Chronic Multisymptom Illness in Gulf War
Veterans: Case Definitions Reexamined

Committee on the Development of a Consensus Case Definition for Chronic
Multisymptom Illness in 1990–1991 Gulf War Veterans

Board on the Health of Select Populations

INSTITUTE OF MEDICINE
         OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, D.C.
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Committee on the Development of a Consensus Case Definition for Chronic Multisymptom Illness in 1990–1991 Gulf War Veterans Board on the Health of Select Populations

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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 competencies and with regard for appropriate balance. This study was supported by Contract VA240-13-D-0024 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 authors and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-29876-6 International Standard Book Number-10: 0-309-29876-8 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2014 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. IOM (Institute of Medicine). 2014. Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. Washington, DC: The National Academies Press.

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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. C. D. Mote, Jr., 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. C. D. Mote, Jr., are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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COMMITTEE ON THE DEVELOPMENT OF A CONSENSUS CASE DEFINITION FOR CHRONIC MULTISYMPTOM ILLNESS IN 1990–1991 GULF WAR VETERANS KENNETH SHINE (Chair), Special Adviser to the Chancellor, University of Texas System, Austin, TX FLOYD E. BLOOM, Professor Emeritus, Molecular and Integrative Neuroscience Department, The Scripps Research Institute, La Jolla, CA KARON FRANCES COOK, Research Associate Professor, Northwestern University Feinberg School of Medicine, Chicago, IL DEBORAH A. CORY-SLECHTA, Professor, Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, NY FRED FRIEDBERG, Research Associate Professor, Department of Psychiatry and Behavioral Science, Stony Brook University, Stony Brook, NY JOANNA G. KATZMAN, Director, University of New Mexico Pain Center and Associate Professor, Department of Neurosurgery, University of New Mexico School of Medicine, Albuquerque, NM HOWARD M. KIPEN, Professor of Environmental and Occupational Medicine and Chief, Clinical Research and Occupational Medicine Division, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ JEANNIE-MARIE S. LEOUTSAKOS, Assistant Professor, Director, Psychiatry Biostatistics and Methodology Core, Johns Hopkins University School of Medicine, Baltimore, MD JAMES L. LEVENSON, Professor of Psychiatry, Internal Medicine and Surgery, Virginia Commonwealth University, Richmond, VA CATHERINE LOMEN-HOERTH, Director, ALS Center, Professor of Neurology, University of California, San Francisco, Medical Center, San Francisco, CA THOMAS J. MASON, Professor, Department of Environmental and Occupational Health, College of Public Health, Department of Internal Medicine, College of Medicine, University of South Florida, Tampa, FL LINDA ANH B. NGUYEN, Clinical Assistant Professor, Director, GI Motility and Neurogastroenterology, Stanford University, Palo Alto, CA F. JAVIER NIETO, Helfaer Professor of Public Health, Professor of Population Health Sciences and Family Medicine, University of Wisconsin, School of Medicine and Public Health, Madison, WI ANNE LOUISE OAKLANDER, Associate Professor of Neurology, Harvard Medical School, Assistant in Pathology (Neuropathology), Massachusetts General Hospital, Boston, MA RON F. TEICHMAN, Teichman Occupational Health Associates, Inc., West Orange, NJ SUZANNE D. VERNON, Scientific Director, The CFIDS Association of America, Charlotte, NC v

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IOM Staff CAROLYN FULCO, Scholar RENEE WLORDCZYK, Associate Program Officer (until August 2013) CARY HAVER, Associate Program Officer NORMAN GROSSBLATT, Senior Editor JOSEPH GOODMAN, Senior Program Assistant SULVIA DOJA, Senior Program Assistant DORIS ROMERO, Financial Associate FREDERICK ERDTMANN, Director, Board on the Health of Select Populations Consultants MIRIAM DAVIS, Independent Consultant, Silver Spring, MD ANDREW KAYSER, Ernest Gallo Clinic & Research Center, University of California, San Francisco vi

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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 thank the following for their review of this report: John C. Bailar, University of Chicago Dan G. Blazer, Duke University Medical Center Kenneth W. Kizer, University of California, Davis David Korn, Harvard University Kurt Kroenke, Indiana University School of Medicine Eric B. Larson, Group Health Research Institute Stephen R. Mitchell, Georgetown University School of Medicine Rebecca Nugent, Carnegie Mellon University Tyler Smith, National University Simon Wessely, Kings College London 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 the report was overseen by Huda Akil, University of Michigan, and Harold C. Sox, Dartmouth Institute for Health Policy and Clinical Practice. Appointed by the National Research Council and the Institute of Medicine, they were responsible for making certain that an independent examination of the report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of the report rests entirely with the authoring committee and the institution. vii

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CONTENTS SUMMARY ........................................................................................................................................................... 1 1 INTRODUCTION ........................................................................................................................................... 15 Background ..................................................................................................................................................... 15 The Gulf War Setting ...................................................................................................................................... 16 Charge to the Committee ................................................................................................................................ 19 How the Committee Approached Its Charge .................................................................................................. 20 Organization of the Report.............................................................................................................................. 20 References....................................................................................................................................................... 21 2 CASE DEFINITIONS ..................................................................................................................................... 23 Addressing Chronic Multisymptom Illness in Gulf War Veterans ................................................................. 23 Developing Case Definitions .......................................................................................................................... 25 References....................................................................................................................................................... 27 3 STUDIES OF SYMPTOMS IN GULF WAR VETERANS ........................................................................... 31 General Limitations of Gulf War Studies ....................................................................................................... 31 Population-Based Studies ............................................................................................................................... 35 Military Unit–Based Studies ........................................................................................................................... 42 Registry Studies .............................................................................................................................................. 45 Summary ......................................................................................................................................................... 48 References....................................................................................................................................................... 63 4 FACTOR ANALYSIS AND ITS USE IN STUDIES OF SYMPTOMS IN GULF WAR VETERANS ........ 67 Factor Analysis ............................................................................................................................................... 67 Factor-Analysis Studies .................................................................................................................................. 70 Cluster-Analysis Studies ................................................................................................................................. 76 Summary and Conclusions ............................................................................................................................. 77 References....................................................................................................................................................... 84 5 CHRONIC MULTISYMPTOM ILLNESS CASE DEFINITIONS AND RECOMMENDATIONS ............. 87 Existing Case Definitions ............................................................................................................................... 88 Discussion of Existing Case Definitions ......................................................................................................... 96 Conclusions..................................................................................................................................................... 98 Recommendations ........................................................................................................................................... 98 Considerations for Future Research ................................................................................................................ 99 References..................................................................................................................................................... 100 APPENDIXES A ADDITIONAL INFORMATION ABOUT FACTOR ANALYSIS AND CLUSTER ANALYSIS ............ 103 B PERCENTAGES OF VETERANS REPORTING SYMPTOMS IN STUDIES OF GULF WAR VETERANS AND MILITARY PERSONNEL ................................................................................................................. 113 ix

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