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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War
GULF WAR and HEALTH
VOLUME 8
Update of Health Effects of Serving in the Gulf War
Committee on Gulf War and Health: Health Effects of Serving in the Gulf War, Update 2009
Board on the Health of Select Populations
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 8: Update of Health Effects of Serving in the Gulf War
THE NATIONAL ACADEMIES PRESS
500 Fifth Street, N.W.
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 No. V101 (93) P-2136, TO 101-E8709(17) between the National Academy of Sciences and 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-13: 978-0-309-14921-1
International Standard Book Number-10: 0-309-14921-5
Additional copies of this report are available from the
National Academies Press,
500 Fifth Street, N.W., 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 2010 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.
Suggested citation: IOM (Institute of Medicine). 2010. Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press.
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War
“Knowing is not enough; we must apply.
Willing is not enough; we must do.”
—Goethe
INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES
Advising the Nation. Improving Health.
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War
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. Charles M. Vest 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. Charles M. Vest are chair and vice chair, respectively, of the National Research Council.
www.national-academies.org
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War
COMMITTEE ON GULF WAR AND HEALTH: HEALTH EFFECTS OF SERVING IN THE GULF WAR, UPDATE 2009
STEPHEN L. HAUSER (Chair), Professor and Chair of Neurology,
University of California, San Francisco, School of Medicine
ALVARO ALONSO, Assistant Professor,
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota
ROBERT H. BROWN, JR., Chair and Professor of Neurology,
University of Massachusetts School of Medicine
DOUGLAS A. DROSSMAN, Co-director,
University of North Carolina Center for Functional GI and Motility Disorder, and
Professor of Medicine and Psychiatry,
University of North Carolina School of Medicine
W. DANA FLANDERS, Professor of Epidemiology, Biostatistics and Bioinformatics,
Emory University Rollins School of Public Health
MATTHEW C. KEIFER, Co-director,
Pacific Northwest Agricultural Safety and Health Center, and
Professor of Occupational Medicine,
University of Washington Harborview Medical Center
FRANCINE LADEN, Associate Professor of Environmental Epidemiology,
Harvard School of Public Health, and
Assistant Professor of Medicine,
Channing Laboratory, Brigham & Women’s Hospital
JENNIFER D. PECK, Assistant Professor of Epidemiology,
University of Oklahoma Health Sciences Center
BEATE R. RITZ, Professor,
Department of Epidemiology, Department of Environmental Health Sciences, and
Vice Chair,
Department of Epidemiology at the University of California, Los Angeles, School of Public Health
REBECCA P. SMITH, Assistant Clinical Professor,
Department of Psychiatry, Mount Sinai Hospital and School of Medicine
EZRA S. SUSSER, Professor of Epidemiology,
Mailman School of Public Health and
Professor of Psychiatry,
College of Physicians and Surgeons at Columbia University
CHRISTINA M. WOLFSON, Director,
Division of Clinical Epidemiology, McGill University Health Centre, and
Professor,
Department of Epidemiology and Biostatistics and Occupational Health, Department of Medicine, McGill University
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War
STUDY STAFF
ROBERTA WEDGE, Study Director
RENEE WLODARCZYK, Senior Program Associate
PATRICK BAUR, Research Associate
JOSEPH GOODMAN, Senior Program Assistant
CHRISTIE BELL, Financial Officer
FREDRICK ERDTMANN, Director,
Board on the Health of Select Populations
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War
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 (NRC’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 for 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 individuals for their review of this report:
Alberto Ascherio, Department of Epidemiology, Harvard University School of Public Health
Floyd E. Bloom, Department of Molecular and Integrative Neuroscience, The Scripps Research Institute
Gregory L. Burke, Division of Public Health Sciences, Wake Forest University School of Medicine
Edward V. Loftus, Jr., Division of Gastroenterology and Hepatology, Mayo Clinic
Anne Louise Oaklander, Center for Shingles and Postherpetic Neuralgia, Massachusetts General Hospital
Robert D. Sparks, California Medical Association Foundation
Carol A. Tamminga, Department of Psychiatry, The University of Texas Southwestern Medical Center
Nancy Fugate Woods, University of Washington School of Nursing
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 Harold C. Sox, American College of Physicians of Internal Medicine. Appointed by the NRC and the Institute of Medicine, he was 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 author committee and the institution.
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Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War
PREFACE
In war, there are no unwounded soldiers.
—José Narosky
The committee began its task with a sense of deep obligation to the servicemen and women who fought so bravely on our behalf in the Gulf War theater. Our appreciation of the risks, privations, and sacrifices that these courageous servicemembers undertook only deepened as our knowledge of the combat mission increased during the course of the committee’s meetings. There is no greater service that a human being can provide to one’s fellow citizens than to risk life and health on their behalf. We are honored to dedicate this report to these troops.
As scientists and clinicians, the committee members are also aware of our responsibilities not only to those who served in the Gulf War coalition but also to the cause of science and evidence-based medicine. Only by being true to the latter do we serve the former.
There is no doubt that many of the veterans deployed to the gulf region during 1990-1991 have continued to experience troubling constellations of symptoms involving multiple body systems; these have been variously termed multisymptom illness or Gulf War illness, and as such are emblazoned in the public’s mind as a consequence of military service in this battleground. Many other veterans have not experienced the full array of Gulf War illness symptoms but continue to suffer from seemingly related symptoms, including persistent fatigue, chronic fatigue syndrome, irritable bowel syndrome, memory problems, headache, bodily pains, disturbances of sleep, as well as other physical and emotional problems. Many of these symptoms are difficult to categorize as they have no known cause, no objective findings on clinical examination, no diagnostic biomarkers, no known tissue pathology, and no curative therapy. The inadequate basic understanding of the root cause of these symptoms highlights the limitations of current medical science and clinical practice. The committee recognizes that symptoms that cannot be easily quantified are sometimes dismissed—incorrectly—as insignificant, and that they receive inadequate attention—and funding—by the medical and scientific establishment. For example, chronic pain is experienced by 81 million people in the United States alone, yet funding to understand the biology of pain is woefully inadequate, clinical care pathways for individuals suffering from pain are underdeveloped, and training in pain medicine for clinicians lags behind the training for far less common maladies.
Many of the complaints experienced by Gulf War veterans, veterans who arrived in the Gulf War theater after the hostilities ended, and nondeployed veterans, are also seen in the general population. It is beyond dispute, however, that the prevalence of symptoms such as headaches, joint pain, and difficulty concentrating is higher in veterans deployed to the Gulf War theater than the others.
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During the past decade two groups, the Institute of Medicine (IOM) and the congressionally mandated Research Advisory Committee on Gulf War Veterans’ Illnesses (RAC) have been charged with evaluating the health of and research on Gulf War veterans. In the 2006 IOM report Gulf War and Health, Volume 4: Health Effects of Serving in the Gulf War, the authoring committee concluded that although Gulf War veterans reported higher levels of symptoms that might be associated with exposures in the field, no associations with any specific exposures could be identified. In contrast, a report issued by the RAC in November 2008 concluded that Gulf War illness resulted from exposure to pyridostigmine bromide, pesticides, and possibly other exposures.
Although not formally charged with investigating evidence that exposure to specific environmental hazards may have been associated with multisymptom illness, this committee was asked by General Shinseki, Secretary of the Department of Veterans Affairs, to comment on it and did so in an appendix. To ignore this question would not serve the larger purpose of our inquiry. We conclude that current evidence is inadequate to determine whether an association exists between multisymptom illness and any specific battlefield exposure or exposures. Veterans who continue to suffer from these discouraging symptoms deserve the very best that modern science and medicine can offer to delineate the true underlying cause of these symptoms in order to speed the development of effective treatments, cures, and, it is hoped, preventions. The committee suggests a path forward to accomplish these goals and we believe that, through a concerted national effort and rigorous scientific input, answers can likely be found.
The committee would like to thank the many Gulf War veterans who spoke with us about their experiences in the gulf and upon their return to the United States. They provided valuable insights into the symptoms and medical conditions that have been the legacy of the Gulf War for many of the men and women who served in the military. The committee also appreciated hearing from representatives from the Department of Veterans Affairs about the facilities and programs available to Gulf War veterans and from representatives of the RAC who presented the findings of that committee and answered this committee’s questions. And finally, the committee would like to thank the IOM staff—Patrick Baur, Joseph Goodman, Renee Wlodarczyk—who assisted in this effort. In particular, we thank Roberta Wedge, who guided the entire process with flexibility, provided many invaluable insights, and displayed a sure hand at every step along our path.
Stephen L. Hauser (Chair)
Committee on Gulf War and Health: Health Effects of Serving in the Gulf War, Update 2009
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CONTENTS
PREFACE
ix
ACRONYMS
xvii
SUMMARY
1
Charge to the Committee
2
Committee’s Approach
2
Volume 4 Conclusions
3
Considerations in Identifying and Evaluating the Literature
4
Primary and Secondary Studies
4
Categories of Association
5
Major Cohort Studies
6
Health Outcomes
6
Quality of the Studies
7
Recommendations
9
1
INTRODUCTION
11
Background
11
The Gulf War Setting
12
Deployment
13
Living Conditions
13
Environmental and Chemical Exposures
13
Threat of Chemical and Biologic Warfare
14
Charge to the Committee
15
Committee’s Approach to Its Charge
16
Complexities in Resolving Gulf War and Health Issues
17
Multiple Exposures and Chemical Interactions
17
Limitations of Exposure Information
17
Individual Variability
18
Volume 4 Conclusions
18
Organization of the Report
20
References
20
2
CONSIDERATIONS IN IDENTIFYING AND EVALUATING THE LITERATURE
23
Identification of the Literature
23
Types of Evidence
25
Epidemiologic Studies
25
Associations in Epidemiologic Studies
25
Inferring Causality
27
Types of Epidemiologic Studies
28
Cohort Studies
28
Case-Control Studies
29
Cross-Sectional Studies
30
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Standardized Mortality Studies
31
Inclusion Criteria
31
Methodologic Rigor
32
Exposure Assessment
32
Health Outcome Assessment
32
Considerations in Assessing the Strength of Evidence
33
Categories of Association
33
Additional Considerations
35
Bias
35
Confounding
35
Sampling Error
35
Multiple Comparisons
36
Limitations of Gulf War Veteran Studies
36
References
36
3
MAJOR COHORT STUDIES
39
General Limitations of Gulf War Cohort Studies and Derivative Studies
39
Organization of this Chapter
41
Department of Veterans Affairs Study
45
The Iowa Persian Gulf Study
49
United Kingdom Veteran Studies
51
Australian Veteran Studies
54
Danish Peacekeeper Studies
56
Oregon and Washington Veteran Studies
57
Canadian Gulf War Veterans Study
58
Kansas Veteran Study
58
Fort Devens and New Orleans Cohort Studies
59
Seabee Studies
60
Pennsylvania Air National Guard Study
62
Hawaii and Pennsylvania Active Duty and Reserve Study
62
New Orleans Reservist Studies
63
References
63
4
HEALTH OUTCOMES
71
Organization of the Chapter
71
Cancer
73
Summary of Volume 4
73
Updated and Supplemental Literature
75
Summary and Conclusions
78
Diseases of the Blood and Blood-Forming Organs
83
Updated and Supplemental Literature
83
Summary and Conclusions
85
Endocrine, Nutritional, and Metabolic Diseases
89
Diabetes
89
Thyroid Disease
91
Obesity
92
Hospitalization Studies
93
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Mortality Studies
95
Summary and Conclusions
95
Mental and Behavioral Disorders
99
Summary of Volume 4
101
Updated and Supplemental Literature
105
Summary and Conclusion
108
Neurocognitive and Neurobehavioral Outcomes
115
Summary of Volume 4
115
Updated and Supplemental Literature
116
Summary and Conclusions
118
Diseases of the Nervous System
121
Peripheral Neuropathy and Myopathy
121
Multiple Sclerosis
124
Amyotrophic Lateral Sclerosis
126
Other Neurodegenerative Diseases
129
Other Neurological Outcomes
130
Diseases of the Circulatory System
135
Summary of Volume 4
135
Updated and Supplemental Literature
136
Summary and Conclusions
140
Diseases of the Respiratory System
145
Summary of Volume 4
145
Updated and Supplemental Literature
147
Summary and Conclusions
149
Diseases of the Digestive System
154
Summary of Volume 4
155
Updated and Supplemental Epidemiologic Literature
156
Summary and Conclusions
159
Skin Diseases
164
Summary of Volume 4
164
Updated and Supplemental Literature
165
Summary and Conclusions
167
Diseases of the Musculoskeletal System
169
Summary of Volume 4
169
Updated and Supplemental Literature
170
Summary and Conclusion
171
Fibromyalgia and Chronic Widespread Pain
175
Summary of Volume 4
175
Updated and Supplemental Literature
176
Summary and Conclusion
178
Diseases of the Genitourinary System
180
Genitourinary Outcomes
180
Hospitalization for Genitourinary System Diseases
183
Summary and Conclusions
184
Adverse Reproductive and Perinatal Outcomes
189
Birth Defects
189
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Adverse Pregnancy Outcomes
193
Fertility
195
Sexual Dysfunction
198
Multisymptom Illnesses
204
Factor Analyses and Surveys
204
Hospitalization Studies
207
Other Reports
208
Summary and Conclusions
210
Chronic Fatigue Syndrome
210
External Causes of Mortality
221
Summary of Volume 4
221
Updated and Supplemental Literature
222
Summary and Conclusions
224
Female Veterans’ Health
228
Deployment Experiences
228
Health Effects
229
Mental Health Effects
231
Military Sexual Assault and Harassment
232
Hospitalization and Mortality
233
Summary and Conclusions
234
References
235
5
CONCLUSIONS AND RECOMMENDATIONS
255
Quality of the Studies
258
Possible Causes of Multisymptom Illness in Veterans
259
The Path Forward
260
APPENDIX A
CHOLINESTERASE INHIBITORS AND MULTISYMPTOM ILLNESSES
265
Exposures to Cholinesterase Inhibitors and Other Pesticides During the Gulf War
266
Pesticides
266
Long-Term Effects of Low Doses of Cholinesterase Inhibitors
270
Studies in Gulf War Populations
271
Animal Studies
275
Genetic Susceptibility to Cholinesterase Inhibitors
276
The Role of Cholinesterase Inhibitors and Pesticides in Multisymptom Illness
278
References
279
APPENDIX B
COMMITTEE BIOGRAPHICAL SKETCHES
285
INDEX
289
Tables and Boxes
TABLE 3-1
Reference and Derivative Studies for the Major Gulf War Cohorts
42
TABLE 4-1
Cancer
79
TABLE 4-2
Diseases of the Blood and Blood-Forming Organs
86
TABLE 4-3
Endocrine, Nutritional, and Metabolic Diseases
96
TABLE 4-4
Mental and Behavioral Disorders
110
TABLE 4-5
Neurobehavioral and Neurocognitive Outcomes
119
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TABLE 4-6
Nervous System Diseases
132
TABLE 4-7
Circulatory System Diseases
141
TABLE 4-8
Respiratory System Diseases
150
TABLE 4-9
Digestive System Diseases
162
TABLE 4-10
Skin Diseases
168
TABLE 4-11
Musculoskeletal Diseases
172
TABLE 4-12
Fibromyalgia and Chronic Widespread Pain
179
TABLE 4-13
Diseases of the Genitourinary System
186
TABLE 4-14
Adverse Reproductive and Perinatal Outcomes
200
TABLE 4-15
Multisymptom Illnesses
215
TABLE 4-16
External Causes of Mortality
225
BOX S-1
Summary of Findings Regarding Associations Between Deployment to the Gulf War and Specific Health Outcomes
8
BOX 1-1
Brief Summary of Findings and Recommendations
19
BOX 4-1
CDC Case Definition of Chronic Fatigue Syndrome
212
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ACRONYMS
AChE acetylcholinesterase
ACR American College of Rheumatology
AFQT Armed Forces Qualifying Test
ALS amyotrophic lateral sclerosis
ANCOVA analysis of covariance
BAI Beck Anxiety Inventory
BDI Beck Depression Inventory
BIRLS Beneficiary Identification Records Locator System
BMI body mass index
BSI Brief Symptom Inventory
BuChE butyrylcholinesterase
CAPS Clinician Administered PTSD Scale
CCD Canadian Cancer Database
CCEP Comprehensive Clinical Evaluation Program
CDC Centers for Disease Control and Prevention
CES Combat Exposure Scale
CFS chronic fatigue syndrome
CI confidence interval
CIDI Composite International Diagnostic Interview
CMD Canadian Mortality Database
CMI chronic multisymptom illness
CMV cytomegalovirus
CNS central nervous system
COD cause of death
COSHPD California Office of Statewide Health Planning and Development
CRP C-reactive protein
CVLT California Verbal Learning Test
CWP chronic widespread pain
DASA Defence Analytical Services Agency (United Kingdom)
DMDC Defense Manpower Data Center
DNA deoxyribonucleic acid
DND Department of National Defence (Canada)
DoD Department of Defense
DSM Diagnostic and Statistical Manual of Mental Disorders
DSP distal symmetric polyneuropathy
DU depleted uranium
EBV Epstein-Barr virus
EEG electroencephalography
ESR erythrocyte sedimentation rate
FARS Fatality Analysis Reporting System
FEV1 forced expiratory volume in 1 second
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FGID functional gastrointestinal disorder
FSH follicle stimulating hormone
FVC forced vital capacity
GAD generalized anxiety disorder
GAO Government Accountability Office
GHQ-12 12-item General Health Questionnaire
GI gastrointestinal
GW Gulf War
GWV Gulf War deployed veterans
HIV human immunodeficiency virus
HPA hypothalamic-pituitary-adrenal axis
HR hazard ratio
HSC Health Symptoms Checklist
IBS irritable bowel syndrome
ICD International Statistical Classification of Diseases and Related Health Problems
IOM Institute of Medicine
LH luteinizing hormone
MANOVA multivariate analysis of variance
MCH mean corpuscular hemoglobin
MCS multiple chemical sensitivity
MCV mean corpuscular volume
MDD major depressive disorder
MRR mortality rate ratio
MS multiple sclerosis
NART National Adults Reading Test
NAS National Academy of Sciences
NDI National Death Index
NDV nondeployed veterans
NIH National Institutes of Health
NIS neuropathy impairment score
NOAA National Oceanic and Atmospheric Administration
NTE neuropathy target esterase
ODTP Oregon Dual Task Procedure
OPIDP organophosphate-induced delayed polyneuropathy
OR odds ratio
PASAT Paced Auditory Serial Addition Test
PB pyridostigmine bromide
PCL patient checklist
PCL-C Patient Checklist-Civilian
PCL-M Patient Checklist-Military
PFT pulmonary function test
PHQ Patient Health Questionnaire
PIR proportional incidence ratio
PMR proportional morbidity ratio
PON1 paraoxonase-1
POW prisoner of war
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PR prevalence ratio
PRIME-MD Primary Care Evaluation of Mental Disorders
PTSD posttraumatic stress disorder
QoLI quality of life index
RAC VA Research Advisory Committee on Gulf War Veterans’ Illnesses
RoM ratio of means
RR relative risk (or risk ratio as indicated in text)
SCAN Schedule for Clinical Assessment and Diagnosis
SCID Structured Clinical Interview for DSM-III-R
Sd standard deviation
SF-12 12-Item Short Form Health Survey
SF-36 36-Item Short Form Health Survey
SMR standardized mortality ratio
SNAP Schedule for Nonadaptive and Adaptive Personality
SSA Social Security Administration
TBI traumatic brain injury
TOMM Test of Memory Malingering
UK United Kingdom
VA Department of Veterans Affairs
WAIS Wechsler Adult Intelligence Scale
WCST Wisconsin Card Sorting Test
WHO World Health Organization
WMS Wechsler Memory Scale
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