GULF WAR and HEALTH

Volume 5
INFECTIOUS DISEASES

Abigail E. Mitchell, Laura B. Sivitz, Robert E. Black, Editors

Committee on Gulf War and Health: Infectious Diseases

Board on Population Health and Public Health Practice

INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.
www.nap.edu



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Gulf War and Health: Volume 5. Infectious Diseases GULF WAR and HEALTH Volume 5 INFECTIOUS DISEASES Abigail E. Mitchell, Laura B. Sivitz, Robert E. Black, Editors Committee on Gulf War and Health: Infectious Diseases Board on Population Health and Public Health Practice INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Gulf War and Health: Volume 5. Infectious Diseases THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by Contract V101(93)P-2155 between the National Academy of Sciences and the Department of Veterans Affairs. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-10: 0-309-10106-9 (Book) International Standard Book Number-13: 978-0-309-10106-6 (Book) International Standard Book Number-10: 0-309-65706-7 (PDF) International Standard Book Number-13: 978-0-309-65706-8 (PDF) Library of Congress Control Number: 2006934962 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, NW, Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at www.iom.edu. Copyright 2007 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.

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Gulf War and Health: Volume 5. Infectious Diseases “Knowing is not enough; we must apply. Willing is not enough; we must do” —Gothe INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES Advising the Nation. Improving Health.

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Gulf War and Health: Volume 5. Infectious Diseases THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Gulf War and Health: Volume 5. Infectious Diseases COMMITTEE ON GULF WAR AND HEALTH: INFECTIOUS DISEASES ROBERT E. BLACK, MD, MPH, Edgar Berman Professor and Chair, Department of International Health, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD MARTIN J. BLASER, MD, Frederick H. King Professor of Internal Medicine, Chair of the Department of Medicine, and Professor of Microbiology, New York University School of Medicine, New York RICHARD D. CLOVER, MD, Dean and Professor, School of Public Health and Information Sciences, University of Louisville, KY MYRON S. COHEN, MD, J. Herbert Bate Distinguished Professor of Medicine and Microbiology, Immunology and Public Health, University of North Carolina School of Medicine, Chapel Hill JERROLD J. ELLNER, MD, Professor and Chair of the New Jersey Medical School at the University of Medicine and Dentistry of New Jersey, Newark JEANNE MARRAZZO, MD, MPH, Associate Professor, Department of Medicine, University of Washington School of Medicine, Seattle MEGAN MURRAY, MD, ScD, MPH, Assistant Professor of Epidemiology, Harvard University, School of Public Health, Boston, MA EDWARD C. OLDFIELD III, MD, Director, Division of Infectious Diseases, Eastern Virginia Medical School, Norfolk RANDALL R. REVES, MD, MSc, Professor, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver EDWARD T. RYAN, MD, Director, Tropical and Geographic Medicine Center, Massachusetts General Hospital, and Associate Professor of Medicine, Harvard Medical School, Boston, MA STEN H. VERMUND, MD, PhD, Amos Christie Chair and Director, Vanderbilt University Institute for Global Health, and Professor of Pediatrics, Medicine, Preventive Medicine, and Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, TN DAWN M. WESSON, PhD, Associate Professor, Tulane School of Public Health and Tropical Medicine, New Orleans, LA

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Gulf War and Health: Volume 5. Infectious Diseases STAFF ABIGAIL E. MITCHELL, PhD, Senior Program Officer LAURA B. SIVITZ, MSJ, Senior Program Associate DEEPALI M. PATEL, Senior Program Associate MICHAEL J. SCHNEIDER, MPH, Senior Program Associate PETER JAMES, Research Associate DAMIKA WEBB, Research Assistant DAVID J. TOLLERUD, Program Assistant RENEE WLODARCZYK, Program Assistant NORMAN GROSSBLATT, Senior Editor ROSE MARIE MARTINEZ, ScD, Director, Board on Population Health and Public Health Practice

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Gulf War and Health: Volume 5. Infectious Diseases REVIEWERS This report has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards of objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following for their review of this report: Lawrence R. Ash, Professor Emeritus, Department of Epidemiology, University of California, Los Angeles School of Public Health Michele Barry, Tropical Medicine and International Health Programs, Yale University School of Medicine Herbert DuPont, School of Public Health, University of Texas Health Science Center at Houston and St. Luke’s Episcopal Hospital Robert Edelman, Travelers’ Health Clinic, University of Maryland David Hill, National Travel Health Network and Centre, Hospital for Tropical Diseases, London Richard T. Johnson, Department of Neurology, The Johns Hopkins Hospital Arthur Reingold, Division of Epidemiology, University of California, Berkeley Philip K. Russell, Professor Emeritus, Johns Hopkins School of Public Health Mark Wallace, Independent Infectious Diseases Consultant and United States Navy, Retired Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations nor did they see the final draft of the report before its release. The review of this report was overseen by George Rutherford, Institute of Global Health, University of California, San Francisco, and Elaine L. Larson, School of Nursing, Columbia University. Appointed by the National Research Council, they were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

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Gulf War and Health: Volume 5. Infectious Diseases PREFACE Infectious diseases have been a problem for military personnel throughout history. The consequences in previous conflicts have ranged from frequent illnesses disrupting daily activities and readiness to widespread deaths. Preventive measures, early diagnosis, and treatment greatly limit the exposures and acute illnesses of troops today in comparison with those in armies of the past, but infections and consequent acute illnesses still occur. In addition, long-term adverse health outcomes of some pathogens are increasingly recognized. The deployment of about 700,000 US troops to the Persian Gulf region in the Gulf War of 1991 potentially exposed them to pathogens that they had not encountered at home. After returning from that short campaign, some veterans reported symptoms and expressed the concern that they may have been exposed to biologic, chemical, or physical agents during their service in the Persian Gulf. In response to those concerns, the US Department of Veterans Affairs (VA) commissioned the Institute of Medicine (IOM) to review the scientific evidence on possible long-term adverse health outcomes of exposure to specific biologic, chemical, and physical agents and to draw conclusions on the strength of that evidence with regard to delayed and chronic illnesses of the veterans. The authorizing legislation for the work of IOM included several infectious diseases endemic in the Persian Gulf region. In the charge to our committee, VA asked that we not limit consideration to those diseases but rather include all infectious exposures that had been documented in troops and consider their possible long-term adverse health outcomes. It further requested that the time and geographic dimensions of the committee’s work be widened to include military personnel deployed as part of Operation Enduring Freedom (OEF) in Afghanistan and Operation Iraqi Freedom (OIF) in the Persian Gulf region. OEF began in 2001, and OIF in 2003; they continued as this report went to press. The number of military personnel involved in the more recent conflicts now exceeds that in the 1991 Gulf War. Furthermore, they have remained for much longer periods on the average than in the Gulf War, and many have been deployed for more than one tour in this region. Thus, the potential for exposure to endemic pathogens is greater in these troops than in those deployed to the Gulf War. Because the possible exposures are relatively recent, there has been only a short time to observe long-term adverse health outcomes. The committee needed to rely on observations from the Gulf War, information on infectious diseases in OEF and OIF, and evidence in the scientific literature to allow conclusions to be drawn on possible long-term adverse health outcomes. With further time to observe the possible consequences of infectious exposures, the knowledge base will increase. Given the continuing presence of troops in the areas and the variable nature of infectious diseases, the exposures may change. Valuable contributions were made to this study by a number of people who shared their expertise on infectious diseases. On behalf of the committee, I thank several of them—K. Craig Hyams, MD, MPH, chief consultant, Occupational and Environmental Health Strategic Healthcare Group, VA; Michael Kilpatrick, MD, deputy director, Deployment Health Support, Department of Defense (DOD); and Alan Magill, MD, science director, Walter Reed Army Institute of Research, for presenting information on infectious diseases that have been diagnosed in military personnel during the Gulf War, OIF, and OEF and Richard Reithinger, PhD,

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Gulf War and Health: Volume 5. Infectious Diseases infectious diseases consultant, for presenting information on infectious diseases that are endemic in southwest and south-central Asia to the committee at its May 26, 2005 meeting. I also thank William Winkenwerder, Jr., MD, MBA, assistant secretary for defense for health affairs, and his staff at DOD’s Deployment Health Support for expeditiously providing information to the committee on DOD health-related policies. Finally, the committee is grateful for the insight provided by representatives of veteran service organizations, veterans, and others who spoke with the committee or sent in written testimony. I am grateful for the great expertise the committee members brought to bear on this subject. Furthermore, the report would not have been successfully completed without the diligent and expert contributions of the IOM staff, led by Abigail Mitchell and including Laura Sivitz, Deepali Patel, Michael Schneider, Peter James, Damika Webb, David Tollerud, and Renee Wlodarczyk. Robert E. Black, MD, MPH, Chair

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Gulf War and Health: Volume 5. Infectious Diseases CONTENTS     Summary   1      Methodology   1      Identifying the Pathogens to Study   2      Development of Conclusions   3      Summary of Conclusions   4      Sufficient Evidence of a Causal Relationship   4      Sufficient Evidence of an Association   5      Limited or Suggestive Evidence of an Association   6      Inadequate or Insufficient Evidence to Determine Whether an Association Exists   6      Limited or Suggestive Evidence of No Association   7      Department of Defense Policies on Tuberculin Skin Testing and Predeployment and Postdeployment Serum Collection   7 1   Introduction   9      Identifying the Infectious Diseases to Study   13      The Committee’s Approach to Its Charge   15      Organization of the Report   16      References   16 2   Methodology   19      Identifying the Infectious Diseases to Study   19      Geographic Boundaries   19      Infectious Diseases Endemic to Southwest and South-Central Asia That Have Long-Term Adverse Health Outcomes   20      Direct Attribution to Military Service in Southwest and South-Central Asia   24      Timing of Appearance of Long-Term Adverse Health Outcomes   27      The Infectious Diseases to Be Studied for Strength of Association with Long-Term Adverse Health Outcomes   27      Comments on Diseases and Agents of Special Interest to Gulf War, OEF, and OIF Veterans   28      Review and Evaluation of the Literature   29      Selection of the Literature   29      Amassing the Literature   29      Reviewing the Literature   29      Categories of Strength of Association   30      Origin and Evolution of the Categories   30      Sufficient Evidence of a Causal Relationship   30      Sufficient Evidence of an Association   31      Limited or Suggestive Evidence of an Association   31      Inadequate or Insufficient Evidence to Determine Whether an Association Exists   31

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Gulf War and Health: Volume 5. Infectious Diseases      Limited or Suggestive Evidence of No Association   31      References   31 3   Infectious Diseases Endemic to Southwest and South-Central Asia That Have Long-Term Adverse Health Outcomes   35      References   60 4   Infectious Diseases Diagnosed in US Troops Who Served in the Persian Gulf War, Operation Enduring Freedom, or Operation Iraqi Freedom   61      Diarrheal Disease   62      Enteric Infections in the Gulf War   62      Gastroenteritis in Operation Enduring Freedom and Operation Iraqi Freedom   69      Respiratory Disease   74      Mild Acute Respiratory Disease in the Gulf War   74      Severe Acute Respiratory Disease in the Gulf War   76      Respiratory Disease in Operation Enduring Freedom and Operation Iraqi Freedom   76      Insect-Borne Diseases   78      Leishmaniasis   78      Malaria   82      West Nile Fever   84      Brucellosis   84      Chicken Pox (Varicella)   85      Meningococcal Disease   85      Nosocomial Infections   85      Gulf War   85      Operation Enduring Freedom and Operation Iraqi Freedom   86      Q Fever   88      Q Fever Contracted During the Gulf War   89      Q Fever Contracted During Operation Enduring Freedom and Operation Iraqi Freedom   89      Viral Hepatitis   90      Tuberculosis   90      Department of Defense Medical Databases   91      Department of Defense Policy Regarding Predeployment and Postdeployment Serum Collection   93      References   94 5   Levels of Association Between Select Diseases and Long-Term Adverse Health Outcomes   101      Diarrheal Diseases: Campylobacter, Non-typhoid Salmonella, and Shigella Infections   103      Campylobacter Infection   103      Nontyphoidal Salmonella Infection   108      Shigella Infection   110

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Gulf War and Health: Volume 5. Infectious Diseases      Brucellosis   112      Transmission and Endemicity of Brucellosis   113      Acute Brucellosis   114      Treatments for Brucellosis and Related Long-Term Toxicity   115      Coinfection   115      Long-Term Adverse Health Outcomes of Brucellosis   115      Leishmaniasis   118      Transmission of Leishmaniasis   119      Endemicity in Southwest and South-Central Asia   120      Acute Leishmaniasis   120      Diagnosis of Leishmaniasis   121      Treatments for Leishmaniasis and Related Long-Term Toxicity   121      Coinfection by Leishmania Parasite and Human Immunodeficiency Virus   122      Long-Term Adverse Health Outcomes of Leishmaniasis   122      Malaria   123      Transmission of Malaria   124      Endemicity in Southwest and South-Central Asia   124      Acute Malaria   125      Treatments for Malaria and Related Long-Term Toxicity   125      Coinfection with Plasmodium Spp. and Human Immunodeficiency Virus   126      Long-Term Adverse Health Outcomes of Infection with Plasmodium Spp   126      Q Fever (Infection by Coxiella burnetii)   129      Transmission of Coxiella burnetii   129      Endemicity in Southwest and South-Central Asia   130      Acute Q Fever   130      Diagnosing Q Fever   131      Coinfection with Coxiella burnetii and Human Immunodeficiency Virus   131      Long-Term Adverse Health Outcomes of Q Fever   132      Tuberculosis   135      Transmission of Tuberculosis   135      Endemicity in Southwest and South-Central Asia   137      Risk of Progression from Latent Tuberculosis Infection to Active Tuberculosis   137      Treatment for Latent Tuberculosis Infection to Prevent Active Tuberculosis   140      Active Tuberculosis   140      Late Manifestations of Active Tuberculosis   142      Potential Relationships Between Tuberculosis and Military Service   144      West Nile Virus Infection   149      Transmission of West Nile Virus Infection   150      Endemicity in Southwest and South-Central Asia   150      Acute West Nile Fever   151      Diagnosis of West Nile Fever   151      Treatment of West Nile Virus Infection   152      Long-Term Adverse Health Outcomes of Infection with West Nile Virus   152      Recommendation   155      References   155

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Gulf War and Health: Volume 5. Infectious Diseases 6   Diseases and Agents of Special Concern to Veterans of the Gulf War, Operation Iraqi Freedom, and Operation Enduring Freedom   181      Al Eskan Disease   181      Description of Acute Illness   182      Long-Term Adverse Health Outcomes   182      Pathogenesis   182      Treatment   183      Summary   183      Idiopathic Acute Eosinophilic Pneumonia   183      Description of Acute Illness   183      Long-Term Adverse Health Outcomes   183      Pathogenesis   184      Treatment   184      Summary   184      Wound and Nosocomial Infections (Including Infections with Acinetobacter Spp.)   184      Concerns Regarding Acinetobacter baumannii   185      Other Wound Infections   186      Other Nosocomial Infections   187      Regional Experiences in Non-Americans   188      Summary   190      Mycoplasmas   190      Mycoplasmas and “Gulf War Illness”   191      Summary   193      Biologic-Warfare Agents   193      Summary   194      References   194     Appendix Biographical Sketches for Members of the Committee   201     Index   205