Paramyxoviridae 158  Parainfluenza Viruses  1937 Michael G. Ison 159  Mumps Virus  1942 Nathan Litman and Stephen G. Baum 160  Respiratory Syncytial Virus (RSV)  1948 Edward E. Walsh and Caroline Breese Hall 161  Human Metapneumovirus  1961 Ann R. Falsey 162  Measles Virus (Rubeola)  1967 Anne A. Gershon 163  Zoonotic Paramyxoviruses: Nipah, Hendra, and

Menangle  1974

Anna R. Thorner and Raphael Dolin

f.  Rhabdoviridae 164  Vesicular Stomatitis Virus and Related

Vesiculoviruses  1981 Steven M. Fine

165  Rabies (Rhabdoviruses)  1984 Kamaljit Singh, Charles E. Rupprecht, and Thomas P. Bleck

g.  Filoviridae 166  Marburg and Ebola Hemorrhagic Fevers

(Filoviruses)  1995 Thomas W. Geisbert


xxxiii

h.  Orthomyxoviridae Influenza)  2000 John J. Treanor

i.  Bunyaviridae 168  California Encephalitis, Hantavirus Pulmonary

Syndrome, and Bunyavirus Hemorrhagic Fevers  2025 Dennis A. Bente

j.  Arenaviridae 169  Lymphocytic Choriomeningitis, Lassa Fever,

and the South American Hemorrhagic Fevers (Arenaviruses)  2031 Alexey Seregin, Nadezhda Yun, and Slobodan Paessler

k.  Retroviridae 170  Human T-Lymphotropic Virus (HTLV)  2038 Edward L. Murphy and Roberta L. Bruhn 171  Human Immunodeficiency Viruses  2054 Marvin S. Reitz, Jr., and Robert C. Gallo

l.  Picornaviridae 172  Introduction to the Human Enteroviruses and

Parechoviruses  2066

José R. Romero and John F. Modlin 173  Poliovirus  2073 José R. Romero and John F. Modlin 174  Coxsackieviruses, Echoviruses, and Numbered

Enteroviruses  2080

José R. Romero and John F. Modlin 175  Human Parechoviruses  2091 José R. Romero and John F. Modlin 176  Hepatitis A Virus  2095 Francisco Averhoff, Yury Khudyakov, and Beth P. Bell 177  Rhinovirus  2113 Ronald B. Turner

iii.  Caliciviridae and Other Gastrointestinal Viruses 178  Noroviruses and Sapoviruses

(Caliciviruses)  2122

Raphael Dolin and John J. Treanor 179  Astroviruses and Picobirnaviruses  2128 Raphael Dolin and John J. Treanor

iv.  Unclassified Viruses 180  Hepatitis E Virus  2131 Stephen R. Walsh

181  Prions and Prion Diseases of the Central

Nervous System (Transmissible Neurodegenerative Diseases)  2142 Patrick J. Bosque and Kenneth L. Tyler

C Chlamydial Diseases 182  Chlamydia trachomatis (Trachoma, Genital

Infections, Perinatal Infections, and Lymphogranuloma Venereum)  2154 Byron E. Batteiger and Ming Tan

183  Psittacosis (Due to Chlamydia psittaci)  2171 David Schlossberg 184  Chlamydia pneumoniae  2174 Margaret R. Hammerschlag, Stephan A. Kohlhoff, and Charlotte A. Gaydos

D Mycoplasma Diseases 185  Mycoplasma pneumoniae and Atypical

Pneumonia  2183

Robert S. Holzman and Michael S. Simberkoff 186  Genital Mycoplasmas: Mycoplasma genitalium,

Mycoplasma hominis, and Ureaplasma Species  2190 David H. Martin

E Rickettsioses, Ehrlichioses, and

Anaplasmosis

187  Introduction to Rickettsioses, Ehrlichioses, and

Anaplasmosis  2194 Didier Raoult

188  Rickettsia rickettsii and Other Spotted

Fever Group Rickettsiae (Rocky Mountain Spotted Fever and Other Spotted Fevers)  2198 David H. Walker and Lucas S. Blanton

189  Rickettsia akari (Rickettsialpox)  2206 Didier Raoult 190  Coxiella burnetii (Q Fever)  2208 Thomas J. Marrie and Didier Raoult 191  Rickettsia prowazekii (Epidemic or Louse-Borne

Typhus)  2217

Lucas S. Blanton and David H. Walker 192  Rickettsia typhi (Murine Typhus)  2221 Lucas S. Blanton, J. Stephen Dumler, and David H. Walker 193  Orientia tsutsugamushi (Scrub Typhus)  2225 Didier Raoult 194  Ehrlichia chaffeensis (Human Monocytotropic

Ehrlichiosis), Anaplasma phagocytophilum (Human Granulocytotropic Anaplasmosis), and Other Anaplasmataceae  2227 J. Stephen Dumler and David H. Walker

Contents

167  Influenza (Including Avian Influenza and Swine

B Prion Diseases


xxxiv

Contents

F Bacterial Diseases 195  Introduction to Bacteria and Bacterial

Diseases  2234

Jennifer A. Philips and Martin J. Blaser

i.  Gram-Positive Cocci 196  Staphylococcus aureus (Including

Staphylococcal Toxic Shock Syndrome)  2237 Yok-Ai Que and Philippe Moreillon

197  Staphylococcus epidermidis and Other

Coagulase-Negative Staphylococci  2272 Mark E. Rupp and Paul D. Fey

198  Classification of Streptococci  2283 Kathryn L. Ruoff and Alan L. Bisno 199  Streptococcus pyogenes  2285 Amy E. Bryant and Dennis L. Stevens 200  Nonsuppurative Poststreptococcal Sequelae:

Rheumatic Fever and Glomerulonephritis  2300 Stanford T. Shulman and Alan L. Bisno

201  Streptococcus pneumoniae  2310 Edward N. Janoff and Daniel M. Musher 202  Enterococcus Species, Streptococcus gallolyticus

Group, and Leuconostoc Species  2328

Cesar A. Arias and Barbara E. Murray

203  Streptococcus agalactiae (Group B

Streptococcus)  2340

Morven S. Edwards and Carol J. Baker 204  Viridans Streptococci, Nutritionally Variant

Streptococci, Groups C and G Streptococci, and Other Related Organisms  2349 Scott W. Sinner and Allan R. Tunkel

205  Streptococcus anginosus Group  2362 Cathy A. Petti and Charles W. Stratton IV

ii.  Gram-Positive Bacilli 206  Corynebacterium diphtheriae

(Diphtheria)  2366 Rob Roy MacGregor

207  Other Coryneform Bacteria and

Rhodococci  2373

Rose Kim and Annette C. Reboli 208  Listeria monocytogenes  2383 Bennett Lorber 209  Bacillus anthracis (Anthrax)  2391 Gregory J. Martin and Arthur M. Friedlander 210  Bacillus Species and Related Genera Other

Than Bacillus anthracis  2410

Thomas Fekete

iii.  Gram-Negative Cocci 213  Neisseria meningitidis  2425 David S. Stephens and Michael A. Apicella 214  Neisseria gonorrhoeae (Gonorrhea)  2446 Jeanne M. Marrazzo and Michael A. Apicella 215  Moraxella catarrhalis, Kingella, and Other

Gram-Negative Cocci  2463 Timothy F. Murphy

iv.  Gram-Negative Bacilli 216  Vibrio cholerae  2471 Matthew K. Waldor and Edward T. Ryan 217  Other Pathogenic Vibrios  2480 Marguerite A. Neill and Charles C. J. Carpenter 218  Campylobacter jejuni and Related

Species  2485

Ban Mishu Allos, Nicole M. Iovine, and Martin J. Blaser 219  Helicobacter pylori and Other Gastric

Helicobacter Species  2494

Timothy L. Cover and Martin J. Blaser 220  Enterobacteriaceae  2503 Michael S. Donnenberg 221  Pseudomonas aeruginosa and Other

Pseudomonas Species  2518

Erika D’Agata

222  Stenotrophomonas maltophilia and

Burkholderia cepacia  2532 Amar Safdar

223  Burkholderia pseudomallei and Burkholderia

mallei: Melioidosis and Glanders  2541 Bart J. Currie

224  Acinetobacter Species  2552 Michael Phillips 225  Salmonella Species  2559 David A. Pegues and Samuel I. Miller 226  Bacillary Dysentery: Shigella and Enteroinvasive

Escherichia coli  2569 Herbert L. DuPont

227  Haemophilus Species, Including H. influenzae

and H. ducreyi (Chancroid)  2575

Timothy F. Murphy

228  Brucellosis (Brucella Species)  2584 H. Cem Gul and Hakan Erdem 229  Francisella tularensis (Tularemia)  2590 Robert L. Penn 230  Pasteurella Species  2603 John J. Zurlo

211  Erysipelothrix rhusiopathiae  2415 Annette C. Reboli

231  Yersinia Species (Including Plague)  2607 Paul S. Mead

212  Whipple’s Disease  2418 Thomas Marth and Thomas Schneider

232  Bordetella pertussis  2619 Valerie Waters and Scott A. Halperin


xxxv 233  Rat-Bite Fever: Streptobacillus moniliformis

and Spirillum minus  2629

234  Legionnaires’ Disease and Pontiac

Fever  2633

Paul H. Edelstein and Craig R. Roy 235  Capnocytophaga  2645 J. Michael Janda 236  Bartonella, Including Cat-Scratch

Disease  2649

Tejal N. Gandhi, Leonard N. Slater, David F. Welch, and Jane E. Koehler 237  Klebsiella granulomatis (Donovanosis,

Granuloma Inguinale)  2664 Ronald C. Ballard

238  Other Gram-Negative and Gram-Variable

Bacilli  2667

James P. Steinberg and Eileen M. Burd

v.  Spirochetes 239  Syphilis (Treponema pallidum)  2684 Justin D. Radolf, Edmund C. Tramont, and Juan C. Salazar 240  Endemic Treponematoses  2710 Edward W. Hook III 241  Leptospira Species (Leptospirosis)  2714 David A. Haake and Paul N. Levett 242  Relapsing Fever Caused by Borrelia

Species  2721 James M. Horton

243  Lyme Disease (Lyme Borreliosis) Due to Borrelia

burgdorferi  2725 Allen C. Steere

vi.  Anaerobic Bacteria 244  Anaerobic Infections: General Concepts  2736 Ronit Cohen-Poradosu and Dennis L. Kasper 245  Clostridium difficile Infection  2744 Dale N. Gerding and Vincent B. Young 246  Tetanus (Clostridium tetani)  2757 Aimee Hodowanec and Thomas P. Bleck 247  Botulism (Clostridium botulinum)  2763 Aimee Hodowanec and Thomas P. Bleck 248  Gas Gangrene and Other

Clostridium-Associated Diseases  2768 Andrew B. Onderdonk and Wendy S. Garrett

249  Bacteroides, Prevotella, Porphyromonas, and

Fusobacterium Species (and Other Medically Important Anaerobic Gram-Negative Bacilli)  2773 Wendy S. Garrett and Andrew B. Onderdonk

250  Anaerobic Cocci and Anaerobic Gram-Positive

Nonsporulating Bacilli  2781 Eija Könönen

251  Mycobacterium tuberculosis  2787 Daniel W. Fitzgerald, Timothy R. Sterling, and David W. Haas 252  Mycobacterium leprae (Leprosy)  2819 Cybèle A. Renault and Joel D. Ernst 253  Mycobacterium avium Complex  2832 Fred M. Gordin and C. Robert Horsburgh, Jr. 254  Infections Caused by Nontuberculous

Mycobacteria Other than Mycobacterium avium Complex  2844

Barbara A. Brown-Elliott and Richard J. Wallace, Jr.

viii.  Higher Bacterial Diseases 255  Nocardia Species  2853 Tania C. Sorrell, David H. Mitchell, Jonathan R. Iredell, and Sharon C-A. Chen 256  Agents of Actinomycosis  2864 Thomas A. Russo

G Mycoses 257  Introduction to Mycoses  2874 John E. Bennett 258  Candida Species  2879 John E. Edwards, Jr. 259  Aspergillus Species  2895 Thomas F. Patterson 260  Agents of Mucormycosis and

Entomophthoramycosis  2909

Dimitrios P. Kontoyiannis and Russell E. Lewis 261  Sporothrix schenckii  2920 John H. Rex and Pablo C. Okhuysen 262  Agents of Chromoblastomycosis  2925 Duane R. Hospenthal 263  Agents of Mycetoma  2929 Duane R. Hospenthal 264  Cryptococcosis (Cryptococcus neoformans and

Cryptococcus gattii)  2934 John R. Perfect

265  Histoplasma capsulatum (Histoplasmosis)  2949 George S. Deepe, Jr. 266  Blastomycosis  2963 Robert W. Bradsher, Jr. 267  Coccidioidomycosis (Coccidioides

Species)  2974 John N. Galgiani

268  Dermatophytosis (Ringworm) and Other

Superficial Mycoses  2985 Roderick J. Hay

269  Paracoccidioidomycosis  2995 Angela Restrepo, Angela María Tobón, and Luz Elena Cano

Contents

Ronald G. Washburn

vii.  Mycobacterial Diseases


Contents

xxxvi 270  Uncommon Fungi and Related Species  3003 Duane R. Hospenthal

288  Intestinal Nematodes (Roundworms)  3199 James H. Maguire

271  Pneumocystis Species  3016 Peter D. Walzer, A. George Smulian, and Robert F. Miller

289  Tissue Nematodes (Trichinellosis, Dracunculiasis,

272  Microsporidiosis  3031 Louis M. Weiss

Filariasis, Loiasis, and Onchocerciasis)  3208 James W. Kazura

290  Trematodes (Schistosomes and Liver, Intestinal,

and Lung Flukes)  3216

H Protozoal Diseases 273  Introduction to Protozoal Diseases  3045 Poonum S. Korpe, Jonathan I. Ravdin, and William A. Petri, Jr.

James H. Maguire

291  Tapeworms (Cestodes)  3227 Charles H. King and Jessica K. Fairley 292  Visceral Larva Migrans and Other Uncommon

Helminth Infections  3237

274  Entamoeba Species, Including Amebic Colitis

Theodore E. Nash

and Liver Abscess  3047

William A. Petri, Jr., and Rashidul Haque 275  Free-Living Amebae  3059 Anita A. Koshy, Brian G. Blackburn, and Upinder Singh 276  Malaria (Plasmodium Species)  3070 Rick M. Fairhurst and Thomas E. Wellems 277  Leishmania Species: Visceral (Kala-Azar),

Cutaneous, and Mucosal Leishmaniasis  3091 Alan J. Magill

278  Trypanosoma Species (American

Trypanosomiasis, Chagas’ Disease): Biology of Trypanosomes  3108 Louis V. Kirchhoff

279  Agents of African Trypanosomiasis (Sleeping

Sickness)  3116 Louis V. Kirchhoff

280  Toxoplasma gondii  3122 José G. Montoya, John C. Boothroyd, and Joseph A. Kovacs 281  Giardia lamblia  3154 David R. Hill and Theodore E. Nash 282  Trichomonas vaginalis  3161 Jane R. Schwebke

K Ectoparasitic Diseases 293  Introduction to Ectoparasitic Diseases  3243 James H. Diaz 294  Lice (Pediculosis)  3246 James H. Diaz 295  Scabies  3250 James H. Diaz 296  Myiasis and Tungiasis  3255 James H. Diaz 297  Mites, Including Chiggers  3260 James H. Diaz 298  Ticks, Including Tick Paralysis  3266 James H. Diaz

L Diseases of Unknown Etiology 299  Kawasaki Disease  3280 Jane C. Burns

IV 

Special Problems

A Nosocomial Infections

283  Babesia Species  3165 Jeffrey A. Gelfand and Edouard G. Vannier

300  Infection Prevention in the Health Care

284  Cryptosporidiosis (Cryptosporidium

Michael B. Edmond and Richard P. Wenzel

Species)  3173

A. Clinton White, Jr. 285  Cyclospora cayetanensis, Cystoisospora

(Isospora) belli, Sarcocystis Species, Balantidium coli, and Blastocystis Species  3184

Kathryn N. Suh, Phyllis Kozarsky, and Jay S. Keystone

I

Diseases Due to Toxic Algae

286  Human Illness Associated with Harmful Algal

Blooms  3192

J. Glenn Morris, Jr.

J

Diseases Due to Helminths

287  Introduction to Helminth Infections  3196 James H. Maguire

Setting  3286

301  Disinfection, Sterilization, and Control of

Hospital Waste  3294

William A. Rutala and David J. Weber 302  Infections Caused by Percutaneous

Intravascular Devices  3310

Susan E. Beekmann and David K. Henderson 303  Nosocomial Pneumonia  3325 Michael Klompas 304  Nosocomial Urinary Tract Infections  3334 Thomas M. Hooton 305  Health Care–Acquired Hepatitis  3347 Kent A. Sepkowitz 306  Transfusion- and Transplantation-Transmitted

Infections  3351

Matthew J. Kuehnert and Sridhar V. Basavaraju


xxxvii 307  Human Immunodeficiency Virus in Health Care

Settings  3361

308  Nosocomial Herpesvirus Infections  3376 Tara N. Palmore and David K. Henderson

B Infections in Special Hosts 309  Infections in the Immunocompromised Host:

General Principles  3384

J. Peter Donnelly, Nicole M. A. Blijlevens, and Walter J. F. M. van der Velden 310  Prophylaxis and Empirical Therapy of Infection

in Cancer Patients  3395

Elio Castagnola, Małgorzata Mikulska, and Claudio Viscoli 311  Risk Factors and Approaches to Infections in

Transplant Recipients  3414

J. Stephen Dummer and Lora D. Thomas 312  Infections in Recipients of Hematopoietic Stem

Cell Transplants  3425

Jo-Anne H. Young and Daniel J. Weisdorf 313  Infections in Solid-Organ Transplant

Recipients  3440

Nina Singh and Ajit P. Limaye 314  Infections in Patients with Spinal Cord

Injury  3453

Rabih O. Darouiche 315  Infections in the Elderly  3459 Kent B. Crossley and Phillip K. Peterson

317  Infections in Injection Drug Users  3475 Donald P. Levine and Patricia D. Brown 318  Surgical Site Infections and Antimicrobial

Prophylaxis  3492 Thomas R. Talbot

C Surgical- and Trauma-Related Infections 319  Burns  3505 Clinton K. Murray 320  Bites  3510 Ellie J. C. Goldstein and Fredrick M. Abrahamian

D Immunization 321  Immunization  3516 Andrew T. Kroger, Larry K. Pickering, Melinda Wharton, Alison Mawle, Alan R. Hinman, and Walter A. Orenstein

E Zoonoses 322  Zoonoses  3554 W. Ian Lipkin

F Protection of Travelers 323  Protection of Travelers  3559 David O. Freedman 324  Infections in Returning Travelers  3568 David O. Freedman

Contents

David K. Henderson

316  Infections in Asplenic Patients  3466 Janet R. Gilsdorf


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14 

Emerging and Reemerging Infectious Disease Threats Rima Khabbaz, Beth P. Bell, Anne Schuchat, Stephen M. Ostroff, Robin Moseley, Alexandra Levitt, and James M. Hughes

Throughout history, infectious diseases have been inextricably linked with human health, affecting the development and advancement of societies as well as human evolution.1,2 Those linkages remain well defined today, as infectious pathogens find new ways to exploit human vulnerabilities and elude control efforts across a highly connected world. Widespread movement of people, animals, and goods, exploding population numbers, urban development, environmental degradation, centralized food production, and other contributing factors (Table 14-1) have given microbes rapid and easy access to new populations and geographic areas and spawned a host of emerging and reemerging infectious diseases—the majority of which are zoonotic (Table 14-2).3 With their remarkable adaptability, emerging infections can spread quickly and gain strongholds to become endemic diseases, as most profoundly demonstrated by the decades-long pandemic of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). Data from the Global Burden of Disease Study 2010 (GBD 2010), a landmark collaboration of 486 scientists from 302 institutions across 50 countries,4 indicate that nearly one fourth of the estimated 52.8 million deaths that occurred in 2010 were associated with infectious diseases.5 From 1990 to 2010, overall deaths from communicable diseases declined, with significant decreases in mortality from lower respiratory tract infections (from 3.4 to 2.8 million) and diarrheal diseases (from 2.5 to 1.4 million).5 However, infectious diseases remained leading killers, especially among young children (Fig. 14-1) and accounted for large burdens of disability-adjusted life years worldwide.5,6 Although deaths from HIV infection/AIDS peaked in 2006 and have since showed steady declines owing to fewer new infections and increased availability of antiretroviral therapy and care, HIV infection/ AIDS remains a leading cause of disease burden and death—responsible for an estimated 1.5 million deaths in 2010.5 Tuberculosis and malaria also continue to exact a tremendous toll, each causing approximately 1.2 million deaths in 2010.5 The multifactorial impact of infectious diseases is most prominent in low-income countries, with infectious diseases causing severe morbidity, impeding economic development, and compromising political stability. Beyond infectious diseases, microbial agents have been identified as the cause or contributing factor in a number of chronic diseases (Table 14-3). In 2008, approximately 2 million new cancer cases were linked to infections.7 Among the leading causes of cancer-related deaths, three are caused by infectious agents: hepatocellular carcinoma by hepatitis B and C viruses, cervical cancer by human papillomavirus, and gastric cancer by Helicobacter pylori bacteria. Many other potential infectious/chronic disease linkages are also being explored, including Chlamydia pneumoniae and multiple sclerosis,8,9 Alzheimer’s disease,9 and atherosclerosis10; enteroviruses and type 1 diabetes11,12; and rhinoviruses and childhood asthma.13 In addition, several genetic factors have been shown to influence infectious disease susceptibility and disease progression (Table 14-4) and hundreds of others are under investigation.14 The past few decades have provided numerous examples of the ongoing threat of infectious diseases and the ability of microbes to evolve, adapt, and survive. In particular, acute respiratory viruses are often among the most recognized emerging and reemerging infectious diseases because of the high disease burden they produce. Examples in the past decade include a novel coronavirus that resulted in the 2003 global outbreak of severe acute respiratory syndrome (SARS),15 pandemic influenza A (H1N1) in 200916; a newly recognized coronavirus causing severe disease in 2012 (Middle Eastern respiratory syndrome coronavirus [MERS-CoV])17; and avian influenza A H7N9 in China in 158

2013.18 Emerging and reemerging vector-borne infections also remain priorities, as mosquito-borne viruses such as dengue and chikungunya continue to appear in new areas and tick-borne diseases continue their steady rise. In addition, increased attention is being given to environmental fungi as a cause of human and animal infections. Recent examples include the emergence of Cryptococcus gattii infections in the U.S. Pacific Northwest,19,20 increasing numbers of Coccidioides infections, which are a major cause of community-acquired pneumonia in California and the southwest United States,21 and novel fungal infections as a cause of health care–associated infections (HAIs).22 International trade and travel along with globally mobile populations present particular challenges for controlling infectious diseases, highlighting concerns for spread of known infections such as tuberculosis23 and vaccine-preventable diseases24 along with introduction of new threats.25 In 2011, international tourist arrivals approached 1 billion worldwide, and they are expected to nearly double over the coming decades (Fig. 14-2).26 Moreover, today’s globalized food supply has resulted in an increasing number of foodborne illnesses, many of which have severe consequences—especially for more vulnerable populations such as children, immunocompromised individuals, and the elderly. Also on a global level is the growing problem of resistance to antimicrobial agents, which continues to impede treatment and control efforts for an increasing number of pathogens.

REEMERGING VACCINEPREVENTABLE DISEASES

The development of safe, effective vaccines coupled with large-scale immunization programs represents the ultimate solution to infectious diseases.27 Routine childhood immunization in the United States prevents approximately 20 million illnesses and 42,000 premature deaths, while saving nearly $70 billion in direct and societal costs for each birth cohort vaccinated.28 Although vaccination led to the eradication of smallpox in 1980 and has brought the world closer than ever to eradication of poliomyelitis, vaccine-preventable diseases can reemerge even in the setting of high-functioning immunization programs. A variety of factors contribute to outbreaks of vaccine-preventable diseases in the vaccination era (Table 14-5).29-32 Recently, countries in the Americas and Europe have confronted the reemergence of measles, mumps, and pertussis owing to diverse underlying causes.33-35 Most resurgences of vaccine-preventable diseases stem from low immunization coverage. In many parts of the world, weak primary health care systems and limited access to the most vulnerable populations result in many children being unimmunized. More recently, reduced vaccine acceptance in several affluent countries has emerged as a threat to protecting communities from vaccine-preventable diseases. Whereas in the United States less than 1% of children receive no vaccines at all,36 some parents refuse one or more vaccines or decide to delay or increase intervals between vaccinations.

Measles

Two doses of measles-containing vaccines provide 95% vaccine efficacy, but at least 94% of the population must be vaccinated to ensure herd immunity, or population protection. Infants too young to be immunized and people who are immune compromised depend on herd immunity for protection. Accumulation of susceptible people in a community can result in periodic outbreaks when measles virus is circulating.30 Endemic transmission of measles has been interrupted in the United States since 2000,37 but travelers to areas where the virus still circulates account for 50 to 100 importations to the United States most years. Aggressive public health investigation of each suspected


158.e1

KEYWORDS

Chapter 14  Emerging and Reemerging Infectious Disease Threats

acute respiratory infections; antibiotics; antimicrobial resistance; avian influenza; Campylobacter; carbapenem-resistant Enterobacteriaceae; chikungunya; cholera; Clostridium difficile; coronavirus; Cryptosporidium; dengue; diarrheal disease; Ebola hemorrhagic fever; emerging infectious diseases; epidemiology; Escherichia coli; foodborne disease; gastroenteritis; H1N1; H3N2; H5N1; H7N9; health care–associated infections; Heartland virus; human bocavirus; human metapneumovirus; immunizations; infectious diseases; influenza; Marburg hemorrhagic fever; measles; MERS-CoV; methicillin-resistant Staphylococcus aureus; mumps; norovirus; One Health; pandemic influenza; pertussis; reemerging infectious diseases; Salmonella; SARS; Shigella; vaccine-preventable diseases; vaccines; variant influenza A; vector-borne diseases; Vibrio cholerae; West Nile virus; zoonotic diseases


159 Ensuring appropriate infection control practices and complete immunization histories or evidence of immunity among health care workers is especially important given the infectiousness of measles virus. Although in the Americas endemic transmission of measles has been eliminated and in the Western Pacific Region reaching this target is near, measles continues to cause more than 100,000 deaths each

Injuries, 13.5%

Noncommunicable diseases, 10.9%

TABLE 14-1  Factors That Contribute to the Emergence and Reemergence of Infectious Diseases Human demographics and behavior Human susceptibility to infection Technology and industry Economic development and land use International travel and commerce Microbial adaptation and change Climate and weather Changing ecosystems Breakdown of public health measures Poverty and social inequality War and famine Lack of political will Intent to harm Data from Smolinski MS, Hamburg MA, Lederberg J, eds, for the Committee on Emerging Microbial Threats to Health in the 21st Century, Board on Global Health, Institute of Medicine. Microbial Threats to Health: Emergence, Detection, and Response. Washington, DC: National Academy Press; 2003.

Malaria, 20.8%

Nutritional deficiencies, 7.2% Congenital anomalies, 2.5%

Diarrheal diseases, 11.9%

Other communicable, maternal, neonatal, and nutritional disorders, 5.1% Tuberculosis, 1.3%

Lower respiratory tract infections, 12.4%

Typhoid and Measles, paratyphoid 3.8% fevers, 1.5%

HIV/ AIDS, 4.9%

Diarrheal diseases, 11.9% HIV/AIDS, 4.9% Meningitis and encephalitis, 4.2%

FIGURE 14-1  Causes of deaths for children 1 to 4 years of age, worldwide, 2010 (1,969,567 deaths). (Modified from Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2095-2128.)

TABLE 14-2  Examples of Recent Outbreaks, Pathogen Discoveries, and Other Notable Infectious Disease Events YEAR

EVENT

2000

Outbreak of Rift Valley fever in Saudi Arabia and Yemen, representing the first reported cases of the disease outside the African continent

2003

Global outbreak of severe acute respiratory syndrome (SARS) caused by a previously unknown coronavirus associated with Chinese horseshoe bats

2003

Cases of monkeypox in the United States linked to exotic pets imported from Central Africa

2003

Reemergence of avian influenza A (H5N1) in Southeast Asia and subsequent outbreaks in Africa

2005

Marburg hemorrhagic fever outbreak in Angola

2005-2006

Large outbreak of chikungunya in the Indian Ocean islands of Réunion and Mauritius

2006

Rift Valley fever outbreak in Kenya

2007

Ebola hemorrhagic fever outbreak in the Democratic Republic of the Congo

2007

Outbreak of Nipah virus encephalitis in Bangladesh

2007

First detection in Italy of mosquito-borne transmission of chikungunya fever, previously detected only in parts of Africa and South and Southeast Asia

2007

Hemorrhagic fever outbreak in Uganda caused by a new stain of Ebola: Bundibugyo Ebola virus

2007

Outbreak of Marburg hemorrhagic fever in Uganda

2008

Ebola-Reston virus detected in pigs in the Philippines

2008

Ebola-like outbreak in Zambia due to a previously unknown virus: Lujo hemorrhagic fever virus, an arenavirus related to Lassa fever virus, which is associated with rodents

2009

Outbreak of severe fever with thrombocytopenia syndrome (SFTS) in China caused by a novel phlebovirus (the SFTS virus)

2009

Discovery of two novel tick-borne pathogens in the United States: the Heartland phlebovirus in Missouri and a pathogenic Ehrlichia species in Wisconsin and Minnesota

2009-2010

Influenza pandemic caused by a new influenza strain, influenza A(H1N1)

2009-2010

Locally transmitted dengue in Florida, representing the first cases acquired in the continental United States outside the Texas-Mexico border since 1945

2012

Ebola hemorrhagic fever outbreaks in Uganda and the Democratic Republic of the Congo

2012

Outbreak of Marburg hemorrhagic fever in Uganda

2011-2012

Influenza cases in the United States traced to a variant swine influenza A(H3N2) virus carried by pigs exhibited at agricultural fairs

2012

Outbreak of hantavirus pulmonary syndrome in Yosemite National Park, California

2012

A novel rhabdovirus (Bas-Congo virus) identified by whole-genome sequencing as the cause of an outbreak of acute hemorrhagic fever in the Democratic Republic of the Congo

2012-2013

Outbreak of severe respiratory disease in the Middle East caused by a novel coronavirus (MERS-CoV) that belongs to the same viral family as the SARS coronavirus

2012-2013

Influenza cases in China traced to avian influenza A(H7N9) virus in poultry

Chapter 14  Emerging and Reemerging Infectious Disease Threats

measles case is conducted to limit spread of the virus. Recently, several measles outbreaks in the United States have been associated with transmission among people who have not been vaccinated, intentionally, due to personal beliefs. In 2011, 222 measles cases occurred in the United States, the largest number of annual cases reported since 1996.38 The most important source of imported virus in 2011 was Europe, where large outbreaks affected multiple countries. A very large outbreak in France (where an estimated 20,000 cases occurred)39 was linked with importations to multiple countries in the Americas.38,40 Public health response to each outbreak is expensive.24 Because measles is rarely seen in the United States, missed diagnosis can lead to sustained exposures particularly in health care settings (Fig. 14-3).41


year—primarily in developing countries.42 Enormous progress in measles immunization through supplemental immunization activities and increasing routine coverage, particularly in Africa, has led to a 74% reduction in worldwide measles deaths.43 Despite this progress, the weak underlying immunization systems, famine, limited access associated with political disruption, and delayed emergency campaigns explain resurgences of measles in the Horn of Africa and southern Africa.44 Low first-dose measles coverage and long intervals between campaigns offering second-dose opportunities allow rapid accumulation of children susceptible to measles and can lead to large outbreaks. Poor vaccine acceptance in selected communities, ranging from the Roma communities45 to anthroposophists in Switzerland has led to sizable outbreaks in Europe as well.46

TABLE 14-4  Examples of Genetic Factors That Influence Susceptibility to Disease or Disease Progression GENETIC FACTOR

DISEASE INFLUENCE

Alleles of the chemokine receptor gene CCR5

Partial protection against acquisition of HIV and development of acquired immunodeficiency syndrome

Globin gene alleles (e.g., sickle globin and α- and β-thalassemias)

Partial protection against malaria

Lack of the Duffy blood group on red cells (due to a mutation in a chemokine receptor gene)

Complete protection against Plasmodium vivax malaria

Blood group O

Increased susceptibility to severe cholera

HLA alleles

May influence susceptibility to infection or course of disease with HIV, hepatitis B virus, measles, hantavirus pulmonary syndrome, malaria, tuberculosis, human papillomavirus infection, and coccidioidomycosis

TABLE 14-3  Examples of Infectious Agents That Cause or Contribute to Chronic Diseases PATHOGEN Bacteria

CHRONIC CONDITION CAUSED/ EXACERBATED BY THIS PATHOGEN

Borrelia burgdorferi

Chronic arthritis

Helicobacter pylori

Chronic gastritis and peptic ulcers

HIV, human immunodeficiency virus; HLA, human leukocyte antigen. Modified from Levitt AM, Khan AS, Hughes JM. Emerging and re-emerging pathogens and diseases. In: Cohen J, Powderly WG, Opal SM, eds. Infectious Diseases. 3rd ed. St. Louis: Mosby; 2010.

Gastric carcinoma Mucosa-associated lymphoid tissue lymphoma

Viruses Epstein-Barr virus

Hepatitis B and C viruses

Burkitt’s lymphoma

TABLE 14-5  Factors That Contribute to the Reemergence of Vaccine-Preventable Diseases

Post-transplant lymphoproliferative disease

FACTOR

SELECTED EXAMPLES

REFERENCES

B-cell lymphoma

Failure to vaccinate by health care system

Missed opportunities related to clinician practice, financial, or system constraints Weak or interrupted immunization services, as in humanitarian emergencies

29, 44

Failure to be vaccinated due to patient or parental refusal or deferral

Personal belief and religious exemptions Vaccine hesitancy

32, 33

Vaccine failure, including moderate or low vaccine efficacy and waning of immunity over time

Mumps vaccine efficacy in the setting of high force of infection Waning of immunity after acellular pertussis vaccination

34, 35

Pathogen “escape” from vaccine-induced immunity

Serotype replacement including capsular switching in Streptococcus pneumoniae

31

Nasopharyngeal carcinoma (undifferentiated)

Cirrhosis Hepatocellular carcinoma

Human herpesvirus 8

Kaposi sarcoma

Human immunodeficiency virus

Lymphoma

Human papillomavirus

Cervical carcinoma

HIV-related neurocognitive disorders and peripheral neuropathy Anogenital and oropharyngeal cancers

Human T-lymphotropic virus type 1 (HTLV-1)

Adult T-cell leukemia/lymphoma

Parasites Liver flukes

Cholangiocarcinoma

Schistosoma haematobium

Bladder cancer

Prions Variant Creutzfeldt-Jakob disease prion

Degenerative brain disorder

International Tourist Arrivals Received (million)

Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

160

Actual

1800

Forecasts 1.8 bn

1600 1400

1.4 bn

Africa

1200

Middle East

1000

Asia and the Pacific

800

Americans 940 mm

Europe

600 400 200 0 1950

1960

1970

1980

1990

2000

2010

2020

2030

FIGURE 14-2  International tourist arrivals, actual trends and forecast, 1950-2030. (From World Tourism Organization [UNWTO]. UNWTO Tourism Highlights, 2012 edition. Madrid: UNWTO; 2012. Available at http://mkt.unwto.org/en/publication/unwto-tourism-highlights-2012-edition.)


161

FIGURE 14-3  Measles in a child.

300,000 250,000 200,000 150,000

45,000 40,000 35,000 30,000 25,000 20,000 15,000 10,000 5,000 0 1990

Acute Respiratory Tract Infection

1995

2000

2005

2010

100,000 50,000 0 1922 1930 1940 1950 1960 1970 1980 1990 2000 2010 Year FIGURE 14-4  Cases of pertussis reported to the National Notifiable Diseases Surveillance System: 1922-2012.

Mumps

Although mumps has decreased by nearly 99% since the prevaccination era in the United States, several large outbreaks have occurred in the United States and Europe in the past decade.34,47,48-51 Outbreakassociated disease has occurred mainly in adolescents and young adults. Despite high two-dose coverage, importation of mumps virus has been linked to outbreaks in summer camps,52 college campuses,47,49,53 and religious schools.34,51 These outbreaks were difficult to control, and although the highest risk occurred among unvaccinated persons, many case-patients had received one or two doses of mumpscontaining vaccine, consistent with only 80% to 85% vaccine efficacy for one- and two-dose regimens.48,50 Although factors associated with disease include intense crowding, there is no evidence to support immune escape.54 Recent outbreaks have been notable for very little transmission to the broader community. Although some proponents exist, the value of administering a third dose of mumps-containing vaccine in outbreaks that occur despite high two-dose coverage has been unclear because disease tends to be decreasing by the time additional doses are provided.55 Because most mumps outbreaks have occurred in unusual settings where there is extreme crowding or extensive personal contacts and most mumps is self-limited and relatively mild, it is unlikely major investments will be made to attempt to improve the efficacy of mumps vaccines.

Pertussis

Despite decades of vaccination with first the whole-cell pertussis vaccine and, since the 1990s, acellular pertussis vaccine, pertussis is currently the least well-controlled vaccine-preventable disease in the United States. Cyclical increases are typical for pertussis, but since the 1990s the United States has experienced a continuing rise in incidence that exceeds changes due to better laboratory diagnostics or disease reporting (Fig. 14-4). The highest rates of disease, hospitalizations, and fatalities occur among infants younger than 1 year of life.56 Reported cases in teens and older children have been increasing since 2010.57 It has become increasingly clear that the transition from whole-cell

Infections involving the respiratory tract represent one of the most dynamic areas for emerging and reemerging diseases, producing dramatic examples such as the first recognized outbreaks of legionellosis in the 1970s and hantavirus pulmonary syndrome in the 1990s. Examples in the 21st century include newly recognized pathogens such as human metapneumovirus (first identified in 2001),61 the coronavirus associated with SARS (identified in 2003),15 human bocavirus (identified in 2005),62 pandemic influenza A (H1N1) (identified in 2009),16 and a Middle Eastern novel coronavirus associated with severe respiratory illness identified in 2012.17 Other newly recognized respiratory viruses include two additional coronaviruses (NL63 and HKU1), novel human polyomaviruses KI and WU, rhinovirus groups C and D, and parechoviruses, although in some instances the role of these agents as pathogens is still being clarified.63 More virulent strains of known respiratory pathogens have also emerged. Examples of this phenomenon include human disease associated with avian influenza viruses (especially highly pathogenic avian influenza A [H5N1] and avian influenza H7N918,64), severe disease due to adenovirus type 14,65 and extensively drug-resistant tuberculosis.66 Acute respiratory tract infection constitutes a broad category of diseases that include infections of both the upper and lower respiratory tracts, such as acute pharyngitis, epiglottitis, bronchitis, pneumonia, and influenza. Although upper respiratory tract infections are capable of causing severe illness, virtually all (98%) respiratory disease–related deaths are a consequence of infection of the lower respiratory tract, especially pneumonia. Acute respiratory infections remain the leading cause of mortality from infectious diseases in the United States and around the world. The World Health Organization (WHO) estimates that 4.2 million deaths resulted from lower respiratory tract infections in 2004, accounting for 7.1% of all deaths that year.67 Among persons who died of lower respiratory tract infections, 70% (2.9 million) were residents of low-income countries. Lower respiratory tract infections are the number one cause of death in the developing world. Even in high income countries, lower respiratory tract infections are the fourth leading cause of death, responsible for 4% of all-cause mortality. Mortality from lower respiratory tract infections has the greatest impact on young children. On a global basis, 42% of all deaths from lower respiratory tract infections (mostly due to pneumonia) occur in children younger than 5 years of age.67 Significant influenza- and pneumoniaassociated mortality also occurs in persons older than 65 years of age and in individuals with chronic underlying pulmonary disease. In the United States, influenza and pneumonia are the leading cause of infectious disease–related mortality and the eighth most frequent cause of death.68

Human Metapneumovirus

In 2001, human metapneumovirus (hMPV) was first reported as a cause of acute respiratory tract infections when the virus was isolated

Chapter 14  Emerging and Reemerging Infectious Disease Threats

pertussis virus vaccine “backbone” to acellular vaccines has changed the epidemiology of pertussis. In 2010, California reported the highest rates of pertussis in 50 years. A retrospective analysis conducted there revealed vaccine efficacy was more than 95% within 3 years of receiving the last dose of acellular pertussis but decreased substantially by 5 years since vaccination.35,58 This explained the predominance of 7- to 10-year olds in the 2010 resurgence. By 2012, high rates of disease occurred in Washington State and several other areas,57 with surprising increases also noted among 11- and 13-year olds. Questions have been raised about whether there is differential performance of Tdap booster vaccinations among teenagers who had received acellular vaccines as young children compared with the earlier experience of teenagers who received Tdap after earlier exposure to whole-cell vaccines. Although some have speculated that bacterial strain changes noted recently might account for disease resurgence,59 the dominant view is that acellular vaccines provide good short-term protection but provide immunity that wanes more rapidly than initially expected. Program priorities in this context are to target reduction of deaths, which mainly affect infants in the first few months of life. Hence, recent recommendations for women to be vaccinated during every pregnancy are a priority for disease control.60


Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

162 infection.70,81 Ribavirin and immune globulin have been used to treat severe disease but have not been systematically assessed, and efforts are underway to develop candidate vaccines against hMPV.69,82 Genetic analyses have demonstrated two major hMPV types, designated groups A and B, with two subtypes (1 and 2) within each group; subtype variants have also been reported.69 The geographic distribution of groups and subtypes changes over time, and multiple variants can cocirculate. Periodic shifts in predominant circulating strains are thought to coincide with upsurges in disease incidence and severity. In some studies, group A viruses have been associated with more severe disease compared with group B viruses, although other series have found the opposite result or have not suggested a difference in disease severity between the two groups.

from specimens collected over a 20-year period from hospitalized children in the Netherlands with undiagnosed upper and lower respiratory tract illnesses.61 Subsequent serologic and virologic analyses of banked specimens have demonstrated evidence of hMPV infection as far back as the 1950s, and genetic studies suggest the virus is considerably older.61,69 A paramyxovirus, hMPV is closely related to respiratory syncytial virus (RSV), another member of the Paramyxoviridae subfamily of Paramyxoviridae.69,70 These related viruses have many clinical and epidemiologic features in common, and coinfections with these two pathogens have even been described.71 Studies examining whether hMPV and RSV coinfections produce more severe illness have shown conflicting results.71 Since hMPV was first identified, major strides have been made in our understanding of the impact of this agent, which appears similar to other major viral respiratory pathogens. It is known to occur globally in both high- and low-income countries, and by 5 years of age virtually all children demonstrate evidence of prior hMPV infection.72 Clinically significant illness and severe disease most commonly occur in children younger than 2 years of age, but hMPV-related illness can occur throughout childhood.73,74 In most studies, this virus (either alone or with copathogens) has been identified in 2% to 20% of children with acute respiratory tract infections, and in 3% to 7% of children hospitalized with acute respiratory tract infections or fever.69,73 Variation in rates of hMPV detection is likely due to patient selection criteria, sample collection, and diagnostic test methods. In contrast, hMPV is rarely (<1%) identified in children or adults who are not ill and when found is usually present in much lower titers than when detected during illness.69,73,75 A recent multiyear, multicenter prospective study suggests that hMPV produces 20,000 hospitalizations, 263,000 emergency department visits, and 1 million outpatient visits annually among children younger than 5 years of age in the United States.75 Because disease is also found in older children and in adults, these numbers represent an unknown proportion of the overall burden of illness due to hMPV. Multiyear studies of hMPV infection show that incidence varies from year to year and by season, with most infections in temperate locations occurring in winter and early spring.70 In children, most severe hMPV disease manifests as pneumonia or bronchiolitis and a substantial proportion of hospitalized children have underlying medical conditions, particularly asthma.73-76 Intensive care can be necessary and fatal illnesses have occurred in children with hMPV infections.77 Human metapneumovirus has also been associated with childhood upper respiratory tract infections (up to 10% in some series) as well as acute otitis media.70 Most infections with hMPV in adults are mild, but severe disease can occur, especially in the elderly and in persons with chronic pulmonary disease or congestive heart failure.78,79 This virus has been estimated to involve 3% to 7% of acute respiratory tract infections and 4.5% of acute respiratory tract infection hospitalizations in adults.79 Outbreaks associated with hMPV have been reported in both children and adults, especially among long-term institutionalized elderly, with case-fatality rates as high as 33%.79,80 As with RSV, hMPV can produce severe and recurrent disease in immunocompromised hosts, including transplant recipients, those with hematologic malignancies, and HIV

Human Coronaviruses

Although coronaviruses were once considered to be pathogens most typically associated with the common cold, their public health sig­ nificance has changed considerably in recent years.83 The 2003 outbreak of SARS is widely considered to be the most consequential emerging infectious disease event of the early 21st century, with profound public health, economic, sociologic, and political ramifications.84 The expanded research and monitoring of coronaviruses that resulted from the SARS episode led to the recognition of two additional human coronaviruses (NL63 and HKU1) associated with upper respiratory tract infections.83-86 Most recently, a novel coronavirus was identified in 2012 among patients in the Middle East or patients linked to the Middle East.17 This new virus, which is distinct from the SARS coronavirus, is also associated with severe and fatal pulmonary disease. A number of studies suggest that the human coronaviruses appear to be zoonotic in origin, with bats being especially important reservoirs.87 Because bats harbor many coronaviruses, there is the potential for future pathogenic coronaviruses to emerge from this reservoir. SARS was recognized in February 2003 when an explosive outbreak of adult respiratory distress syndrome was carried globally by more than a dozen individuals who were all guests at a Hong Kong hotel over a single weekend while a physician from adjacent Guangdong Province with fatal respiratory illness was also present.88-90 Before traveling to Hong Kong, the source physician had been caring for patients with a similar illness, with 305 cases of undiagnosed respiratory diseases occurring in Guangdong Province since the previous November. A global consortium of laboratories rapidly identified the causative agent as a previously unrecognized betacoronavirus (SARS coronavirus [SARS-CoV]).15 The outbreak was contained within 4 months of recognition, primarily through the employment of public health measures such as community isolation and quarantine.88-90 In the interim, a total of 8,096 cases of SARS were recorded in 29 countries on five continents, with 774 (9.6%) fatalities.91 However, 98% of the cases occurred in just five locations (Table 14-6); only 8 cases were confirmed in the United States. The following winter, four symptomatic and one asymptomatic community-acquired SARS cases occurred in Guangzhou. There was also a series of laboratory acquired infections in Taiwan, Singapore, and mainland China over the same time period.88 No cases of SARS have been recognized anywhere in the world since 2004.

TABLE 14-6  Cumulative Number of Confirmed and Probable Severe Acute Respiratory Syndrome (SARS) Cases by Location, November 2002 to July 2003 CASE-FATALITY RATIO (%)

NO. OF CASES IN HEALTH CARE WORKERS

PERCENT OF CASES IN HEALTH CARE WORKERS

349

7%

1002

19%

299

17%

386

22%

346

37

11%

68

20%

Canada

251

43

17%

109

43%

Singapore

238

33

14%

97

41%

All others

179

13

7%

44

25%

8096

774

10%

1706

21%

LOCATION

NO. OF CASES

NO. OF FATALITIES

China

5327

Hong Kong

1755

Taiwan

TOTAL

Data from World Health Organization. Summary of Probable SARS Cases with Onset of Illness from 1 November 2002 to 31 July 2003. Available at http://www.who.int/csr/ sars/country/table2004_04_21/en/index.html.


163

Influenza

No disease is more closely intertwined with the subject of emerging and reemerging infectious diseases than influenza.108,109 Arguably the most dramatic example of infectious disease emergence is the 19181919 Spanish influenza A H1N1 pandemic. This virus swept across the globe in successive waves with profound societal disruption in the midst of World War I, leaving in its wake an estimated number of fatalities ranging as high as 50 to 100 million people.109 In the United States alone, an estimated 675,000 deaths occurred, increasing the overall mortality rate for that period by almost 40%.109,110 Two less consequential pandemics (caused by influenza A H2N2 in 1957 and influenza A H3N2 in 1968), but with excess mortality, also were observed in the 20th century. Influenza has proven to be even more volatile in the 21st century. Traditional dogma regarding which influenza A hemagglutinin subtypes (H1, H2, and H3) are responsible for illness in humans has been reconsidered based on recent events. These include cases of severe human disease due to highly pathogenic avian influenza A H5N1 that have been occurring since 2003 and the increasing recognition of human disease caused by other viruses (H7, H9, H10) usually considered avian subtypes.111-113 As the attention of the public health community was focused on the pandemic potential of these avian subtypes, in 2009 another influenza virus (a triple reassortant A H1N1) suddenly appeared in North America to produce the first pandemic of the 21st century.114 In the aftermath of the H1N1 pandemic, a variant strain of influenza A H3N2 that produces human disease in association with swine contact, mostly at agricultural fairs, has been recognized in the United States.115 Further complicating the picture, in early 2013 an outbreak of influenza due to avian influenza A (H7N9) virus, not known to have previously infected humans, was reported across a wide area of eastern China.18 The novel H7N9 virus is associated with unusually high mortality in humans but is a low pathogenicity variant in poultry.116 These examples highlight the unpredictable nature of influenza and the critical need to maintain a high state of vigilance for this disease through global surveillance in people and animals along with research to develop improved treatment, prevention, and control measures.

Avian Influenza

Human disease due to highly pathogenic avian influenza (HPAI) H5N1 was first recognized when a fatal illness occurred in a 3-year old child in Hong Kong in the spring of 1997.117 “Highly pathogenic” is the designation used to describe avian influenza viruses with certain genetic traits that produce lethal disease outbreaks in poultry. This case was followed later in the year by a series of 18 human illnesses (6 fatal) in children and young adults that led to the mass culling of poultry in Hong Kong as a measure to control bird-to-human transmission.118 The virus responsible for this outbreak is referred to as A/Goose/ Guangdong/1/96 H5N1 because it was first identified in a goose in southern China the previous year. All subsequent human H5N1 illnesses, as well as the animal outbreaks that have led to the natural death and culling of more than 250 million poultry and wild birds, have been caused by descendants of the 1996 goose Guangdong lineage.119,120 This virus has evolved into two major clades (1 and 2) and numerous additional clades and subtypes that have spread over three continents during sequential waves believed to originate in southern China.119,121 After the initial 1997 Hong Kong outbreak, episodes of human illness due to avian influenza subtypes (especially H7 and H9) were identified in Europe, Asia, and North America, producing both respiratory disease and conjunctivitis.122-124 In early 2003, a father and son from Hong Kong who had traveled to southern China were diagnosed with H5N1 influenza at the time that the outbreak that became SARS was recognized, briefly raising concern this may have been the etiology of the outbreak.125 However, it was not until late 2003, when SARS had subsided, that the current outbreak of H5N1 human illnesses began when cases were recognized in Vietnam and Thailand.126,127 In contrast to previous episodes, these cases were more widely dispersed and there was evidence of widespread circulation of HPAI H5N1 in poultry, waterfowl, and wild birds in the affected areas.

Chapter 14  Emerging and Reemerging Infectious Disease Threats

Several features of SARS are especially noteworthy. These include (1) a relatively long incubation period (mean 4.6 days, range 2 to 14 days); (2) minimal transmissibility early in the course of illness (viral shedding in respiratory secretions followed a crescendo-decrescendo pattern with peak titers on day 10 of illness); (3) a high proportion of illnesses (21%) in health care workers; (4) a low-to-moderate basic reproductive number (R0), estimated at 2 to 4 secondary cases per average infectious case92; (5) the occurrence of “super-spreader” events facilitated by inpatient therapeutic procedures that promoted aerosolization of the virus and accounted for much of the observed personto-person transmission (the majority of cases resulted in no secondary transmission); (6) a rarity of asymptomatic infections; and (7) a striking age-dependent case-fatality ratio (<1% in persons <24 years of age vs. >50% in those >65 years).88-90 Epidemiologic investigations found that people with early SARS cases in Guangdong Province often had contact with exotic live animal markets. Several species (especially palm civet cats) in the live markets had evidence of SARS-CoV infection, leading to mass culling as a control measure.88 The virus was not detected in these animals in the wild, and experimental infections showed the animals developed SARS-like symptoms. Both factors suggested they were not the natural host. In 2005, viruses similar to SARS-CoV (SARS-like coronaviruses [SL-CoV]) were identified in horseshoe bats in southern China and bats are now considered to represent the natural reservoir.87,93-95 Subsequent studies have shown bats in many parts of the world harbor SL-CoVs.87,95 Various therapies were employed during the SARS outbreak, including ribavirin, corticosteroids, antiretroviral drugs, and immunotherapy. Some appeared beneficial, but none could be systematically evaluated.89 SARS-CoV is known to act through a spike protein that targets angiotensin-converting enzyme 2, offering potential therapeutic options.88,96 Vaccine development research using a variety of approaches is underway.97 A novel human coronavirus (initially referred to as HCoV-EMC for Erasmus Medical Center in the Netherlands and now known as Middle East respiratory syndrome coronavirus [MERS-CoV]) was first identified in July 2012 in a 60-year-old man from Saudi Arabia with fatal lower respiratory tract infection.17 As of July 2013, a total of 81 laboratory-confirmed cases of infection with this virus have been reported internationally.98 Cases have been reported from nine countries, all with a direct or indirect link to locations in and around the Arabian peninsula. The earliest recognized cases were retrospectively identified in 2 persons in Jordan who were part of an 11-person hospital cluster of respiratory illnesses in April 2012.99 Of the 81 confirmed cases, the median age is 55 years (range, 2 to 94 years) and 45 (56%) have died; 64% of the cases for whom gender is known occurred in males. Illness has been characterized by severe respiratory distress and pneumonia often requiring mechanical ventilation, and some cases have been accompanied by renal insufficiency.99 A three-person cluster in Great Britain where the index case was exposed in the Middle East and disease subsequently occurred in two close contacts in Great Britain with no history of travel, as well as an instance of nosocomial transmission in France where the index case was exposed in the Middle East, provide evidence the virus can be spread person to person.99 In addition to the 2012 Jordanian hospital cluster, another outbreak in April 2013 involving 22 persons, including health care workers, and 9 deaths in an eastern Saudi Arabian hospital suggests nosocomial transmission.100 Genetic analyses of this novel coronavirus show it is the first lineage C betacoronavirus infecting humans and has a close relationship to betacoronaviruses HKU4 and HKU5 found in bats, including insectivorous bat species present in the Middle East.101-103 A virus with 100% sequence homology to the MERS-CoV isolated from the 2012 Saudi Arabian index case was found in an Egyptian tomb bat (Tapho­ zous perforatus) trapped in the vicinity of that patient’s home.104 These findings suggest bats play an important role in the ecology of MERSCoV and could be the reservoir for this new coronavirus. The virus targets a unique receptor and appears capable of infecting multiple mammalian cell lines, suggesting the potential for a zoonotic intermediary, and serologic evidence of infection with MERS-CoV has been reported in mammalian species.105-107


even as influenza surveillance, including surveillance during and after the H1N1 pandemic, has improved in affected areas. Better surveillance would likely detect less severely ill individuals. Although human illness has been identified in 15 countries, 79% of all H5N1 cases have been reported from just three locations (Indonesia, Egypt, and Vietnam) (Fig. 14-6). This may reflect distribution of the virus in poultry reservoirs, local agricultural practices, intensity of surveillance, and other unknown factors. Between 2009 and 2012, human disease has only been found in six countries (Indonesia, Egypt, Vietnam, China, Cambodia, and Bangladesh).136 Among countries with at least 20 reported cases, mortality has been highest in Cambodia (90%) and Indonesia (83%) and lowest in Egypt (36%). Reasons for variations in mortality are unclear, but data indicate that persons with H5N1 infections in Egypt are younger than those in other locations and overall mortality appears to be age dependent. In an analysis of a large dataset of H5N1 cases, mortality was reported to be six times higher in 10- to 29-year-olds than in children younger than 10 years old and almost five times higher in adults 30 years of age and older than in children younger than 10 years old.141,142 Early hospitalization has also been reported to reduce mortality,141 and observational studies have suggested that early administration of oseltamivir also reduces mortality.64,143,144 Differences in a variety of laboratory and clinical parameters have also been described between fatal and nonfatal cases.64,144,145 It is unclear if variation in mortality rates can be attributed to specific clades or subtypes of H5N1. Human disease from H5N1 mainly affects children and young adults, making the high mortality especially remarkable. Among reported cases, the median age has been 18 years with a range of 3 months to 81 years.64,141 Less than 10% of reported cases have occurred

Since late 2003, the virus has spread widely and has been found in 63 countries in Africa, Asia, and Europe, with more than 7000 avian outbreaks reported to the World Organisation for Animal Health.128 HPAI H5N1 is believed to have spread through multiple modes, including bird migration, international trade in poultry and poultry products, and illegal bird transport, although the relative contribution of these modes is unclear.111,129,130 A variety of strategies, including depopulation, enhanced biosecurity and sanitary measures, and poultry vaccination, have been employed in veterinary settings to control and prevent HPAI H5N1.120,131,132 However, owing to the widespread distribution of this virus, its continuous evolution into multiple lineages, poultry husbandry practices in many parts of Asia, its presence in wild birds and waterfowl, and the human and financial resources needed to implement control measures, the success of these strategies has been variable.133 Because studies in several countries have demonstrated a strong correlation between the detection of H5N1 outbreaks in poultry and the location and timing of human disease, veterinary public health measures to control the virus must remain an integral part of efforts to reduce the risk to humans from H5N1 and other avian influenza viruses.134,135 From 2003 through the end of 2012, the WHO has recorded 610 human cases of H5N1 in 15 countries, with 360 (59%) of these cases being fatal—an unprecedented case-fatality rate for influenza.136 It has been argued that the observed case-fatality rate may appear artificially high owing to restrictive case definitions and surveillance methods that miss milder and asymptomatic infections.137 However, H5N1 serosurveys, even in high-risk poultry workers, tend to yield low seroprevalence, and this argument has been challenged.137-140 Furthermore, the case-fatality rate has not changed appreciably over time (Fig. 14-5)

Number of Cases

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Year FIGURE 14-5  Annual number of cases of human influenza A (H5N1) and associated mortality rates, 2003-2012. (Courtesy World Health Organization.)

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Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

164

Mortality Rate

200 180 160 140 120 100 80 60 40 20 0 Indonesia

Egypt

Vietnam

China

Thailand Cambodia All Others

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

Location FIGURE 14-6  Cumulative number of cases of human influenza A (H5N1) and mortality rates by country, 2003-2012. (World Health Organization.)


165 Another unusual feature of the H7N9 outbreak is the age and gender distribution of recognized cases. The median age is 61 years (range, 2 to 91 years) with 21% of cases in persons 75 years of age or older.158,159 In addition, males comprise 71% of recognized cases. It is unclear if these epidemiologic features result from differential exposure to the virus source or differences in population immunity, clinical presentation, or illness severity or represent surveillance artifact. However, these features stand in stark contrast to the experience with H5N1 and the 2009 pandemic, both of which predominantly impacted younger age groups. Among H7N9 patients with available information, epidemiologic investigations suggest that most (77%), but not all, had exposure to animals (predominantly chickens and ducks) on farms or in urban wet markets.159 Interventions that included closure and depopulation of wet markets in Shanghai coincided with a decline in newly recognized cases in that location. Clinical information on early cases indicates that virtually all (99%) required hospitalization and that most (97%) had evidence of pneumonia followed by acute respiratory distress syndrome and a majority (61%) had underlying health conditions placing them at increased risk for complications and fatal outcomes.159,160

Pandemic Influenza H1N1

In April 2009, two epidemiologically unlinked children living near the Mexican border in California were determined to have respiratory illness caused by a novel form of influenza A (H1N1).161 The novel virus (referred to as pandemic H1N1 [pH1N1]) had not been previously recognized and contained six segments from influenza viruses known to be circulating in North American swine since 1998 and two segments of a Eurasian avian-like swine virus.162 Viruses in the North American lineage that donated the segments found in pH1N1 were themselves triple reassortants, containing genetic material derived from avian, human, and classic swine viruses, and had occasionally produced human disease.162 However, among the small number of humans identified with triple-reassortant North American swine H1 influenza, a history of close contact with pigs could usually be elicited.163 In contrast, neither of the California children was found to have such an exposure. Both the novelty of the virus and the lack of swine contact in these children raised immediate concern that the virus was transmitted from person to person and therefore posed a pandemic threat.16 Furthermore, only weeks earlier, Mexican health authorities had reported to the Pan American Health Organization an outbreak of severe respiratory illness associated with more than 800 hospitalizations and 100 deaths, mostly in children and young adults.164 The same pH1N1 virus was subsequently identified in more than 40% of samples tested from Mexican patients that were part of this outbreak.164 Epidemiologic investigations in Mexico suggested that illnesses with this virus occurred as early as February 2009 in an area of Veracruz State with nearby swine farms.165 Within 3 weeks of its detection in the United States, more than 600 additional illnesses with pH1N1, including clusters, had been recognized in 41 states.16 The virus was also quickly detected on other continents,166 and by June 11, 2009, the WHO declared that an influenza pandemic due to pH1N1 was underway.167 Subsequent modeling studies suggest that the Mexican outbreak was much larger in scale (>30,000 cases) than initially recognized and was not nearly as severe as first reported, with an estimated casefatality rate of only 0.4%.165 There is also evidence that pH1N1 spread quickly from its initial focus in Mexico to other locations. Among early cases in the United States, 18% had a history of recent travel to Mexico, and early cases in Europe and elsewhere had a similar travel history.16,166 A modeling analysis also suggested a strong relationship between air passenger traffic to and from Mexico and locations that had early importations of pH1N1.168 By late May 2009, pH1N1 was already reported from 48 countries and the total number of identified cases was escalating quickly. Once the pandemic was declared over, a total of 214 countries, overseas territories, or communities worldwide had reported cases of pH1N1.169 In the United States, the pandemic occurred in two waves: a spring wave was followed by a much larger autumn wave, which peaked in late October.170 During the pandemic period, more than 99% of all subtyped influenza viruses in the United States were pH1N1.170 The fall

Chapter 14â&#x20AC;&#x201A; Emerging and Reemerging Infectious Disease Threats

in persons older than 40 years of age. There has been a slight female preponderance among reported cases, and cases have most commonly been seen in the winter and early spring (mirroring patterns of poultry outbreaks).141 The incubation period has been estimated to be up to 7 days and is most typically 2 to 5 days.64 Virtually all human cases are sporadic, with exposure to sick and dying poultry or to poultry products being the most commonly reported risk factor (96% of cases in one series).111,141 In China, urban cases have been linked to exposure to poultry in live bird markets.146,147 A number of small clusters indicating limited person-to-person transmission have been reported.148 In a report summarizing the experience in Indonesia, 26 case clusters were identified with an average size of 2.5 persons; the largest involved eight members of a family with three cycles of transmission.149 The severity of illness, high mortality, and limited person-to-person transmissibility may be explained by the higher tropism of currently circulating H5N1 viruses to receptors in the lower but not upper respiratory tract. Most human illness has exhibited clinical and radiographic evidence of pneumonia, which is associated with substantial morbidity and mortality in influenza.64,111 Human-to-human transmissibility is a key requirement for pandemic influenza viruses, and the ability of circulating H5N1 viruses to acquire this attribute has been of keen interest to the public health community. Two recent experiments, one through in vitro genetic reassortment and the other through sitedirected mutagenesis and serial passage in ferrets, provided evidence that H5N1 can mutate in ways that facilitate transmission between ferrets, the usual surrogate for human influenza.150,151 These â&#x20AC;&#x153;gain-offunctionâ&#x20AC;? experiments produced considerable debate and international alarm, resulting in delayed publication of the studies and prompting a temporary moratorium on such research until additional safeguards were in place to minimize the potential for inadvertent laboratory release or intentional misuse.152,153 They also highlighted the need to continue preparedness efforts to develop countermeasures against H5N1 and other pandemic threats in case such mutations occur in nature. Neuraminidase inhibitors could be used prophylactically and therapeutically in the event of widespread H5N1 disease. In addition, a number of licensed pre-pandemic H5N1 vaccines have been produced by different approaches; in the United States, H5N1 vaccine is being stockpiled by the federal government as a contingency measure.154,155 In March 2013, an outbreak of influenza due to a previously unrecognized influenza A (H7N9) virus was detected in eastern China.18 The earliest known illness associated with this outbreak occurred in Shanghai in February 2013 in an 87-year-old man.18 This outbreak is notable for several unusual features. Analysis of the virus finds it to be a quadruple reassortant with all genetic segments originating in Eurasian lineage avian viruses (H7N3, H9N2, H9N7) with acquired mutations that enhance adaptation to humans.18,116,156 The virus is of low pathogenicity to poultry and other bird species, meaning it produces minimal overt illness in bird hosts.18 This makes it difficult to track and complicates application of control measures such as culling. Testing of avian species and environmental samples in affected areas of China found H7N9 viruses similar to those causing human illness in chickens, ducks, and pigeons, although at a very low prevalence (0.07% of 68,060 samples) given the rapid increase in recognized human cases.157 By the summer of 2013, a total of 135 confirmed human illnesses had been detected with a 33% case-fatality rate. The number of H7N9 cases recognized after only 5 months of monitoring is higher than the greatest number of H5N1 cases seen in any year since it emerged in 1997. These H7N9 cases were found in nine contiguous eastern China provinces in addition to Beijing and Shanghai, although 79% of cases were in Shanghai and adjacent Jiangsu and Zhejiang provinces.157 This demonstrates a wide zone of circulation in urban and rural locations either through natural spread or commercial transport and movement of poultry and other birds. An additional case was identified in Taiwan in an individual who had returned from an affected area of mainland China 3 days before illness onset.158 As of the summer of 2013, all identified cases appeared to be sporadic except for three family clusters that could represent possible limited person-to-person spread.159 However, monitoring of almost 1700 health care workers, family members, and close social contacts of ill individuals did not find any culture-confirmed illness to suggest that person-to-person transmission of the virus had occurred.159


range, 7 days).177,183 The incubation period was similar to estimated serial intervals (mean, 2.6 to 3.9 days) for spread of illness in households, where the estimated secondary infection rate reported in studies varied from 3% to 38%; higher secondary infection rates were seen in children than in adults.184 The basic reproductive number (R0, the number of additional cases generated by each infection) was estimated at 1.3 to 1.7 (which is slightly higher than seasonal disease), although reproductive numbers as high as 3.3 were found in some school settings.183 The most common severe complication during the pandemic was viral pneumonitis or secondary bacterial pneumonia.183 Several groups were notably at higher risk for developing severe and fatal illness. These include pregnant women, especially in the third trimester of pregnancy, which accounted for half of the hospitalizations of pregnant women.185 Whereas approximately 1% of the population is pregnant at any time, pregnant women accounted for 6.3% of hospitalizations, 5.9% of intensive care unit admissions, and 5.7% of deaths during the pandemic and had a relative risk for hospitalization of 6.8 compared with all women of childbearing age.185,186 Obesity, particularly morbid obesity (body mass index >40), was also found to be a risk factor for severe disease. In the United States, morbidly obese persons with no other chronic medical conditions had a statistically significant odds of hospitalization of 4.9 and an odds of death if hospitalized of 7.6 compared with nonobese persons.187 In a global pooled data analysis, the relative risk of death among the morbidly obese was 36.3.186 The increased risk for severe outcomes in both pregnant women and obese persons is likely multifactorial but could include relative immune suppression or impaired pulmonary function. Another high-risk group for severe illness was children with neurologic disease. In the United States, 43% of fatalities in those younger than 18 years of age had neurologic disease; 94% of these children had neurodevelopmental disorders such as cerebral palsy and intellectual impairment.188 A variety of nonpharmaceutical interventions, including school closure, were implemented to mitigate the impact of the 2009 influenza pandemic. Once pH1N1 was recognized to pose a pandemic threat, efforts were immediately initiated to develop monovalent vaccines. Trials in the United States showed that candidate vaccines produced using standard methods were immunogenic and safe, and large-scale production was initiated under government purchase and distribution.189 Priority groups for vaccination representing 159 million persons were identified by the Advisory Committee for Immunization Practices and the CDC, and a more limited priority group of 62 million persons was identified for the anticipated initial limited vaccine supply (Table 14-7). Ultimately, the first vaccine supplies did not become available until the beginning of October 2009, only weeks before the second wave of illness peaked. This was too late to have a substantial short-term impact, and allocation and distribution of limited supplies were challenging.189,190 Pandemic vaccine was shown to have a safety profile

wave did not begin simultaneously throughout the country, and analyses suggest that its timing in a location correlated with the beginning of the school year.171 Schools appeared to play an important role in community spread of the virus.172 A number of countries, including the United States, promulgated school closure policies, and observational studies suggest these policies led to reductions in transmission and in the occurrence of respiratory illness.173-175 Using a variety of data sources, the Centers for Disease Control and Prevention (CDC) estimates that between 43 million and 89 million (mid-range 61 million) illnesses due to pH1N1 occurred over the course of the pandemic (April 2009 to April 2010) in the United States, representing between 14% and 29% of the population based on 2010 U.S. census data.176 These proportions are not substantially different from those reported in other parts of the world.177 In the United States, these illnesses led to an estimated 274,000 hospitalizations (range, 195,000 to 403,000) and 12,470 deaths (range, 8,870 to 18,300), with a resulting hospitalization rate of 0.45% and case-fatality rate of 0.02.176 However, these illnesses were not equally distributed by age. Children and young adults were disproportionately impacted by the pH1N1 pandemic, with 33% of all cases occurring in those younger than 18 years of age. In contrast, only 10% of all cases occurred in persons in the 65 and older age group. The estimated overall attack rate in children was 26%, and in persons older than 18 years it was 18.5%.178 In contrast to mortality patterns with seasonal influenza, where 90% of all deaths occur in persons older than age 65 years, 87% of all influenza-related deaths in the United States during the pandemic were in persons younger than age 65 years and the median age of death was 37 years.178,179 However, the case-fatality rate was estimated to be more than four times higher in persons older than 65 years of age than in children younger than 18 years of age.178 Globally, the estimated number of respiratory and cardiovascular deaths associated with pH1N1 was 284,500 (range, 151,700 to 575,500), with 80% of these deaths in persons younger than 65 years of age.180 Serologic surveys performed in multiple locations support the findings of a higher incidence of infection in children and teenagers (20% to 60%) than in older age groups.181 These surveys also found that the presence of cross-protective immunity in pre- or early-pandemic specimens was age dependent, being very low in children and peaking in persons older than 60 years, and suggest that older individuals were protected during the pandemic by residual immunity from exposure to pre-1950s cross-reactive H1N1 viruses.181 Another study that examined laboratory-confirmed pH1N1 infections and hospitalizations found a marked decline in risk for persons born in the 1950s and attributed this reduction to exposure to H1N1 viruses circulating before the 1957 Asian H2N2 pandemic.182 The clinical features of illness from pH1N1 were typical of those seen with seasonal influenza, with fever and cough most common (Fig. 14-7) and an incubation period estimated to be 1.5 to 3 days (upper

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166

Sign/Symptom FIGURE 14-7  Composite of signs and symptoms reported by 11,334 patients with laboratory-confirmed pandemic influenza A (H1N1). Data are from multiple locations and surveys and involve outpatients, hospitalized patients, and specific settings, exclusively or in combination. The number of patients in each category reporting presence or absence of symptoms varies. (From Cheng VC, To KK, Tse H, et al. Two years after pandemic influenza A/2009/H1N1: what have we learned? Clin Microbiol Rev. 2012;25:223-263.)


167

TABLE 14-7  Priority Groups Recommended for Vaccination during the 2009 Influenza A (H1N1) Pandemic by the Advisory Committee for Immunization Practices and the Centers for Disease Control and Prevention RISK GROUP

LIMITED SUPPLY RISK GROUP

RATIONALE FOR PRIORITIZATION

Pregnant women

Pregnant women

Higher risk for complications; protection of infants

Household contacts and caregivers of infants aged <6 mo

Household contact and caregivers of infants aged <6 mo

Infants at higher risk for complications and cannot receive vaccine

Health care and emergency service personnel

Health care and emergency service personnel with direct contact with patients or infectious material

Higher risk for exposure; potential exposure of higher-risk patients; reduced absenteeism

Persons aged 6 mo-24 yr

Children aged 6 mo-4 yr

Higher disease burden and transmission

Persons aged 25-64 yr with medical conditions placing them at higher risk for influenza complications

Children 5-18 yr with medical conditions placing them at higher risk for influenza complications

Higher risk for complications

The first column includes priority groups for vaccination representing 159 million persons; the second column includes a limited subset of priority groups for vaccination during periods when vaccine supply is limited representing 62 million persons. Data from Centers for Disease Control and Prevention. Use of influenza A (H1N1) 2009 monovalent vaccine, recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR Recomm Rep. 2009;58(RR-10):1-8.

TR-SIV A (H3N2)

demonstrated that antiviral drugs administered early in the course of illness reduced adverse outcomes.196 The pandemic influenza A (H1N1) virus has continued to circulate since the pandemic was declared over by the WHO in August 2010.

Variant Influenza A (H3N2)

In 2012, a multistate outbreak of influenza caused by a swine-origin (variant) influenza A (H3N2) virus occurred in the United States, with 307 recorded cases in 11 Midwestern and Middle Atlantic states.197 Additional single cases were identified in Utah and Hawaii. The resulting illness had typical clinical features of influenza; 16 cases (5%) required hospitalization and one fatality occurred in an adult.197 However, most cases (93%) were recognized in persons younger than 18 years, and the median age was 6 years. The outbreak occurred between July and September during the major period when agricultural and state fairs that exhibit swine occur.198 Most ill persons (>90%) had a history of participation in or attendance at these events, with a history of direct or indirect contact (often sustained) with swine, and there was evidence of only limited person-to-person transmission.198 Similar H3N2v viruses were identified in exhibited swine in some locations.198 In response, the CDC recommended that persons at high risk for complications of influenza, including individuals younger than 5 and those 65 years of age and older, avoid contact with swine or swine barns at agricultural fairs during 2012. The variant H3N2 virus is a descendent of a lineage of a triplereassortant H3N2 virus with human, avian, and swine segments that began widely circulating in North American pigs in 1997-1998.199 The first human infection caused by this variant was not recognized until 2005 in Kansas, and only sporadic human cases were recognized before 2011.200 In 2010, the virus was observed to have acquired the M (matrix) segment from the pandemic H1N1 virus (Fig. 14-8) and to have become more frequent in swine, raising concerns about enhanced transmissibility and an increased burden of disease in humans.201 After that reassortment event was recognized in swine, 12 human cases were recognized in 2011 in five states.202 Similar to the larger 2012 outbreak, disease occurred mostly in children and agricultural event exposure was prominent with limited person-to-person transmission.203 Serologic studies demonstrated little cross-protective immunity in young children.204 In contrast, a significant proportion of older children and adults appeared to have such immunity, likely owing to similarities with H3N2 viruses that circulated in the 1990s and earlier.204 Studies show that current trivalent influenza vaccines offer little protection against the variant H3N2 virus.204 The emergence of this virus provides a further demonstration of the critical role swine play in influenza

Influenza A (H3N2)v

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Classic swine influenza, North American lineage Avian influenza, North American lineage Human-origin influenza (H3N2) Eurasian swine influenza lineage FIGURE 14-8  Origins of gene segments of novel influenza A (H3N2) viruses isolated from humans, United States, in 2011-2012. (From Lindstrom S, Garten R, Balish A, et al. Human infections with novel reassortant influenza A (H3N2)v viruses, United States, 2011. Emerg Infect Dis. 2012;18:834-837.)

Chapter 14  Emerging and Reemerging Infectious Disease Threats

similar to seasonal trivalent influenza vaccine, and studies generally showed 70% to 90% effectiveness against laboratory-confirmed disease.189,191 Through the end of 2009, approximately 81 million doses of vaccine were shipped and 61 million doses were administered, with 74% given to priority targeted groups.192 Neuraminidase inhibitors were widely employed for treatment, with an estimated 8.2 million prescriptions filled during the pandemic.193 Investigational intravenous peramivir and zanamivir were also successfully used in almost 1500 persons in the United States.194,195 A number of observational studies


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Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

virus evolution and the need for a “One Health” approach to influenza prevention and control (see “Vector-borne and Zoonotic Diseases”).

Human Bocaviruses

Human bocaviruses were first detected in 2005 in Sweden when investigators used molecular virus screening methods by taking cell-free, filtered supernatants of stored respiratory specimens looking for virus-sized particles and then performing random polymerase chain reaction (PCR) amplification of the genetic material.62 Among the sequences identified was a previously unrecognized parvovirus most closely related to animal viruses of the genus Bocavirus. Since the original identification of bocavirus DNA in respiratory specimens, three additional bocaviruses have been found in stool specimens; these agents are now referred to as HBoV1 to HBoV4. HBoV2 to HBoV4 are believed to be associated with gastrointestinal illness, whereas HBoV1 causes predominantly respiratory disease.205 Human bocaviruses have been challenging to study because of the lack of in vitro or animal models. However, numerous studies suggest HBoV1 can be found in 2% to 19% of patients with acute respiratory tract infections, and, as often as 83% of the time, is present with other coinfecting respiratory pathogens.205,206 This latter finding calls into question whether HBoV1 is a pathogen, especially because HBoV1 has been shown to persist in respiratory specimens for months after acute infection, meaning it can be detected in asymptomatic individuals.205,206 However, in most studies HBoV1 has been found more commonly in children with acute respiratory disease than asymptomatic children; copy numbers of the virus are higher in monoinfections than coinfections and are usually low in asymptomatic children. Serology also suggests HBoV1 is a pathogen.205-207 Children aged 6 to 24 months are most commonly infected; serologic studies show that almost all children have evidence of previous HBoV1 infection by 6 years of age.205,207 Illness is most common in winter. Infection can produce either upper or lower respiratory tract infection and in children is often accompanied by wheezing; pneumonia and bronchiolitis can also be seen.205,206,208 Of note, DNA has been detected in serum and urine of children with acute infections, suggesting systemic infections can occur.205

Diarrheal Disease

Diarrheal disease is the second leading cause of infectious disease morbidity and third leading cause of mortality worldwide, resulting in an estimated 90 million disability-adjusted life years and 1.4 million deaths in 2010.5,6,209 Although diarrheal disease affects persons of all age groups and in all geographic locations, the greatest burden of severe illness and death falls on infants and young children in developing countries. In 2010, diarrhea ranked third behind malaria and lower respiratory tract infections among the leading causes of death in children younger than 1 to 4 years of age. Undernutrition is an important underlying cause of many of these deaths.210 Diarrheal disease also produces substantial morbidity, affecting growth and cognitive development211,212 and resulting in illness of more than 2 weeks in duration in 10% of cases.213 Studies among children in developing countries have found a range of 1 to 10 episodes of diarrhea per child each year, with most children experiencing 3 to 5 episodes per year.214,215 A survey among the general U.S. population reported a rate of 1.4 episodes of diarrhea per year, translating to 200 to 375 million episodes annually.216 The pathogens that produce diarrhea are transmitted primarily by three main routes: foodborne, waterborne, and person to person; many enteric pathogens can be transmitted by more than one route, including simultaneously. Although systematic studies are difficult to perform, it is likely that the relative importance of these transmission patterns varies in different settings. Estimates in the United States suggest that 48 million episodes of foodborne illness occur annually, resulting in approximately 128,000 hospitalizations and approximately 3,000 fatalities217,218 and that endemic waterborne disease results in 4.3 to 32.8 million cases of acute gastrointestinal illness annually.219,220 The pathogens that cause diarrheal illness differ in their primary modes of transmission. For example, nontyphoidal Salmonella species and Campylobacter jejuni are transmitted principally through food, Shigella species are transmitted primarily from person to person, and

Cryptosporidium parvum is principally waterborne. Determination of the patterns of distribution of enteric pathogens in a geographic area may suggest the relative importance of different modes of transmission in that locale. The causes of diarrheal disease do not remain static over time, even in a single location. Fluctuations may result from the introduction of an organism not previously present, the recognition of a new agent, changing levels of sanitation resulting from man-made or natural disasters, climatic variations, or lifestyle changes, such as increases in recreational water exposure.221,222 Two dramatic examples from the past 25 years involve the introduction of Vibrio cholerae O1 into the Western Hemisphere. Cholera had not been recognized in South America during the 20th century, but in January 1991 cases were identified in coastal areas of Peru.223 Within weeks, thousands of cases were occurring and cholera quickly became the most commonly diagnosed cause of diarrheal illness in many parts of Peru.224,225 During the next 3 years, the disease spread throughout mainland South and Central America, significantly altering the distribution patterns of etiologic agents of diarrheal disease. The incidence of the disease in Latin America has subsequently declined dramatically. In October 2010, just 9 months after a severe earthquake, a cholera epidemic was identified in Haiti that spread within 2 months to the entire country and across the border to the Dominican Republic.226,227 Molecular epidemiologic studies have indicated that the V. cholerae strain is very similar to South Asian strains,228 and epidemiologic investigations revealed that initial cases occurred downstream from a camp where United Nations peacekeepers from Nepal were stationed.229,230 The source of introduction of the epidemic strain remains a politically sensitive topic.231 Although the case-fatality rate has been reduced, the epidemic persists.232 Cases in Haiti and the Dominican Republic accounted for more than 60% of the global reported cases to the WHO in 2011.233 In addition to cases in the Dominican Republic, imported cases have been identified in the United States234 and elsewhere in the Western Hemisphere.233 V. cholerae O139 is an example of a recently recognized pathogen that had a major impact on the distribution of diarrheal disease– producing pathogens in Asia. This serotype was first detected in South Asia in 1992 and quickly spread to many regions of India and Bangladesh.235,236 Studies conducted in Bangladesh suggested that shortly after its introduction V. cholerae O139 became the agent most commonly linked to clinical cholera in that country. Since then, its impact has fluctuated in place and time throughout South and Southeast Asia236238 ; in 2011, only China reported cases to the WHO.233 One other emerging issue with V. cholerae merits mention. Variant El Tor strains that express the cholera toxin produced by classic strains resulting in more severe illness have been identified, initially in Bangladesh and more recently elsewhere in Asia, Africa, and Hispaniola.233,239 The international movement of foods can also alter the spectrum of diarrheal pathogens. In 1996, thousands of cases of cyclosporiasis due to Cyclospora cayetanensis occurred in the United States and Canada among persons who consumed fresh raspberries imported from Guatemala.240 Before this episode, only small numbers of cases, primarily associated with travel to developing countries,241 had been reported in North America. In 2008, a large nationwide foodborne outbreak caused by Salmonella enterica serotype Saintpaul occurred in the United States. Initial investigation suggested that contaminated tomatoes imported from Mexico were the source. However, subsequent investigation implicated jalapeño and serrano peppers from Mexico.242 International spread of a multidrug-resistant clone of S. enterica serotype Kentucky with high-level resistance to ciprofloxacin has been reported.243 The clone appears to have originated in Egypt during the 1990s and has spread to other countries in Africa and the Middle East. Cases that are predominantly travel associated have also been identified through national surveillance systems in France, England and Wales, Denmark, and the United States.243 Escherichia coli O157:H7 (Shiga toxin [ST]-producing strains [STEC]) significantly affected pathogen distribution patterns in developed parts of the world after the agent was first recognized.244 After its recognition in the United States in 1982, this foodborne agent rapidly became the most commonly identified cause of bloody diarrhea in


169 245

than age 2 years, who often develop dehydrating diarrhea from the infection.274,275 As recently developed rotavirus vaccines are introduced into more countries in Africa and Asia, the impact of rotavirus infection on the total diarrheal disease burden will decrease. Rotavirus is also an important cause of childhood diarrhea and hospitalization in developed countries.274 In the United States in recent years, rotavirus infection has resulted in an estimated 55,000 to 70,000 hospitalizations, 205,000 to 272,000 emergency department visits, and 410,000 physician visits and has caused an estimated 20 to 60 deaths per year.276 After licensure of a new rotavirus vaccine and recommendations for its use in infants in early 2006, surveillance indicated that the 2007-2008 rotavirus season had a delayed onset and a reduction in disease burden.277 A recent study during the 2009-2010 and 2010-2011 rotavirus seasons documented the effectiveness of both rotavirus vaccines in reducing the risk for emergency department visits and hospitalizations combined in children younger than 5 years of age.278 As a result, noroviruses have now replaced rotaviruses as the leading cause of medically attended gastroenteritis in U.S. children.266 Systematic studies in the United States indicate that among the bacterial diarrheal pathogens, C. jejuni was the most commonly diagnosed agent in the early 1990s, followed by nontyphoidal Salmonella species, Shigella, and E. coli O157:H7.245 More recent data from FoodNet sites for 2012 indicate that Salmonella serotypes are now the most common bacterial pathogen, followed by Campylobacter and Shi­ gella.247 In 2012, the incidence of E. coli serotypes other than O157:H7 exceeded that of E. coli O157:H7 strains. The incidence of Campylo­ bacter and Vibrio infections was higher in 2012 compared with that in 2006 to 2008, while the incidence of infections caused by most major foodborne bacterial pathogens was unchanged.247 Continued surveillance along with detailed information on patient exposures and strain subtypes can help assess the impact of control measures on Campylo­ bacter infections, including new standards for chicken and turkey processors issued by the U.S. Department of Agriculture in 2011. In addition, despite a significant increase in Vibrio infections, the number of these infections continues to be low.247,279 Foodborne sources remain an important cause of bacterial diarrheal disease in the developed world, because all but Shigella species are transmitted principally through foods. Notifiable disease data demonstrate trends in the occurrence of these pathogens but severely underestimate their incidence. As an example, 45,970 cases of salmonellosis were reported in the United States in 1995 but estimates suggest that almost 2 million U.S. infections with the bacteria occur each year.280 The incidence and severity of Clostridium difficile–associated disease has recently increased dramatically in adults and children in the United States, Canada, Europe, and Australia.281-284,285 In the United States during 2010 in Emerging Infections Program sites, 94% of C. difficile infections were health care associated whereas 6% occurred in patients with no recent health care setting exposure.283 Disease due to a strain of restriction endonuclease analysis group BI, pulsed-field gel electrophoresis type NAP1, and PCR ribotype O27 (BI/NAP1/O27) is responsible for much of this increase, including many nosocomial outbreaks.286-288 Two distinct epidemic lineages, both of which are resistant to fluoroquinolone antibiotics, have recently been identified.284 The FQR1 lineage, first seen in 2001, is associated with North American outbreaks and sporadic infections in South Korea and Switzerland. The FQR2 lineage originated in 2003 in North America but subsequently spread more widely, causing hospital outbreaks in the United Kingdom, continental Europe, and Australia.289 Of the HAIs, 75% of persons had onset of illness outside acute care hospitals (in the community or in nursing homes).289,290 These strains can cause severe disease, particularly in elderly patients. Since 2005, another C. difficile strain (PCR ribotype O78) has emerged in the Netherlands and in the United Kingdom.291 This strain also appears to be hypervirulent and is more likely to affect younger persons and to be associated with community-onset disease.291 Isolates of C. difficile also have been obtained from retail ground meat samples,292 prompting the need for evaluation of the potential role of foodborne transmission in community-associated cases. Recent experiences with fecal microbiota transplantation have suggested an important role for this approach in the management of patients with severe C. difficile infections.293,294

Chapter 14  Emerging and Reemerging Infectious Disease Threats

many locations in North America. Surveys conducted in the 1990s and in 2007 found it was the fourth most commonly isolated bacterial agent of diarrheal disease in the United States.245,246 In 2012, STEC non-O157 strains ranked fifth and STEC O157 strains ranked sixth in incidence per 100,000 population among laboratory-confirmed cases of foodborne infections in the 10 states participating in the Foodborne Diseases Active Surveillance Network (FoodNet).247 In early May 2011, a large outbreak of bloody diarrhea and hemolytic-uremic syndrome was recognized in northern Germany.248,249 Investigation identified a unique single clone of E. coli O104:H4 as the etiologic agent.249,250 The strain contained a prophage encoding Shiga toxin 2, genes from enteroaggregative E. coli, and a plasmid-encoded extended spectrum β-lactamase gene.249,251 Epidemiologic investigation identified fenugreek sprouts as the food vehicle252,253; the sprouts were grown from seeds of Egyptian origin.249 The outbreak involved more than 4000 illnesses, primarily in adults,254 approximately 800 cases of hemolytic-uremic syndrome (HUS), and 50 deaths in Germany and 15 other countries249 and provides yet another reminder of the global nature of today’s food supply. Outbreaks of diarrheal diseases are particularly affected by deteriorations in public health infrastructure, as dramatically illustrated by the introduction of cholera into Haiti after the 2010 earthquake. Shigellosis is known to emerge rapidly in areas with social disruption caused by war and political unrest, especially when large numbers of refugees have lacked access to water and sanitation services.255 As a result of the Rwanda crisis in 1994, cholera outbreaks in the refugee camps in Goma, the Congo, caused at least 48,000 cases and 23,800 deaths within 1 month.256 Similarly, a large cholera outbreak occurred in Zimbabwe in 2008-2009 during a period of political turmoil and economic collapse.257,258 The disease spread across borders to South Africa, Botswana, and Mozambique.258 Viruses are an increasingly recognized cause of sporadic and outbreak-associated diarrheal diseases. Noroviruses (members of the Caliciviridae) are transmitted not only from person to person but also by food and water and by contact with contaminated environmental surfaces.259-261 These viruses have become an important cause of diarrheal illness outbreaks among cruise ship passengers, hospitalized patients, nursing home residents, college students, restaurant patrons, and military personnel, reflecting the high infectivity and low infectious dose (<20 viral particles).262 A systematic literature review published in 2008 indicated that severe norovirus disease occurs among persons in both developed and developing countries, annually resulting in an estimated 64,000 episodes of diarrhea requiring hospitalization and 900,000 clinic visits by children in developed countries and as many as 200,000 deaths among children younger than 5 years of age in developing countries.263 Noroviruses are the leading cause of epidemic gastroenteritis in the United States.264,265 After the introduction and use of rotavirus vaccines, noroviruses have also become the leading cause of medically attended acute gastroenteritis in U.S. children younger than 5 years of age; these viruses were found in 21% of children seeking medical care for acute gastroenteritis in 2009-2010.266 New strains emerge every few years. In March 2012, a new GII.4 norovirus strain named GII.4 Sydney was identified in Australia and subsequently spread to the United States, United Kingdom, and a number of other countries.267 GII.4 norovirus outbreaks have been associated with higher rates of hospitalization and mortality compared with outbreaks caused by other genotypes.268 Because the pathogens responsible for diarrheal disease vary over time, even in the same location, longitudinal studies are important for defining the etiology of diarrheal disease. Data from the Global Enteric Multicenter Study (GEMS) conducted using standardized methods269-271 over 3 years in seven developing countries in Africa and Asia indicated that the leading pathogens in children younger than 5 years of age with moderate to severe diarrhea across all sites were rotavirus, Cryptosporidium, enterotoxigenic E. coli strains producing heat-stable enterotoxin, and Shigella.272 Compared with control children, those with moderate-to-severe diarrhea had an 8.5-fold increased risk for death during follow-up.272 Rotavirus infections affect all age groups and have been the leading cause of severe acute diarrhea among young children worldwide.273 Most severe illnesses and hospitalizations occur in children younger


Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

170 Multiple drug resistance in bacterial enteric pathogens has emerged in the United States and internationally. The problem is most severe in foodborne pathogens of animal origin (primarily in Campylobacter and Salmonella strains).295 A multidrug-resistant strain of S. enterica serotype Typhimurium known as definitive type 104 (DT104) emerged in the United States and Europe in the 1990s.296,297 Patients infected with multiply-resistant strains are more likely to be hospitalized.298 Fluoroquinolone-resistant strains of C. jejuni infections have also emerged; some infections are associated with foreign travel whereas others are acquired domestically and have been associated with poultry consumption.299 In a study of resistance in over 1100 Shigella isolates in FoodNet sites from 2008 to 2010, 74% were resistant to ampicillin, 36% to trimethoprim-sulfamethoxazole, 28% to tetracycline, and 0.5% to ciprofloxacin300; 5% of isolates were resistant to five or more antimicrobial agents.300 Resistance was more common in persons with a history of recent foreign travel. A foodborne outbreak in Los Angeles in 2012 was caused by Shigella sonnei with decreased susceptibility to azithromycin, the first such outbreak identified in the United States.301 The global pattern of diarrheal disease is likely to continue to evolve, and efforts to develop effective vaccines against causative agents are ongoing. New formulations of rotavirus vaccine have been developed after an initial tetravalent rhesus/human reassortant rotavirus vaccine was linked to intussusception in infants and was withdrawn from the market.302 These new rotavirus vaccines have the potential to decrease the burden of diarrheal disease among persons in the developing world, and a major effort is in progress to introduce these vaccines into all national immunization programs as recommended by the WHO.303 In addition, food production practices are changing, with greater amounts of fresh fruits and vegetables grown in the developing world for export to developed countries. Such practices have resulted in the transfer of agents such as C. cayetanensis, V. cholerae, and S. enterica serotype Enteritidis in exported products—a situation that is likely to continue.240,304,305 Changes in food distribution practices increase the potential for widespread, multinational disease outbreaks. The increasing numbers of immunocompromised individuals who are at risk for infections with a broader array of pathogens responsible for diarrheal illness and increasing global travel will likely influence future trends in diarrheal disease in ways that may be difficult to predict.306,307 Another example is the emergence of a new strain of multidrugresistant S. enterica serotype Typhimurium (multilocus sequence type ST313) in sub-Saharan Africa. The strain causes invasive nontyphoidal disease, sometimes accompanied by diarrhea, primarily in patients with HIV infection, malaria, and malnutrition.308,309 Application of whole-genome sequence-based phylogenetic methods has identified two closely related, highly clustered lineages estimated to have emerged independently approximately 52 and 35 years ago. Lineage II strains have replaced lineage I strains, perhaps because of their acquisition of chloramphenicol resistance.309 Climate change has been reported to affect the spread of cholera and Vibrio parahaemolyticus infections. In 2004, a large outbreak of V. parahaemolyticus infection associated with consumption of raw oysters occurred among passengers aboard a cruise ship in Prince William Sound in Alaska.310 The oysters were harvested in the Sound during summer months when daily water temperatures exceeded 15° C. This outbreak extended by 1000 km the northernmost documented source of oysters associated with V. parahaemolyticus infection. Efforts to decrease the emergence and enhance the control of diarrheal disease and associated antimicrobial resistance in the United States and internationally require strengthened disease surveillance systems to monitor disease trends and changes in food consumption patterns. Advances in molecular diagnostic techniques for rapid diagnosis and characterization of isolates311,312 offer advantages over current techniques, but the shift to this new paradigm away from pathogen isolation will pose challenges in the near term for many current infectious disease surveillance systems that rely on characterization of bacterial isolates.313,314 Interstate foodborne disease outbreaks will continue to pose challenges,315-317 as will the international spread of drugresistant enteric pathogens.243 The role of food in the transmission of drug-resistant organisms will require continued attention.318 The potential importance of several enteric pathogen candidates such as

enterotoxigenic Bacteroides fragilis,319 V. cholerae serogroups O75320 and O141,321 bocavirus species HBoV2,322 Klebsiella oxytoca in patients with antibiotic-associated diarrhea323 and hemorrhagic colitis,324 and enterohemorrhagic E. coli O26:H11/H− strain recently identified in Europe325 require further evaluation. Use of advanced molecular diagnostics and other emerging technologies may be useful in assessing the role of currently unrecognized etiologic agents and alterations in the intestinal microbiome in patients with sporadic unexplained diarrheal illness and Brainerd diarrhea.326,327 Patients who develop traveler’s diarrhea while abroad306,307 and those who develop unexplained diarrhea in hospital settings328 represent ideal sentinel populations for further study to identify additional etiologic agents. Certain high-risk foods such as raw milk329 and unpasteurized cheeses330,331 require continual attention from public health authorities. Because recent antimicrobial exposure has been identified as a risk factor for acquisition of enteric infections in animal models332 and in humans,333,334 continued emphasis on judicious antimicrobial use is critical. Finally, because human contact with animals and their environments remains an important mode of acquisition of important enteric pathogens, especially Salmo­ nella, Campylobacter, and Cryptosporidium,335-339 increased interdisciplinary collaborative efforts at the human, animal, environmental interface as promoted by the “One Health” model are a priority (see “Vector-borne and Zoonotic Diseases”).

VECTOR-BORNE AND ZOONOTIC DISEASES

Most of the emerging infections recognized during the past decade have been zoonoses (see Table 14-2).3,340 Some zoonotic microbes have “jumped” from animals to humans to become major human pathogens (e.g., the simian virus that evolved into HIV341), whereas others are maintained in animal reservoirs, including domesticated animals (e.g., cattle infected with Rift Valley fever virus342) or wildlife (e.g., bat species that carry Nipah or Hendra viruses343 and monkeys and rodents that carry monkeypox344). Bats have become an increasingly important source of emerging infections and have been linked to SARS coronavirus as well as Nipah, Hendra, and Ebola and Marburg viruses. Some vector-borne diseases are also zoonotic (e.g., West Nile disease, caused by a mosquito-borne virus maintained in birds, or Lyme disease, caused by a tick-borne bacteria maintained in deer and rodents), whereas for others humans are the principal host (e.g., dengue and human species of malaria). Emerging public health concerns related to vector-borne and zoonotic infections include the geographic spread of mosquito-borne diseases such as dengue, chikungunya, and West Nile fever, the rising incidence of tick-borne infections such as Lyme disease, and recurring outbreaks of Ebola and Marburg hemorrhagic fever in Uganda and the Democratic Republic of the Congo.345 In addition, animal influenza strains that cause disease in humans (e.g., avian influenza A [H5N1],346 avian influenza A [H7N9],18,347 and influenza A [H3N2] variant virus203,348) remain ongoing concerns because of their potential to evolve into pandemic strains. The origin and reservoir of a recently identified coronavirus, named Middle Eastern respiratory syndrome coronavirus (MERS-CoV), although presumed to be a zoonotic infection, has not yet been identified (see “Acute Respiratory Tract Infection”). The recognition that the majority of new human pathogens emerge from animal reservoirs has led to increased medical, veterinary, and scientific support for a “One Health” approach to infectious disease control, a growing consensus about the importance of intensifying efforts to link infectious disease identification, prevention and control at the human, animal, and environmental interface.349,350 Areas of “One Health” focus include identifying emerging drug resistance in zoonotic pathogens that infect domestic animals and humans; evaluating the efficacy of veterinary vaccines in reducing the incidence of animal pathogens that can infect humans (e.g., Rift Valley fever virus351); and developing new methods and strategies to prevent infections carried by ticks or mosquitoes. Public health and animal health scientists are also exploring strategies for predicting and preventing the emergence of novel zoonotic pathogens, making use of pathogen discovery tools and mathematical modeling techniques.352 These efforts require detailed understanding


171

1970

2004

FIGURE 14-9  Geographic distribution of Aedes aegypti in the Americas in 1930, 1970, and 2004. (From Gubler DJ. The changing epidemiology of yellow fever and dengue, 1900 to 2003: full circle? Comp Immunol Microbiol Infect Dis. 2004;27:319-330.)

of specific ecologic and behavioral factors that facilitate the introduction of animal pathogens into human populations (e.g., increased human presence or other changes in wildlife habitats) and allow newly introduced pathogens to become established in new areas (e.g., suitable insect vectors).353

Dengue

Dengue is the most important mosquito-borne viral disease that affects humans. Its global distribution is comparable to that of malaria, and an estimated 2.5 billion people live in areas at risk for epidemic transmission. The disease is endemic in Africa, the Americas, and parts of the Middle East, Asia, and the western Pacific. The frequency of dengue and its more severe complications—dengue hemorrhagic fever (DHF) and dengue shock syndrome—has been increasing dramatically since 1980.354 It is generally estimated that 50 to 100 million infections occur annually, but recent data suggest that approximately 390 million dengue infections occurred worldwide in 2010, including 96 million symptomatic illnesses.355 Dengue is caused by any of four antigenically distinct virus serotypes (DEN-1, -2, -3, -4) of the genus Flavivirus. Infection with one of these serotypes is not cross protective. Infection with dengue viruses produces a spectrum of clinical illness that ranges from a nonspecific viral syndrome to severe and fatal hemorrhagic disease.356 DHF is a life-threatening condition characterized by capillary permeability that may lead to hypovolemic shock and death. Important risk factors for DHF include the strain and serotype of the infecting virus, as well as the age, immune status, and genetic predisposition of the patient. In endemic areas, most deaths from dengue infection occur in children younger than 15 years of age.356 Economic impact analyses in both the Americas and Asia indicate that the burden of dengue-related illness in children is substantial, especially when nonhospitalized patients are considered.357,358 Dengue is transmitted primarily by Aedes aegypti, a domestic, daybiting mosquito, and secondarily by A. albopictus. A. aegypti was historically found in Africa but spread throughout the tropical regions of the world during the past 2 centuries through international commerce. It is well adapted to the urban environment, feeding on humans and breeding in containers in areas where water is stored or allowed to accumulate, such as discarded cans, bottles, plastic containers, and tires. Epidemics caused by multiple serotypes (hyperendemicity) have become more frequent, and the geographic distribution of both the viruses and their mosquito vectors has expanded. The emergence of dengue and DHF in the Americas has been dramatic. In an effort to prevent urban yellow fever, which is also transmitted by A. aegypti, the Pan American Health Organization established a program in the 1950s and 1960s to eradicate the species from most of Central and South America.353 As a result, epidemic dengue occurred

only sporadically in some Caribbean islands during this period. The success of the program, however, led to its gradual discontinuation beginning in 1970. Since that time, A. aegypti has reestablished itself firmly in the region, now exceeding the extent of distribution that was seen before the eradication program began (Fig. 14-9). Epidemics of dengue fever now routinely occur in Venezuela, Colombia, Brazil, and other locations in Latin America and the Caribbean.359 Puerto Rico, which has experienced epidemic dengue activity periodically since 1963, suffered the largest dengue outbreak in its history in 2010, affecting more than 21,000 people.360 In 2009 and 2010, Florida reported the first cases of dengue acquired in the continental United States outside the Texas-Mexico border since 1945.361 Multiple outbreaks in Africa were identified in 2013.362 A number of lines of evidence suggest that dengue is endemic in Africa on a par with the Americas but is not well recognized.355,363 No therapy is effective for dengue infection, and treatment is supportive, with particular attention to fluid management.354 In Puerto Rico, deaths from dengue were reduced by training physicians in early detection and appropriate supportive care of patients with dengue hemorrhagic fever.364 A U.S. Food and Drug Administration (FDA)approved, real-time polymerase chain reaction (RT-PCR) assay that can detect all four dengue serotypes in the first 7 days after symptom onset was developed by the CDC and is available from the agency at the time of this writing, although wider availability through commercial sources is desirable (www.cdc.gov/dengue/resources/rt_pcr/ CDCPackageInsert.pdf28). It has been a long-standing challenge to develop a safe dengue vaccine that is effective against all four serotypes, complicated by concerns that vaccination might predispose to the severe form of dengue infection and by the poor understanding of the immunologic correlates of immunity. However, there has been considerable progress in the recent past and a number of candidate dengue vaccines are currently being evaluated, including live attenuated, inactivated, chimeric, DNA, and viral-vector vaccines.365 Results of a phase IIb trial of the vaccine candidate farthest along in clinical trials, a recombinant live-attenuated tetravalent vaccine manufactured by Sanofi Pasteur, showed that the vaccine was safe but the protective efficacy was only 30.2% with a confidence interval that included zero.366 Several other candidate vaccines currently are in phase II trials. Efforts to reverse the recent trend of increased epidemic activity and geographic expansion of dengue are not promising. New dengue virus strains and serotypes will likely continue to be introduced into many areas with high population levels of A. aegypti. In the absence of a vaccine or new mosquito control technology, public health authorities have emphasized disease prevention and mosquito control through community efforts to reduce larval breeding sources. Improved

Chapter 14  Emerging and Reemerging Infectious Disease Threats

1930s


Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

172 laboratory-based surveillance systems and other innovative approaches that can provide early warning of a potential dengue epidemic are also needed to alert the public to take protective action and physicians to diagnose and properly treat cases.

Chikungunya

Chikungunya shares many similarities with dengue, both in terms of epidemiology and clinical illness. Like dengue virus, chikungunya virus is transmitted by A. aegypti and Aedes albopictus mosquitoes and is characterized by acute onset of fever, joint and muscle pain, headache, nausea, fatigue, and rash. Indeed, chikungunya is frequently misdiagnosed as dengue, and outbreaks of the two diseases can occur simultaneously.367 Chikungunya is, however, caused by a member of the family Togaviridae, genus Alphavirus. Chikungunya virus infection is noteworthy in that joint pain is a prominent feature of the disease, a condition that may persist for months. Joints most commonly involved include ankle, knee, wrist, and small joints of the hands. Chikungunya was first detected in Tanzania in 1953 and spread to other parts of Africa and parts of Asia.368,369 Chikungunya virus is an important cause of febrile illness370 in Africa and Asia, including the Indian subcontinent. Epidemic cycles occur with interepidemic periods ranging from 4 to 30 years.371 Since 2004, chikungunya has caused large outbreaks in a wide range throughout Asia and Africa. In 2004, an outbreak was identified in Kenya, and subsequently outbreaks occurred in Indian Ocean islands and South India during 2005-2006.367,369 These outbreaks were characterized by high clinically apparent attack rates and were noteworthy in that higher than expected crude death rates occurred among affected populations, especially among the oldest age groups.372 From March 2005 through April 2006, an estimated 255,000 cases of chikungunya occurred in Réunion (population 770,000), and excess deaths were recorded, suggesting a case-fatality rate of approximately 1 in 1000, mainly in persons 75 years of age and older.372 Similar elevated mortality rates were seen among the elderly in Mauritius during the 2006 outbreak.373 In India, more than 1.25 million suspect chikungunya cases were reported from 151 districts in eight states in 2006, with attack rates reaching 45% in some communities.367 Between July and September 2007, an outbreak of chikungunya occurred in northeastern Italy, the first chikungunya outbreak to occur in a temperate region. The index case was likely a traveler from India who developed symptoms while visiting relatives in the outbreak region. More than 200 suspected cases were reported between July and September 2007, and chikungunya virus sequences were detected in pools of A. albopictus mosquitoes by PCR assay.374 Humans infected with chikungunya virus have viremias of sufficient titers to infect feeding vector mosquitoes and are thus an ideal source for virus dissemination and introduction into new regions. In addition, one of the principal vectors, A. albopictus, has been introduced into many areas of Europe and North America, raising concern that temperate and tropical regions around the world may be receptive to future outbreaks of chikungunya.375 Recent studies suggest that the virus is adapting to facilitate transmission by this species.376 Preparedness and response strategies focus on early detection of cases, timely and appropriate epidemiologic investigation, and the institution of measures to mitigate spread.371 The recognition of chikungunya as an emerging health threat has also stimulated innovative research on vaccine development377-379 and on new antiviral therapies that involve viral or host targets.380

West Nile Virus

West Nile virus (WNV) is another example of a vector-borne pathogen that has spread rapidly into new areas. WNV was first isolated in 1937 from an apparently healthy individual from the West Nile district of Uganda.381 For decades, WNV was recognized as an important endemic and occasionally epidemic disease in Africa and the Middle East, causing primarily minor febrile illness.382 However, since 1998, major outbreaks associated with severe neurologic disease have occurred in Romania,383 Russia,384 Israel,385 the United States,386 and Canada.387 The disease was first reported in North America in 1999 when the virus caused an outbreak of severe neuroinvasive disease that resulted in seven deaths in New York City.386 Since then, WNV has spread across

the continental United States, becoming endemic and the leading cause of arboviral disease in the country—affecting thousands of people each year.388,389 By 2005 the virus had spread to an area extending from central Canada to southern Argentina.390-392 WNV is recognized as the most widely distributed arbovirus in the world.393 Major U.S. outbreaks occurred in 2002 (2945 cases of neuroinvasive disease and 284 deaths), in 2003 (2866 neuroinvasive disease cases and 264 deaths), and in 2012 (2873 neuroinvasive disease cases and 286 deaths).394 Texas was at the epicenter of the 2012 outbreak,395 reporting about one third of all cases. It is estimated that a cumulative 2 million to 4 million infections and 0.4 million to 1 million resulting illnesses occurred in the United States from 1999 to 2010.389 WNV is a single-stranded RNA virus of the Flaviviridae (genus Flavivirus), which is part of the Japanese encephalitis virus antigenic complex. In addition to Japanese encephalitis, this complex includes St. Louis encephalitis virus, Murray Valley encephalitis virus, and Kunjin virus, a subtype of WNV.382 WNV is transmitted to humans primarily through the bite of infected mosquitoes, but person-to-person transmission can occur through transfusion of infected blood products or solid-organ transplantation.396-398 Because the U.S. blood supply has been routinely screened for WNV RNA since 2003, transfusion-associated WNV infection is rare. The virus is maintained in a bird-mosquito-bird cycle, with birds developing high levels of viremia and serving as amplifying hosts. Mosquitoes primarily of the genus Culex transmit WNV, although the virus has been isolated from many genera and species of mosquitoes. Although most species of infected birds generally remain asymptomatic, WNV-related mortality has been noted in more than 160 avian species in the United States and Canada.399 Crows and related birds of the Corvidae are especially susceptible to mortality from WNV infection, and die-offs of these birds have been used as one indicator of active WNV transmission.399 Equines are frequently infected with WNV, with 36 U.S. states reporting equine infections in 2009.400 Approximately 80% of WNV infections in humans are asymptomatic, 20% develop fever, and less than 1% are WNV neuroinvasive disease. Most symptomatic persons have an acute febrile illness consisting of headache, myalgia, or arthralgia that lasts from 3 to 6 days.401 WNV neuroinvasive disease is characterized by acute neurologic manifestations, usually encephalitis, meningoencephalitis, or acute flaccid paralysis.384,396,402 The mortality rate from WNV neuroinvasive disease is approximately 10%. Long-term outcome among survivors varies, with some persons showing little neurologic and functional improvement and others experiencing substantial gains.403 Persons suffering paralytic disease with respiratory involvement are at greatest risk for death and have a poor long-term outcome.401-403 Although WNV strains circulating in the United States have genotypic differences and the predominant circulating strain has changed over time,404,405 no strain-specific differences in virulence or clinical disease in humans have been documented, and no antigenic differences have been identified that would pose a challenge to vaccine development. Nevertheless, the sporadic and unpredictable pattern of WNV incidence represents a considerable barrier to randomized clinical trials of vaccines or treatments.406 Although vaccines for use in horses are licensed—and phase I and II clinical trials of candidate vaccines for human use have been completed—no phase III trials in humans have been attempted.407 At the present time, prevention of WNV infection relies on a cadre of efforts that include mosquito, bird, and human disease surveillance; mosquito control; the use of personal protective measures; and screening of the blood supply. There is no treatment of proven efficacy for WNV infection.392

Ebola and Marburg Hemorrhagic Fevers

Ebola and Marburg hemorrhagic fevers are severe, often-fatal diseases in humans and nonhuman primates (monkeys, gorillas, and chimpanzees). Symptoms include fever, headache, joint and muscle aches, sore throat, and weakness, followed by diarrhea, vomiting, and stomach pain. Some patients also exhibit a rash, red eyes, hiccups, and internal and external bleeding. There is no vaccine or standard treatment for Ebola or Marburg. Supportive therapy involves balancing fluids and electrolytes, maintaining oxygen status and blood pressure, and providing treatment for any complicating infections.408


173

TICK-BORNE DISEASES

Public health concern about tick-borne diseases has increased in the United States, owing to the geographic spread of Lyme disease (along with its vector, the black-legged tick, Ixodes scapularis),437-439 and the discovery of a new vector (the brown dog tick, Rhipicephalus san­ guineus) for Rocky Mountain spotted fever, identified during the investigation of outbreaks in Arizona.440 Moreover, two new tickborne pathogens have been identified in the United States whose

epidemiology and transmission patterns are the subject of ongoing study: an Ehrlichia muris–like agent in Minnesota and Wisconsin441 and the Heartland virus in Missouri.442 Based on small numbers of patients, the Ehrlichia muris–like agent appears to cause fever, malaise, fatigue, headache, nausea, and vomiting, whereas the Heartland virus is associated with a flulike illness, with fever, fatigue, loss of appetite, and diarrhea. Like the mosquito-borne Rift Valley fever virus, the Heartland virus is a phlebovirus, a genus of the Bunyaviridae family of negative-stranded, enveloped RNA viruses. It is the first tick-borne phlebovirus known to cause human disease in the Americas. Another novel phlebovirus—also thought to be tick-borne—was recently reported in China as the cause of an outbreak of severe fever with thrombocytopenia syndrome, with a case-fatality rate of 12% (171 confirmed cases and 21 deaths).443,444 The severe fever with thrombocytopenia syndrome virus, which can cause fever, vomiting, diarrhea, and multiple organ failure, may be transmitted to humans by Haema­ physalis longicornis ticks carried by domestic animals443,444 and may also spread from person to person through direct contact with infected blood or mucus.445-447

ANTIMICROBIAL RESISTANCE

Although the introduction of antibiotics in the early to mid-20th century remains one of the most significant health achievements to date, antimicrobial resistance is regarded as one of the greatest threats to human health worldwide.448-450,451,452,453 The widespread availability and use of antimicrobial agents among humans and animals, along with a globalized society in which emerging resistant strains can quickly spread worldwide, has created an environment of antibiotic exposure thus intensifying selective pressure and boosting the inherent capacity of microbes to develop resistance genes. Each year, antibioticresistant infections cost the U.S. health care system more than $20 billion and are responsible for more than 8 million additional hospital days.454,455 Moreover, these infections often require the use of less effective, more expensive, and often more toxic drugs. Areas of particular concern include continued threats from multi- and pan-resistant strains of Mycobacterium tuberculosis, health care– and communityassociated methicillin-resistant Staphylococcus aureus (MRSA) infections with continued evolution and global spread of highly virulent clones, along with newer challenges including increases in highly resistant gram-negative bacteria, particularly carbapenem-resistant Enterobacteriaceae and increasing resistance to third-generation cephalosporins in persons infected with Neisseria gonorrhoeae.456 Also of concern are increases in severe, life-threatening C. difficile infections, usually associated with recent antibiotic use and often occurring among hospitalized patients (see “Diarrheal Disease”). As conduit and amplifier of antimicrobial resistance, health care settings are critical to its control. The evolving nature of microbes defines antimicrobial resistance. Resistance genes have been found in humans and animals in areas with limited to no antibiotic exposure, in bacterial DNA frozen in the Arctic for 30,000 years, and in bacteria from underground caves isolated for 4 million years, some of which were resistant to synthetic antibiotics developed in the 20th century.457-459 Enhancing this evolutionary process is antibiotic exposure. After introduction of each new class of antibiotics has come global spread of resistant strains, with factors such as global travel and trade accelerating this spread (Fig. 14-10). As early as the 1930s, sulfonamide-resistant strains of Streptococcus pyogenes were noted in military hospitals, and numerous bacterial strains, including S. aureus, were found to be resistant to penicillin shortly after its introduction and use in the 1940s.460,461 In 1961, just 2 years after the introduction of methicillin, MRSA strains emerged in British hospitals,462,463 and strains exhibiting intermediate or high level resistance to vancomycin have been identified since 1996.464,465,466,467 Similar patterns of resistance have emerged in other important pathogens. For N. gonorrhoeae, resistance to sulfonamides was common by the 1940s, and penicillin- and tetracycline-resistant strains became widespread during the 1980s.468 Fluoroquinolone-resistant strains emerged during the 1990s and 2000s and spread quickly, leaving cephalosporins as the only remaining antimicrobial agents for treatment of gonococcal infections.469 In recent years, the emergence of strains with decreased susceptibility to cephalosporins has threatened a

Chapter 14  Emerging and Reemerging Infectious Disease Threats

The causative agents of Ebola and Marburg hemorrhagic fevers are filoviruses, belonging to the Filoviridae. These viruses are associated with fruit bats, which may be their natural animal reservoirs.409-412 Marburg virus was detected first, in 1967, when 31 cases (7 fatal) occurred in Germany and Yugoslavia among laboratory workers handling tissues from African green monkeys.413 Eight years later, in 1975, a traveler returning from Rhodesia (now Zimbabwe) died in a hospital in Johannesburg, South Africa; his traveling companion and a nurse subsequently became ill, although both survived.414 During the 1980s, two cases of Marburg hemorrhagic fever were reported in visitors to Kitum Cave in Mount Elgon National Park, Kenya.415,416 Ebola virus was first detected in 1976 as the cause of outbreaks with high fatality rates in Zaire (now the Democratic Republic of the Congo)417 and the Sudan.418 The Ebola strains associated with the 1976 outbreaks were named Ebola-Zaire and Ebola-Sudan. Other Ebola strains that cause human disease include Ebola-Ivory Coast (isolated in 1994 when a scientist became ill after conducting an autopsy on a chimpanzee from the Tai Forest)419 and Ebola-Bundibugyo (isolated in 2007 during an outbreak in Uganda).420 A case of Ebola-Sudan was reported in the United Kingdom in 1976 in a laboratory worker infected via the accidental stick of a contaminated needle,421 and a case of Ebola-Zaire was reported in South Africa in 1996 in a physician who had traveled to Johannesburg after treating Ebola virus–infected patients in Gabon (the site of three Ebola outbreaks during the 1990s). The physician survived, but a nurse who took care of him became infected and died.422 A fifth strain of Ebola was identified in Reston, Virginia, as the cause of severe illness and death in Philippine monkeys imported by research facilities in the United States in 1989 and 1990423,424 and Italy in 1992.425 In 2008, Ebola-Reston was detected in pigs on two farms in the Philippines.426 Six workers from the pig farm and from a slaughterhouse developed antibodies but did not become ill. Outbreaks of Ebola have recurred multiple times in central and East Africa over the past decade, in the Republic of the Congo in 2003,427,428 in the Sudan in 2004,429 in the Democratic Republic of the Congo in 2007,410 2008-2009,430 and 2012,345 and in Uganda in 2007-2008420 and twice in 2012.345,431 Outbreaks of Marburg occurred in the Democratic Republic of the Congo in 1998 to 2000 among workers at a gold mine,432 in Angola in 2005,433 and in Uganda in 2007434 and 2012.345,431 Although viral hemorrhagic fever outbreaks have lasted from a few months to more than a year, the Ebola and Marburg outbreaks that occurred in Uganda in 2012 were contained within 3 weeks. Hemorrhagic fever outbreaks typically result from a single or small number of spillover events from the virus reservoir with subsequent chains of human-to-human transmission in community (sometimes associated with funerals) and hospital settings.435 Transmission in health care settings can be prevented by adherence to basic infection control practices and proper disposal of potentially infectious items.436 The four distinct filovirus outbreaks that occurred in Uganda and the Democratic Republic of the Congo in 2012 were quickly identified and brought under control. That these outbreaks were kept relatively small is attributable in part to the availability of in-country filovirus diagnostics at the viral hemorrhagic fever reference laboratory located at the Uganda Viral Research Institute (UVRI) in Entebbe. This laboratory is a component of a viral hemorrhagic fever surveillance program established in 2010 by the UVRI and the Uganda Ministry of Health, in collaboration with the CDC.345,431 Current challenges include improving regional disease surveillance, developing additional diagnostic tools to assist in early diagnosis, and conducting ecologic investigations of Ebola and Marburg viruses. A better understanding of the natural reservoirs of these viruses and how they are spread may help prevent future outbreaks.


174

Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

Gentamicin Methicillin

Penicillin

Nalidixic Acid

Tetracyclines

1930

1940

1950

Norfloxacin

1960

PRSA

1970

1980

MRSA

1990 ESBL AmpC VRE

Sulfonamides

Vancomycin

Tigecycline

Ceftriaxone

2000

2010 NDM-1

KPC VRSA

Linezolid

Polymyxins Cephalexin

Imipenem

Daptomycin

Erythromycin FIGURE 14-10  Antibiotic and resistance timeline. This timeline indicates the approximate dates that the major antibiotic classes or important antibiotics of each class were introduced into clinical use. The dates that resistant organisms were identified are shown in the center of the timeline. AmpC, AmpC-producing Enterobacteriaceae; ESBL, extended-spectrum β-lactamase–producing Enterobacteriaceae; KPC, Klebsiella pneumoniae carbapenemase–producing Enterobacteriaceae; MRSA, methicillin-resistant Staphylococcus aureus; NDM-1, New Delhi metallo-β-lactamase-1–producing Enterobacteriaceae; PRSA, penicillin-resistant S. aureus; VRE, vancomycin-resistant Enterococcus; VRSA, vancomycin-resistant S. aureus. (From Molton JS, Tambyah PA, Ang BS, et al. The global spread of healthcare-associated multidrug-resistant bacteria: a perspective from Asia. Clin Infect Dis. 2013;56: 1310-1318.)

return to potentially untreatable gonorrhea and prompted changes in U.S. gonorrhea treatment guidelines to prolong the effectiveness of these drugs.470,471 Over the past 2 decades, highly drug-resistant strains of M. tuberculosis have also emerged worldwide,472 including multidrug-resistant tuberculosis (defined as tuberculosis that is resistant to isoniazid and rifampin, the two most effective first-line tuberculosis drugs) and extensively drug-resistant tuberculosis (defined as multidrug-resistant tuberculosis that is also resistant to any fluoroquinolone drug and at least one of three second-line injectable drugs: amikacin, kanamycin, or capreomycin). A survey of more than 25 international reference laboratories conducted by the WHO and CDC found that during 2000 to 2004, among 17,690 M. tuberculosis isolates, 20% were multidrug resistant and 2% were extensively drug resistant.473 Although tuberculosis cases in the United States continue to decline, an estimated one third of the world’s population is infected with M. tuberculosis, and each year approximately 9 million people develop tubercular disease and 2 million die from tuberculosis-related deaths.474 These infections present serious public health challenges and raise the specter of virtually untreatable tuberculosis outbreaks.475 Carbapenem-resistant Enterobacteriaceae are also particularly alarming, with some showing resistance to all available antibiotics.476,477 These infections are primarily transmitted in health care settings and can be severe, with mortality rates of 40% to 50%.478-480 Patients who require prolonged hospitalization and critically ill patients exposed to invasive medical devices (e.g., ventilators and central venous catheters) are at special risk. Resistance to carbapenem antibiotics is mediated through the production of carbapenemases (enzymes that inactivate carbapenems), including Klebsiella pneumoniae carbapenemase (KPC), first identified in 2001 in the United States,481 and New Delhi β-lactamase (NDM), first identified in 2008 in India.482 The genes encoding KPC and NDM (carried on plasmids) have spread from K. pneumoniae to other gram-negative bacteria, including E. coli, Klebsi­ ella species, and Enterobacter species. The problem of antimicrobial resistance extends beyond bacteria and includes many priority viral (e.g., HIV, influenza), fungal (e.g., Candida, Aspergillus), and parasitic (e.g., malaria) infections. However, the increasing use of antibiotics in both humans and animals, the spread of HAIs into communities, and a virtual standstill in antibiotic

development have escalated bacterial antibiotic resistance to crisis levels and garnered the attention of public health, clinical, and policy leaders worldwide. Efforts to reduce antimicrobial resistance have largely focused on surveillance and infection control in health care settings, along with educational campaigns targeted to health care providers and consumers on judicious antimicrobial use, such as the CDC’s “Get Smart: Know When Antibiotics Work” campaign.483 In recent years, impressive gains have been made by U.S. health care settings in reducing several types of HAIs, many of which are drug resistant.484 As an example, invasive hospital-acquired MRSA infections declined 28% from 2005 through 2008485 and MRSA bloodstream infections in hospitals decreased nearly 50% between 1997 and 2007.486 These and other declines in hospital-acquired infections followed targeted, multifaceted efforts undertaken to increase adherence to recommended infection control practices, educate patients and providers, issue facility-specific guidelines for prescription and use of antimicrobial agents, and implement appropriate isolation and cohorting of patients infected or colonized with drug-resistant organisms. In addition, hospital-acquired infections are reported and tracked by the Centers for Medicare and Medicaid Services (CMS) and through reporting mandates in many states using the CDC’s National Healthcare Safety Network (NHSN). This secure, Internet-based surveillance system collects data from more than 12,000 facilities in all 50 states on hospital-acquired infections and related issues, including the incidence or prevalence of multidrug-resistant organisms, health care personnel safety and vaccination, and the occurrence of transfusion-related adverse events. Reviews of antibiotic stewardship programs in both large and small hospitals have documented their effectiveness, with facility-specific reductions in antibiotic use of 22% to 36% and related annual cost savings of $200,000 to $900,000.487,488 With 50% of antibiotic prescriptions estimated to be unnecessary,489 education of patients and providers on the importance of and health benefits from responsible use of antibiotics remains paramount. Use of antibiotics as growth promoters in healthy food-producing animals is also a significant concern. Globally, the amount of antibiotics used in food-producing animals surpasses the amount of antibiotics used to treat human disease.450 The human health implications of this


175 (e.g., fecal transplants to treat C. difficile) also offer tremendous promise for reducing antimicrobial resistance. Vaccines represent the optimal solution to addressing infections and antimicrobial resistance, and research and development of new vaccines is an urgent need. Effective immunization programs have stopped emergence of resistant strains and precluded the need for new antimicrobial agents for multiple infectious diseases, allowing focus to be shifted to diseases for which drug resistance remains a major global health threat. A recent example of this impact includes the pneumococcal conjugate vaccine. Over the past several years, use of this vaccine not only has reduced the rate of disease but also has decreased antibiotic resistance by targeting pneumococcal strains that are most often resistant.499-501

CONTROLLING THE THREATS

The cross-border spread of infectious diseases, the upsurge in newly identified infections along with the emergence of known infections in new geographic regions, the unrelenting evolution of resistant organisms, and continued concerns about bioterrorism serve as compelling reminders of the importance of ensuring strong and sustainable clinical, public health, and laboratory capacity and collaborations at the local, national, and international levels.502 These fundamental elements can help create globally linked surveillance and laboratory systems that can facilitate rapid recognition of and response to infectious disease events.503,504 The World Health Organization has long played a major role in establishing and supporting such global health collaborations. A primary example is the Global Influenza Surveillance and Response System (GISRS) (Fig. 14-11), in operation for more than 6 decades.505 Formerly known as the Global Influenza Surveillance Network, GISRS currently comprises six WHO collaborating centers, four WHO Essential Regulatory Laboratories, and 141 institutions across 111 countries (WHO member states). Responsibilities include monitoring the evolution of influenza viruses and providing recommendations on laboratory diagnostics, vaccine development, and risk assessment. Also critical is WHOâ&#x20AC;&#x2122;s Global Outbreak Alert and Response Network (GOARN),506 a collaboration of existing networks and institutions

National Influenza Center WHO Collaborating Center for Reference and Research on Influenza WHO Collaborating Center for the Surveillance, Epidemiology and Control of Influenza WHO Collaborating Center for Studies on the Ecology of Influenza in Animals WHO Essential Regulatory Laboratory WHO H5 Reference Laboratory

Not applicable

FIGURE 14-11â&#x20AC;&#x192; WHO Global Influenza Surveillance and Response System. (From World Health Organization [http://www.who.int/influenza/ gisrs_laboratory/en/]. Available at http://www.who.int/whr/2007/media_centre/07_chap2_fig02_en.pdf.)

Chapter 14â&#x20AC;&#x201A; Emerging and Reemerging Infectious Disease Threats

use are increasingly being recognized. A recent study comparing workers in industrial and antibiotic-free livestock operations found livestock-associated MRSA and multidrug-resistant S. aureus carriage only among the industrial workers.490 Linkages have also been found between E. coli isolates from retail meat (chicken) and extraintestinal pathogenic E. coli urinary tract infections in humans, potentially affecting treatment of these common infections.491 Several nations have taken steps to address the nontherapeutic use of antibiotics in foodproducing animals, beginning with Sweden in 1986 and extending to the European Union in 2006, with bans on agricultural growth promoters.492 The FDA strategy to promote the judicious use of antibiotics important in treating humans recommends that such antibiotics be used in food-producing animals only under veterinary oversight and only to address animal health needs, not to promote growth.493 For antimicrobial drug development, the outlook is grim. Despite the continued rise in antibiotic-resistant pathogens, the development of new antibiotics has dramatically slowed. For the 5-year period 1983 to 1987, 16 new systemic antibiotics were approved for use in humans by the FDA; from 2008 to 2012, only 2 were approved.494 Particularly troubling, there have been no new classes of drugs to treat gramnegative bacteria in 4 decades.488 With the discovery of new antimicrobial agents more scientifically challenging compared with earlier years, unfavorable profit margins from short-course therapies, and other disincentives, many pharmaceutical companies have abandoned the market. Several U.S. policy steps have been taken to counteract these effects, including the FDA Safety and Innovation Act,495 passed into law in 2012, which seeks to increase the development of and patient access to new antimicrobial agents. More recent efforts have focused on the use of new technologies and host targets to better understand and reduce antimicrobial resistance. Whole-genome sequencing techniques have been used to track bacterial transmission from person to person and to better define and determine transmission linkages in outbreaks of resistant HAIs.496-498 As these technologies continue to advance, rapid, point-of-care diagnostic tests could be used to quickly identify resistant infections and target treatment. Efforts to prevent and control infectious diseases by altering the host-microbe interaction as opposed to targeting microbes


Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

176 established in 2000 to address threats from epidemic-prone and emerging infectious threats. GOARN provides an operational framework to ensure the availability of skills, expertise, and resources needed to keep the international community aware of and ready to respond to potential outbreaks.507 In the aftermath of the 2003 SARS outbreak, the global public health community completed work on new International Health Regulations (IHR), an international treaty that gives the WHO authority over and places requirements on its member states for detecting, reporting, and controlling infectious diseases.508 Adopted by the World Health Assembly in 2005 and made effective in 2007, the new regulations require prompt reporting of all public health emergencies of international concern, expanding beyond infectious diseases to include events resulting from biological, chemical, or radionuclear threats as well as natural disasters. In addition to reporting of public health emergencies of international concern, the regulations require member states to notify the WHO of a single case of smallpox; poliomyelitis due to wild-type poliovirus; SARS; and human influenza caused by a new subtype. With the goal of controlling health threats at the local level, the new regulations allow for the use of surveillance information beyond official state notification and have established new requirements for member states to support existing global surveillance and response systems and to develop proactive systems for strengthening national and international capacities. Significant contributions to global health and infectious disease control have also been made through private-sector support. A leading example is the Bill and Melinda Gates Foundation (www .gatesfoundation.org), a privately funded effort begun in 2000 focused on reducing health disparities across the world and helping to address the global health challenges outlined by the 2000 Millennium Development Goals (www.un.org/millenniumgoals). Priorities for the Gates Foundation include efforts to reduce HIV infection/AIDS, malaria, tuberculosis, vaccine-preventable diseases, diarrheal diseases, pneumonia, and neglected infectious diseases. Other important global health initiatives supported by both government and nongovernment donors include the Global Alliance for Vaccines and Immunizations (GAVI Alliance; www.gavialliance.org) and the Global Fund to Fight AIDS, Tuberculosis, and Malaria (www.theglobalfund.org). Two large U.S.-led efforts, the President’s Malaria Initiative (PMI; www .fightingmalaria.gov) and the President’s Emergency Plan for AIDS Relief (PEPFAR; www.pepfar.gov) provide targeted prevention and treatment support in countries most heavily affected by these leading killers. In particular, the impact of PEPFAR has been dramatic. Begun in 2004, the program requires country ownership and results-based efforts with goals for sustainability. In 2011 alone, PEPFAR supported treatment of nearly 4 million people, supported antiretroviral therapy for more than 1.5 HIV-infected pregnant women to prevent perinatal infection, and supported diagnostic testing for more than 40 million individuals.509 Although national and global partnerships are critical to controlling infectious disease threats, local clinical, public health, and laboratory capacity remains the cornerstone for initial disease recognition and response. In the early 1980s, concerns by staff in the CDC’s

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parasitic disease drug service regarding requests from physicians in New York and California for pentamidine isethionate for treatment of Pneumocystis carinii (now Pneumocystis jirovecii) pneumonia in patients with no known cause of immunodeficiency hinted at the first U.S. cases of AIDS.510 Recognition of unusually severe respiratory disease by observant clinicians signaled hantavirus pulmonary syndrome in 1993, and suspicion of anthrax by alert clinical and laboratory staff in Florida in 2001 suggested a possible bioterrorist event. A February 10, 2003, email posted by a physician on ProMED, an informal online infectious disease reporting program of the International Society for Infectious Diseases, is widely regarded as the first notification of the global outbreak of SARS.511 Such observations have not been limited to the medical and scientific community, however. In the mid1970s, two Connecticut mothers questioning what was believed to be an unusually large number of juvenile rheumatoid arthritis cases in their community led researchers to the discovery of Lyme disease and a concerned American Legion official provided the first indication to health authorities of the emergence of legionnaires’ disease.512 Although today’s globalized world has created a perfect environment for rapid emergence and spread of infectious diseases, it has also brought significant scientific, technologic, and communication advances for their control. Next-generation sequencing technologies and expanded bioinformatics capacities are revolutionizing the field of microbiology, reducing the amount of time needed for pathogen detection and analysis and generating data for a more detailed understanding of infectious agents.503,513 These tools offer new opportunities to improve public health efforts to detect and control outbreaks, determine antimicrobial susceptibility, and develop and target vaccines.313,314,497,498 Scientists are also gaining new understanding of the role of the microbiome and microbial sensors in infectious diseases,514,515 offering new insight into pathogen-host complexities and disease treatment and prevention. Continued advances in electronic communications are facilitating earlier recognition of emerging problems and rapid exchange of information. In particular, early warning systems such as ProMED-mail, the Public Health Agency of Canada’s Global Public Health Intelligence Network (GPHIN), and HealthMap, collect, categorize, and display outbreak and disease information from a variety of formal and informal sources—enhancing disease surveillance and tracking capabilities.516-518 Expansions in Internet access and use and far-reaching social media networks have also increased the exchange of health information and broadened public health partnerships to include nontraditional partners such as law enforcement, the media, and members of the public at local, national, and global levels. Whereas focus on emerging and reemerging infections is paramount, requiring ongoing vigilance and a globally linked infrastructure, priority attention must remain on reducing high-burden infections that account for the majority of disease and disability caused by microbial agents.5,6 These efforts should ideally work in tandem, enabling rapid recognition and effective response to emerging infections and other public health emergencies along with implementation of new and proven measures to reduce the burden of endemic infectious diseases and advance global health equity.

swine-origin influenza A (H1N1) virus in humans. N Engl J Med. 2009;360:2605-2615. 17. Zaki AM, van Boheemen S, Bestebroer TM, et al. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med. 2012;367:1814-1820. 18. Gao R, Cao B, Hu Y, et al. Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med. 2013; 368:1888-1897. 33. Sugarman DE, Barskey AE, Delea MG, et al. Measles outbreak in a highly vaccinated population, San Diego, 2008: role of the intentionally undervaccinated. Pediatrics. 2010; 125:747-755. 35. Misegades LK, Winter K, Harriman K, et al. Association of childhood pertussis with receipt of 5 doses of pertussis vaccine by time since last vaccine dose, California, 2010. JAMA. 2012;308:2126-2132. 40. De Serres G, Markowski F, Toth E, et al. Largest measles epidemic in North America in a decade–Quebec, Canada, 2011: contribution of susceptibility, serendipity, and superspreading events. J Infect Dis. 2013;207:990-998.

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177.e1

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Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

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Chapter 14  Emerging and Reemerging Infectious Disease Threats

Available at http://www.cdc.gov/h1n1flu/estimates_2009 _h1n1.htm. 177. Cheng VC, To KK, Tse H, et al. Two years after pandemic influenza A/2009/H1N1: what have we learned? Clin Microbiol Rev. 2012;25:223-263. 178. Shrestha SS, Swerdlow DL, Borse RH, et al. Estimating the burden of 2009 pandemic influenza A (H1N1) in the United States (April 2009-April 2010). Clin Infect Dis. 2011;52S1:S75-S82. 179. Viboud C, Miller M, Olson D, et al. Preliminary estimates of mortality and years of life lost associated with the 2009 A/H1N1 pandemic in the US and comparison with past influenza seasons. PLoS Curr. 2010;2:RRN1153. 180. Dawood FS, Iuliano AD, Reed C, et al. Estimated global mortality associated with the first 12 months of 2009 pandemic influenza A H1N1 virus circulation: a modelling study. Lancet Infect Dis. 2012;12:687-695. 181. Broberg E, Nicoll A, Amato-Gauci A. Seroprevalence to influenza A(H1N1) 2009 virus—where are we? Clin Vacc Immunol. 2011;18:1205-1212. 182. Jacobs JH, Archer BN, Baker MG, et al. Searching for sharp drops in the incidence of pandemic A/H1N1 influenza by single year of age. PloS One. 2012;7:e42328. 183. Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. N Engl J Med. 2010;362:1708-1719. 184. Lau LL, Nishiura H, Kelly H, et al. Household transmission of 2009 pandemic influenza A (H1N1): a systematic review and meta-analysis. Epidemiology. 2012;23:531-542. 185. Mosby LG, Rasmussen SA, Jamieson DJ. 2009 pandemic influenza A (H1N1) in pregnancy: a systematic review of the literature. Am J Obstet Gynecol. 2011;205:10-18. 186. Van Kerkhove MD, Vandemaele1 KA, Shinde V, et al. Risk factors for severe outcomes following 2009 influenza A (H1N1) infection: a global pooled analysis. PLoS Med. 2011;8:e1001053. 187. Morgan OW, Bramley A, Fowlkes A, et al. Morbid obesity as a risk factor for hospitalization and death due to 2009 pandemic influenza A (H1N1) disease. PLoS One. 2010;5:e9694. 188. Blanton L, Peacock G, Cox C, et al. Neurologic disorders among pediatric deaths associated with the 2009 pandemic influenza. Pediatrics. 2012;130:390-396. 189. Broadbent AJ, Subbarao K. Influenza virus vaccines: lessons from the 2009 H1N1 pandemic. Curr Opin Virol. 2011;1:254-262. 190. Rebmann T, Zelicoff A. Vaccination against influenza: role and limitations in pandemic intervention plans. Expert Rev Vaccines. 2012;11;1009-1019. 191. Yin JK, Khandaker G, Rashid H, et al. Immunogenicity and safety of pandemic influenza A (H1N1) 2009 vaccine: systematic review and meta-analysis. Influenza Other Respir Viruses. 2011;5:299-305. 192. Centers for Disease Control and Prevention. Interim results: influenza A (H1N1) 2009 monovalent vaccination coverage—United States, October-December 2009. MMWR Morb Mortal Wkly Rep. 2010;59:44-48. 193. Atkins CY, Patel A, Taylor TH, et al. Estimating effect of antiviral drug use during pandemic (H1N1) 2009 outbreak, United States. Emerg Infect Dis. 2011;17:1591-1598. 194. Yu Y, Garg S, Yu PA, et al. Peramivir use for treatment of hospitalized patients with influenza A(H1N1)pdm09 under emergency use authorization, October 2009-June 2010. Clin Infect Dis. 2012;55:8-15. 195. Chan-Tack KM, Gao A, Himaya AC, et al. Clinical experience with intravenous zanamivir under an emergency investigational new drug program in the United States. J Infect Dis. 2013;207:196-198. 196. Muthuri SG, Myles PR, Venkatesan S, et al. Impact of neuraminidase inhibitor treatment on outcomes of public health importance during the 2009–2010 influenza A(H1N1) pandemic: a systematic review and meta-analysis in hospitalized patients. J Infect Dis. 2013;207:553-563. 197. Centers for Disease Control and Prevention. Case Count: Detected U.S. Human Infections with H3N2v by State since August 2011. Available at http://www.cdc.gov/flu/swineflu/ h3n2v-case-count.htm. 198. Centers for Disease Control and Prevention. Update: influenza activity—United States and worldwide, May 20– September 22, 2012. MMWR Morb Mortal Wkly Rep. 2012;61:785-789. 199. Pearce MB, Jayaraman A, Pappas C, et al. Pathogenesis and transmission of swine origin A (H3N2)v influenza viruses in ferrets. Proc Natl Acad Sci U S A. 2012;109: 3944-3949. 200. Cox CM, Neises D, Garten RJ, et al. Swine influenza virus A (H3N2) infection in human, Kansas, USA, 2009. Emerg Infect Dis. 2011;17:1143-1144. 201. Nelson MI, Vincent AL, Kitikoon P, et al. Evolution of novel reassortant A/H3N2 influenza viruses in North American swine and humans, 2009–2011. J Virol. 2012;86:8872-8878. 202. Lindstrom S, Garten R, Balish A, et al. Human infections with novel reassortant influenza A (H3N2)v viruses, United States, 2011. Emerg Infect Dis. 2012;18:834-837.


Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

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Chapter 14  Emerging and Reemerging Infectious Disease Threats

347. Wu S, Wu F, He J. Emerging risk of H7N9 influenza in China. Lancet. 2013;381:1539-1540. 348. Centers for Disease Control and Prevention. Influenza A (H3N2) variant virus-related hospitalizations: Ohio, 2012. MMWR Morb Mortal Wkly Rep. 2012;61:764-767. 349. King LJ, Anderson LR, Blackmore CG, et al. Executive summary of the AVMA One Health Initiative Task Force report. J Am Vet Med Assoc. 2008;233:259-261. 350. Karesh WB, Dobson A, Lloyd-Smith JO, et al. Ecology of zoonoses: natural and unnatural histories. Lancet. 2012; 380:1936-1945. 351. Bird BH, Nichol ST. Breaking the chain: Rift Valley fever virus control via livestock vaccination. Curr Opin Virol. 2012;2:315-323. 352. Morse SS, Mazet JA, Woolhouse M, et al. Prediction and prevention of the next pandemic zoonosis. Lancet. 2012; 380:1956-1965. 353. Kilpatrick AM, Randolph SE. Drivers, dynamics, and control of emerging vector-borne zoonotic diseases. Lancet. 2012;380:1946-1955. 354. Gubler DJ. Epidemic dengue/dengue hemorrhagic fever as a public health, social, and economic problem in the 21st century. Trends Microbiol. 2002;10:100-103. 355. Bhatt S, Gething PW, Brady OJ, et al. The global distribution and burden of dengue. Nature. 2013;496:504-507. 356. Kautner I, Robinson MJ, Kuhnle U. Dengue virus infection: epidemiology, pathogenesis, clinical presentation, diagnosis, and prevention. J Pediatr. 1997;131:516-524. 357. Meltzer MI, Rigau-Perez JG, Clark GG, et al. Using disability-adjusted life years to assess the economic impact of dengue in Puerto Rico: 1984-1994. Am J Trop Med Hyg. 1998;59:265-271. 358. Anderson KB, Chunsuttiwat S, Nisalak A, et al. Burden of symptomatic dengue infection in children at primary school in Thailand: a prospective study. Lancet. 2007;369: 1452-1459. 359. Brathwaite DO, San Martín JL, Montoya RH, et al. The history of dengue outbreaks in the Americas. Am J Trop Med Hyg. 2012;87:584-593. 360. Centers for Disease Control and Prevention. Notes from the field: dengue epidemic—Puerto Rico, January–July 2010. MMWR Morb Mortal Wkly Rep. 2010;59;878. 361. Centers for Disease Control and Prevention. Locally acquired dengue—Key West, Florida, 2009–2010. MMWR Morb Mortal Wkly Rep. 2010;59;577-581. 362. Centers for Disease Control and Prevention. Ongoing dengue epidemic—Angola, June 2013. MMWR Morb Mortal Wkly Rep. 2013;62:504-507. 363. Amarasinghe A, Kuritsky JN, Letson GW, Margolis HS. Dengue virus infection in Africa. Emerg Infect Dis. 2011; 17:1349-1354. 364. Tomashek KM, Gregory CJ, Rivera Sánchez A, et al. Dengue deaths in Puerto Rico: lessons learned from the 2007 epidemic. PLoS Negl Trop Dis. 2012;6:e1614. 365. Webster DP, Farrar J, Rowland-Jones S. Progress towards a dengue vaccine. Lancet Infect Dis. 2009;9:678-687. 366. Sabchareon A, Wallace D, Sirivichayakul C, et al. Protective efficacy of the recombinant, live attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. Lancet. 2012;380:1559-1567. 367. World Health Organization. Chikungunya and Dengue in the Southwest Indian Ocean. Global Alert and Response. March 17, 2006. Available at http://www.who.int/csr/don/ 2006_03_17. 368. Burt FJ, Rolph MS, Rulli NE, et al. Chikungunya: a reemerging virus. Lancet. 2012;379:662-671. 369. Chretien J-P, Linthicum KJ. Chikungunya in Europe: what’s next? Lancet. 2007;70:1805-1806. 370. World Health Organization. Chikungunya. Fact Sheet 327. March 2008. Available at http://www.who.int/mediacentre/ factsheets/fs327. 371. Pan American Health Organization. Preparedness and Response for Chikungunya Virus: Introduction in the Ameri­ cas. Washington, DC: PAHO; 2011. 372. Josseran L, Paquet C, Zehgnoun A, et al. Chikungunya disease outbreak, Réunion Island. Emerg Infect Dis. 2008; 12:1994-1995. 373. Beesoon S, Funkhouser E, Kotea N, et al. Chikungunya fever, Mauritius, 2006. Emerg Infect Dis. 2008;14:337-338. 374. Rezza G, Nicoletti L, Angelini R, et al. Infection with chikungunya virus in Italy: an outbreak in a temperate region. Lancet. 2007;370:1840-1846. 375. Charrel RM, de Lamballerie X, Raoult D. Seasonality of mosquitoes and chikungunya in Italy. Lancet Infect. 2008; 8:5-6. 376. de Lamballerie X, Leroy E, Charrel RN, et al. Chikungunya virus adapts to tiger mosquito via evolutionary convergence: a sign of things to come? Virol J. 2008;5:33. 377. Weaver SC, Osorio JE, Livengood JA, et al. Chikungunya virus and prospects for a vaccine. Expert Rev Vaccines. 2012;9:1087-1101. 378. Chattopadhyay A, Wang E, Seymour R, et al. A chimeric vesiculo/alphavirus is an effective alphavirus vaccine. J Virol. 2013;87:395-402.


Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

177.e6 440. Demma LJ, Traeger MS, Nicholson WL, et al. Rocky Mountain spotted fever from an unexpected tick vector in Arizona. N Engl J Med. 2005;353:587-594. 441. Pritt BS, Sloan LM, Johnson DK, et al. Emergence of a new pathogenic Ehrlichia species, Wisconsin and Minnesota, 2009. N Engl J Med. 2011;365:422-429. 442. McMullan LK, Folk SM, Kelly AJ, et al. A new phlebovirus associated with severe febrile illness in Missouri. N Engl J Med. 2012;367:834-841. 443. Yu XJ, Liang MF, Zhang SY, et al. Fever with thrombocytopenia associated with a novel bunyavirus in China. N Engl J Med. 2011;364:1523-1532. 444. Zhao L, Zhai S, Wen H, et al. Severe fever with thrombocytopenia syndrome virus, Shandong Province, China. Emerg Infect Dis. 2012;18:963-965. 445. Tao WY, Li X, Chen Y, et al. A family cluster of infections by a newly recognized bunyavirus in eastern China, 2007: further evidence of person-to-person transmission. Clin Infect Dis. 2011;53:1208-1214. 446. Liu Y, Li Q, Hu W, et al. Person-to-person transmission of severe fever with thrombocytopenia syndrome virus. Vector Borne Zoonotic Dis. 2012;12:156-160. 447. Tang X, Wu W, Wang H, et al. Human-to-human transmission of severe fever with thrombocytopenia syndrome bunyavirus through contact with infectious blood. J Infect Dis. 2013;207:736-739. 448. Howell L, ed. Global Risks 2013, Eighth Edition: An Initia­ tive of the Risk Response Network. World Economic Forum; 2013. Available at http://www3.weforum.org/docs/WEF _GlobalRisks_Report_2013.pdf. 449. Infectious Diseases Society of America. The 10 × ’20 initiative: pursuing a global commitment to develop 10 new antibacterial drugs by 2020. Clin Infect Dis. 2010;50: 1081-1083. 450. World Health Organization. The Evolving Threat of Antimi­ crobial Resistance: Options for Action. Geneva: World Health Organization; 2012. Available at http://www.who .int/patientsafety/implementation/amr/publication/en/. 451. G-Science Academies Statements 2013. Drug Resistance in Infectious Agents—a Global Threat to Humanity. Available at http://www.interacademies.net/File.aspx?id=21873. 452. Infectious Diseases Society of America. Combatting antimicrobial resistance: policy recommendations to save lives. Clin Infect Dis. 2011;52(suppl 5):S397-S428. 453. European Centre for Disease Prevention and Control, European Medicines Agency. Joint Technical Report. The Bacte­ rial Challenge: Time to React. Stockholm: ECDC; 2009. 454. Roberts RR, Hota B, Ahmad I, et al. Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clin Infect Dis. 2009;49:1175-1184. 455. Antibiotic-Resistant Infections Cost the US Healthcare System in Excess of $20 Billion Annually [press release]. Boston, MA: Alliance for the Prudent Use of Antibiotics and bioMérieux; October 19, 2009. Available at http:// www.prnewswire.com/news-releases/antibiotic-resistantinfections-cost-the-us-healthcare-system-in-excess-of-20billion-annually-64727562.html. 456. Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2013. Available at http://www.cdc.gov/drugresistance/threat-report-2013/ index.html. 457. Molton JS, Tambyah PA, Ang BS, et al. The global spread of healthcare-associated multidrug-resistant bacteria: a perspective from Asia. Clin Infect Dis. 2013;56:1310-1318. 458. Rolain JM, Canton R, Cornaglia G. Emergence of antibiotic resistance: need for a new paradigm. Clin Microbiol Infect. 2012;18:615-616. 459. Bhullar K, Waglechner N, Pawlowski A, et al. Antibiotic resistance is prevalent in an isolated cave microbiome. PLoS One. 2012;7:e34953. 460. Levy SB. Microbial resistance to antibiotics: an evolving and persistent problem. Lancet. 1982;2:83-88. 461. Barber M, Rozwadowski-Dowzenko M. Infection by penicillin-resistant staphylococci. Lancet. 1948;2:641-644. 462. Barber M. Methicillin-resistant staphylococci. J Clin Pathol. 1961;14:385-393. 463. van Belkum A, Verbrugh H. 40 years of methicillin resistant Staphylococcus aureus. BMJ. 2001;323:644-645. 464. Hiramatsu K, Hanaki H, Ino T, et al. Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility. J Antimicrob Chemother. 1997;40: 135-136. 465. Smith TL, Pearson ML, Wilcox KR, et al. Emergence of vancomycin resistance in Staphylococcus aureus. N Engl J Med. 1999;340:493-501. 466. Centers for Disease Control and Prevention. Staphylococ­ cus aureus resistant to vancomycin—United States, 2002. MMWR Morb Mortal Wkly Rep. 2002;51:565-567. 467. Fridkin SK. Vancomycin-intermediate and -resistant Staphylococcus aureus: what the infectious disease specialist needs to know. Clin Infect Dis. 2001;32:108-115.

468. Centers for Disease Control and Prevention. CDC Grand Rounds: the growing threat of multidrug-resistant gonorrhea. MMWR Morb Mortal Wkly Rep. 2013;62:103-106. 469. Centers for Disease Control and Prevention. Update to CDC’s sexually transmitted diseases treatment guidelines, 2006: fluoroquinolones no longer recommended for treatment of gonococcal infections. MMWR Morb Mortal Wkly Rep. 2007;56:332-336. 470. Bolan GA, Sparling PF, Wasserheit JN. The emerging threat of untreatable gonococcal infection. N Engl J Med. 2012; 66:485-487. 471. Centers for Disease Control and Prevention. Update to CDC’s sexually transmitted diseases treatment guidelines, 2010: oral cephalosporins no longer a recommended treatment for gonococcal infections. MMWR Morb Mortal Wkly Rep. 2012;61:590-594. 472. Shah NS, Wright A, Gill-Han B, et al. Worldwide emergence of extensively drug-resistant tuberculosis. Emerg Infect Dis. 2007;13:380-387. 473. Centers for Disease Control and Prevention. Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs—worldwide, 2000-2004. MMWR Morb Mortal Wkly Rep. 2006;55:301-305. 474. World Health Organization. Global Tuberculosis Control 2008; Surveillance, Planning, Financing. Publication No. WHO/HTM/TB/2008.393. Geneva: World Health Organization; 2008. 475. Centers for Disease Control and Prevention. Plan to combat extensively drug-resistant tuberculosis: recommendations of the Federal Tuberculosis Task Force. MMWR Recomm Rep. 2009;58(RR-3):1-43. 476. Schwaber MJ, Carmeli Y. Carbapenem-resistant Enterobacteriaceae: a potential threat. JAMA. 2008;300: 2911-2913. 477. Nordmann P, Naas T, Poirel L. Global spread of carbapenemase-producing Enterobacteriaceae. Emerg Infect Dis. 2011;17:1791-1798. 478. Patel G, Huprikar S, Factor SH, et al. Outcomes of carbapenem-resistant Klebsiella pneumoniae infection and the impact of antimicrobial and adjunctive therapies. Infect Control Hosp Epidemiol. 2008;29:1099-1106. 479. Schwaber MJ, Lev B, Israeli A, et al. Containment of a country-wide outbreak of carbapenem-resistant Klebsiella pneumoniae in Israeli hospitals via a nationally implemented intervention. Clin Infect Dis. 2011;52:848-855. 480. Chitnis AS, Caruthers PS, Rao AK, et al. Outbreak of carbapenem-resistant Enterobacteriaceae at a long-term acute care hospital: sustained reductions in transmission through active surveillance and targeted interventions. Infect Control Hosp Epidemiol. 2012;33:984-992. 481. Yigit H, Queenan AM, Anderson GJ, et al. Novel carbapenem-hydrolyzing beta-lactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae. Antimicrob Agents Chemother. 2008;45:1151-1161. 482. Kumarasamy KK, Toleman MA, Walsh TR, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis. 2010;10:597-602. 483. Centers for Disease Control and Prevention. Get Smart: Know When Antibiotics Work. Available at http://www .cdc.gov/getsmart/. 484. Malpiedi PJ, Peterson KD, Soe MM, et al. 2011 National and State Healthcare-Associated Infection Standardized Infection Ratio Report. February 11, 2013. Available at http://www.cdc.gov/hai/national-annual-sir/index.html. 485. Kallen AJ, Mu Y, Bulens S, et al. Health care–associated invasive MRSA infections, 2005-2008. JAMA. 2010;304: 641-648. 486. Centers for Disease Control and Prevention. National Healthcare Safety Network (unpublished data). 487. Delit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:159-177. 488. Bartlet JG. A call to arms: the imperative for antimicrobial stewardship. Clin Infect Dis. 2011;53(suppl 1):S4-S7. 489. Centers for Disease Control and Prevention. Office-related antibiotic prescribing for persons aged ≤14 years—United States, 1993-1994 to 2007-2008. MMWR Morb Mortal Wkly Rep. 2011;60:1153-1156. 490. Rinsky J, Nadimpalli M, Wing S, et al. Livestock-associated methicillin and multidrug resistant Staphylococcus aureus is present among industrial workers, not antibiotic-free livestock operation workers in North Carolina. PLoS One. 2013;8:e67641. 491. Bergeron CR, Prussing C, Boerlin P, et al. Chicken as reservoir for extraintestinal pathogenic Escherichia coli in humans. Emerg Infect Dis. 2012;18:415-421. 492. Cogliani C, Goossens H, Greko C. Restricting antimicrobial use in food animals: lessons from Europe. Microbe. 2011;6:274-279.

493. U.S. Food and Drug Administration, Animal and Veterinary. Judicious Use of Antimicrobials. Available at http:// www.fda.gov/AnimalVeterinar y/%20SafetyHealth/ AntimicrobialResistance/JudiciousUseofAntimicrobials/ default.htm. 494. Spellberg B. New antibiotic development: barriers and opportunities in 2012. Alliance for the Prudent Use of Anti­ biotics Newsletter. 2012;30(1). 495. Food and Drug Administration Safety and Innovation Act (FDASIA). Available at http://www.fda.gov/Regulatory Information/Legislation/FederalFoodDrugandCosmetic ActFDCAct/SignificantAmendmentstotheFDCAct/ FDASIA/default.htm. 496. Harris SR, Cartwright EJ, Török ME, et al. Whole-genome sequencing for analysis of an outbreak of methicillinresistant Staphylococcus aureus: a descriptive study. Lancet Infect Dis. 2013;13:130-136. 497. Snitkin ES, Zelazny AM, Thomas PJ, et al. Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneu­ moniae with whole-genome sequencing. Sci Transl Med. 2012;4:148ra116. 498. Köser CU, Holden MT, Ellington MJ, et al. Rapid wholegenome sequencing for investigation of a neonatal MRSA outbreak. N Engl J Med. 2012;366:2267-2275. 499. Kyaw MH, Lynfield R, Schaffner W, et al. Effect of intro­ duction of the pneumococcal conjugate vaccine on drugresistant Streptococcus pneumoniae. N Engl J Med. 2006;354: 1455-1463. 500. Pilishvili T, Lexau C, Farley MM, et al. Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis. 2010;201:32-41. 501. Griffin MR, Zhu Y, Moore M, et al. U.S. hospitalizations for pneumonia after a decade of pneumococcal vaccination. N Engl J Med. 2013;369:155-163. 502. Smolinski MS, Hamburg MA, Lederberg J, eds, for the Committee on Emerging Microbial Threats to Health in the 21st Century, Board on Global Health, Institute of Medicine. Microbial Threats to Health: Emergence, Detec­ tion, and Response. Washington, DC: National Academy Press; 2003. 503. Lipkin WI. The changing face of pathogen discovery and surveillance. Nat Rev Microbiol. 2013;11:133-141. 504. Chan EH, Brewer TF, Madoff LC, et al. Global capacity for emerging infectious disease detection. Proc Natl Acad Sci U S A. 2010;107:21701-21706. 505. World Health Organization. Global Influenza Surveillance and Response System (GISRS). Available at http://www .who.int/influenza/gisrs_laboratory/en/. 506. World Health Organization. Global Alert and Response. Global Outbreak Alert and Response Network. Available at http://www.who.int/csr/outbreaknetwork/en/. 507. Heymann DL, Rodier GR. Hot spots in a wired world: WHO surveillance of emerging and re-emerging infectious diseases. Lancet Infect Dis. 2001;1:345-353. 508. World Health Organization. International Health Regulations (2005). 2nd ed. Geneva, 2008. Available at http:// www.who.int/ihr/9789241596664/en/index.html. 509. Goosby E, Dybul M, Fauci AS. The United States President’s Emergency Plan for AIDS Relief: a story of partnerships and smart investments to turn the tide of the global AIDS pandemic. J Acquir Immune Defic Syndr. 2012; 60(suppl 3):S51-S56. 510. Curran JW, Jaffe HW, Centers for Disease Control and Prevention. AIDS: the early years and CDC’s response. MMWR Surveill Summ. 2011;60(suppl 4):64-69. 511. International Society for Infectious Diseases. ProMEDmail. Archive number 20030210.0357. February 10, 2003. Available at http://www.promedmail.org. 512. Dato V, Wagner MM, Fapohunda A. How outbreaks of infectious disease are detected: a review of surveillance systems and outbreaks. Public Health Rep. 2004;119: 464-471. 513. Relman DA. Microbial genomics and infectious diseases. N Engl J Med. 2011;365:347-357. 514. Hooper LV, Littman DR, MacPherson AJ. Interactions between the microbiota and the immune system. Science. 2012;336:1268-1273. 515. Pothlichet J, Quintana-Murci L. The genetics of innate immunity sensors and human disease. Int Rev Immunol. 2013;32:157-208. 516. Madoff LC. ProMED-mail: an early warning system for emerging diseases. Clin Infect Dis. 2004;39:227-232. 517. Mykhalovskiy E, Weir L. The Global Public Health Intelligence Network and early warning outbreak detection: a Canadian contribution to global public health. Can J Public Health. 2006;97:42-44. 518. Freifeld CC, Mandi KD, Reis BY, et al. HealthMap: global infectious disease monitoring through automated classification and visualization of internet media reports. J Am Med Inform Assoc. 2008;15:150-157.


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44 

Antiviral Drugs for Influenza and Other Respiratory Virus Infections Fred Y. Aoki SHORT VIEW SUMMARY

INFLUENZA A AND B: NEURAMINIDASE INHIBITORS Oseltamivir

• Orally administered oseltamivir is effective in prevention and treatment of uncomplicated influenza in otherwise healthy adults. • Observational studies suggest it is beneficial in serious illness. • Toxicity is primarily gastrointestinal.

Zanamivir

• Administration is through oral inhalation as a powder. • Effectiveness is similar to that of oseltamivir. • It is active against some oseltamivir-resistant strains. • Bronchospasm may occur in individuals with asthma or chronic obstructive pulmonary disease.

INFLUENZA A: ADAMANTANES Amantadine and Rimantadine

• Widespread resistance to these agents is present in currently circulating influenza A

viruses, and they should not be used unless sensitivity of isolates is demonstrated. • Orally administered, they have shown efficacy against uncomplicated influenza A. • Effectiveness in serious illness is not established. • Toxicity with amantadine is primarily evident as central nervous system symptoms; with rimantadine it is gastrointestinal intolerance.

INVESTIGATIONAL AGENTS AGAINST INFLUENZA

• Peramivir: intravenously administrated neuraminidase inhibitor • Laninamivir: orally inhaled neuraminidase inhibitor with prolonged presence in the respiratory tract

RESPIRATORY SYNCYTIAL VIRUS Ribavirin

• A guanosine analogue, ribavirin has activity against a broad variety of viruses, including respiratory syncytial virus (RSV) and influenza.

In this chapter, antiviral agents against influenza viruses and certain other respiratory viruses such as parainfluenza and respiratory syn­ cytial virus are reviewed (Table 44-1). The antiviral agents are pre­ sented in alphabetical order and include licensed (approved) as well as investigational agents. Agents that have been investigated in rhino­ virus infections but have been utilized primarily in non–respiratory tract infections, such as interferons and pleconaril, are discussed in Chapter 47.

AMANTADINE AND RIMANTADINE Spectrum

Amantadine (1-adamantanamine hydrochloride; Symmetrel) and rimantadine (α-methyl-1-adamantane methylamine hydrochloride; Flumadine) are symmetrical tricyclic amines (Fig. 44-1A and B) that specifically inhibit the replication of influenza A viruses at low con­ centrations (<1 µg/mL). Influenza B and C viruses are resistant.1 In the past, epidemic human and avian strains of influenza viruses have generally been susceptible to amantadine.2 However, since 20082009, isolates of influenza A/H1N1 and H3N2, highly pathogenic avian H5N1, and A (H1N1)pdm09 are resistant to amantadine and rimantadine (see later discussion).3 By plaque assay, inhibitory con­ centrations of the drugs range from 0.1 to 0.4 µg/mL or less for sensi­ tive human influenza A viruses. Rimantadine is 4 to 10 times more active than amantadine in some assay systems. Both drugs are inhibi­ tory for virus containing the M protein from the 1918 pandemic strain.4 Higher concentrations (10 to 50 µg/mL) inhibit other enveloped viruses in vitro, including parainfluenza, influenza B, rubella, dengue, several arenaviruses (Junin, Lassa, Pichinde), rabies, and African swine fever virus, but these concentrations are not achievable clinically and can be cytotoxic in vitro.5 Rimantadine has pH-dependent

• It is approved for aerosol administration to children hospitalized with RSV pneumonia or bronchiolitis and has been used to treat viral respiratory tract infections in immunosuppressed patients. • It is teratogenic and should not be used near potentially pregnant staff.

RSV604

• An investigational agent, RSV604 inhibits RSV through interaction with the nucleocapsid protein. • It is well absorbed orally, and phase II studies are underway.

PARAINFLUENZA VIRUSES DAS181 (Fludase)

• DAS181 is an investigational compound with activity against parainfluenza and influenza viruses. • An orally inhaled sialidase, it reduces virus binding to epithelial cells. • It has been used to treat parainfluenza virus type 3 infections in immunosuppressed patients.

trypanocidal activity at concentrations of approximately 1 µg/mL6; amantadine at the same concentration in combination with doxycy­ cline inhibits Coxiella burnetii.7 Amantadine may transiently inhibit hepatitis C virus (HCV) replication in humans.8 These agents have prophylactic and therapeutic activity in experi­ mental influenza A virus infection of animals after oral or parenteral dosing. Combinations of M2 inhibitors and neuraminidase inhibitors and ribavirin show enhanced antiviral and therapeutic effects in vitro or in animal models of influenza.9-12

Mechanism of Action

Amantadine and rimantadine share two concentration-dependent mechanisms of anti-influenza action. Low concentrations inhibit the ion channel function of the M2 protein of influenza A viruses, which affects two different stages in virus replication.13-15 The primary effect involves inhibition of viral uncoating or disassembly of the virion during endocytosis. For subtype H5 and H7 viruses, a late effect on hemagglutinin maturation and viral assembly is presumably mediated through altered pH regulation of the trans-Golgi network. Amantadine and rimantadine block proton permeation and prevent M2-mediated changes in pH. This action probably accounts for inhibition of the acid-mediated dissociation of the matrix protein from the ribonucleo­ protein complex within endosomes early in replication and potentia­ tion of acidic pH–induced alterations in the hemagglutinin during its transport late in infection. Amantadine and rimantadine are also concentrated in the lyso­ somal fraction of mammalian cells. Drug-mediated increases in lyso­ somal pH may inhibit virus-induced membrane fusion events and account for the broader antiviral spectrum at higher concentrations. In contrast, the selective anti–influenza A virus effects are quickly lost after removal of the drug from the surrounding medium, which 531


531.e1

KEYWORDS

Chapter 44â&#x20AC;&#x201A; Antiviral Drugs for Influenza and Other Respiratory Virus Infections

amantadine; chemoprophylaxis; chemotherapy; DAS181 (Fludase); influenza; inhaled; laninamivir; oseltamivir; outbreak (control); peramivir; pharmacokinetics; postexposure; resistance; respiratory syncytial virus; ribavirin; rimantadine; RSV604; seasonal; zanamivir


Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

532 TABLE 44-1  Antiviral Agents of Established Therapeutic Effectiveness for Respiratory   Virus Infection VIRAL INFECTION Influenza A and B viruses

Influenza A virus

Respiratory syncytial virus

DRUG

ROUTE

USUAL ADULT DOSAGE

Oseltamivir

Oral

75 mg bid for 5 daysa

Peramivir

Intravenous

300 or 600 mg once

Zanamivir

Inhalation

10 mg bid by inhaler for 5 daysb

Laninamivir octanoate

Inhalation

40 mg oncec

Amantadine

Oral

100 mg bid for 5 days for treatmentd

Rimantadine

Oral

100 mg bid for 5 days for treatmente

Ribavirin

Aerosol

Aerosol treatment 18 hr/day for 3-7 daysf

a Pediatric dosages: For infants 2 wk to <1 yr of age dose is 3 mg/kg twice daily. For children ≥1 yr of age, doses are weight adjusted: 30 mg bid for <15 kg, 45 mg bid for 16-23 kg, 60 mg bid for 24-40 kg, and 75 mg bid for >40 kg. Prophylactic dosage is given once daily (one half of total daily treatment dosage). Not FDA approved currently for prophylaxis in children <1 yr old or treatment in children <2 wk old. b FDA approved at same dosage for treatment of children ≥7 yr of age. Prophylactic dosage is 10 mg inhaled once daily for adults and children ≥5 yr of age. c Adult dose and for children ≥10 yr of age. Pediatric dose: 20 mg once for children <10 yr of age. d Maximum recommended dosage for older adults (≥65 yr) is 100 mg/day. Recommended pediatric dosage is 5 mg/kg/day up to a maximum of 150 mg/day in divided doses. For prophylaxis, the same daily dosage should be given for period at risk. e Pediatric dosage is 5 mg/kg up to a maximum of 150 mg/day in divided doses. Not approved by FDA for treatment in children <13 yr of age. For prophylaxis, same daily dosage should be given for period at risk. f Reservoir concentration of 20 mg/mL. Special aerosol-generating device (available from manufacturer) and expert respiratory therapy monitoring for administration are required. Higher reservoir concentration (60 mg/mL) given for 2 hr tid is an alternative. Note: Please consult text and manufacturer’s product prescribing information for dosage adjustments in renal or hepatic insufficiency and in other circumstances.

NH2 NH2

H

HCl

C

HCl CH3

transmission of drug-resistant virus may occur after cessation of drug use. Before 2003, a small percentage of untreated patients (<1%) had infection with resistant influenza A virus.18 Approximately 30% of drug-treated ambulatory children and adults and 80% of hospitalized children or immunocompromised patients shed resistant virus.19-21 Immunocompetent individuals shedding resistant virus resolve their illness promptly,22 whereas immunocompromised hosts may experi­ ence prolonged illness associated with persistent virus shedding.20 Transmission of M2 inhibitor–resistant virus, associated with failure of drug prophylaxis, occurs in household contacts of treated index cases23 and in nursing home residents.24 Resistant variants can cause typical influenza illness. It is prudent to avoid contact between treated patients and susceptible high-risk contacts and to avoid use of treat­ ment (specifically of young children) and postexposure prophylaxis in the same household. Globally, up to 2003, epidemic influenza A H1N1 and H3N2 strains were M2 inhibitor sensitive. Since 2003, the prevalence of amantadine resistance has increased progressively, although rates vary by virus type and geography.25,26 Among H3N2 isolates, amantadine resistance increased from 12% worldwide in 200325 to 91% by 2005 and greater than 95% in 2008-2009.26 In the United States prior to March 2009, nearly all of the A/H1N1 isolates tested were sensitive to the adaman­ tanes and, subsequently, virtually all A/H1N1 isolates have been resis­ tant up to the present, including the A (H1N1)pdm09 virus.27 Among nonpandemic H1N1 isolates, the prevalence of amantadine resistance was 4% in 2004-2005 worldwide and 16% in isolates from 2005-2006, with rates ranging from 2% in South Korea to 72% in China.26,28,29 The reason for the emergence and global spread of amantadine-resistant strains is unclear. Widespread inappropriate use of amantadine30 and acquisition of undefined advantageous mutations combined with lack of fitness impairment may have been contributing factors. Ribavirin and the neuraminidase inhibitors zanamivir and oseltamivir carboxyl­ ate are active in vitro against M2 inhibitor–resistant strains. The triple combination of amantadine, oseltamivir, and ribavirin impedes the selection of drug-resistant influenza A virus in vitro at clinically achievable concentrations31 compared with double combina­ tions and the agents used singly in vitro.32 The same combination of drugs was also synergistic in vitro in inhibiting the growth of both amantadine- and oseltamivir-resistant influenza A virus strains at con­ centrations that had no activity as single agents.32

Pharmacokinetics

The clinical pharmacokinetic characteristics of amantadine and riman­ tadine are shown in Table 44-2.

Amantadine

A

Amantadine

B

Rimantadine

FIGURE 44-1  Chemical structures of amantadine hydrochloride (A) and rimantadine hydrochloride (B).

suggests that drug must be present in extracellular fluid early in the replicative cycle. Amantadine inhibits the ion channel activity of expressed HCV p7 protein at low concentrations,16 an effect that might account for its reported anti-HCV effects in vivo. Neither agent inhibits HCV enzyme functions or internal ribosome entry in biochemical assays.17

Resistance

Amantadine-resistant virus is readily selected by virus passage in the presence of drug. Resistance with more than 100-fold increases in inhibitory concentrations has been associated with single amino-acid substitutions at critical sites (positions 26, 27, 30, 31, 34) in the transmembrane region of the M2 protein.13 Amantadine and rimantadine share cross-resistance. In avian models, resistant viruses are virulent, genetically stable, and able to compete with wild-type virus so that

Amantadine is well absorbed after oral administration of capsule, tablet, or syrup forms.5 Steady-state peak plasma concentrations average 0.5 to 0.8 µg/mL with a 100-mg twice-daily regimen in healthy young adults. Older adults require only one half of the weight-adjusted dosage needed for young adults to achieve equivalent trough plasma levels of 0.3 µg/mL. Plasma protein binding of amantadine is about 67%, and amantadine’s volume of distribution (Vd) is large (4 to 5 L/ kg). Nasal secretion and salivary levels of amantadine approximate those found in the serum. Cerebrospinal fluid levels are 52% to 96% of those in plasma, and amantadine is excreted in breast milk. Amantadine is eliminated largely unchanged in the urine by glo­ merular filtration and probably by tubular secretion by a bicarbonatedependent organic cation transporter.33 The plasma elimination half-life ( t 12 elim) is 12 to 18 hours, ranges widely, and correlates with the creatinine clearance (CrCl). Because of age-related declines in renal function, t 12 elim increases twofold in older adults and even more in patients with impaired renal function. Dosage reductions are required in renal insufficiency (Table 44-3). Amantadine is inefficiently cleared in patients receiving hemodialysis or continuous ambulatory perito­ neal dialysis, and additional doses are not required. Monitoring of plasma concentrations in such patients is desirable but impractical. Amantadine pharmacokinetics remained unaffected by concurrent administration of oseltamivir and ribavirin in healthy adult volunteers or stable immunocompromised patients.34


533

AMANTADINE Young Elderly

CHARACTERISTIC Relative oral bioavailability (%)

RIMANTADINE Young Elderly

62-93

53-100

75-93

NA

Vd (L/kg) at 200 mg/day

6.1 ± 2.1

3.6 ± 1.1

18.4 ± 9.6

11.5 ± 2.9

Plasma protein binding (%)

67

NA

40

NA

Clearance (mL/min/kg)   Plasma or total   Renal

5 ± 2.1

2 ± 0.9

6.1 ± 1.9

6.4 ± 3.7

2 ± 1.1

1.2 ± 0.4

4.7 ± 2 NA

0

0

6.4 ± 1.4

NA

62-93

53-100

8.3-43

NA

14.8 ± 6.2

26.1 ± 9.7

29.1 ± 9.7

36.5 ± 14.5

   200 mg/day

475 ± 110

416 ± 108

447 ± 108

   100 mg/day

362 ± 158

  Nonrenal Urinary excretion of unchanged drug (%) Plasma half-life (hr) Therapeutic range (ng/mL)   Cmax

  Ctrough    200 mg/day

302 ± 80

300 ± 75

310 ± 87

   100 mg/day

301 ± 75

NA, not available. Adapted from Hayden FG, Aoki FY. Amantadine, rimantadine, and related agents. In: Yu VL, Edwards D, McKinnon S, et al, eds. Antimicrobial Therapy and Vaccines. 2nd ed. Pittsburgh: E Sun Technologies; 2002:714.

TABLE 44-3  Amantadine Dosage Regimens for Prophylaxis and Alterations in Renal Failure CONDITION No Renal Insufficiency

SUGGESTED DOSAGE

Children 1-9 yr

5 mg/kg/day in two divided doses, ≤150 mg/day

Ages 10-64 yr

100 mg twice daily

Ages ≥65 yr

100 mg once daily*

Creatinine Clearance (mL/min/1.73 m2)† ≥80

100 mg (1.4 mg/kg) twice daily

79-35

100 mg once daily

34-25

100 mg every 2 days

24-15

100 mg every 3 days

<15

100 mg every 7 days

Older Adults and Creatinine Clearance (mL/min/1.73 m2)‡ ≥80

100 mg daily

60-79

100 mg and 50 mg on alternate days

40-59

100 mg every 2 days

30-39

100 mg twice weekly

20-29

50 mg twice weekly

10-19

100 mg and 50 mg on alternate weeks

*Use weight-adjusted dosing for smaller patients (<50 kg). Dosages of 1.4 mg/kg/ day have been suggested.5 † Based on adult dosage of 200 mg/day. Proportionate reductions should be made for older adults receiving lower dosages and for children. ‡ This dosing schedule for older adults with renal insufficiency is taken from the Canadian guidelines and has been found to be reasonably well tolerated.44 Modified from Wu MJ, Ing TS, Soung LS, et al. Amantadine hydrochloride pharmacokinetics in patients with impaired renal function. Clin Nephrol. 1982;17:19-23.

Rimantadine

Rimantadine is well but slowly absorbed, with the time to peak plasma concentration averaging 2 to 6 hours. Absorption does not seem to be decreased by food. With multiple doses of 100 mg twice daily, the steady-state peak and trough plasma concentrations in healthy adults are 0.4 to 0.5 µg/mL and 0.2 to 0.4 µg/mL. In infants receiving dosages

of 3 mg/kg each day, peak serum levels range from 0.1 to 0.6 µg/mL. No important age-related changes in pharmacokinetics have been found in healthy older adults or in children. However, steady-state plasma concentrations in older nursing home residents receiving 100 mg twice daily average more than twofold higher (mean, 1.2 µg/ mL) than concentrations observed in healthy adults, which indicates the need for lower dosages in these patients. Plasma protein binding is about 40%. Rimantadine has a very large Vd (~12 L/kg), and concentra­ tions in nasal mucus average 50% higher than those in plasma. In contrast to amantadine, rimantadine undergoes extensive metabolism by hydroxylation, conjugation, and glucuronidation before renal excretion.5 The plasma t 12 elim of rimantadine averages 24 to 36 hours. No clinically important differences in pharmacokinetics are found in patients with chronic liver disease without significant hepa­ tocellular dysfunction. In hemodialysis patients with severe renal failure, the clearance of rimantadine is decreased by 40% and the t 12 elim is about 55% longer. Reducing dosages by one half (e.g., to 100 mg/ day) is recommended for marked hepatic or renal insufficiency (CrCl <10 mL/min). Hemodialysis removes only a small amount of riman­ tadine, so supplemental doses are not required.

Interactions

The risks for central nervous system (CNS) adverse effects with amantadine and possibly with rimantadine are increased by concomi­ tant ingestion of antihistamines, antidepressants, anticholinergic drugs, and other drugs affecting CNS function. Concurrent use of trimethoprim-sulfamethoxazole or triamterene-hydrochlorothiazide has been associated with CNS toxicity resulting from decreased renal clearance of amantadine. Cimetidine is associated with 15% to 20% increases, and aspirin or acetaminophen is associated with 10% decreases in plasma rimantadine concentrations, but such changes are unlikely to be significant. Neither adverse clinical nor adverse pharma­ cokinetic effects are observed when amantadine and oseltamivir are co-administered.35 Concurrent administration of recommended doses of amantadine, oseltamivir, and ribavirin for 10 days was well tolerated.34

Toxicity

Amantadine or rimantadine given in treatment courses of 5 days is generally well tolerated in young healthy adults.36 Longer periods of administration, such as 6 weeks for seasonal prophylaxis in young adults,36 and administration to fragile, elderly nursing home residents, such as octogenarians, for 10 days for outbreak control are associated with a significant frequency of adverse reactions and drug withdrawals.37 A case-control study demonstrated that in children younger than 12 months of age, amantadine and rimantadine were well tolerated, as was oseltamivir.38 No evidence of adverse maternal or neonatal out­ comes were observed after antepartum influenza treatment with ada­ mantane antiviral agents.39 The most common side effects related to amantadine ingestion are minor, dose-related gastrointestinal and CNS complaints, including nervousness, lightheadedness, difficulty concentrating, confusion, insomnia, and loss of appetite or nausea.40 Complaints typically develop within the first week of administration, often resolve despite continued ingestion, and are reversible on drug discontinuation. CNS side effects occur in 5% to 33% of amantadine recipients at dosages of 200 mg/day but are significantly less frequent with rimantadine. When used for influenza prophylaxis in ambulatory adults, dosages of 200 mg/day are associated with excess withdrawals in 6% to 11% of recipients because of drug side effects. Dosages of 100 mg/day are better tolerated and may be protective against influenza illness. Amantadine dosage reduc­ tions are required in older adults (100 mg/day), but 20% to 40% of nursing home residents experience significant adverse effects on this lower dosage despite some adjustment for renal insufficiency.41-43 Con­ sequently, further dosage reductions based on CrCl are warranted in this population.44 In the setting of renal insufficiency or high dosages, serious neuro­ toxic reactions, including delirium, hostility, hallucinations, tremor, myoclonus, seizures, or coma; cardiac arrhythmias; and death can occur in association with elevated amantadine plasma concentrations

Chapter 44  Antiviral Drugs for Influenza and Other Respiratory Virus Infections

TABLE 44-2  Clinical Pharmacokinetic Characteristics of Amantadine and Rimantadine in Healthy Adults


Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

534 (1 to 5 µg/mL).45 Neurotoxic reactions may be transiently reversed by physostigmine administration, and lidocaine has been used to treat ventricular arrhythmias. Long-term amantadine ingestion has been associated with livedo reticularis, peripheral edema, orthostatic hypo­ tension, and, rarely, congestive heart failure, vision loss, or urinary retention. Peripheral edema and livedo reticularis may improve if treatment is switched from amantadine to rimantadine.46 Patients with preexisting seizure disorders have an increased frequency of major motor seizures during amantadine use, and dosage reductions are advised. Psychiatric side effects in patients with Parkinson’s disease and psychotic exacerbations in patients with schizophrenia may occur with addition of amantadine. Rash and leukopenia have been described rarely. Rimantadine administration is associated with dose-related side effects similar to side effects observed with amantadine, although the risk for CNS side effects is lower with rimantadine at dosages of 200 mg/day or 300 mg/day in ambulatory adults.5 During prophylaxis, excess withdrawal rates are usually less than 5%. In older nursing home residents, dosages of 200 mg/day are associated with higher side effect rates, whereas dosages of 100 mg/day seem to be better tolerated.41,47 Rimantadine may uncommonly cause exacerbations of seizures in patients not receiving anticonvulsants and was associated with an unexplained excess mortality in one nursing home study.47 The clinical observations of dry mouth, pupillary dilation, toxic psychosis, and urinary retention in acute amantadine overdose suggest that anticholinergic activity is present in humans. Amantadine shows activity on the adrenergic nervous system by affecting accumulation, release, and reuptake of catecholamines in the CNS and in the periph­ eral nervous system. Malignant ventricular arrhythmia after amanta­ dine overdose has been described in humans. Amantadine and rimantadine lack mutagenicity in vitro; carcino­ genicity studies have not been reported for either. Amantadine is tera­ togenic and embryotoxic in rats, and rimantadine may cause teratogenic effects in rabbits and maternal toxicity and embryotoxicity at high dosages in rodents. Both drugs are classified in pregnancy category C. Birth defects have been reported after amantadine exposure during pregnancy.48 The safety of neither amantadine nor rimantadine has been established in pregnancy. Because of excretion in breast milk, use is not recommended in nursing mothers.

Clinical Studies Influenza A

Amantadine and rimantadine have been efficacious for the prevention and treatment of influenza A virus infections in young healthy adults.5,40,49 A systematic review of published studies in children and the elderly concluded that available data only demonstrate that aman­ tadine has prophylactic efficacy and a modest therapeutic effect in children.50 In the elderly, no data were available to support a conclu­ sion of prophylactic or therapeutic efficacy of either adamantane. The emergence of widespread and nearly complete amantadine resistance among influenza A/H3N2 isolates,26 as well as the amantadine resis­ tance of the pandemic A (H1N1)pdm09 strains, precludes the empiri­ cal use of adamantanes for management of an untyped influenza A outbreak. Amantadine and rimantadine, both at a dosage of 200 mg/ day in adults, are about 70% to 90% protective against clinical illness caused by various susceptible influenza A subtypes, including suscep­ tible pandemic strains.51 Prophylaxis is effective in preventing nosoco­ mial influenza and possibly in curtailing nosocomial outbreaks caused by such strains. Protection seems to be additive to that provided by vaccine.52 Rimantadine was less effective than zanamivir in reducing cases of influenza A illness in adults in a long-term care facility.53 The difference in protective efficacy was largely due to the emergence of rimantadineresistant viruses that caused rimantadine prophylactic failure; no zanamivir-resistant viruses were isolated. Rimantadine administration to school-aged children (5 mg/kg/day) decreased the risk for influenza A illness in recipients and possibly in their family contacts. Postexpo­ sure prophylaxis with these drugs provided inconsistent protection to family contacts, however, in part, depending on whether ill index chil­ dren were treated.19 Dosages of 100 mg/day seem to be protective against influenza A illness and are well tolerated in adults.54

Amantadine and rimantadine are also effective therapies for un­ complicated adamantane-susceptible influenza A illness in healthy adults,5,22 but it is uncertain whether treatment reduces the risk for complications in high-risk patients or is useful in patients with estab­ lished pulmonary complications. Early treatment in ambulatory adults (200 mg/day for 5 days) reduces the duration of fever and systemic complaints by 1 to 2 days, decreases virus shedding, and shortens time to resumption of usual activities.22 In illness caused by H3N2-subtype influenza viruses, certain abnormalities of peripheral airways function, but not of airway hyperreactivity, resolve more quickly in amantadinetreated patients. Amantadine or rimantadine treatment in adults with leukemia or stem cell transplantation may reduce the risk for pneumo­ nia,55 but more recent data suggest that in stem cell transplant recipi­ ents, early neuraminidase inhibitor therapy may be preferred to adamantanes, because it may prevent progression to pneumonia and decrease viral shedding, thereby possibly preventing both influenzarelated death in index patients and nosocomial transmission to others.56 In children, rimantadine treatment is associated with lower symptom burden, fever, and viral titers during the first 2 days of treatment com­ pared with acetaminophen administration, but rimantadine-treated children have more prolonged shedding of virus. Treatment generally does not seem to affect humoral immune responses to infection, but may blunt secretory antibody levels.57 Intermittent aerosol administration of amantadine or rimantadine seems to be therapeutically useful in uncomplicated influenza. No injectable formulation of either drug is available in the United States.

Other Viruses

Amantadine has been used in multiple trials for treatment of chronic hepatitis C with inconsistent evidence for increases in sustained viral response (SVR). In treatment-naïve patients, the addition of amanta­ dine (200 mg daily in single or divided doses) to interferon58,59 or to interferon plus ribavirin60 may modestly increase biochemical responses and the likelihood of SVR. In re-treatment of interferon nonresponders, the combination of interferon plus amantadine is inef­ fective61 but the addition of amantadine to the combination of inter­ feron plus ribavirin may be associated with SVR in 10% to 25%.62 Amantadine plus combined pegylated interferon and ribavirin may increase SVR modestly in treatment-experienced patients compared with pegylated interferon plus ribavirin.63 Reports of possible activity in bornavirus infections and associated neuropsychiatric symptoms require confirmation.

DAS181 (FLUDASE)

DAS181 is an investigational antiviral agent with activity against influ­ enza A and B viruses and parainfluenza viruses types 1-3.64-69 It has a novel mechanism of action in that it is a sialidase from Actinomyces viscosus (Fig. 44-2) linked to a respiratory epithelium-anchoring domain.70 It cleaves the terminal sialic acid residues on the surface of human respiratory cells, thus reducing the binding of respiratory viruses, which use those as receptors. Desialylation is rapid and results in an antiviral effect, which lasts for at least 2 days.64 The effective concentration (EC) for 50% of all isolates (EC50) against influenza A and B viruses ranges from 0.04 to 0.9 µM.65 DAS181 is active against influenza viruses that are resistant to neuraminidase inhibitors.71 Lowlevel resistance to DAS181 can be induced, but resistant variants appear to be reduced in fitness.72 DAS181 is administered by oral inhalation and appears to be gener­ ally well tolerated. A phase II placebo-controlled study was recently conducted in 177 subjects with influenza A and B virus infections.73 DAS181 was administered either as a single 10-mg dose or as a daily 10-mg dose for 3 days. Compared with placebo recipients, DAS181 recipients had a statistically significant decrease in virus load deter­ mined by polymerase chain reaction (PCR) assay between days 1 and 3 and days 1 and 5. However, there were no differences in resolution of clinical illness among the groups. Administration of DAS181 appeared to be generally well tolerated, although transient elevations in alkaline phosphatase level were reported.73 DAS181 has also been utilized to treat parainfluenza virus type 3 infections in lung transplant and stem cell transplant patients.74,75 These case reports described clinical improvement, increased pulmonary


535 function, and decreased virus loads. Additional clinical studies of DAS181 are being planned. Laninamivir octanoate (Inavir) is an investigational drug except for its approval in Japan. It is the prodrug of laninamivir, an inhibitor of influenza A and B neuraminidases.76 Laninamivir is (2R,3R,4S)-3acetamido-2-[CIR,2R-2,3-dihydroxy-1-methoxypropyl]-4-quanidino3,4-dihydro-2-H-pyram-6-carboxylic acid (Fig. 44-3D). Laninamivir octanoate consists of an octanoic acid ester side chain attached at the C3 position of laninamivir. Laninamivir octanoate, like polymeric zanamivir conjugates, shares the pharmacokinetic characteristic of persisting for a prolonged period in the respiratory tract after admin­ istration intranasally or intratracheally in animals or by oral inhalation in humans. These observations have presaged therapeutic effects of a single dose in animals with experimentally induced influenza in patients as well.

Laninamivir octanoate exhibits little or no influenza virus neuramini­ dase inhibitory activity in vitro.77 However, its hydrolysis product is a potent inhibitor of neuraminidases of N1 to N9 influenza A viruses plus influenza B and their replication in cell culture at nanomolar concentrations.78 These include seasonal and pandemic influenza A/ H1N1, highly pathogenic avian influenza (HPAI) H5N1 viruses, and clinical isolates of oseltamivir-resistant H1N1, H3N2, H5N1, and A (H1N1)pdm09. Median inhibitory concentrations in cell culture vary over a wide range and in general appear to be intermediate between those of oseltamivir carboxylate (lower) and zanamivir (higher), but the clinical importance of these differences is not yet known. In preclinical studies, laninamivir octanoate reduced fever in ferrets, mortality in mice, and virus concentrations in lung in ferrets and mice and brain in mice after induced influenza with a variety of viruses: A/PR/8/34, HPAI H5N1, A (H1N1)pdm09, B/Malaysia/2506/ 2004, as well as oseltamivir-resistant A H1N1 and HPAI H5N1 clinical isolates possessing the H274Y mutation, as reviewed by Yamashita and associates.78 In these studies, laninamivir octanoate was administered as a single intranasal dose after intranasal inoculation of virus and was either as or more efficacious than multiple doses of oral oseltamivir or intranasal zanamivir. The results of these studies in animals with exper­ imental influenza have been replicated in part in therapeutic trials of a single laninamivir octanoate dose in the clinic (see later). Single doses of laninamivir octanoate are also efficacious prophy­ lactically in mice. One dose prevents mortality and reduces virus con­ centration in lungs and brain when administered as much as 7 days before virus challenge.79

Mechanism of Action

FIGURE 44-2  Molecular model of DAS181. The catalytic domain of the sialidase (AvCD) is shown in green and the protruding anchoring domain (AR) on the carboxyl terminus in blue. (From Malakhov M, Aschenbrenner L, Smee D, et al. Sialidase fusion protein as a novel broad-spectrum inhibitor of influenza virus infection. Antimicrob Agents Chemother. 2006;50:1470.)

See subsequent discussion of mechanism of action under “Oseltamivir.” The basis for the prolonged persistence of laninamivir in the respi­ ratory tract after intranasal or intratracheal administration of lanina­ mivir octanoate in animals or oral inhalation in humans is not completely understood. In human volunteers, bronchoalveolar lavage samples obtained serially over 24 hours after oral inhalation of a single 40-mg dose of laninamivir octanoate reveal concentrations that exceed influenza virus neuraminidase inhibitory concentrations at all test times.80 In mice, intranasal administration of carbon-14 (14C)–labeled laninamivir octanoate demonstrates prolonged retention of laninami­ vir in lung tissues. Microautoradiography indicates that laninamivir octanoate is taken into airway epithelial cells, seemingly hydrolyzed to the antiviral molecule laninamivir by intracellular esterases, and then released slowly extracellularly, perhaps as a result of its hydrophobic

O O

OH H OH

OH HN

NH2 O Oseltamivir

NH

H2N H3C

C

NH

B

O

NHC(NH)NH2 Zanamivir O

O

HN

H3C

OCH3 H

O

OH

H 3C H3C

OH

HO

HN

A

O O

H

O Peramivir

OH

H3C

OH NH O

D

O

HN

CO2H

NH

H2N

Laninamivir

FIGURE 44-3  Chemical structures of oseltamivir carboxylate (A), zanamivir (B), peramivir (C) and laninamivir (D).

Chapter 44  Antiviral Drugs for Influenza and Other Respiratory Virus Infections

LANINAMIVIR OCTANOATE

Spectrum


536

Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

poor membrane permeability.81 The cellular and molecular processes underlying these observations are not yet determined.

Resistance

No extensive studies have been reported on the emergence of laninamivir-resistant strains after laninamivir exposure in vitro or laninamivir octanoate treatment in animals or patients. However, in one study in mice infected with an A H1N1 virus, no viruses with reduced susceptibility to laninamivir were recovered.82

Pharmacokinetics

Epithelial lining fluid concentrations of laninamivir octanoate and laninamivir calculated from analysis of bronchoalveolar lavage wash­ ings after a single oral inhalation of 40 mg laninamivir octanoate were 102.4 and 8.6 µg/mL, respectively, at 4 hours in healthy adult volun­ teers.76 The disappearance half-times in bronchoalveolar lavage fluid were 41 and 141 to 241 hours, respectively. The plasma t 12 elim values were 2.6 and 45.7 hours, respectively. Laninamivir concentrations in epithelial lining fluid exceeded the median inhibitory concentrations for influenza neuraminidases at all time points for 240 hours after dose inhalation. In other healthy adult volunteers, evaluation of the phar­ macokinetics of laninamivir octanoate and laninamivir was done after oral inhalation of single doses from 5 to 120 mg.83 Laninamivir octano­ ate appeared rapidly in plasma with a Cmax at 0.5 to 1.0 hour compared with 4.0 hours for laninamivir. Plasma t 12 elim values were 1.8 and 71.6 to 80.8 hours, respectively. The plasma area under the concentrationtime curve (AUC) of laninamivir octanoate was linearly related to dose, while that of laninamivir increased disproproportionately. The mean cumulative excretion in urine over 144 hours was 2.3% to 3.6% and 10.7% to 14.6%, respectively. After intravenous administration of 14C-laninamivir in rats, almost 90% of the radioactivity was recovered in urine.84 In human volunteers, the clearance of both laninamivir octanoate and laninamivir is linearly related to CrCl.85 In subjects with none, mild, moderate, or severe renal impairment given a single orally inhaled dose of 20 mg laninamivir octanoate, the renal clearance of laninamivir octanoate and laninami­ vir is directly related to CrCl, whereas t 12 elim values are not. Geometric mean laninamivir octanoate clearance values declined from 26.0 mL/ min in normal control subjects to 6.5 mL/min in patients with severe renal impairment. However, t 12 elim values were 2.3 to 3.5 hours and not different among the four groups. Laninamivir renal clearance declined from 65.0 to 12.7 mL/min across the four groups, whereas t 12 elim was not different among the groups, ranging from 53.2 to 57.0 hours. The likely explanation is that the elimination of both laninamivir octanoate and laninamivir reflect slow release of these compounds from tissues into plasma, rather than renal elimination, a pharmacokinetic concept called “flip-flop.”86 These pharmacokinetic data indicate that reduction of laninamivir octanoate doses may be appropriate for patients with renal impairment for pharmacokinetic reasons, but the lack of clear dose-related toxicity (see later) and the minimal absorption of orally inhaled drugs suggest that no dose adjustment will be needed.

Toxicity

Like orally inhaled zanamivir, orally inhaled laninamivir octanoate powder is well tolerated. In a double-blind study in healthy adult vol­ unteers, single doses from 5 to 120 mg or multiple doses of 20 or 40 mg twice daily for 5 days were as well tolerated as placebo.85 In clinical trials, patients with influenza were randomized to single laninamivir octanoate doses of 20 or 40 mg in adults or children 10 years old or older, 20 mg in children younger than 10 years old, or inhaled zanamivir as the control neuraminidase inhibitor treat­ ments. Laninamivir octanoate inhaled once was as well tolerated as inhaled zanamivir 20 mg twice daily for 5 days.87 In a double-blind trial in children 9 years of age or younger with influenza, a single dose of inhaled laninamivir octanoate of 20 or 40 mg was as well toler­ ated as oseltamivir at 2 mg/kg body weight twice daily for 5 days.88 In a phase III double-blind trial in adults 20 years of age or older with influenza, a single dose of inhaled laninamivir octanoate of 20 or 40 mg was as well tolerated as oral oseltamivir at 75 mg twice daily for 5 days.89 Notwithstanding the lack of data from large, randomized, placebo-controlled, double-blind trials to establish the tolerability of

laninamivir octanoate across the range of persons in healthy and highrisk groups, these published data on laninamivir octanoate tolerance plus those from studies of orally inhaled zanamivir collectively suggest that orally inhaled laninamivir octanoate will likely prove to be well tolerated and safe in the clinic. Postmarketing studies of laninamivir octanoate in Japan concluded that the safety profile of laninamivir octanoate for abnormal behavior/ delirium and syncope is similar to that of other neuraminidase inhibi­ tors.90 In Japan, it is recommended in the product labeling that teenage patients inhaling laninamivir octanoate should remain under constant parental supervision for at least 2 days to monitor for behavioral changes to prevent associated self-injury. To avoid syncope, patients should inhale laninamivir octanoate in a relaxed sitting position. In another postmarketing survey for laninamivir octanoate tolerance, 50 patients of 3542 (1.4%) reported an adverse event.91 Commonly reported adverse events included psychiatric disorders (abnormal behavior), gastrointestinal symptoms, and nervous system disorders such as dizziness, with frequencies of 0.48%, 0.45%, and 0.17%, respec­ tively. These usually appeared on the day of laninamivir octanoate treatment and resolved in 3 days. These adverse reactions and their frequency were considered comparable to those previously observed during clinical trials, and thus were believed to confirm no noticeable problem with safety.

Clinical Studies

Limited data from controlled trials are available on the efficacy of orally inhaled laninamivir octanoate for influenza treatment, although three randomized, controlled trials on the efficacy and tolerance of lanina­ mivir octanoate and one observational study comparing it with other neuraminidase inhibitors have been reported. In these trials, lanina­ mivir octanoate has been administered as an orally inhaled powder with a proprietary device that has two containers of 10-mg dry lanina­ mivir octanoate powder. The manufacturer’s instructions recommend two inhalations from each 10-mg changer. For children, four inhala­ tions are necessary, whereas eight inhalations from two devices are required for adults. Occasionally, young children do not inhale the medication completely owing to technical difficulty with the device.87 Of 87 pediatric patients with influenza of less than 48 hours in duration, 44 were randomized to treatment with a single inhaled dose of laninamivir octanoate (N = 55), 20 or 40 mg, according to age, or inhaled zanamivir, 10 mg twice daily for 5 days (N = 41).87 Median times to fever resolution were 36 hours in the laninamivir octanoate groups and 37 hours in the zanamivir-treated group. This relatively small study suggested that a single dose of inhaled laninamivir octano­ ate was as efficacious as the recommended 5-day treatment with zana­ mivir. In another study, 180 children 9 years or younger with influenza of less than 36 hours in duration were randomized to a single oral inhalation of 40 (N = 61) or 20 mg (N = 61) laninamivir octanoate or oseltamivir 2 mg/kg (N = 62) ingested twice daily for 5 days.88 Of the 180 children, 62% (112) were infected with influenza A H1N1 virus, of which all but 4 possessed the H274Y mutation, mediating oseltami­ vir resistance. Oseltamivir therapy was likely not to have been different from placebo. The median times to alleviation of influenza illness in children were significantly less (49.6 and 44.3 hours) in the 40- and 20-mg laninamivir groups, respectively, than in the oseltamivir-treated group (110.5 hours). Treatment effects on virus concentration and persistence in upper airway secretions were inconsistent, although on day 3, 10%, none, and 25% of subjects in the three groups, respectively, were still excreting virus. There were no clinical therapeutic or viro­ logic differences among children infected with influenza A H3N2 or B viruses, but the numbers of cases were small. In a double-blind, randomized noninferiority trial, 1003 young healthy adults with febrile influenza for no more than 36 hours were randomized to receive either 40 mg or 20 mg of laninamivir octanoate by oral inhalation once or oseltamivir, 75 mg twice daily orally, for 5 days.89 The primary end point was time to influenza illness alleviation. Unfortunately, as in the pediatric study of Sugaya and Ohashi,88 66% of the subjects were infected with oseltamivir-resistant influenza A H1N1 virus. The median times to resolution of illness in patients infected with this virus were 74.0, 85.8, and 77.8 hours, respectively, which were not different. Virus was detected by culture significantly


537

OSELTAMIVIR Spectrum

Oseltamivir phosphate (Tamiflu) is the ethyl ester prodrug of oselta­ mivir carboxylate, a sialic acid analogue (see Fig. 44-3A) that is a potent, specific inhibitor of the neuraminidases of influenza A and B viruses.93,94 The metabolite, oseltamivir carboxylate, is approximately 50-fold more potent than the phosphate prodrug.95 Oseltamivir car­ boxylate competitively and reversibly interacts with the active enzyme site to inhibit neuraminidase activity at low nanomolar concentra­ tions.96 Inhibitory concentrations for neuraminidase inhibitors in cell culture have a broad range (≥1000-fold), depending on the assay method, and may not correlate with in vivo activity.97,98 Oseltamivir carboxylate is active against viruses containing all nine influenza A neuraminidase subtypes recognized in nature, including more recent pathogenic avian viruses (H5N1, H7N7, H9N2), reassortant virus con­ taining neuraminidase from the 1918 pandemic strain, M2 inhibitor– resistant strains,4,99 and the recently circulating (2009) pandemic A/ H1N1 viruses (S-OIV).27 Resistance to oseltamivir has been recently reported in an H7N9 isolate.100 Influenza B viruses are 10-fold to 20-fold less susceptible to oselta­ mivir carboxylate than influenza A viruses, and influenza B virus illness responds less well clinically and virologically to oseltamivir than influenza A illness.101,102,103 The carboxylate is not cytotoxic and inhibits neuraminidases from mammalian sources or other pathogens only at 106-fold higher concentrations. Oral oseltamivir is active in murine and ferret models of influenza.94,97 A prophylactic regimen given orally twice daily for 10 days completely protected ferrets against morbidity and mortality caused by H5N1 infection and did not interfere with development of a protective immunity against subsequent H5N1 infec­ tion.104 Neuraminidase inhibitors combined with M2 inhibitors or ribavirin show enhanced antiviral activity in vitro and in animal models of influenza A virus infection,105 including H5N1 virus.106,107 Amantadine combined with oseltamivir prevented the emergence of amantadine resistance in cell culture.108

Mechanism of Action

The neuraminidase inhibitor drugs oseltamivir, zanamivir, peramivir, and laninamivir share a common mechanism of action. Influenza

neuraminidase cleaves terminal sialic acid residues on glycoconjugates and destroys the receptors recognized by viral hemagglutinin on cells, on newly released virions, and on respiratory tract mucins. This action is essential for release of virus from infected cells and for spread within the respiratory tract.109 Inhibition of neuraminidase action causes newly formed virions to adhere to the cell surface and to form viral aggregates. Inhibitors limit spread of virus within the respiratory tract and may prevent virus penetration of respiratory secretions to initiate replication.

Resistance

Resistant variants selected by in vitro passage with oseltamivir carbox­ ylate or zanamivir have point mutations in the viral hemagglutinin or neuraminidase genes.98,110 Hemagglutinin variants generally have mutations in or near the receptor binding site that make them less dependent on neuraminidase action for release from cells in vitro and that confer cross-resistance among neuraminidase inhibitors. Most of these variants retain full susceptibility in vivo.98 Neuraminidase vari­ ants contain single amino-acid substitutions in the framework or cata­ lytic residues of the active enzyme site that alter drug binding and cause approximately 30-fold to more than 1000-fold reduced suscepti­ bility in enzyme inhibition assays.96 Influenza A variants selected by oseltamivir carboxylate are subtype specific, most commonly Arg292Lys in N2 and H275Y in N1, without cross-resistance to zana­ mivir. The altered neuraminidases have reduced activity or stability in vitro, and early studies of these variants usually demonstrated decreased infectivity and transmissibility in animals.111 Oseltamivir therapy has been associated with recovery of viruses with reduced susceptibility in about 1% of immunocompetent adult and 18% of pediatric recipients.112,113 Generally, emergence of resistant variants has not been associated with clinical worsening, although prolonged recovery of resistant variants, sometimes in combination with M2 inhibitor resistance, has been observed in highly immuno­ compromised hosts.114 Transmission of oseltamivir-resistant virus has been documented.115,116 Although isolation of oseltamivir-resistant strains from treated immunocompetent patients was uncommon, in 2007-2008, oseltamivirresistant seasonal H1N1 virus appeared widely in immunocompetent individuals in Norway in the absence of antiviral pressure.117 This mutant virus became the transmissible, pathogenic prevalent global H1N1 virus strain. Similarly, during the 2009 A (H1N1)pdm09 pan­ demic, there was no linkage between prevalent use of oseltamivir in immunocompetent patients and the appearance of oseltamivir-resistant A (H1N1)pdm09 strains, which was uncommon. The prevalence of oseltamivir-resistance ranged from 0.6% (5/804 strains) tested in Ontario, Canada,118 to 1.0% in the United States119 and 1.1% (16/1488 isolates) in Southeast Asia.120 The prevalence was 8.11% in children whose immunocompetence was not specified.121 On the other hand, oseltamivir-resistant isolates are not uncom­ monly recovered from immunocompromised patients being treated with the drug. Reports indicated that some of the A (H1N1)pdm09 oseltamivir-resistant strains retained replicative fitness,116 transmissi­ bility,122 and pathogenicity comparable with wild-type oseltamivir strains in murine and ferret models of influenza infection.123 Clinical illness caused by oseltamivir-resistant H1N1 strains in immunocom­ petent children responded less well to oseltamivir,124 as evidenced by higher fever at day 4 or 5 of treatment, although some found no evi­ dence of prolonged illness in children infected with drug-resistant virus.125 Others reported a significantly longer time to achieve nonde­ tectable virus load in patients with oseltamivir-resistant H1N1 com­ pared with oseltamivir-sensitive strains.126

Pharmacokinetics

Oral oseltamivir is rapidly absorbed and metabolized by esterases in the gastrointestinal tract, liver, and blood to the active carboxylate. The estimated bioavailability of the carboxylate is approximately 80%,127 and its time to maximal plasma concentrations averages 2 to 4 hours. Dose proportionality of oseltamivir has been reported over the dose range from 75 to 675 mg. Only low blood levels of the pro­ drug are detectable. Rarely, possession of a constitutive variant of car­ boxylesterase 1, the enzyme that normally catalyzes the conversion of

Chapter 44  Antiviral Drugs for Influenza and Other Respiratory Virus Infections

less often at day 3 in the laninamivir octanoate 40-mg (28%) and 20-mg (32%) groups than in the oseltamivir group, which might be con­ sidered analogous to a placebo-treated cohort. Among individuals infected with influenza A H3N2 virus, median times to illness allevia­ tion were not different between those treated with laninamivir octano­ ate 40 mg (73.5 hours) and oseltamivir (67.5 hours) but significantly longer in the group treated with laninamivir octanoate 20 mg (91.2 hours). There were no differences among the groups in H3N2 virus concentration in upper airway secretions or persistence. The 95% con­ fidence intervals of the pooled analysis of all data were less than the prescribed noninferiority margin. It was concluded that a single inha­ lation of laninamivir octanoate is effective for treatment of seasonal influenza including that caused by oseltamivir-resistant virus in adults. In an observational study, 211 children with febrile influenza of less than 48 hours due to influenza A H3N2 infection and 45 with A (H1N1)pdm09 infection were treated according to the recommenda­ tions of clinicians and the preference of patients or their guardians.92 Of the 256 children, 119 were treated with oseltamivir in weightappropriate doses, zanamivir (124 cases), one dose of intravenous pera­ mivir (4 children),79 or a single dose of orally inhaled laninamivir octanoate of 40 mg for children 10 years or older or 20 mg for those younger than 10 years (9 children). The primary end point was dura­ tion of fever from the first dose of neuraminidase inhibitor. There were no differences in the duration of fever among the oseltamivir, zanami­ vir, or laninamivir octanoate groups. The median time to resolution of fever in the peramivir group (17.0 hours) was significantly less than in the other three groups. Available data suggest that a single inhaled dose of laninamivir octanoate is efficacious in children with influenza of less than 48 hours, but efficacy in other populations, especially those with high-risk condi­ tions, remains to be evaluated, as does the impact on complications of influenza.


Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

538 oseltamivir phosphate to carboxylate, can markedly impair the hydro­ lysis of the parent compound, resulting in the potential for a compro­ mised antiviral effect after oseltamivir administration.128,129 Ingestion with food delays absorption slightly but does not decrease overall bioavailability. Oseltamivir administered via a nasogastric tube to patients with respiratory failure requiring mechanical ventilation was well absorbed and converted to oseltamivir carboxylate.130,131 In healthy adults, peak and trough plasma concentrations average 0.35 µg/mL and 0.14 µg/mL after 75-mg doses.132 In infants up to 1 year of age, systemic exposure (AUC0-12 hr) to the carboxylate exhibits decreasing variability while clearance increases.121 Recommended doses of oselta­ mivir are 3.0 mg/kg twice daily for infants from birth to 8 months of age and 3.5 mg/kg twice daily for those 9 to 11 months of age. In children older than 1 year, carboxylate exposure increases gradually with increasing age132 so that weight-based dosing is recommended.133 In healthy elderly adults, overall drug exposure is about 25% greater than in younger adults, most likely owing to differences in renal elimi­ nation. Morbid obesity (body mass index ≥40 kg/m2) does not alter oseltamivir pharmacokinetics.134 The effects of pregnancy on the phar­ macokinetics of oseltamivir are unclear. One study reported no differ­ ences among women in the third trimester of pregnancy and historical controls,135 whereas another reported a 25% to 30% reduction in systemic (AUC0-12 hr) oseltamivir-carboxylate exposure in pregnant women compared with concurrent nonpregnant controls, perhaps suggesting a need for 75 mg three times a day of oseltamivir for treatment.136 Plasma protein binding of the prodrug (42%) and the carboxylate (<3%) is low.127 The Vd is moderate (23 to 26 L). In animals, lower respiratory tract levels are similar to or exceed the levels in blood137; and in humans, the carboxylate is detectable in middle ear and maxil­ lary sinus fluid at concentrations similar to those in plasma.138 Oseltamivir concentrations occur in breast milk.139 In the ex vivo human placenta model, oseltamivir was extensively metabolized to the carboxylate moiety, but transplacental passage of oseltamivir carboxyl­ ate occurred at a low rate, inferring that fetal exposure during maternal treatment with oseltamivir may be minimal.140 No carboxylate was detected in cerebrospinal fluid in one child,141 whereas Cmax values in cerebrospinal fluid were 2.1% and 3.5% for corresponding plasma con­ centrations for oseltamivir and oseltamivir carboxylate in eight healthy adults after ingestion of 150 mg of oseltamivir.142 After oral oseltamivir, the plasma t 12 elim of the carboxylate averages 6 to 10 hours in healthy adults. The prodrug and carboxylate are excreted primarily unchanged through the kidney; the carboxylate is eliminated by glomerular filtra­ tion and tubular secretion via a probenecid-sensitive anionic trans­ porter. Clearance varies linearly with CrCl, such that t 12 elim increases to 22 hours in patients with CrCl less than 30 mL/min, and dosage reductions are needed.127 Oseltamivir carboxylate is removed with dif­ ferent degrees of efficiency by different renal replacement therapies (peritoneal, hemodialysis, and continuous renal replacement thera­ pies). Doses of oseltamivir for patients with renal impairment receiving renal replacement therapy have been published.143 Uncomplicated influenza illness does not seem to alter the pharma­ cokinetics of oseltamivir.127 Cystic fibrosis patients appear to clear osel­ tamivir carboxylate more rapidly than patients who do not have the disease.144

Interactions

Probenecid reduces renal clearance of oseltamivir by about 50%.145 Few other clinically important drug interactions have been recognized. Sotalol appeared to induce a torsades de pointes cardiac arrhythmia during oseltamivir therapy for influenza.146 Specific studies have found no interactions with antacids, acetaminophen, or aspirin or known inhibitors of selected renal tubular secretion pathways, amoxicillin, cimetidine, cyclosporine, mycophenolate, tacrolimus,127,147 warfarin,148 or rimantadine.149

Toxicity

Preclinical studies have found no evidence of mutagenic, teratogenic, or oncogenic effects. High-dose oseltamivir causes renal tubular min­ eralization in mice and maternal toxicity in rabbits. It is classified as pregnancy category C.

Oseltamivir is generally well tolerated in patients of all ages, includ­ ing pregnant women and fetuses,150,151 and no serious end-organ toxic­ ity has been recognized.97,152-154 Oral administration is associated with nausea, epigastric distress, or emesis in 10% to 15% of adults receiving 75 to 150 mg twice daily. These gastrointestinal complaints are usually mild to moderate in intensity, resolve despite continued dosing, and are ameliorated by administration with food. Nausea and vomiting (and possibly, dizziness) are dose related in adults.155 Discontinuation rates of 1% to 2% were observed in controlled treatment studies. The mechanism of nausea and vomiting is uncertain, but the risk seems to be lower in older adults. Long-term prophylaxis has not been associ­ ated with an increased risk for adverse events,97,156 although headache may occur in older recipients. Self-injury, delirium, and psychiatric illness have been reported in patients, primarily pediatric or adoles­ cent, with influenza treated with oseltamivir, mostly in Japan.157 Analy­ ses of neuropsychiatric reactions among patients with influenza treated with oseltamivir in three large U.S. administrative databases did not demonstrate such an association.158-160 The decline in cases in Japan after a regulatory recommendation to restrict oseltamivir use in chil­ dren 10 to 19 years of age has been associated with a decline in oseltamivir-related cases but a corresponding rise in cases associated with zanamivir, the inhaled, minimally systemically bioavailable neur­ aminidase inhibitor. The latter fact raises further doubts about a causal association between oseltamivir therapy and neuropsychiatric and behavioral adverse reactions in patients with influenza.161 Erythema­ tous rashes and rare instances of severe eruptions or Stevens-Johnson syndrome, hepatic inflammation, hemorrhagic colitis, anaphylaxis, and thrombocytopenia have been reported, but their relationship to oseltamivir is uncertain.

Clinical Studies

Oseltamivir is efficacious for the prevention and treatment of influenza A and B virus infection. In the United States, it is approved for the prevention of influenza in patients 1 year and older and the treatment of acute uncomplicated influenza in patients 2 weeks of age and older who have been symptomatic for no more than 2 days.133 In early clinical experiments in volunteers with induced influenza it was demonstrated that oral oseltamivir is highly protective against experimental human influenza, and early treatment is associated with reductions in viral titers, symptoms, nasal cytokines, and middle ear pressure abnormalities.97 Subsequent controlled trials in patients— mostly healthy adults and children with naturally acquired seasonal influenza A infection—demonstrated that early oseltamivir treatment of acute influenza reduces the time to illness alleviation by 1 to 1 1 2 days, fever duration, and viral titers in the upper respiratory tract.112,162-164 Earlier treatment maximizes the speed of resolution of illness.165 Treat­ ment of children reduces the risk for otitis media and decreases overall antibiotic use.112 In healthy and high-risk adults, early treatment has been reported to decrease the risk for lower respiratory tract complica­ tions leading to antibiotic administration and to hospitalization,166 but this has been questioned.167 A meta-analysis of observational studies of high-risk patients with seasonal influenza concluded that oseltamivir treatment may reduce hospitalization, whereas treatment of hospital­ ized patients reduces respiratory failure, intensive care unit admission, and mortality.168,169 A recent meta-analysis based on a large number of observational data from individual cases suggested that oseltamivir treatment may be associated with a reduction in mortality risk.169a However, a Cochrane analysis did not conclude that the evidence indi­ cated that oseltamivir treatment reduced complications or hospitaliza­ tions.169b In hospitalized patients with infection with influenza A (H1N1)pdm09, oseltamivir provides similar benefits even if treatment is started more than 48 hours after clinical illness has begun.170-172 It is uncertain to what extent oseltamivir treatment may reduce transmission, although a review of four trials of prophylaxis suggests that oseltamivir may have reduced transmission.173,174 Oseltamivir is less efficacious for the treatment of influenza B than for influenza A virus infection in children175,176 and adults.176 An analy­ sis of 284 cumulated cases of influenza A (H5N1) infections in a global registry demonstrated that crude mortality was significantly less in those treated with oseltamivir (40%) than in those not treated (76%) when started up to 6 to 8 days after symptoms onset.177


539

PERAMIVIR Spectrum

Peramivir ([1S,2S,3S,4R]-3-[(1S)-1-(acetylamino)-2-ethylbutyl]-4[(aminoiminomethyl)amino]-2-hydroxy-cyclopentanecarboxylic acid; Rapiacta) (see Fig. 44-3C) is an investigational agent in the United States but is approved in Japan, China, and South Korea. It is a potent, selective inhibitor of influenza A and B virus neuraminidases, includ­ ing that of all nine avian NA subtypes185 and influenza A (H1N1) pdm09.186 It is a sialic acid analogue designed to be structurally distinct from oseltamivir and zanamivir such that cross-resistance to it among oseltamivir-resistant and zanamivir-resistant strains is not consistently observed.187,188 Like oseltamivir and zanamivir, peramivir inhibits influenza neuraminidase in enzyme assays at nanomolar concentra­ tions189 and requires micromolar concentrations to inhibit influenza replication in cell culture.190 It is a more potent inhibitor of influenza A than B viruses in vitro than is oseltamivir or zanamivir.190 The clini­ cal relevance of this difference has not yet been evaluated. Combina­ tion treatment of influenza A virus infection in cell culture and in mice with peramivir and ribavirin yields additive or synergistic interactions with no increase in toxicity.191 The antiviral effect of combinations of peramivir plus rimantadine in vitro is variable, ranging from additive to synergistic.192 In mice with experimental influenza infections, the combination of peramivir and rimantadine is synergistic.193 In murine and ferret models of influenza infection, peramivir is effective when administered intranasally,194 orally,195 and intramuscularly.196

Mechanism of Action

See previous discussion of mechanism of action under “Oseltamivir.”

Resistance

Peramivir-resistant influenza virus has been selected in vitro,187,188,197,198 but not from peramivir-treated mice with experimental influenza infection,199 healthy volunteers given peramivir for prevention or treat­ ment of experimentally induced influenza A or B infection, or healthy treated patients.200 A peramivir-resistant virus possessing the H275Y mutation emerged during intravenous therapy for pandemic 2009 influenza A/H1N1 in an immunocompromised patient.201 Peramivirresistant mutants generated in vitro may possess unaltered or dimin­ ished virulence and replicative capacity in mice and ferrets.202 Peramivir resistance associated solely with an alteration in the hemagglutinin gene conferred cross-resistance to oseltamivir and zanamivir and could cause lethal disease in mice. Infection with the resistant virus in mice was still amenable to peramivir therapy, however.198 Naturally occurring oseltamivir-resistant influenza viruses possess­ ing the H275Y mutation have a 100-186 to 661-fold202 reduced suscep­ tibility to peramivir, less than that of oseltamivir (982-fold). Studies suggest that infection due to viruses possessing the H275Y mutation may be successfully treated with higher dose regimens of injected peramivir in mice203 and high-risk patients.204 However, intravenous peramivir was not more effective than oseltamivir in a case report201 and in an observational study of influenza caused by H275Y mutant strains.204 In 2009, the World Health Organization recommended that for treatment of infection due to influenza A (H1N1)pdm-09 strains

possessing the H275Y mutation, intravenous peramivir is likely to be suboptimal and intravenous zanamivir is preferred.205

Pharmacokinetics

The absolute oral bioavailability of peramivir is 2%.206 As a result, clini­ cal development has focused on its efficacy and safety after intramus­ cular and intravenous injection. Fortunately, its long elimination half-life supports single-dose intravenous treatment regimens. At doses up to 2 mg/kg in adults, plasma t 12 and AUC0-α increase in pro­ portion to dose. At higher doses of greater than 2 mg/kg being used in clinical trials in adults, the plasma t 12 in healthy adults is approxi­ mately 20 hours, which supports single-dose treatment; apparent Vd is approximately 2 L/kg, and systemic clearance is 85 mL/hr/kg. The cor­ responding values for children with mean age of 9 years are 7.7 hours, 0.3 L/kg, and 173 mL/hr/kg.207 The physiologic counterpart of this large Vd is unknown, because no locus of drug sequestration has been identified. Plasma protein binding is less than 30%. Peramivir concen­ trations in plasma are 10-fold to 50-fold higher than concurrent levels in nasal wash or pharyngeal gargle solutions.206 Peramivir is detectable at these sites 24 hours after dosing, at concentrations greater than levels that inhibit neuraminidases of most strains of influenza virus. The clinical relevance of these data is unknown. A 300-mg dose injected intravenously once in young healthy adults with influenza illness of less than 48 hours’ duration is efficacious and well tolerated.208 Infusion of this dose over a median of 38 minutes produced median plasma concentrations of 18,100 ng/mL at the end of the infusion and 14.8 ng/mL 18 to 24 hours later. The 600-mg dose yielded corresponding values of 36,300 and 32.8 ng/mL. The median inhibitory concentration for 50% of isolates (IC50) for the neuramini­ dase of the patient viruses ranged from 1.15 nmol/L for influenza A/ H1N1, 1.36 nmol/L for influenza A/H3N2, and 2.81 nmol/L for influ­ enza B isolates.204 In pediatric patients 1 month to 15 years of age infected with influenza A (H1N1)pdm09, an intravenous infusion of 10 mg/kg once daily produced comparable plasma concentrations to those seen in young healthy adults (see earlier): median peramivir plasma concentrations were 33,150 ng/mL at the end of the infusion and 20.7 ng/mL 18 to 24 hours later.207 The relationship of these plasma concentration data to efficacy is unclear. In mice, plasma AUC of pera­ mivir is the pharmacokinetic characteristic related to efficacy.209 Data on peramivir distribution into breast milk in humans are unavailable.206 Less than 5% of 14C-labeled peramivir administered to rats is recovered in breast milk. Peramivir is eliminated unchanged into urine by glomerular filtration, and probenecid does not affect its excre­ tion. In patients with renal insufficiency, mean t 12 ranges from 24 to 30 hours in subjects with mean CrCl of 21 to 68 mL/min. In individu­ als with dialysis-dependent renal failure, t 12 averages 79 hours. In October 2009, the U.S. Food and Drug Administration issued an Emergency Use Authorization (EUA) for the administration of intra­ venous peramivir for the treatment of hospitalized patients with sus­ pected or confirmed cases of influenza A (H1N1)pdm09 infection, because no other intravenous neuraminidase inhibitor drug was avail­ able. In adults with normal renal function, the recommended intrave­ nous dose was 600 mg/day; and in children 6 to 17 years of age it was 10 mg/kg intravenously once daily. Doses for other age groups and patients with renal impairment including end-stage renal disease requiring different renal-replacement therapies have been suggested.210 The EUA was terminated in 2010, and peramivir was to be available only through clinical trials (see “Clinical Studies,” later).

Interactions

Adverse drug-drug interactions have not been reported in subjects given peramivir, but the number of individuals exposed is still modest. No pharmacokinetic interaction of intravenous peramivir and oral oseltamivir or rimantadine was observed in healthy volunteers.211 Drug-drug interactions in individuals receiving peramivir are unlikely because it neither induces nor inhibits important drug-metabolizing cytochrome P-450 enzymes.

Toxicity

Peramivir is generally nontoxic and well tolerated. Preclinical studies revealed no genotoxicity, reproductive toxicity, or developmental

Chapter 44  Antiviral Drugs for Influenza and Other Respiratory Virus Infections

Oseltamivir treatment of hematopoietic stem cell transplant recipi­ ents with influenza may prevent the development of pneumonia and virus shedding, thereby both preventing influenza-related death in index patients and nosocomial transmission to others.178 Of 21 patients with leukemia who developed influenza and were treated with oselta­ mivir, none died, compared with 3 of 8 who were not treated.179 Prophylactic administration of once-daily oral oseltamivir (75 mg) is highly effective in reducing the risk for developing febrile illness during influenza season in unimmunized adults (efficacy 84%),180 immunized nursing home residents (efficacy 92%),181 and transplant recipients (efficacy 80%).156 Prevention of influenza may reduce sec­ ondary complications in institutionalized older adults.181 Once-daily oseltamivir for 7 to 10 days is also effective for postexposure prophy­ laxis in household contacts, including children, and when ill index cases receive concurrent treatment.182,183 Oseltamivir chemoprophy­ laxis has been used to control institutional outbreaks of influenza A continuing despite M2 inhibitor use and of influenza B.184


Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

540 toxicity.206 In multiple species of animals, the only apparent adverse effect is reversible nephrotoxicity, which is species (rabbit only) and gender (female) specific. The nephrotoxic dose is greater than 200 mg/ kg/day intravenously for 9 days. The largest doses administered to humans, 800 mg orally200 and 600 mg intravenously,208 have not been associated with consistent adverse symptoms or laboratory abnormalities compared with placebo.208 In placebo-controlled clinical trials of peramivir orally up to 800 mg/day for 4 to 5 days,200 300 mg/day intramuscularly once,212 and 600 mg intravenously once,208 adverse symptoms were not reported more frequently in peramivir recipients than in placebo recipients. In controlled, blinded trials as well as uncontrolled studies of intra­ venous peramivir, it has been generally well tolerated and safe. In a randomized, double-blind study comparing a single dose of peramivir of 300 or 600 mg and a matching placebo given intravenously to 300 young healthy adults in an outpatient setting,208 nausea may have been reported more frequently in drug recipients (3.0%, 6.1%, and 1.0%, respectively, in the three groups). Extensive blood and urine laboratory tests revealed no differences among groups. In a randomized, doubleblind, double-dummy trial in young healthy adults with influenza treated with peramivir, 300 mg and 600 mg intravenously once, or oseltamivir, 75 mg orally twice daily for 5 days, the overall incidence of adverse effects was lowest in the 300-mg group: 14.0% compared with 18.1% and 20.0% in the other groups, respectively. Diarrhea (3.8%, 5.5%, and 5.2%), nausea (0.5%, 1.9%, and 4.4%), and a decreased neutrophil count (2.5%, 3.8%, and 3.6%) all tended to be lowest in the 300-mg peramivir group.213 In a randomized, unblinded study in hos­ pitalized patients treated for influenza with intravenous peramivir at 200 or 400 mg once daily, or oseltamivir at 75 mg orally twice daily, all for 5 days, the “incidence of adverse events was low and generally similar among treatment groups.”214 Assessment of side effects of intravenous peramivir in uncontrolled studies in hospitalized adults with high-risk comorbid conditions204 also suggested that the drug was generally well tolerated. A single case of dilated cardiomyopathy or myocarditis in a volunteer infected with an influenza B challenge virus and treated with peramivir has been reported.200 The relationship of the cardiac disorder to the drug is unknown.

Clinical Studies

In a study in serosusceptible volunteers, peramivir prophylaxis with 50 to 800 mg orally daily or placebo, initiated 24 hours before influenza A or B virus challenge and continued for 5 days, tended to prevent illness at doses of 200 mg or greater and to reduce viral shedding and titer in nasal washings in subjects inoculated with influenza A virus. No effect on preventing illness caused by influenza B virus was observed, although the duration of virus shedding tended to be less in individuals receiving 400 mg and 800 mg of peramivir.200 In early studies in patients with influenza, oral peramivir therapy with doses of 400 to 800 mg daily for 5 days200 and single intramuscular doses of 150 or 300 mg206 reduced median times to relief of symptoms, but the differences were not statistically significant from controls. Sub­ sequently, controlled trials with an intravenous formulation demon­ strated peramivir therapeutic efficacy and tolerance in patients with influenza due to susceptible virus strains. Peramivir treatment of natu­ rally acquired influenza in young adults with illness of 48 hours’ dura­ tion or less with 300 or 600 mg injected once intravenously versus placebo, reduced median time to relief of symptoms significantly from 82 hours in the placebo group to 59 hours and 60 hours in the pera­ mivir 300-mg and 600-mg groups in the outpatient setting.208 Perami­ vir treatments also significantly reduced the proportion of subjects still excreting virus in nasal and throat secretions at day 3 from 51% in placebo recipients to 26% to 37% in those treated with peramivir, 600 or 300 mg, respectively.208 In 137 hospitalized patients randomized to 5 days’ treatment with intravenous peramivir, 200 or 400 g/day, compared with historical reports with oral oseltamivir at 75 mg twice daily, the reduction in virus concentration in nasopharyngeal secretion was similar across the three treatments.211 An additional study utilizing a higher dose of pera­ mivir (300 mg twice daily or 600 mg four times a day) in 234 hospital­ ized patients also showed no differences in virologic or clinical end

O

O N

H 2N N HO

CH2

N

O

H2N HO

OH OH

A

Ribavirin

N

HN N CH2

N O

OH OH

B

Guanosine

FIGURE 44-4  Chemical structure of ribavirin (A) and the nucleoside guanosine (B).

points among the peramivir-treated regimens or compared with reported patients treated with oseltamivir.215 A randomized controlled study of intravenously administered peramivir plus standard of care versus standard of care alone in patients hospitalized with influenza was recently terminated because of futility to show a difference between the peramivir and control groups.215,216 As noted earlier, intravenous peramivir is probably not effective for treatment of patients with oseltamivir resistance due to possession of the H275Y mutation; intravenous zanamivir has been recommended.

RIBAVIRIN Spectrum

Ribavirin (1-β-d-ribofuranosyl-1,2,4-thiazole-3-carboxamide; Vira­ zole, Rebetol, Copegus) is a guanosine analogue (Fig. 44-4A) in which the base and the d-ribose sugar are necessary for antiviral activity. Ribavirin inhibits the in vitro replication of a wide range of RNA and DNA viruses, including myxoviruses, paramyxoviruses, arenavi­ ruses, flaviviruses, bunyaviruses, coronaviruses, togaviruses, reovi­ ruses, herpesviruses, adenoviruses, poxviruses, and retroviruses. By plaque assay, inhibitory concentrations range from 3 to 10 µg/mL for influenza, parainfluenza, and respiratory syncytial virus (RSV). High concentrations inhibit group C adenoviruses214 and pathogenic flavivi­ ruses,217 including West Nile virus in neural cells. Ribavirin does not inhibit severe acute respiratory virus (SARS) coronavirus in vitro.218 Low concentrations of ribavirin (1 to 10 µg/mL) reversibly inhibit macromolecular synthesis and the proliferation of rapidly dividing cells.219 Ribavirin decreases nucleic acid and protein synthesis, inhibits interferon-γ release, and increases apoptosis in human peripheral blood mononuclear cells in vitro,218,220 but it does not adversely affect polymorphonuclear leukocyte functions.221 Ribavirin has been postu­ lated to enhance cell-mediated immune responses by increasing type 1 and suppressing type 2 cytokine responses in T cells221 and to decrease proinflammatory cytokine elaboration and inflammatory cell numbers. Inhibition of mast cell secretory responses occurs in vitro. Aerosol administration is more effective than parenteral dosing in animal models of influenza and RSV infection. Parenteral ribavirin has antiviral and therapeutic activity in animal models of infection with Lassa virus, other arenaviruses, and bunyavirus (see Chapters 47, 168, and 169). Combinations of ribavirin with immunoglobulin in RSV infection and with M2 or neuraminidase inhibitors in influenza A infection or with neuraminidase inhibitors in influenza B infection show enhanced antiviral activity.12 The use of ribavirin in treatment of hepatitis B and C is discussed in Chapter 46.

Mechanism of Action

The antiviral mechanisms of action of ribavirin are complex and most likely vary for different viruses. Ribavirin causes alterations of cellular nucleotide pools, inhibits viral RNA synthesis, and may cause lethal mutagenesis of certain RNA virus genomes.221-223 Intracellular phos­ phorylation to the monophosphate, diphosphate, and triphosphate derivatives is mediated by host cell enzymes. In uninfected and RSVinfected cells, the predominant derivative (>80%) is the triphosphate, which is rapidly lost, with an intracellular t 12 elim of less than 2 hours. Ribavirin monophosphate competitively inhibits inosine mono­ phosphate dehydrogenase and interferes with the synthesis of


541

Resistance

Antiviral resistance to ribavirin has been documented only in Sindbis virus and HCV to date. One HCV RNA polymerase variant (F415Y) selected in genotype 1a–infected, ribavirin-treated patients has been associated with ribavirin resistance in vitro.226 No ribavirin-resistant RSVs have been detected during aerosol therapy of children.

Pharmacokinetics

Oral ribavirin is well absorbed, but bioavailability averages 45% to 65% in adults because of first-pass metabolism.227-230 Administration with food increases absorption and peak plasma concentrations by 70%.227 After single oral doses of 600 mg, 1200 mg, or 2400 mg, peak plasma concentrations occur at 1 to 2 hours and average 1.3 µg/mL, 2.5 µg/ mL, and 3.2 µg/mL. Plasma concentrations average approximately 24 µg/mL and 17 µg/mL after intravenous doses of 1000 mg and 500 mg in patients with Lassa fever. During long-term administration, overall exposure and t 12 elim increase substantially.227 Steady-state plasma levels of about 1 to 4 µg/mL occur by about 4 weeks with weightadjusted dosing in chronic hepatitis C, and higher concentrations at 4 weeks correlate with decline in hemoglobin and likelihood of sustained viral responses.231 Plasma protein binding is negligible, and ribavirin has a large Vd (>2000 L). At steady state, cerebrospinal fluid levels are about 70% of those in plasma.229 The disposition of ribavirin is complex, involving renal elimination and metabolism. After rapid initial distribution, there is a prolonged terminal t 12 elim of 37 to 79 hours.227-229 Ribavirin triphosphate concen­ trates in erythrocytes with an erythrocyte-to-plasma ratio of 40 : 1 or greater, and erythrocyte levels gradually decrease, with an apparent t 12 of 40 days. Renal excretion accounts for 30% to 60% of ribavirin’s overall clearance, but hepatic metabolism is contributory. About 5% to 10% is recovered unchanged in the urine, and a much greater fraction is excreted as triazole carboxamide and carboxylic acid metabolites.227 Plasma clearance is reduced threefold in patients with advanced renal impairment (CrCl ≤30 mL/min). Dosage adjustments are needed for renal insufficiency, and ribavirin should be used with caution in patients with CrCl less than 50 mL/min. Hemodialysis and hemofiltra­ tion remove small amounts of drug. Higher initial blood levels occur in severe hepatic dysfunction.230 With aerosol administration, systemic absorption is low (<1% of deposited dose). Peak plasma levels range from 0.5 to 2.2 µg/mL after 8 hours’ exposure and from 0.8 to 3.3 µg/mL after 20 hours in pediatric patients. Respiratory secretion levels often exceed 1000 µg/mL and persist with a t 12 of 1.4 to 2.5 hours. A special aerosol generator (SPAG2, ICN Pharmaceuticals) is needed to produce particles of proper aero­ dynamic size to reach the lower respiratory tract. The delivered dose is twice as high in infants (1.8 mg/kg/hr) than in adults.

Toxicity

Systemic ribavirin causes dose-related anemia because of extravascular hemolysis and, at higher dosages, suppression of bone marrow release of erythroid elements.232 Reversible increases of serum bilirubin (in one fourth of recipients), serum iron, and uric acid concentrations

occur during short-term oral administration. Long-term use of oral ribavirin at dosages greater than 800 mg daily causes hemoglobin decreases of 2 to 4 g/dL in most recipients, usually within 4 weeks. When used in combination with interferon, hemoglobin levels less than 11 g/dL develop in 25% to 30% of patients.233 Renal impairment increases the risk for hemolysis. Severe anemia requires dosage reduc­ tion or cessation, although erythropoietin has been used effectively.233 Other reported side effects include pruritus, myalgia, rash, nausea, depression, nervousness, and cough or respiratory symptoms.234 Highdose intravenous ribavirin is associated with headache, hypomagnese­ mia, and hypocalcemia.235 Bolus intravenous dosing may cause rigors, and infusion over 10 to 15 minutes is advised. Aerosolized ribavirin may cause conjunctival irritation, rash, bron­ chospasm, reversible deterioration in pulmonary function, and, rarely, acute water intoxication. No adverse hematologic effects have been associated with aerosolized ribavirin. The drug may precipitate on contact lenses, so they should not be worn during aerosol exposure. Ribavirin exposure may occur in health care workers working in the environment of aerosol-treated infants.235,236 Health care worker expo­ sure is higher during delivery by oxygen hood than by ventilator or vacuum-exhausted hood systems.235 Use of aerosol containment and scavenging systems, turning off the aerosol generator before providing routine care, and use of personal protective equipment have been recommended.236 When ribavirin is used in conjunction with mechanical ventilation, in-line filters, modified circuitry, and frequent monitoring are required to prevent plugging of ventilator valves and tubing with precipitates of ribavirin. The possible effects of such modifications on drug delivery to the lower respiratory tract are undefined. In preclinical studies, ribavirin is mutagenic, gonadotoxic, and tera­ togenic.232 Low oral dosages have been teratogenic or embryotoxic in multiple species. Use of ribavirin is relatively contraindicated during pregnancy, and pregnant women should not directly care for patients receiving ribavirin aerosol. Ribavirin is categorized as pregnancy cat­ egory X, and effective means of contraception for men and women are recommended for at least 6 months after discontinuation of treatment or exposure.

Interactions

Antacids slightly decrease the oral bioavailability of ribavirin. During co-administration clinically, ribavirin, amantadine, and oseltamivir do not interact pharmacokinetically.34 Ribavirin antagonizes the antiHIV-1 effects of zidovudine but enhances the activity of purine dide­ oxynucleosides. Ribavirin use in patients who are coinfected with HIV and HCV and on antiretroviral drugs, particularly combined with didanosine, seems to increase the risk for mitochondrial toxicity and lactic acidosis. Ribavirin may inhibit the effect of warfarin.

Clinical Studies

Ribavirin aerosol is approved in the United States for treatment of RSV bronchiolitis and pneumonia in hospitalized children. Oral ribavirin in combination with various interferons is approved for treatment of chronic hepatitis C. The following describes only clinical studies on the prevention and treatment of respiratory virus infection with ribavirin. Treatment for infection with HCV is discussed elsewhere (see Chapters 46, 119, and 156).

Respiratory Syncytial Virus

Aerosolized ribavirin (18-hour exposure daily for 3 to 6 days) variably shortens the duration of virus shedding and may improve certain clini­ cal measures in infants hospitalized with RSV illness.238 No consistent reductions in need for ventilatory support or duration of hospitaliza­ tion have been documented, however. In infants receiving mechanical ventilation for RSV-related respiratory failure, no significant reduc­ tions in duration of ventilatory support, hospitalization, or mortality have been found.238,239 Intermittent, high-dose therapy (2-hour expo­ sures three times daily for 5 days) is well tolerated and may be as effective as prolonged exposure.240 Use of aerosolized ribavirin is limited by concerns regarding its efficacy, ease of administration, risk of occupational exposure, and cost. The American Academy of Pediatrics states that aerosol treatment

Chapter 44  Antiviral Drugs for Influenza and Other Respiratory Virus Infections

guanosine triphosphate (GTP) and with nucleic acid synthesis. Decreased concentrations of competing GTP likely potentiate ribavi­ rin’s other antiviral effects. Ribavirin triphosphate inhibits influenza virus RNA polymerase activity and the GTP-dependent 5′-capping of viral mRNA. The monophosphate is incorporated inefficiently into viral RNA genomes, and this may lead to lethal mutagenesis and con­ tribute to antiviral activity.222 HCV RNA polymerase incorporates riba­ virin monophosphate into viral RNA, which causes mutations and inhibits viral RNA synthesis.224 Ribavirin diphosphates and triphos­ phates also inhibit human immunodeficiency virus (HIV) reverse tran­ scriptase activity.225 Ribavirin has immunosuppressive effects in experimental animals and shows therapeutic activity against transplantable virus-induced tumors and certain autoimmune diseases. Ribavirin increases type 1 cytokine–mediated immune responses in vivo, an effect that may con­ tribute to its therapeutic activities,221 and seems to augment type-1 cytokine responses ex vivo in peripheral blood mononuclear cells from patients with chronic hepatitis C.223


Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

542 for RSV infection “is not recommended for routine use but may be considered for use in selected patients with documented, potentially life-threatening RSV infection.”241 Decreased RSV-specific serum neu­ tralizing antibody titers and diminished nasopharyngeal secretion RSV-specific IgE and IgA responses may occur in ribavirin-treated children. No long-term adverse or beneficial effects of ribavirin therapy have been documented in children.242 Combinations of aerosolized ribavirin and intravenous immuno­ globulin or palivizumab may be beneficial in treating RSV pneumonia in hematopoietic stem cell transplant recipients,243-246 whereas intrave­ nous ribavirin alone is ineffective.247 Therapy with either aerosolized248-250 or oral251,252 ribavirin appears to prevent progression from upper to lower respiratory tract illness in such patients. A similar benefit of preemptive treatment of RSV upper respiratory tract infection in lung transplant recipients with oral and inhaled ribavirin has been reported.253,254

Other Respiratory Viruses

Intravenous and aerosolized forms of ribavirin have been used to treat severe influenza virus infections.255,256 Aerosolized ribavirin inconsis­ tently reduces viral titers and illness measures in adults with uncom­ plicated influenza A or B and has modest efficacy in children hospitalized with influenza.257 However, oral ribavirin 300 mg three times per day combined with amantadine and oseltamivir may possibly be effective for treatment of influenza A (H1N1)pdm09 disease and more so than oseltamivir alone.258 Oral, intravenous, and aerosolized ribavirin have been used in immunosuppressed patients with severe parainfluenza virus and adenovirus infections with inconsistent clinical benefits.255,259,260 Intravenous ribavirin has been used to treat adenovirus-associated hemorrhagic cystitis, pneumonia, and invasive infections in immunocompromised patients, and it may be effective even in severe disease.261,262 Treatment with intravenous263,264 and oral265 ribavirin of human metapneumovirus pneumonia in immunocompro­ mised patients has been associated with resolution. Aerosolized riba­ virin has been used in treating parainfluenza virus infections in solid-organ transplant recipients, but seems ineffective in parainflu­ enza virus pneumonia in hematopoietic stem cell transplant recipi­ ents.259 Oral ribavirin was effective in accelerating functional graft recovery and reducing late bronchiolitis obliterans in 38 lung trans­ plant recipients266 and in a bone marrow transplant recipient267 with paramyxovirus respiratory infection. Intravenous ribavirin therapy was associated with successful treatment of paramyxovirus type 3 respiratory infection in cardiac transplant recipients.268,269 Ribavirin has been used extensively in treating SARS coronavirus infections without proven antiviral effects in vitro218 or in patients270 and has been associated with frequent adverse effects.235 Intravenous ribavirin seems to be ineffective in treatment of hantavirus cardiopulmonary syn­ drome.271 However, it inhibits Andes virus in vitro, an important cause of this syndrome, and is effective in a hamster model of hantavirus cardiopulmonary syndrome caused by this virus (see Chapter 168).272

RSV604

RSV604 is an oral benzodiazepine compound (C22H17FN4O2) under development for treatment of RSV infections (Fig. 44-5).273,274 It inhib­ its both RSV A and B subtypes at submicromolar concentrations. Its antiviral activity is expressed through interaction with the RSV F HN O

HN O

HN

N

FIGURE 44-5  Chemical structure of RSV604.

nucleocapsid (N) protein, which is highly conserved.275 The drug is well absorbed orally, and a single dose per day is sufficient to achieve anti­ viral EC90 levels. In vitro resistance can be elicited, at an apparent low rate, and resistant virus appears similarly fit to wild-type RSV in terms of replication.275 Phase II studies of RSV604 are underway in transplant patients with RSV infections.

ZANAMIVIR Spectrum

Zanamivir (4-guanidino-2,4-dideoxy-N-acetylneuraminic acid; Relen­ za) is a sialic acid analogue (see Fig. 44-3B) that is a potent and specific inhibitor of the neuraminidases of influenza A and B viruses.276 It inhibits influenza neuraminidase activity at nanomolar concentrations but has a higher and broader range of inhibitory concentrations in cell culture.277,278 Compared with oseltamivir carboxylate, zanamivir is more active against influenza B, and data from a comparative trial in children indicate that this difference is clinically important.279 Zana­ mivir is less active against neuraminidases of influenza A/N2 clinical isolates,280 but the clinical importance of this difference is uncertain. Zanamivir inhibits certain influenza A neuraminidase variants that are resistant to oseltamivir carboxylate.96 Combinations of zanamivir plus rimantadine inhibit strains of influenza A/H1N1 and H3N2 viruses synergistically, but some concentrations seem antagonistic when assessed by reductions in cell-associated virus yield.281 Zanamivir is not cytotoxic and is highly selective for influenza neuraminidase, inhibit­ ing neuraminidases from human282 and other mammalian sources or other pathogens only at 106-fold higher concentrations. Millimolar concentrations inhibit parainfluenza virus type 3 in cell culture, most likely by blocking attachment.283 Topical zanamivir in the respiratory tract is active in murine and ferret models of influenza.277

Resistance

Resistance to neuraminidase inhibitor drugs has developed less fre­ quently than to the adamantane compounds and less frequently to zanamivir than to oseltamivir. A recent systematic review of the prevalence of neuraminidase inhibitor resistance among influenza viruses cultured from immuno­ competent ambulatory adults enrolled in prophylactic and therapeutic trials of zanamivir found no reports of zanamivir resistance.284 In surveys of other collections of influenza isolates, a similar absence or dearth of zanamivir resistance was reported: influenza A H1N1 viruses circulating in the 2008-2009 influenza season in the United States prior to emergence of the 2009 pandemic were resistant to oseltamivir but susceptible to zanamivir.285 Among 391 nonpandemic A/H1N1 isolates from Australia and Southeast Asia patients from 2006 to 2008, 2.3% were resistant to zanamivir286 but susceptible to oseltamivir. Zanamivir resistance was not demonstrated among 3359 influenza A (H1N1)pdm09 global isolates287 nor among 304 oseltamivir-resistant isolates reported by the World Health Organization to August 2010.288 Avian influenza A/H5N1 isolates from 2003 to 2005 were susceptible to zanamivir.289 Of 680 influenza B viruses isolated in China from 2010 and 2011, one with D197N amino-acid substitution was resistant to zanamivir.290 Several neuraminidase mutations mediate diminished susceptibil­ ity to zanamivir: Q136K in an A (H1N1) seasonal virus (300-fold reduction in zanamivir susceptibility)286 and S274N291 in nonpandemic A/H1N1 virus and I223R (5-fold reduction)292 in an A (H1N1)pdm09 isolate. The relationship of these virus resistance mutations and prior zanamivir therapy and immune competence was not consistently apparent. An influenza B virus with an Arg152Lys mutation resistant to both zanamivir and oseltamivir was recovered from an immuno­ compromised child with prolonged virus excretion despite receipt of nebulized zanamivir.293 The effect of these neuraminidase mutations on infectivity and transmissibility compared with the wild-type parental strains is variable, but only some mutants have been characterized in this regard.293-295 An observational study in pediatric patients with influenza treated with oseltamivir or zanamivir suggested that the lower prevalence of zanamivir than oseltamivir resistance is more related to the intrinsic properties of the drugs than to differences in the prevalence of use of the drugs.296


543

Pharmacokinetics

Interactions

No clinically significant drug interactions have been recognized for inhaled zanamivir. No clinically relevant pharmacokinetic interaction was demonstrated between oseltamivir, 150 mg taken orally twice daily, and zanamivir, 600 mg administered intravenously every 12 hours, in healthy volunteers.304 Zanamivir does not affect the immune response to injected inactivated influenza vaccine, but, similar to all antiviral medications, it has the potential to impair the immunogenic­ ity of attenuated live influenza vaccine administered concurrently. Zanamivir should not be administered from 48 hours before to 2 weeks after intranasal administration of an attenuated influenza vaccine.305

Toxicity

Preclinical studies of zanamivir found no evidence of mutagenic, tera­ togenic, or oncogenic effects. In cell culture, the inhibitory effect of zanamivir on influenza virus replication was not impaired by analge­ sics, antihistamines, decongestants, or antibacterial drugs.306 Zanami­ vir is classified as a pregnancy category C agent. Orally inhaled zanamivir is generally well tolerated, and the fre­ quencies of complaints are not significantly different from those in placebo recipients among adults and children 5 years old or older.277,306,307 This includes once-daily oral inhalation for prophylaxis by adults for 16 weeks.308 Most reported symptoms in treatment studies are likely the result of the underlying illness. Similarly, in high-risk patients receiving zanamivir or placebo, no differences in adverse reactions have been seen in controlled trials.309 In patients with mild to moderate asthma or chronic obstructive pulmonary disease, orally inhaled zanamivir is associated with fewer bronchitis episodes, similar mea­ surements of forced expired volume in 1 second, and more rapid

improvement in peak expiratory flow rate than with inhaled placebo.310 However, postmarketing reports indicate a potential risk for acute bronchospasm, respiratory arrest, or worsening of chronic obstructive pulmonary disease accompanied by pulmonary edema after zanamivir inhalation, particularly in patients with underlying airway disease.311 Apparent declines in respiratory function have also been rarely reported in patients without recognized airway disease. Consequently, use in patients with underlying airway disease is not generally recom­ mended in the United States, although treatment in at-risk patients is used in other countries.312 If used in patients with obstructive airway disease, zanamivir should be administered cautiously under close observation and with availability of fast-acting bronchodilators. Zanamivir inhaled as an experimental nebulized solution contain­ ing 16 mg/mL for 10 minutes four times a day for 5 days for treatment of serious influenza with lower respiratory tract signs in hospitalized patients 10 years or older was well tolerated.313 However, when the oral formulation containing lactose has been reformulated as a solution and administered into the airway during mechanical ventilation, lactose precipitation in the airway filters has caused obstruction,314 precluding the reformulation of the powder in the orally inhaled formulation into a solution for nebulization and inhalation. Zanamivir injected intravenously to healthy volunteers in doses from 50 to 600 mg twice daily for 5 days was also well tolerated.315 In 130 hospitalized adults with influenza treated with zanamivir, 600 mg intravenously twice daily for 5 days, or reduced doses in those with renal impairment, no safety signals or clinically significant trends in laboratory values, vital signs, or electrocardiograms were identified that were considered attributable to the drug.316

Clinical Studies

Zanamivir has been administered to patients intranasally as a spray, by oral inhalation as a dry powder, by nasal inhalation as an aerosol from a nebulized solution, and by intravenous injections. Intranasal and intravenous zanamivir are highly protective against experimental human influenza, and early treatment is associated with reductions in viral titers, symptoms, and middle ear pressure abnor­ malities.163,277,317 Orally inhaled zanamivir powder is approved in the United States for prevention of influenza in individuals 5 years old and older, and for treatment of influenza in individuals 7 years old and older. Zanamivir (10 mg twice daily for 5 days) inhaled early in the course of illness for treatment of uncomplicated influenza in previously healthy adults and children 5 to 12 years old shortens the times to illness resolution and return to usual activities by 1 to 3 days.307,318,319 Treatment benefits seem to be greater in patients with severe symptoms at entry, in patients older than 50 years, and in higher-risk patients.320 Inhaled zanamivir treatment in adults is associated with a 40% reduc­ tion in lower respiratory tract events leading to antibiotic use and a 28% overall reduction in antibiotic prescriptions.321 Zanamivir inhaled orally is equally efficacious for treatment of influenza A and B infection.319,322 In individuals with influenza B illness, zanamivir reduces the median duration of fever by 32%, from 53 hours to 36 hours, compared with oseltamivir.279 In high-risk patients with primarily mild to moderate asthma or other chronic cardiopulmonary conditions, orally inhaled zanamivir treatment reduces illness duration and the incidence of complications leading to antibiotic use.310,323 It has been used to treat immunocompromised hosts with influenza A and B infections,324 including a child to whom an aqueous zanamivir solu­ tion (16 mg/mL) was administered by aerosol and nebulizer via an endotracheal tube.325 More recently, in an observational study, orally inhaled zanamivir was more efficacious for treatment of oseltamivirresistant influenza A/H1N1 than oseltamivir.326 Prophylactic administration of once-daily inhaled zanamivir (10 mg) prevents febrile influenza illness during influenza season (84% efficacy),327 or when used for postexposure prophylaxis in households with or without treatment of the ill index case (82% efficacy).328,329 In an observational study with limited numbers of patients, orally inhaled zanamivir and oral oseltamivir were not different for prevention of secondary cases during nosocomial outbreaks on pediatric wards.330 In nursing home residents, 2 weeks of inhaled zanamivir was superior to oral rimantadine in preventing influenza A infection, in part because of a high frequency of rimantadine resistance,331 and inhaled zanamivir

Chapter 44  Antiviral Drugs for Influenza and Other Respiratory Virus Infections

The oral bioavailability of zanamivir is low (<5%). The approved for­ mulation is a dry powder containing a lactose carrier delivered by oral inhalation with a proprietary Diskhaler device. The proprietary inhaler device for delivering zanamivir is breath activated and requires a coop­ erative, trained patient. The use of the Diskhaler device is unreliable in young children, very infirm or elderly patients, or cognitively impaired patients. Although the inhaler has been used effectively in many older adults,297 more than half of hospitalized older adults could not correctly use the device after instruction.298 After inhalation of the dry powder using the Diskhaler, approxi­ mately 15% is deposited in the lower respiratory tract while the remainder is deposited in the oropharynx.277 Zanamivir concentrations in epithelial lining fluid obtained by bronchoalveolar lavage may approximate concentrations in alveoli. Median epithelial lining fluid concentrations of zanamivir 12 hours after oral inhalation of the rec­ ommended 10-mg dose by Diskhaler in healthy volunteers ranged from 0.3 to 0.9 µg/mL.299 In other uninfected individuals, median zanamivir levels in induced sputum were 1.34 µg/mL, 0.30 µg/mL, and 0.05 µg/mL at 6 hours, 12 hours, and 24 hours after dosing, with the pulmonary t 12 elim estimated to be 2.8 hours.300 Approximately 4% to 17% of an inhaled dose is absorbed systemically, and peak plasma levels are low, averaging 0.04 to 0.05 µg/mL.277 Because of the low bioavailability of zanamivir inhaled orally, dosage adjustments are not indicated in renal insufficiency. After intravenous dosing, the plasma t 12 elim of zanamivir ranges from 1.6 to 2.9 hours,277,299 with about 90% eliminated unchanged in the urine.277 After intravenous administration of 600 mg zanamivir to healthy adults, the median serum Cmax is 39.4 µg/mL, AUC0-12 hr is 86.6 µg/mL, and Ctrough is 0.6 µg/mL. The median epithelial lining fluid concentration 12 hours after dosing is 0.4 µg/mL, very similar to the value after inhalation of 10 mg (see earlier). This is 552 to 1653 times the in vitro IC50 for influenza A and B neuraminidases, respectively.280 The pharmacokinetics of zanamivir in 103 adults with influenza receiving 600 mg intravenously twice daily with dose adjustments for renal impairment were similar to those in previously described studies.301 Zanamivir renal clearance declines linearly with increasing renal impairment.302 The suggested dose for adults with normal renal function is 600 mg intravenously given twice daily. Doses for children and for patients with renal impairment who are or are not receiving replacement therapy have been published.303


Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

544 has been used to curtail transmission of amantadine-resistant influ­ enza A in nursing homes.297 Orally inhaled zanamivir has been administered in combination with oral oseltamivir. For postexposure prophylaxis in families, such combined zanamivir-oseltamivir administration was not more effica­ cious than either agent alone.332 However, a subgroup analysis suggests greater efficacy of the combination treatment among contacts whose prophylaxis was begun within 24 hours of exposure to the index case compared with oseltamivir or zanamivir alone. For treatment of adults with mainly A/H3N2 influenza, zanamivir-oseltamivir combination treatment was not more efficacious than zanamivir alone and was less efficacious than oseltamivir monotherapy.333 Zanamivir has been administered intravenously to treat patients seriously ill with influenza who could not receive or who had failed oral oseltamivir therapy. Immunocompetent334 and immunocompro­ mised335,336 patients who were infected with oseltamivir-resistant337 and oseltamivir-susceptible336,338 influenza A/H1N1 nonpandemic viruses or oseltamivir-resistant pandemic virus339 or oseltamivirsensitive influenza A (H1N1)pdm09 virus335,340 have been successfully treated with intravenous zanamivir. There is a sense that intravenous zanamivir may be lifesaving.341 However, an apparent lack of a relation­ ship between intravenous zanamivir treatment–associated reductions in pandemic virus load in upper and lower respiratory tract secretions and mortality have prompted questions about its effectiveness in seri­ ously ill patients.342 A phase III study comparing intravenous zanamivir and oseltamivir in hospitalized patients is underway.

POLYMERIC ZANAMIVIR CONJUGATES

Polymeric zanamivir conjugates are experimental, high-molecularweight anti-influenza compounds comprising multiple zanamivir monomers connected at the 7-0 position to backbone or linker mol­ ecules of various types and lengths.343-349 These compounds are poten­ tial second-generation inhaled neuraminidase inhibitors for influenza chemoprophylaxis and therapy with enhanced potency and prolonged lung retention time compared with zanamivir. In mice, one of these compounds has been associated with prophylactic efficacy for 7 days after a single intranasal administration.

Spectrum

Polymeric zanamivir conjugates exhibit broad-spectrum anti-influenza activity, inhibiting human influenza A N1, N2, and B viruses and an avian influenza A/H5N1 virus.343 Inhibitory potency varies according to the length345 and type of linker molecule344 and the number of zana­ mivir derivatives, whether dimeric,343 trimeric, or tetrameric.346 The most potent polymeric zanamivir conjugate is a dimer with a 14-carbon linker, which is 10-fold less potent in a neuraminidase assay enzyme inhibition test (IC50, 7.86 nM vs. 0.76 nM for zanamivir) but is 500,000fold more potent in inhibiting influenza A/WSN/33 (H1N1) in a cyto­ pathic reduction assay (IC50, 0.0001 nM vs. 56 nM for zanamivir).343 In mice, this dimeric conjugate is 100 times more potent than zanamivir in preventing influenza virus replication in the lung for 7 days after a single intranasal dose of drug and 1 day after intranasal virus challenge (drug doses to reduce lung virus titer by 90% were 0.03 mg/kg and 2.92 mg/kg for the dimeric conjugate and zanamivir). The prophylactic effect is associated with prolonged persistence of dimer conjugate in lung tissue after intranasal administration, as discussed in the section

Key References The complete reference list is available online at Expert Consult. 5. Hayden FG, Aoki FY. Amantadine, rimantadine, and related agents. In: Yu VL, Merigan TC, White NJ, et al, eds. Antimicrobial Therapy and Vaccines. Baltimore: Williams & Wilkins; 1999:1344-1365. 25. Bright RA, Medina MJ, Xu X, et al. Incidence of adaman­ tane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern. Lancet. 2005;366:1175-1181. 31. Hoopes JD, Driebe EM, Kelley E, et al. Triple combination antiviral drug (TCAD) composed of amantadine, oseltami­ vir, and ribavirin impedes the selection of drug-resistant influenza A virus. PLoS One. 2011;6:E29778.

on pharmacokinetics. The specificity of polymeric zanamivir conju­ gates for influenza A and B neuraminidase is presumed but not yet reported. A zanamivir polymer can overcome zanamivir resistance. A zana­ mivir polymer bound to the neuraminidase of zanamivir-resistant avian influenza A viruses possessing a resistance mutation at position 119 bound as much as 2000 times more strongly than did monomeric zanamivir.350

Mechanism of Action

The synthesis of polymeric conjugates of zanamivir that retain neur­ aminidase inhibitory activity is possible because of the unique position of the molecule when it is docked in the enzymatic pocket, with the 7-OH group pointing out and away from the target site, making it accessible to linkage to different backbone molecules. Electron micro­ graphs show influenza virus clumping in the presence of dimeric zana­ mivir conjugates. The marked potency of some conjugates is postulated to reflect clumping caused by three types of bivalent binding: between two neuraminidase molecules in the tetrameric transmembrane spike protein (intratetramer), binding between sites on different tetramers on the same virion (intravirionic), and head-to-head binding between different neuraminidase sites on separate virions (intervirionic binding).343 An additional mechanism for the marked enhancement of potency observed by synthesis of polymer-attached zanamivir is postulated to be the result of interference with intracellular trafficking of endocy­ tosed virus and subsequent virus-endosome fusion.351

Resistance

Studies describing attempts to induce resistance in vitro by repeated passage in the presence of drug have not been reported.

Pharmacokinetics

Prolonged retention of polymeric zanamivir compared with mono­ meric zanamivir in lung tissue accounts for the enhanced antiviral effect of polymeric conjugates. After intratracheal instillation of the same single dose of a polymeric zanamivir conjugate or monomeric zanamivir solution to rats, lung homogenate drug concentrations of the polymeric compound after 48 hours and 168 hours are 35 times and 160 times greater than zanamivir concentrations.343 Generally, lung retention time is directly related to molecular weight because small polar molecules leave the lung by passing through tight junctions between cells. Prolonged retention of high-molecular-weight poly­ meric conjugates compared with monomeric zanamivir is expected. However, the prolonged lung retention time of some smaller conju­ gates indicates that aqueous insolubility and aggregate formation plus partitioning into cell membrane phospholipids may also play a role in the prolonged retention of zanamivir polymeric conjugates in the lung after inhalation.343

Interactions and Toxicity

Toxicity studies have been limited to assessments of in vitro cyto­ toxicity. For a series of dimeric conjugates, concentrations of 100 to 1000 ng/mL caused no cytotoxicity.345

Clinical Studies

No clinical studies have been reported.

34. Seo S, Englund JA, Nguyen JT, et al. Combination therapy with amantadine, oseltamivir, and ribavirin for influenza A infection: safety and pharmacokinetics. Antivir Ther. 2013;18:377-386. 36. Jefferson T, Demicheli V, DiPietrantorj C, et al. Amanta­ dine and rimantadine for influenza A in adults. Cochrane Database Syst Rev. 2006;(2):CD001169. 38. Kimberlin DW, Shalabi M, Abzug MJ, et al. Safety of oselta­ mivir compared with the adamantanes in children less than 12 months of age. Pediatr Infect Dis J. 2010;29:195-198. 50. Alves Galvao MG, Rocha Crispino Santos MA, Alves da Cunha AJ. Amantadine and rimantadine for influenza A in children and the elderly. Cochrane Database Syst Rev. 2012;(1):CD002745. 53. Gravenstein S, Drinka P, Osterweil D, et al. Inhaled zana­ mivir versus rimantadine for the control of influenza in a

highly-vaccinated long-term care population. J Am Med Dir Assoc. 2005;6:359-366. 64. Ison MG. Expanding the armamentarium against respira­ tory viral infections: DAS181. J Infect Dis. 2012;206: 1806-1808. 78. Yamashita M. Laninamivir and its prodrug, CS-8958: longacting neuraminidase inhibitors for the treatment of influ­ enza. Antivir Chem Chemother. 2010;21:71-84. 87. Katsumi Y, Otabe O, Matsui F, et al. Effect of a single inhalation of laninamivir octanoate in children with influ­ enza. Pediatrics. 2012;129:e1431-e1436. 102. Kawai N, Ikematsu H, Iwaki N, et al. A comparison of the effectiveness of oseltamivir for the treatment of influenza A and influenza B: a Japanese multicenter study of the 2003-2004 and 2004-2005 influenza seasons. Clin Infect Dis. 2006;43:439-444.


545 180. Hayden FG, Atmar RL, Schilling M, et al. Use of the selec­ tive oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med. 1999;341:1336-1343. 182. Welliver R, Monto AS, Carewicz O, et al. Effectiveness of oseltamivir in preventing influenza in household con­ tacts: a randomized controlled trial. JAMA. 2001;285:748754. 185. Govorkova EA, Ieneva IA, Goloubeva OG, et al. Compari­ son of efficacies of RWJ-270201, zanamivir, and oseltamivir against H5N1, H9N2, and other avian influenza viruses. Antimicrob Agents Chemother. 2001;45:2723. 200. Barrosa L, Treanor J, Gubareva L, et al. Efficacy and toler­ ability of the oral neuraminidase inhibitor peramivir in experimental human influenza: randomised, controlled trials for prophylaxis and treatment. Antivir Ther. 2005;10: 901. 207. Sugaya N, Kohno S, Ishibashi T, et al. Efficacy, safety and pharmacokinetics of intravenous peramivir in children with 2009 pandemic H1N1 influenza virus infection. Antimicrob Agents Chemother. 2012;56:369-377. 210. Peramivir. In: Clinical Pharmacology. Tampa, FL: Elsevier/ Gold Standard; 2009. Available at http://download.thelancet .com/flatcontentassets/H1N1-flu/treatment/treatment-53 .pdf. 238. Randolph AG, Wang EE. Ribavirin for respiratory syncytial virus lower respiratory tract infection: a systematic over­ view. Arch Pediatr Adolesc Med. 1996;150:942-947. 248. Boeckh M, Englund J, Li Y, et al. Randomized controlled multicenter trial of aerosolized ribavirin for respiratory syncytial virus upper respiratory tract infection in hema­ topoietic cell transplant recipients. Clin Infect Dis. 2007; 44:245-249. 258. Kim Y, Young Suh G, Huh JW, et al. Triple-combination antiviral drug for pandemic H1N1 influenza virus infec­ tion in critically ill patients on mechanical ventilation. Antimicrob Agents Chemother. 2011;55:5703-5709. 259. Nichols WG, Corey L, Gooley T, et al. Parainfluenza virus infections after hematopoietic stem cell transplantation: risk factors, response to antiviral therapy, and effect on transplant outcome. Blood. 2001;98:573-578. 261. Souza ILA, Schnert L, Goto JM, et al. Oral ribavirin in treatment of adenovirus infection in hematologic patients: experience from a Brazilian university hospital. Clin Microbiol Infect. 2010;16:S24.

262. Gavin PJ, Katz BZ. Intravenous ribavirin treatment for severe adenovirus disease in immunocompromised chil­ dren. Pediatrics. 2002;110:E9. 263. Bonney D, Razati H, Turner A, et al. Successful treatment of human metapneumovirus pneumonia using combina­ tion therapy with intravenous ribavirin and immune globulin. Br J Haematol. 2009;45:667-679. 266. Fuehner T, Dierich M, Duesbert C, et al. Single-centre experience with oral ribavirin in lung transplant recipients with paramyxovirus infections. Antivir Ther. 2011;16: 1733-1740. 275. Chapman J, Abbott E, Alber D, et al. RSV604, a novel inhibitor of respiratory syncytial virus replication. Antimicrob Agents Chemother. 2007;51:3346-3353. 279. Kawai N, Ikematsu H, Iwaki N, et al. Comparison of the effectiveness of zanamivir and oseltamivir for the treatment of influenza A and B. J Infect. 2008;36:51-57. 287. Gubareva LV, Trujillo AA, Okimo-Achiambo M, et al. Comprehensive assessment of 2009 pandemic influenza A(H1N1) virus drug susceptibility in vitro. Antivir Ther. 2010;15:1151-1159. 293. Gubareva LV, Matrosovich MN, Brenner MK, et al. Evi­ dence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis. 1998; 178:1257-1262. 296. Tamura D, Sugaya N, Ogawa M, et al. Frequency of drugresistant viruses and virus shedding in pediatric influenza patients treated with neuraminidase inhibitors. Clin Infect Dis. 2011;52:e56-e93. 318. Hayden FG, Osterhaus ADME, Treanor JJ, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections. N Engl J Med. 1997;337:874-879. 325. Gukareva LV, Matrosovich MN, Brenner MK, et al. Evi­ dence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis. 1998; 178:1257-1262. 327. Monto AS, Robinson DP, Herlocher L, et al. Zanamivir in the prevention of influenza among healthy adults. JAMA. 1999;282:31-36. 336. Dohna-Schwake C, Schweiger B, Felderhoff-Muser U, et al. Severe H1N1 infection in a pediatric liver transplant recipi­ ent treated with intravenous zanamivir: efficiency and complications. Transplantation. 2010;90:223-224.

Chapter 44  Antiviral Drugs for Influenza and Other Respiratory Virus Infections

112. Whitley RJ, Hayden FG, Reisinger K, et al. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J. 2001;20:127-133. 121. Kimberlin DW, Acosta EP, Pritchard MN, et al. Oseltamivir pharmacokinetics, dosing and resistance among children aged 2 years with influenza. J Infect Dis. 2013;207:709-720. 127. He G, Massarella J, Ward P. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet. 1999;37:471-484. 135. Greer LG, Leff RD, Rogers VL, et al. Pharmacokinetics of oseltamivir according to trimester of pregnancy. Am J Obstet Gynecol. 2011;204(suppl 6):S89-S93. 136. Beigi RH, Han K, Venkataramanan R, et al. Pharmacoki­ netics of oseltamivir among pregnant and nonpregnant women. Am J Obstet Gynecol. 2011;204(suppl 1):S84-S88. 167. Jefferson T, Jones M, Doshi P, et al. Neuraminidase inhibi­ tors for preventing and treating influenza in healthy adults: systematic review and meta-analysis. BMJ. 2009; 339:b5106. 168. Hsu J, Santesso N, Mustafa R, et al. Antivirals for treat­ ment of influenza: a systematic review and meta-analysis of observational studies. Ann Intern Med. 2012;156:512524. 169a.  Muthuru SG, Venkatersan S, Myles PG, et al. Effectiveness of neuraminidase inhibitors in reducing the mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med. 2014;2:395-404. 169b.  Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev. 2014;4: CD008965. 170. Muthuri SG, Myles PR, Vankatesan S, et al. Impact of neur­ aminidase inhibitor treatment on outcomes of public health importance during the 2009-2010 influenza A (H1N1) pandemic in a systematic review and metaanalysis in hospitalized patients. J Infect Dis. 2013;207:533-563. 172. Siston AM, Rasmussen SA, Honein MA, et al. Pandemic 2009 influenza A (H1N1) virus illness among pregnant women in the United States. JAMA. 2010;303:1517-1525. 178. Nichols WG, Guthrie KA, Corey L, et al. Influenza infec­ tions after hematopoietic stem cell transplantation: risk factors, mortality and the effect of antiviral therapy. Clin Infect Dis. 2004;39:1300-1306.


545.e1

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Chapter 44  Antiviral Drugs for Influenza and Other Respiratory Virus Infections

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Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

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2003-2004 and 2004-2005 influenza seasons. Clin Infect Dis. 2006;43:439-444. 103. Sato M, Saito R, Sato I, et al. Effectiveness of oseltamivir treatment among children with influenza A or B virus infections during successive winters in Niigata City, Japan. Tokoku J Exp Med. 2008;214:113-120. 104. Boltz DA, Rehg JE, McClaren J, et al. Oseltamivir pro­ phylactic regimens prevent H5N1 influenza morbidity and mortality in a ferret model. J Infect Dis. 2008;197: 1315-1323. 105. Smee DF, Wong MH, Bailey KW, et al. Activities of oselta­ mivir and ribavirin used alone and in combination against infection in mice with recent isolates of influenza A (H1N1) and B viruses. Antiviral Chem Chemother. 2006; 17:185-192. 106. Ilyushina NA, Hay A, Yilmaz N, et al. Oseltamivir-ribavirin combination therapy for highly pathogenic H5N1 influ­ enza infections in mice. Antimicrob Agents Chemother. 2008;52:3889-3897. 107. Smee DF, Hurst BL, Wong MH, et al. Effects of double combinations of amantadine, oseltamivir and ribavirin on influenza A (H5N1) virus infections in cell culture and in mice. Antimicrob Agents Chemother. 2009;53:2120-2128. 108. Ilyushina NA, Bovin NV, Webster RG, et al. Combination chemotherapy, a potential strategy for reducing the emer­ gence of drug-resistant influenza A variants. Antiviral Res. 2006;70:121-131. 109. Colman PM. Influenza virus neuraminidase: structure, antibodies, and inhibitors. Protein Sci. 1994;3:1687-1696. 110. Zambon M, Hayden FG. Position statement: global neur­ aminidase inhibitor susceptibility network. Antiviral Res. 2001;49:147-156. 111. Carr J, Ives J, Kelly L, et al. Influenza virus carrying neur­ aminidase with reduced sensitivity to oseltamivir carboxyl­ ate has altered properties in vitro and is compromised for infectivity and replicative ability in vivo. Antiviral Res. 2002;54:79-88. 112. Whitley RJ, Hayden FG, Reisinger K, et al. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J. 2001;20:127-133. 113. Jackson HC, Roberts N, Wang Z, et al. Management of influenza: use of new antivirals and resistance in perspec­ tive. Clin Drug Invest. 2000;20:447-454. 114. Weinstock DM, Gubareva LV, Zuccotti G. Prolonged shedding of multidrug-resistant influenza A virus in an immunocompromised patient. N Engl J Med. 2003;348: 867-868. 115. Hurt AC, Hardie K, Wilson NJ, et al. Community transmis­ sion of oseltamivir-resistant A(H1N1)pdm09 influenza. N Engl J Med. 2011;365:2541-2542. 116. Hurt AC, Hardi K, Wilson NJ, et al. Characteristics of a widespread community cluster of H275Y oseltamivirresistant A(H1N1)pdm09 influenza in Australia. J Infect Dis. 2012;206:148-157. 117. Hauge SH, Blix HS, Borgen K, et al. Sales of oseltamivir in Norway prior to the emergence of oseltamivir resistant influenza A(H1N1) viruses in 2007-2008. Virol J. 2009;6:54. 118. Longtin J, Patel S, Eshaghi A, et al. Neuraminidaseinhibitor resistance testing for pandemic influenza A(H1N1) 2009 in Ontario, Canada. J Clin Virol. 2011;50: 257-261. 119. Storms AD, Gubareva LV, Su S, et al. Oseltamivir-resistant pandemic (H1N1) 2009 virus infections, United States, 2010-2011. Emerg Infect Dis. 2012;18:308-311. 120. Hurt AC, Deng YM, Ernest J, et al. Oseltamivir-resistant influenza viruses circulating during the first year of the influenza A(H1N1) 2009 pandemic in the Asia-Pacific region, March 2009 to March 2010. Euro Surveill. 2011;16: 19770. 121. Kimberlin DW, Acosta EP, Pritchard MN, et al. Oseltamivir pharmacokinetics, dosing and resistance among children aged 2 years with influenza. J Infect Dis. 2013;207:709-720. 122. Wong DD, Choy KT, Chan RW, et al. Comparable fitness and transmissibility between oseltamivir-resistant pan­ demic 2009 and seasonal H1N1 influenza viruses with the H275Y neuraminidase mutation. J Virol. 2012;86: 10558-10570. 123. Hamelin ME, Baz M, Abed Y, et al. Oseltamivir-resistant pandemic A/H1N1 virus is as virulent as its wild-type counterpart in mice and ferrets. PLoS Pathog. 2010;6: e1001015. 124. Saito R, Sato I, Suzuki Y, et al. Reduced effectiveness of oseltamivir in children infected with oseltamivir-resistant influenza A(H1N1) viruses with His275Tyr mutation. Pediatr Infect Dis. 2010;29:898-904. 125. Stephenson I, Democratis J, Lackenby A, et al. Neuramini­ dase inhibitor resistance after oseltamivir treatment of acute influenza A and B in children. Clin Infect Dis. 2009; 48:389-396. 126. Rath B, von Kleist M, Tief F, et al. Virus load kinetics and resistance development during oseltamivir treatment in infants and children infected with influenza A(H1N1) 2009 and influenza B viruses. Pediatr Infect Dis J. 2012;31: 899-905.

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202. Pizzorno A, Abed Y, Bouhy X, et al. Impact of mutations at residue I223 of the neuraminidase protein on the resis­ tance profile, replication level, and virulence of the 2009 pandemic influenza virus. Antimicrob Agents Chemother. 2012;56:1208-1214. 203. Abed Y, Pizzorno A, Boivin G. Therapeutic activity of intra­ muscular peramivir in mice infected with a recombinant influenza A/WSN/33 (H1N1) virus containing the H27Y neuraminidase mutation. Antimicrob Agents Chemother. 2012;56:4375-4379. 204. Kohno S, Kida H, Mizugichi M, et al. Intravenous perami­ vir for treatment of influenza A and B virus infection in high-risk patients. Antimicrob Agents Chemother. 2011;55: 2803-2812. 205. World Health Organization. WHO Guidelines for Pharma­ cologic Management of Pandemic Influenza A (H1N1) 2009 and Other Influenza Viruses. Available at: http:// www.who.int/csr/resources/publications/swineflu/h1n1_ guidelines_pharmaceutical_mngt.pdf. Accessed Novem­ ber 9, 2010. 206. Peramivir Investigator Brochure. Cary, NC: Biocryst Phar­ maceuticals; 2007. 207. Sugaya N, Kohno S, Ishibashi T, et al. Efficacy, safety and pharmacokinetics of intravenous peramivir in children with 2009 pandemic H1N1 influenza virus infection. Antimicrob Agents Chemother. 2012;56:369-377. 208. Kohno S, Kida H, Mizuguchi M, et al. Efficacy and safety of intravenous peramivir for treatment of seasonal influ­ enza virus infection. Antimicrob Agents Chemother. 2010; 54:4568-4574. 209. Drusano GL, Preston SL, Smee D, et al. Pharmacodynamic evaluation of RWJ-270-201, a novel neuraminidase inhibi­ tor, in a lethal murine model predicts efficacy for once daily dosing. Antimicrob Agents Chemother. 2001;45: 2115-2118. 210. Peramivir. In: Clinical Pharmacology. Tampa, FL: Elsevier/ Gold Standard; 2009. Available at http://download.thelancet .com/flatcontentassets/H1N1-flu/treatment/treatment-53 .pdf. 211. Ison MG, Hui DS, Clezy K, et al. A clinical trial of intrave­ nous peramivir compared with oral oseltamivir for the treatment of seasonal influenza in hospitalized adults. Antivir Ther. 2013;18:651-661. 212. Alexander JW. Peramivir: An investigational antiviral therapy for seasonal and pandemic influenza. Presented at the Xth International Symposium on Respiratory Viral Infections. Singapore, February 28-March 2, 2008. 213. Kohno S, Yen M-Y, Cheong M-J, et al. Phase III random­ ized, double-blind study comparing single-dose intrave­ nous peramivir with oral oseltamivir in patients with seasonal influenza virus infection. Antimicrob Agents Chemother. 2011;55:5267-5276. 214. Morfin F, Dupuis-Girod S, Carrington D, et al. Adenovirus susceptibility to antiviral drugs is genogroup-dependent. Poster V-282. Presented at the 43rd Interscience Confer­ ence on Antimicrobial Agents and Chemotherapy. Chicago, September 14-17, 2003. 215. Ison MG, Fraiz J, Heller B, et al. Intravenous peramivir for treatment of influenza in hospitalized patients. Antivir Ther. 2013; Aug 28 [Epub ahead of print]. 216. BioCryst Pharmaceuticals, Inc. BioCryst Announces Out­ come from the Peramivir Phase 3 Interim Analysis [Press release]. 2012. Available at http://www.businesswire.com/ news/home/20121107006831/en/BioCryst-Announces -Outcome-Peramivir-Phase-3-Interim. 217. Crance JM, Scaramozzino N, Jouan A, et al. Interferon, ribavirin, 6-azauridine and glycyrrhizin: antiviral com­ pounds active against pathogenic flaviviruses. Antiviral Res. 2003;58:73-79. 218. Cinatl J, Morgenstern B, Bauer G, et al. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet. 2003;361:2045-2046. 219. Heagy W, Crumpacker C, Lopez PA, et al. Inhibition of immune functions by antiviral drugs. J Clin Invest. 1991; 87:1916-1924. 220. Meier V, Burger E, Mihm S, et al. Ribavirin inhibits DNA, RNA, and protein synthesis in PHA-stimulated human peripheral blood mononuclear cells: possible explanation for therapeutic efficacy in patients with chronic HCV infection. J Med Virol. 2003;69:50-58. 221. Tam RC, Lau JY, Hong Z. Mechanisms of action of ribavirin in antiviral therapies. Antivir Chem Chemother. 2002;12: 261-272. 222. Graci JD, Cameron CE. Quasispecies, error catastrophe, and the antiviral activity of ribavirin. Virology. 2002;298: 175-180. 223. Hong Z, Cameron CE. Pleiotropic mechanisms of ribavirin antiviral activities. Prog Drug Res. 2002;59:41-69. 224. Vo NV, Young KC, Lai MM. Mutagenic and inhibitory effects of ribavirin on hepatitis C virus RNA polymerase. Biochemistry. 2003;42:10462-10471. 225. Fernandez-Larsson R, Patterson JL. Ribavirin is an inhibi­ tor of human immunodeficiency virus reverse transcrip­ tase. Mol Pharmacol. 1990;38:766-770.

Chapter 44  Antiviral Drugs for Influenza and Other Respiratory Virus Infections

155. Dutkowski R, Smith JR, Davies BE. Safety and pharmaco­ kinetics of oseltamivir at standard and high dosages. Int J Antimicrob Agents. 2010;35:461-467. 156. Ison MG, Szakaly P, Shapira MY, et al. Efficacy and safety of oral oseltamivir for influenza prophylaxis in transplant recipients. Antivir Ther. 2012;17:955-964. 157. Tamiflu 2006 Product Monograph. 158. Casscells SW, Granger E, Kress AM, et al. The association between oseltamivir use and adverse neuropsychiatric out­ comes among TRICARE beneficiaries, ages 1 through 21 years diagnosed with influenza. Int J Adolesc Med Health. 2009;21:79-89. 159. Smith JR, Sacks S. Incidence of neuropsychiatric and adverse events in influenza patients treated with oseltami­ vir or no antiviral treatment. Int J Clin Pract. 2009;63: 596-605. 160. Greene SK, Li L, Shay DK, et al. Risk of adverse events following oseltamivir treatment in influenza outpatients, Vaccine Safety Datalink Project, 2007-2010. Pharmacoepidemiol Drug Saf. 2013;22:335-344. 161. Urushihara H, Doi Y, Arai M, et al. Oseltamivir prescrip­ tion and regulatory actions vis-à-vis abnormal behavior risk in Japan: drug utilization study using a nationwide pharmacy database. PLoS One. 2011;6:e28483. 162. Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza. JAMA. 2000;283:1016-1024. 163. Cooper NJ, Sutton AJ, Abrams KR, et al. Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomised controlled trials. BMJ. 2003;326:1235-1239. 164. Boivin G, Coulombe Z, Wat C. Quantification of the influ­ enza virus load by real-time polymerase chain reaction in nasopharyngeal swabs of patients treated with oseltamivir. J Infect Dis. 2003;188:578-580. 165. Aoki FY, Macleod MD, Paggiaro P, et al. Early administra­ tion of oral oseltamivir increases the benefits of influenza treatment. J Antimicrob Chemother. 2003;51:123-129. 166. Kaiser L, Wat C, Mills T, et al. Impact of oseltamivir treat­ ment on influenza-related lower respiratory tract compli­ cations and hospitalizations. Arch Intern Med. 2003;163: 1667-1672. 167. Jefferson T, Jones M, Doshi P, et al. Neuraminidase inhibi­ tors for preventing and treating influenza in healthy adults: systematic review and meta-analysis. BMJ. 2009;339:b5106. 168. Hsu J, Santesso N, Mustafa R, et al. Antivirals for treatment of influenza: a systematic review and meta-analysis of observational studies. Ann Intern Med. 2012;156:512-524. 169. McGeer A, Green KA, Plevneshi A, et al. Antiviral therapy and outcomes of influenza requiring hospitalization in Ontario, Canada. Clin Infect Dis. 2007;45:1568-1575. 169a.  Muthuru SG, Venkatersan S, Myles PG, et al. Effectiveness of neuraminidase inhibitors in reducing the mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med. 2014;2:395-404. 169b.  Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev. 2014;4: CD008965. 170. Muthuri SG, Myles PR, Vankatesan S, et al. Impact of neur­ aminidase inhibitor treatment on outcomes of public health importance during the 2009-2010 influenza A (H1N1) pandemic in a systematic review and metaanalysis in hospitalized patients. J Infect Dis. 2013;207:533-563. 171. Yang S-G, Cao B, Liang L-R, et al. Antiviral therapy and outcomes of patients with pneumonia caused by influenza A pandemic (H1N1) virus. PLoS One. 2012;7:29652. 172. Siston AM, Rasmussen SA, Honein MA, et al. Pandemic 2009 influenza A (H1N1) virus illness among pregnant women in the United States. JAMA. 2010;303:1517-1525. 173. Halloran ME, Hayden FG, Yang Y, et al. Antiviral effects in influenza viral transmission and pathogenicity: observa­ tions from household based trials. Am J Epidemiol. 2006; 165:212-221. 174. Ng S, Cowling BJ, Fang VJ, et al. Effects of oseltamivir treatment on duration of clinical illness and viral shedding and household transmission of influenza virus. Clin Infect Dis. 2009;50:707-714. 175. Sugaya N, Mitamura K, Yamazaki M, et al. Lower clinical effectiveness of oseltamivir against influenza B contrasted with influenza A infection in children. Clin Infect Dis. 2007;44:197-202. 176. Kawai N, Ikematsu H, Iwaki N, et al. A comparison of the effectiveness of oseltamivir for the treatment of influenza A and influenza B: a Japanese multicenter study of the 2003-2004 and 2004-2005 influenza seasons. Clin Infect Dis. 2006;43:439-444. 177. Adisasmito W, Chan PKS, Lee N, et al. Effectiveness of antiviral treatment in human influenza A (H5N1) infec­ tions: analysis of a global registry. J Infect Dis. 2010;202: 1154-1160. 178. Nichols WG, Guthrie KA, Corey L, et al. Influenza infec­ tions after hematopoietic stem cell transplantation: risk


Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

545.e4 226. Young KC, Lindsay KL, Lee KJ, et al. Identification of a ribavirin-resistant NS5B mutation of hepatitis C virus during ribavirin monotherapy. Hepatology. 2003;38: 869-878. 227. Glue P. The clinical pharmacology of ribavirin. Semin Liver Dis. 1999;19(suppl 1):17-24. 228. Preston SL, Drusano GL, Glue P, et al. Pharmacokinetics and absolute bioavailability of ribavirin in healthy volun­ teers as determined by stable-isotope methodology. Antimicrob Agents Chemother. 1999;43:2451-2456. 229. Laskin OL, Longstreth JA, Hart CC, et al. Ribavirin disposi­ tion in high-risk patients for acquired immunodeficiency syndrome. Clin Pharmacol Ther. 1987;41:546-555. 230. Glue P, Schenker S, Gupta S, et al. The single dose pharma­ cokinetics of ribavirin in subjects with chronic liver disease. J Clin Pharmacol. 2000;49:417-421. 231. Jen JF, Glue P, Gupta S, et al. Population pharmacokinetic and pharmacodynamic analysis of ribavirin in patients with chronic hepatitis C. Ther Drug Monit. 2000;22: 555-565. 232. ICN Pharmaceuticals ICMC. Investigational Drug Bro­ chure, Intravenous Ribavirin IND 9,076. February 2001. 233. Dieterich DT, Spivak JL. Hematologic disorders associated with hepatitis C virus infection and their management. Clin Infect Dis. 2003;37:533-541. 234. Di Bisceglie AM, Conjeevaram HS, Fried MW, et al. Riba­ virin as therapy for chronic hepatitis C: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1995;123:897-903. 235. Knowles SR, Phillips EJ, Dresser L, et al. Common adverse events associated with the use of ribavirin for severe acute respiratory syndrome in Canada. Clin Infect Dis. 2003;37: 1139-1142. 236. Bradley JS, Connor JD, Compogiannis LS, et al. Exposure of health care workers to ribavirin during therapy for respi­ ratory syncytial virus infections. Antimicrob Agents Chemother. 1990;34:668-670. 237. Deleted in proofs. 238. Randolph AG, Wang EE. Ribavirin for respiratory syncytial virus lower respiratory tract infection: a systematic over­ view. Arch Pediatr Adolesc Med. 1996;150:942-947. 239. Guerguerian AM, Gauthier M, Lebel MH, et al. Ribavirin in ventilated respiratory syncytial virus bronchiolitis: a randomized, placebo-controlled trial. Am J Respir Crit Care Med. 1999;160:829-834. 240. Englund JA, Piedra PA, Jefferson LS, et al. High-dose, short-duration ribavirin aerosol therapy in children with suspected respiratory syncytial virus infection. J Pediatr. 1990;117:313-320. 241. American Academy of Pediatrics. Respiratory syncytial virus. In: Pickering LK, Baker CJ, Kimberlin W, et al, eds. Red Book. 2012 Report of the Committee on Infectious Diseases. Elk Grove Village, IL: American Academy of Pediat­ rics; 2012:609-618. 242. Long CE, Voter KZ, Barker WH, et al. Long term follow-up of children hospitalized with respiratory syncytial virus lower respiratory tract infection and randomly treated with ribavirin or placebo. Pediatr Infect Dis J. 1997;16: 1023-1028. 243. Small TN, Casson A, Malak SF, et al. Respiratory syncytial virus infection following hematopoietic stem cell trans­ plantation. Bone Marrow Transplant. 2002;29:321-327. 244. Boeckh M, Berrey MM, Bowden RA, et al. Phase 1 evalu­ ation of the respiratory syncytial virus–specific monoclo­ nal antibody palivizumab in recipients of hematopoietic stem cell transplants. J Infect Dis. 2001;184:350-354. 245. Krilov LR. Respiratory syncytial virus disease: update on treatment and prevention. Expert Rev Anti Infect Ther. 2011;9:27-32. 246. Llungman P, Ward KN, Crooks RN, et al. Respiratory tract infection after stem cell transplantation: a prospective study from the Infectious Diseases Working Group of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2001;28:479-484. 247. Lewinsohn DM, Bowden RA, Mattson D, et al. Phase I study of intravenous ribavirin treatment of respiratory syn­ cytial virus pneumonia after marrow transplantation. Antimicrob Agents Chemother. 1996;40:2555-2557. 248. Boeckh M, Englund J, Li Y, et al. Randomized controlled multicenter trial of aerosolized ribavirin for respiratory syncytial virus upper respiratory tract infection in hema­ topoietic cell transplant recipients. Clin Infect Dis. 2007; 44:245-249. 249. Chemaly RF, Torres HA, Munsell MF, et al. An adaptive randomized trial of an intermittent dosing schedule of aerosolized ribavirin in patients with cancer and respiratory syncytial virus infection. J Infect Dis. 2012;206:136-171. 250. McCoy D, Wong E, Kuyumjian AG, et al. Treatment of respiratory syncytial virus infection in adult patients with hematologic malignancies based on an institution-specific guideline. Transpl Infect Dis. 2011;13:117-121. 251. Khanna N, Widmer AF, Decker M, et al. Respiratory syn­ cytial virus infection in patients with hematological dis­ eases: single-center study and review of the literature. Clin Infect Dis. 2008;46:402-412.

252. Gueller S, Duenzinger U, Wolf T, et al. Treatment of respi­ ratory syncytial virus–induced tracheobronchitis and pneumonia occurring pre-engagement in allogeneic hema­ topoietic stem cell transplant recipients can be safely treated with high-dose ribavirin. Bone Marrow Transpl. 2010;45:S215. 253. Li L, Avery R, Budev M, et al. Oral versus inhaled ribavi­ rin therapy for respiratory syncytial virus infection after lung transplantation. J Heart Lung Transpl. 2012;31:839844. 254. Pelaez A, Lyon GM, Force SD, et al. Efficacy of oral ribavi­ rin in lung transplant patients with respiratory syncytial virus lower respiratory tract infection. J Heart Lung Transpl. 2009;28:67-71. 255. Hayden FG, Sable CA, Connor JD, et al. Intravenous riba­ virin by constant infusion for serious influenza and para­ influenzavirus infection. Antiviral Ther. 1996;1:51-56. 256. Chan-Tack KM, Murray JS, Birnkrant DB. Use of ribavirin to treat influenza. N Engl J Med. 2009;361:1713-1714. 257. Rodriguez WJ, Hall CB, Welliver R, et al. Efficacy and safety of aerosolized ribavirin in young children hospital­ ized with influenza: a double-blind, multicenter, placebocontrolled trial. J Pediatr. 1994;125:129-135. 258. Kim Y, Young Suh G, Huh JW, et al. Triple-combination antiviral drug for pandemic H1N1 influenza virus infec­ tion in critically ill patients on mechanical ventilation. Antimicrob Agents Chemother. 2011;55:5703-5709. 259. Nichols WG, Corey L, Gooley T, et al. Parainfluenza virus infections after hematopoietic stem cell transplantation: risk factors, response to antiviral therapy, and effect on transplant outcome. Blood. 2001;98:573-578. 260. Chakrabarti S, Collingham KE, Holder K, et al. Preemptive oral ribavirin therapy of paramyxovirus infections after haematopoietic stem cell transplantation: a pilot study. Bone Marrow Transplant. 2001;28:759-763. 261. Souza ILA, Schnert L, Goto JM, et al. Oral ribavirin in treatment of adenovirus infection in hematologic patients: experience from a Brazilian university hospital. Clin Microbiol Infect. 2010;16:S24. 262. Gavin PJ, Katz BZ. Intravenous ribavirin treatment for severe adenovirus disease in immunocompromised chil­ dren. Pediatrics. 2002;110:E9. 263. Bonney D, Razati H, Turner A, et al. Successful treatment of human metapneumovirus pneumonia using combina­ tion therapy with intravenous ribavirin and immune globulin. Br J Haematol. 2009;45:667-679. 264. Raza K, Ismailjee SB, Crespo M, et al. Successful outcome of human metapneumovirus (hMPV) pneumonia in a lung transplant recipient treated with intravenous ribavirin. J Heart Lung Transpl. 2007;26:862-864. 265. Schachor-Meyouhas Y, Ben-Barak A, Kassis I. Treatment with oral ribavirin and IVIG of severe human metapneu­ movirus pneumonia in immune compromised child. Pediatr Blood Cancer. 2011;57:350-351. 266. Fuehner T, Dierich M, Duesbert C, et al. Single-centre experience with oral ribavirin in lung transplant recipients with paramyxovirus infections. Antivir Ther. 2011;16: 1733-1740. 267. Shima T, Yoshimoto G, Nonami A, et al. Successful treat­ ment of parainfluenza virus 3 pneumonia with oral ribavi­ rin and methylprednisolone in a bone marrow transplant recipient. Int J Hematol. 2008;88:336-340. 268. Wright JJ, O’Driscoll G. Treatment of parainfluenza virus 3 pneumonia in a cardiac transplant recipient with intra­ venous ribavirin and methylprednisone. J Heart Lung Transpl. 2005;24:343-346. 269. Kanji J, Vaudry W. Successful cardiac transplantation in a 4-year-old child with active parainfluenza-3 infection: experience with systemic ribavirin therapy. Can J Infect Dis Med Microbiol. 2011;22:16A. 270. Mazzulli T, Farcas GA, Poutanen SM, et al. Severe acute respiratory syndrome–associated coronavirus in lung tissue. Emerg Infect Dis. 2004;10:20-24. 271. Chapman LE, Mertz GJ, Peters CJ, et al. Intravenous riba­ virin for hantavirus pulmonary syndrome: safety and toler­ ance during 1 year of open-label experience. Ribavirin Study Group. Antivir Ther. 1999;4:211-219. 272. Safronetz D, Haddock E, Feldmann H, et al. In vitro and in vivo activity against Andes virus infection. PLoS One. 2011;6:e23560. 273. Henderson E, Alber D, Baxter R, et al. 1,4-Benzodiazepines as inhibitors of respiratory syncytial virus: the identifica­ tion of a clinical candidate. J Med Chem. 2007;50: 1685-1692. 274. Olszewska W, Openshaw P. Emerging drugs for respiratory syncytial virus infection. Expert Opin Emerg Drugs. 2009;14:207-217. 275. Chapman J, Abbott E, Alber D, et al. RSV604, a novel inhibitor of respiratory syncytial virus replication. Antimicrob Agents Chemother. 2007;51:3346-3353. 276. von Itzstein M, Wu WY, Kok GB, et al. Rational design of potent sialidase-based inhibitors of influenza virus replica­ tion. Nature. 1993;363:418-423. 277. Cheer SM, Wagstaff AJ. Zanamivir: an update of its use in influenza. Drugs. 2002;62:71-106.

278. Woods JM, Bethell RC, Coates JA, et al. 4-Guanidino2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid is a highly effective inhibitor both of the sialidase (neuramini­ dase) and of growth of a wide range of influenza A and B viruses in vitro. Antimicrob Agents Chemother. 1993;37: 1473-1479. 279. Kawai N, Ikematsu H, Iwaki N, et al. Comparison of the effectiveness of zanamivir and oseltamivir for the treatment of influenza A and B. J Infect. 2008;36:51-57. 280. McKimm-Breschkin J, Trivedi T, Hampson A, et al. Neur­ aminidase sequence analysis and susceptibilities of influ­ enza virus clinical isolates to zanamivir and oseltamivir. Antimicrob Agents Chemother. 2003;47:2264-2272. 281. Govorkova FA, Fang H-B, Tam M, et al. Neuraminidase inhibitor-rimantadine combinations exert additive and synergistic anti-influenza virus effects in MDCK cells. Antimicrob Agents Chemother. 2004;48:4855. 282. Hata K, Koseki K, Yamaguchi K, et al. Limited inhibitory effect of oseltamivir and zanamivir on human sialadases. Antimicrob Agents Chemother. 2008;52:3484-3491. 283. Murrell M, Porotto M, Weber T, et al. Mutations in human parainfluenza virus type 3 hemagglutinin-neuraminidase causing increased receptor binding activity and resistance to the transition state sialic acid analog 4-GU-DANA (Zanamivir). J Virol. 2003;77:309-317. 284. Thorlund K, Awad T, Boivin G, et al. Systematic review of influenza resistance to the neuraminidase inhibitors. BMC Infect Dis. 2011;11:134. Also available at http://www .biomedcentral.com/1471-2334/11/134. 285. World Health Organization. Influenza A (H1N1) virus resistance to oseltamivir—2008/2009 influenza season, northern hemisphere, 18 March 2009. Available at http:// www.who.int/influenza/resources/documents/H1N1web update20090318_ed_ns.pdf. Accessed February 23, 2012. 286. Hurt AC, Holien JK, Parker M, et al. Zanamivir-resistant influenza viruses with a novel neuraminidase mutation. J Virol. 2009;83:10366-10373. 287. Gubareva LV, Trujillo AA, Okimo-Achiambo M, et al. Comprehensive assessment of 2009 pandemic influenza A(H1N1) virus drug susceptibility in vitro. Antivir Ther. 2010;15:1151-1159. 288. World Health Organization. Weekly update on oseltamivir resistance to influenza A (H1N1) 2009 viruses. Available at http://www.who.int/csr/disease/swineflu/oseltamivir resistant20/00820pdf. Accessed December 30, 2010. 289. McKimm-Breschkin JL, Selleck PW, Usman TB, et al. Reduced sensitivity of influenza A (H5N1) to oseltamivir. Emerg Infect Dis. 2007;13:1354-1357. 290. Wang D, Sleeman K, Huang W, et al. Neuraminidase inhib­ itor susceptibility testing of influenza type B viruses in China during 2010 and 2011 identifies viruses with reduced susceptibility to oseltamivir and zanamivir. Antiviral Res. 2013;97:240-244. 291. Hurt AC, Lee RT, Leang SK, et al. Increased detection in Australia and Singapore of a novel influenza A (H1N1) 2009 variant with reduced oseltamivir and zanamivir sen­ sitivity due to a S274N neuraminidase mutation. Euro Surveill. 2011;16:19884. 292. LeGoff J, Rousset D, Abou-Jaoude G, et al. I223R mutation in influenza A(H1N1)pdm09 neuraminidase confers reduced susceptibility to oseltamivir and zanamivir and enhanced resistance with H275Y. PLoS One. 2012;7:e37095. 293. Gubareva LV, Matrosovich MN, Brenner MK, et al. Evi­ dence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis. 1998; 178:1257-1262. 294. Pizzorno A, Abed Y, Bouhy X, et al. Impact of mutations at residue I223 of the neuraminidase protein on the resis­ tance profile, replication level, and virulence of the 2009 pandemic influenza virus. Antimicrob Agents Chemother. 2012;56:1208-1214. 295. Ilyushina NA, Seiler JP, Rehg JE, et al. Effect of neuramini­ dase inhibitor–resistant mutations on pathogenicity of clade 2.2 A/Turkey/15/06/(H5N1) influenza virus in ferrets. PLos Pathog. 2010;6:e1000933. 296. Tamura D, Sugaya N, Ogawa M, et al. Frequency of drugresistant viruses and virus shedding in pediatric influenza patients treated with neuraminidase inhibitors. Clin Infect Dis. 2011;52:e56-e93. 297. Lee C, Loeb M, Phillips A, et al. Zanamivir use during trans­ mission of amantadine-resistant influenza A in a nursing home. Infect Control Hosp Epidemiol. 2000;21:700-704. 298. Diggory P, Fernandez C, Humphrey A, et al. Comparison of elderly people’s technique in using two dry powder inhalers to deliver zanamivir: randomised controlled trial. BMJ. 2001;322:1-4. 299. Shelton MJ, Lovern M, Bg-Cashin J, et al. Zanamivir phar­ macokinetics and pulmonary penetration into epithelial lung fluid following intravenous or oral inhaled adminis­ tration to healthy adult subjects. Antimicrob Agents Chemother. 2011;55:5178-5184. 300. Peng AW, Milleri S, Stein DS. Direct measurement of the anti-influenza agent zanamivir in the respiratory tract fol­ lowing inhalation. Antimicrob Agents Chemother. 2000;44: 1974-1976.


545.e5 318. Hayden FG, Osterhaus ADME, Treanor JJ, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections. N Engl J Med. 1997;337:874-879. 319. MIST (Management of Influenza in the Southern Hemi­ sphere Trialists) Study Group. Randomized trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. Lancet. 1998;352:1877-1881. 320. Monto AS, Webster A, Keene O. Randomized, placebocontrolled studies of inhaled zanamivir in the treatment of influenza A and B: pooled efficacy analysis. J Antimicrob Chemother. 1999;44:23-29. 321. Kaiser L, Keene ON, Hammond J, et al. Impact of zanami­ vir on antibiotics use for respiratory events following acute influenza in adolescents and adults. Arch Intern Med. 2000;160:3234-3240. 322. Kawai N, Ikematsu H, Iwaki N, et al. Zanamivir treatment is equally effective for both influenza A and influenza B [letter]. Clin Infect Dis. 2007;44:1666. 323. Lalezari JP, Elliott M, Keene O. Zanamivir for the treatment of influenza A and B infection in high-risk patients [abstract]. Arch Intern Med. 2001;161:212-217. 324. Johny AA, Clark A, Price N, et al. The use of zanamivir to treat influenza A and B infection after allogeneic stem cell transplantation. Bone Marrow Transplant. 2002;29: 113-115. 325. Gukareva LV, Matrosovich MN, Brenner MK, et al. Evi­ dence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis. 1998; 178:1257-1262. 326. Kawai N, Ikematsu H, Hirotsu N. Clinical effectiveness of oseltamivir and zanamivir for treatment of influenza A virus subtype H1N1 with the H274Y mutation: a Japanese, multicenter study of the 2007-2008 and 2008-2009 influ­ enza seasons. Clin Infect Dis. 2009;49:1828-1835. 327. Monto AS, Robinson DP, Herlocher L, et al. Zanamivir in the prevention of influenza among healthy adults. JAMA. 1999;282:31-36. 328. Hayden FG, Gubareva LV, Monto AS, et al. Inhaled zana­ mivir for preventing influenza in families. N Engl J Med. 2000;343:1282-1289. 329. Monto AS, Pichichero ME, Blanckenberg SJ, et al. Zanami­ vir prophylaxis: an effective strategy for the prevention of influenza types A and B within households. J Infect Dis. 2002;186:1582-1588. 330. Shinjoh M, Takano Y, Takahashi T, et al. Postexposure pro­ phylaxis for influenza in pediatric wards: oseltamivir or zanamivir after rapid antigen detection. Pediatr Infect Dis J. 2012;31:1119-1123. 331. Gravenstein S, Drinka P, Osterweil D, et al. A multicenter prospective double-blind randomized controlled trial com­ paring the relative safety and efficacy of zanamivir to rimantadine for nursing home influenza outbreak control [abstract 1155]. Presented at the 40th Interscience Confer­ ence on Antimicrobial Agents and Chemotherapy. Toronto, September 17-20, 2000. 332. Carrat F, Duval X, Tubach F, et al. Effect of oseltamivir, zanamivir, or oseltamivir-zanamivir combination treat­ ments on transmission of influenza in households. Antivir Ther. 2012;17:1085-1090. 333. Duval X, van der Werf S, Blanchon T, et al. Efficacy of oseltamivir-zanamivir combination compared to each monotherapy for seasonal influenza: a randomized placebo-controlled trial. PLoS Med. 2010;7:e1000362. 334. Biatto JF, Costa EL, Pastore L, et al. Prone position ventila­ tion, recruitment maneuver and intravenous zanamivir in severe refractory hypoxemia caused by influenza A (H1N1). Clinics (Sao Paulo, Brazil). 2010;65:1211-1213.

335. Ghosh S, Adams O, Schuster FR, et al. Efficient control of pandemic 2009 H1N1 virus infection with intravenous zanamivir despite the lack of immune function. Transpl Infect Dis. 2012;14:657-659. 336. Dohna-Schwake C, Schweiger B, Felderhoff-Muser U, et al. Severe H1N1 infection in a pediatric liver transplant recipi­ ent treated with intravenous zanamivir: efficiency and complications. Transplantation. 2010;90:223-224. 337. Guar AH, Bagga B, Barman S, et al. Intravenous zanamivir for oseltamivir-resistant 2009 H1N1 influenza. N Engl J Med. 2010;362:88-89. 338. Kidd IM, Down J, Nastouli E, et al. H1N1 pneumonitis treated with intravenous zanamivir. Lancet. 2009;374: 1036. 339. Dulek DE, Williams JV, Creech CB, et al. Use of intrave­ nous zanamivir after development of oseltamivir resistance in a critically ill immune-suppressed child infected with 2009 pandemic influenza A (H1N1) virus. Clin Infect Dis. 2010;50:1493-1496. 340. Harter G, Zimmermann O, Maier L, et al. Intravenous zanamivir for patients with pneumonitis due to pandemic (H1N1) 2009 influenza virus. Clin Infect Dis. 2010;50: 1249-1251. 341. Uhl D. [New influenza: zanamivir intravenous administra­ tion seems life-saving]. Dtsch Apoth Ztg. 2009;149:47 [in German]. 342. Fry AM, Perez A, Finelli L. Use of intravenous neur­ aminidase inhibitors during the 2009 pandemic: results from population-based surveillance. JAMA. 2011;306:160162. 343. Macdonald SJF, Cameron R, Demaine DA, et al. Dimeric zanamivir conjugates with various linking groups are potent long-lasting inhibitors of influenza neuraminidase dose including H5N1 avian influenza. J Med Chem. 2005; 48:2964-2971. 344. Masuda T, Yoshida S, Arai M, et al. Synthesis and antiinfluenza evaluation of polyvalent sialadose inhibitors bearing 4-quanidino-Neu5Acw2en derivatives. Chem Pharm Bull. 2003;51:1386-1398. 345. Macdonald SJF, Watson KG, Cameron R, et al. Potent and long-acting dimeric inhibitors of influenza virus neur­ aminidase are effective at a once-weekly dosing regimen. Antimicrob Agents Chemother. 2004;48:4542-4549. 346. Watson KG, Cameron R, Fenton RJ, et al. Highly potent and long-acting trimeric and tetrameric inhibitors of influ­ enza virus neuraminidase. Bioorg Med Chem Lett. 2004; 14:1589-1592. 347. Honda T, Masuda T, Yoshida S, et al. Synthesis and antiinfluenza virus activity of 4-quanidino-7-substituted Neu5A-c2en derivatives. Bioorg Med Chem Lett. 2002;12: 1921-1924. 348. Honda T, Toshida S, Arai M, et al. Synthesis and antiinfluenza evaluation of polyvalent sialidase inhibitors bearing 4-quanidino-Neu5Ac2en derivatives. Bioorg Med Chem Lett. 2002;12:1929-1932. 349. Honda T, Masuda T, Yoshida S, et al. Synthesis and anti-influenza virus activity of 7-0-alkylated derivatives related to zanamivir. Bioorg Med Chem Lett. 2002;12: 1925-1928. 350. Weight AK, Haldar J, Alvarez de Cienfuegos L, et al. Attaching zanamivir to a polymer markedly enhances its activity against drug-resistant strains of influenza A virus. J Pharm Sci. 2011;100:831-835. 351. Lee CM, Weight AK, Haldar J, et al. Polymer-attached zanamivir inhibits synergistically both early and late stages of influenza virus infection. Proc Natl Acad Sci U S A. 2012;109:20385-20390.

Chapter 44  Antiviral Drugs for Influenza and Other Respiratory Virus Infections

301. Weller S, Thamlikitkul V, Francois B, et al. Pharmacokinet­ ics of intravenous zanamivir in hospitalized adults with influenza: interim results from open-label phase II study NAI 113678 [abstract 764]. Presented at the Annual Meeting of the Infectious Diseases Society of America. Vancouver, Canada, October 21-24, 2010. 302. Cass LMR, Efthymiopoulas C, March J, et al. Effect of renal impairment on the pharmacokinetics of intravenous zana­ mivir. Clin Pharmacokinet. 1999;36(suppl 1):13-19. 303. European Medicines Agency. Conditions of Use, Condi­ tions for Distribution and Patients Targeted and Conditions for Safety Monitoring Addressed to Member States for IV Zanamivir Available for Compassionate Use. June 23, 2011. Available at http://www.ema.europa.eu/docs/en_GB/ document_library/Other/2010/02/WC500074124.pdf. Accessed January 15, 2014. 304. Pukrittayakamee S, Jittamala P, Stepniewska K, et al. An op-label crossover study to evaluate potential pharmacoki­ netic interactions between oral oseltamivir and intrave­ nous zanamivir in healthy Thai adults. Antimicrob Agents Chemother. 2011;55:4050-4057. 305. Centers for Disease Control and Prevention. Recommen­ dation of the Advisory Committee on Immunization Prac­ tices (ACIP), 2008: prevention and control of influenza. MMWR Recomm Rep. 2008;157(RR):1-60. 306. Freund B, Gravenstein S, Elliott M, et al. Zanamivir: a review of clinical safety. Drug Saf. 1999;21:267-281. 307. Hedrick JA, Barzilai A, Behre U, et al. Zanamivir for treat­ ment of symptomatic influenza A and B infection in chil­ dren five to twelve years of age: a randomized controlled trial. Pediatr Infect Dis J. 2000;19:410-417. 308. Anekthananon T, Pukritayakamee S, Ratanasuwan W, et al. Oseltamivir and inhaled zanamivir as influenza prophy­ laxis in Thai health workers: a randomized, double-blind, placebo-controlled safety trial over 16 weeks. J Antimicrob Chemother. 2013;68:697-707. 309. Gravenstein S, Johnston SL, Loeschel E, et al. Zanamivir: a review of clinical safety in individuals at high risk of developing influenza-related complications. Drug Saf. 2001;24:1113-1125. 310. Murphy K, Eivindson A, Pauksens K, et al. Efficacy and safety of inhaled zanamivir for the treatment of influenza in patients with asthma or chronic obstructive pulmonary disease. Clin Drug Invest. 2000;20:337-349. 311. FDA Public Health Advisory. Safe and Appropriate Use of Influenza Drugs. Available at http://www.fda.gov/cder/ drug/advisory/influenza.htm. Accessed January 12, 2000. 312. Fleming DM. Zanamivir in the treatment of influenza. Expert Opin Pharmacother. 2003;4:799-805. 313. Ison MG, Gnann JW Jr, Nagy-Agren S, et al. Safety and efficacy of nebulized zanamivir in hospitalized patients with serious influenza. Antivir Ther. 2003;8:183-190. 314. Kiatboonsri S, Kiatboonsri C, Theerawit P. Fatal respiratory events caused by zanamivir nebulization. Clin Infect Dis. 2010;50:620. 315. Cass LMR, Efthymiopoulas C, Bye A. Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration in healthy volunteers. Clin Pharmcokinet. 1999;36(suppl 1):1-11. 316. Poster 1626: Safety, tolerability and pharmacokinetics of intravenous zanamivir treatment in hospitalized adults with influenza: a phase 2 open-label, multicenter, singlearm study. Presented at ID Week, Infectious Diseases Society of America. San Diego, CA, October 17-21, 2012. 317. Walker JB, Hussey EK, Treanor JJ, et al. Effects of the neur­ aminidase inhibitor zanamivir on otologic manifestations of experimental human influenza. J Infect Dis. 1997;176: 1417-1422.


61 

Croup in Children (Acute Laryngotracheobronchitis) John Bower and John T. McBride SHORT VIEW SUMMARY

Definition

• Croup is an acute viral infection of the upper airway presenting as stridor and a brassy cough. • Most children develop croup only once, but a few children develop recurrent episodes called spasmodic croup.

Epidemiology

• Croup can be sporadic but usually occurs in epidemics in the fall that in temperate climates recently have been worse in odd-numbered years.

Etiology and Microbiology

• Parainfluenza type 1 virus infection is the most common cause of viral croup.

• The other parainfluenza viruses, respiratory syncytial virus (RSV), adenovirus, and measles are a few of the other agents associated with viral croup. • Bacterial infections of the airway, including epiglottitis (Haemophilus influenzae type b) and tracheitis (Staphylococcus aureus, Streptococcus), represent medical emergencies and should be rapidly discriminated from viral croup. • Diphtheria should be considered in the developing world and in nonimmunized populations.

Diagnosis

• Diagnosis is clinical, although radiographs of the upper airway may be helpful.

… the sharp stridulous voice which I can resemble to nothing more nearly than the crowing of a cock … is the true diagnostic sign of the disease. Francis Home, 17651 Croup is an age-specific viral infection of the upper and lower respiratory tracts that produces inflammation in the subglottic area and results in a striking picture of dyspnea accompanied on inspiration by the characteristic stridulous notes of croup. Croup demonstrates the piquant interaction of host and microorganism. Age, gender, an undefined predisposition of the child, and the specific virus all seem to influence whether a child’s respiratory tract infection manifests as croup and how severe it is.

HISTORY

Home first introduced the word “croup” in his treatise, “An Inquiry into the Nature, Causes and Cure of the Croup,” in which he described 12 patients with croup.1 The term croup is descended from an AngloSaxon word kropan2 or the old Scottish term roup, which meant “to cry out in a shrill voice.” For the next century, the term croup was applied to numerous probably viral and bacterial diseases, which included diphtheria and “cynache trachealis,” which was often called “membranous” or “true” croup, as opposed to “spasmodic” or “false” croup. Differentiation awaited Klebs’ discovery of Corynebacterium diphtheriae in 1883. In 1948, Rabe3 classified the forms of infectious croup according to etiology—bacterial or nonbacterial—and suggested that the latter, larger group was viral in origin. He was able to identify a pathogen—C. diphtheriae or Haemophilus influenzae type b—in only 15% of his 347 patients.

NOMENCLATURE

The term croup now generally refers to an acute respiratory tract illness characterized by a distinctive barking cough, hoarseness, and inspiratory stridor in a young child, usually between 6 months and 3 years old. This syndrome results from inflammation of varying levels of the upper respiratory tract, which sometimes spreads to the lower respiratory tract, producing concomitant lower respiratory tract findings. 762

• Children with epiglottitis and bacterial tracheitis are typically toxic and have difficulty swallowing and usually lack the brassy cough and harsh stridor. • Recurrent (spasmodic) croup may be more common in children with atopy or gastroesophageal reflux.

Therapy

• Home remedies including mist and cold air have not been proven to be effective. • A single dose of a systemic corticosteroid decreases the severity and length of croup.

Croup is primarily laryngotracheitis and encompasses a spectrum of infections from laryngitis to laryngotracheobronchitis and sometimes laryngotracheobronchopneumonitis. Most common among the clinical argot of croup are recurrent, allergic, and spasmodic croup. Most children develop croup only once or twice despite multiple infections with the viruses that are prime etiologic agents. Some children have recurrent episodes of croup, however, which is often referred to as “spasmodic croup.” Spasmodic croup and “allergic croup” also have been applied to cases that tend to be sudden in onset, often at night, with minimal coryza and fever, and that occur among children with a family history of croup or atopy.4 Spasmodic croup generally cannot be differentiated from a single episode of the usual type of croup, however, in its clinical manifestations or in its etiology, which is usually viral.

INCIDENCE

Croup is a common illness among outpatients, but few cases require hospitalization.4-7 Croup occurs in 2% to 6% of young children each year. About 10% to 16% of all children experience at least one attack of croup, and 5% have recurrent croup, consisting of three or more episodes. The peak occurrence is in the second year of life, with most cases occurring between 3 months and 3 years of age. In a Seattle prepaid group practice, the annual incidence of croup was 7 per 1000 for all children younger than 6 years, and the peak incidence in the second year of life was 14.9 per 1000 children.7 Among children younger than 2 years of age presenting to emergency departments in Alberta, Canada, for the period 1999 to 2005, the rates of croup ranged from 30.9 to 49.6 per 1000 emergency department visits.8 Hospital admissions have significantly declined in recent years in correlation with the use of effective outpatient therapy for croup. From 1979 to 1997, croup cases associated with parainfluenza viruses, estimated from the National Hospital Discharge Survey, showed that the number of admissions among children younger than 5 years decreased by approximately one third.5 The average annual rates of hospitalizations for croup during 1972 to 1984 compared with 1994 to 1997 for children younger than 1 year decreased by 25% from 2.8 to 2.1 per 1000 children per year; and for children 1 to 4 years old, the annual


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KEYWORDS

Chapter 61â&#x20AC;&#x201A; Croup in Children (Acute Laryngotracheobronchitis)

bacterial tracheitis; croup; dexamethasone; epiglottitis; laryngotracheobronchitis; nebulized epinephrine; parainfluenza virus; spasmodic croup; stridor; upper airway obstruction


763

ETIOLOGY

Among children evaluated for croup in an emergency department, one or more viral agents were identified in 80% of specimens by reversetranscriptase polymerase chain reaction (RT-PCR) assay; the parainfluenza viruses were detected most frequently.10 No matter what means of detection were used, studies over decades have consistently shown that the parainfluenza viruses, especially type 1, are the most frequent cause of croup.4-7,10-12 Only the parainfluenza viruses are associated with the major peaks of occurrence of croup cases (Fig. 61-1). Parainfluenza type 1 has been identified in approximately one fourth to one third of cases. Parainfluenza type 3 generally is the second most commonly associated virus, accounting for 6% to 10% of cases. A small proportion of all influenza illnesses among children is associated with croup, but among croup cases, influenza accounts for 1% to 10% of cases depending on the year and circulating strain. Similarly, although respiratory syncytial virus (RSV) infections are particularly prevalent among this age group, relatively few (about 5% of RSV infections) manifest as croup. More recent studies using RT-PCR methods have suggested an etiologic role for viruses other than the parainfluenza viruses. Rhinoviruses, enteroviruses, adenoviruses, and bocavirus have been detected in 9% to 13% of specimens from children with croup.10,12,13 Croup has also been observed in a small percentage of children younger than 5 years of age infected with metapneumovirus.14 The human coronaviruses (hCoV) have been identified in up to 7% of young children with acute respiratory tract infections, with the NL63 strain most often associated with croup.15 In Seoul, South Korea, hCoV NL63 was the second most commonly isolated virus from children presenting with croup.16 The significance of these associations, however, is unclear because respiratory viruses often appear as coinfections and studies have been limited by small sample sizes. Larger studies are needed to confirm these findings.17

Jan Feb Mar Apr May June July Aug Sep Oct Nov Dec Croup cases Parainfluenza type 1 Parainfluenza type 2 Parainfluenza type 3 Picornaviruses (rhino, enteroviruses)

Respiratory syncytial virus (RSV) Influenza viruses Bocavirus Adenovirus

FIGURE 61-1  The seasonal occurrence of croup cases is shown in relation to the epidemiologic activity of the respiratory viruses associated with croup. The major seasons of croup cases in temperate climates occur in the fall to winter every other year when outbreaks of parainfluenza type 1 virus occur and in the spring to summer when parainfluenza type 3 is prominent. Influenza and respiratory syncytial virus are epidemic during the winter to spring but contribute small proportions of cases. The picornaviruses, adenovirus, coronaviruses, and bocavirus are present through many months of the year.

Outbreaks of measles in the United States and elsewhere serve as a reminder that rubeola in the prevaccine era often resulted in severe and complicated croup. During the 1989 to 1991 upsurge of measles cases in the United States, laryngotracheobronchitis complicated approximately 20% of the cases of measles among hospitalized patients in Los Angeles and Houston.18,19 Children with croup as a complication of measles tended to be younger, they had a more severe course, and 17% to 22% required intubation. In some children, the outcome was fatal.

EPIDEMIOLOGY

The epidemiologic patterns of croup reflect mainly the seasonal predilection of the major agents (see Fig. 61-1). Parainfluenza virus type 1 predominantly occurs every other year in the fall, resulting in the major outbreaks of croup recognized biennially in odd-numbered years since 1993.5,11 Other parainfluenza viruses have less distinctive seasonal patterns. Parainfluenza type 2 virus also contributes to the cases occurring in the fall and winter, but irregularly and at lower levels.20 Parainfluenza type 3 virus appears yearly, and although it may be present throughout much of the year, parainfluenza type 3 virus predominantly occurs in the spring to fall and is the major cause of the swell of croup cases observed each spring. Influenza A and B viruses and RSV also contribute to the cases in the winter and spring. Rhinoviruses, enteroviruses, bocavirus, and coronaviruses are present through most of the year. In some areas, enteroviruses have an increased prevalence during the summer and fall and bocavirus is prevalent during the fall to spring (see Fig. 61-1).

PATHOPHYSIOLOGY

The shrill sonorous inspiration so characteristic of this complaint, marks very unequivocally its seat.… From some cause there is an unusual approximation of the sides of the glottis … the influence being very analogous to that produced by too strong compression of the reed against the mouthpiece of the clarinet by the lips of one who has made no great proficiency in that instrument, when a harsh, squeaking sound is produced abundantly discordant and grating to the ear. Hugh Ley, 183621

The virus initially infects the upper respiratory tract and usually produces congestion of the nasal passages and nasopharynx. Subsequently, especially during primary infection, the larynx, the trachea, and sometimes the bronchi become involved. The classic signs of croup—stridor, hoarseness, and cough—arise mostly from the inflammation of the larynx and trachea. The resulting obstruction is greatest at the sub­ glottic level because this is the least distensible part of the airway because it is encircled by the cricoid cartilage, with the narrow anterior ring and the larger posterior quadrangular lamina forming a “signet ring.” The impeded flow of air through this narrowed area produces the classic high-pitched vibratory sounds, or stridor. This is most apparent on inspiration because high linear velocity in the already narrowed airway creates a negative intraluminal pressure, narrowing the extrathoracic airway further, much as sucking on a partially occluded paper straw causes it to collapse inwardly. Airway collapse is enhanced in young children because of the increased compliance of their airway walls.22 Even minimal inflammation of the membranes lining the narrow passages of the larynx and glottis in a young child results in an appreciable degree of obstruction because resistance to airflow is inversely related to the fourth power of the radius of the airway. The mucous membrane is also looser and more vascular, and the cricoid cartilage is less rigid. Nasal obstruction and crying can aggravate the dynamic narrowing of the child’s airway further. With the subglottic obstruction, the child’s tidal volume initially declines. This is compensated by an increase in the respiratory rate to maintain adequate alveolar ventilation (Fig. 61-2). If the degree of obstruction worsens, the work of breathing may increase such that the child tires and can no longer maintain an adequate respiratory effort. The tidal volume may decrease further, and, as the respiratory rate declines, hypercarbia and secondary hypoxemia ensue. In addition to airway narrowing related to mucosal swelling and dynamic collapse, it is possible that upper airway inflammation leads

Chapter 61  Croup in Children (Acute Laryngotracheobronchitis)

rates decreased by 33% from 1.8 to 1.2. In Ontario, the estimated annual rates of hospitalization from 1988 to 2002 also showed a decline among children younger than 5 years, and the rates were lower among children 1 to 4 years old than among infants.9 The decline did not begin until after the winter of 1993 to 1994, however, when the annual rate per 1000 children younger than 5 years was 2.67. In 2001 to 2002, the rate had declined by 86% to 0.37.


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Part II  Major Clinical Syndromes

Viral infection Inflammation Airways and lung parenchyma

Subglottic area Airflow

Ventilation to perfusion ratio

Respiratory effort Hypoxemia

O2 therapy

Fatigue

Ventilation

Respiratory failure

Normal PaO2

Normal PaO2

FIGURE 61-2  Physiologic abnormalities in croup.

to active constriction of the muscles of the upper trachea and larynx that might contribute to airway narrowing in some children with croup, particularly those with spasmodic croup. This might explain the association between recurrent croup and asthma or airway hyperreactivity.

CLINICAL MANIFESTATIONS

The disease generally comes on in the evening after the little patient has been exposed to the weather during the day and often after a slight catarrh of some days’ standing. At first his voice is observed to be hoarse and pulling … he awakens with a most unusual cough, rough, and stridulous. And now his breathing is laborious, each inspiration being accompanied by a harsh, shrill noise. John Cheyne, 18142

Although abrupt onset of stridor at night may be the initial indication of illness, most children have a prodrome of mild upper respiratory tract signs of rhinorrhea, cough, and sometimes fever 12 to 48 hours before the onset of the distinctive “rough and stridulous” cough of croup. The deepening cough and hoarseness herald the onset of the respiratory stridor. The cough is not productive but has the striking deep brassy tone of a “seal’s bark.”* The respiratory stridor may be accompanied by retractions of the chest wall, which are usually most marked in the supraclavicular and suprasternal areas. Some children may progress to have inspiratory and expiratory stridor. The respiratory rate may be slightly elevated, but rates greater than 50 per minute are unusual in children with croup, in contrast to the marked tachypnea that is often evident with bronchiolitis. The onset of stridor commonly occurs at night; in milder cases it may improve in the morning, only to worsen again at night. Children whose croup is characterized by abrupt nighttime onset with little prodrome of a respiratory tract infection, followed by daytime improvement, are often designated as having “spasmodic croup.” These children tend to have repeated episodes over several days or separated by months. Generally, an episode of recurrent croup cannot be differentiated from the usual case of viral croup clinically or by viral etiology.12 A viral etiology was identified by RT-PCR in 68% of the children, and the proportion with an identified viral infection was not significantly different between children with single and recurrent episodes of croup. A few children with recurrent croup have an underlying condition such as subglottic stenosis or gastroesophageal reflux. For most children, the course of croup is less than 3 to 4 days. Although the cough may persist longer, the characteristic barking quality resolves within 2 days in most children.23

*The characteristic cough and stridor have also been described by Ley in 183621 as “the crowing of a cock, the yelping of a fox, the barking of a dog, the braying of an ass, or a ringing sound, as if the voice came from a brazen tube.”

FIGURE 61-3  Radiograph of the neck of a child with viral croup that shows the characteristic narrowing of the air shadow of the trachea in the subglottic area.

DIAGNOSIS

The diagnosis of croup can almost always be made on the basis of the characteristic epidemiologic features, the clinical manifestations, and the history, especially in children 6 months through 3 years of age. Diagnostic procedures that upset the child may worsen the respiratory distress and should be avoided.7 Laboratory analysis generally should be limited to tests necessary for management of a more severely ill child, such as tests used to assess dehydration and oxygenation. White blood cell counts and differentials are rarely helpful or distinctive in diagnosing croup. Identification of the specific viral agent also is usually unnecessary, and obtaining respiratory tract swabs and secretions is likely to augment the child’s respiratory distress. Viral identification may be warranted when specific antiviral therapy is being considered, such as for severely ill or high-risk children with influenza. In most instances, a rapid antigen assay, such as immunofluorescent and enzyme immunoassays, is used.24 Rapid multiplex PCR assays for respiratory viruses provide an increasingly available alternative with improved sensitivity and relatively short turnaround times.

Radiographic Findings

Radiographic evaluation is usually unnecessary for the diagnosis of croup and, as noted earlier, should be undertaken with caution and careful monitoring of the child. Among atypical cases, however, the radiologic picture may be helpful in the differential diagnosis. The characteristic manifestation of viral croup noted on an anteroposterior neck film is a 5- to 10-mm narrowed shadow of the trachea in the subglottic area. This is often described as the “hourglass” or “steeple” sign (Fig. 61-3). The lateral view of the neck may show an increased width of the airspace in the hypopharyngeal area. Dilation of the pharyngeal airway often is seen and is indicative of the child’s increased respiratory effort. The diagnostic value of these radiographic findings is nevertheless questionable. They are not consistently observed in all cases of viral croup, and some studies have shown them to be of low specificity and sensitivity for confirming or ruling out viral croup.

Differential Diagnosis

For children presenting with atypical features or history, a broad range of diagnoses should be considered.25 A case should be considered


765 Occasionally, recurrent episodes of stridor may be related to gastrointestinal reflux.33

THERAPY

Appropriate therapy for croup is determined by the severity of the child’s illness. Accurate assessment of the child’s clinical status is essential. The natural fluctuations in the course of croup often confound this evaluation, however, as well as complicate assessment of the success of therapy. Most children with mild croup may be cared for at home. Keeping a child with croup comfortable and avoiding disturbing procedures are particularly important, because anxiety and crying may enhance the respiratory distress. The child should be given adequate liquids and antipyretics if necessary. Despite a plethora of home therapies for croup, none has proved consistently effective. Taking a child with croup outside to breathe cold air or into a shower to breathe warm mist are commonly recommended. Vaporizers and other means of producing mist in the home have long been advised. In the past century, steaming tea kettles were an integral and often primary mode of therapy. Nevertheless, the beneficial effects of mist have not been proved.7,34-37 Multiple scoring systems have been used to assess the severity of croup. The scoring system most frequently used is the Westley clinical score.38 The major findings on physical examination used for this score are the degree of stridor, chest wall retractions, air entry, level of consciousness or fatigue, and presence of cyanosis. Guidelines for the management of croup generally have classified croup as mild, moderate, and severe, with patients with mild cases having corresponding Westley scores of 0 to 2, those with moderately severe cases having scores of 3 to 7, those with severe cases having scores of 8 to 11, and patients at risk for imminent respiratory failure having scores of 12 to 17 (Table 61-1).4,7 The therapy recommended varies according to the assessed level of severity, but the mainstay of therapy beyond supportive care is dexamethasone. One dose of dexamethasone orally or, if necessary, intramuscularly, administered to outpatients and in emergency departments has been shown to be effective in reducing the need for hospitalization.7,39,40,41 Repeated doses are seldom necessary. Nebulized epinephrine, racemic epinephrine, or l-epinephrine may be added to the dexamethasone for children with severe croup.38,42 Because improvement after nebulized epinephrine is transient, treatment may be repeated. A child treated with one of these aerosols should be observed for at least 2 hours (see Table 61-1) prior to discharge. Administration of a mixture of helium and oxygen has long been used to improve gas exchange in various obstructive disorders of the upper and lower respiratory tract. Little evidence exists, however, that administering heliox to children with croup is beneficial.43-45

TABLE 61-1  Evaluation and Management of Children with Croup Mild (≤2)

CROUP SEVERITY (WESTLEY SCORE) Moderate (3-7) Severe (≥8)

Barking cough, hoarseness; no stridor, no or minimal chest wall retractions at rest

Stridor and chest wall retractions at rest; no agitation

Stridor, sternal contractions at rest, accompanied by agitation or fatigue

Decongestants, cough suppressants, antibiotics

Not recommended

Not recommended

Not recommended

Humidification

Not proven beneficial

Not effective

Not effective

Corticosteroids

Dexamethasone (0.6 mg/kg, 1 dose PO)

Dexamethasone (0.6 mg/kg, 1 dose PO or IM)

Dexamethasone (0.6 mg/kg, 1 dose PO or IM)

Nebulized epinephrine

Not recommended

Not recommended

Nebulized racemic epinephrine (2.25%, 0.5 mL in 2.5 mL of saline or L-epinephrine (1 : 1000 dilution in 5 mL of saline)

Disposition

Discharge home

Discharge to home if no stridor and no retractions at rest. If no improvement in 4 hr, consider hospitalization.

Observe for 2 hr

Therapy

IM, intramuscularly; PO, orally.

Good response: no recurrence, no stridor, no retractions at rest. Discharge to home possible. Poor response: stridor, retractions at rest after 2 epinephrine doses. Hospitalize.

Chapter 61  Croup in Children (Acute Laryngotracheobronchitis)

atypical if the child does not have the most characteristic features of croup, especially the seal’s bark cough and hoarseness. The physician’s most important clinical responsibility in evaluating a child with inspiratory upper airway obstruction is differentiating children with the common and usually benign viral croup from the few children who have life-threatening obstruction from bacterial epiglottitis or tracheitis. The history of a rapidly progressive course, high fever, a toxic appearance, and drooling are most characteristic of these bacterial processes, and the brassy cough of viral croup is characteristically absent. Children with these symptoms demand careful evaluation and management. Acute bacterial epiglottitis is usually due to infection with H. influenzae type b and has become rare since the widespread use of vaccination.25,26 The differentiating features of epiglottitis include the strikingly rapid onset and progression of the illness, high fever, and toxic appearance. The child is often sitting, leaning forward, and anxious and may have a muffled voice, marked dysphagia, and drooling. The history of an upper respiratory tract infection with rhinorrhea and laryngitis usually is not present. Epiglottitis is almost always an indication for prompt antibiotic therapy and securing the airway by intubation in a controlled environment. Bacterial tracheitis has an acute onset and presentation similar to that of epiglottitis.7,26-29 Its rapid and dramatic onset is characterized by high fever, stridor, and dyspnea with copious amounts of purulent sputum. The child may progress rapidly to complete airway obstruction. The course is unresponsive to therapy with nebulized epinephrine, and suspected cases should be managed as a medical emergency. Bacterial cellulitis and abscesses of the deep neck spaces, including peritonsillar and retropharyngeal abscesses, may also manifest with similar findings of high fever, dysphagia, and drooling.30,31 The characteristic upper respiratory tract signs, hoarseness and barking cough, are usually not present. C. diphtheriae, although a major cause of stridor in the past, is now rarely seen in the United States and other developed countries but should still be considered in countries with low rates of immunization.32 All of these diagnoses represent pediatric emergencies, and, as with epiglottitis, usually justify careful intubation. Noninfectious causes of obstruction that mimic croup include aspiration of a foreign body, which is common in the same age group as that of viral croup; trauma to the upper airway, such as from toxic ingestions; and angioneurotic edema.25 Anatomic abnormalities, such as vocal cord paralysis and anomalies that impinge on the laryngotracheal area, may cause stridor, especially when a respiratory tract infection augments the obstruction to airflow. These include tracheal stenosis, laryngeal webs, and papillomas. In most cases, the history and lack of acute signs of respiratory tract infection allow differentiation. In the older child, pulmonary function testing may be helpful.


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OUTCOME

Croup remains a common illness among young children. With the currently available modalities for management, most children may be cared for at home, and the illness usually resolves within 3 to 4 days.23 Most have mild symptoms, and only about 5% of children discharged from the emergency department after corticosteroid therapy need to return because of worsening of symptoms.46 If the child’s symptoms are minimal at discharge, return within 24 hours is

Key References The complete reference list is available online at Expert Consult. 8. Rosychu RJ, Klassen TP, Metes D, et al. Croup presentations to emergency departments in Alberta, Canada: a large population-based study. Pediatr Pulmonol. 2010;45:83-91. 11. Weinberg GA, Hall CB, Iwane MK, et al. Parainfluenza virus infection of young children: estimates of the populationbased burden of hospitalization. J Pediatr. 2009;154: 694-699. 13. Iwane MK, Prill MM, Miller EK, et al. Human rhinovirus species associated with hospitalizations for acute respiratory

unlikely. In Canada, of all children with croup, about 4% have been estimated to require hospitalization and intubation was required for only 1 of the 170 hospitalized children or 1 in 4500 of all children with croup.7,23

ACKNOWLEDGMENT

Most of this chapter was written originally by Caroline Breese Hall, MD, 1939-2013.

illness in young US children. J Infect Dis. 2011;204: 1702-1710. 14. Prill MM, Iwane MK, Edwards KM, et al. Human coronavirus in young children hospitalized for acute respiratory illness and asymptomatic controls. Pediatr Infect Dis J. 2012; 31:235-240. 15. Edwards KM, Zhu Y, Griffin MR, et al. Burden of human metapneumovirus infection in young children. N Engl J Med. 2013;368:633-643. 16. Sung JY, Lee HJ, Eun BW, et al. Role of human coronavirus NL63 in hospitalized children with croup. Pediatr Infect Dis J. 2010;29:822-826.

17. McIntosh K. Proving etiologic relationships to disease: the particular problem of human coronaviruses. Pediatr Infect Dis J. 2012;31:241-242. 40. Russell KF, Liang Y, O’Gorman K, et al. Glucocorticoids for croup. Cochrane Database Syst Rev. 2011;(1):CD001955. 42. Bjornson C, Russell KF, Vandermeer B, et al. Nebulized epinephrine for croup in children evidence-based child health. Cochrane Database Syst Rev. 2011;(2):CD006619. 45. Vorwerk C, Coats T. Heliox for croup in children. Cochrane Database Syst Rev. 2010;(2):CD006822.


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References

31. Johnson R, Stewart M. The contemporary approach to diagnosis and management of peritonsillar abscess. Curr Opin Otolaryngol Head Neck Surg. 2005;13:157-160. 32. Galazka A, Robertson S, Oblapenko G. Resurgence of diphtheria. Eur J Epidemiol. 1995;11:95-105. 33. Kwong K, Hoa M, Coticchia J. Recurrent croup presentation, diagnosis, and management. Am J Otolaryngol. 2007;28: 401-407. 34. Neto G, Kentab O, Klassen T, et al. A randomized controlled trial of mist in the acute treatment of moderate croup. Acad Emerg Med. 2002;9:873-879. 35. Scolnik D, Coates A, Stephens D, et al. Controlled delivery of high vs low humidity vs mist therapy for croup in emergency departments: a randomized controlled trial. JAMA. 2006;295:1274-1280. 36. Moore M, Little P. Humidified air inhalation for treating croup. Cochrane Database Syst Rev. 2006;(3):CD002870. 37. Lavine E, Scolnik D. Lack of efficacy of humidification in the treatment of croup: why do physicians persist in using an unproven modality? Can J Emerg Med. 2001;3:209-212. 38. Westley C, Cotton E, Brooks J. Nebulized racemic epinephrine by IPPB for the treatment of croup: a double-blind study. Am J Dis Child. 1978;132:484-487. 39. Bjornson C, Klassen T, Williamson J, et al. A randomized trial of a single dose of oral dexamethasone for mild croup. N Engl J Med. 2004;351:1306-1313. 40. Russell KF, Liang Y, O’Gorman K, et al. Glucocorticoids for croup. Cochrane Database Syst Rev. 2011;(1):CD001955. 41. Johnson D. Croup. BMJ Clin Evid. 2007;12:321. 42. Bjornson C, Russell KF, Vandermeer B, et al. Nebulized epinephrine for croup in children evidence-based child health. Cochrane Database Syst Rev. 2011;(2):CD006619. 43. Myers T. Use of heliox in children. Respir Care. 2006;51: 619-631. 44. Vorwerk C, Coats T. Use of helium-oxygen mixtures in the treatment of croup: a systematic review. Emerg Med J. 2008; 25:547-550. 45. Vorwerk C, Coats T. Heliox for croup in children. Cochrane Database Syst Rev. 2010;(2):CD006822. 46. Brown J. The management of croup. Br Med Bull. 2002;61: 189-202.

Chapter 61  Croup in Children (Acute Laryngotracheobronchitis)

1. Home F. An Inquiry into the Nature, Causes and Cure of the Croup. Edinburgh; 1765. 2. Cherry J. Croup. In: Kiple K, ed. Cambridge History and Geography of Human Disease Project. Bowling Green, OH: University of Cambridge Press; 1990:654-657. 3. Rabe E. Infectious croup, I. Etiology. Pediatrics. 1948;2: 255-265. 4. Cherry J. Clinical practice: croup. N Engl J Med. 2008;358: 384-391. 5. Counihan M, Shay D, Holman R, et al. Human parainfluenza virus–associated hospitalizations among children less than five years of age in the United States. Pediatr Infect Dis J. 2001;20:646-653. 6. Foy H, Cooney M, Maletzky A, et al. Incidence and etiology of pneumonia, croup, and bronchiolitis in preschool children belonging to a prepaid medical care group over a fouryear period. Am J Epidemiol. 1973;97:80-92. 7. Alberta Clinical Practice Guideline Working Group. Guideline for the Diagnosis and Management of Croup, 2008. Available at http://www.topalbertadoctors.org/PDF/ complete%20set/Croup/croup_guideline.pdf. Accessed November 10, 2008. 8. Rosychu RJ, Klassen TP, Metes D, et al. Croup presentations to emergency departments in Alberta, Canada: a large population-based study. Pediatr Pulmonol. 2010;45:83-91. 9. Segal A, Crighton E, Moineddin R, et al. Croup hospitalizations in Ontario: a 14-year time-series analysis. Pediatrics. 2005;116:51-55. 10. Rihkanen H, Ronkko E, Nieminen T, et al. Respiratory viruses in laryngeal croup of young children. J Pediatr. 2008;152:661-665. 11. Weinberg GA, Hall CB, Iwane MK, et al. Parainfluenza virus infection of young children: estimates of the populationbased burden of hospitalization. J Pediatr. 2009;154:694-699. 12. Wall S, Wat D, Spiller B, et al. The viral aetiology of croup and recurrent croup. Arch Dis Child. 2009;94:359-360. 13. Iwane MK, Prill MM, Miller EK, et al. Human rhinovirus species associated with hospitalizations for acute respiratory illness in young US children. J Infect Dis. 2011;204: 1702-1710. 14. Prill MM, Iwane MK, Edwards KM, et al. Human coronavirus in young children hospitalized for acute respiratory

illness and asymptomatic controls. Pediatr Infect Dis J. 2012; 31:235-240. 15. Edwards KM, Zhu Y, Griffin MR, et al. Burden of human metapneumovirus infection in young children. N Engl J Med. 2013;368:633-643. 16. Sung JY, Lee HJ, Eun BW, et al. Role of human coronavirus NL63 in hospitalized children with croup. Pediatr Infect Dis J. 2010;29:822-826. 17. McIntosh K. Proving etiologic relationships to disease: the particular problem of human coronaviruses. Pediatr Infect Dis J. 2012;31:241-242. 18. Ross L, Mason W, Lanson J, et al. Severe laryngotracheobronchitis as a complication of measles during an urban epidemic. J Pediatr. 1992;121:511-515. 19. Fortenberry J, Mariscalco M, Louis P, et al. Severe laryngotracheobronchitis complicating measles. Am J Dis Child. 1992;146:1040-1043. 20. Hall C. Respiratory syncytial virus and parainfluenza virus. N Engl J Med. 2001;344:1917-1928. 21. Ley H. An Essay on the Laryngismus Stridulus or Croup-like Inspiration of Infants. London: Churchill; 1836:6. 22. McBride J. Stridor in childhood. J Fam Pract. 1984;19: 782-790. 23. Johnson D, Williamson J. Croup: duration of symptoms and impact on family functioning. Pediatr Res. 2001;49:83A. 24. Henrickson K, Hall C. Diagnostic assays for respiratory syncytial virus disease. Pediatr Infect Dis J. 2007;26:S36-S40. 25. Sobol S, Zapata S. Epiglottitis and croup. Otolaryngol Clin North Am. 2008;41:551-566. 26. Shah S, Sharieff G. Pediatric respiratory infections. Emerg Med Clin North Am. 2007;25:961-979. 27. Donnelly B, McMillan J, Weiner L. Bacterial tracheitis: report of eight new cases and review. Rev Infect Dis. 1990; 12:729-735. 28. Hopkins A, Lahiri T, Salerno R, et al. Changing epide­ miology of life-threatening upper airway infections: the reemergence of bacterial tracheitis. Pediatrics. 2006;118: 1418-1421. 29. Long S. Bacterial tracheitis. Report on Pediatric Infectious Diseases. 1992;2:29-31. 30. Page N, Bauer E, Lieu J. Clinical features and treatment of retropharyngeal abscess in children. Otolaryngol Head Neck Surg. 2008;138:300-306.


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103 

Foodborne Disease Rajal K. Mody and Patricia M. Griffin

SHORT VIEW SUMMARY Definition

• Foodborne diseases are illnesses that are acquired through ingestion of food contaminated with pathogenic microorganisms, bacterial and nonbacterial toxins, or other substances.

Epidemiology

• An estimated 48 million foodborne illnesses caused by pathogens or their toxins are acquired annually in the United States. • Many agents that cause foodborne infection can also be acquired in other ways, including ingestion of contaminated drinking or recreational water, through contact with animals or their environment, and from one person to another directly or through fomites. • Some foodborne diseases can lead to long-term sequelae, such as impaired kidney function after Shiga toxin–producing Escherichia coli infection, Guillain-Barré syndrome after Campylobacter infection, and reactive arthritis and irritable bowel syndrome after a variety of infections.

• Groups at higher risk of acquiring or experiencing more severe foodborne disease include infants, young children, pregnant women, older adults, and immunocompromised persons. • A foodborne disease outbreak should be considered when an acute illness, especially with gastrointestinal or neurologic manifestations, affects two or more people who shared a meal. However, most foodborne diseases do not occur in the context of an outbreak.

Microbiology

• Many pathogens, including bacteria, viruses, and parasites, can cause foodborne disease. • Some illnesses are caused by ingestion of chemicals (e.g., heavy metals, mushroom toxins) or preformed microbial toxins (e.g., staphylococcal toxin, botulinum toxin).

Diagnosis

• Detection of pathogens has mostly relied on isolating bacterial pathogens in culture, by visualizing parasites by microscopy, and by enzyme-linked immunosorbent assays.

Foodborne diseases result from ingestion of a wide variety of foods contaminated with pathogenic microorganisms, microbial toxins, and chemicals. Many diseases transmitted commonly through food can be acquired via other routes of transmission as well. For sporadic cases (i.e., those that are not part of recognized outbreaks), the route of transmission is generally unknown. Although the majority of foodborne illnesses are sporadic, investigation of outbreaks is an important way to identify the types of foods and contaminants associated with foodborne illness. The major source of information for this chapter comes from foodborne disease outbreak investigations in the United States, and the major focus is on U.S. illnesses. During 2009 and 2010, a mean of 764 outbreaks of foodborne disease, affecting a mean of 14,700 people annually in the United States, were reported to the Centers for Disease Control and Prevention (CDC) (Table 103-1).1 However, these figures, restricted to outbreak cases, greatly underestimate the magnitude of the problem. The actual number of foodborne illnesses in the United States is unknown but was estimated in 2011 to be approximately 48 million cases, with 128,000 hospitalizations and 3000 deaths each year (Table 103-2).2,3 The annual cost incurred from these illnesses has been estimated to be between $51.0 and $77.7 billion.4 Thus, foodborne diseases are common, can be severe, and lead to considerable economic burden. Since 1996, in several sites that now comprise 15% of the U.S. population, the CDC’s Foodborne Diseases Active Surveillance Network has conducted active surveillance for nine pathogens that can be transmitted through food. Comparison of incidence rates in 2012 with rates from 1996 to 1998 shows decreases in the incidence of Campylobacter,

• Newer molecular tests pose opportunities and challenges to both clinical practice and public health surveillance. • Many intoxications must be diagnosed based on clinical suspicion alone.

Therapy

• Therapy for most foodborne diseases is supportive; replacing fluid and electrolyte losses is important in diarrheal illnesses. • Antimicrobial agents are used to treat parasitic infections and selected bacterial infections. • Resistance to antimicrobial agents complicates treatment and can increase the likelihood of clinically apparent infection.

Prevention

• To reduce contamination, food producers identify points where the risk of contamination can be controlled and use production systems that decrease the hazards. • Outbreak investigation is important to identify food safety gaps that may be present anywhere in the food production chain, from the farm to the table. • Individuals can reduce their risk of illness by adhering to safe food handling practices.

Listeria, Shigella, Shiga toxin–producing Escherichia coli (STEC) O157, and Yersinia infections (except for Shigella, nearly all of these declines occurred before 2004); no change in Salmonella and Cryptosporidium infections; and an increase in infections caused by Vibrio species (data and figures available at www.cdc.gov/foodnet).5 Clearly, food safety programs need to be intensified. The spectrum of foodborne diseases has expanded in recent decades in many ways. Noroviruses are now recognized as the most frequent cause of foodborne illness in the United States.3 Known agents continue to be newly recognized as causes of foodborne disease, including enteroaggregative E. coli,6,7 including novel strains that produce Shiga toxin8; Cronobacter (formerly Enterobacter) sakazakii9; and, in South America, Trypanosoma cruzi, causing Chagas’ disease.10 Previously uncommonly recognized food vehicles, such as fresh fruits and vegetables, have become important sources.11,12 Some pathogens have become increasingly resistant to antimicrobial drugs.13,14 New discoveries can be anticipated. Although Clostridium difficile, has been found in retail meat samples, foodborne transmission remains undocumented.15 In addition, identification of more foodborne pathogens is likely as newer molecular diagnostic technology allows detection of more agents.16 Centralization of the food supply in the United States has increased the risk for nationwide outbreaks.17 Global food trade, which is growing faster than increases in food production, forms a complex network that facilitates spread of contaminated foods throughout the world and can delay identification of the source of contamination causing outbreaks.18 1283


1283.e1

KEYWORDS

Chapter 103  Foodborne Disease

Bacillus cereus; Brainerd diarrhea; Campylobacter; ciguatera; Clostridium botulinum; Clostridium perfringens; Cryptosporidium; Cyclospora; disease outbreaks; epidemiology; foodborne diseases; food contamination; food poisoning; gastroenteritis; Giardia; Guillain-Barré syndrome; heavy metal poisoning; hemolytic-uremic syndrome; Listeria monocytogenes; mushroom poisoning; norovirus; paralysis; public health surveillance; reactive arthritis; Salmonella; scombroid poisoning; shellfish poisoning; Shiga toxin–producing Escherichia coli; Shigella; Staphylococcus aureus; toxins; Toxoplasma gondii; Trichinella; Vibrio; vulnerable populations; Yersinia enterocolitica


1284

Part II  Major Clinical Syndromes

TABLE 103-1  Foodborne Disease Outbreaks and Outbreak-Associated Illnesses of Known Cause Reported to the CDC, 2009-2010 OUTBREAKS ETIOLOGIC AGENT Bacterial

%

25

2

427

2

1

0

4

0

40

4

600

2

Clostridium botulinum

3

0

6

0

Clostridium perfringens

57

6

3225

11

STEC

60

6

651

2

9

1

49

0

243

24

7089

24

Bacillus cereus Brucella Campylobacter

Listeria monocytogenes Salmonella Shigella

No.

OUTBREAK-ASSOCIATED ILLNESSES %

No.

8

1

508

2

19

2

252

1

ETEC

3

0

85

0

EPEC

1

0

7

0

Vibrio parahaemolyticus

7

1

33

0

Vibrio, other

1

0

4

0

Other bacteria

3

0

187

1

Staphylococcus aureus

Nonbacterial Toxins Ciguatoxin

15

1

61

0

Heavy metals

0

0

0

0

Mushroom and other mycotoxins

2

0

8

0

Scombrotoxin

18

2

76

0

Shellfish toxin

1

0

3

0

Other chemicals

7

0

61

0

Cyclospora cayetanensis

1

0

8

0

Giardia intestinalis

1

0

5

0

Other viral

1

0

13

0

Hepatitis A

4

0

47

0

491

48

9737

33

Parasitic

Viral

Norovirus Rotavirus

Unknown Etiology Multiple Etiology TOTAL

1

0

28

0

475

31

5454

19

30

2

816

3

1527

99

29,444

100

CDC, Centers for Disease Control and Prevention; EPEC, enteropathogenic Escherichia coli; ETEC, enterotoxigenic E. coli; STEC, Shiga toxin–producing E. coli. Modified from Centers for Disease Control and Prevention. Surveillance for foodborne disease outbreaks—United States, 2009-2010. MMWR Morb Mortal Wkly Rep. 2013;62(3):41-47.

PATHOGENESIS AND CLINICAL MANIFESTATIONS

Foodborne disease can appear as an isolated sporadic case or, less frequently, as an outbreak of illness affecting a group of people after a common food exposure. A foodborne disease outbreak should be considered when an acute illness, especially one with gastrointestinal or neurologic manifestations, affects two or more people who shared a common meal. The following section divides acute foodborne diseases into a variety of syndromes based on acute signs and symptoms and typical time of onset after consumption of contaminated food. Agents most likely responsible for each syndrome are described. The incubation period in an individual illness is usually unknown, but it is often apparent in the focal outbreak setting.

Foodborne Syndromes Caused by Microbial Agents or Their Toxins

For this next section, the times shown are those that are typically encountered after exposure to a known foodborne source carrying a pathogen or its toxins. Nausea and Vomiting within 1 to 8 Hours.  The major etiologic considerations are Staphylococcus aureus and Bacillus cereus (see Chapters 196 and 210). The short incubation period reflects the fact that these diseases are caused by preformed enterotoxins. Staphylococcal

food poisoning is characterized by vomiting (87% of cases), diarrhea (89%), and abdominal cramps (72%); fever is uncommon (9%).19 Staphylococci responsible for food poisoning produce one or more serologically distinct enterotoxins (SEs A through V, excluding F) but not all cause vomiting.20 The SEs are very resistant to proteolytic enzymes and therefore pass through the stomach intact. All are heat resistant. Strains producing SEA alone account for most of the reported outbreaks of staphylococcal food poisoning in the United States.21,22 In studies of rhesus monkeys, a smaller dose of SEA, compared with doses of SEB, SEC and SED, was required to produce emesis.23 The mechanisms by which enterotoxins lead to emesis may involve vagus nerve stimulation.20 Rarely, other enterotoxigenic coagulase-positive staphylococcal species have been implicated in outbreaks.20 Although enterotoxigenic coagulase-negative staphylococci exist, very few reports have associated these strains with foodborne disease outbreaks.24,25 B. cereus strains can cause two types of food poisoning syndromes, one with an incubation period of 0.5 to 6 hours (short-incubation emetic syndrome) and a second with an incubation period of 8 to 16 hours (long-incubation diarrheal syndrome).26 The emetic syndrome is characterized by vomiting (100% of cases), abdominal cramps (100%), and, less frequently, diarrhea (33%).26,27 The emetic toxin is cereulide, a peptide resistant to heat, proteolysis, and is stable at pH 2


1285 TABLE 103-2  Estimated Annual Number of Illnesses Caused by Pathogens That Can Be Transmitted through Food in the United States

Bacillus cereus Brucella spp. Campylobacter spp. Clostridium botulinum Clostridium perfringens STEC O157 STEC non-O157 ETEC Other diarrheagenic Escherichia coli Listeria monocytogenes

TOTAL NO. OF ILLNESSES *

Salmonella serotype Typhi Shigella spp.

845,024

17.1

0.1

*

55

82.6

17.3

*

965,958

0.6

<0.1

63,153

46.2

0.5

168,698

112,752

12.8

0.3

17,894

0.8

39,871

11,982

0.8

0

1662

1607

94.0

15.9

*

0

208

60

55

4.7

1,229,007

1,027,561

27.2

0.5

5752

1821

75.7

0

494,908

131,254

20.2

0.1

241,148

6.4

<0.1

*

Vibrio spp., other

0.9

96,534

Streptococcus spp.

Vibrio vulnificus

0

1,322,137

*

Vibrio parahaemolyticus

0.4 55

PERCENT DIED

839

Staphylococcus aureus Vibrio cholerae, toxigenic

63,400

PERCENT HOSPITALIZED

2003

Mycobacterium bovis Nontyphoidal Salmonella

TOTAL NO. OF DOMESTICALLY ACQUIRED FOODBORNE ILLNESSES

11,217

0.2

0

277

84

43.1

0

44,950

34,664

22.5

0.9

207

96

91.3

34.8

34,585

17,564

37.1

3.7

116,716

97,656

34.4

2.0

Cryptosporidium parvum

748,123

57,616

25.0

0.3

Cyclospora cayetanensis

19,808

11,407

6.5

Giardia intestinalis

1,221,564

76,840

8.8

0.1

Toxoplasma gondii

173,995

86,686

2.6

0.2

132

156

24.3

0.2

3,090,384

15,433

0.4

<0.1

35,769

1566

31.5

Norovirus

20,865,958

5,461,731

Rotavirus

3,090,384

Sapovirus

3,090,384

SUBTOTAL

37,220,098

9,388,075

Yersinia enterocolitica

Parasitic

Trichinella spp.

0

Viral Astrovirus Hepatitis A

2.4

0.03

<0.1

15,433

1.7

<0.1

15,433

0.4

<0.1

0.2

<0.1

Unknown Pathogens

38,400,000

TOTAL

47,788,075

*Recent estimates are not available. ETEC, enterotoxigenic E. coli; STEC, Shiga toxin–producing E. coli. Modified from Scallan E, Griffin PM, Angulo FJ, et al. Foodborne illness acquired in the United States—unspecified agents. Emerg Infect Dis. 2011;17(1):16-22; and Scallan E, Hoekstra RM, Angulo FJ, et al. Foodborne illness acquired in the United States—major pathogens. Emerg Infect Dis. 2011;17(1):7-15.

to 11. Cereulide stimulates the vagus afferent nerve by binding to the 5-hydroxytryptamine-3 (5-HT3) receptor.28 Rarely, fulminant liver failure may develop via impairment of fatty acid oxidation caused by cereulide’s toxicity to mitochondria.26 Another clue to the cause of staphylococcal and emetic B. cereus illnesses is that their duration is typically less than 24 hours,20,26 and often less than 12 hours.22,27 Abdominal Cramps and Diarrhea within 8 to 16 Hours.  The major etiologic considerations for this enterotoxin-mediated syndrome are Clostridium perfringens type A and B. cereus. In contrast to staphylococcal food poisoning and the emetic B. cereus disease, which are caused by preformed enterotoxins, C. perfringens (see Chapter 100) food poisoning is caused by toxins produced in vivo, accounting for the longer incubation period.19 For B. cereus diarrheal toxins, the toxins themselves are often detected in foods, but it has been postulated that the disease is also caused by ingested vegetative cells that produce enterotoxin within the host’s intestinal tract. It is possible that both modes of infectivity coexist. In C. perfringens type A food poisoning, the most common symptoms are diarrhea (91%) and abdominal cramps (73%); only 14% of patients experience vomiting, and only 5%

report fever.19,29 The incubation period is 9 to 12 hours.19 C. perfringens can produce at least 11 toxins in addition to C. perfringens enterotoxin (CPE). Toxinotype A strains always produce α toxin, and those that result in gastrointestinal illness also express CPE, which is produced as the ingested vegetative cells sporulate within the intestine.30 The toxin binds to the apical membrane of epithelial tight junctions in the small intestines, triggering formation of pores through which influx and efflux of water, ions, and other small molecules may lead to diarrhea and cytotoxicity.31 B. cereus strains that cause a similar long-incubation syndrome, including diarrhea (96%), abdominal cramps (75%), sometimes vomiting (33%), and rarely fever,27 elaborate either separately or together with two three-component enterotoxins (hemolysin BL [HBL] and nonhemolytic enterotoxin [NHE]). A single-protein enterotoxin (CytK) has also been described.26,28 Although these illnesses last longer than staphylococcal and emetic B. cereus food poisoning, symptoms usually resolve within 24 to 48 hours.26,32 In contrast, some B. cereus illnesses last several days,28,33 and in one outbreak attributed to B. cereus, some patients had bloody diarrhea and three died.34 In an outbreak of C. perfringens type A

Chapter 103  Foodborne Disease

DISEASE OR AGENT Bacterial


Part II  Major Clinical Syndromes

1286 infections, severe necrotizing colitis developed in patients with a history of chronic, likely medication-induced, constipation.35 A foodborne infection, fatal in about 20% of patients, is caused by C. perfringens type C in persons with low protein intake; the disease is rare outside of Papua New Guinea.32 Fever, Abdominal Cramps, and Diarrhea within 6 to 48 Hours.  The major etiologic considerations for this syndrome are nontyphoidal Salmonella, Shigella, and Vibrio species, especially V. parahaemolyticus (see Chapters 216, 217, 225, and 226).36,37,38-40 Campylobacter jejuni, Shiga toxin–producing Escherichia coli (STEC), and Yersinia enterocolitica should also be considered but typically have a longer incubation period, and fever is less common with STEC (see Chapters 100, 218, and 231). Norovirus does not consistently cause fever but should be considered. These pathogens, with the exception of norovirus, can cause an inflammatory diarrhea, some by invading of the intestinal epithelium and some damaging it via secreted cytotoxins.41,42 Bloody diarrhea and vomiting may occur in a varying proportion. These illnesses usually resolve within 2 to 7 days.36 Nontyphoidal Salmonella is the most common bacterial cause of foodborne illnesses and outbreaks in the United States.1,3 The median incubation period is 6 to 48 hours. However, C. jejuni, with a typical incubation period of 3 to 4 days, is the most common bacterial cause of gastroenteritis, including both foodborne and nonfoodborne routes of transmission.3 Infrequent outbreaks of diarrhea with fever caused by Listeria monocytogenes (see Chapter 208) have been reported among previously healthy persons.43-45 This syndrome is characterized by watery and frequent diarrhea, fever, abdominal cramps, headache, and myalgias, with a median incubation period of 20 to 31 hours. Abdominal Cramps and Watery Diarrhea within 16 to 72 Hours.  The major etiologic considerations for this syndrome are enterotoxigenic strains of E. coli (ETEC) and V. parahaemolyticus. In the United States, other Vibrio species, including V. cholerae (including strains that produce and strains that do not produce cholera toxin), and V. mimicus, cause this foodborne disease syndrome; outbreaks are uncommon, but cases are reported every year.40,46,47 Epidemic cholera manifests as a profuse, watery diarrhea accompanied by muscular cramps; by definition, it is caused by cholera toxin–producing strains of V. cholerae O1 and O139. V. cholerae O141 and O75 can also produce cholera toxin and cause a similar syndrome (see Chapter 217).47,48 C. jejuni, Salmonella, Shigella, STEC, and norovirus may also cause watery diarrhea during this time period. Enterotoxins expressed in vivo are responsible for illness caused by ETEC49 and by cholera toxin–producing strains of V. cholerae.50 The virulence factors of V. parahaemolyticus include both secreted toxins and effector proteins delivered directly into the cytoplasm of the host cell via type III secretion systems.41 The median duration of diarrhea caused by V. parahaemolyticus is 6 days; most patients have abdominal cramping (89%), half have vomiting or fever, and 29% have bloody diarrhea.37 Diarrhea caused by ETEC lasts for a median of 6 days, often accompanied by abdominal cramping for the full duration of illness.51 In one ETEC outbreak, uncommon symptoms included vomiting (13% of cases) and fever (19%).51 Vomiting and Nonbloody Diarrhea within 10 to 51 Hours.  Noroviruses are the most common of known foodborne pathogens (see Chapter 178). They are estimated to cause 5.5 million foodborne illnesses per year in the United States.3 Even more cases of acute gastroenteritis are caused by nonfoodborne transmission of noroviruses, directly from one person to another or by fomite contamination.52 The median incubation period reported in foodborne norovirus outbreaks is 33 hours.53 Norovirus illness is characterized by acute onset of nonbloody diarrhea, vomiting, or both, accompanied by nausea and abdominal pain. Fever occurs in about 40% of patients, is usually low grade, and lasts for less than 24 hours. Symptoms usually resolve in 2 to 3 days, but 12% of patients require medical care and 1.5% are hospitalized for rehydration.53,54 A group of related viruses in the Caliciviridae family, most notably the sapoviruses, can cause similar illness.55 Fever and Abdominal Cramps within 1 to 11 Days, with or without Diarrhea.  Although febrile diarrhea is the most common presentation of Yersinia enterocolitica (see Chapter 231) infection in young children,56,57,58 in older children and adults, the illness may

present as either a diarrheal illness or as a pseudoappendicular syndrome; as ileocecitis, consisting of abdominal pain (resembling that of appendicitis); fever; leukocytosis; and, in some patients, nausea and vomiting.59 Joint pain (see postinfection syndromes later), beginning about 1 week after onset of diarrhea, is more common in adults59 Sore throat and rash can affect patients of all ages. The median duration of diarrhea is 2 weeks, but other symptoms may last longer.60 Of note, Campylobacter and Salmonella can also cause an ileocecitis that mimics appendicitis. Bloody Diarrhea with Minimal Fever within 3 to 8 Days.  The distinctive syndrome of hemorrhagic colitis has been linked to Shiga toxin–producing E. coli (STEC), most often serogroup O157 (see Chapter 226).61 These strains produce one or both types of Shiga toxins (Shiga toxin 1 or 2). Shiga toxins, also referred to as verotoxins, are cytotoxins that damage vascular endothelial cells in target organs such as the gut and kidney.62 In general, strains that produce Shiga toxin 2 tend to be more virulent.63 To cause disease, STEC must also possess additional virulence factors, including those that lead to adherence to the intestinal epithelium.62 The illness is characterized by severe abdominal cramping and diarrhea, which is initially watery but may quickly become grossly bloody.61,64 About one third of patients report a short-lived low-grade fever that typically resolves before seeking medical attention.61,65 Most patients fully recover within 7 days.61 However, overall 6% (15% in children aged <5 years) of patients develop hemolytic-uremic syndrome (HUS), which is typically diagnosed about 1 week after the beginning of the diarrheal illness, when the diarrhea is resolving.66 The fatality rate for HUS is 3% in children aged younger than 5 years and 33% in persons aged 60 years or older. For most age groups, deaths in persons without HUS are rare, but 2% of adults aged 60 years or older with only hemorrhagic colitis die.66 Non-O157 STEC are diverse in their virulence properties, causing illness ranging from uncomplicated watery diarrhea to hemorrhagic colitis and HUS. Outbreaks reported in the United States have involved serogroups O26, O103, O111, O121, O145, and O104 (serotype O104:H21, but not O104:H4).67 A large outbreak of infections caused by a strain of enteroaggregative E. coli O104:H4, which had acquired a Shiga toxin 2 gene, occurred in Germany in 2011.8 The median incubation period for illness was 8 days, and HUS developed in approximately 20% of patients.68 Paralysis within 18 to 36 Hours.  A cluster of two or more illnesses characterized by symmetrical cranial nerve palsies, followed by symmetrical descending flaccid paralysis that may progress to respiratory arrest, is pathognomonic for foodborne botulism (see Chapter 247). The diagnosis should also be strongly suspected in individual patients presenting with these findings. Paralysis may coincide with or be preceded by nausea and vomiting in approximately 50% of patients and diarrhea in nearly 20%, but constipation is common once the neurologic syndrome is well established.69 Botulism is usually caused by one of four immunologically distinct, heat-labile protein neurotoxins, designated botulinum toxins A, B, E, and rarely F.70 The toxins irreversibly block acetylcholine release at the neuromuscular junction. Foodborne botulism results from ingestion of preformed toxin. Nerve endings regenerate slowly, so recovery typically takes weeks to months70 but is longer for some patients.71 The syndromes of infant botulism and adult intestinal colonization result from ingestion of spores, with subsequent toxin production in vivo.70,72 Clinical suspicion is important for botulism to be correctly diagnosed.73 Persistent Diarrhea within 1 to 3 Weeks.  Parasites, including Cryptosporidium, Giardia, and Cyclospora, are the most common causes of persistent (lasting ≥14 days) foodborne diarrhea (see Chapters 281, 284, and 285). In the mid-1990s, outbreaks of cyclosporiasis linked to various types of imported fresh produce were recognized in the United States.74 The incubation period averages about 1 week (range, about 2 days to 2 or more weeks), and the most common symptom is watery diarrhea. Other common symptoms include anorexia, weight loss, abdominal cramps, nausea, and body aches. Vomiting and low-grade fever may occur. Untreated illness can last for weeks or months, with a remittingrelapsing course and prolonged fatigue.74 A distinctive chronic watery diarrhea, known as Brainerd diarrhea, was first described in persons who had consumed raw milk.75 After a


1287

mean incubation period of 15 days, affected persons developed acute, watery diarrhea with marked urgency and abdominal cramping. Diarrhea persisted for more than a year in 75% of patients. Several restaurant-associated outbreaks and a cruise ship–associated outbreak of a similar illness have suggested that water also transmits the agent, which has not been identified.76-79 Systemic Illness.  Some foodborne diseases manifest mainly as invasive infections in immunocompromised patients. Invasive listeriosis typically affects pregnant women, fetuses, and persons with compromised cellular immunity (see Chapter 208). In pregnant women, infection may be asymptomatic or present as a mild flulike illness; 20% of pregnancies in infected women end in miscarriage.80 Neonatal listeriosis is acquired in utero or at birth and manifests as either earlyonset sepsis during the first several days of life or as late-onset meningitis during the first several weeks after birth; the neonatal fatality rate is approximately 20% to 30%.81 In the elderly and immunocompromised persons, listeriosis causes meningitis, sepsis, and focal infections.81 The incubation period ranges from 3 to 70 days, with a median of 3 weeks. Vibrio vulnificus can cause septicemia after ingestion of contaminated food, typically raw oysters (see Chapter 216). This severe syndrome, often accompanied by bullous skin lesions (Figure 103-1), is seen almost exclusively in patients with impaired immunity, especially those with chronic liver disease, including cirrhosis, alcoholic liver disease, and hepatitis.82 The association with liver disease may be related to portal hypertension, resulting in reduced hepatic phagocytic function, elevated serum iron levels that promote growth of V. vulnificus, or achlorhydria. The overall mortality rate is 30% and varies by the timeliness of antibiotic administration.39,83 On occasion, other Vibrio species, including V. parahaemolyticus and strains of V. cholerae that do not produce cholera toxin cause septicemia.41,46 Nontyphoidal Salmonella can cause bacteremia and focal infections, often in persons at the extremes of age, or in persons with sickle cell anemia, inflammatory bowel disease, or an immunocompromising condition.84 Consumption of foods contaminated with Toxoplasma gondii oocysts excreted from cats or meats containing tissue cysts can cause different manifestations of toxoplasmosis, depending on the host (see Chapter 280).85 In healthy children and adults, up to 90% of infections are asymptomatic, but the remainder lead to nontender, nonsuppurative lymphadenopathy, lasting weeks to months, or chorioretinitis. Fever, malaise, night sweats, myalgias, sore throat, maculopapular rash, and hepatosplenomegaly may occur; other manifestations (e.g., disseminated disease, pneumonitis, hepatitis, encephalitis, myocarditis, and myositis) are rare. Both asymptomatic and symptomatic acute infections lead to latent infections that can reactivate into

Foodborne Syndromes Caused by Nonbacterial Toxins

A description of all nonbacterial toxins that can cause foodborne illness is beyond the scope of this chapter. Illness caused by natural substances found in staple fruits and vegetables, spices, medicinal herbs and oils, and mycotoxins (other than those in mushrooms) are not covered95; neither are food allergies96 or illnesses caused by additives,95 methylmercury,97 or niacin.98 Nausea, Vomiting, and Abdominal Cramps within 1 Hour.  The major etiologic considerations for this syndrome are heavy metals; copper, zinc, tin, and cadmium have caused foodborne outbreaks.99-105 Latency periods for symptom onset most often range from 5 to 15 minutes after ingestion of contaminated beverages but can be longer with contaminated foods.101 Nausea, vomiting, and abdominal cramps result from direct irritation of the gastric and intestinal mucosa and usually resolve within 2 to 3 hours if minor amounts are ingested. Progression to serious illness and even death is possible if larger amounts are consumed.

Chapter 103  Foodborne Disease

FIGURE 103-1  Hemorrhagic bullae of the leg secondary to Vibrio vulnificus infection. (From Millet CR, Halpern AV, Reboli A, et al. Bacterial diseases. In: Bolognia JL, Jorizzo JL, Schaffer JV, et al, eds. Dermatology. 3rd ed. Philadelphia: Mosby; 2012:1187-1220.)

life-threatening central nervous system infections if a person later becomes immunocompromised. The manifestations of congenitally acquired toxoplasmosis include subclinical infection (which may reactivate during childhood or adulthood), a diverse array of abnormalities at birth (e.g., hydrocephalus, cerebral calcifications, chorioretinitis, thrombocytopenia, and anemia), and perinatal death.85 Several species of Trichinella roundworms cause trichinosis in humans, who are only accidental hosts, when raw or undercooked pork or wild game meat contaminated with larvae is consumed (see Chapter 289). The signs and symptoms depend partly on number of larvae ingested and the person’s immunity. Gastrointestinal symptoms, such as nausea, diarrhea, vomiting, and abdominal cramps may develop as early as 24 to 48 hours after ingestion, corresponding to the enteral phase of infection. This may be followed by a constellation of signs and symptoms, including fever, myalgias, periorbital or facial edema, headache, or eosinophilia lasting up to several weeks to months, corresponding to the parenteral phase of infection.86 Other infectious agents and diseases with primary symptoms outside the gastrointestinal tract and neurologic systems that can be transmitted by foods include (with a food vehicle example) group A β-hemolytic streptococci (e.g., from cold egg–containing salads),87 typhoid fever (raw produce exposed to human sewage or foods contaminated by asymptomatic human carriers),88 brucellosis (goat’s milk cheese), anthrax (meat), tuberculosis (raw milk), Q fever (raw milk), hepatitis A (shellfish or raw produce), various trematode infections (fish and aquatic invertebrates),89 anisakiasis (fish), and cysticercosis (foods contaminated by Taenia solium eggs shed in human feces of persons with intestinal pork tapeworms). Postinfection Syndromes.  Although arthropathy has been reported after a variety of enteric infections, most experts agree that the term reactive arthritis should only be applied to infections caused by Salmonella, Yersinia, Campylobacter, or Shigella.90 Reactive arthritis can occur as part of the triad of aseptic inflammatory polyarthritis, urethritis, and conjunctivitis described by Reiter. Attack rates of reactive arthritis after salmonellosis vary from 1.2% in studies using more objective case definitions to 14% to 29% in studies using more subjective case definitions.90 Although associations between HLA-B27 positivity and reactive arthritis have been identified, the association may exist only for patients with more severe joint or extra-articular involvement. In studies consisting of mostly mild cases, no associations with HLA-B27 were found.90 Worldwide, 31% of Guillain-Barré syndrome (GBS) cases have been attributed to recent Campylobacter jejuni infection (see Chapter 218).91 When preceding diarrheal illness is reported, it typically occurs 1 to 3 weeks before the onset of neurologic symptoms.92 In contrast to botulism, this syndrome is usually manifested by an ascending paralysis accompanied by sensory findings and abnormal nerve conduction velocity. Several enteric pathogens, including Campylobacter, Shiga toxin– producing E. coli, Salmonella, Shigella, Giardia, and norovirus may lead to the development of postinfectious irritable bowel syndrome or other functional gastrointestinal disorders in some patients.93,94


1288

Part II  Major Clinical Syndromes

TABLE 103-3  Etiology of Foodborne Disease Outbreaks by Commonly Implicated Foods, Season, and Geographic Predilection ETIOLOGY Bacterial

COMMONLY IMPLICATED FOODS

PEAK SEASON(S)

GEOGRAPHIC PREDILECTION

Salmonella

Beef, poultry, eggs, dairy products, produce

Summer, fall

None

Staphylococcus aureus

Ham, poultry, salads, sandwiches, (unpasteurized dairy products in some countries [e.g., France])

Summer

None

Campylobacter jejuni

Poultry, unpasteurized (raw) milk and dairy products

Spring, summer

None

Clostridium botulinum

Home-canned vegetables, preserved fish, honey (infants)

Summer, fall

Type E common in Alaska

Clostridium perfringens

Beef, poultry, gravy

Fall, winter, spring

None

Shigella

Egg salad, lettuce

Summer

None

Vibrio parahaemolyticus

Shellfish

Spring, summer, fall

Coastal states

Bacillus cereus

Fried rice, meats, vegetables

Yersinia enterocolitica

Milk, pork, chitterlings

Vibrio cholerae O1

Shellfish

Vibrio cholerae non-O1

Shellfish

Shiga toxin–producing Escherichia coli

Ground beef, unpasteurized milk, fresh produce

Summer, fall

Northern United States

Salads, shellfish

Winter

None

None Winter

Unknown Tropical, Gulf Coast, Latin America Tropical, Gulf Coast

Viral Noroviruses

Parasitic Toxoplasma gondii

Undercooked meat, raw shellfish, produce

Trichinella

Game meat, less commonly pork in the United States

Cyclospora cayetanensis

Imported fresh produce

Spring, summer

None

Cryptosporidium

Unpasteurized apple cider

Summer

Northern United States

Giardia

Raw produce and a variety of other foods

Summer

Northern United States

None None

Chemical Ciguatera

Barracuda, snapper, amberjack, grouper

Tropical reefs

Histamine fish poisoning (scombroid)

Tuna, mackerel, bonito, skipjack, mahi-mahi

Coastal areas

Shellfish poisoning

Shellfish

Mushroom poisoning

Mushrooms

Heavy metals

Acidic beverages

Diarrhea within 30 Minutes to 12 Hours.  Outbreaks of diarrhetic shellfish poisoning have been reported from throughout the world but not from the United States. Diarrhea is caused by ingestion of filterfeeding bivalve mollusks, such as mussels and scallops, contaminated with okadaic acid produced by certain dinoflagellates, a type of algae. Vomiting may be present, and symptoms resolve within 3 days.106,107 Outbreaks of azaspiracid shellfish poisoning, causing a similar syndrome, have been reported in Europe.106 Paresthesias within 1 to 3 Hours.  When patients have this symptom, fish and shellfish poisonings are possibilities. Histamine fish poisoning (scombroid poisoning) is characterized by symptoms resembling those of a histamine reaction. Perioral paresthesias, flushing, headache, palpitations, sweating, rash, pruritus, abdominal cramps, nausea, vomiting, and diarrhea are common. In severe cases, urticaria and bronchospasm may also occur.107 Histamine can accumulate in fish flesh that has a high concentration of histidine if postmortem spoilage occurs from inadequate refrigeration. Marine bacteria catalyze the decarboxylation of histidine to heat-stable histamine. Symptoms usually resolve within 24 hours. Unlike seafood allergies, scrombroid fish poisonings have a very high attack rate.108 Puffer fish poisoning, caused by tetrodotoxin, is rare outside of East Asia, but an outbreak in the United States resulted from fish transported in a suitcase. Rapid ascending paralysis occurs, and 14% of patients die.107 Two types of shellfish poisoning present with paresthesias: paralytic (PSP) and neurotoxic (NSP). Mild PSP is characterized by paresthesias of the mouth, lips, face, and extremities. Larger intoxications progress rapidly to include headache, vomiting, diarrhea, dyspnea, dysphagia, muscle weakness or frank paralysis, ataxia, and respiratory insufficiency or failure.106,107 The disease is caused by saxitoxins produced by certain dinoflagellates. Bivalve mollusks and some fish feed on these dinoflagellates; the toxins are concentrated in their flesh. Saxitoxin is heat stable and blocks the propagation of nerve and muscle action potentials by interfering with sodium channel permeability. Patients typically recover in hours to a few days.93

Coastal areas Spring, fall

Temperate None

The features of NSP are similar to those of PSP, except they are less severe. Reverse temperature perception may occur.106,107 Brevetoxins produced by certain dinoflagellates are responsible. Brevetoxins cause an influx of sodium into nerve and muscle cells, leading to continuous activation, causing paralysis and fatigue.106 Symptoms typically resolve within 48 hours.107 Paresthesias within 3 to 30 Hours.  The major cause of this syndrome is ciguatera fish poisoning (Table 103-3). Ciguatera is characterized by a broad array of neurologic, gastrointestinal, and cardiovascular symptoms. Some characteristic symptoms include facial, perioral, and extremity parestheisias, hot and cold temperature sensation reversal, metallic taste, headache, dizziness, nausea, vomiting, bradycardia, and hypotension. In severe cases, respiratory distress and death may occur. Gastrointestinal and cardiovascular symptoms resolve in a few days, but neurologic symptoms can last for weeks or years.107,109 Ciguatoxins are lipid-soluble, heat-stable dinoflagellate toxins that open voltage-sensitive sodium channels in neuromuscular junctions. The dinoflagellates are consumed by small fish, which are then consumed by carnivorous fish where the toxins concentrate. Some dinoflagellates that produce ciguatoxins also produce maitotoxin. Although maitotoxin opens cell membrane calcium channels, its role in ciguatera is uncertain given its water-soluble nature.107,109 Vomiting and Diarrhea in Less Than 24 Hours or Neurologic Symptoms in Less Than 48 Hours.  Rare outbreaks of amnesic shellfish poisoning have been reported. Gastrointestinal symptoms predominate in persons aged younger than 40 years. Neurologic symptoms, including headache, visual disturbances, cranial nerve palsies, anterograde amnesia, coma, and death, are more common in persons aged older than 50 years. The illness is caused by the toxin domoic acid, which is produced by certain dinoflagellates and concentrated in shellfish.106,107 Miscellaneous Mushroom Poisoning Syndromes with Onset within 2 Hours.  Several syndromes may occur after ingestion of toxic


1289 TABLE 103-4  Mushroom Poisoning Syndromes TOXINS

Delirium, restlessness

Amanita muscaria, Amanita pantherina

Ibotenic acid, muscimol

Parasympathetic hyperactivity

Inocybe spp., Clitocybe spp., Boletus spp.

Muscarine

Hallucinations, somnolence, dysphoria

Psilocybe spp., Panaeolus spp., Conocybe spp.

Psilocybin

Disulfiram reaction

Coprinus atramentarius

Coprine

Gastroenteritis

Many

Various uncharacterized irritants

Gastroenteritis, hepatorenal failure

Amanita phalloides, Amanita virosa, and other Amanitia; Galerina, Cortinarius, and Lepiota spp.

Cyclopeptides (i.e., amatoxins, phallotoxins)

Gastroenteritis, muscle cramping, hepatic failure, hemolysis, seizures, coma

Gyromitra spp.

Gyromitrin

Gastroenteritis, acute renal failure (temporary)

Amanita smithiana

Allenic norleucine

Gastroenteritis, acute renal failure (often irreversible)

Cortinarius spp.

Orellanine

Long Incubation

mushrooms; identification of the syndromes is more important than knowing the associated species (Table 103-4).110,111,112 Species containing ibotenic acid and muscimol cause an illness that mimics alcohol intoxication and is characterized by confusion, restlessness, and visual disturbances, followed by lethargy; symptoms usually resolve within 12 hours. Muscarine-containing mushrooms cause parasympathetic hyperactivity (e.g., salivation, lacrimation, diaphoresis, blurred vision, abdominal cramps, diarrhea). Some patients experience miosis, bradycardia, and bronchospasm. Symptoms usually resolve within 24 hours. Species containing psilocybin cause hallucinations and inappropriate behavior, which usually resolve within 8 hours. Mushrooms containing a disulfiram-like substance, coprine, cause headache, flushing, paresthesias, vomiting, and tachycardia if alcohol is consumed within 72 hours after ingestion. Species containing allenic norleucine cause gastrointestinal symptoms (e.g., anorexia, nausea, vomiting, diarrhea) within 30 minutes to 12 hours after ingestion. Progression to liver injury and acute renal failure typically occurs 4 to 6 days after ingestion. A variety of mushrooms can cause typically mild gastrointestinal irritation.111 Abdominal Cramps and Diarrhea within 6 to 24 Hours, Followed by Hepatorenal Failure.  Mushrooms containing cyclopeptides (amatoxins and phallotoxins) are responsible for greater than 90% of all mushroom poisoning fatalities (see Table 103-4). The most common implicated mushrooms are Amanita phalloides and Amanita virosa.110 The illness is biphasic. Severe abdominal cramps, vomiting, and severe diarrhea present acutely and usually resolve within 12 to 24 hours. The patient then remains well for 12 to 24 hours. Two to 4 days after ingestion, hepatic and renal failure supervene. The mortality rate in adults is about 10% to 30%.110 A similar syndrome occurs after ingestion of mushrooms containing gyromitrin. Although renal failure is not a feature, hemolysis, seizures, and coma may occur.111 Vomiting and Diarrhea within 4 to 48 Hours, Followed by Renal Failure.  Aminita smithiana mushrooms contain toxins that cause nausea, vomiting, and sometimes diarrhea 4 to 11 hours after ingestion; renal failure may develop 4 to 6 days after ingestion.112 Cortinarius species containing orellanine cause nausea, vomiting, and diarrhea 6 to 48 hours after ingestion; renal injury may develop 2 days to 3 weeks after exposure.111

In addition to the clinical syndrome and incubation period, other clues to the cause of an outbreak may be provided by the type of food responsible and the setting (see Table 103-3).

Foods

Outbreaks of staphylococcal food poisoning are associated with foods of high protein content. In the United States, the foods most frequently implicated include ham, poultry, beef, potato and egg salads, pasta dishes, and sandwiches, which are thought to be contaminated during preparation by a food handler.19 In the classic staphylococcal foodborne outbreak, a food handler’s hand has a purulent skin lesion, but this is true in only a minority of outbreaks. In countries such as France, with greater consumption of unpasteurized cheese, dairy products are the most common vehicles. Masititis in dairy animals is a possible source of contamination.113 In contrast, outbreaks of emetic B. cereus food poisoning are most often associated with starchy foods, especially rice, that have been cooked and held warm for extended periods, during which heat-resistant spores can germinate into vegetative cells that multiply and produce toxin.26,28 C. perfringens outbreaks usually occur after the ingestion of meat (especially beef and poultry) that has not been cooked or stored properly.29 Organisms have been isolated from raw meat, poultry, and fish. Outbreaks are more likely to occur when these items are held between 15° C (59° F) and 50° C (122° F) after cooking, allowing spores to germinate and vegetative cells to rapidly multiply.30,32 B. cereus, resulting in the diarrheal syndrome, is frequently associated with proteinaceous meat, dairy, and vegetable dishes.28 One large B. cereus diarrheal outbreak was attributed to barbecued pork that was unrefrigerated for 18 hours after cooking114; another outbreak was traced to a meal delivery service in which food was held at and above room temperature for an extended period.115 E. coli O157 outbreaks were initially recognized mostly after consumption of undercooked ground beef, and this remains the most commonly recognized source in the United States. However, outbreaks have been traced to a broad range of foods, including leafy greens, apple cider, alfalfa sprouts, venison, salami, and cookie dough.116,117 Healthy cattle commonly carry E. coli O157 in their intestines and excrete it in manure; this organism is not commonly found in other food animals. Produce may become contaminated with E. coli O157 through environmental contamination by feces (from cattle or other animals, such as feral swine or deer)118,119 or by use of water in processing that has been contaminated with fecal matter. Outbreaks of nonO157 STEC infections have been associated with a range of food vehicles. Nontyphoidal Salmonella is carried in the intestines of many animals, including wild reptiles, amphibians, birds, mammals, as well as most food production animals. Consequently, it is common in the environment and food chain, leading to potential contamination of many types of foods. Outbreaks have been associated with contaminated poultry, beef, fish, egg, dairy products, produce, juice, peanut butter, chocolate, cereals, and frozen processed foods. Salmonella serotype Enteritidis, common in poultry flocks, can internally contaminate shell eggs through an ovarian infection in the hen.120 In the United States during 1998 through 2008, eggs and poultry were the predominant sources in outbreaks caused by S. serotype Enteritidis121; these foods are also the dominant sources of sporadic infections of this serotype.122,123 Illnesses caused by E. coli O157:H7, other STEC, Salmonella, Campylobacter, Brucella, Listeria, and Shigella have been associated with consumption of raw milk. Despite these risks, raw milk is still legally sold in many states. From 1993 to 2006, a total of 73 foodborne disease outbreaks caused by nonpasteurized milk or cheese were reported to CDC, accounting for 1571 illnesses, 202 hospitalizations, and 2 deaths; 75% of these outbreaks occurred in the 21 states that permitted sale of nonpasteurized dairy products.124 Shigella outbreaks are most often associated with cool, moist foods consumed raw or that require handling after cooking, such as lettucebased salads, potato and egg salads, salsas, dips, and oysters.125 The organism is carried by humans, not animals. Many foodborne Shigella outbreaks are restaurant associated, and are usually attributable to ill

Chapter 103  Foodborne Disease

SYNDROME Short Incubation

COMMONLY IMPLICATED MUSHROOMS

EPIDEMIOLOGY


Part II  Major Clinical Syndromes

1290 food workers.125 Less than half of Shigella infections are estimated to be aquired through food; most are transmitted from one person to another directly or via fomites. The major food source for Campylobacter infection is poultry. Foodborne illness occurs from consumption of undercooked poultry and from consumption of other foods, especially produce cross-contaminated from poultry in the kitchen or earlier in the farm-to-table continuum. Cattle also carry Campylobacter, and unpasteurized dairy products are an important source.126 Listeriosis outbreaks have been traced to delicatessen meats, frankfurters, raw soft cheeses (such as queso fresco), and produce. Delicatessen meats and frankfurters, which had caused large outbreaks of infections, have been infrequently implicated in outbreaks occurring since 2005, probably because of several regulatory initiatives.127 In the United States, raw produce has been recognized as the source of three recent listeriosis outbreaks: 2008 (raw sprouts), 2010 (precut celery in chicken salad), and 2011 (whole cantaloupe).127-129 Vibrio outbreaks are rare in the United States and have been caused by V. parahaemolyticus, toxigenic V. cholerae, and V. mimicus, usually associated with the ingestion of shellfish.37,40,46,47 Sporadic foodborne cases of Vibrio illness are also typically linked to ingestion of shellfish, especially oysters.46 Toxigenic strains of V. cholerae have been acquired from domestically-grown shellfish. Crabs brought in travelers’ luggage have caused cholera.130 Relative to some European countries, the incidence of Y. enterocolitica infections in the United States is considerably lower.56,131,132 Outbreaks occur occasionally and have been associated with consumption of pork products and contaminated milk; produce has been implicated less frequently.57,58,133-135 Fewer infections now appear attributable to cross-contamination from the preparation of pork chitterlings in the household.57,131 Although diarrhea caused by ETEC is usually thought to be acquired primarily through exposures encountered during travel outside developed countries or on cruise ships,136,137 outbreaks caused by ETEC do occur in the United States and are most commonly associated with foods that require extensive handling to prepare and are often served cold, such as seafood, fresh produce, herbs, or salads.138-142 Foodborne ETEC infections are typically associated with a breech in hygiene and sanitation during food production, transport, or preparation.143 Clostridium botulinum spores can germinate into cells that can grow and produce toxins only in foods that provide an anaerobic environment, a pH of less than 4.5, low salt and sugar content, and a temperature of 4° to 121° C.70 Botulism outbreaks are most often associated with home-canned vegetables, fruits, and fish. Additional vehicles have included baked potatoes, sautéed onions, and commercial chopped garlic in oil lacking a growth inhibitor.144 Recent outbreaks caused by bottled carrot juice and canned chili sauce were the first related to commercial products in almost 20 years.145,146 Honey is a recognized source of C. botulinum spores in infant botulism; therefore, parents are advised to not feed honey to infants younger than 1 year old.72 In norovirus outbreaks, food is most often contaminated by a food handler; contamination can also occur either directly with human fecal matter at the source of production, such as shellfish caught in sewagecontaminated waters or produce irrigated with water contaminated by sewage.53 Foods that require handling without subsequent cooking are typically implicated, including sandwiches, leafy vegetables, fruits, and shellfish.53 In one large multistate outbreak, steamed shellfish from the Gulf Coast were implicated. These were probably contaminated by ill oystermen, who, lacking toilet facilities on their oyster boats, defecated and vomited directly into shallow oyster beds.147 Cyclospora infection results from ingestion of mature (infective) oocysts in contaminated food or water. Cyclosporiasis is endemic in various tropical and subtropical regions. Outbreaks of cyclosporiasis in the United States have been linked to multiple types of imported fresh produce, including raspberries, basil, mesclun lettuce, and snow peas.74,148 Foodborne toxoplasmosis is acquired through consumption of undercooked meat (especially pork, lamb, and game meat) that contain tissue cysts or uncooked foods (primarily fruits and vegetables, but also raw shellfish) contaminated with oocysts originating from cat feces.65,149 Free-range organically raised meats, which are growing in popularity,

may be more likely to be contaminated.149 Trichinosis caused by consumption of contaminated pork still occurs infrequently in the United States. However, largely because of improvements in swine husbandry in the past several decades, and likely because of efforts to educate consumers on cooking pork thoroughly to kill any Trichinella larvae present, the most frequent source of trichinosis cases and outbreaks in the United States has shifted from commercial pork to wild game meat, especially bear meat.150,151 Outbreaks of heavy metal poisoning are most often associated with acidic beverages, such as tea, lemonade, fruit punch, and carbonated drinks that have been stored in corroded metallic containers for periods sufficient to leach the metallic ions from the container.99-104 Although histamine, or scombroid, fish poisoning is named after the Scombroidiae family, which includes fish such as tuna, mackerel, bonito, and skipjack, many nonscombroid fish, including, but not limited to, mahi-mahi, bluefish, and escolar, can also cause histamine fish poisoning.107,108,152,153 Ciguatera fish poisoning is associated with consumption of many different large reef-dwelling carnivorous fish, including barracuda, red snapper, amberjack, and grouper caught between 35° north and south of the equator.107 Shellfish poisonings mostly occur after ingestion of bivalve mollusks, most often oysters, clams, mussels, and scallops.106 However, cases of PSP in Florida have followed consumption of local pufferfish.154 The possibility that foodborne illness could be the result of an intentional contamination should also be considered. An outbreak of salmonellosis in Oregon in 1984 involved 751 persons who ate or worked at 10 area restaurants. Epidemiologic investigation determined that illness was associated with eating from salad bars. A subsequent criminal investigation revealed that members of a religious commune had deliberately contaminated the salad bars.155 In 1996, an outbreak of Shigella dysenteriae type 2 infections, affecting 12 persons, was caused by consumption of deliberately contaminated muffins.156 In 2003, ground beef was intentionally contaminated with nicotine at a supermarket.157

Nonfoodborne Transmission

The evaluation of a suspected foodborne outbreak may reveal other modes of transmission, including consumption of water (drinking or recreational),158,159 or contact with infected animals160 or persons.52 Some pathogens incriminated in waterborne disease outbreaks are different from those most often responsible for foodborne disease. Giardia is a frequently recognized pathogen in outbreaks associated with drinking water, including several large outbreaks traced to municipal water supplies.161-163 Foodborne giardiasis outbreaks in the United States are rare and are usually caused by infected food handlers.164 Giardiasis is characterized by diarrhea, nausea, abdominal pain, bloating, flatulence, and occasionally malabsorption. The incubation period is typically 1 to 2 weeks, and the duration of illness may be several weeks, occasionally longer. Cryptosporidium is the most common infectious cause of outbreaks caused by contaminated recreational water intended for swimming.159 Cryptosporidium outbreaks caused by contaminated food and a massive outbreak caused by contaminated drinking water have occurred.164,165 Other waterborne outbreaks have been caused by E. coli O157:H7,166,167 Shigella,168 hepatitis A,169 Salmonella serotype Typhi,170 nontyphoidal Salmonella,171 ETEC,172 C. jejuni,126,173-175 noroviruses,176-178 Toxoplasma,179 and V. cholerae.

Vulnerable Populations

Some people are more susceptible to acquiring a foodborne infection or to experiencing more severe illness than are others.180 Most host factors associated with increased risk are related to inadequate immune response. Immune-related factors include, but are not limited to, the following: age younger than 5 years, age 65 years or older, primary immunodeficiencies, pregnancy, human immunodeficiency virus (HIV) infection, leukemia, immunosuppressive medications (e.g., chemotherapy, corticosteroids, agents used to treat autoimmune conditions), diabetes, and nutritional deficiencies.180 Persons with excessive iron stores, such as occurs in cirrhosis and hemochromatosis, are more susceptible to infection with foodborne pathogens that grow more rapidly in the presence of iron.180 The protection against foodborne infections conferred by gastric acid is reduced in persons who consume


1291

Seasonality

Illnesses caused by S. aureus, Salmonella, Shigella, C. jejuni, Vibrio spp., STEC, Giardia, and Cryptosporidium are most common during the summer months. Similarly, shellfish-associated Vibrio infections peak during warmer months and are closely related to the temperature of the water in the oyster beds.183 Illnesses caused by C. perfringens occur throughout the year but least often during the summer months.29 Among black children in the United States, Y. enterocolitica infections have occurred primarily after winter holidays at which pork chitterlings are served. However, likely in part a result of education efforts, the winter seasonality of these infections in black children has diminished considerably during 2000 to 2009, and Y. enterocolitica infections occur throughout the year for other demographic groups.131 Although transmitted year-round, winter is the season of peak norovirus activity, which provides additional opportunity for foodborne contamination with this pathogen.54 With a few exceptions, chemical food poisoning occurs throughout the year. Shellfish poisonings and ciguatera occur in association with harmful algal blooms, such as a red tide. These blooms can occur at any time of the year, but may be more common in late summer and fall in Florida. Mushroom poisoning is most common in the spring, late summer, and fall.

Geographic Location

The geographic setting may also provide a clue to the cause of foodborne disease. In the United States, E. coli O157 infections and outbreaks are more common in the northern states bordering Canada, for unexplained reasons.116,184 In Germany, areas of higher frequency of human E. coli O157 and some non-O157 STEC infections are those with higher cattle density.185 In the United States, V. parahaemolyticus outbreaks are most frequently reported from coastal states (Gulf Coast, Atlantic, and Pacific).37 Cases of toxigenic and nontoxigenic V. cholerae infection have been

most often reported from the Gulf Coast of the United States. Type E botulism is most common in Alaska.186 Most ciguatera fish poisoning outbreaks in the United States have been reported from the Caribbean, Florida, or Hawaii.187 Travelers who return from these areas with the characteristic syndrome should be questioned regarding fish consumption. Transport of fish from endemic areas has caused outbreaks in nonendemic locations.188,189 PSP and NSP outbreaks occur more frequently in coastal areas. Globalization and centralization of the world’s food supply has led to increased detection of multistate and multinational outbreaks.17 Seemingly isolated illnesses within a geographic area may actually be part of a larger multistate or multinational outbreak.

Epidemiologic Assessment

If an outbreak of foodborne disease is suspected, public health authorities should be contacted so that it can be investigated. Investigating the outbreak is important to identify and rapidly control the source. There are several stages during an outbreak investigation, progressing from confirmation of an outbreak to identifying the likely factors leading to contamination at some point in the food chain.190 Every investigation is unique. However, to increase likelihood of solving the outbreak, all investigations, at a minimum, require development of case definitions and thorough detective work to generate hypotheses as to the likely vehicles. Hypothesis generation is an iterative process and involves synthesis of multiple types of information, including (1) the distribution of cases by person, place, and time; (2) existing knowledge about the pathogen; and (3) exposures reported through patient interviews. A refined hypothesis can be tested in various ways to yield the following three types of evidence, which together can implicate a food item as a vehicle: (1) statistical association between illness and consumption of the food, (2) detection of the outbreak strain in the food, and (3) identification of a single point in the food production and distribution chain to which food consumed by multiple patients can be traced. Typically, a strong basis for public health action is met when any two of these types of evidence are present. However, particularly severe outbreaks may require less stringent criteria to justify action such as recalling products or alerting the public. Sometimes, a common meal shared by all or most patients is identified. In this situation, a cohort study can be performed. Both ill and well persons who ate at the meal must be interviewed. For each item served, the proportion of persons who became ill (attack rate) should be determined for persons who consumed the item and for persons who did not consume the item (Table 103-5). To be incriminated on statistical grounds, a food must have a significantly higher attack rate among those who ate it than for those who did not. Because significant associations may reflect chance findings, it is important to substantiate significant associations with other factors, including the magnitude of association (e.g., relative risk), evidence of a dose-response relationship between the food and illness, and biologic plausibility.190 On occasion, more than one food item may be statistically associated with illness. A

TABLE 103-5  Example of Use of Food-Specific Attack Rates and Stratified Analysis to Identify Food Vehicle in a Foodborne Outbreak FOOD-SPECIFIC ATTACK RATES No. of People Eating Food No. of People Not Eating Food Total Ill % Ill Total Ill % Ill Meat loaf Gravy

100

88

88*

10

2

20*

80

80

100†

30

10

33†

Potatoes

95

78

82

15

12

80

Salad

90

74

82

20

16

80

Water

70

58

82

40

32

80

STRATIFIED ANALYSIS No. of People Eating Meat Loaf No. of People Not Eating Meat Loaf Total Ill % Ill Total Ill % Ill No. of people eating gravy

75

67

89†

5

1

20*

No. of people* not eating gravy

25

21

84†

5

1

20

*P < .05 (Fisher’s exact test). † P < .05 (chi-square analysis).

Chapter 103  Foodborne Disease

antacids (especially proton-pump inhibitors), large volumes of liquid, or fatty foods.180 The increasing average age and accompanying chronic illnesses in many countries means that more of the population has a heightened susceptibility to severe foodborne infections. People with compromised immunity caused by HIV infection have higher reported rates of salmonellosis, campylobacteriosis, shigellosis, invasive listeriosis, and cyclosporiasis than do persons not infected with HIV.181,182 Most of these infections are more likely to be severe, recurrent, or persistent in such patients.181,182 Rates of cryptosporidiosis have decreased since the advent of highly active antiretroviral therapy. Persons who consume unpasteurized (raw) milk are at increased risk of acquiring foodborne infections. Immigrant and refugee populations may have certain customs that involve consumption of raw or undercooked food. Severe mushroom poisonings have occurred among immigrants who mistook poison mushrooms as safe mushrooms from their place of origin.110

46


Part II  Major Clinical Syndromes

1292 stratified analysis may indicate whether both items were contaminated by the etiologic agent or whether one item was contaminated while the other was often consumed with it (e.g., meat loaf and gravy) (see Table 103-5). For example, if meat loaf and gravy were both statistically associated with illness, stratified analysis may indicate that attack rates were high for those who ate meat loaf, regardless of whether they ate gravy, and were low for those who did not eat meat loaf, regardless of whether they ate gravy, indicating that the meat loaf alone was likely responsible for the outbreak. Other outbreaks are the result of a food that was contaminated before it was distributed to restaurants, grocery stores, and kitchens, so that cases may be dispersed across a broad geographic area. Such a cluster of presumably related cases can be identified by subtype-based surveillance, such as Salmonella serotype surveillance and PulseNet.191 Hypothesis-generating interviews of patients in a dispersed cluster may suggest that some foods are more often consumed than is expected. Once a specific food exposure is suspected, a case-control study involving systematic interviews of a group of ill persons and a group of comparable healthy people may provide statistical evidence associating illness with a food vehicle. Establishing statistical evidence can be challenging if the contamination was present on an ingredient that most people do not know they consumed (a stealthy vehicle [e.g., a sprout garnish]),192,193 an ingredient that is present in many different products (a common ingredient [e.g., peanut butter]),194 or an ingredient consumed frequently by both ill and well persons (universal exposure [e.g., tap water]).195 In these outbreaks, careful hypothesis generation is needed to piece together more subtle aspects of patient-reported exposures. Epidemiologic tools that supplement patients’ recall of exposures can help.192-196 Once a food vehicle for the infections is identified, the investigation turns to the question of how contamination is likely to have occurred. Steps of food preparation, holding temperatures, and hygienic circumstances in the kitchen are assessed. Investigation into the sources of food ingredients may lead to assessments of the originating farm or processing plant. These assessments may result in changes in industry practices to prevent future illnesses.

LABORATORY DIAGNOSIS

Most diarrheal illnesses do not require diagnostic testing. Guidelines exist that describe clinical presentations that should prompt testing.197 However, in the context of a possible outbreak, determining an etiology is always important for identification of additional cases and for investigation into the possible sources of infection. To confirm the etiologic agent in outbreaks, appropriate specimens (e.g., stool or vomitus) should be tested from multiple patients. In addition, as guided by epidemiologic findings, samples from leftover food, the food preparation environment, and food handlers may be examined. Specimen types vary by etiologic agent, and proper specimen collection and transport are important to successful diagnosis198; guidance is available at www.cdc.gov/outbreaknet/references_resources. To date, detection of infectious agents in the clinical setting has been performed nearly entirely by isolating bacterial pathogens in culture, by visualizing parasites by microscopy, or, in more recent years, by detecting presence of antigens or toxins of pathogens in stool or food samples by immunoassays. Because some pathogens require specific culture media, culture conditions, or stains, diagnosis may depend on the skill of the clinician or laboratory choosing methods that could identify the causative agent. Some bacterial foodborne pathogens are not readily identified from cultures alone (e.g., diarrheagenic E. coli other than E. coli O157, such as non-O157 STEC and ETEC).143,199 In addition, most clinical laboratories do not have capacity to test for norovirus. Therefore, to identify some etiologies, human specimens must be sent to reference laboratories where selective methods are available, and food specimens must be sent to food microbiology laboratories that can detect bacterial or nonbacterial toxins and chemicals. Reference laboratories can identify non-O157 STEC isolates from Shiga toxin–positive specimens received from clinical laboratories,199 identify other diarrheagenic E. coli (e.g., ETEC, enteroaggregative, enteropathogenic, and enteroinvasive E. coli) by detection of virulence genes or toxins that define specific pathotypes, and can identify norovirus by polymerase chain reaction (PCR).200

Newer commercially available molecular diagnostic assays, such as those that use multiplex PCR to simultaneously detect and distinguish between multiple enteric pathogens, including several undetectable by traditional methods (e.g., ETEC, norovirus), are now available in the clinical setting.201,202 These multipathogen assays can yield results within several hours. Because of the multipathogen nature of these newer molecular tests, they are likely to increase the number of illnesses for which two or more enteric pathogens are identified. Over time, this may improve understanding of pathogen interactions. However, it will become increasingly important to interpret positive results in a clinical context because the pathogens detected may not be causing illness.16,201,202 Despite the clinical advantages molecular methods may offer (speed, number of detectable pathogens, and possibly lower cost), bacterial culture remains necessary for antimicrobial susceptibility testing and for pathogen subtyping that aids outbreak detection and investigation. The identification, investigation, and confirmation of foodborne outbreaks of bacterial etiology have been aided greatly by the establishment of standardized pulsed-field gel electrophoresis (PFGE) methods in public health laboratories in the United States and Canada, a subtyping network called PulseNet.191 Bacterial isolates received from clinical laboratories that are routinely subtyped by PFGE include E. coli O157 and other STEC, Salmonella, L. monocytogenes, V. cholerae, and C. botulinum. Campylobacter, Shigella, and other Vibrio species are sometimes subtyped. Other pathogens may be subtyped by PFGE to confirm an outbreak. PulseNet is growing internationally, which will enable better detection of outbreaks of international scale,203 and newer molecular subtyping methods may improve the results. Outbreaks of staphylococcal food poisoning can be confirmed by isolation of S. aureus of the same PFGE pattern from vomitus or feces of two or more ill people or from both patient and food samples, or by detection of enterotoxin or the isolation of greater than 105 organisms per gram in epidemiologically implicated food.204 However, because S. aureus (but not the enterotoxins they produce) is heat sen­ sitive, it is often difficult to isolate the organism from heat-treated foods. The identification of specific S. aureus enterotoxins (SE types A through E) in food is accomplished, most commonly, by reverse passive latex agglutination (RPLA) or enzyme-linked immunosorbent assay (ELISA) platforms, which are available commercially. The tests will distinguish SE types A through E and are useful for identifying the types of enterotoxins involved in foodborne outbreaks. More recently, mass spectrometry has been used to quantify enterotoxins in foods. Although PCR detection alone of enterotoxin genes directly from contaminated foods and specimens cannot be used to confirm staphylococcal food poisoning, it can confirm isolation and direct toxin testing results. B. cereus outbreaks may be documented by isolating organisms from the feces of two or more ill people who shared the same meal or by isolating 105 or more B. cereus organisms per gram of incriminated food. Because nontoxigenic B. cereus is commonly found in foods, testing for enterotoxin genes in several isolates is advised. If available, multilocus sequence typing,205 plasmid analysis, or serotyping206 may be of value in confirming that isolates were derived from a common source, because 14% of healthy adults have been reported to have transient gastrointestinal colonization with B. cereus.207 Commercial immunoassays are available for two of the diarrheagenic enterotoxins of B. cereus.26 A wild boar sperm assay has proven to be a simple and effective way to screen for cereulide-producing B. cereus isolates.208 PCR assays that detect the ces gene (cereulide) in emetic strains have been developed.209 Because C. perfringens organisms are part of the normal flora in many people, it is not sufficient to isolate the organism from the stool of two or more ill people to confirm C. perfringens as the etiologic agent in an outbreak. In addition, because only less than 5% of C. perfringens type A strains produce CPE,31 toxin assessment is needed. A reverse passive agglutination kit for detection of CPE directly from stools is commercially available. PCR can detect the cpe gene, but detection may not indicate expression of the protein. Therefore, detection of toxin in stool is the best indicator of infection. PFGE can confirm that the same strains are present in both implicated foods and patients.32 Because both heat-sensitive and heat-resistant strains of C. perfringens


1293 unknown etiology may decrease as molecular methods that can detect a wider array of pathogens become increasingly available. Enterococci and gram-negative rods (Aeromonas hydrophila, Klebsiella, Enterobacter, Proteus, Citrobacter, and Pseudomonas) have been reported as causes of foodborne outbreaks on rare occasions. However, because these organisms may be present in foods without causing illness and may be part of the normal human fecal flora, documenting their role in foodborne disease outbreaks is difficult.

THERAPY

Supportive measures are the mainstay of therapy for most foodborne illnesses. In any diarrheal illness, gastrointestinal fluid losses should be replaced. Usually any over-the-counter oral rehydration solution is sufficient; for severe dehydration, intravenous hydration may be required.197 Early intravenous hydration may reduce the risk of oligoanuric hemolytic-uremic syndrome in patients with STEC O157 infection215; patients that develop hemolytic-uremic syndrome frequently require blood transfusions.61 Antiemetics and antimotility agents offer symptomatic relief among adults, although the latter are contraindicated in patients with high fever, bloody diarrhea, or fecal leukocytes indicative of inflammatory diarrhea. Antiemetics and antimotility agents are usually not recommended for children. Supportive intensive care is essential in the management of botulism; access to mechanical ventilation greatly reduces the mortality rate.70 The most lethal foodborne diseases are botulism, invasive listeriosis (affecting neonates, the elderly, and immunocompromised persons), V. vulnificus infection (in those with liver disease), paralytic shellfish poisoning, and longincubation mushroom poisoning. With other pathogens, fatalities most often occur in the elderly or immunocompromised persons. Antimicrobial agents are lifesaving in invasive salmonellosis, invasive listeriosis, Vibrio septicemia, and typhoid fever. Azithromycin, doxycycline, and tetracycline shorten both the duration of cholera diarrhea and the excretion of toxigenic V. cholerae O1 and are first-line agents (in combination with rehydration) in patients with moderate to severe illness. Most diarrheal illness caused by Campylobacter and Shigella species is self-limited. Early treatment of Campylobacter infection with fluoroquinolones, erythromycin, or azithromycin can shorten the duration of illness. However, domestically acquired fluoroquinoloneresistant Campylobacter infections emerged after the approval of these agents for use in poultry. Antibiotic treatment of shigellosis is recommended for patients with severe infections, dysentery, or who are immunocompromised. Antimicrobial susceptibility testing of Shigella isolates is important as resistance is common and reduced susceptibility to azithromycin has been recently identified.14 Antimicrobial agents are used to treat parasitic infections. More information on treating parasitic infections can be found at www.cdc.gov/parasites. Most bacterial diarrheal illnesses are self-limited and do not require antimicrobial therapy in healthy hosts who are not at the extremes of age. Antibiotic treatment of nontyphoidal Salmonella gastroenteritis may increase the risk of long-term carriage.216 Antibiotic treatment of STEC O157 infections may increase the risk of hemolytic-uremic syndrome.217 Antibiotics are of no value in the management of staphylococcal, C. perfringens, and B. cereus food poisoning. Resistant strains can complicate treatment and are associated with a greater risk of invasive infection and hospitalization.218 Asymptomatic Salmonella infection may become clinically apparent when an unrelated condition is treated with an antimicrobial agent to which the Salmonella organism is resistant; such treatment also lowers the infectious dose.219 The proportion of resistant isolates varies widely by serotype. Salmonella serotype Typhimurium resistant to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline emerged globally, particularly in Europe and the United States, in the 1990s.220,221 However, the proportion of serotype Typhimurium strains with this resistance pattern isolated from humans and tested in the National Antimicrobial Resistance Monitoring System (NARMS) declined from 32% in 1996 to 18% in 2009.13 Salmonella serotype Newport resistant to amoxicillin/clavulanate, ampicillin, cefoxitin, cephalothin, chloramphenicol, streptomycin, sulfonamides, and tetracycline and with decreased susceptibility to ceftriaxone emerged in the United States in the early 2000s. It is associated with consumption of undercooked ground beef.222 The proportion of

Chapter 103â&#x20AC;&#x201A; Foodborne Disease

type A have been implicated in food poisoning, selective isolation procedures involving heat treatment of food and fecal specimens should not be used. STEC (including E. coli O157), Salmonella, Shigella, C. jejuni, Vibrio, and Y. enterocolitica outbreaks may be detected by isolation of the organisms from the feces of ill people. However, pathogens identified as part of a routine stool culture typically only include Salmonella, Shigella, Campylobacter, and sometimes E. coli O157. To identify other bacterial pathogens in culture, the clinical laboratory needs to be notified so that special media can be used.84 Infection with STEC O157 can be diagnosed by isolating sorbitol-negative E. coli from stools of ill persons on selective and differential media, such as sorbitolMacConkey, and confirming the serogroup as O157, and then either confirming the H7 antigen, the detection of Shiga toxin, or the presence of stx genes that encode for the expression of the toxin. Non-O157 STEC can be identified by demonstration of Shiga toxin in stool by enzyme immunoassay (EIA) or stx genes in stool by PCR at the clinical laboratory, with subsequent isolation of the organism by culture at a reference laboratory. In the United States, isolates of E. coli O157 or Shiga toxinâ&#x20AC;&#x201C;positive broth cultures should be forwarded to a public health laboratory for full characterization and PFGE subtyping.199 Although immunoassays for detection of Campylobacter in stool are available, the accuracy of these tests varies considerably.210 Testing of sera, especially paired serum from the acute and convalescent phases of illness, may be helpful in confirming the diagnosis of patients in outbreaks of STEC, cholera, and typhoid fever. Patients with suspected botulism should be treated before the diagnosis is confirmed. Tests that can help narrow the differential diagnosis include lumbar puncture (a high cerebrospinal fluid [CSF] protein level is suggestive of GBS and Miller Fisher syndrome [a variant of GBS] and can be confused with botulism), the Tensilon test (to diagnose myasthenia gravis), and electromyography (findings of neuromuscular junction blockade, normal axonal conduction, and potentiation with rapid repetitive stimulation are suggestive of botulism).70 Botulism may be confirmed by the demonstration of botulinum toxin in the serum, gastric secretions, stool, or in the incriminated food by the mouse neutralization test, or by the isolation of C. botulinum from stool or the incriminated food; these tests can be arranged through contact with state health departments.70 Laboratory confirmation by testing of clinical specimens can be obtained in about 70% to 75% of botulism cases.211,212 The gold standard laboratory detection methods for many enteric parasitic pathogens require visualization of characteristic forms in the feces. Physicians should specifically request testing for Cyclospora and Cryptosporidium, if indicated, because these pathogens are not typically detected via routine ova and parasite examination and require specialized techniques. In addition, sensitive, commercially available antigen detection and molecular assays exist for Cryptosporidium and Giardia. Toxoplasmosis can be diagnosed by both serology and PCR.85 Trichinosis is diagnosed by serologic testing and, less frequently, by muscle biopsy. Additional information on the diagnosis of parasitic infections can be found at www.dpd.cdc.gov/dpdx. Outbreaks caused by heavy metals may be documented by demonstration of the metal in the incriminated food or stool specimens from ill persons. Marine toxin syndromes are diagnosed by clinical presentation and history of seafood consumption in the preceding 24 hours; diagnostic tests are not available in the clinical setting.107,213 However, detection of toxin in implicated foods may be possible. Mushroom poisonings should be diagnosed by clinical suspicion, and may be confirmed either by the identification of the responsible toxin in gastric contents, blood, urine, or fecal specimens or by the identification of the mushroom by a mycologist.110 About one third of the reported foodborne disease outbreaks in the United States are of unknown etiology.1 In many cases, appropriate diagnostic procedures are not conducted, or specimens are not collected in a timely manner, not transported properly, or they are transported under suboptimal conditions. Many of these unknown outbreaks may be due to typical agents.214 In others, no agent is identified despite testing, raising the possibility that etiologic agents not routinely tested for are responsible; possibilities include ETEC, enteroaggregative E. coli, and sapovirus. The frequency of outbreaks of


Part II  Major Clinical Syndromes

1294 serotype Newport isolates with this resistance pattern tested in NARMS increased from none in 1996 to a peak of 25% in 2001, and it declined to 7% in 2009.13 However, other resistance patterns are emerging. From 1996 through 2009 in NARMS surveillance, the percentage of Salmonella isolates resistant to ceftriaxone increased from 0.2% to 3.4%, and the percentage with nonsusceptiblity to ciprofloxacin increased from 0.4% to 2.4%.13 The emergence of these multidrug-resistant Salmonella was probably related to agricultural uses of antimicrobials. This highlights the interconnected pool of pathogens between animal reservoirs and people and underlines the need for prudent use of antimicrobials in both sectors. Medical care providers who suspect botulism should implement close observation and supportive care and immediately call their state health department’s emergency 24-hour telephone number. The state health department will contact the CDC to arrange a clinical consultation by telephone and, if indicated, release of botulinum antitoxin. Management of botulism is discussed in Chapter 247. Patients with paralytic shellfish poisoning and some patients with ciguatera may require ventilatory support, usually for only a few days. Although case reports and unblinded randomized studies have suggested that intravenous mannitol may ameliorate the acute neurologic symptoms of ciguatera, a double-blind randomized trial showed no benefit.223 Case reports have suggested that amitriptyline and tocainide may improve persistent dysesthesias.213 Therapy is otherwise supportive; no antitoxins are available. If not contraindicated by the presence of ileus, enemas or cathartics may be administered in an effort to remove unabsorbed toxin from the intestinal tract. Because of the severe dysesthesias associated with ciguatera, analgesics may also be required. Scombroid poisoning may be treated with a combination of H1 and H2 antihistamines. In severe cases with bronchospasm, epinephrine may be required.224 Therapy for short-incubation types of mushroom poisoning is primarily supportive. Patients with severe parasympathetic hyperactivity caused by muscarine poisoning may be treated with atropine.111 Therapy for cyclopeptide poisonings includes cathartics to remove unabsorbed toxin in the minority of patents who present before the onset of severe gastrointestinal symptoms and many additional unproven measures.110 Pyridoxine is indicated for treatment of neurologic manifestations of gyromitrin poisonings.111 Therapy for acute heavy metal poisoning is supportive. Emesis should be induced if it does not occur spontaneously. Antiemetics are contraindicated, because retention of the toxic ions in the gut and subsequent systemic absorption may result. In severe cases of heavy metal toxicity, use of specific antidotes may be considered, but that is rarely necessary.

SURVEILLANCE

Surveillance of enteric diseases address four objectives: (1) individual case investigation for localized disease control activities, (2) outbreak detection to protect the population and to identify gaps in control measures, (3) assessment of disease burden and trends to prioritize and assess impact of control measures, and (4) microbiologic characterization of infectious agents to improve understanding of their epidemiology, antimicrobial resistance, and virulence factors.210 State public health laws determine reportable conditions for each state and who is responsible for reporting. In turn, state public health officials voluntarily submit data to the CDC for nationwide surveillance. Disease conditions reportable by law may vary among states; the information about reportable conditions is available through state and local health departments. Case definitions for nationally notifiable infectious diseases are available at wwwn.cdc.gov/nndss/. Surveillance systems can be classified as provider based (e.g., reports of illnesses from clinicians) or laboratory based (e.g., reports of test results from public health laboratories). Although both types of surveillance are important and needed, laboratory-based surveillance has proven especially valuable because of information gleaned from subtyping. For Salmonella, Shigella, Shiga toxin–producing E. coli, and Listeria, clinical laboratories should send isolates to a reference laboratory for serotyping and molecular subtyping by pulsedfield gel electrophoresis (PFGE). In the United States, all state public health laboratories participate in PulseNet.191 Similarly, many U.S.

public health laboratories, as part of CaliciNet, can perform genetic sequencing of PCR products to link multiple norovirus cases and environmental sources.225 Although knowing the specific serotype or PFGE pattern is rarely of importance in the management of a single case, this or other subtyping information is essential to the investigation of many outbreaks and is fundamental to the recognition of multistate outbreaks. This means that a diagnostic culture is not only of benefit to the patient but to society as a whole. However, diagnostic practices are changing. The use of culture-independent methods, such as EIA or PCR, that do not yield isolates that can be subtyped is increasing.210 Until culture-independent diagnostic tests are developed that provide subtype information, it is important to reflexively culture any specimen that tests positive by a culture-independent test so that the public health functions of laboratory-based surveillance are not impaired. Efforts are underway to develop new diagnostic methods that serve both clinical and public health needs. One approach is metagenomics, the sequencing of all the genetic material in a stool sample. Although this technology has not reached a stage that is useful for routine diagnostic testing or surveillance, it was used in a retrospective study of an STEC outbreak.226,227 A report of illness in a single person who has attended a daycare center, family gathering, or other setting often leads to discovery of an outbreak. Outbreaks can be apparent even before the causative agent is not known, and early investigation can control a source. This means that the astute clinician or microbiologist who calls the public health department epidemiologist to discuss a case plays an important role in the control of foodborne and other diseases.

PREVENTION

Monitoring of food production systems is increasingly important as the global food supply becomes more interconnected, centralized, and preprocessed for the convenience of the consumer. Prevention of foodborne disease depends on careful handling of animals, raw products, and processed foods all the way from the farm to the table, and on practices that reduce or eliminate contamination in food. Raw animal products, including meat, milk, eggs, and shellfish, are common sources of contamination leading to foodborne diseases. Contamination of raw animal products can be reduced by interventions targeted at both animal production and slaughter practices. On the farm, interventions currently in use or being studied include (1) good hygienic practices and environmental microbiologic moni­ toring; (2) measures that minimize food animals’ exposure to wild animals, rodents, and insects that may carry human pathogens; (3) provision of microbiologically safe feed and water; (4) administration of agents to animals that inhibit pathogen colonization (e.g., prebiotics and probiotics) or inactivate pathogens (e.g., bacteriophage and bacteriocins); and (5) vaccination against Salmonella or E. coli O157.228 Reducing contamination during animal slaughter or food processing relies on a systematic approach to risk reduction, the Hazard Analysis Critical Control Point (HACCP) program. HACCP requires a food producer to identify points where the risk of contamination can be controlled and to use production systems that eliminate the hazards, thereby focusing on preventing contamination, rather than relying on a final inspection step to detect it after it has occurred. Milk pasteurization and commercial canning practices are longestablished technologies that make foods safe. Strategies being applied now include monitoring of processing plant equipment for contamination, and acid rinses and steam scalding of carcasses. Newer and lesser used approaches include application of bacteriophage to meats229 and gamma, electron-beam, and x-irradiation of meats and some types of produce.230 Because pathogens can stick to produce even after washing, the key to reducing the growing number of foodborne illness associated with consumption of raw produce is to prevent contamination before foods arrive in kitchens.11 There are many points where produce can become contaminated during growth and harvesting, processing and washing, transport, and final processing. The surface of plants and fruits may be contaminated by soil, manure, or feces of animals or agricultural workers. Agricultural practices that may reduce the risk of contamination generally include use of clean water and ice for irrigation, pesticide


1295 example, routine use of pasteurized eggs instead of shell eggs could prevent many nosocomial salmonellosis outbreaks. Low microbial (or neutropenic) diets are advised for some especially vulnerable patients.180,233 Some foods pose such high risk of infection that they should be avoided by even healthy nonhospitalized persons; these include raw milk (which can transmit Salmonella, C. jejuni, STEC, and Mycobacterium tuberculosis)124 and inadequately heat-processed homecanned foods (botulism). Except for scombroid fish poisoning, food-handling errors resulting in chemical intoxication are different from those leading to bacterial outbreaks. Heavy metal poisoning occurs when acidic beverages are stored in defective metallic containers. Ciguatera and shellfish poisoning occur when seafood are obtained from unsafe sources; seafood containing the toxins appear and taste normal, and cooking does not provide protection because the toxins are heat stable. Scombroid fish poisoning can be prevented through refrigeration of raw fish.108 The role of the clinician goes beyond that of diagnosis and treatment to prevention. This means educating patients or caregivers, especially those more vulnerable to foodborne disease (e.g., parents of infants, pregnant women, older adults, and immunocompromised persons) about food safety measures. Such persons may choose to avoid high-risk foods, and everyone can benefit from following good food handling practices (Table 103-6). Clinicians and microbiologists have an important role in the detection of outbreaks, in particular in obtaining appropriate diagnostic tests for foodborne pathogens and reporting them to public health

TABLE 103-6  Control and Prevention of Foodborne Diseases General Recommendations for All Persons • Thoroughly cook raw food from animal sources, such as beef, pork, poultry, fish, and eggs, to temperatures that eliminate most pathogens.* • Wash raw fruits and vegetables before eating. • Keep uncooked meats separate from fruits, vegetables, cooked foods, and ready-to-eat foods. • Do not thaw meat, poultry, or fish on the counter (instead, thaw in a refrigerator, in cold water, or in a microwave oven). • Wash hands before, during, and after preparing food and before eating food. • Wash knives, other utensils, and cutting boards after handling uncooked foods. • Keep refrigerators set to below 40° F and freezers set to 0° F or lower, and verify with a thermometer. • Refrigerate perishable foods within 2 hr (or within 1 hr if left out at temperatures >90° F). • Read and follow all cooking and storage instructions on food product packaging. This is especially important for foods prepared in microwave ovens because these ovens heat foods unevenly. Even foods that may appear ready to eat may require thorough cooking. • Persons with diarrhea or vomiting possibly caused by an infectious agent should not prepare foods for others. • Keep all animals, including reptiles and amphibians, away from surfaces where foods or drinks are prepared. • Do not drink unpasteurized (raw) milk or eat foods made from unpasteurized milk. (Exception: hard cheeses made from raw milk that have been aged >60 days are generally safe to eat.) • Do not eat home-canned foods that were not known to be adequately heat processed during canning.

Recommendations for Persons at High Risk, Such as Pregnant Women and People with Weakened Immune Systems, in Addition to the Recommendations Listed Above Measures to Prevent a Variety of Bacterial Infections • Do not eat uncooked sprouts. • Do not drink prepackaged juice or juice-containing beverages that have not been processed to reduce or eliminate microbial contamination (for instance, by pasteurization).

Listeriosis Prevention Measures • Do not eat soft cheeses, such as feta, Brie, and Camembert; blue-veined cheeses; and Mexican-style cheeses, such as queso blanco, queso fresco, and panela, unless the package has a label that clearly states that the cheese is made from pasteurized milk. • Do not eat refrigerated pâtés or meat spreads. Canned or shelf-stable pâtés and meat spreads are safe to eat. • Do not eat refrigerated smoked seafood, unless it is contained in a cooked dish, such as a casserole. Refrigerated smoked seafood, such as salmon, trout, whitefish, cod, tuna, and mackerel, is most often labeled as “nova-style,” “lox,” “kippered,” “smoked,” or “jerky.” The fish is found in the refrigerator section or sold at delicatessen counters of grocery stores and delicatessens. Canned or shelf-stable smoked seafood is safe to eat. • Do not eat hot dogs, luncheon meats, or delicatessen meats, unless they are reheated until steaming hot. • Avoid getting fluid from hot-dog packages on other foods, utensils, and food preparation surfaces, and wash hands after handling hot dogs, luncheon meats, and delicatessen meats.

Salmonellosis Prevention Measures • Choose pasteurized eggs.

Vibriosis, Toxoplasmosis, and Norovirus Prevention Measures • Do not eat raw or lightly steamed oysters, clams, or other raw shellfish (especially important for patients with liver disease). *Poultry: 165° F (73.9° C); ground meats: 160° F (71.1° C); intact cuts of beef, pork, ham, veal, and lamb: 145° F (62.8° C) and allow to rest for at least 3 minutes before eating; fish and shellfish: 145° F (62.8° C); egg dishes: 160° F (71.1° C). More food safety information can be found at www.foodsafety.gov/keep/index.html.

Chapter 103  Foodborne Disease

application and transport, protection from on-farm fecal contamination, washing and sanitizing fresh produce, refrigeration, and protection against contamination by food handlers.11,228 The extra handling required to prepare foods such as salads and salsas and the time delay between preparation and consumption may increase the risks associated with contaminated produce.231 Pasteurizing juice and implementing HACCP programs can reduce contamination.232 Much foodborne disease can be prevented if food is selected, prepared, and stored properly. In large kitchens and in homes, careful cooking and storage are necessary to kill pathogens and to prevent their growth when food is contaminated after cooking. Bacterial pathogens grow in food at temperatures ranging from 40° to 140° F; growth may be prevented if cold food is adequately refrigerated and hot food is held at temperatures higher than 140° F before serving. Although thorough cooking of food just before consumption eliminates the risk of many illnesses, protection against staphylococcal food poisoning is not provided because the staphylococcal enterotoxins are heat stable. Particular care in handling and cooking of raw poultry, beef, pork, shellfish, and eggs is important to prevent many foodborne diseases. Contamination in the kitchen may occur if cooked foods or ready-to-eat foods come in contact with raw foods of animal origin or with equipment such as knives and cutting boards. Poor personal hygiene by food handlers frequently contributes to norovirus, Staphylococcus, Shigella, and hepatitis A outbreaks. Because they serve high-risk populations, the kitchens of hospitals and nursing homes must pay particular attention to food safety.233 For


Part II  Major Clinical Syndromes

1296 authorities. Public health surveillance of foodborne infections and outbreaks is important for appreciating the magnitude and complexity of the problem and guiding targeted prevention efforts. Reporting is essential if investigations are to be conducted to identify the source of the outbreak so that it can be corrected. Prompt reporting may also lead to the prevention of additional cases; there are well-documented

Key References The complete reference list is available online at Expert Consult. 1. Centers for Disease Control and Prevention. Surveillance for foodborne disease outbreaks—United States, 20092010. MMWR Morb Mortal Wkly Rep. 2013;62:41-47. 11. Lynch MF, Tauxe RV, Hedberg CW. The growing burden of foodborne outbreaks due to contaminated fresh produce: risks and opportunities. Epidemiol Infect. 2009;137: 307-315. 13. Medalla F, Hoekstra RM, Whichard JM, et al. Increase in resistance to ceftriaxone and nonsusceptibility to ciprofloxacin and decrease in multidrug resistance among Salmonella strains, United States, 1996-2009. Foodborne Pathog Dis. 2013;10:302-309. 16. Guarino A, Giannattasio A. New molecular approaches in the diagnosis of acute diarrhea: advantages for clinicians and researchers. Curr Opin Gastroenterol. 2011;27: 24-29. 17. Sobel J, Griffin PM, Slutsker L, et al. Investigation of multistate foodborne disease outbreaks. Public Health Rep. 2002;117:8-19. 19. Bennett SD, Walsh KA, Gould LH. Foodborne disease outbreaks caused by Bacillus cereus, Clostridium perfringens, and Staphylococcus aureus, United States, 1998-2008. Clin Infect Dis. 2013;57:425-433. 26. Logan NA. Bacillus and relatives in foodborne illness. J Appl Microbiol. 2012;112:417-429. 32. Brynestad S, Granum P. Clostridium perfringens and foodborne infections. Int J Food Microbiol. 2002;74:195-202. 36. DuPont HL. Clinical practice. Bacterial diarrhea. N Engl J Med. 2009;361:1560-1569. 37. Daniels NA, MacKinnon L, Bishop R, et al. Vibrio parahaemolyticus infections in the United States, 1973-1998. J Infect Dis. 2000;181:1661-1666. 46. Morris JG Jr. Cholera and other types of vibriosis: a story of human pandemics and oysters on the half shell. Clin Infect Dis. 2003;37:272-280. 52. Wikswo ME, Hall AJ. Outbreaks of acute gastroenteritis transmitted by person-to-person contact—United States, 2009-2010. MMWR Surveill Summ. 2012;61:1-12. 53. Hall AJ, Eisenbart VG, Etingue AL, et al. Epidemiology of foodborne norovirus outbreaks, United States, 2001-2008. Emerg Infect Dis. 2012;18:1566-1573. 54. Glass RI, Parashar UD, Estes MK. Norovirus gastroenteritis. N Engl J Med. 2009;361:1776-1785. 57. Jones TF. From pig to pacifier: chitterling-associated yersiniosis outbreak among black infants. Emerg Infect Dis. 2003;9:1007-1009.

outbreaks of botulism,234 salmonellosis,235 and E. coli O157:H7236 in which recognition and reporting of the initial illness could have prevented many subsequent cases. Diagnosing and reporting of illnesses with the potential for intrafamilial spread or for spread within institutions, such as daycare centers (e.g., shigellosis, E. coli O157:H7 infection), can prevent secondary transmission.237

59. Cover TL, Aber RC. Yersinia enterocolitica. N Engl J Med. 1989;321:16-24. 61. Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet. 2005;365:1073-1086. 65. Gould LH, Mody RK, Ong KL, et al. Increased recognition of non-O157 Shiga toxin-producing Escherichia coli infections in the United States during 2000-2010: epidemiologic features and comparison with E. coli O157 Infections. Foodborne Pathog Dis. 2013;10:453-460. 70. Sobel J. Botulism. Clin Infect Dis. 2005;41:1167-1173. 75. Osterholm MT, MacDonald KL, White KE, et al. An outbreak of a newly recognized chronic diarrhea syndrome associated with raw milk consumption. JAMA. 1986;256: 484-490. 81. Braden CR. Listeriosis. Pediatr Infect Dis J. 2003;22: 745-746. 82. Daniels NA. Vibrio vulnificus oysters: pearls and perils. Clin Infect Dis. 2011;52:788-792. 84. DuPont HL. Approach to the patient with infectious colitis. Curr Opin Gastroenterol. 2012;28:39-46. 85. Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet. 2004; 363:1965-1976. 92. Allos BM. Campylobacter jejuni infection as a cause of the Guillain-Barré syndrome. Infect Dis Clin North Am. 1998; 12:173-184. 93. Dupont HL. Gastrointestinal infections and the development of irritable bowel syndrome. Curr Opin Infect Dis. 2011;24:503-508. 107. Sobel J, Painter J. Illnesses caused by marine toxins. Clin Infect Dis. 2005;41:1290-1296. 110. Berger KJ, Guss DA. Mycotoxins revisited, Part I. J Emerg Med. 2005;28:53-62. 111. Berger KJ, Guss DA. Mycotoxins revisited, Part II. J Emerg Med. 2005;28:175-183. 116. Rangel JM, Sparling PH, Crowe C, et al. Epidemiology of Escherichia coli O157:H7 outbreaks, United States, 19822002. Emerg Infect Dis. 2005;11:603-609. 124. Langer AJ, Ayers T, Grass J, et al. Nonpasteurized dairy products, disease outbreaks, and state laws—United States, 1993-2006. Emerg Infect Dis. 2012;18:385-391. 125. Nygren BL, Schilling KA, Blanton EM, et al. Foodborne outbreaks of shigellosis in the USA, 1998-2008. Epidemiol Infect. Feb 24, 2012:1-9. [Epub ahead of print]. 126. Taylor EV, Herman KM, Ailes EC, et al. Common source outbreaks of Campylobacter infection in the USA, 19972008. Epidemiol Infect. 2013;141:987-996. 127. Cartwright EJ, Jackson KA, Johnson SD, et al. Listeriosis outbreaks and associated food vehicles, United States, 1998-2008. Emerg Infect Dis. 2013;19:1-9.

143. Daniels NA. Enterotoxigenic Escherichia coli: traveler’s diarrhea comes home. Clin Infect Dis. 2006;42:335-336. 144. Shapiro RL, Hatheway C, Swerdlow DL. Botulism in the United States: a clinical and epidemiologic review. Ann Intern Med. 1998;129:221-228. 149. Jones JL, Dubey JP. Foodborne toxoplasmosis. Clin Infect Dis. 2012;55:845-851. 158. Brunkard J, Ailes E, Roberts V, et al. Surveillance for waterborne disease outbreaks associated with drinking water— United States, 2007-2008. MMWR Surveill Summ. 2011; 60:38-68. 159. Hlavsa MC, Roberts VA, Anderson AR, et al. Surveillance for waterborne disease outbreaks and other health events associated with recreational water—United States, 20072008. MMWR Surveill Summ. 2011;60:1-32. 160. Hale CR, Scallan E, Cronquist AB, et al. Estimates of enteric illness attributable to contact with animals and their environments in the United States. Clin Infect Dis. 2012; 54(suppl 5):S472-S479. 180. Lund BM, O’Brien SJ. The occurrence and prevention of foodborne disease in vulnerable people. Foodborne Pathog Dis. 2011;8:961-973. 190. Reingold AL. Outbreak investigations—a perspective. Emerg Infect Dis. 1998;4:21-27. 197. Guerrant RL, Van Gilder T, Steiner TS, et al. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis. 2001;32:331-351. 202. Operario DJ, Houpt E. Defining the causes of diarrhea: novel approaches. Curr Opin Infect Dis. 2011;24: 464-471. 210. Cronquist AB, Mody RK, Atkinson R, et al. Impacts of culture-independent diagnostic practices on public health surveillance for bacterial enteric pathogens. Clin Infect Dis. 2012;54(suppl 5):S432-S439. 217. Wong CS, Mooney JC, Brandt JR, et al. Risk factors for the hemolytic uremic syndrome in children infected with Escherichia coli O157:H7: a multivariable analysis. Clin Infect Dis. 2012;55:33-41. 219. Cohen ML, Tauxe RV. Drug-resistant Salmonella in the United States: an epidemiologic perspective. Science. 1986; 234:964-969. 227. Relman DA. Metagenomics, infectious disease diagnostics, and outbreak investigations: sequence first, ask questions later? JAMA. 2013;309:1531-1532. 228. Doyle MP, Erickson MC. Opportunities for mitigating pathogen contamination during on-farm food production. Int J Food Microbiol. 2012;152:54-74. 230. Tauxe RV. Food safety and irradiation: protecting the public from foodborne infections. Emerg Infect Dis. 2001; 7(suppl 3):516-521.


1296.e1

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Chapter 103  Foodborne Disease

1. Centers for Disease Control and Prevention. Surveillance for foodborne disease outbreaks—United States, 20092010. MMWR Morb Mortal Wkly Rep. 2013;62:41-47. 2. Scallan E, Griffin PM, Angulo FJ, et al. Foodborne illness acquired in the United States—unspecified agents. Emerg Infect Dis. 2011;17:16-22. 3. Scallan E, Hoekstra RM, Angulo FJ, et al. Foodborne illness acquired in the United States—major pathogens. Emerg Infect Dis. 2011;17:7-15. 4. Scharff R. Economic burden from health losses due to foodborne illness in the United States. J Food Prot. 2012; 75:123-131. 5. Centers for Disease Control and Prevention. Incidence and trends of infection with pathogens transmitted commonly through food—foodborne diseases active surveillance network, 10 U.S. sites, 1996-2012. MMWR Morb Mortal Wkly Rep. 2013;62:283-287. 6. Itoh Y, Nagano I, Kunishima M, et al. Laboratory investigation of enteroaggregative Escherichia coli O untypeable:H10 associated with a massive outbreak of gastrointestinal illness. J Clin Microbiol. 1997;35:2546-2550. 7. Scavia G, Staffolani M, Fisichella S, et al. Enteroaggregative Escherichia coli associated with a foodborne outbreak of gastroenteritis. J Med Microbiol. 2008;57(pt 9):1141-1146. 8. Bielaszewska M, Mellmann A, Zhang W, et al. Characterisation of the Escherichia coli strain associated with an outbreak of haemolytic uraemic syndrome in Germany, 2011: a microbiological study. Lancet Infect Dis. 2011;11: 671-676. 9. Jason J. Prevention of invasive Cronobacter infections in young infants fed powdered infant formulas. Pediatrics. 2012;130:e1076-e1084. 10. Pereira KS, Schmidt FL, Guaraldo AM, et al. Chagas’ disease as a foodborne illness. J Food Prot. 2009;72:441-446. 11. Lynch MF, Tauxe RV, Hedberg CW. The growing burden of foodborne outbreaks due to contaminated fresh produce: risks and opportunities. Epidemiol Infect. 2009;137: 307-315. 12. Sivapalasingam S, Friedman CR, Cohen L, et al. Fresh produce: a growing cause of outbreaks of foodborne illness in the United States, 1973 through 1997. J Food Prot. 2004; 67:2342-2353. 13. Medalla F, Hoekstra RM, Whichard JM, et al. Increase in resistance to ceftriaxone and nonsusceptibility to ciprofloxacin and decrease in multidrug resistance among Salmonella strains, United States, 1996-2009. Foodborne Pathog Dis. 2013;10:302-309. 14. Sjolund Karlsson M, Bowen A, Reporter R, et al. Outbreak of infections caused by Shigella sonnei with reduced susceptibility to azithromycin in the United States. Antimicrob Agents Chemother. 2013;57:1559-1560. 15. Gould LH, Limbago B. Clostridium difficile in food and domestic animals: a new foodborne pathogen? Clin Infect Dis. 2010;51:577-582. 16. Guarino A, Giannattasio A. New molecular approaches in the diagnosis of acute diarrhea: advantages for clinicians and researchers. Curr Opin Gastroenterol. 2011;27: 24-29. 17. Sobel J, Griffin PM, Slutsker L, et al. Investigation of multistate foodborne disease outbreaks. Public Health Rep. 2002;117:8-19. 18. Ercsey-Ravasz M, Toroczkai Z, Lakner Z, et al. Complexity of the international agro-food trade network and its impact on food safety. PloS One. 2012;7:e37810. 19. Bennett SD, Walsh KA, Gould LH. Foodborne disease outbreaks caused by Bacillus cereus, Clostridium perfringens, and Staphylococcus aureus, United States, 1998-2008. Clin Infect Dis. 2013;57:425-433. 20. Hennekinne J-A, De Buyser M-L, Dragacci S. Staphylococcus aureus and its food poisoning toxins: characterization and outbreak investigation. FEMS Microbiol Rev. 2012; 36:815-836. 21. Dinges MM, Orwin PM, Schlievert PM. Exotoxins of Staphylococcus aureus. Clin Microbiol Rev. 2000;13: 16-34. 22. Holmberg SD, Blake PA. Staphylococcal food poisoning in the United States. New facts and old misconceptions. JAMA. 1984;251:487-489. 23. Bergdoll MS. Staphylococcus aureus. In: Doyle MP, ed. Foodborne Bacterial Pathogens. New York: Marcel Dekker; 1989:463-523. 24. Breckinridge JC, Bergdoll MS. Outbreak of food-borne gastroenteritis due to a coagulase-negative enterotoxinproducing staphylococcus. N Engl J Med. 1971;284: 541-543. 25. Veras J, do Carmo L, Tong L, et al. A study of the enterotoxigenicity of coagulase-negative and coagulase-positive staphylococcal isolates from food poisoning outbreaks in Minas Gerais, Brazil. Int J Infect Dis. 2008;12:410-415. 26. Logan NA. Bacillus and relatives in foodborne illness. J Appl Microbiol. 2012;112:417-429. 27. Terranova W, Blake PA. Bacillus cereus food poisoning. N Engl J Med. 1978;298:143-144.

28. Stenfors Arnesen L, Fagerlund A, Granum P. From soil to gut: Bacillus cereus and its food poisoning toxins. FEMS Microbiol Rev. 2008;32:579-606. 29. Grass JE, Gould LH, Mahon BE. Epidemiology of foodborne disease outbreaks caused by Clostridium perfringens, United States, 1998-2010. Foodborne Pathog Dis. 2013; 10:131-136. 30. Lindström M, Heikinheimo A, Lahti Pi, et al. Novel insights into the epidemiology of Clostridium perfringens type A food poisoning. Food Microbiol. 2011;28: 192-198. 31. Smedley JG, Fisher DJ, Sayeed S, et al. The enteric toxins of Clostridium perfringens. Rev Physiol Biochem Pharmacol. 2004;152:183-204. 32. Brynestad S, Granum P. Clostridium perfringens and foodborne infections. Int J Food Microbiol. 2002;74:195-202. 33. Giannella RA, Brasile L. A hospital food-borne outbreak of diarrhea caused by Bacillus cereus: clinical, epidemiologic, and microbiologic studies. J Infect Dis. 1979;139: 366-370. 34. Lund T, De Buyser ML, Granum PE. A new cytotoxin from Bacillus cereus that may cause necrotic enteritis. Mol Microbiol. 2000;38:254-261. 35. Bos J, Smithee L, McClane B, et al. Fatal necrotizing colitis following a foodborne outbreak of enterotoxigenic Clostridium perfringens type A infection. Clin Infect Dis. 2005; 40:e78-e83. 36. DuPont HL. Clinical practice. Bacterial diarrhea. N Engl J Med. 2009;361:1560-1569. 37. Daniels NA, MacKinnon L, Bishop R, et al. Vibrio parahaemolyticus infections in the United States, 1973-1998. J Infect Dis. 2000;181:1661-1666. 38. Morris JG. Non-O group 1 Vibrio cholerae: a look at the epidemiology of an occasional pathogen. Epidemiol Rev. 1990;12:179-191. 39. Klontz KC, Lieb S, Schreiber M, et al. Syndromes of Vibrio vulnificus infections. Clinical and epidemiologic features in Florida cases, 1981-1987. Ann Intern Med. 1988;109: 318-323. 40. Kay MK, Cartwright EJ, Maceachern D, et al. Vibrio mimicus infection associated with crayfish consumption, Spokane, Washington, 2010. J Food Prot. 2012;75: 762-764. 41. Broberg CA, Calder TJ, Orth K. Vibrio parahaemolyticus cell biology and pathogenicity determinants. Microbes Infect. 2011;13:992-1001. 42. Navaneethan U, Giannella RA. Mechanisms of infectious diarrhea. Nat Clin Pract Gastroenterol Hepatol. 2008;5: 637-647. 43. Aureli P, Fiorucci GC, Caroli D, et al. An outbreak of febrile gastroenteritis associated with corn contaminated by Listeria monocytogenes. N Engl J Med. 2000;342: 1236-1241. 44. Dalton CB, Austin CC, Sobel J, et al. An outbreak of gastroenteritis and fever due to Listeria monocytogenes in milk. N Engl J Med. 1997;336:100-105. 45. Gottlieb S, Newbern EC, Griffin P, et al. Multistate outbreak of listeriosis linked to turkey deli meat and subsequent changes in US regulatory policy. Clin Infect Dis. 2006; 42:29-36. 46. Morris JG Jr. Cholera and other types of vibriosis: a story of human pandemics and oysters on the half shell. Clin Infect Dis. 2003;37:272-280. 47. Onifade TJ, Hutchinson R, Van Zile K, et al. Toxin producing Vibrio cholerae O75 outbreak, United States, March to April 2011. Euro Surveill. 2011;16:19870. 48. Crump JA, Bopp CA, Greene KD, et al. Toxigenic Vibrio cholerae serogroup O141-associated cholera-like diarrhea and bloodstream infection in the United States. J Infect Dis. 2003;187:866-868. 49. Sizemore DR, Roland KL, Ryan US. Enterotoxigenic Escherichia coli virulence factors and vaccine approaches. Expert Rev Vaccines. 2004;3:585-595. 50. Reidl J, Klose KE. Vibrio cholerae and cholera: out of the water and into the host. FEMS Microbiol Rev. 2002;26: 125-139. 51. Roels TH, Proctor ME, Robinson LC, et al. Clinical features of infections due to Escherichia coli producing heat-stable toxin during an outbreak in Wisconsin: a rarely suspected cause of diarrhea in the United States. Clin Infect Dis. 1998;26:898-902. 52. Wikswo ME, Hall AJ. Outbreaks of acute gastroenteritis transmitted by person-to-person contact—United States, 2009-2010. MMWR Surveill Summ. 2012;61:1-12. 53. Hall AJ, Eisenbart VG, Etingue AL, et al. Epidemiology of foodborne norovirus outbreaks, United States, 2001-2008. Emerg Infect Dis. 2012;18:1566-1573. 54. Glass RI, Parashar UD, Estes MK. Norovirus gastroenteritis. N Engl J Med. 2009;361:1776-1785. 55. Lee LE, Cebelinski EA, Fuller C, et al. Sapovirus outbreaks in long-term care facilities, Oregon and Minnesota, USA, 2002-2009. Emerg Infect Dis. 2012;18:873-876. 56. Boqvist S, Pettersson H, Svensson A, et al. Sources of sporadic Yersinia enterocolitica infection in children in


Part II  Major Clinical Syndromes

1296.e2 88. Olsen SJ, Bleasdale SC, Magnano AR, et al. Outbreaks of typhoid fever in the United States, 1960-99. Epidemiol Infect. 2003;130:13-21. 89. Fried B, Abruzzi A. Food-borne trematode infections of humans in the United States of America. Parasitol Res. 2010;106:1263-1280. 90. Townes JM. Reactive arthritis after enteric infections in the United States: the problem of definition. Clin Infect Dis. 2010;50:247-254. 91. Poropatich KO, Walker CL, Black RE. Quantifying the association between Campylobacter infection and GuillainBarré syndrome: a systematic review. J Health Popul Nutr. 2010;28:545-552. 92. Allos BM. Campylobacter jejuni infection as a cause of the Guillain-Barré syndrome. Infect Dis Clin North Am. 1998; 12:173-184. 93. Dupont HL. Gastrointestinal infections and the development of irritable bowel syndrome. Curr Opin Infect Dis. 2011;24:503-508. 94. Porter CK, Faix DJ, Shiau D, et al. Postinfectious gastrointestinal disorders following norovirus outbreaks. Clin Infect Dis. 2012;55:915-922. 95. Barceloux DG. Medical Toxicology of Natural Substances: Foods, Fungi, Medicinal Herbs, Plants, and Venomous Animals. Hoboken, NJ: John Wiley and Sons; 2008. 96. Sicherer SH, Sampson HA. Food allergy. J Allergy Clin Immunol. 2010;125(2 suppl 2):S116-S125. 97. Yorifuji T, Tsuda T, Inoue S, et al. Critical appraisal of the 1977 diagnostic criteria for Minamata disease. Arch Environ Occup Health. 2013;68:22-29. 98. Hudson P, Vogt R. A foodborne outbreak traced to niacin overenrichment. J Food Prot. 1985;48:249-251. 99. Nicholas PO. Food-poisoning due to copper in the morning tea. Lancet. 1968;2:40-42. 100. Semple AB, Parry WH, Phillips DE. Acute copper poisoning. An outbreak traced to contaminated water from a corroded geyser. Lancet. 1960;2:700-701. 101. Brown MA, Thom JV, Orth GL, et al. Food poisoning involving zinc contamination. Arch Environ Occup Health. 1964;8:657-660. 102. Centers for Disease Control and Prevention. Illness associated with elevated levels of zinc in fruit punch—New Mexico. MMWR Morb Mortal Wkly Rep. 1983;32: 257-258. 103. Barker WH, Runte V. Tomato juice-associated gastroenteritis, Washington and Oregon, 1969. Am J Epidemiol. 1972;96:219-226. 104. Warburton S, Udler W, Ewert RM, et al. Outbreak of foodborne illness attributed to tin. Public Health Rep. 1962; 77:798-800. 105. Baker TD, Hafner WG. Cadmium poisoning from a refrigerator shelf used as an improvised barbecue grill. Public Health Rep. 1961;76:543-544. 106. James KJ, Carey B, O’Halloran J, et al. Shellfish toxicity: human health implications of marine algal toxins. Epidemiol Infect. 2010;138:927-940. 107. Sobel J, Painter J. Illnesses caused by marine toxins. Clin Infect Dis. 2005;41:1290-1296. 108. Hungerford JM. Scombroid poisoning: a review. Toxicon. 2010;56:231-243. 109. Dickey RW, Plakas SM. Ciguatera: a public health perspective. Toxicon. 2010;56:123-136. 110. Berger KJ, Guss DA. Mycotoxins revisited, Part I. J Emerg Med. 2005;28:53-62. 111. Berger KJ, Guss DA. Mycotoxins revisited, Part II. J Emerg Med. 2005;28:175-183. 112. Leathem AM, Purssell RA, Chan VR, et al. Renal failure caused by mushroom poisoning. J Toxicol Clin Toxicol. 1997;35:67-75. 113. Le Loir Y, Baron F, Gautier M. Staphylococcus aureus and food poisoning. Genet Mol Res. 2003;2:63-76. 114. Luby S, Jones J, Dowda H, et al. A large outbreak of gastroenteritis caused by diarrheal toxin-producing Bacillus cereus. J Infect Dis. 1993;167:1452-1455. 115. Jephcott AE, Barton BW, Gilbert RJ, et al. An unusual outbreak of food-poisoning associated with meals-on-wheels. Lancet. 1977;2:129-130. 116. Rangel JM, Sparling PH, Crowe C, et al. Epidemiology of Escherichia coli O157:H7 outbreaks, United States, 19822002. Emerg Infect Dis. 2005;11:603-609. 117. Neil KP, Biggerstaff G, MacDonald JK, et al. A novel vehicle for transmission of Escherichia coli O157:H7 to humans: multistate outbreak of E. coli O157:H7 infections associated with consumption of ready-to-bake commercial prepackaged cookie dough—United States, 2009. Clin Infect Dis. 2012;54:511-518. 118. Jay MT, Cooley M, Carychao D, et al. Escherichia coli O157:H7 in feral swine near spinach fields and cattle, central California coast. Emerg Infect Dis. 2007;13: 1908-1911. 119. Cody SH, Glynn MK, Farrar J, et al. An outbreak of Escherichia coli O157:H7 infection from unpasteurized commercial apple juice. Ann Intern Med. 1999;130: 202-209.

120. St. Louis ME, Morse DL, Potter ME, et al. The emergence of grade A eggs as a major source of Salmonella enteritidis infections. New implications for the control of salmonellosis. JAMA. 1988;259:2103-2107. 121. Gould LH, Walsh KA, Vieira AR, et al. Surveillance for foodborne disease outbreaks—United States, 1998–2008. MMWR Surveill Summ. 2013;62:1-34. 122. Marcus R, Varma JK, Medus C, et al. Re-assessment of risk factors for sporadic Salmonella serotype Enteritidis infections: a case-control study in five FoodNet Sites, 20022003. Epidemiol Infect. 2007;135:84-92. 123. O’Brien SJ. The “decline and fall” of nontyphoidal Salmonella in the United Kingdom. Clin Infect Dis. 2013;56: 705-710. 124. Langer AJ, Ayers T, Grass J, et al. Nonpasteurized dairy products, disease outbreaks, and state laws—United States, 1993-2006. Emerg Infect Dis. 2012;18:385-391. 125. Nygren BL, Schilling KA, Blanton EM, et al. Foodborne outbreaks of shigellosis in the USA, 1998-2008. Epidemiol Infect. Feb 24, 2012:1-9 [Epub ahead of print]. 126. Taylor EV, Herman KM, Ailes EC, et al. Common source outbreaks of Campylobacter infection in the USA, 19972008. Epidemiol Infect. 2013;141:987-996. 127. Cartwright EJ, Jackson KA, Johnson SD, et al. Listeriosis outbreaks and associated food vehicles, United States, 1998-2008. Emerg Infect Dis. 2013;19:1-9. 128. Centers for Disease Control and Prevention. Multistate outbreak of listeriosis associated with Jensen Farms cantaloupe—United States, August-September 2011. MMWR Morb Mortal Wkly Rep. 2011;60:1357-1358. 129. Gaul L, Farag N, Shim T, et al. Hospital-acquired listeriosis outbreak caused by contaminated diced celery—Texas, 2010. Clin Infect Dis. 2013;56:20-26. 130. Finelli L, Swerdlow D, Mertz K, et al. Outbreak of cholera associated with crab brought from an area with epidemic disease. J Infect Dis. 1992;166:1433-1435. 131. Ong KL, Gould LH, Chen DL, et al. Changing epidemiology of Yersinia enterocolitica infections: markedly decreased rates in young black children, Foodborne Diseases Active Surveillance Network (FoodNet), 1996-2009. Clin Infect Dis. 2012;54(suppl 5):S385-S390. 132. Rosner BM, Stark K, Werber D. Epidemiology of reported Yersinia enterocolitica infections in Germany, 2001-2008. BMC Public Health. 2010;10:337. 133. Ackers ML, Schoenfeld S, Markman J, et al. An outbreak of Yersinia enterocolitica O:8 infections associated with pasteurized milk. J Infect Dis. 2000;181:1834-1837. 134. Black RE, Jackson RJ, Tsai T, et al. Epidemic Yersinia enterocolitica infection due to contaminated chocolate milk. N Engl J Med. 1978;298:76-79. 135. MacDonald E, Heier BT, Nygard K, et al. Yersinia enterocolitica outbreak associated with ready-to-eat salad mix, Norway, 2011. Emerg Infect Dis. 2012;18:1496-1499. 136. Daniels NA, Neimann J, Karpati A, et al. Traveler’s diarrhea at sea: three outbreaks of waterborne enterotoxigenic Escherichia coli on cruise ships. J Infect Dis. 2000;181: 1491-1495. 137. Merson MH, Morris GK, Sack DA, et al. Travelers’ diarrhea in Mexico. A prospective study of physicians and family members attending a congress. N Engl J Med. 1976;294: 1299-1305. 138. Dalton CB, Mintz ED, Wells JG, et al. Outbreaks of enterotoxigenic Escherichia coli infection in American adults: a clinical and epidemiologic profile. Epidemiol Infect. 1999; 123:9-16. 139. Jain S, Chen L, Dechet A, et al. An outbreak of enterotoxigenic Escherichia coli associated with sushi restaurants in Nevada, 2004. Clin Infect Dis. 2008;47:1-7. 140. Beatty ME, Bopp CA, Wells JG, et al. Enterotoxinproducing Escherichia coli O169:H41, United States. Emerg Infect Dis. 2004;10:518-521. 141. Naimi TS, Wicklund JH, Olsen SJ, et al. Concurrent outbreaks of Shigella sonnei and enterotoxigenic Escherichia coli infections associated with parsley: implications for surveillance and control of foodborne illness. J Food Prot. 2003;66:535-541. 142. Beatty ME, Adcock PM, Smith SW, et al. Epidemic diarrhea due to enterotoxigenic Escherichia coli. Clin Infect Dis. 2006;42:329-334. 143. Daniels NA. Enterotoxigenic Escherichia coli: traveler’s diarrhea comes home. Clin Infect Dis. 2006;42:335-336. 144. Shapiro RL, Hatheway C, Swerdlow DL. Botulism in the United States: a clinical and epidemiologic review. Ann Intern Med. 1998;129:221-228. 145. Centers for Disease Control and Prevention. Botulism associated with commercial carrot juice—Georgia and Florida, September 2006. MMWR Morb Mortal Wkly Rep. 2006;55:1098-1099. 146. Centers for Disease Control and Prevention. Botulism associated with commercially canned chili sauce—Texas and Indiana, July 2007. MMWR Morb Mortal Wkly Rep. 2007;56:767-769. 147. Kohn MA, Farley TA, Ando T, et al. An outbreak of Norwalk virus gastroenteritis associated with eating raw

oysters. Implications for maintaining safe oyster beds. JAMA. 1995;273:466-471. 148. Ortega YR, Sanchez R. Update on Cyclospora cayetanensis, a food-borne and waterborne parasite. Clin Microbiol Rev. 2010;23:218-234. 149. Jones JL, Dubey JP. Foodborne toxoplasmosis. Clin Infect Dis. 2012;55:845-851. 150. Centers for Disease Control and Prevention. Trichinellosis surveillance—United States, 2002-2007. Surveillance summaries. MMWR Surveill Summ. 2009;58:1-7. 151. Centers for Disease Control and Prevention. Trichinellosis surveillance—United States, 1997-2001. Surveillance summaries. MMWR Surveill Summ. 2003;52:1-8. 152. Etkind P, Wilson ME, Gallagher K, et al. Bluefish-associated scombroid poisoning. An example of the expanding spectrum of food poisoning from seafood. JAMA. 1987;258: 3409-3410. 153. Feldman KA, Werner SB, Cronan S, et al. A large outbreak of scombroid fish poisoning associated with eating escolar fish (Lepidocybium flavobrunneum). Epidemiol Infect. 2005; 133:29-33. 154. Centers for Disease Control and Prevention. Neurologic illness associated with eating Florida pufferfish, 2002. MMWR Morb Mortal Wkly Rep. 2002;51:321-323. 155. Török TJ, Tauxe RV, Wise RP, et al. A large community outbreak of salmonellosis caused by intentional contamination of restaurant salad bars. JAMA. 1997;278: 389-395. 156. Kolavic SA, Kimura A, Simons SL, et al. An outbreak of Shigella dysenteriae type 2 among laboratory workers due to intentional food contamination. JAMA. 1997;278: 396-398. 157. Centers for Disease Control and Prevention. Nicotine poisoning after ingestion of contaminated ground beef— Michigan, 2003. MMWR Morb Mortal Wkly Rep. 2003; 52:413-416. 158. Brunkard J, Ailes E, Roberts V, et al. Surveillance for waterborne disease outbreaks associated with drinking water— United States, 2007-2008. MMWR Surveill Summ. 2011; 60:38-68. 159. Hlavsa MC, Roberts VA, Anderson AR, et al. Surveillance for waterborne disease outbreaks and other health events associated with recreational water—United States, 20072008. MMWR Surveill Summ. 2011;60:1-32. 160. Hale CR, Scallan E, Cronquist AB, et al. Estimates of enteric illness attributable to contact with animals and their environments in the United States. Clin Infect Dis. 2012; 54(suppl 5):S472-S479. 161. Craun GF, Brunkard JM, Yoder JS, et al. Causes of outbreaks associated with drinking water in the United States from 1971 to 2006. Clin Microbiol Rev. 2010;23: 507-528. 162. Dykes AC, Juranek DD, Lorenz RA, et al. Municipal waterborne giardiasis: an epidemilogic investigation. Beavers implicated as a possible reservoir. Ann Intern Med. 1980; 92(2 pt 1):165-170. 163. Kent GP, Greenspan JR, Herndon JL, et al. Epidemic giardiasis caused by a contaminated public water supply. Am J Public Health. 1988;78:139-143. 164. Smith HV, Caccio SM, Cook N, et al. Cryptosporidium and Giardia as foodborne zoonoses. Vet Parasitol. 2007; 149:29-40. 165. MacKenzie WR, Hoxie NJ, Proctor ME, et al. A massive outbreak in Milwaukee of Cryptosporidium infection transmitted through the public water supply. N Engl J Med. 1994; 331:161-167. 166. Olsen SJ, Miller G, Breuer T, et al. A waterborne outbreak of Escherichia coli O157:H7 infections and hemolytic uremic syndrome: implications for rural water systems. Emerg Infect Dis. 2002;8:370-375. 167. Swerdlow DL, Woodruff BA, Brady RC, et al. A waterborne outbreak in Missouri of Escherichia coli O157:H7 associated with bloody diarrhea and death. Ann Intern Med. 1992;117:812-819. 168. Weissman JB, Craun GF, Lawrence DN, et al. An epidemic of gastroenteritis traced to a contaminated public water supply. Am J Epidemiol. 1976;103:391-398. 169. Bergeisen GH, Hinds MW, Skaggs JW. A waterborne outbreak of hepatitis A in Meade County, Kentucky. Am J Public Health. 1985;75:161-164. 170. Feldman RE, Baine WB, Nitzkin JL, et al. Epidemiology of Salmonella typhi infection in a migrant labor camp in Dade County, Floida. J Infect Dis. 1974;130:335-342. 171. Ailes E, Budge P, Shankar M, et al. Economic and health Impacts associated with a Salmonella Typhimurium drinking water outbreak—Alamosa, CO, 2008. PloS One. 2013; 8:e57439. 172. Rosenberg ML, Koplan JP, Wachsmuth IK, et al. Epidemic diarrhea at Crater Lake from enterotoxigenic Escherichia coli. A large waterborne outbreak. Ann Intern Med. 1977; 86:714-718. 173. Palmer SR, Gully PR, White JM, et al. Water-borne outbreak of Campylobacter gastroenteritis. Lancet. 1983; 1:287-290.


1296.e3 membership cards provide critical clues to identify the source. Epidemiol Infect. 2012:1-9. 197. Guerrant RL, Van Gilder T, Steiner TS, et al. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis. 2001;32:331-351. 198. Lew JF, LeBaron CW, Glass RI, et al. Recommendations for collection of laboratory specimens associated with outbreaks of gastroenteritis. MMWR Recomm Rep. 1990; 39(RR-14):1-13. 199. Gould LH, Bopp C, Strockbine N, et al. Recommendations for diagnosis of Shiga toxin–producing Escherichia coli infections by clinical laboratories. MMWR Recomm Rep. 2009;58(RR-12):1-14. 200. Blanton LH, Adams SM, Beard RS, et al. Molecular and epidemiologic trends of caliciviruses associated with outbreaks of acute gastroenteritis in the United States, 20002004. J Infect Dis. 2006;193:413-421. 201. Kahlau P, Malecki M, Schildgen V, et al. Utility of two novel multiplexing assays for the detection of gastrointestinal pathogens—a first experience. Springerplus. 2013;2:106. 202. Operario DJ, Houpt E. Defining the causes of diarrhea: novel approaches. Curr Opin Infect Dis. 2011;24: 464-471. 203. Swaminathan B, Gerner-Smidt P, Ng LK, et al. Building PulseNet International: an interconnected system of laboratory networks to facilitate timely public health recognition and response to foodborne disease outbreaks and emerging foodborne diseases. Foodborne Pathog Dis. 2006; 3:36-50. 204. Hennekinne J-A, Ostyn A, Guillier F, et al. How should staphylococcal food poisoning outbreaks be characterized? Toxins. 2010;2:2106-2116. 205. Hoffmaster AR, Novak RT, Marston CK, et al. Genetic diversity of clinical isolates of Bacillus cereus using multilocus sequence typing. BMC Microbiol. 2008;8:191. 206. DeBuono BA, Brondum J, Kramer JM, et al. Plasmid, serotypic, and enterotoxin analysis of Bacillus cereus in an outbreak setting. J Clin Microbiol. 1988;26:1571-1574. 207. Ghosh AC. Prevalence of Bacillus cereus in the faeces of healthy adults. J Hyg (Lond). 1978;80:233-236. 208. Andersson MA, Jääskeläinen EL, Shaheen R, et al. Sperm bioassay for rapid detection of cereulide-producing Bacillus cereus in food and related environments. Int J Food Microbiol. 2004;94:175-183. 209. Fricker M, Messelhäusser U, Busch U, et al. Diagnostic real-time PCR assays for the detection of emetic Bacillus cereus strains in foods and recent food-borne outbreaks. Appl Environ Microbiol. 2007;73:1892-1898. 210. Cronquist AB, Mody RK, Atkinson R, et al. Impacts of culture-independent diagnostic practices on public health surveillance for bacterial enteric pathogens. Clin Infect Dis. 2012;54(suppl 5):S432-S439. 211. Dowell VR, McCroskey LM, Hatheway CL, et al. Coproexamination for botulinal toxin and Clostridium botulinum. A new procedure for laboratory diagnosis of botulism. JAMA. 1977;238:1829-1832. 212. Woodruff BA, Griffin PM, McCroskey LM, et al. Clinical and laboratory comparison of botulism from toxin types A, B, and E in the United States, 1975-1988. J Infect Dis. 1992;166:1281-1286. 213. Isbister GK, Kiernan MC. Neurotoxic marine poisoning. Lancet Neurol. 2005;4:219-228. 214. Hedberg CW, Palazzi-Churas KL, Radke VJ, et al. The use of clinical profiles in the investigation of foodborne outbreaks in restaurants: United States, 1982-1997. Epidemiol Infect. 2008;136:65-72. 215. Hickey CA, Beattie TJ, Cowieson J, et al. Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome. Arch Pediatr Adolesc Med. 2011;165:884-889. 216. Sirinavin S, Garner P. Antibiotics for treating Salmonella gut infections. Cochrane Database Syst Rev. 2000; (2): CD001167.

217. Wong CS, Mooney JC, Brandt JR, et al. Risk factors for the hemolytic uremic syndrome in children infected with Escherichia coli O157:H7: a multivariable analysis. Clin Infect Dis. 2012;55:33-41. 218. Varma JK, Molbak K, Barrett TJ, et al. Antimicrobialresistant nontyphoidal Salmonella is associated with excess bloodstream infections and hospitalizations. J Infect Dis. 2005;191:554-561. 219. Cohen ML, Tauxe RV. Drug-resistant Salmonella in the United States: an epidemiologic perspective. Science. 1986; 234:964-969. 220. Glynn MK, Bopp C, Dewitt W, et al. Emergence of multidrug-resistant Salmonella enterica serotype typhimurium DT104 infections in the United States. N Engl J Med. 1998;338:1333-1338. 221. Helms M, Ethelberg S, Mølbak K. International Salmonella Typhimurium DT104 infections, 1992-2001. Emerg Infect Dis. 2005;11:859-867. 222. Centers for Disease Control and Prevention. Outbreak of multidrug-resistant Salmonella Newport—United States, January-April 2002. MMWR Morb Mortal Wkly Rep. 2002; 51:545-548. 223. Schnorf H, Taurarii M, Cundy T. Ciguatera fish poisoning: a double-blind randomized trial of mannitol therapy. Neurology. 2002;58:873-880. 224. Lawrence DT, Dobmeier SG, Bechtel LK, et al. Food poisoning. Emerg Med Clin North Am. 2007;25:357-373. 225. Vega E, Barclay L, Gregoricus N, et al. Novel surveillance network for norovirus gastroenteritis outbreaks, United States. Emerg Infect Dis. 2011;17:1389-1395. 226. Loman NJ, Constantinidou C, Christner M, et al. A culture-independent sequence-based metagenomics approach to the investigation of an outbreak of Shigatoxigenic Escherichia coli O104:H4. JAMA. 2013;309: 1502-1510. 227. Relman DA. Metagenomics, infectious disease diagnostics, and outbreak investigations: sequence first, ask questions later? JAMA. 2013;309:1531-1532. 228. Doyle MP, Erickson MC. Opportunities for mitigating pathogen contamination during on-farm food production. Int J Food Microbiol. 2012;152:54-74. 229. Brovko LY, Anany H, Griffiths MW. Bacteriophages for detection and control of bacterial pathogens in food and food-processing environment. Adv Food Nutr Res. 2012; 67:241-288. 230. Tauxe RV. Food safety and irradiation: protecting the public from foodborne infections. Emerg Infect Dis. 2001; 7(suppl 3):516-521. 231. Kendall ME, Mody RK, Mahon BE, et al. Emergence of salsa and guacamole as frequent vehicles of foodborne disease outbreaks in the United States, 1973-2008. Foodborne Pathog Dis. 2013;10:316-322. 232. Vojdani JD, Beuchat LR, Tauxe RV. Juice-associated outbreaks of human illness in the United States, 1995 through 2005. J Food Prot. 2008;71:356-364. 233. Lund B, O’Brien S. Microbiological safety of food in hospitals and other healthcare settings. J Hosp Infect. 2009; 73:109-120. 234. Horwitz MA, Marr JS, Merson MH, et al. A continuing common-source outbreak of botulism in a family. Lancet. 1975;2:861-863. 235. Payne DJ, Scudamore JM. Outbreaks of Salmonella foodpoisoning over a period of eight years from a common source. Lancet. 1977;1:1249-1250. 236. Cieslak PR, Noble SJ, Maxson DJ, et al. Hamburgerassociated Escherichia coli O157:H7 infection in Las Vegas: a hidden epidemic. Am J Public Health. 1997;87: 176-180. 237. Mody RK, Griffin PM. Fecal shedding of Shiga toxinproducing Escherichia coli: what should be done to prevent secondary cases? Clin Infect Dis. 2013;56:1141-1144.

Chapter 103  Foodborne Disease

174. Vogt RL, Sours HE, Barrett T, et al. Campylobacter enteritis associated with contaminated water. Ann Intern Med. 1982; 96:292-296. 175. Richardson G, Thomas DR, Smith RMM, et al. A community outbreak of Campylobacter jejuni infection from a chlorinated public water supply. Epidemiol Infect. 2007; 135:1151-1158. 176. Anderson AD, Heryford AG, Sarisky JP, et al. A waterborne outbreak of Norwalk-like virus among snowmobilersWyoming, 2001. J Infect Dis. 2003;187:303-306. 177. Kaplan JE, Goodman RA, Schonberger LB, et al. Gastroenteritis due to Norwalk virus: an outbreak associated with a municipal water system. J Infect Dis. 1982;146:190-197. 178. Wilson R, Anderson LJ, Holman RC, et al. Waterborne gastroenteritis due to the Norwalk agent: clinical and epidemiologic investigation. Am J Public Health. 1982;72: 72-74. 179. Bowie WR, King AS, Werker DH, et al. Outbreak of toxoplasmosis associated with municipal drinking water. The BC Toxoplasma Investigation Team. Lancet. 1997; 350:173-177. 180. Lund BM, O’Brien SJ. The occurrence and prevention of foodborne disease in vulnerable people. Foodborne Pathog Dis. 2011;8:961-973. 181. Angulo FJ, Swerdlow DL. Bacterial enteric infections in persons infected with human immunodeficiency virus. Clin Infect Dis. 1995;21(suppl 1):S84-S93. 182. Stark D, Barratt JL, van Hal S, et al. Clinical significance of enteric protozoa in the immunosuppressed human population. Clin Microbiol Rev. 2009;22:634-650. 183. Shapiro RL, Altekruse S, Hutwagner L, et al. The role of Gulf Coast oysters harvested in warmer months in Vibrio vulnificus infections in the United States, 1988-1996. Vibrio Working Group. J Infect Dis. 1998;178:752-759. 184. Slutsker L, Ries AA, Greene KD, Wells JG, et al. Escherichia coli O157:H7 diarrhea in the United States: clinical and epidemiologic features. Ann Intern Med. 1997;126: 505-513. 185. Frank C, Kapfhammer S, Werber D, et al. Cattle density and Shiga toxin-producing Escherichia coli infection in Germany: increased risk for most but not all serogroups. Vector Borne Zoonotic Dis. 2008;8:635-643. 186. Fagan RP, McLaughlin JB, Castrodale LJ, et al. Endemic foodborne botulism among Alaska Native persons— Alaska, 1947-2007. Clin Infect Dis. 2011;52:585-592. 187. Swift AE, Swift TR. Ciguatera. J Toxicol Clin Toxicol. 1993;31:1-29. 188. Centers for Disease Control and Prevention. Ciguatera fish poisoning—New York City, 2010-2011. MMWR Morb Mortal Wkly Rep. 2013;62:61-65. 189. Centers for Disease Control and Prevention. Cluster of ciguatera fish poisoning—North Carolina, 2007. MMWR Morb Mortal Wkly Rep. 2009;58:283-285. 190. Reingold AL. Outbreak investigations—a perspective. Emerg Infect Dis. 1998;4:21-27. 191. Gerner-Smidt P, Hise K, Kincaid J, et al. PulseNet USA: a five-year update. Foodborne Pathog Dis. 2006;3:9-19. 192. Buchholz U, Bernard H, Werber D, et al. German outbreak of Escherichia coli O104:H4 associated with sprouts. N Engl J Med. 2011;365:1763-1770. 193. Mody RK, Greene SA, Gaul L, et al. National outbreak of Salmonella serotype Saintpaul infections: importance of Texas restaurant investigations in implicating jalapeno peppers. PloS One. 2011;6:e16579. 194. Cavallaro E, Date K, Medus C, et al. Salmonella typhimurium infections associated with peanut products. N Engl J Med. 2011;365:601-610. 195. Tostmann A, Bousema T, Oliver I. Investigation of outbreaks complicated by universal exposure. Emerg Infect Dis. 2012;18:1717-1722. 196. Gieraltowski L, Julian E, Pringle J, et al. Nationwide outbreak of Salmonella Montevideo infections associated with contaminated imported black and red pepper: warehouse


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Neurologic Diseases Caused by Human Immunodeficiency Virus Type 1 and Opportunistic Infections Omar K. Siddiqi and Igor J. Koralnik SHORT VIEW SUMMARY

Definition

• Human immunodeficiency virus (HIV) and associated infections can adversely affect any aspect of the central and peripheral nervous system.

Epidemiology

• Ten percent of HIV-positive patients initially present with neurologic disease. • Thirty to fifty percent of HIV-positive patients have neurologic complications. • Eighty percent of HIV-positive patients have nervous system involvement at autopsy.

Cognitive Manifestations

• HIV-associated neurocognitive disorder occurs in 15% of patients with AIDS and can be the first manifestation of disease in 3% to 10% of patients.

Central Nervous System (CNS) Mass Lesions

• Toxoplasmosis is the most frequent cerebral mass lesion. Incidence depends on the seropositivity of the population. Empiric treatment with pyrimethamine and sulfadiazine is useful when clinical and radiologic findings are consistent with the diagnosis. • Primary CNS lymphoma is the most common HIV-associated brain malignancy and is associated with Epstein-Barr virus infection. • Progressive multifocal leukoencephalopathy is caused by JC polyomavirus, which induces lytic infection of oligodendrocytes causing multifocal CNS demyelination.

Spinal Cord

• Vacuolar myelopathy is present at autopsy in 17% to 46% of patients with acquired immunodeficiency syndrome.

Neurologic manifestations are frequent in human immunodeficiency virus type 1 (HIV-1) infection. In the era before combined antiretroviral therapy (ART) or in settings where antiretroviral drugs are not available, neurologic disease constituted the initial presentation in 10% of patients, and neurologic complications developed in 30% to 50% during the course of the disease.1,2 Autopsies have shown involvement of the nervous system in up to 80% of cases.3,4 With the advent of ART, the overall incidence of the most frequent HIV-associated neurologic diseases has decreased. The most consistent impact has been a decreased incidence of acquired immunodeficiency syndrome (AIDS)associated dementia, but decreases in HIV-associated polyneuropathy and central nervous system (CNS) opportunistic infections have also been observed.5-8 Diagnosis of neurologic complications in patients with HIV-1 infection poses a particular challenge for clinicians. Indeed, HIVinfected individuals are often severely debilitated and present with multiple constitutional symptoms related to systemic infections or tumors that might overshadow or mimic a primary neurologic condition. In addition, HIV-infected individuals are usually treated with a combination of prophylactic drugs and a rapidly growing number of antiretroviral medications. Drug interactions and neurologic side effects of these medications are common, which adds another level of complexity for care providers. However, certain rules can be applied to facilitate the understanding of these challenging cases: 1. The spectrum of neurologic manifestations in HIV-1 infected individuals depends on their degree of immunosuppression, reflected by CD4+ T-lymphocyte counts, and the speed of disease progression, as estimated by measurement of plasma HIV-1 viral load. 2. Multiple pathologies may coexist in the context of immunosuppression. The peripheral nervous system and CNS are frequently affected concomitantly in HIV-1 infected individuals, and opportunistic infections of the brain may be superimposed on primary HIV-1associated neurologic disorders. 1574

• Presenting symptoms are gait disturbance, weakness, sensory changes, and urinary dysfunction. • Diagnosis is one of exclusion. • Etiology is unclear.

Peripheral Nervous System

• HIV-associated distal sensory polyneuropathy is the most common peripheral neuropathy seen in HIV. Symmetrical paresthesia, numbness, and painful dysesthesia of the lower extremities can occur. • Nucleoside neuropathy is associated with nucleoside analogue reverse-transcriptase inhibitors zalcitabine, didanosine, and stavudine. • Clinical and electrophysiologic manifestations are indistinguishable from DSNP. Symptoms can improve upon discontinuation of offending medication.

3. Antiretroviral medications and prophylactic drugs taken by HIV infected individuals often cause neurologic side effects, which must be included in the differential diagnosis of these patients. 4. Immune recovery associated with ART may be associated with an inflammatory reaction within the CNS.

PRINCIPAL NEUROLOGIC MANIFESTATIONS OF HIV TYPE 1 INFECTION Meningeal Syndrome Patient Otherwise Asymptomatic, CD4+ T-Lymphocyte Counts Greater Than 200 cells/µL: Aseptic Meningitis

Clinical Presentation.  Headache, stiff neck, and fever, associated with nausea and vomiting, can be the first manifestations of HIV-1 infection. It is a self-limited illness that subsides spontaneously after several weeks. In some cases, transient cranial neuropathies may develop, affecting mostly the fifth, seventh, and eighth cranial nerves.9 In addition, patients may present with symptoms of encephalopathy, and postmortem examination of individuals who died of unrelated causes in this early stage showed mild meningeal inflammation, focal cerebral white matter myelin damage, and perivascular inflammatory infiltrates and gliosis.10,11 Laboratory Investigations.  Cerebrospinal fluid (CSF) analysis shows a moderate lymphocytic pleocytosis (10 to 100 cells/µL), which is typical of viral meningitis.12 This aseptic meningitis can occur as soon as 1 week after the primary infection, when HIV-1 conventional serology is still negative. HIV-1 RNA, however, should be detectable in blood and CSF, and the HIV-1 p24 antigen might be detected in the blood. Repeat serology testing after 6 weeks usually helps to clarify this situation. Treatment.  Interestingly, early onset of aseptic meningitis has not been associated with late neurologic manifestations in HIV-1


1574.e1

KEYWORDS

Chapter 127â&#x20AC;&#x201A; Neurologic Diseases Caused by Human Immunodeficiency Virus Type 1 and Opportunistic Infections

acute inflammatory demyelinating polyneuropathy (AIDP); cognitive disorders; distal sensory polyneuropathy (DSPN); human immunodeficiency virusâ&#x20AC;&#x201C;associated neurocognitive disorder (HAND); myopathy; neurodegenerative disorders; primary central nervous system lymphoma (PCNSL); progressive multifocal leukoencephalopathy (PML); vacuolar myelopathy


1575

Patient at Any Stage of HIV Type 1 Infection and CD4+ T-Lymphocyte Counts at Any Level: Syphilitic Meningitis

Clinical Presentation.  In the United States, up to 6% of HIV-infected individuals have a history of syphilis. Treponema pallidum infection can also occur at any time during HIV-1 infection and mimics neurologic complications of AIDS. Indeed, both conditions may cause acute or chronic meningitis, myelopathy, cranial or peripheral neuropathies, cerebrovascular disease, and dementia. Therefore, it is paramount to distinguish neurosyphilis from latent disease with positive serology and normal physical examination in HIV-infected patients because it has a direct impact on treatment. Neurosyphilis can occur as early as 1 year or as late as 30 years after initial infection. In this chapter, we discuss only syphilitic meningitis; other neurologic complications of this disease are covered in Chapter 239. Laboratory Investigations.  Elevation of protein concentration and leukocyte counts can be found in the CSF of approximately 15% of patients with primary syphilis and up to 40% of patients with secondary syphilis. Some of these patients eventually experience spontaneous cure of this earlier CNS infection, but the persistence of asymptomatic CSF abnormalities for more than 5 years in the untreated patient is highly predictive of the development of clinical neurosyphilis. Persistent mononuclear pleocytosis and elevated protein concentration can be found in the CSF of HIV-1-infected patients with neurosyphilis,13 as well as an elevated immunoglobulin G synthesis rate and oligoclonal bands. This is of no help in establishing the diagnosis of neurosyphilis in the context of HIV-1 infection because these findings occur as well in asymptomatic HIV-1 seropositive patients, especially when they have detectable HIV-1 RNA in their CSF. Using either the criterion of elevated CSF protein of greater than 50 mg/dL or white blood cells greater than 10 cells/µL in HIV-positive patients with reactive rapid plasma reagin may lead to overdiagnosis of neurosyphilis in the absence of clinical symptoms. Follow-up lumbar puncture after 12 months showed persistence of CSF abnormalities in 62% of cases.14 A positive CSF Venereal Disease Research Laboratories (VDRL) test result establishes the diagnosis of neurosyphilis if the tap is not bloody. However, this test may be negative in HIV-1 infection.15,16 A reactive CSF fluorescent treponemal antibody absorbed test increases the likelihood of T. pallidum infection but is less specific because it can result from treated neurosyphilis or from contamination of the CSF with small amounts of blood containing antibody at the time of the lumbar puncture. Acute symptomatic syphilitic meningitis is usually the earliest clinical manifestation of neurosyphilis, which occurs within the first year of infection and can be associated with cranial nerve palsies, including isolated eighth nerve palsy, and signs and symptoms of hydrocephalus. CSF abnormalities are similar to those of asymptomatic neurosyphilis, except that the CSF VDRL test result is nearly always positive (also see Chapter 239). Treatment.  HIV-1–infected individuals with a positive serum rapid plasma reagin (RPR) test result, unexplained CSF pleocytosis, and elevated protein concentration, as well as symptoms consistent with neurosyphilis, should be treated with intravenous penicillin even in the absence of a positive VDRL test result in the CSF. Treatment consists of intravenous penicillin G (3 to 4 million units IV every 4 hours for 10 to 14 days). In case of allergy to penicillin, ceftriaxone (2 g IV once daily for at least 14 days) is another option. A careful follow-up of these patients is necessary, and a repeat spinal tap 1 month after onset of treatment should show a normalization of the CSF

cellularity and protein concentration. Normalization of serum RPR predicted normalization of CSF and clinical abnormalities 13 months after treatment in more than 90% of a cohort composed mostly of HIV-infected men. This was more frequent in those receiving ART than in untreated patients.17 Some patients have a transient increase in CSF HIV-1 viral load to more than 100,000 copies/mL associated with neurosyphilis, which subsides after antibiotic treatment. Neurosyphilis may amplify intrathecal HIV replication, possibly through immune activation that persists even after syphilis treatment.18 As is the case with other opportunistic infections of the brain, this viral burden is likely carried by activated circulating lymphocytes and monocytes coming to combat the CNS infection and should not be interpreted as a manifestation of HIV-1 encephalitis.

Patient with AIDS, CD4+ T-Lymphocyte Counts of Less Than 200 Cells/µL: Cryptococcal Meningitis

Clinical Presentation.  This is the most common opportunistic meningitis in AIDS, which affected 10% of patients before the ART era19 but has decreased in incidence since then (also see Chapter 264).20 Cryptococcal meningitis differs from aseptic meningitis in that meningismus is present in less than 40% of cases, and patients may present with only fever and headache, which become progressively more debilitating. Confusion, blindness, or altered state of consciousness occurs in severe cases. Laboratory Investigations.  The detection of Cryptococcus neoformans antigen titers by enzyme immunoassay in the CSF provides a rapid diagnosis, which is confirmed subsequently by CSF culture. Because false-positive results occur with all the antigen tests, confirmation by culture is essential to establish the diagnosis of cryptococcal meningitis. Other CSF findings include markedly elevated opening pressure, mononuclear pleocytosis, elevated protein and decreased glucose concentration in 50% of the cases, and direct detection of the organism by India ink staining in 80% of the cases. Serum cryptococcal antigen is usually detected in cryptococcal meningitis in AIDS patients, and blood and urine cultures may also be positive. Brain imaging is usually negative unless an associated cryptococcoma or hydrocephalus is present. Poor prognosis factors include altered mental status, absence of CSF pleocytosis, CSF antigen titer greater than 1 : 1024, a positive blood culture, and hyponatremia. Treatment.  Treatment should begin with amphotericin B (0.7 mg/ kg) with flucytosine (100 mg/kg PO in four divided doses per day) until the patient is clearly responding and for not less than 2 weeks, which is associated with significantly increased rates of yeast clearance from CSF and decreased mortality compared with amphotericin B alone. Combination of fluconazole with amphotericin B showed no survival benefit.21 Use of fluconazole alone as initial therapy is associated with much slower culture conversion and is not recommended.22 Consolidation therapy then consists of fluconazole (400 mg PO once or twice daily) administered for 8 weeks or until CSF cultures are sterile. Lipid formulations of amphotericin B may be used for patients with renal insufficiency, and itraconazole may be substituted for fluconazole if patients can tolerate fluconazole but is clearly inferior to the latter. Lifelong maintenance therapy using fluconazole 200 mg/day has been previously recommended to prevent relapses.23 Updated recommendations state that maintenance therapy can be discontinued if a patient has received a minimum of 12 months of antifungal treatment, CD4+ counts reach greater than 100 cells/µL, and there is a sustained undetectable or very low HIV RNA level for ≥3 months.23a The outcome is generally favorable within 2 weeks, but early mortality still reaches 6%.26 In a study done in Botswana, the in-hospital mortality was significantly lower among those patients who were on ART at the time of diagnosis of cryptococcal meningitis compared with untreated patients (8% vs. 21%).27 Complications such as increased intracranial pressure greater than 200 mm H2O occur in nearly all patients. Such a complication should be recognized and treated aggressively with mechanical drainage, including repeat lumbar punctures, temporary external lumbar drainage, or intraventricular shunts.28,29 Corticosteroids, acetazolamide, and mannitol have not been shown to be effective. Neurologic deterioration after commencing ART occurs in 26% of patients and is caused by cryptococcosis-associated immune

Chapter 127  Neurologic Diseases Caused by Human Immunodeficiency Virus Type 1 and Opportunistic Infections

infection, and patients may remain asymptomatic for many years before developing other symptoms of HIV-1 infection. If not properly diagnosed at the time of their acute illness, these patients may therefore unwittingly infect a number of sexual partners. It is therefore crucial to include HIV-1 in the differential diagnosis of aseptic meningitis. This condition might recur at any time throughout the course of the disease, although CSF pleocytosis becomes less common with advanced immunosuppression. Treatment is symptomatic. The decision to start on antiretroviral medications should be based on current guidelines that generally recommend treatment of initial HIV-1 infection (see Chapter 130).


Part II  Major Clinical Syndromes

1576 reconstitution inflammatory syndrome (C-IRIS).30 It is more frequent if ART is given 7 days after compared with 28 days after onset of antifungal therapy.31 Persistent CSF cryptococcal growth at ART initiation and poor CD4+ T-cell increases on ART are strong predictors of C-IRIS.30 Management of C-IRIS includes continuation of ART, antifungal therapy, and a course of corticosteroids.32

Differential Diagnosis of Meningitis

Other CNS infections in AIDS include tuberculosis, histoplasmosis, aspergillosis, coccidioidomycosis, amebiasis, Candida albicans infection, Trypanosoma cruzii infection, herpes simplex and herpes zoster infections, and Nocardia asteroides. Geographic differences account for variations in local prevalence. Estimates indicate that more than 1 million people worldwide have tuberculosis (TB) and HIV coinfection with the highest number of individuals in sub-Saharan Africa. CNS tuberculosis can present in numerous ways, including as a tuberculoma, abscess, spinal cord lesion, and most commonly as tuberculous meningitis (TBM). TBM is a highly treatable condition in resourceslimited settings (RLS) because its presentation is commonly subacute and antituberculosis treatment is widely available. However, TBM diagnosis remains a challenge throughout the world. Acid-fast bacilli staining on CSF has a sensitivity of 10% to 20% that varies greatly on the basis of technical expertise.33 CSF culture has a sensitivity of approximately 50% and can take as long as 6 weeks to become positive.34 Neither of these techniques is practical in an RLS. As a result, treatment is often initiated empirically with minimal objective testing for guidance except for hypoglycorrachia and high CSF total protein, where biochemical tests are available. Bacterial meningitis is more commonly a problem for HIV-infected patients in resource- limited settings compared with resource-rich settings.35,36 HIV-infected patients are at risk for pneumococcal infection,37 and pneumococcal meningitis usually arises from spread of an untreated primary infection. These cases are more likely in RLS where patients present at later stages of disease and have limited access to health services.

COGNITIVE AND MOTOR SYNDROMES HIV Type 1 Associated Neurocognitive Disorder

Clinical Presentation.  This common CNS complication of HIV-1 infection occurs in 15% of patients with AIDS and can be the first manifestation of the disease in 3% to 10%.38 In the past, this condition has also been named AIDS dementia complex, HIV-1 encephalopathy, or HIV-associated major cognitive disorder. A less severe entity named HIV-1-associated minor cognitive/motor disorder (MND) occurs in an additional 20% to 25%, and asymptomatic neurocognitive impairment is used to categorize individuals with subclinical impairment.39,40 Risk factors include an AIDS-defining illness, increased age and survival duration, lower nadir of CD4+ T-cell counts, and higher baseline HIV viral loads.41 The clinical characteristics of this disorder can be subdivided into three main categories: cognitive, behavioral, and motor (Table 127-1). Initial symptoms are usually subtle. Patients often report difficulty with memory and note a slowness of thinking. They have trouble concentrating. Complex mental activities become more time consuming and difficult to perform. A loss of interest in social and professional activities soon follows, and such apathy and social withdrawal may be mistaken for depression. Although cognitive and behavioral symptoms are prominent in most patients, some mainly present with motor

TABLE 127-1  Clinical Triad in Human Immunodeficiency Virus Type 1–Associated Neurocognitive Disorder COGNITION

BEHAVIORAL

MOTOR

Forgetfulness

Apathy

Gait instability

Mental slowing

Social withdrawal

Poor coordination

Decreased concentration

Lack of spontaneity

Leg weakness

dysfunction, which includes decreased coordination, altered handwriting, loss of balance, and gait instability. The mental status examination reveals minor psychomotor slowing, inattention, decreased short-term memory, inability to perform simple calculations, and frontal release signs. Ocular movement testing shows saccadic pursuit. Other frequent findings are brisk reflexes, mild postural tremor, slowing of rapid alternating movements, and gait instability when performing half-turns. If untreated, dementia becomes more global, profoundly impairing orientation, memory, and cognition. Confusional or psychotic episodes have been reported, but seizures are a rare occurrence. Despite the extent of the cerebral involvement, there is usually no aphasia, apraxia, or other signs of discrete cortical dysfunction, except in terminal stages. Therefore, this syndrome has been classified as a frontal-subcortical dementia. A rapid bedside evaluation can be performed with the HIV Dementia Scale.42 However, this screening test is not as sensitive as a more detailed neuropsychological evaluation, which should include tests of attention, memory, and psychomotor speed such as trail making, digit span, verbal fluency, grooved pegboard, symbol digit modalities, and Rey auditory verbal learning tests.43 An international dementia scale can be used to identify individuals at risk of HIV-associated dementia despite language barriers.44,45 Unfortunately, cognitive dysfunction persists despite ART. A crosssectional study of 1555 HIV-infected adults in the United States showed neuropsychological impairment in 52%. Prevalence estimates for specific HIV-associated neurocognitive disorder (HAND) diagnoses were 33% for asymptomatic neurocognitive impairment, 12% for MND, and 2% for HIV-associated dementia.46 Laboratory Investigations.  Numerous groups have detected early neurologic dysfunction in HIV-1-infected asymptomatic individuals.47-49 Subtle electrophysiologic abnormalities can be found in early HIV-1 infection (on electroencephalography, evoked potentials, nerve conduction studies), but they do not seem to have a predictive value for the later onset of AIDS dementia, which occurs generally when the CD4+ T-lymphocyte counts are less than 200 cells/µL. CSF analysis shows mild lymphocytic pleocytosis in 25% and elevated protein in 55%,50 which can also be found in nondemented patients. Increased CSF levels of nonspecific markers of immune activation or neuronal injury have been reported, but their use in patients’ management is limited because these markers are also elevated during opportunistic infections of the CNS and because these assays are not readily available in the clinical setting.51 Measurement of the HIV-1 CSF viral load has been evaluated as a surrogate marker in HIV-1 infected individuals with cognitive dysfunction. A wide overlap was found between CSF HIV-1 viral load values of demented and nondemented individuals, and concomitant opportunistic infections of the CNS must be ruled out because they also contribute to transient elevation of HIV-1 viral burden in the CSF.52 These findings suggest that there may be two phases of HIV-1 infection in the CSF. (1) A transitory infection of the CNS may occur early in the disease via trafficking lymphocytes. These viral strains have a lymphotropic phenotype (using CXCR4 co-receptor) and may respond to therapy in parallel to plasma virus load. (2) A more autonomous infection of CNS monocytes/macrophages may take place at a later stage; with macrophage tropic strains (using CCR5 co-receptor).53 Such patients may need higher drug penetration in the CNS. Whether measurement of the HIV-1 CSF viral load provides an accurate representation of the viral replication occurring in the CNS is unclear. However, subsets of patients with higher CSF than plasma viral loads have been recognized in whom intrathecal viral replication correlates with neurologic deficits. Because HIV-1–associated dementia complex is a diagnosis of exclusion, CSF examination is indicated for bacterial, fungal, and acid-fast bacteria cultures; cryptococcal antigen; VDRL test; and cytology. In addition, CSF polymerase chain reaction (PCR) for JC virus (JCV), the agent of progressive multifocal leukoencephalopathy (PML), is indicated because this condition is often difficult to distinguish from HIV-1 encephalopathy on brain imaging studies (see later and also see Chapter 147). Imaging Studies.  Computed tomography (CT) and magnetic resonance imaging (MRI) may show greater subcortical atrophy than cortical atrophy, which is not proportional to the degree of


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Chapter 127  Neurologic Diseases Caused by Human Immunodeficiency Virus Type 1 and Opportunistic Infections

dementia. MRI may also demonstrate multiple hyperintense signals in T2-weighted images, which are nonenhancing, poorly demarcated, and localized bilaterally in the subcortical white matter (Fig. 127-1). MRI is superior to CT for distinguishing these abnormalities from confounding illnesses such as PML. Unlike lesions of PML, there is no associated hypointensity in T1-weighted images. The severity of global brain atrophy and signal changes in basal ganglia correlates with cognitive impairment.54 Brain Biopsy and Histologic Analysis.  There is no indication to perform a brain biopsy in patients with HAND, unless imaging studies suggest the presence of another process. Postmortem examination reveals encephalitis with multinucleated giant cells and microglial nodules, as well as astrocytosis and perivascular mononuclear cell infiltrates. HIV-1 has been found in microglial nodules, perivascular macrophages, and multinucleated giant cells. The latter are the result of the fusion of infected macrophages. The virus can also infect astrocytes.55 HIV-1 has also been found in endothelial cells,56 and abnormalities of the cerebral microcirculation are characterized by increased cellularity and pleomorphism of endothelial cells, as well as prominent perivascular aggregates of HIV-infected macrophages. These findings are sometimes related to microinfarcts and are postulated to give rise to increased vascular permeability.57 Indeed, early enhancement has been detected in the basal ganglia of patients with HAND, suggesting a disruption of the blood-brain barrier (BBB) in these regions.58 HIV-1 does not infect glial cells in adults, whereas a limited expression of viral regulatory gene products has been demonstrated in glial cells from children with AIDS.59 White matter pallor involving primarily the centrum semiovale is a hallmark of HIV-1 encephalopathy in adults, which may be caused by seepage of macromolecules and edema fluid in the brain parenchyma through the permeable BBB and may cause injury to the myelinated fibers. Finally, HIV-1 does not infect neurons. Therefore, quantitative neuronal loss, decrease in cell size, or dendritic injury found in the cortex of demented patients60 may only be secondary to infection of other cells and associated immune activation.61 Treatment.  Although the pathophysiology of HAND is not entirely elucidated, HIV-1 remains the main triggering factor, and it is therefore reasonable to prevent viral replication in the CNS. However, antiretroviral drugs have variable penetration through the BBB, and evaluation of CNS concentration and pharmacokinetics of these medications is incomplete. On the basis of available pharmacologic data, antiretrovirals can be classified according to their penetration through the BBB. A CSF penetration effectiveness (CPE) score62 is given to each medication going from 1 (low) up to 4 (high) (Table 127-2). The CPE score of an ART regimen is calculated by summing the score of each individual antiretroviral. Patients with higher penetration-effectiveness scores tended to have lower HIV RNA levels in the CSF. Drugs with the highest CPE scores include zidovudine, nevirapine, and ritonavir-boosted indinavir.

A

B FIGURE 127-1  Brain magnetic resonance images of a 42-year-old man with human immunodeficiency virus–associated neurocognitive disorder. The T2-weighted image (A) shows bilateral, ill-defined hyperintense signal in the periventricular white matter and centrum semiovale, which does not enhance with gadolinium injection on the T1-weighted image (B). The ventricles are slightly enlarged, consistent with subcortical atrophy.

TABLE 127-2  Cerebrospinal Fluid Penetration Effectiveness Score* Nucleoside analogue reverse-transcriptase inhibitors

4

3

2

1

Zidovudine

Abacavir

Didanosine

Tenofovir

Emtricitabine

Lamivudine

Zalcitabine

Stavudine Non-nucleoside analogue reverse-transcriptase inhibitors

Nevirapine

Protease inhibitors

Indinavir-r

Delavirdine

Etravirine

Efavirenz Darunavir-r

Atazanavir-r

Nelfinavir

Fosamprenavir-r

Atazanavir

Ritonavir

Indinavir

Fosamprenavir

Saquinavir-r

Lopinavir-r

Saquinavir Tipranavir

Fusion/Entry inhibitors

Maraviroc

Integrase inhibitors

Raltegravir

*Numerical score of 4 is highest and 1 is lowest by method of Letendre.62 -r, ritonavir-boosted.

Enfuvirtide


Part II  Major Clinical Syndromes

1578 Since 1996, the availability of protease inhibitors (PIs) and the use of three or more drugs in ART regimens have made a major impact on the incidence of neurologic disease in HIV-1-infected patients.63-65 This is somewhat surprising; PIs in general have a very low CSF-toplasma ratio because they are highly protein bound. Nevertheless, the incidence of HAND, which was estimated at 6.49 per 1000 personyears pre-1997, has decreased to 0.66 by 2003 to 2006, an approximately 10-fold decrease.63,66 Although ART is now the treatment of choice for advanced HIV-1 disease, the optimal drug combination for HAND has not been established. Whether regimens containing several drugs with good penetration through the BBB were advantageous has been investigated. In ART-experienced patients with CD4+ T-cell counts of less than 200 cells/µL, those who received multiple CSF penetrating agents had a greater reduction of CSF HIV-1 RNA.67,68 These results have been confirmed in recent studies, showing that higher CPE scores of long-term ART are associated with better viral suppression in CSF61-63and decreased risk of cognitive impairment.69,70 However, other studies have shown that discontinuation of efavirenz was associated with cognitive improvement in scheduled treatment interruption regimens71 and in otherwise asymptomatic HIV-infected individuals,72 suggesting that some antiretrovirals might have neurotoxic properties, which was also demonstrated in vitro.73 The hypothesis that discordant mutations are present in blood and CSF has been confirmed by the analysis of HIV-1 genotypes in paired samples. Mutations of the reverse transcriptase and protease genes of CSF strains, but not in the corresponding blood isolates, were detected in 10 of 23 subjects (43%). Interestingly, mutations conferring resistance to low or high CSF-penetrating agents occurred at similar frequencies.74 Reverse-transcriptase mutation patterns differed in 14 of 21 (67%) paired samples from plasma and CSF in one study, and HIV RNA responses and reverse-transcriptase genotypes were discordant between CSF and plasma in some subjects.75,76 In a study of HIVinfected children starting ART, 8 of 11 had identical resistance patterns in both CSF and plasma at baseline, whereas at week 48 of treatment, only 1 of 9 children had similar genotypes, suggesting discordant viral evolution in these two compartments.77 CSF viral escape was reported recently in 10 patients with progressive neurologic dysfunction despite well controlled plasma viral load and good immunologic response on ART. In general, these patients had a higher CSF viral load compared with plasma. The patients also had CSF pleocytosis and elevated protein concentration, MRI abnormalities, and unique CSF resistance mutations compared with plasma and improved clinically after optimization of ART.78 Long-term follow-up of a patient who developed HAND and elevated CSF viral load despite low plasma viral load and high CD4 counts confirmed the importance of concomitant genotype testing in CSF and plasma. Subsequent change of ART targeting CSF strains was associated with suppression of CSF HIV replication, as well as a marked clinical and radiologic improvement.78 Failure to recognize the occurrence of different genotypic resistance patterns in plasma and CSF may lead to uncontrolled viral replication in the CNS and worsening neurologic symptoms despite evidence of viral clearance in the periphery. These resistant isolates may, in turn, spill back into the circulation and contribute to the progression of HIV-1 disease. Therefore, genotypic analysis of CSF HIV-1 strains is indicated in patients with cognitive dysfunction who have good virologic response to ART in the plasma but persistence of an elevated HIV-1 CSF viral load. In addition to antiretroviral treatment, other experimental compounds have been tested for the treatment of HAND, but without evidence of clear benefit so far. These include a calcium channel blocker (nimodipine); antioxidants (vitamin E, thioctic acid, CPI-1189); a tumor necrosis factor-α antagonist (pentoxifylline); a noncompetitive N-methyl-d-aspartate inhibitor (memantine); peptide T; selegiline; and, more recently, minocycline.79

CENTRAL NERVOUS SYSTEM MASS LESIONS

In patients with AIDS presenting with change in mental status or abnormal neurologic examination results, brain lesions are frequently revealed on CT or MRI. These can be quite extensive and may represent life-threatening emergencies.

Toxoplasma Encephalitis

At the beginning of the AIDS epidemic, Toxoplasma encephalitis (TE) was the most common cerebral mass lesion in patients with AIDS. TE is caused by a reactivation of latent infection by the pro­ tozoan Toxoplasma gondii as a result of progressive loss of cellular immunity. In the United States, where the incidence of seropositivity for T. gondii is approximately 30% in the adult population, TE formerly developed in 3% to 10% of patients with AIDS.80 In Europe and Africa, where the overall seroprevalence is higher, up to 25% to 50% of patients with AIDS presented with this condition. The incidence of TE has decreased initially thanks to widespread prophylaxis for Pneumocystis jirovecii pneumonia using trimethoprim-sulfamethoxazole, which also prevents CNS toxoplasmosis.81 Since the era of ART, there has been a further trend for a decreased incidence of this condition,20 and it accounted for only 28% of focal brain lesions occurring in patients with AIDS in 199882 and for 26% of patients with neurologic disorders in 2004.83 Nevertheless, TE continues to be a severe health problem. Patients who develop TE nowadays either did not receive or had not taken ART adequately.84 Therefore, toxoplasmosis still represents the most frequent complication affecting the CNS of patients with AIDS. Clinical Presentation.  Almost 90% of patients with TE have CD4+ T-lymphocyte counts less than 200 cells/µL, and 75% have CD4+ counts less than 100 cells/µL at the time of clinical presentation. The most common symptoms include headache, confusion, fever, and lethargy. Seizures develop in up to 30% of patients.85 Seventy percent of patients have focal signs on the neurologic examination, such as hemiparesis, cranial nerve palsies, ataxia, and sensory deficits. The clinical presentation is usually subacute, ranging from a few days to a month (see Chapter 280). Laboratory Investigations.  As is the case in the general population, serum anti-Toxoplasma immunoglobulin G antibodies can be detected in patients with TE, whereas immunoglobulin M antibodies are less commonly found, supporting the notion that most cases represent a reactivation of latent infection. Measurement of antibody titers is not helpful to establish the diagnosis. On enzyme-linked immunosorbent assay, only 7% of patients known to be seropositive for T. gondii had lost their antibodies at the time of presentation.80 Therefore, a negative serology orients toward another entity, whereas a positive serology is not diagnostic (see Chapter 280). A slight increase in CSF protein concentration and a moderate mononucleated pleocytosis (<60 cells/µL) are common, but nonspecific, and may be due to the underlying HIV-1 infection. A slight decrease in the CSF glucose has been reported but is not a constant finding. The PCR technique has been less useful for detection of T. gondii DNA in the CSF compared with other pathogens, with a sensitivity of only 44% to 65% and a specificity of 100%.86 However, this low sensitivity may be improved by the use of stage-specific PCR primers.87 CSF analysis is therefore more useful to rule out other infectious processes than to confirm the diagnosis of TE. Imaging Studies.  Neuroimaging with head CT or MRI demonstrates CNS lesions in almost all cases, with the exception of the rare diffuse encephalitic form of toxoplasmosis. Lesions are multiple in two thirds of the cases, and 90% of them display ring enhancement after administration of contrast material. MRI is more sensitive than CT in detecting multiple lesions. These are generally localized at the corticomedullary junction, in the white matter, or in the basal ganglia; are surrounded by edema; and induce mass effect on surrounding structures (Fig. 127-2). Unfortunately, the neuroradiologic characteristics of TE are not pathognomonic and may be observed in other conditions such as primary CNS lymphoma (PCNSL) (see later). Brain Biopsy.  Because of the good response to therapy, histologic examination is not required for the diagnosis of TE, and an empirical therapeutic trial is recommended when the clinical and radiologic findings are consistent with this diagnosis. Histologic examination shows mainly necrotic abscesses with blood vessel thrombosis and necrosis. Cysts containing bradyzoites, the dormant form of T. gondii, coexist with numerous active tachyzoites. Treatment.  Treatment consists of a combination of pyrimethamine and sulfadiazine, which cause a synergistic and sequential block on the folic acid metabolism necessary for the development of the


1579

B

C

D

FIGURE 127-2  Brain magnetic resonance images of a 38-year-old man with acquired immunodeficiency syndrome and Toxoplasma encephalitis. The T1-weighted image after gadolinium injection shows a large enhancing lesion in the left frontal lobe (A), surrounded by edema, as demonstrated on the T2-weighted image (B). Additional smaller enhancing lesions can be seen on coronal cuts in the right thalamus and at the left convexity (C) and in the right cerebellum and right temporal lobe (D).

parasite. Standard acute therapy consists of pyrimethamine 200 mg PO the first day of treatment, followed by 75 mg/day PO, sulfadiazine 4-6 g/day PO in four divided doses, and folinic acid 10 to 25 mg/day PO for 6 weeks. Clindamycin 600 mg IV or 450 mg PO four times daily is an adequate alternative to sulfadiazine in the previous regimen for patients allergic to sulfonamides. Side effects, which consist of cytopenia, rashes, diarrhea, and increased liver enzymes, have been reported in 40% to 70% of patients receiving pyrimethamine and sulfadiazine and in 36% of those receiving pyrimethamine and clindamycin. These can cause early discontinuation of therapy. Azithromycin 900 to 1200 mg PO once daily or atovaquone 1500 mg PO two times daily can also be combined with pyrimethamine and folinic acid. Although corticosteroids are frequently prescribed to diminish cerebral edema, their use has been shown to be neither beneficial nor harmful in TE.88 Because high doses of steroids also decrease the size of CNS lymphoma lesions, they should be administered only in cases with impending cerebral herniation during the initial medical treatment of presumed TE so as not to cloud the diagnosis. Neurologic improvement is clinically apparent in more than half the cases by day 3 of therapy and in most cases

by day 7. Nevertheless, the death rate at 1 year varies from 10% to 60%.83,89 Persistent neurologic sequelae remained in 37% of survivors.90 A failure to improve or a worsening of the symptoms should prompt repeat imaging studies by days 10 to 14 to determine the need for a brain biopsy. TE-IRIS presenting simultaneously with initiation of ART has been reported in six patients, including five who were supposed to take effective prophylaxis. Brain biopsy showed intense angiocentric infiltrate consisting predominantly of CD8+ T lymphocytes in two of them.91 Secondary Prophylaxis.  T. gondii is sensitive to treatment only when in tachyzoite form. Because dormant cystic forms may rupture and reinitiate the infectious process at any time, maintenance therapy is necessary to prevent a relapse, which is likely to occur after a delay of 6 to 8 weeks of interruption of treatment. Standard maintenance therapy consists of pyrimethamine 25 mg/day with folinic acid 10 to 25 mg/day and either sulfadiazine 2 g/day in four divided doses or clindamycin 450 mg PO four times daily. Patients with sustained CD4+ T-cell counts higher than 200 cells/µL for more than 3 months can discontinue their secondary prophylaxis.92 Relapse occurred in only one of 22 (5%) patients.93

Chapter 127  Neurologic Diseases Caused by Human Immunodeficiency Virus Type 1 and Opportunistic Infections

A


Part II  Major Clinical Syndromes

1580 If the diagnosis is made in a timely fashion and the patient does not become intolerant to the treatment, TE is currently an opportunistic infection with a relatively high therapeutic success rate, and death is usually caused by other complications of AIDS.

Primary Central Nervous System Lymphoma

This condition, which affected 2% of patients with AIDS at the beginning of the epidemic, has seen its incidence decrease considerably in the ART era.20 In 1998, it accounted for only 12% of AIDS-related focal brain lesions.82 Its radiographic appearance makes it the principal differential diagnosis of TE. Clinical Presentation.  The onset of symptoms is generally subacute, lasting weeks to months. Confusion, lethargy, and memory loss are the most frequent symptoms. As the disease progresses, hemiparesis, aphasia, seizures, and cranial nerve palsies occur.94 Fever, headaches, and constitutional symptoms are generally absent, which helps distinguish PCNSL from TE. At the time of diagnosis, the average CD4+ T-lymphocyte counts are usually very low (≈50 cells/µL). Laboratory Investigations.  A mild mononuclear pleocytosis (<30 cells/µL) and an increase in the protein concentration in the CSF are common findings in patients with PCNSL but are nonspecific and may be due to the underlying HIV-1 infection. High protein levels (≤590 mg/ dL) have been reported in patients with extensive lymphomatous infiltration of both cerebral hemispheres. Hypoglycorrhachia is a rare finding. It is important to perform cytologic analysis of the CSF because the presence of atypical or malignant lymphomatous cells can establish the diagnosis. Flow cytometry immunophenotyping has at least 25% higher sensitivity than conventional cytomorphologic methods for the detection of malignant cells.95 Systemic extracerebral lymphomas, which have an increased incidence in AIDS patients, can also cause lymphomatous meningitis but do not generally spread to the brain itself. Similarly, PCNSL does not metastasize systemically. The EpsteinBarr virus (EBV) genome can be detected in tumor cells of nearly all PCNSLs, but only in some systemic lymphomas of AIDS patients, and rarely in primary brain lymphoma tissue from patients without immunodeficiency.96 When testing is performed in a research setting, detection of EBV DNA by PCR in the CSF has a reported sensitivity of 80% to 90% and a specificity of 87% to 98% for the diagnosis of PCNSL. Measurement of the EBV CSF viral load by quantified PCR in the CSF may improve the sensitivity of this test and be clinically useful in monitoring responses to treatment.97 However, other groups have found EBV DNA in the CSF of patients who did not have PCNSL, which raises doubts regarding the true predictive value of this test when performed in the clinical setting.98,99 Imaging Studies.  Head CT or MRI usually shows findings consistent with a CNS tumor. Solitary mass lesions are as frequent as multiple lesions.94 Most lesions display some degree of enhancement, which is usually nodular or patchy. Ring enhancement, identical to that commonly seen in TE, can occur and correlate with central tumor necrosis. Subependymal enhancement seems more specific of CNS lymphoma, but this is a rare feature. Lesions are frequently located in the corpus callosum, the periventricular white matter, or the cortex. Involvement of the posterior fossa occurs only in 10% of cases.100 Lesions can be surrounded by edema, which may induce variable mass effect on neighboring structures (Fig. 127-3).101 MRI is more sensitive than CT in revealing multiple lesions, which can be useful if a biopsy is being considered. Thallium 201 single-photon emission CT shows an accumulation of isotope in the tumor due to increased metabolic activity.102 In one series comparing enhancing brain lesions caused by toxoplasmosis and lymphoma, the thallium index of each lesion, measured as the ratio of the mean uptake in the lesion to that of the corresponding contralateral side, was increased and a significant predictor of lymphoma only in lesions 2 cm or larger, yielding 100% sensitivity and 89% specificity.103 However, the usefulness of this method in differentiating CNS lymphoma from opportunistic infections may depend heavily on the resolution of the images, and appropriate technology may not be available in every center. Fludeoxyglucose (FDG) positron emission tomography (PET) scan has also shown utility in differentiating TE from PCNSL in a small series.104

A

B FIGURE 127-3  Brain magnetic resonance images of a 50-year-old man with primary central nervous system lymphoma. A 2-cm ringenhancing lesion is present in the right parietal lobe, surrounded by edema (A). The T2-weighted image shows low signal intensity centrally, which is more consistent with cellular proliferation than with an infectious process (B).

Brain Biopsy.  If the CSF cytology fails to reveal lymphomatous cells and if EBV PCR is negative in the CSF, an image-guided stereotactic brain biopsy using CT or MRI is the only way to ascertain the diagnosis. The macroscopic appearance of these tumors is generally that of a multifocal, diffusely infiltrating and expanding nonhemorrhagic mass, without well-demarcated borders, simulating the appearance of an infiltrating glioma. However, well-circumscribed, largely necrotic masses can also resemble abscesses. Microscopic analysis reveals a variety of patterns, including large cells, small noncleaved cells, and immunoblastic or mixed cellular components. These are generally of B-lymphocyte lineage. EBV is present in tumor cells, suggesting that this virus may have a role in tumorigenesis,105 as is the case in Burkitt’s lymphoma and in nasopharyngeal carcinoma. Treatment.  The response to steroids seen in lymphomas of nonAIDS patients is not always seen in AIDS patients. In patients with altered mental status, debilitating focal symptoms, or impending herniation, dexamethasone 10 mg IV or PO followed by 4 mg IV or PO every 6 hours can provide temporary improvement. The treatment of CNS lymphoma in AIDS consists of whole-brain irradiation with a


1581

Progressive Multifocal Leukoencephalopathy

Before the AIDS era, PML was a rare disease affecting mainly patients with chronic lymphocytic leukemia, those with non-Hodgkin’s lymphoma, or organ transplant recipients.111 At the beginning of the AIDS epidemic, up to 5% of patients developed PML.112 Despite the availability of ART, up to 28% of focal brain lesions in AIDS patients were attributed to PML in 1998,82 which equals the number of TE cases. The incidence of PML in ART-treated patients is 0.6 to 1.3/1000 personyears.113,114 PML is caused by the polyomavirus JCV. This doublestranded DNA virus infects 90% of the normal adult population worldwide and remains quiescent in the kidneys without causing any disease. In the setting of immunosuppression, JCV is reactivated and induces a lytic infection of oligodendrocytes, causing multifocal demyelination of the CNS (see Chapter 147).115 Clinical Presentation.  Classic PML usually develops when CD4+ T-lymphocyte counts decrease to fewer than 200 cells/µL.112 The most common presenting symptoms are limb weakness (hemiparesis or monoparesis), altered mental status, gait ataxia, and visual symptoms, including hemianopsia, diplopia, and third nerve palsy. Approximately 80% of patients have focal neurologic findings.116 However, PML lesions can occur anywhere in the CNS white matter, particularly at the subcortical level, although the optic nerves and the spinal cord are rarely involved.117 Because subcortical lesions prevent the transmission of information to and from the cortical areas, presentation implying cerebral cortical dysfunction such as aphasia, apraxia, memory loss, and visual agnosia does not rule out this diagnosis. In fact, seizures, which are usually considered to be of cortical origin, occur in 18% of PML patients.118 Some symptoms can also be attributed to HAND, which is often superimposed on other CNS pathologies in the end stages of AIDS. Laboratory Investigations.  Laboratory analyses are necessary to establish the diagnosis of PML.119 Conventional CSF analysis is normal or shows a moderate increase in protein concentration and a mild mononucleated pleocytosis (<25 cells/µL), which is nonspecific in the context of HIV-1 infection. Before the ART era, detection of JCV DNA in the CSF by PCR has a sensitivity of 74% to 92% and a specificity of 92% to 96% for the diagnosis of PML.120,121 In patients receiving ART, the sensitivity of this test has decreased to 58%, probably because of decreased JCV replication in the context of a recovering immune system.122 Nevertheless, measurement of JC viral load in the CSF appears to be of value as a correlate of PML disease activity and survival.121,123,124 Imaging Studies.  The hallmark of PML is patchy or confluent areas of low attenuation on CT or hyperintensity on T2-weighted MRI (Fig. 127-4). MRI is twice as sensitive as CT in distinguishing multiple lesions. These generally do not enhance after administration of contrast material, and they are not surrounded by edema, and, hence, substantial mass effect on surrounding structures is absent. However, 8% of lesions can show faint, peripheral, and irregular enhancement. Lesions are usually bilateral, asymmetrical, well demarcated, and localized

A

B FIGURE 127-4  Brain magnetic resonance images of a 43-year-old man with progressive multifocal leukoencephalopathy. Prominent areas of high signal intensity are present in the subcortical white matter of both temporoparietal lobes on T2-weighted images (A). The affected areas are hypointense on T1-weighted images, do not enhance with gadolinium, and are not associated with mass effect or edema (B).

preferentially in the periventricular areas and the subcortical white matter.125 Involvement of the deep gray structures, including the basal ganglia and thalamus, can nevertheless be found in up to 17% of cases. Normal findings on CT or MRI do not rule out PML because microscopic lesions might be smaller than the resolution power of these tests. One such case showed multiple small foci of demyelination disseminated among the cortical U fibers at autopsy.126 HIV-1 encephalopathy can be easily mistaken for PML on brain imaging studies. As in PML, white matter lesions without mass effect or contrast enhancement are the radiologic hallmarks of this disease. However, HIV-1 encephalopathy lesions tend to be symmetrical and less clearly demarcated than the lesions of PML and are not associated with focal neurologic deficits. Proton magnetic resonance spectroscopy and magnetization transfer studies have shown promising potential in differentiating PML lesions from HIV-1 encephalopathy.127 The typical proton magnetic resonance spectroscopy pattern in PML lesions includes a decreased N-acetylaspartate-to-creatine ratio, consistent with axonal compromise; increased choline/creatine ratio, indicating cell membrane breakdown and turnover; and an occasional increase in lipid/

Chapter 127  Neurologic Diseases Caused by Human Immunodeficiency Virus Type 1 and Opportunistic Infections

total of 3000 cGy over a 3-week period. Steroids are added to decrease peritumoral edema and mass effect.100 The palliative response rate before the ART era was 53%.106 In a series of 25 patients in the United States seen between 1995 and 2001, the median survival was 87 days. However, patients who received ART after diagnosis had a longer survival; 6 of 7 patients receiving ART were alive compared with 0 of 18 untreated patients at a median follow-up time of 1.8 years. Furthermore, the median survival was only 29 days for 11 patients who received neither radiation nor ART.107 In a recent study, the estimated 3-year overall survival (OS) rate of HIV-associated PCNSL after whole brain radiation was 64%. Results were influenced by the performance status at presentation, with patients with good performance status having a 100% 3-year OS vs. 38% in those with poor performance status.108 Combination treatment including radiation and chemotherapy is difficult to tolerate because of high toxicity. A pilot trial using a combination of zidovudine, ganciclovir, and interleukin-2 showed promising results.109 In any event, immune recovery induced by ART leads to dramatic improvement in survival of patients with AIDSassociated PCNSL.110


Part II  Major Clinical Syndromes

1582 lactate and myo-inositol.128-130 In one study, patients who had the longest survival had the highest myo-inositol level, consistent with glial activity and inflammation in PML lesions.128 Metabolic alterations consistent with inflammation detected on proton magnetic resonance spectroscopy in PML lesions are associated with a cellular immune response against JCV. This inflammatory reaction, occurring early after disease onset, appears to be instrumental in the containment of PML.131 Brain Biopsy.  A brain biopsy may be necessary to establish the diagnosis of PML, when the JC viral load is too low to be detected by PCR in the CSF.132 Such cases have become more frequent in the era of ART.82 Histologic examination shows areas of demyelination in subcortical white matter or at the gray-white junction, as well as large, hyper-chromatic oligodendrocytic nuclei that stain positively for JCV by immunohistochemistry and contain large amounts of JC virions detectable by electron microscopy. Other histologic features of PML include large, bizarre astrocytes with lobulated nuclei and lipid-laden macrophages engaged in removing myelin breakdown products. Demyelinating lesions may be entirely circumscribed within the cortical gray matter.115 Treatment.  There is no specific treatment for PML. Numerous therapeutic attempts in HIV-infected patients included cytosine arabinoside,133 interferon-α,134 topotecan,135 cidofovir,136,137 mirtazapine, and mefloquine,138 but none showed any benefit compared with antiretroviral treatment alone. Serotonin receptors are used by JCV to enter astroglial cells in vitro.139 Therefore, serotonin receptor blockers, such as mirtazapine, which downregulate receptors on the cell surface, have been used empirically with variable success.140 It is important to realize that there is a large diversity in the natural evolution of PML. In patients with AIDS who are profoundly immunosuppressed, the course of the disease used to be rapidly progressive, leading to death within 2 to 4 months from the time of symptom presentation. However, approximately 10% of patients had a protracted course and survived more than a year. Since the ART era, median survival has increased to 10.5 months,141 and 40% to 50% of the patients survive PML, although some have devastating neurologic sequelae.142 Predictive factors for longer survival include CD4+ T-lymphocyte counts greater than 300 cells/µL at disease onset. Study of the cellular immune response against JCV showed that detection of JCV-specific cytotoxic T lymphocytes in the peripheral blood mononuclear cells of HIV-infected patients with PML was associated with long-term survival, whereas those with undetectable cellular immune responses against the virus had a progressive neurologic disease and a fatal outcome.143-146 Strategies aimed at boosting this immune response may prove useful for preventing uncontrolled replication of JCV and the spread of PML.147 For the time being, optimization of ART and avoidance of immunosuppression remain the best available therapeutic option for patients with PML.

Inflammatory Progressive Multifocal Leukoencephalopathy

Inflammatory forms of PML occur frequently in the setting of IRIS in patients taking ART. PML-IRIS is characterized by contrast-enhancing lesions and even swelling on neuroimaging studies or inflammatory infiltrates on a brain biopsy specimen,148 or both, and their outcome is usually favorable,149 but fatal cases have been reported.150 PML-IRIS often causes a paradoxical worsening of neurologic symptoms and can be distinguished from the natural evolution of PML by MR spectroscopy.151 Clinicians should not disregard the diagnosis of PML in the presence of contrast-enhancing brain lesions and should use caution before treating these immunosuppressed individuals with steroids.

Cytomegalovirus Encephalitis

Cytomegalovirus (CMV) may cause necrotizing focal encephalitis and ventriculoencephalitis.152 It occurs in patients with CD4+ counts of fewer than 50 cells/µL and is often concomitant with CMV infection of other organs, including retinitis, adrenalitis, and pneumonitis (see Chapter 140). The incidence of CMV disease, including CMV encephalitis (CMVE), has decreased considerably since the availability of ART.153 Clinical Presentation.  Patients with CMVE show features similar to those with AIDS dementia but tend to have a more acute onset

and more prominent confusion/disorientation or apathy/withdrawal. Hyponatremia and cranial nerve involvement, which are usually not present in AIDS dementia, are also helpful for establishing the diagnosis.154 Laboratory Investigations.  The conventional CSF examination is generally nonspecific because it is either normal or shows a slight protein increase and mononucleated pleocytosis. CMV culture often remains negative. However, the detection of CMV DNA by PCR in the CSF is both sensitive and specific.155 Imaging Studies.  Focal necrotizing lesions associated with periventricular and meningeal enhancement or hydrocephalus may be seen on brain imaging studies.156 Although MRI has better resolution than CT, it often lacks sensitivity for diagnosing CMVE.157 Brain Biopsy.  Microglial nodule encephalitis with CMV inclusions can be readily diagnosed by histologic examination. Interestingly, similar findings can be found at autopsy in 6% to 40% of patients with AIDS and dementia.152 However, autopsy findings of CMV infection of the brain do not always correlate with the presence of cognitive dysfunction. Treatment.  The management of CMVE is difficult.158 In one autopsy-confirmed series, half of the patients were taking maintenance doses of ganciclovir for the treatment of CMV retinitis. CMVE developed in others during first full-dose inductions with ganciclovir or foscarnet for retinitis.156 The possibility of viral resistance to antivirals should be considered if treatment failure occurs. The treatment is similar to that for CMV retinitis, with induction therapy with ganciclovir at 5 mg/kg/day IV every 12 hours for 14 to 21 days, followed by maintenance at 5 mg/kg IV daily indefinitely. If ganciclovir resistance is suspected, foscarnet should be used, with foscarnet induction at 90 mg/kg IV every 12 hours for 14 to 21 days, followed by maintenance 90 to 120 mg/kg/day indefinitely. Blood levels of oral valganciclovir at a dose of 900 mg are equivalent to those of intravenous ganciclovir at a dose of 5 mg/kg. The prognosis is usually poor, with median survival not exceeding 5 weeks. Therefore, combination therapy with ganciclovir and foscarnet at the doses mentioned earlier should be considered. Cidofovir may be used in patients in whom ganciclovir or foscarnet has failed or who have become intolerant to these drugs. The cidofovir dose is 5 mg/kg/wk for 2 weeks, followed by 5 mg/kg every 2 weeks. This drug is nephrotoxic and should be given with intravenous hydration and high doses of probenecid before and after cidofovir injection (see Chapter 140).

Miscellaneous Mass Lesions and Rationale for Brain Biopsy

Brain biopsy used to be considered the gold standard for the diagnosis of CNS mass lesions in AIDS. The biopsy is the most specific, but not always the most sensitive, test. Indeed, sensitivities of 64% to 96% have been reported in AIDS patients. In addition, this procedure is not without significant risks in this patient population. Brain biopsy has a mortality rate of 0% to 3%, a major morbidity rate of 0.5% to 9%, and a minor morbidity rate of 2% to 4%.159-161,162 Brain biopsy is often impractical because of the location of the lesion. In addition, several disease processes can coincide in patients with multiple lesions, and multiple biopsies are rarely performed. Finally, change of therapy indicated by the result of the biopsy is not always possible in patients with advanced AIDS, and overall survival was improved by only a couple of months before the era of ART.160,162 The availability of molecular diagnosis by PCR in the CSF has considerably changed the management of these patients. A decision analysis was performed on 136 consecutive HIV-1 patients presenting with mass lesions between 1991 and 1995.161 After 3 weeks of empirical therapy for TE, patients with progressive disease underwent a brain biopsy. CSF PCR amplification for T. gondii, EBV, and JCV DNA was performed in 66 patients. The presence or absence of mass effect surrounding the brain lesions, knowledge of the patient’s serologic status for T. gondii, and prophylactic regimen with trimethoprimsulfamethoxazole, as well as PCR results, were used in this analysis. The probability of TE was 0.87 in Toxoplasma-seropositive patients with mass effect who were not receiving trimethoprim-sulfamethoxazole, but only 0.59 for those receiving prophylaxis. For Toxoplasmaseropositive patients receiving trimethoprim-sulfamethoxazole, the


1583 HIV-infected patient with CNS symptoms CD4+ T lymphocyte counts/HIV viral load

Lesion(s) without mass effect

CT/MRI

-

Impending herniation

TE serology ? TE prophylaxis Thallium-201 SPECT

+ Steroids Open biopsy Decompression

CSF

+

Safe to perform LP

-

-

Biopsy

Safe to perform LP

+

-

CSF

Anti-TE trial

+ Specific treatment

-

+ +

Clinical and radiologic improvement after 2 wk

+

Continue treatment

+ Specific treatment

FIGURE 127-5  Management of the human immunodeficiency virus (HIV) type 1–infected patient with central nervous system (CNS) mass lesions. The elements in italics represent data that contribute to the decision-making process (see text for details). CSF, cerebrospinal fluid; CT, computed tomography; LP, lumbar puncture; MRI, magnetic resonance imaging; SPECT, single-photon emission computed tomography; TE, Toxoplasma encephalitis.

probability of PCNSL was 0.36. Conversely, in Toxoplasma-seronegative patients with mass effect, the likelihood of PCNSL was 0.74, which increased to 0.96 if the EBV PCR result was positive in the CSF. Among focal brain lesions without mass effect, the probability of PML was 0.81, which increased to 0.99 if JCV DNA was detected in the CSF. Therefore, brain biopsy is not necessary to confirm a diagnosis of PML, and JCV PCR in the CSF is now being used as a diagnostic test and for inclusion of patients in treatment studies.163 Bypassing the need for tissue diagnosis is more controversial in patients with suspicion of PCNSL, who have a positive result on EBV PCR in the CSF. Because treatment consists of whole-brain radiation, the risk of a false-positive PCR result has to be balanced with the risks of brain biopsy and by the fact that this technique does not always yield a definitive diagnosis. An algorithm for the management of HIV-1-infected patients with CNS mass lesions is shown in Figure 127-5.

SPINAL SYNDROME

Myelopathy is a frequent finding at autopsy in patients with AIDS and is probably underrecognized clinically. It can be primarily HIV-1 associated or caused by other opportunistic infections or tumors.

Vacuolar Myelopathy

Vacuolar myelopathy (VM) is present at autopsy in 17% to 46% of patients with AIDS.164-166 This disorder occurs with advanced immunosuppression, and the symptoms are often overlooked or attributed to debilitation. Clinical Presentation.  Symptoms are often overshadowed by coexisting central or peripheral nervous system impairment, such as AIDS dementia, which occurs late in the course of the disease.164 Usually, patients report progressive, painless gait disturbance; weakness and sensory disturbances in the legs; impotence in men; and urinary frequency and urgency. The evolution is usually progressive and leads to severe paralysis of the legs and loss of sphincter control. Neurologic signs include spastic paraparesis, hyperreflexia, extensor plantar responses, and mild sensory impairment, with vibratory and position sense being disproportionately affected. There is usually no associated sensory level. Laboratory Investigations.  CSF analysis is either normal or demonstrates a slight increase in protein and lymphocytosis frequently seen in HIV-1 infection. Opposite to what is observed in AIDS dementia, the CSF HIV-1 viral load is not increased in patients with VM.167 CSF examination is, however, a useful test to rule out other treatable infections (see later).

Imaging Studies.  Findings on MRI of the spinal cord are usually normal in patients with VM. However, this examination is useful to rule out an extradural or intradural mass lesion or an epidural abscess.168 Histologic Studies.  Because an anatomic diagnosis is not possible, VM remains a clinical diagnosis of exclusion. At autopsy, discrete or coalescent 10- to 100-µm vacuoles containing cellular debris or macrophages and, rarely, axonal swelling can be seen in the white matter of the spinal cord, involving principally the posterior or lateral columns, or both. These lesions are usually symmetrical and more frequent at the middle to lower thoracic levels. Vacuoles appear to be the result of focal swelling within the myelin sheath. Ultrastructural studies indicate both axonal and myelin injury,169 although axonal destruction is seen only in areas of intense vacuolation. The etiology of VM is still unknown. Consistent with the absence of an increased HIV-1 CSF viral load, immunohistochemistry studies did not demonstrate an association between HIV-1 antigens and VM.165,170 Therefore, the role of HIV-1 may only be indirect. Because histologic findings are similar to those of subacute combined degeneration of the spinal cord and because patients with VM usually have normal serum levels of vitamin B12 and folic acid, it was suggested that abnormal metabolism of the vitamin B12-dependent transmethylation pathway may be important in the pathogenesis of VM. Indeed, S-adenosylmethionine and methionine were decreased in the CSF and serum of patients with VM, respectively.171 The underlying cause of this metabolic disorder is unclear. Macrophage activation might generate substrates that are metabolized by methylation and therefore trigger a local deficit of methyl group donors in the spinal cord, leading to myelin vacuolization. Treatment.  An open-label pilot clinical trial suggested that patients with VM may benefit from supplements of l-methionine 3 g twice daily for 6 months.172 However, there are also reports indicating a role for ART in the treatment of myelopathy in an antiretroviral-naïve HIVinfected patient173 and for the combination of lopinavir/ritonavir in an ART-experienced patient.174 Because there is no way to confirm the diagnosis of VM outside of a postmortem examination, it is possible that the patients who responded to various ART formulations were instead affected by HIV-1 myelitis,175 which has the same histologic features as HIV-1 encephalitis, and therefore may benefit from antiretroviral treatment.

Differential Diagnosis of a Noncompressive Myelopathy

Other etiologies of noncompressive myelopathy in patients with advanced HIV-1 infection include other viral infections such as CMV,

Chapter 127  Neurologic Diseases Caused by Human Immunodeficiency Virus Type 1 and Opportunistic Infections

Lesion(s) with mass effect


Part II  Major Clinical Syndromes

1584 varicella-zoster virus, and herpes simplex virus types 1 and 2, as well as human T-cell lymphotropic virus type 1. Human T-cell lymphotropic virus type 1 is also transmitted sexually or through transfusion of cellular blood products and is the agent of a chronic spastic paraparesis called human T-cell lymphotropic virus type 1–associated myelopathy (see Chapter 170).176 Syphilitic meningomyelitis and rare fungal or parasitic infections are diagnosed by appropriate serologies and cultures.177

PERIPHERAL NERVOUS SYSTEM SYNDROMES

Peripheral neuropathies have become the most common neurologic complication of HIV infection. Neuropathies include several entities that are thought to be directly associated with HIV and occur at different stages of immunosuppression. Other forms are caused by opportunistic pathogens, such as CMV. Finally, the peripheral nervous system can also be affected by antiretroviral treatment toxicities.

HIV-Associated Neuropathies Inflammatory Demyelinating Polyneuropathy

These entities can occur at the time of seroconversion but are generally diagnosed in seropositive patients who are otherwise asymptomatic and not yet profoundly immunosuppressed, although some cases have also been reported in late stages of the disease.178 Acute inflammatory demyelinating polyneuropathy (AIDP) has clinical features similar to those of Guillain-Barré syndrome. Sensory symptoms such as paresthesias may precede an acute, progressive weakness of distal and proximal muscles of two or more limbs, associated with areflexia. Respiratory muscles may be involved, and patients sometimes require assisted ventilation.179 Sensory signs are usually mild, even in the setting of severe weakness. The maximal weakness is usually reached within the first 4 weeks. Patients with a more protracted course are affected by the chronic form of inflammatory demyelinating polyneuropathy, which may be monophasic or relapsing.180 A severe case of AIDP was observed in a patient with advanced AIDS 4 weeks after starting on ART, concomitant with immune reconstitution.181 AIDP should therefore be included in the growing number of ART-induced immune reconstitution inflammatory syndromes in HIV-infected individuals. Laboratory Investigations.  The CSF analysis often differs from that of HIV-1-seronegative patients with Guillain-Barré syndrome by the presence of a mononuclear pleocytosis of 20 to 50 cells/µL. The CSF protein concentration is usually elevated to levels as high as 250 mg/dL, and a polyclonal gammaglobulinemia can be detected. Electrophysiologic Studies.  Demyelination is demonstrated by decreased motor nerve conduction velocities or prolonged distal latencies and minimum F-wave latencies in two or more nerves. Conduction block is often prominent. Nerve Biopsy.  Sural nerve biopsy generally demonstrates the presence of a perivascular and endoneural mononuclear cell infiltrate with macrophage-mediated segmental demyelination. In severe cases, wallerian-like degeneration of axons can be seen. Similar to GuillainBarré syndrome occurring in immunocompetent individuals, the etiology of AIDP in HIV-infected patients is thought to be autoimmune. Antiperipheral nerve myelin antibodies have been found in HIV-1– positive patients with AIDP, as well as increased levels of soluble CD8 and neopterin in the CSF, indicating an abnormal immune activation. CMV was found at autopsy in the peripheral nerves of one patient with AIDS who presented with AIDP.182 Treatment.  Spontaneous recovery is usually the outcome of AIDP, although HIV-1–infected patients tend to have a more severe course with a slower recovery than immunocompetent individuals with Guillain-Barré syndrome. Plasmapheresis is indicated if the illness is sufficiently severe to warrant treatment. Patients with chronic inflammatory demyelinating polyneuropathy benefit from treatment with prednisone or plasmapheresis.183,184 However, prednisone should be used with great caution in patients with immunosuppression. Other treatments such as intravenous immunoglobulin have also been used successfully in HIV-1–positive patients with inflammatory demyelinating polyneuropathy, sometimes in combination with plasmapheresis.185 In cases of AIDP occurring in late stages of the disease, a trial of ganciclovir may be warranted if other treatments are not efficient.182

Distal Sensory Polyneuropathy

HIV Associated.  This is the most common cause of peripheral neuropathy in HIV-1 infection, which is symptomatic in 38% of patients and asymptomatic in an additional 20%.185,186 Moreover, histologic abnormalities can be detected at autopsy in most patients dying of AIDS.187 Distal sensory polyneuropathy (DSPN) occurs despite ART; 87% of affected individuals have an HIV-1 virus load less than 400 cps/ mL, and 70% have CD4+ T cell counts greater than 350/µL.188 DSPN is associated with older age, low CD4 nadir, diabetes, and past nucleoside analogue reverse-transcriptase inhibitor (NRTI) exposure. In the United States, HIV-positive African-American women had a higher incidence of DSPN (41.3%) compared with whites (34.8%) and Hispanics (24.7%).189 Clinical Presentation.  DSPN is characterized by the progressive onset of symmetrical paresthesia, numbness, and painful dysesthesia of the lower extremities. The pain is often described as an aching or burning sensation and is worse on the soles of the feet. Some patients have a lower pain threshold (hyperalgesia) or pain induced by non-noxious stimuli (allodynia), such as the contact with bed covers at night. Symptoms may remain stable or progress over months and ascend in a length-dependent fashion up the legs. Fingertips may become affected when symptoms reach the knees. Although wearing shoes and walking may exacerbate the pain for some patients, others report maximal discomfort when they are barefoot in bed. Therefore, DSPN may have a major negative impact on patients’ ability to ambulate and the quality of their sleep. Perception of noxious stimuli, temperature, and vibrations is usually more affected than light touch and proprioception. DSPN may even have several forms because some patients only have decreased sensation for noxious stimuli and temperature, indicating dysfunction of small unmyelinated sensory fibers; some only have decreased vibration sense and proprioception, consistent with dysfunction of large myelinated fibers; and others have decreased sensation for all modalities. Hyporeflexia of the lower extremities is a common finding, and gait ataxia with a positive Romberg’s sign is present in severe cases. Weakness is rarely found on the examination or is confined to the intrinsic foot muscles. Laboratory Investigations.  CSF analysis shows only nonspecific findings with mild elevation of protein concentration and mononucleated pleocytosis, which is common in HIV-1 infection. Electrophysiologic Studies.  Nerve conduction studies show lowamplitude or absent sural nerve action potentials. Sensory and motor nerve conduction velocities are normal or only mildly reduced. Electromyographic studies demonstrate acute denervation and chronic reinnervation in distal leg muscles. These findings are consistent with an axonal distal symmetrical, predominantly sensory, polyneuropathy. Nerve and Skin Biopsy.  Sural nerve biopsy confirms the diagnosis of axonal degeneration of myelinated and unmyelinated axons. Punch skin biopsies show evidence of decreased epidermal nerve fiber density in the distal leg. In patients with advanced HIV infection, epidermal nerve fiber density correlated with the clinical and electrophysiologic severity of DSPN.190 A modest dorsal root ganglion (DRG) neuronal loss has also been demonstrated in DSPN,191 as well as selective degeneration of the axons and myelin sheaths in the cervical and upper thoracic levels of the gracile tracts. This process therefore represents the degeneration of the centrally directed extension of the sensory neurons.192 Inflammatory infiltrates around peripheral nerve fibers and in DRGs consist of activated macrophages, with local release of cytokines such as tumor necrosis factor-α, interferon-γ, and interleukin-6.187 As is the case in VM and, to some extent, in HIV encephalitis, productive HIV-1 replication in the peripheral nerves and DRGs is sparse and limited to monocyte/macrophages. Therefore, the presence of activated macrophages secreting inflammatory cytokines, rather than the virus itself, seems to account for most of the peripheral nerve damage.193 How activated macrophages penetrate DRGs and peripheral nerve fibers is unclear, and it has been hypothesized that the blood-nerve barrier, like the BBB, may be affected in HIV-infected patients.187 Finally, experimental models in animals suggest that it is still possible that HIV, or HIV-1 proteins, may have a direct toxic effect on the neuropathic pain of DSPN.194


1585

Nucleoside Neuropathy

Clinical Presentation.  Dose-dependent neurotoxicity of the NRTIs zalcitabine, didanosine, and stavudine (d4T) has been detected in approximately 30% of patients taking these medications.195 The risk is increased in patients on regimens containing a combination of didanosine and d4T.196 The clinical presentation and electrophysiologic study results were indistinguishable from those of DSPN, and the diagnosis can only be established by a temporal association between initiation of a dideoxynucleoside NRTI and the onset of the symptoms, which can occur as early as 1 week. Discontinuation of the offending medication may lead to symptomatic improvement over several weeks in two thirds of patients, although it is often preceded by a transient worsening of symptoms known as “coasting.”197 Laboratory Investigations.  The pathogenetic mechanism of nucleoside neuropathy appears to be most likely related to nucleosideinduced mitochondrial dysfunction. Indeed, NRTIs inhibit mitochondrial polymerase in vitro, resulting in tissue-specific injury. Zidovudine toxicity affects mainly skeletal muscle (see later), whereas didanosine and d4T cause pancreatitis in addition to neuropathy. Nucleoside neuropathy occurs more frequently in individuals with preexisting DSPN, and administration of NRTIs to healthy animals does not result in neuropathy.187 These data suggest that NRTI may only exacerbate an inflammatory process triggered by activated macrophages in peripheral nerve fibers or DRGs of HIV-infected individuals. Clinicians should therefore use caution before removing didanosine or d4T from successful ART regimens, unless there is a clear temporal association between the administration of these medications and the onset of the symptoms or an elevated serum lactate level.198 A list of neurotoxic medications that have been associated with DSPN in HIV-infected patients is shown in Table 127-3. Treatment.  There is no available therapy that leads to the regeneration of nerve fibers and DRGs and reversal of symptoms. Suppression of viral replication with ART is unfortunately not associated with clinical improvement in DSPN. Therefore, treatment of neuropathic pain in DSPN is purely symptomatic and is aimed primarily at attenuating the painful dysesthesia and improving the quality of life of these patients. Treatment should not be administered if numbness and decreased sensation for noxious stimuli and temperature are the only symptoms because they do not improve.

TABLE 127-3  Neurotoxic Medications Used in Human Immunodeficiency Virus–1 Infection NAME CLINICAL PRESENTATION Nucleoside Analogue Reverse-Transcriptase Inhibitors Zidovudine

Myopathy

Zalcitabine

DSPN

Didanosine

DSPN

Stavudine

DSPN

Non-nucleoside Analogue Reverse-Transcriptase Inhibitors Efavirenz

Vivid dreams

Antiviral Agent Foscarnet

Seizures

Antibacterial Agents Isoniazid

DSPN

Dapsone

DSMP

Metronidazole*

DSPN

Antineoplastic Agents Vincristine

DSMP, CN

Cisplatin

DSPN

*High doses only. CN, cranial neuropathy; DSMP, distal sensory motor polyneuropathy; DSPN, distal sensory polyneuropathy.

First-line therapies include nonsteroidal anti-inflammatory drugs and acetaminophen, as well as topical application of capsaicin199,200 or 5% lidocaine gel.201 Anticonvulsant medications are the second line of treatment. Medications such as carbamazepine and phenytoin that are commonly used in other forms of painful neuropathies are contraindicated because both are metabolized by the liver, which may cause unwanted interactions in patients taking PIs. Gabapentin is metabolized by the kidneys and is usually well tolerated by HIV-infected individuals.202 Treatment starts using 300 mg PO at bedtime and is increased to 300 mg PO three times daily over 1 week. The extent of symptomatic relief is variable, and some patients may need doses as high as 1200 mg three times daily for a significant reduction in their discomfort. Fatigue and sleepiness are infrequent but may be limiting in some patients. Another anticonvulsant, lamotrigine, showed substantial pain reduction in a subgroup of patients receiving neurotoxic NRTIs but no difference compared with placebo in patients with DSPN who were not receiving nucleosides.203 Pregabalin is a newer drug used for neuropathic pain in diabetics and may be useful in HIV-infected patients as well. Amitriptyline, which is commonly used for the treatment of diabetic neuropathy, is not superior to placebo in HIV-infected patients with DSPN.204 However, adjunction of tricyclics with lower anticholinergic side effects, such as nortriptyline, may benefit patients who remain symptomatic on adequate doses of anticonvulsants. In refractory cases, a combination of anticonvulsant, tricyclic, nonsteroidal anti-inflammatory drug, and topical medications may be necessary to achieve significant relief. Narcotic analgesics should be kept as the last resort because of their addictive potential in the context of a chronic pain syndrome. Tramadol shares properties with opioid analgesics but is less likely to cause dependence and lead to abuse.205 Long-acting opioid agonists such as fentanyl patches should be preferred to short-acting agents. Smoked cannabis may be as efficient as oral drugs for treatment of neuropathic pain.206,207 Numerous experimental drugs and therapies have been disappointing in the treatment of DSPN, including mexiletine, memantine, prosaptide, peptide T, recombinant human nerve growth factor, plasmapheresis, and acupuncture (for reviews, see Simpson208 and Gonzalez-Duarte and colleagues209). Depletion of acetylcarnitine, a substrate in the production of energy during β-oxidation of free fatty acids, was implicated in the pathogenesis of DSPN,210 but this was not confirmed in a larger sample of patients.211

Mononeuritis Multiplex

Patients with previously asymptomatic HIV-1 infection and CD4+ T-lymphocyte counts greater than 200 cells/µL, as well as patients with AIDS and profound immunosuppression, can be affected by mononeuritis multiplex. Clinical Presentation.  Patients present with acute onset of sensory or motor deficit limited to one or more peripheral nerves. Involvement of a facial or laryngeal nerve has also been reported. The asymmetrical nature of this disorder and the prominent weakness differentiate it from other HIV-associated neuropathies. The course can be selflimited in early HIV-1 infection212 or more severe in patients with advanced disease. Laboratory Investigations.  CSF analysis is nonspecific and shows only a mild elevation of protein concentration and a mononuclear pleocytosis. Cryoglobulinemia was reported in one case.213 Electrophysiologic Studies.  Nerve conduction studies reveal a reduction of the amplitude of sensory nerve action potentials and compound muscle action potentials, as well as a mild reduction in nerve conduction velocities in the distribution of single nerves. The electromyographic examination is also consistent with focal or asymmetrical multifocal axonal degeneration, although considerable overlap may exist with DSPN and inflammatory demyelinating polyneuropathy. Nerve Biopsy.  Similar to its clinical presentation, the nerve biopsy specimen of patients with mononeuritis multiplex shows a spectrum of pathologies rather than a single pattern. Axonal degeneration and perivascular inflammatory infiltrates are found in patients with early HIV-1 infection and limited clinical involvement. Patients with AIDS and CMV infection usually have mixed axonal and demyelinating lesions with inflammatory infiltrates also containing polymorphonuclear cells,

Chapter 127  Neurologic Diseases Caused by Human Immunodeficiency Virus Type 1 and Opportunistic Infections

Because a similar type of polyneuropathy is common in the HIV-1–seronegative population, other etiologies such as vitamin B12 deficiency, neurotoxic medications, alcoholism, and diabetes mellitus should be ruled out.


Part II  Major Clinical Syndromes

1586 as well as, sometimes, characteristic cytomegalic inclusion bodies.214 The most aggressive form consists of a necrotizing arteritis with necrosis of endoneurial or epineurial vessels and might be caused by circulating immune complexes. Treatment.  Mild forms of mononeuritis multiplex developing in patients who are otherwise asymptomatic might improve without specific treatment. Others might benefit from therapies such as plasmapheresis213 or intravenous immunoglobulin.215 Corticosteroids and cyclophosphamide should be reserved for aggressive cases of mononeuritis multiplex with vasculitis proved by nerve biopsy. In late HIV-1 infection, especially in patients with concurrent systemic CMV infection, empirical therapy with ganciclovir for CMV should be considered.216

Progressive Polyradiculopathy

Because it occurs late in the course of HIV-1 infection, in patients with low CD4+ T-lymphocyte counts and concurrent systemic illnesses, progressive polyradiculopathy is often underrecognized. Clinical Presentation.  Initially patients report lower extremity and sacral paresthesia and, sometimes, radicular pain in the cauda equina distribution. These symptoms are followed by a rapidly progressive areflexive paraparesis and ascending sensory loss, often accompanied by urine retention. The upper extremities are relatively spared. A thoracic sensory level, if present, indicates concomitant medullary involvement, but other features indicating upper motor neuron damage such as spasticity and hyperreflexia are usually absent. A prominent infection with CMV, mainly retinitis, esophagitis, or colitis, is conspicuously present in a majority of cases. Laboratory Investigations.  In contrast to other peripheral nervous system diseases associated with HIV-1 infection, the CSF analysis is useful in establishing the diagnosis. A marked polymorphonuclear cell pleocytosis, elevated protein concentration, and hypoglycorrhachia are the hallmarks of this syndrome.217 CSF cultures demonstrate the presence of CMV in 60% of the cases.218 Cultures may take as long as 2 weeks to grow, and CSF samples must be kept on ice immediately after the lumbar puncture. As is the case with CMVE,155 CMV DNA may be detectable in the CSF by PCR. Because of the frequent concomitant systemic infection with CMV, blood culture may also be positive for this virus. Urine culture is nonspecific because many AIDS patients shed CMV in the urine asymptomatically. Cytologic studies can reveal cytomegalic cells with intranuclear and intracytoplasmic CMV inclusions. Electrophysiologic Studies.  Electromyographic examination is useful to differentiate this syndrome from AIDP. Severe and widespread proximal axonal damage in lumbar nerve root distribution is correlated by fibrillation potentials, complex repetitive discharges, and motor unit recruitment patterns in lower extremity muscles. Motor nerve conduction velocities are minimally altered, but affected muscles display prolonged or absent F waves. These findings are consistent with extensive denervation of the lower extremity muscles, which is characteristic in this syndrome. Nerve Biopsy.  Because of the radicular localization of the lesions, a nerve biopsy is not helpful for diagnosis. Autopsy studies reveal a severe inflammation associated with necrosis of the ventral and dorsal nerve roots. Cytomegalic inclusions can be detected within the nucleus and cytoplasm of Schwann, ependymal, and endothelial cells, which are also positive for CMV by in situ hybridization studies. Similar findings have been reported in cranial nerves at the site of exit from the brainstem. Despite the strong association of polyradiculopathy and CMV in patients with AIDS, other possibilities include neurosyphilis and lymphomatous meningitis, which should be ruled out by the CSF analysis. Treatment.  The treatment of CMV-associated progressive polyradiculopathy is similar to that of CMVE (see earlier). It consists of intravenous ganciclovir or foscarnet, or both.219 Newer anti-CMV medication such as valganciclovir and cidofovir have not been evaluated for progressive polyradiculopathy. Phenotypic and genotypic characterization of viral isolates should be considered in case of resistance to treatment.220 The clinical response is variable but usually best if therapy is started within days after the onset of symptoms.

Because the results of PCR for CMV DNA in the CSF can take 1 to 2 weeks to obtain, empirical treatment can be justified in this entity, especially if the workup reveals a polymorphonuclear pleo­ cytosis in the CSF or widespread systemic infection with this virus. The rationale is to prevent irreversible necrosis of the nerve roots. In patients who are already paraplegic several weeks after the onset of their symptoms, treatment can achieve stabilization, but no real improvement should be expected. Neutropenia is the most common dose-limiting toxicity of ganciclovir and may preclude concomitant use of other myelotoxic drugs such as zidovudine. Concomitant treatment with granulocyte colony-stimulating factor may become necessary in that setting.

Diffuse Infiltrative Lymphocytosis Syndrome-Associated Neuropathy

A small subset of HIV-infected patients develops persistent CD8 hyper-lymphocytosis and a Sjögren’s syndrome–like illness associated with multivisceral CD8 T-cell infiltration, known as diffuse infiltrative lymphocytosis syndrome. These individuals usually have parotid enlargement and generally have higher CD4+ T-lymphocyte counts, fewer opportunistic infections, and longer survival times than do other HIV-infected patients.221 Some of these patients may develop a primary B-cell lymphoma. Clinical Presentation.  Some of these patients present with an acute or subacute sensorimotor distal symmetrical neuropathy, which is always painful.222 Electrophysiologic Studies.  Electromyographic and nerve conduction study results are consistent with axonal neuropathy. Nerve Biopsy.  A nerve biopsy specimen shows marked angiocentric CD8+ infiltrates without mural necrosis and abundant expression of HIV-1 p24 protein in macrophages. The lymphocytic infiltrate is polyclonal in most patients. The HIV-1 proviral load in peripheral nerve is much higher than in other types of HIV-associated neuropathy.223 Treatment.  Zidovudine and steroid therapy was associated with improvement in a small group of patients.222 The prevalence of diffuse infiltrative lymphocytosis syndrome has significantly decreased in the ART era, suggesting that this condition is an antigen-driven response against HIV and should be treated with anti-HIV therapy.224

Amyotrophic Lateral Sclerosis-Like Syndrome

During the past 20 years, at least 19 cases of amyotrophic lateral sclerosis (ALS) or ALS-like syndromes have been reported in HIV-infected individuals.225-227 These cases differed from classic ALS because they occurred in younger patients, were unusually rapidly progressive, and improved after the institution of ART. Case studies at autopsy exhibited pathology outside the motor neuron pool. The etiology of this syndrome is unclear because HIV-1 does not infect neurons. It has also been suggested that ALS is caused by another, yet unidentified, retrovirus, and retroviral enzyme reverse transcriptase has been found in 50% to 56% of sera from HIV-1 negative ALS patients, but not in CSF, at levels comparable to those of HIV reverse transcriptase, compared with 7% to 19% of controls.228,229 However, this causality is not proven, and there is no indication for administering antiretroviral treatment to HIV-1–negative patients with ALS. ALS and HIV-1 infection can also be coincidental,230 and these data indicate that HIV-1 should be included in the differential diagnosis of ALS.231

MUSCULOSKELETAL SYNDROMES

Muscular disorders have been described in HIV-1-infected individuals and can occur at any stage of the disease.

Myopathy

Clinical Presentation.  Myopathy occurs in 17% of patients treated with zidovudine for periods longer than 270 days232 and in 0.22% of HIV-infected patients who are not taking this medication.233 The clinical presentation is similar in these two groups. Patients report mainly lower extremity weakness, characterized by difficulty in rising from a chair or climbing stairs, as well as fatigue. Myalgias are present in as many as half of the cases, and the neurologic examination reveals proximal symmetrical weakness, predominant at the level of the hip


1587 234

Other Musculoskeletal Conditions Associated with HIV

Rare cases of nemaline rod myopathy, sporadic inclusion body myositis, pyomyositis, and cardiomyopathy have also been reported in HIVinfected individuals.240 Sporadic inclusion body myositis is characterized by an antigen-driven inflammatory response and vacuolar degeneration. In one study, a subset of CD8+ T cells surrounding muscle fibers were HIV specific and may play a role in the disease mechanism by cross-reacting with antigens on the surface of muscle fibers.241 More worrisome is the prospect of statin-associated rhabdomyolysis.242 Indeed, increased cholesterol and triglyceride values are frequent in HIV-infected patients on ART, requiring therapy with statins with the aim of preventing cardiovascular complications. Most statins are metabolized by the liver cytochrome P-450 isoenzyme 3A4. Similarly, PIs are both substrates for and inhibitors of cytochrome P-450 iso­ enzyme 3A4 and substrates for P-glycoprotein, a bidirectional drug transporter that is also inhibited by statins to varying degrees. Pharmacokinetic studies have shown that PIs may greatly increase statin concentrations. Statin-associated rhabdomyolysis occurs within weeks from onset of treatment and may be fatal.243 HIV-infected patients on ART often complain of arthralgias, and cases of frozen shoulder, tendonitis, and temporomandibular joint

dysfunction have been described within a year of starting on indinavir. A survey using an anonymous questionnaire answered by 292 HIVinfected patients in Europe indicated that arthralgias were more frequent in patients taking PIs, especially indinavir (40.6%) or ritonavir plus saquinavir (41.9%) compared with non-nucleoside analogue reverse-transcriptase inhibitors (NNRTIs) (26.5%) or NRTIs (25.3%).244 Indinavir causes urolithiasis by crystallizing in the urinary tract, and indinavir crystals have been found in the joint fluid of patients with frozen shoulder. Temporary interruption of the PI or replacement with NNRTI should be considered on the basis of the patient’s discomfort, ART history, and HIV-1 genotype studies. The principal neuromuscular syndromes found in HIV-1 infection are listed in Table 127-4.

Seizures

HIV+ patients have an increased risk to develop seizure activity due to HIV-associated brain lesions and metabolic disturbances. The incidence of seizures depends on the degree of immunosuppression. CNS mass lesions and meningitis are the major causes of seizures, but no identifiable cause other than HIV-1 infection can be detected in up to 25% of cases.245 Unless a reversible cause can be readily identified and treated, anticonvulsant therapy should be initiated after the first seizure. Antiepileptic drugs (AEDs) and antiretrovirals can adversely affect each other when co-administered. The adverse effects can include breakthrough seizures, virologic failure, or drug toxicity. One of the recommendations is that it may be important to avoid cytochrome P-450 enzyme-inducing AEDs in people on antiretroviral regimens that include protease inhibitors or non-nucleoside reverse transcriptase inhibitors because pharmacokinetic interactions may result in virologic failure.246 This particularly applies to the older generation AEDs—primidone, phenytoin, phenobarbital, and carbamazepine. In addition, protein binding must be considered. Most AEDs and PIs are highly protein bound, as are other medications taken by HIVinfected patients such as trimethoprim-sulfamethoxazole. This may result in competition for available protein binding sites. Valproic acid and phenytoin commonly displace other drugs from albumin and thus may result in increased free drug levels, side effects, and toxicity. Conversely, PIs may also displace AEDs such as carbamazepine from protein binding sites and result in toxicity. There have been no studies of the outcome of seizure management in HIV-infected patients on ART. Until these data are available, clinicians should favor the use of AEDs that have no effect on the cytochrome P-450 system and have limited protein binding such as levetiracetam, lacosamide, gabapentin, and pregabalin.247 The choice of the AED or combination thereof depends on the type of seizure presented by the patient. In the case of status epilepticus or emergencies in which intravenous treatment is indicated, traditional AEDs such as phenytoin or phenobarbital should be used temporarily in the acute phase and should then be replaced by medications that have lower interaction potential with PIs once seizure control has been achieved. A summary of the principal neurologic complications of HIV infection is provided in Figure 127-6.

Temporal Trends and Aging in Neurologic Manifestations of   HIV Infection

The spectrum of CNS complications of HIV-1 diseases is constantly evolving, and both quantitative and qualitative changes have been noted in recent years.65,248 Patients are living longer with ART, but they may become resistant to antiretrovirals. The clinical presentation of known diseases such as PML may be altered by ART-induced immune reconstitution,149 and new entities, such as severe HIV-associated leukoencephalopathy, have been described in ART-experienced individuals.248,249 Expanded tropism of JCV to cerebellar neurons has been demonstrated, which may have implications in the pathogenesis of cerebellar atrophy occurring in HIV-infected individuals.250 In addition, PIs are associated with a marked increase in serum cholesterol and triglycerides. Therefore, long-term HIV-1-infected individuals are at increased risk of developing cerebrovascular events.250,251 Stroke usually occurs in younger patients infected with HIV-1 compared with

Chapter 127  Neurologic Diseases Caused by Human Immunodeficiency Virus Type 1 and Opportunistic Infections

flexors. This syndrome must be differentiated from HIV-1 wasting syndrome and may easily be overlooked in a population of debilitated patients who often present with generalized weakness. In addition, it may occur simultaneously with CNS or peripheral nervous system complications of HIV-1 infection. Laboratory Investigations.  There is a mild elevation of creatine phosphokinase in the serum (median, ≅500 IU/L), although creatine phosphokinase can be as high as 7500 IU/L in some cases.233 This may be an incidental finding that orients toward a diagnosis in cases in which muscle strength is still intact. The creatine phosphokinase level correlates with the degree of myonecrosis seen on a muscle biopsy specimen, but not with the weakness. Electrophysiologic Studies.  Electromyographic testing may reveal myopathic motor unit potentials with early recruitment and full interference patterns, predominantly in proximal muscles,234 but it can also be normal in 30% of the cases.233 Therefore, a normal electromyogram does not rule out this diagnosis. Muscle Biopsy.  The etiology of myopathy in AIDS has been a matter of debate235 because both HIV-1 and zidovudine have been incriminated as causative factors. In patients not treated with zidovudine presenting with myopathy, the most common finding is scattered myofiber degeneration, fibrosis, necrosis, and phagocytosis of muscle fibers associated with a variable inflammatory infiltrate similar to that seen in idiopathic polymyositis.233 HIV-1 does not seem to infect muscle fibers, and opportunistic organisms have been detected only exceptionally. Infiltrating cells are predominantly CD8+ T cells and macrophages.236 As is the case for DSPN and VM, it is possible that these cells secrete proinflammatory cytokines that may damage muscle fibers, precipitate muscle antigen exposure, and generate an autoimmune response.237 Interestingly, almost one half of patients with HIV-1 polymyositis also had diffuse infiltrative lymphocytosis syndrome. Because both conditions are extremely rare, their association is not likely to be coincidental.233 In zidovudine myopathy, biopsy results reveal numerous raggedred fibers and abnormal mitochondria.238 Zidovudine-induced mitochondrial toxicity is mediated through the inhibition of the enzyme γ-DNA polymerase, which is responsible for the replication of mitochondrial DNA. This induces an energy shortage within the muscle, which results in overt myopathy over time. Treatment.  Similar to idiopathic polymyositis, patients with HIV-1 polymyositis have had a favorable response with corticosteroids (prednisone 1 mg/kg/day) for an average of 9 months. However, the risk of long-term immunosuppressive therapy should be carefully considered in this population of patients. Other immunologically based therapies such as azathioprine, methotrexate, or intravenous immunoglobulin have also been successful.233 In zidovudine-induced myopathy, treatment consists of zidovudine withdrawal. Objective improvement in muscle strength is expected to occur in most patients after 8 weeks.239


1588

Part II  Major Clinical Syndromes

TABLE 127-4  Neuromuscular Syndromes in Human Immunodeficiency Virus Type–1 Infection DIAGNOSIS

DISEASE STAGE

CLINICAL FEATURES

DIAGNOSTIC STUDIES

AIDP

Early > late

Weakness more than sensory loss

CSF: ↑ WBCs

Early: IVIG, steroids, plasmapheresis

↑↑ Protein

CIDP

TREATMENT Late: consider ganciclovir/foscarnet

NCSs: demyelination MM

Nucleoside

Early or late

NCSs: multifocal axonal neuropathy

Early: none

Biopsy: inflammation/vasculitis

Late: steroids/cyclophosphamide

CMV

Ganciclovir/foscarnet

NCSs: distal axonopathy

Nucleoside withdrawal

Any stage

Distal sensory loss Neuropathic pain

Increased serum lactate

Late

Distal sensory loss

NCSs: distal axonopathy

NSAIDs, capsaicin

Neuropathy DSPN

Multiple painful mononeuropathies

Neuropathic pain

AED, tricyclics

PP

Late

Progressive flaccid paraparesis, urinary dysfunction, LS pain

CSF: increased WBCs (PMNs), CMV PCR+

Ganciclovir/foscarnet Cidofovir

DILS

Late

Sjögren’s syndrome, distal motor and sensory loss, pain

NCSs: axonal neuropathy Biopsy: CD8+ T cells, HIV-1

Zidovudine/ART Steroids

Zidovudine

Any stage

Proximal weakness

EMG: ± irritative

Zidovudine withdrawal

Myalgias

Biopsy: ragged red fibers

Proximal weakness

EMG: ± irritative

Steroids, IVIG

Myalgias

Biopsy: inflammatory infiltrates

Immunosuppressants

Weakness, dysphagia

EMG: neurogenic

ART

Myopathy Polymyositis ALS-like

Any stage Late

AED, antiepileptic drug; AIDP, acute inflammatory demyelinating polyneuropathy; ALS, amyotrophic lateral sclerosis; ART, antiretroviral therapy; CIDP, chronic inflammatory demyelinating polyneuropathy; CMV, cytomegalovirus; CSF, cerebrospinal fluid; DILS, diffuse infiltrative lymphocytosis syndrome; DSPN, distal sensory polyneuropathy; EMG, electromyography; HIV, human immunodeficiency virus; IVIG, intravenous immunoglobulin; LS, lumbosacral; MM, mononeuritis multiplex; NCS, nerve conduction studies; NSAID, nonsteroidal anti-inflammatory drug; PCR, polymerase chain reaction; PMNs, polymorphonuclear leukocytes; PP, progressive polyradiculopathy; WBCs, white blood cells.

CD4+ T-lymphocyte count Seroconversion

200-500/µL

>500/µL

<200/µL AIDS with Ols

Aseptic meningitis

Chronic meningitis

CNS

HAND Vacuolar myelopathy Mononeuritis (e.g., peripheral facial palsy) Inflammatory demyelinating polyneuropathy Mononeuritis multiplex

PNS

Distal sensory polyneuropathy Myopathy FIGURE 127-6  Occurrence of the principal neurologic complications of human immunodeficiency virus (HIV) type 1 infection according to the degree of immunosuppression as measured by CD4+ T-lymphocyte counts (see text for details). AIDS, acquired immunodeficiency virus; CNS, central nervous system; HAND, HIV-associated neurocognitive disorder; OIs, opportunistic infections; PNS, peripheral nervous system.

HIV-negative individuals, and, in some cases, it may be caused by a vasculopathy.252 As this population becomes older, age-related entities are expected to overlap with HIV-associated and treatment-associated neurologic conditions and add another layer of complexity to management of these patients.253,254 Not surprisingly, older age and diabetes were associated with increased frequency of dementia in HIV-infected patients.255,256 In

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addition, cerebral small-vessel ischemic vascular disease may cause white matter lesions and cortical atrophy, thus compounding the effect of HIV on the CNS of older patients.257 Because of these trends and the fact that new clinical entities may potentially warrant different treatments, a brain biopsy should be considered in cases in which molecular diagnosis cannot be obtained, and postmortem analysis should be sought for all patients who did not respond to treatment.

6. Maschke M, Kastrup O, Esser S, et al. Incidence and prevalence of neurological disorders associated with HIV since the introduction of highly active antiretroviral therapy (HAART). J Neurol Neurosurg Psychiatry. 2000;69:376-380. 14. Ghanem KG, Moore RD, Rompalo AM, et al. Neurosyphilis in a clinical cohort of HIV-1-infected patients. AIDS. 2008;22:1145-1151.

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Chapter 127  Neurologic Diseases Caused by Human Immunodeficiency Virus Type 1 and Opportunistic Infections

23a.  Perfect JR, Dismukes WE, Dromer F, et al. Practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010;50:291-322. 29. Manosuthi W, Sungkanuparph S, Chottanapund S, et al. Temporary external lumbar drainage for reducing elevated intracranial pressure in HIV-infected patients with cryptococcal meningitis. Int J STD AIDS. 2008;19:268-271. 40. McArthur JC, Steiner J, Sacktor N, Nath A. Human immunodeficiency virus-associated neurocognitive disorders: mind the gap. Ann Neurol. 2010;67:699-714. 42. Sakamoto M, Marcotte TD, Umlauf A, et al. Concurrent classification accuracy of the HIV dementia scale for HIVassociated neurocognitive disorders in the CHARTER Cohort. J Acquir Immune Defic Syndr. 2013;62:36-42. 43. Valcour V, Paul R, Chiao S, et al. Screening for cognitive impairment in human immunodeficiency virus. Clin Infect Dis. 2011;53:836-842. 44. Sacktor NC, Wong M, Nakasujja N, et al. The International HIV Dementia Scale: a new rapid screening test for HIV dementia. AIDS. 2005;19:1367-1374. 51. Spudich SS, Ances BM. Central nervous system com­ plications of HIV infection. Top Antivir Med. 2011;19: 48-57. 52. Ellis RJ, Moore DJ, Childers ME, et al. Progression to neuropsychological impairment in human immunodeficiency virus infection predicted by elevated cerebrospinal fluid levels of human immunodeficiency virus RNA. Arch Neurol. 2002;59:923-928. 55. Churchill MJ, Wesselingh SL, Cowley D, et al. Extensive astrocyte infection is prominent in human immunodeficiency virus-associated dementia. Ann Neurol. 2009;66: 253-258. 61. Spudich S, Gisslen M, Hagberg L, et al. Central nervous system immune activation characterizes primary human immunodeficiency virus 1 infection even in participants with minimal cerebrospinal fluid viral burden. J Infect Dis. 2011;204:753-760. 62. Letendre SL, Marquie-Beck J, Capparelli E, et al. Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol. 2008;65:65-70. 65. Gray F, Chretien F, Vallat-Decouvelaere AV, et al. The changing pattern of HIV neuropathology in the HAART era. J Neuropathol Exp Neurol. 2003;62:429-440. 70. Ciccarelli N, Fabbiani M, Colafigli M, et al. Revised central nervous system neuropenetration-effectiveness score is associated with cognitive disorders in HIV-infected


1589.e1

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Part II  Major Clinical Syndromes

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126. Gray F, Geny C, Lescs MC, et al. [AIDS-related progressive multifocal leukoencephalopathy limited to U fibers, responsible for subacute encephalopathy with normal CT scan findings]. Arch Anat Cytol Pathol. 1992;40:132-137. 127. Chang L, Ernst T, Tornatore C, et al. Metabolite abnor­ malities in progressive multifocal leukoencephalopathy by proton magnetic resonance spectroscopy. Neurology. 1997; 48:836-845. 128. Chang L, Miller BL, McBride D, et al. Brain lesions in patients with AIDS: H-1 MR spectroscopy. Radiology. 1995;197:525-531. 129. Simone IL, Federico F, Tortorella C, et al. Localised 1H-MR spectroscopy for metabolic characterisation of diffuse and focal brain lesions in patients infected with HIV. J Neurol Neurosurg Psychiatry. 1998;64:516-523. 130. Iranzo A, Moreno A, Pujol J, et al. Proton magnetic resonance spectroscopy pattern of progressive multifocal leukoencephalopathy in AIDS. J Neurol Neurosurg Psychiatry. 1999;66:520-523. 131. Katz-Brull R, Lenkinski RE, Du Pasquier RA, et al. Elevation of myo-inositol is associated with disease containment in PML. Neurology. 2004;63:897-900. 132. Cinque P, Koralnik IJ, Clifford D. The evolving face of progressive multifocal leukoencephalopathy: towards the definition of a consensus terminology. J Neurovirol. 2003;9: 88-92. 133. Hall CD, Dafni U, Simpson D, et al. Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. AIDS Clinical Trials Group 243 Team. N Engl J Med. 1998;338: 1345-1351. 134. Geschwind MD, Skolasky RI, Royal WS, et al. The relative contributions of HAART and alpha-interferon for therapy of progressive multifocal leukoencephalopathy in AIDS. J Neurovirol. 2001;7:353-357. 135. Royal W 3rd, Dupont B, McGuire D, et al. Topotecan in the treatment of acquired immunodeficiency syndromerelated progressive multifocal leukoencephalopathy. J Neurovirol. 2003;9:411-419. 136. Marra CM, Rajicic N, Barker DE, et al. A pilot study of cidofovir for progressive multifocal leukoencephalopathy in AIDS. AIDS. 2002;16:1791-1797. 137. De Luca A, Ammassari A, Pezzotti P, et al; Gesida 9/99, IRINA, ACTG 363 Study Groups. Cidofovir in addition to antiretroviral treatment is not effective for AIDS-associated progressive multifocal leukoencephalopathy: a multicohort analysis. AIDS. 2008;22:1759-1767. 138. Clifford DB, Nath A, Cinque P, et al. A study of mefloquine treatment for progressive multifocal leukoencephalopathy: results and exploration of predictors of PML outcomes. J Neurovirol. 2013;19:351-358. 139. Elphick GF, Querbes W, Jordan JA, et al. The human polyomavirus, JCV, uses serotonin receptors to infect cells. Science. 2004;306:1380-1383. 140. Verma S, Cikurel K, Koralnik IJ, et al. Mirtazapine in progressive multifocal leukoencephalopathy associated with polycythemia vera. J Infect Dis. 2007;196:709-711. 141. Tantisiriwat W, Tebas P, Clifford DB, et al. Progressive multifocal leukoencephalopathy in patients with AIDS receiving highly active antiretroviral therapy. Clin Infect Dis. 1999;28:1152-1154. 142. Marzocchetti A, Tompkins T, Clifford DB, et al. Determinants of survival in progressive multifocal leukoencephalopathy. Neurology. 2009;73:1551-1558. 143. Du Pasquier RA, Clark KW, Smith PS, et al. JCV-specific cellular immune response correlates with a favorable clinical outcome in HIV-infected individuals with progressive multifocal leukoencephalopathy. J Neurovirol. 2001;7:318322. 144. Koralnik IJ, Du Pasquier RA, Kuroda MJ, et al. Association of prolonged survival in HLA-A2+ progressive multifocal leukoencephalopathy patients with a CTL response specific for a commonly recognized JC virus epitope. J Immunol. 2002;168:499-504. 145. Du Pasquier RA, Kuroda MJ, Schmitz JE, et al. Low frequency of cytotoxic T lymphocytes against the novel HLAA*0201-restricted JC virus epitope VP1p36 in patients with proven or possible progressive multifocal leukoencephalopathy. J Virol. 2003;77:11918-11926. 146. Gheuens S, Bord E, Kesari S, et al. Role of CD4+ and CD8+ T-cell responses against JC virus in the outcome of patients with progressive multifocal leukoencephalopathy (PML) and PML with immune reconstitution inflammatory syndrome. J Virol. 2011;85:7256-7263. 147. Marzocchetti A, Lima M, Tompkins T, et al. Efficient in vitro expansion of JC virus-specific CD4+ T cell responses by JCV peptide-stimulated dendritic cells from patients with progressive multifocal leukoencephalopathy. Virology. 2009;383:173-177. 148. Falcó V, Olmo M, del Saz SV, et al. Influence of HAART on the clinical course of HIV-1-infected patients with progressive multifocal leukoencephalopathy: results of an observational multicenter study. J Acquir Immune Defic Syndr. 2008;49:26-31.


1589.e3 to highly active antiretroviral therapy. AIDS. 2002;16: 2367-2369. 175. Feki I, Belahsen F, Ben Jemaa M, et al. [Subacute myelitis revealed by human immunodeficiency virus infection]. Rev Neurol (Paris). 2003;159:577-580. 176. Gessain A, Gout O. Chronic myelopathy associated with human T-lymphotropic virus type I (HTLV-I). Ann Intern Med. 1992;117:933-946. 177. Berger JR, Sabet A. Infectious myelopathies. Semin Neurol. 2002;22:133-142. 178. Brannagan TH 3rd, Zhou Y. HIV-associated Guillain-Barre syndrome. J Neurol Sci. 2003;208:39-42. 179. Cornblath DR, McArthur JC, Kennedy PG, et al. Inflammatory demyelinating peripheral neuropathies associated with human T-cell lymphotropic virus type III infection. Ann Neurol. 1987;21:32-40. 180. Miller RG, Parry GJ, Pfaeffl W, et al. The spectrum of peripheral neuropathy associated with ARC and AIDS. Muscle Nerve. 1988;11:857-863. 181. Piliero PJ, Fish DG, Preston S, et al. Guillain-Barre syndrome associated with immune reconstitution. Clin Infect Dis. 2003;36:111-114. 182. Morgello S, Simpson DM. Multifocal cytomegalovirus demyelinative polyneuropathy associated with AIDS. Muscle Nerve. 1994;17:176-182. 183. Leger JM, Bouche P, Bolgert F, et al. The spectrum of polyneuropathies in patients infected with HIV. J Neurol Neurosurg Psychiatry. 1989;52:1369-1374. 184. Kiprov D, Pfaeffl W, Parry G, et al. Antibody-mediated peripheral neuropathies associated with ARC and AIDS: successful treatment with plasmapheresis. J Clin Apheresis. 1988;4:3-7. 185. Schifitto G, McDermott MP, McArthur JC, et al. Incidence of and risk factors for HIV-associated distal sensory polyneuropathy. Neurology. 2002;58:1764-1768. 186. Ellis RJ, Rosario D, Clifford DB, et al. Continued high prevalence and adverse clinical impact of human immunodeficiency virus-associated sensory neuropathy in the era of combination antiretroviral therapy: the CHARTER Study. Arch Neurol. 2010;67:552-558. 187. Keswani SC, Pardo CA, Cherry CL, et al. HIV-associated sensory neuropathies. AIDS. 2002;16:2105-2117. 188. Evans SR, Ellis RJ, Chen H, et al. Peripheral neuropathy in HIV: prevalence and risk factors. AIDS. 2011;25: 919-928. 189. Anziska Y, Helzner EP, Crystal H, et al. The relationship between race and HIV-distal sensory polyneuropathy in a large cohort of US women. J Neurol Sci. 2012;315: 129-132. 190. Zhou L, Kitch DW, Evans SR, et al. Correlates of epidermal nerve fiber densities in HIV-associated distal sensory polyneuropathy. Neurology. 2007;68:2113-2119. 191. Bradley WG, Shapshak P, Delgado S, et al. Morphometric analysis of the peripheral neuropathy of AIDS. Muscle Nerve. 1998;21:1188-1195. 192. Rance NE, McArthur JC, Cornblath DR, et al. Gracile tract degeneration in patients with sensory neuropathy and AIDS. Neurology. 1988;38:265-271. 193. Tyor WR, Wesselingh SL, Griffin JW, et al. Unifying hypothesis for the pathogenesis of HIV-associated dementia complex, vacuolar myelopathy, and sensory neuropathy. J Acquir Immune Defic Syndr Hum Retrovirol. 1995;9: 379-388. 194. Herzberg U, Sagen J. Peripheral nerve exposure to HIV viral envelope protein gp120 induces neuropathic pain and spinal gliosis. J Neuroimmunol. 2001;116:29-39. 195. Browne MJ, Mayer KH, Chafee SB, et al. 2’,3’-Didehydro3’-deoxythymidine (d4T) in patients with AIDS or AIDSrelated complex: a phase I trial. J Infect Dis. 1993;167: 21-29. 196. Pollard RB, Peterson D, Hardy D, et al. Safety and antiretroviral effects of combined didanosine and stavudine therapy in HIV-infected individuals with CD4 counts of 200 to 500 cells/mm3. J Acquir Immune Defic Syndr. 1999; 22:39-48. 197. Berger AR, Arezzo JC, Schaumburg HH, et al. 2’,3’Dideoxycytidine (ddC) toxic neuropathy: a study of 52 patients. Neurology. 1993;43:358-362. 198. Brew BJ, Tisch S, Law M. Lactate concentrations distinguish between nucleoside neuropathy and HIV neuropathy. AIDS. 2003;17:1094-1096. 199. Paice JA, Ferrans CE, Lashley FR, et al. Topical capsaicin in the management of HIV-associated peripheral neuropathy. J Pain Symptom Manage. 2000;19:45-52. 200. Simpson DM, Brown S, Tobias J, et al. Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy. Neurology. 2008;70:2305-2313. 201. Dorfman D, Dalton A, Khan A, et al. Treatment of painful distal sensory polyneuropathy in HIV-infected patients with a topical agent: results of an open-label trial of 5% lidocaine gel. AIDS. 1999;13:1589-1590. 202. La Spina I, Porazzi D, Maggiolo F, et al. Gabapentin in painful HIV-related neuropathy: a report of 19 patients, preliminary observations. Eur J Neurol. 2001;8:71-75.

203. Simpson DM, McArthur JC, Olney R, et al. Lamotrigine for HIV-associated painful sensory neuropathies: a placebo-controlled trial. Neurology. 2003;60:1508-1514. 204. Kieburtz K, Simpson D, Yiannoutsos C, et al. A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. Neurology. 1998;51:1682-1688. 205. Mendell JR, Sahenk Z. Clinical practice: painful sensory neuropathy. N Engl J Med. 2003;348:1243-1255. 206. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007;68:515-521. 207. Phillips TJ, Cherry CL, Cox S, et al. Pharmacological treatment of painful HIV-associated sensory neuropathy: a systematic review and meta-analysis of randomised controlled trials. PloS One. 2010;5:e14433. 208. Simpson DM. Selected peripheral neuropathies associated with human immunodeficiency virus infection and antiretroviral therapy. J Neurovirol. 2002;8:33-41. 209. Gonzalez-Duarte A, Robinson-Papp J, Simpson DM. Diagnosis and management of HIV-associated neuropathy. Neurol Clin. 2008;26:821-832. 210. Famularo G, Moretti S, Marcellini S, et al. Acetyl-carnitine deficiency in AIDS patients with neurotoxicity on treatment with antiretroviral nucleoside analogues. AIDS. 1997; 11:185-190. 211. Simpson DM, Katzenstein D, Haidich B, et al. Plasma carnitine in HIV-associated neuropathy. AIDS. 2001;15: 2207-2208. 212. Simpson DM, Olney RK. Peripheral neuropathies associated with human immunodeficiency virus infection. Neurol Clin. 1992;10:685-711. 213. Stricker RB, Sanders KA, Owen WF, et al. Mononeuritis multiplex associated with cryoglobulinemia in HIV infection. Neurology. 1992;42:2103-2105. 214. Said G, Lacroix C, Chemouilli P, et al. Cytomegalovirus neuropathy in acquired immunodeficiency syndrome: a clinical and pathological study. Ann Neurol. 1991;29: 139-146. 215. Schifitto G, Barbano RL, Kieburtz KD, et al. HIV related vasculitic mononeuropathy multiplex: a role for IVIg? J Neurol Neurosurg Psychiatry. 1997;63:255-256. 216. Kolson DL, Gonzalez-Scarano F. HIV-associated neuropathies: role of HIV-1, CMV, and other viruses. J Peripher Nerv Syst. 2001;6:2-7. 217. So YT, Olney RK. Acute lumbosacral polyradiculopathy in acquired immunodeficiency syndrome: experience in 23 patients. Ann Neurol. 1994;35:53-58. 218. de Gans J, Portegies P, Tiessens G, et al. Therapy for cytomegalovirus polyradiculomyelitis in patients with AIDS: treatment with ganciclovir. AIDS. 1990;4:421-425. 219. McCutchan JA. Cytomegalovirus infections of the nervous system in patients with AIDS. Clin Infect Dis. 1995;20: 747-754. 220. Smith IL, Shinkai M, Freeman WR, et al. Polyradiculopathy associated with ganciclovir-resistant cytomegalovirus in an AIDS patient: phenotypic and genotypic characterization of sequential virus isolates. J Infect Dis. 1996;173: 1481-1484. 221. Authier FJ, Gheradi RK. Peripheral neuropathies in HIVinfected patients in the era of HAART. Brain Pathol. 2003; 13:223-228. 222. Moulignier A, Authier FJ, Baudrimont M, et al. Peripheral neuropathy in human immunodeficiency virus-infected patients with the diffuse infiltrative lymphocytosis syndrome. Ann Neurol. 1997;41:438-445. 223. Gherardi RK, Chretien F, Delfau-Larue MH, et al. Neuropathy in diffuse infiltrative lymphocytosis syndrome: an HIV neuropathy, not a lymphoma. Neurology. 1998;50: 1041-1044. 224. Basu D, Williams FM, Ahn CW, et al. Changing spectrum of the diffuse infiltrative lymphocytosis syndrome. Arthritis Rheum. 2006;55:466-472. 225. Moulignier A, Moulonguet A, Pialoux G, et al. Reversible ALS-like disorder in HIV infection. Neurology. 2001;57: 995-1001. 226. MacGowan DJ, Scelsa SN, Waldron M. An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy. Neurology. 2001;57:1094-1097. 227. Verma A, Berger JR. ALS syndrome in patients with HIV-1 infection. J Neurol Sci. 2006;240:59-64. 228. MacGowan DJ, Scelsa SN, Imperato TE, et al. A controlled study of reverse transcriptase in serum and CSF of HIV-negative patients with ALS. Neurology. 2007;68: 1944-1946. 229. McCormick AL, Brown RH Jr, Cudkowicz ME, et al. Quantification of reverse transcriptase in ALS and elimination of a novel retroviral candidate. Neurology. 2008;70: 278-283. 230. Zoccolella S, Carbonara S, Minerva D, et al. A case of concomitant amyotrophic lateral sclerosis and HIV infection. Eur J Neurol. 2002;9:180-182. 231. Jubelt B, Berger JR. Does viral disease underlie ALS? Lessons from the AIDS pandemic. Neurology. 2001;57: 945-946.

Chapter 127  Neurologic Diseases Caused by Human Immunodeficiency Virus Type 1 and Opportunistic Infections

149. Du Pasquier RA, Koralnik IJ. Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? J Neurovirol. 2003;9:25-31. 150. Vendrely A, Bienvenu B, Gasnault J, et al. Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy. Acta Neuropathol. 2005;109:449-455. 151. Gheuens S, Ngo L, Wang X, et al. Metabolic profile of PML lesions in patients with and without IRIS: an observational study. Neurology. 2012;79:1041-1048. 152. Morgello S, Cho ES, Nielsen S, et al. Cytomegalovirus encephalitis in patients with acquired immunodeficiency syndrome: an autopsy study of 30 cases and a review of the literature. Hum Pathol. 1987;18:289-297. 153. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med. 1997;337:725-733. 154. Arribas JR, Storch GA, Clifford DB, et al. Cytomegalovirus encephalitis. Ann Intern Med. 1996;125:577-587. 155. Cinque P, Vago L, Brytting M, et al. Cytomegalovirus infection of the central nervous system in patients with AIDS: diagnosis by DNA amplification from cerebrospinal fluid. J Infect Dis. 1992;166:1408-1411. 156. Holland NR, Power C, Mathews VP, et al. Cytomegalovirus encephalitis in acquired immunodeficiency syndrome (AIDS). Neurology. 1994;44:507-514. 157. Clifford DB, Arribas JR, Storch GA, et al. Magnetic resonance brain imaging lacks sensitivity for AIDS associated cytomegalovirus encephalitis. J Neurovirol. 1996;2: 397-403. 158. Whitley RJ, Jacobson MA, Friedberg DN, et al. Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. International AIDS Society—USA. Arch Intern Med. 1998;158:957-969. 159. Levy RM, Russell E, Yungbluth M, et al. The efficacy of image-guided stereotactic brain biopsy in neurologically symptomatic acquired immunodeficiency syndrome patients. Neurosurgery. 1992;30:186-190. 160. Holloway RG, Mushlin AI. Intracranial mass lesions in acquired immunodeficiency syndrome: using decision analysis to determine the effectiveness of stereotactic brain biopsy. Neurology. 1996;46:1010-1015. 161. Antinori A, Ammassari A, De Luca A, et al. Diagnosis of AIDS-related focal brain lesions: a decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase chain reaction assays in CSF. Neurology. 1997;48:687-694. 162. Antinori A, Ammassari A, Luzzati R, et al. Role of brain biopsy in the management of focal brain lesions in HIVinfected patients. Gruppo Italiano Cooperativo AIDS & Tumori. Neurology. 2000;54:993-997. 163. Marra CM, Lockhart D, Zunt JR, et al. Changes in CSF and plasma HIV-1 RNA and cognition after starting potent antiretroviral therapy. Neurology. 2003;60:1388-1390. 164. Petito CK, Navia BA, Cho ES, et al. Vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1985;312:874-879. 165. Henin D, Smith TW, De Girolami U, et al. Neuropathology of the spinal cord in the acquired immunodeficiency syndrome. Hum Pathol. 1992;23:1106-1114. 166. Dal Pan GJ, Glass JD, McArthur JC. Clinicopathologic correlations of HIV-1-associated vacuolar myelopathy: an autopsy-based case-control study. Neurology. 1994;44: 2159-2164. 167. Geraci A, Di Rocco A, Liu M, et al. AIDS myelopathy is not associated with elevated HIV viral load in cerebrospinal fluid. Neurology. 2000;55:440-442. 168. Thurnher MM, Post MJ, Jinkins JR. MRI of infections and neoplasms of the spine and spinal cord in 55 patients with AIDS. Neuroradiology. 2000;42:551-563. 169. Rottnek M, Di Rocco A, Laudier D, et al. Axonal damage is a late component of vacuolar myelopathy. Neurology. 2002;58:479-481. 170. Shepherd EJ, Brettle RP, Liberski PP, et al. Spinal cord pathology and viral burden in homosexuals and drug users with AIDS. Neuropathol Appl Neurobiol. 1999;25:2-10. 171. Di Rocco A, Bottiglieri T, Werner P, et al. Abnormal cobalamin-dependent transmethylation in AIDSassociated myelopathy. Neurology. 2002;58:730-735. 172. Di Rocco A, Tagliati M, Danisi F, et al. A pilot study of L-methionine for the treatment of AIDS-associated myelopathy. Neurology. 1998;51:266-268. 173. Staudinger R, Henry K. Remission of HIV myelopathy after highly active antiretroviral therapy. Neurology. 2000; 54:267-268. 174. Eyer-Silva WA, Couto-Fernandez JC, Caetano MR, et al. Remission of HIV-associated myelopathy after initiation of lopinavir in a patient with extensive previous exposure


Part IIâ&#x20AC;&#x201A; Major Clinical Syndromes

1589.e4 232. Peters BS, Winer J, Landon DN, et al. Mitochondrial myopathy associated with chronic zidovudine therapy in AIDS. Q J Med. 1993;86:5-15. 233. Johnson RW, Williams FM, Kazi S, et al. Human immunodeficiency virus-associated polymyositis: a longitudinal study of outcome. Arthritis Rheum. 2003;49:172-178. 234. Simpson DM, Citak KA, Godfrey E, et al. Myopathies associated with human immunodeficiency virus and zidovudine: can their effects be distinguished? Neurology. 1993; 43:971-976. 235. Dalakas M. HIV or zidovudine myopathy? Neurology. 1994;44:360-361; author reply, 362-364. 236. Illa I, Nath A, Dalakas M. Immunocytochemical and virological characteristics of HIV-associated inflammatory myopathies: similarities with seronegative polymyositis. Ann Neurol. 1991;29:474-481. 237. Dalakas MC. Clinical, immunopathologic, and therapeutic considerations of inflammatory myopathies. Clin Neuropharmacol. 1992;15:327-351. 238. Dalakas MC, Illa I, Pezeshkpour GH, et al. Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med. 1990;322:1098-1105. 239. Grau JM, Masanes F, Pedrol E, et al. Human immunodeficiency virus type 1 infection and myopathy: clinical relevance of zidovudine therapy. Ann Neurol. 1993;34:206-211. 240. Sheikh RA, Yasmeen S, Munn R, et al. AIDS-related myopathy. Med Electron Microsc. 1999;32:79-86. 241. Dalakas MC, Rakocevic G, Shatunov A, et al. Inclusion body myositis with human immunodeficiency virus infection: four cases with clonal expansion of viral-specific T cells. Ann Neurol. 2007;61:466-475.

242. Omar MA, Wilson JP. FDA adverse event reports on statinassociated rhabdomyolysis. Ann Pharmacother. 2002;36: 288-295. 243. Hare CB, Vu MP, Grunfeld C, et al. Simvastatin-nelfinavir interaction implicated in rhabdomyolysis and death. Clin Infect Dis. 2002;35:e111-e112. 244. Florence E, Schrooten W, Verdonck K, et al. Rheumatological complications associated with the use of indinavir and other protease inhibitors. Ann Rheum Dis. 2002;61:82-84. 245. Modi G, Modi M, Martinus I, et al. New-onset seizures associated with HIV infection. Neurology. 2000;55:15581561. 246. Birbeck GL, French JA, Perucca E, et al. Evidence-based guideline: antiepileptic drug selection for people with HIV/ AIDS: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Ad Hoc Task Force of the Commission on Therapeutic Strategies of the International League Against Epilepsy. Neurology. 2012;78: 139-145. 247. Siddiqi O, Birbeck GL. Safe treatment of seizures in the setting of HIV/AIDS. Curr Treat Options Neurol. 2013;15: 529-543. 248. Langford TD, Letendre SL, Larrea GJ, et al. Changing patterns in the neuropathogenesis of HIV during the HAART era. Brain Pathol. 2003;13:195-210. 249. Langford TD, Letendre SL, Marcotte TD, et al. Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy. AIDS. 2002;16:1019-1029. 250. Du Pasquier RA, Corey S, Margolin DH, et al. Productive infection of cerebellar granule cell neurons by JC virus in an HIV+ individual. Neurology. 2003;61:775-782.

251. Vinikoor MJ, Napravnik S, Floris-Moore M, et al. Incidence and clinical features of cerebrovascular disease among HIV-infected adults in the southeastern United States. AIDS Res Human Retroviruses. 2013;29: 1068-1074. 252. Tipping B, de Villiers L, Wainwright H, et al. Stroke in patients with human immunodeficiency virus infection. J Neurol Neurosurg Psychiatry. 2007;78:1320-1324. 253. Morgello S, Mahboob R, Yakoushina T, et al. Autopsy findings in a human immunodeficiency virus-infected population over 2 decades: influences of gender, ethnicity, risk factors, and time. Arch Pathol Lab Med. 2002;126: 182-190. 254. Goodkin K, Wilkie FL, Concha M, et al. Aging and neuroAIDS conditions and the changing spectrum of HIV-1â&#x20AC;&#x201C; associated morbidity and mortality. J Clin Epidemiol. 2001; 54:S35-S43. 255. Valcour V, Shikuma C, Shiramizu B, et al. Higher frequency of dementia in older HIV-1 individuals: the Hawaii Aging with HIV-1 Cohort. Neurology. 2004;63: 822-827. 256. Valcour VG, Shikuma CM, Shiramizu BT, et al. Diabetes, insulin resistance, and dementia among HIV-1-infected patients. J Acquir Immune Defic Syndr. 2005;38:31-36. 257. McMurtray A, Nakamoto B, Shikuma C, et al. Cortical atrophy and white matter hyperintensities in HIV: the Hawaii Aging with HIV Cohort Study. J Stroke Cerebrovasc Dis. 2008;17:212-217.


J  Diseases Due to Helminths

287 

Introduction to Helminth Infections James H. Maguire*

The helminthiases are among the most prevalent infections in the world and a leading cause of morbidity, particularly in low-income and resource-constrained regions. More than one billion persons harbor at least one species of parasitic worm.1,2 The helminths that parasitize humans include the nematodes (roundworms) and platyhelminths (flatworms); the latter group consists of cestodes (tapeworms) and trematodes (schistosomes and other flukes). Leeches, ectoparasites belonging to the phylum Annelida (segmented worms), are not discussed here (see Chapter 293). Some helminths are exclusively or primarily human parasites, whereas others parasitize both humans and various other mammals, and others are parasites of lower mammals and infect human beings incidentally.

BIOLOGY OF HELMINTHS

Helminths are multicellular organisms that range from less than 1 cm to more than 10 m in length. They are covered by a cuticle or tegument that protects them from digestion and environmental stresses. Reproductive organs take up a large part of the body regardless of whether the sexes are separate or the species is hermaphroditic, as is the case with cestodes and nonschistosomal trematodes. Neuromuscular, digestive, excretory, and secretory systems typically are smaller and less complex, in keeping with the parasitic state. The life cycle of all worms includes an egg, one or more larval stages, and the adult. Transmission to humans occurs by ingestion of helminth eggs or larvae, penetration of intact skin by larvae, or inoculation of larvae by biting insects. Depending on the species, humans are the only host; the intermediate host, in which asexual reproduction takes place; or, when there are one or two intermediate hosts, the definitive host in which sexual reproduction occurs. Most helminths are unable to complete their life cycle within the human host, and development of eggs or larvae on soil, in water, within a plant, arthropod, or other animal intermediate host is necessary. Hence, the geographic distribution of these parasites reflects the environ­ mental conditions necessary for development of eggs or larvae or for survival of intermediate hosts and vectors. The only way for the intensity of infection in a person to increase is by further exposure to the infective stage; in the absence of continued exposure, the infection lasts only as long as the life span of the adult worm. In contrast, a few species, most notably Strongyloides stercoralis, are able to reproduce and multiply in numbers within the definitive human host. In the case of Strongyloides, infectious larvae can be passed directly from one person to another, and transmission is possible in all geographic areas. Infection can persist for the life span of the host, and in the setting of immunosuppression, accelerated autoinfection can lead to overwhelming numbers of organisms even after a distant and light exposure.

EPIDEMIOLOGY

The prevalence of helminth disease is highest in warm, developing areas, where climate, environment, and an abundance of vectors favor *This chapter is based in part on the chapter by Adel A.F. Mahmoud in the fifth edition. All material in this chapter is in the public domain, with the exception of any borrowed figures or tables.

3196

completion of the life cycle and where poverty leads to increased exposure to parasites because of poor sanitation, lack of clean water, and inadequate housing. Human activity can facilitate transmission, as seen in the huge numbers of new cases of schistosomiasis and foodborne trematode infections resulting from water resource development projects for hydroelectric power, irrigation, and aquaculture.3,4 Conversely, in some endemic areas, large-scale control programs have led to interruption or dramatically decreased transmission of dracunculiasis (guinea worm disease), filariasis, onchocerciasis, and other parasitic worms.5 Helminth infections are less common in temperate and industrialized areas, where they have been imported after travel or residence in tropical areas or acquired locally from domestic or wild animals, via improperly prepared meat, fish, or vegetables, or from close personal contact, as in the case of pinworm infections. Helminths produce large numbers of eggs or larvae and have a high reproductive capacity, which can lead to an extremely high prevalence of human infection when conditions are conducive to transmission, such as in rural areas in the tropics. Helminths are not uniformly distributed in human populations but are overdispersed, with most infected individuals harboring low worm burdens and only a small number harboring heavy infections.6 The basis for aggregation of helminths in human populations may be related to the intrinsic biology of the parasites and density-dependent constraints on parasites, such as competition for nutrients, parasite-induced pathology, and host factors, including genetic susceptibility to infection, immunity, nutrition, and behavioral factors.

PATHOGENESIS AND HOST-PARASITE RELATIONSHIP

Most infected persons harbor few worms and have few or no signs or symptoms of disease, whereas a small proportion of persons with large numbers of worms are at risk of severe disease. Children with even moderate numbers of worms may be at risk of malnutrition, impaired growth, and impaired intellectual development.7,8 Polyparasitism is widespread throughout the tropics and subtropics, and infection with multiple species of helminths seems to have an additive or multiplicative effect on nutrition and pathology.9 Although mortality rates attributable to helminth infections are low, rates of chronic morbidity and debilitation are substantial. Helminths produce disease by a variety of mechanisms, including mechanical effects such as intestinal obstruction (e.g., ascariasis), invasion of host cells or tissues with damage or loss of function (e.g., trichinellosis), or competition for nutrients (e.g., vitamin B12 deficiency from fish tapeworm infection). The host responses may lead to immunopathologic lesions, such as schistosome egg granulomas, which contribute significantly to disease. Interactions with other pathogens or potential carcinogens may contribute to chronic sequelae, such as advanced liver disease associated with coinfection of hepatitis B or C with Schistosoma mansoni or bladder cancer associated with Schistosoma haematobium.10 Basic to understanding the pathogenesis of helminthiasis is an appreciation of the size of the organisms, the multiplicity of their antigens, and the chronicity of the infection. Host responses are composed of myriad immunologic and nonimmunologic factors, some of which


3196.e1

KEYWORDS

Chapter 287â&#x20AC;&#x201A; Introduction to Helminth Infections

anthelmintics; cestodes; disease elimination or eradication; eosinophilia; helminths; mass drug administration; nematodes; parasitism; trematodes


3197 as malaria and human immunodeficiency virus/acquired immunodeficiency syndrome.15,16 Helminth infections may affect the expression of allergic disease and, in some studies, were associated with decreased risk of asthma and other atopic conditions, although other studies showed increased or no risk.17,18 Worms have successfully developed multiple strategies to evade host protective responses. Mechanisms include encapsulation within a host fibrous reaction (hydatid cyst), intraluminal location (e.g., Ascaris), inhibition and modulation of the immune response (filariae, cysticerci), and acquisition of host antigens (schistosomes).

DIAGNOSIS AND TREATMENT OF HELMINTH INFECTIONS

Recognition of helminth infections requires knowledge of their clinical presentation, geographic distribution, and epidemiologic risk factors. Persons with light infections may be asymptomatic, and the only clues to diagnosis may be a history of travel and potential exposure to the parasite as well as peripheral blood eosinophilia. It should be kept in mind, however, that eosinophilia may be absent, even in persons with invasive infections. The diagnosis of helminth infections rests heavily on microscopic examination of stool, urine, blood, other body fluids, and tissue (Table 287-1).19,20 When eggs or larvae are produced in

TABLE 287-1â&#x20AC;&#x192; Diagnosis of Major Helminth Infections MICROSCOPIC DIAGNOSIS Specimen

PARASITE Roundworms (Nematodes) Intestinal Roundworms

Stage

OTHER METHODS

Ascaris lumbricoides (large intestinal roundworm)

Eggs

Feces

Trichuris trichiura (whipworm)

Eggs

Feces

Ancylostoma duodenale, Necator americanus (hookworm)

Eggs, larvae

Feces

Strongyloides stercoralis (threadworm)

Larvae

Feces, duodenal fluid, sputum

Serology*

Enterobius vermicularis (pinworm)

Eggs

Swab of perianal skin; occasionally in feces

Cellophane tape test; identification of adult worms on skin

Larvae

Muscle biopsy

Serology*

Wuchereria bancrofti, Brugia malayi (lymphatic filariasis)

Microfilariae

Blood, urine (in setting of chyluria)

Serology,* antigen test (blood)

Loa loa (African eye worm)

Microfilariae

Blood

Identification of adult worm in eye, serology

Onchocerca volvulus (river blindness)

Microfilariae

Skin snip

Identification of adult worm in resected nodules

Identification of passed worm

Tissue Roundworms Trichinella spiralis (trichinellosis) Dracunculus medinensis (guinea worm)

Identification of emergent adult worm

Ancylostoma braziliense, other species (cutaneous larva migrans, creeping eruption) Toxocara canis, Toxocara cati (visceral larva migrans), Baylisascaris procyonis

Inspection of rash Larvae

Biopsy of liver, other tissues (usually not necessary)

Serology* (preferred)

Schistosoma mansoni, Schistosoma haematobium, Schistosoma japonicum, Schistosoma mekongi

Eggs

Feces, rectal snips, urine (S. haematobium)

Serology,* antigen test (serum and urine)

Fasciolopsis buski (intestinal fluke)

Eggs

Feces

Heterophyes heterophyes (intestinal fluke)

Eggs

Feces

Metagonimus yokogawai (intestinal fluke)

Eggs

Feces

Clonorchis sinensis, Opisthorchis spp. (liver fluke)

Eggs

Feces, bile

Serology

Fasciola hepatica (liver fluke)

Eggs

Feces, bile

Serology

Paragonimus spp. (lung fluke)

Eggs

Sputum, feces

Serology*

Taenia saginata (beef tapeworm)

Eggs

Stool

Identification of passed proglottid (segment)

Hymenolepis nana (dwarf tapeworm)

Eggs

Stool

Diphyllobothrium latum (fish tapeworm)

Eggs

Stool

Identification of passed proglottid

Taenia solium (pork tapeworm)

Eggs

Stool

Identification of passed proglottid; stool antigen test; serology

Protoscolices, hooklets

Fluid from cyst

Serology,* CT, MRI, or ultrasonography can be diagnostic

Flukes (Trematodes)

Tapeworms (Cestodes) Intestinal Tapeworms

Larval Tapeworms Echinococcus granulosus (cystic hydatid disease) Echinococcus multilocularis (alveolar hydatid disease)

Larvae

Liver biopsy

Serology

Cysticercus (larval Taenia solium)

Larvae

Brain biopsy

Serology,* CT, or MRI of head can be diagnostic

*Serologic test is available through Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, GA. CT, computed tomography; MRI, magnetic resonance imaging.

Chapter 287â&#x20AC;&#x201A; Introduction to Helminth Infections

contribute to disease. Sterilizing immunity to helminth infections does not develop, and the extent to which previous infections with helminths lead to resistance to subsequent reinfection is not well defined. A degree of acquired immunity has been shown in infected individuals who were cured chemotherapeutically and then continued to live under the same conditions of exposure to infection.11 These findings suggest that induction of resistance by vaccines may be a viable control strategy. Eosinophilia is a characteristic of many helminth infections. Peripheral blood, bone marrow, and tissue eosinophilia is associated with the migration or presence of worms in tissues. Eosinophilia is not observed in infections with helminths that reside in the lumen of the human gut (e.g., tapeworms) or are contained in cystic structures (e.g., echinococcal cysts). Eosinophils seem to play a significant role in the killing of helminths and host resistance to helminth infections and are responsible for a considerable amount of inflammatory pathology.12 Chronic infection with worms typically leads to a constant state of immune activation characterized by a dominant Th2 type of cytokine profile and high immunoglobulin E levels, as well as proliferation and activation of eosinophils.13 It is hypothesized that such an immune profile may have an adverse impact on the efficacy of vaccines against other classes of organisms14 and progression of other infections, such


Part III  Infectious Diseases and Their Etiologic Agents

3198 abundance, microscopy can be extremely sensitive, but multiple examinations or concentration procedures may be necessary to detect light infections or infections with organisms such as Strongyloides, which often shed low numbers of larvae in the stool. Serologic tests may offer greater sensitivity than microscopic examination and may be the only way to avoid invasive diagnostic procedures for infections with tissueinvading helminths. Some serologic tests for helminths are available only from reference laboratories, and they may lack sensitivity or specificity and not distinguish between past and present infections. Assays to detect helminth antigens and molecular diagnostic techniques, used mostly for research purposes and monitoring and evaluating control programs, are expected to play a greater role in future diagnosis and management of individual patients.21 Detailed information on laboratory procedures for diagnosis of parasitic infections, an image library, and instructions for obtaining prompt assistance in diagnosis is available on DPDx, the parasitology diagnostic website of the Centers for Disease Control and Prevention (http://dpd.cdc.gov/dpdx). Excellent drugs are available for treating most helminth infections. Because agents such as albendazole, mebendazole, praziquantel, and ivermectin are highly effective in single or a few orally administered doses, as well as being safe and inexpensive, they are suitable for mass drug administration as well as individual treatment.22,23 Heavy use of these drugs in control programs raises concerns for the emergence of resistance and the need for new drugs. A novel approach to treatment of individual persons with onchocerciasis and filariasis is the use of doxycycline to eliminate the endosymbiotic bacteria Wolbachia and thereby sterilize or kill the adult worms.24,25 For infections such as cysticercosis, toxocariasis, and trichinellosis, anti-inflammatory agents are used to minimize tissue damage and symptoms caused by the host’s response to the parasite.

PREVENTION AND CONTROL

Helminth infections are prevented by (1) avoiding ingestion of infective eggs, larvae, or intermediate hosts infected with larvae; (2) preventing

Key References The complete reference list is available online at Expert Consult. 1. Crompton DWT, Savioli L. Handbook of Helminthiases for Public Health. Boca Raton, FL: CRC Press–Taylor and Francis Group; 2007:3-24. 2. Lustigman S, Prichard PK, Gazzinelli A, et al. A research agenda for helminth diseases of humans: the problem of helminthiases. PLoS Negl Trop Dis. 2012;6:e1582.

contact of bare skin with infective larvae; and (3) avoiding bites of infected vectors. At the personal level, these measures entail drinking safe water; properly cleaning, cooking, and otherwise preparing food; adequate hand washing and general hygiene; and using measures to avoid insect bites, among others. Communities can be protected by interventions such as provision of clean water and sanitation; enforcement of appropriate food-producing practices to prevent infection of fish, meat, and vegetables; vector control; and prevention or treatment of infections in domestic animals. Chemoprophylaxis with diethylcarbamazine can prevent infection with Loa loa, and artemisin derivatives have prophylactic activity against Schistosoma japonicum.26,27 Global efforts to eradicate, eliminate, or reduce transmission of helminth diseases are advancing as a result of partnerships among governments, international agencies, nongovernmental organizations, philanthropic institutions, and industry.23,28 The guinea worm eradication program, which relies on community education and participation, provision of filters for drinking water, clean water sources, and case containment, is nearing its goal of zero cases globally.29 The cornerstone of global programs to eliminate onchocerciasis and lymphatic filariasis and reduce disease caused by schistosomiasis and intestinal helminths is periodic mass administration of anthelmintic drugs to populations at risk.30 Pharmaceutical companies have donated and will continue to donate hundreds of millions of tablets of anthelmintic medications in support of these programs, and integration of different large-scale programs is lowering costs and improving efficiency.30 The World Health Organization has set ambitious but realistic targets for the year 2020: global eradication of dracunculiasis, global elimination of lymphatic filariasis; elimination of onchocerciasis from the Americas and elimination as a public health problem elsewhere; and elimination of schistosomiasis from the Americas, Western Pacific region, and selected countries in Africa.31 Ongoing research in support of these programs and to expand efforts to include other helminth diseases focuses on the development of new drugs, diagnostic methods, control strategies, and novel tools such as anthelmintic vaccines.32,33

5. Boatin BA, Basáñez MG, Prichard RK, et al. A research agenda for helminth diseases of humans: towards control and elimination. PLoS Negl Trop Dis. 2012;6:e1547. 19. Garcia LS. Diagnostic Medical Parasitology. 5th ed. Washington, DC: American Society for Microbiology Press; 2006. 20. McCarthy JS, Lustigman S, Yang GJ, et al. A research agenda for helminth diseases of humans: diagnostics for control and elimination programmes. PLoS Negl Trop Dis. 2012;6:e1601. 22. Kappagoda S, Singh U, Blackburn BG. Antiparasitic therapy. Mayo Clin Proc. 2011;86:561-583.

28. Hopkins DR. Disease eradication. N Engl J Med. 2013;368: 54-63. 31. World Health Organization (WHO). Sustaining the Drive to Overcome the Global Impact of Neglected Tropical Diseases: Second WHO Report on Neglected Diseases. Geneva: WHO; 2013. 32. Pritchard RK, Basáñez MG, Boatin BA, et al. A research agenda for helminth diseases of humans: intervention for control and elimination. PLoS Negl Trop Dis. 2012;6:e1549.


3198.e1

References

23. Molyneux D. Control of human parasitic diseases. Adv Parasitol. 2006;61:1-45. 24. Tamarozzi F, Halliday A, Gentil K, et al. Onchocerciasis: the role of Wolbachia bacterial endosymbionts in parasite biology, disease pathogenesis and treatment. Clin Microbiol Rev. 2011:459-468. 25. Hoerauf A, Pfarr K, Mand S, et al. Filariasis in Africa— treatment challenges and prospects. Clin Microbiol Infect. 2011;17:977-985. 26. Nutman TB, Miller KD, Mulligan M, et al. Diethylcarbamazine prophylaxis for human loiasis. Results of a doubleblind study. N Engl J Med. 1988;319:752-756. 27. Pérez del Villar L, Burquillo FJ, López-Abán J, et al. Systematic review and meta-analysis of artemisinin based therapies for the treatment and prevention of schistosomiasis. PLoS One. 2012;7:e45867. 28. Hopkins DR. Disease eradication. N Engl J Med. 2013;368: 54-63. 29. Hopkins DR, Ruiz-Tiben E, Weiss A, et al. Dracunculiasis eradication: and now, South Sudan. Am J Trop Med Hyg. 2013;89:5-10. 30. Hooper PJ, Zoerhoff KL, Kyelem D, et al. Short report: the effects of integration on financing and coverage of neglected tropical disease programs. Am J Trop Med Hyg. 2013;89: 407-410. 31. World Health Organization (WHO). Sustaining the Drive to Overcome the Global Impact of Neglected Tropical Diseases: Second WHO Report on Neglected Diseases. Geneva: WHO; 2013. 32. Pritchard RK, Basáñez MG, Boatin BA, et al. A research agenda for helminth diseases of humans: intervention for control and elimination. PLoS Negl Trop Dis. 2012;6:e1549. 33. Bergquist R, Lustigman S. Control of important helminthic infections: vaccine development as part of the solution. Adv Parasitol. 2010;73:297-326.

Chapter 287  Introduction to Helminth Infections

1. Crompton DWT, Savioli L. Handbook of Helminthiases for Public Health. Boca Raton, FL: CRC Press–Taylor and Francis Group; 2007:3-24. 2. Lustigman S, Prichard PK, Gazzinelli A, et al. A research agenda for helminth diseases of humans: the problem of helminthiases. PLoS Negl Trop Dis. 2012;6:e1582. 3. Graczyk TK, Fried B. Human waterborne trematode and protozoan infections. Adv Parasitol. 2007;64:111-160. 4. Dorny P, Praet N, Deckers N, et al. Emerging food-borne parasites. Vet Parasitol. 2009;163:196-206. 5. Boatin BA, Basáñez MG, Prichard RK, et al. A research agenda for helminth diseases of humans: towards control and elimination. PLoS Negl Trop Dis. 2012;6:e1547. 6. Anderson RM, May RM. Infectious Diseases of Humans: Dynamics and Control. New York: Oxford University Press; 1991:433-606. 7. Hall A, Gillian H, Tuffrey V, et al. A review and metaanalysis of the impact of intestinal worms on child growth and nutrition. Matern Child Nutr. 2008;(suppl 1): 118-236. 8. Taylor-Robinson DC, Maayan N, Soares-Weiser KS, et al. Deworming drugs for soil-transmitted intestinal worms in children: effects on nutritional indicators, haemoglobin and school performance. Cochrane Database Syst Rev. 2012;(11): CD000371. 9. Pullan R, Brooker S. The health impact of polyparasitism in humans: are we underestimating the burden of parasitic diseases? Parasitology. 2008;135:783-794. 10. Zaghloul MS. Bladder cancer and schistosmiasis. J Egypt Natl Cancer Inst. 2012;24:151-159. 11. Sturrock RF, Kimani R, Cottrell JB, et al. Observations on possible immunity to reinfection among Kenyan schoolchildren after treatment for Schistosoma mansoni. Trans R Soc Trop Med Hyg. 1983;77:363-371.

12. Shin MH, Young AL, Min D-K. Eosinophil-mediated tissue inflammatory responses in helminth infection. Korean J Parasitol. 2009;47(suppl):S125-S131. 13. Maizel RM, Hewitson JP, Smith KA. Susceptibilty and immunity to helminth parasites. Curr Opin Immunol. 2012; 24:459-466. 14. Robinson TM, Nelson RG, Boyer JD. Parasitic infection and the polarized Th2 immune response can alter a vaccine induced immune response. DNA Cell Biol. 2003;22:421-430. 15. Hartgers FC, Yazdanbakhsh M. Co-infection of helminths and malaria: modulation of the immune responses to malaria. Parasite Immunol. 2006;28:497-506. 16. Walson JL, John-Stewart G. Treatment of helminth co-infection in HIV-1 infected individuals in resourcelimited settings. Cochrane Database Syst Rev. 2008;(1): CD006419. 17. McSorley HJ, Hewitson JP, Maizels RM. Immunomodulation by helminth parasites: defining mechanisms and mediators. Int J Parasitol. 2013;43:301-310. 18. Pritchard DI, Blount DG, Schmid-Grenelmeier P, et al. Parasitic worm therapy for allergy: is this incongruous or avantgarde medicine? Clin Exp Allergy. 2011;42:505-512. 19. Garcia LS. Diagnostic Medical Parasitology. 5th ed. Washington, DC: American Society for Microbiology Press; 2006. 20. McCarthy JS, Lustigman S, Yang GJ, et al. A research agenda for helminth diseases of humans: diagnostics for control and elimination programmes. PLoS Negl Trop Dis. 2012;6:e1601. 21. Mejia R, Vicuña Y, Broncano N, et al. A novel, multi-parallel, real-time polymerase chain reaction approach for eight gastrointestinal parasites provides improved diagnostic capabilities to resource-limited at-risk populations. Am J Trop Med Hyg. 2013;88:1041-1047. 22. Kappagoda S, Singh U, Blackburn BG. Antiparasitic therapy. Mayo Clin Proc. 2011;86:561-583.


302 

Infections Caused by Percutaneous Intravascular Devices Susan E. Beekmann and David K. Henderson* SHORT VIEW SUMMARY

Definition

• Infections caused by peripheral and central intravenous catheters, including nontunneled central catheters and tunneled (Hickman or Broviac) catheters with or without the Groshong tip, peripherally inserted central venous catheters (PICCs), totally implanted intravascular access devices (ports), pulmonary artery catheters, and arterial lines

Epidemiology

• Rates of central line–associated bloodstream infections (CLABSIs) in 2009 ranged from 1.05 (pooled mean hemodialysis rate) to 1.14 (pooled mean inpatient ward rate) to 1.65 (pooled mean intensive care unit rate) bacteremias per 1000 central venous catheter (CVC) days. • These rates reflect a 58% reduction in total estimated CLABSIs from 2001 to 2009; the reduction in incidence of Staphylococcus aureus CLABSIs was greater than for any other pathogen. • The majority of CLABSIs now occur in inpatient wards and outpatient hemodialysis centers.

Microbiology

• Staphylococci predominate as the most frequently encountered pathogens in device-related infections; coagulase-negative staphylococci are the single most common cause of these infections, whereas S. aureus bacteremias have decreased. • CLABSIs increasingly are caused by multiresistant gram-negative rods.

Diagnosis

• Clinical markers show a poor correlation with intravenous device–related bacteremia. • Blood culture results positive for coagulasenegative staphylococci, S. aureus, or Candida spp., in the absence of any other identifiable source of infection, increase the possibility of intravenous device–related bacteremia. • Quantitative or semiquantitative culture of the catheter combined with two blood cultures (one peripheral and one through the catheter) is most accurate for short-term central catheters. • Paired quantitative blood culture was determined to be the most accurate diagnostic method for long-term devices, including tunneled and totally implanted catheters.

The relentless progress of medical science and technology has been accompanied by the development of a host of new diagnostic and therapeutic medical devices, each of which is associated with its own complications. Included in the list of devices and the complications of their use to be discussed in this chapter are peripheral and central intravenous catheters, including nontunneled central catheters and tunneled (Hickman or Broviac) catheters with or without the Groshong tip (which remains closed unless the catheter is in use), peripherally inserted central venous catheters (PICCs), totally implanted intravascular access devices (ports), pulmonary artery catheters, and arterial lines. As early as 1977, Maki1 suggested that more than 25,000 patients develop device-related bacteremia in the United States each year. The burgeoning use of an ever-expanding array of vascular access devices in medicine has resulted in even more complications associated with their use. Rates of bacteremia associated with the use of intravascular devices increased significantly into the early 2000s. More recent data indicate that the rates of CLABSIs are decreasing, perhaps as a result of prevention programs implemented in many hospitals since 2001. In 2009, the Centers for Disease Control and Prevention (CDC) has estimated that approximately 18,000 central line–associated bloodstream infections (CLABSIs) currently occur in intensive care units (ICUs) each year, compared with 43,000 in 2001.2 An intense focus on prevention of health care–associated infections, including CLABSIs, and requirements for the incorporation of performance measures into regulatory and financial reimbursement systems has the potential to significantly reduce these infections.3,4 *All material in this chapter is in the public domain, with the exception of any borrowed figures or tables.

3310

• Differential time to positivity (between cultures drawn through the catheter and peripherally) compares favorably with quantitative blood cultures for the diagnosis of CLABSIs.

Prevention

• Many CLABSIs can be prevented using simultaneous implementation of an array of practice improvements (i.e., “bundles”). • All health care personnel involved in catheter insertion and maintenance should complete an educational program regarding catheterassociated infections. • Chlorhexidine solutions should be used for skin preparation before catheter insertion. • Maximal sterile barriers should be used during insertion of CVCs. • Do not routinely replace CVCs, PICCs, hemodialysis catheters, peripheral arterial catheters, or pulmonary artery catheters to prevent infection. • Antimicrobial-impregnated catheters, if used, should only be used as part of a comprehensive nosocomial bacteremia prevention strategy.

Such device-associated infections occur as sporadic cases as well as in case clusters caused by the same organism. Vascular catheters have become an increasingly important source of bacteremias, increasing from 3% in the mid-1970s to 19% in the early 1990s.5 Primary bacteremias (i.e., no apparent local infection elsewhere caused by the same organism), including intravascular catheter sources, account for approximately one half of all ICU-related bacteremias.6,7 In cancer patients, 56% of all bloodstream infections from 1999 to 2000 were CLABSIs.8 The problem of iatrogenic, device-associated bacteremia is not unique to the United States; in one prospective study of bacteremia from Australia, nosocomial bacteremias accounted for 40% of all cases of bacteremia, and half of the nosocomial cases were device associated.9 Although most data on CLABSI rates are derived from studies in ICUs, Marschall and colleagues10 reported that the incidence of CLABSIs in non-ICU, general medical patients was comparable to the rate in ICU patients. Both local and systemic infection may result from contamination of intravascular devices. Local cellulitis, abscess formation, septic thrombophlebitis, device-associated bacteremia, and endocarditis all occur as complications of intravascular therapy and monitoring.

PATHOGENESIS

For intravascular device–related bacteremia to occur, microorganisms must gain access to the extraluminal or intraluminal surface of the device. Microbial adherence and incorporation into biofilms then occurs, resulting first in infection and then, in some instances, in hematogenous dissemination.11 Figure 302-1 illustrates the potential points of access to an intravascular device, each of which has been associated with both sporadic cases and case clusters of nosocomial bacteremia. Whereas the skin entry site has long been thought to be


3310.e1

KEYWORDS

Chapter 302â&#x20AC;&#x201A; Infections Caused by Percutaneous Intravascular Devices

antibiotic lock; bacteremia; Broviac; candidemia; catheter; catheter tip culture; central line; central venous catheter (CVC); CLABSI; Hickman; nosocomial; percutaneous; peripheral catheter; PICC; port infection; sepsis; TPN; tunnel infection


3311

In-line filter may trap bacteria but shed endotoxin

Contamination during manufacture Contamination due to malfunctioning air inlet filter Contamination may also enter the system through 1. Pressure measuring devices, transducers 2. Heparinized flush solutions 3. Stopcocks 4. IV piggyback 5. Y junctions 6. Administration of blood products or medications 7. CVP manometers

Contamination may reach circulation at the catheter insertion site

Contamination may enter system at catheter/ administration set junction

FIGURE 302-1  Points of access for microbial contamination in infusion therapy. CVP, central venous pressure; IV, intravenous.

the most important portal of entry for invading microorganisms, the catheter hub–lumen has also been shown to be a major contributor to catheter-related bacteremia.12,13 The most common point of access appears to vary, depending on the duration of time the catheter has been in place. Each of the three major sources of intravenous device– related bacteremia is discussed in the following sections.

Contamination of the Infusate

Contamination of the fluid administered through the device is a major cause of epidemic intravenous device–related bacteremias. Nonetheless, infusate contamination is a rare cause of bacteremia. Infusion-related sepsis has been reviewed in detail,14 and both manufacture-related15 and in-use16 contamination of infusate have been documented as causes of device-associated sepsis. Another factor influencing the pathogenesis of infusate-associated infection is the composition of the fluid. Different infusion fluids support the growth of differing pathogens. The microbiology of outbreaks of infusate-related sepsis is somewhat monotonous; pathogens such as Enterobacter, Citrobacter, and Serratia predominate. No infusate is entirely free of risk; even sterile water for injection can support the growth of Burkholderia cepacia.17 Parenteral nutrition solutions are superb substrates for the growth of certain microorganisms.18 Lipid emulsions support bacterial growth extremely well,19 and their use has also been associated with a risk for fungemia caused by the lipid-dependent yeast Malassezia furfur, although not with contaminated infusates.20 This risk has been primarily identified in the neonatal intensive care setting and has been less commonly seen in adults.20 Several additional outbreaks of bacteremias have been linked to compounding pharmacies that adhere to different quality control standards.21,22 One national outbreak of Serratia marcescens bacteremias occurred as a result of contaminated magnesium sulfate solution,22 and two recent outbreaks were associated with contaminated heparin solutions.21,23

Parenteral nutrition solutions may also become contaminated during compounding in the hospital pharmacy.24,25 Two similar outbreaks of Candida parapsilosis infections were linked to the backflow of yeasts into parenteral nutrition solution because vacuum pumps were used improperly.24,25 The composition of the infusate also influences the degree of irritation of the vascular intima at the site of infusion. Fluids that are not isotonic, those at nonphysiologic pH, and those containing particulates all may irritate the vascular wall, thus provoking thrombus formation. Such thrombi may be seeded with microbes—either hematogenously or by direct extension.

Contamination of the Catheter Hub and Lumen (Intraluminal Source)

Currently, bacteremias associated with long-term catheters appear to arise most frequently from an intraluminal source, perhaps after intraluminal colonization with biofilm-producing microbes.26 Contamination of the catheter hub–infusion tubing junction is a significant contributor to device-associated infection.13,27,28 Endemic coagulasenegative staphylococcal bacteremias often arise as a result of contamination of the catheter hub with these organisms. A randomized study examining the effects of a redesigned protective hub found these hubs to be associated with a significantly lower rate of catheter sepsis and culture-positive catheter hubs,29 suggesting that the hub is a common portal of entry for bacteria. Other investigators have incriminated the hub–tubing junction (particularly when it does not allow a good fit) in the pathogenesis of epidemics of coagulase-negative staphylococcal infection.30,31 Maki and Ringer32 found hub contamination to be the second most heavily weighted risk factor for catheter-associated infection in a large, prospective study. Salzman and colleagues33 noted that greater than 50% of episodes of central venous catheter (CVC)-related sepsis occurring in a neonatal ICU were preceded by colonization of the catheter hub with the incriminated organism. In a subsequent experimental study, these investigators found that swabbing the catheter hub with disinfectant substantially reduced the hub’s microbial burden and that preparations containing 70% ethanol were both more effective and more likely to be safer for the patient than preparations containing chlorhexidine.34 Sherertz35 estimated that the hub, lumen, or both contributed two thirds of the microorganisms that infected long-term catheters and that one fourth of the microorganisms were from the skin. Conversely, some new technologies may be associated with increased risks for catheter-associated infection. Whereas the implementation of needleless intravenous admixture systems provided a safer workplace environment for health care providers, some data suggest that use of these devices may be associated with increased risk for device-associated infection.36,37 Multiple investigations of bacteremia outbreaks associated with needleless devices have suggested that the mechanism for bacteremia may involve contamination from the end cap.38-41 Of interest, different studies have paradoxically found either increased or decreased risk with the same needleless system (e.g., the Interlink device [Baxter, Deerfield, IL]),38,39 leading to the conclusion that the primary risk associated with these devices is related to how the systems are used (e.g., frequency of changing end caps and adherence to recommended infection control procedures) rather than factors intrinsic to the system.39 Appropriate staff education regarding use of these devices and ensuring compliance with the manufacturer’s recommendations is recommended to prevent devicerelated bacteremia.

Contamination of Skin at the Device Insertion Site (Extraluminal Source)

Many authorities believe that the catheter insertion tract provides the major avenue for the ingress of microbial invaders.* Several studies have focused on microbial colonization around the catheter insertion site as a significant risk factor for catheter-associated infection.44 Supporting this contention are the studies of Cooper and Hopkins that demonstrated organisms on the exterior surface of catheters rather than within the catheter lumen.45 In the prospective study of Maki *References 1, 9, 13, 14, 30, 32, 42, 43.

Chapter 302  Infections Caused by Percutaneous Intravascular Devices

Contamination during insertion of administration set spike or during container change

Contamination may reach system through defects in containers


Part IV  Special Problems

3312 and Ringer,32 colonization around the catheter insertion site was the most strongly associated risk factor for local catheter infection. Similarly, Safdar and Maki46 determined that most catheter-related bacteremias occurring with short-term noncuffed central catheters were extralu­minally acquired and derived from the cutaneous microflora. Skin appears to be the primary source of intravenous device–related bacteremia for short-term catheters placed for an average duration of less than 8 days.47-49 Skin colonization is a dynamic process. Atela and co-workers42 conducted a prospective study to assess the turnover of superficial skin colonization by performing serial quantitative cultures of skin and the catheter hub.4 Strains recovered from the targeted superficial skin sites demonstrated a poor correlation both with strains from previous skin cultures and with catheter tip isolates.42 Herwaldt and colleagues50 examined the source of coagulase-negative staphylococcal bacteremias in hematology-oncology patients and found that the same strain was identified in both skin and blood cultures in only 6 of 20 episodes. The matching strain was isolated only from other sites (primarily nares) in the remaining 70% of episodes, leading these investigators to the conclusion that mucous membranes might be a reservoir for strains of coagulase-negative staphylococci causing bacteremia in immunocompromised patients. Of importance, these investigators were unable to identify colonization with the same strain for the majority of bacteremias; only 4 of the 21 nosocomial bloodstream infections were preceded by colonization with the same strain. Most nosocomial coagulase-negative staphylococcal bacteremias in this study appeared to result from extrinsic introduction of the organism.

EPIDEMIOLOGY

According to the CDC’s National Healthcare Safety Network (NHSN), rates of CLABSIs in 2009 ranged from 1.05 (pooled mean hemodialysis rate) to 1.14 (pooled mean inpatient ward rate) to 1.65 (pooled mean ICU rate) bacteremias per 1000 CVC days.2 These rates reflect a 58% reduction in total estimated CLABSIs from 2001 to 2009.2 The majority of CLABSIs now occur not in ICUs but in inpatient wards and out­ patient hemodialysis settings.2 The reduction in incidence of Staphy­ lococcus aureus CLABSIs was greater than for any other pathogen (see later).2 Intravenous device–related bacteremia rates are influenced by patient-related parameters, catheter-related parameters, and hospitalrelated parameters (Table 302-1). Because of methodologic difficulties

TABLE 302-1  Risk Factors for Device-Associated Bacteremia Granulocytopenia Immunosuppressive chemotherapy Hematologic malignancy (versus solid tumor)391 Loss of skin integrity (e.g., burns, psoriasis) Severity of underlying illness Active infection at other site Alteration in patient’s cutaneous microflora Failure of health care provider to wash hands Contaminated ointment or cream Catheter composition/construction   Flexibility/stiffness   Thrombogenicity56   Microbial adherence properties and biofilm production60 Size of catheter Number of catheter lumens65 Catheter function/use Catheter management strategies—number of entries into the system Type of catheter (plastic > steel) Location of catheter (central > peripheral; jugular > femoral > subclavian48,85,392; lower extremity sites > upper extremity sites) Type of placement (cutdown > percutaneous) Duration of placement (at least 72 hr > less than 72 hr)32,206* Emergent placement > elective Skill of venipuncturist (others > intravenous team)80,206 Type/use of catheter (balloon-tipped, flow-directed > percutaneously placed; central venous > implanted central venous)232 Nursing staffing variables (nurse-to-patient ratio,87 lower regular registered nurse-to-patient ratio, and higher float pool registered nurse-to-patient ratio)88,89,388 *Although several studies support this precept, another has questioned it.

in performing appropriate scientific studies to characterize relative risk, many of these risk factors have been identified either retrospectively or in the epidemic setting. Still, each of the patient-related factors identified in Table 302-1 has been associated with an increased risk of device-associated infection.51 Alteration of the patient’s skin microbiota, either as a result of antimicrobial therapy or by colonization with an epidemic strain carried on the hands of hospital personnel, is a common event preceding catheter site infection. Failure of hospital personnel to perform appropriate hand hygiene procedures, particularly in the ICU setting, has been well documented.52-54 Numerous epidemics of device-associated bacteremia have been linked to hospital personnel carrying an epidemic strain on their hands. Manipulating the system for repositioning, for obtaining a sample, or for any other reason increases the likelihood that the catheter may become con­ taminated.55 The increasing prevalence of multiple drug resistance among health care–associated isolates causing these infections (e.g., vancomycin-resistant enterococci, multiresistant Acinetobacter bau­ mannii, carbapenem-resistant Enterobacteriaceae) has magnified this problem in the past decade. Several catheter characteristics or properties have been suggested to be associated with an increased risk for catheter-associated infection. Catheters that irritate the vascular intima and provoke thrombogenesis and catheters that are made of intrinsically thrombogenic materials are likely to be associated with an increased risk for deviceassociated infection.56 Older studies suggest that stiff catheters were associated with higher infection rates.57 Such catheters are likely to be more mobile in the insertion tract and are thought to be more thrombogenic. A clear association has been established between the thrombogenicity of a catheter and the risk for device-associated infection.58,59 Despite differences in thrombogenicity, some authorities believe that all catheters become coated with a fibrin sheath soon after placement.60 Currently, the majority of catheters are manufactured with antithrombogenic polymers, such as polyurethane, Teflon, or others. Catheter composition may influence the risk for infection in another way. Sheth and co-workers61 have shown that certain microorganisms, most notably staphylococci, are able to adhere better to a catheter made from polyvinyl chloride than to a Teflon catheter. Rotrosen and colleagues62 demonstrated increased adherence of Candida spp. to polyvinyl chloride catheters compared with Teflon catheters. In a rabbit model, silicon catheters are easier to infect with S. aureus than are those made of polyurethane, Teflon, or polyvinyl chloride.63 One might hypothesize that materials that facilitate microbial adherence may be associated with an increased risk for deviceassociated infection. Newer therapeutic interventions have focused on diminishing adherence to the ca