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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