SUMMARY

On August 2, 1990, Iraq invaded Kuwait. In response, the United States led a coalition of international armed forces in Operation Desert Shield, a buildup of military personnel and materiel in the Persian Gulf area. Operation Desert Storm began on January 16, 1991, with an air offensive; the 4-day ground war ended on February 28, and a ceasefire was signed in April 1991. Of the almost 700,000 US troops deployed to the Persian Gulf region during the height of the buildup, only about 50,000 US troops were still in the region by June 1991.

Many veterans of the Gulf War have reported a multitude of symptoms that began during or shortly after the war and, in many cases, have persisted to the present. The symptoms include fatigue, musculoskeletal pain, sleep disturbance, cognitive dysfunction, and moodiness. Numerous exposures experienced by veterans during the war have been implicated as the causes of these problems, including exposure to oil-well fire smoke and to the anti–nerve-gas agent prophylactic pyridostigmine bromide. The aggregation of the health problems, often called Gulf War illness or Gulf War syndrome, continues to plague as many as one-third of the veterans who were deployed to the war, and the symptoms are seen in veterans of several of the countries that formed the coalition forces, including the United States, the United Kingdom (UK), Australia, Canada, and Denmark.

In 1998, in response to the growing concerns about the health of the Gulf War veterans, Congress passed two laws: PL 105-277, the Persian Gulf War Veterans Act, and PL 105-368, the Veterans Programs Enhancement Act. Those laws directed the secretary of veterans affairs to enter into a contract with the National Academy of Sciences (NAS) to review and evaluate the scientific and medical literature regarding associations between illness and exposure to toxic agents, environmental or wartime hazards, or preventive medicines or vaccines associated with Gulf War service and directed the secretary to consider the NAS conclusions when making decisions about compensation. NAS assigned the study to the Institute of Medicine (IOM).

Given the large number of agents to study, IOM divided the task into several reviews, which are now complete: Gulf War and Health, Volume 1: Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines; Gulf War and Health, Volume 2: Insecticides and Solvents; Gulf War and Health, Volume 3: Fuels, Combustion Products, and Propellants; Gulf War and Health: Updated Literature Review of Sarin; Amyotrophic Lateral Sclerosis in Veterans: Review of the Scientific Literature; Gulf War and Health, Volume 4: Health Effects of Serving in the Gulf War; Gulf War and Health, Volume 5: Infectious Disease; Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress; and Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury.



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SUMMARY On August 2, 1990, Iraq invaded Kuwait. In response, the United States led a coalition of international armed forces in Operation Desert Shield, a buildup of military personnel and materiel in the Persian Gulf area. Operation Desert Storm began on January 16, 1991, with an air offensive; the 4-day ground war ended on February 28, and a ceasefire was signed in April 1991. Of the almost 700,000 US troops deployed to the Persian Gulf region during the height of the buildup, only about 50,000 US troops were still in the region by June 1991. Many veterans of the Gulf War have reported a multitude of symptoms that began during or shortly after the war and, in many cases, have persisted to the present. The symptoms include fatigue, musculoskeletal pain, sleep disturbance, cognitive dysfunction, and moodiness. Numerous exposures experienced by veterans during the war have been implicated as the causes of these problems, including exposure to oil-well fire smoke and to the anti–nerve-gas agent prophylactic pyridostigmine bromide. The aggregation of the health problems, often called Gulf War illness or Gulf War syndrome, continues to plague as many as one-third of the veterans who were deployed to the war, and the symptoms are seen in veterans of several of the countries that formed the coalition forces, including the United States, the United Kingdom (UK), Australia, Canada, and Denmark. In 1998, in response to the growing concerns about the health of the Gulf War veterans, Congress passed two laws: PL 105-277, the Persian Gulf War Veterans Act, and PL 105-368, the Veterans Programs Enhancement Act. Those laws directed the secretary of veterans affairs to enter into a contract with the National Academy of Sciences (NAS) to review and evaluate the scientific and medical literature regarding associations between illness and exposure to toxic agents, environmental or wartime hazards, or preventive medicines or vaccines associated with Gulf War service and directed the secretary to consider the NAS conclusions when making decisions about compensation. NAS assigned the study to the Institute of Medicine (IOM). Given the large number of agents to study, IOM divided the task into several reviews, which are now complete: Gulf War and Health, Volume 1: Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines; Gulf War and Health, Volume 2: Insecticides and Solvents; Gulf War and Health, Volume 3: Fuels, Combustion Products, and Propellants; Gulf War and Health: Updated Literature Review of Sarin; Amyotrophic Lateral Sclerosis in Veterans: Review of the Scientific Literature; Gulf War and Health, Volume 4: Health Effects of Serving in the Gulf War; Gulf War and Health, Volume 5: Infectious Disease; Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress; and Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury. 1

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2 GULF WAR AND HEALTH CHARGE TO THE COMMITTEE In 2005, the Department of Veterans Affairs (VA) requested that IOM appoint a committee, the Committee on Gulf War and Health: A Review of the Medical Literature Relative to Gulf War Veterans’ Health (the Volume 4 committee), to review that body of literature and to summarize what was known about the current status of veterans’ health. In 2006, the committee produced a report, Gulf War and Health, Volume 4: Health Effects of Serving in the Gulf War, which summarized the overall health effects in veterans and noted which health outcomes were more evident in Gulf War veterans than in their nondeployed counterparts irrespective of the specific exposures experienced by the deployed veterans. The present report is an update of Volume 4 and covers the literature published since 2005 on the health effects seen in veterans deployed to the Persian Gulf in 1990-1991. The specific charge to the Committee on Gulf War and Health: Health Effects of Serving in the Gulf War, Update 2009 (the Update committee), as requested by VA, was to review, evaluate, and summarize the literature on the following health outcomes that were noted in the 2006 report as seeming to have higher incidence or prevalence in Gulf War deployed veterans: cancer (particularly brain and testicular cancer), amyotrophic lateral sclerosis and other neurologic diseases (such as Parkinson’s disease and multiple sclerosis), birth defects and other adverse pregnancy outcomes, and postdeployment psychiatric conditions. The committee was also to review studies of cause-specific mortality in Gulf War veterans as recommended in the 2006 report. Finally, the committee was to examine the literature to identify any emerging health outcomes. Thus, the Update committee limited its review to epidemiologic studies of health outcomes published since the last literature search conducted for Volume 4. The committee included in its review only studies that compared the health status of Gulf War veterans with that of nondeployed veterans or veterans deployed elsewhere, such as in Bosnia or Germany. COMMITTEE’S APPROACH During its deliberations, the Update committee held two public sessions at which it heard from numerous interested parties, including representatives of veteran-service organizations and individual Gulf War veterans. VA Secretary Shinseki also asked the committee to invite representatives of the VA Research Advisory Committee on Gulf War Veterans’ Illnesses (RAC) to make presentations on the findings and conclusions in its report Gulf War Illness and the Health of Gulf War Veterans: Scientific Findings and Recommendations, released in November 2008. Extensive searches of the epidemiologic literature published since 2005 were conducted with the same search strategy as that used for Volume 4; over 1000 new citations were identified. After an assessment of the titles and abstracts found in the initial searches, the committee focused on some 400 potentially relevant epidemiologic studies for further review and evaluation. The committee adopted a policy of using only peer-reviewed publications as the basis of its conclusions except for some government reports. The process of peer review by fellow professionals increases the likelihood of high quality but does not guarantee the validity of a study or the ability to generalize its findings. Accordingly, committee members read each study

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SUMMARY 3 critically and considered its relevance and quality. The committee did not collect original data, nor did it perform any secondary data analysis. To be comprehensive in its approach to the epidemiologic literature, the committee also reviewed the studies that had been included in Volume 4 as primary or secondary studies. The Volume 4 committee did not draw conclusions about the strength of associations between specific exposures experienced during the Gulf War and particular health effects. However, Volume 4 did indicate what health outcomes were more prevalent in deployed veterans than in nondeployed veterans. The Update committee has been asked to determine the strength of associations between being deployed to the Gulf War and specific health effects. To make such a determination, the committee needed to review the studies cited in Volume 4 to assess whether they would still be classified as primary or secondary. The committee also tried to be comprehensive in its review of the literature inasmuch as the strength of an association would rest on a weight-of-the-evidence approach; that is, the committee considered it important to evaluate all primary and secondary studies that identified health outcomes so that a complete picture of the body of evidence could be presented. The Update committee then considered the epidemiologic studies identified in the updated literature search. Those studies were also reviewed and classified as primary or secondary according to the criteria discussed below. Once the committee had assessed the studies cited in Volume 4 and evaluated the new studies identified in the more recent literature, it considered the entire body of relevant literature and determined the strength of associations between being deployed to the Gulf War and specific health outcomes on the basis of all the primary studies and supported by the secondary studies. Because the committee was not attempting to link health outcomes to exposures other than deployment to the Persian Gulf theater, for which there is no known animal model, it did not review toxicologic, animal, or experimental studies comprehensively; however, it did evaluate the key epidemiologic and animal cited in the RAC report (see Appendix A). Epidemiologic studies that attempted to associate health effects in Gulf War veterans with specific exposures, such as oil-well fire smoke or nerve-gas agents, were also considered by the committee. VOLUME 4 CONCLUSIONS The Volume 4 committee cataloged the health outcomes that appeared to be more prevalent in veterans who had been deployed to the Gulf War than in veterans who served in the military at the same time but were not deployed to the Persian Gulf area, but it did not evaluate the strength of associations between deployment to the Gulf War and specific health outcomes. Studies were categorized as to whether the health outcomes seen in veterans were based on self- reports (including self-reports of physician diagnoses) or on objective measures, such as results of physical examinations by health-care providers or of laboratory tests. Using that approach, the Volume 4 committee found that on the basis of self-reports, deployed veterans had more symptoms indicative of multisymptom illness (although the symptoms did not appear to constitute a unique syndrome, illness, or symptom complex), such psychiatric disorders as posttraumatic stress disorder (PTSD), gastrointestinal disorders, skin disorders, joint pain, and respiratory disorders. However, when objective measures were used to diagnose the health outcomes seen in deployed and nondeployed veterans, different results were seen. Deployed veterans were more likely than nondeployed veterans to experience injury or death from

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4 GULF WAR AND HEALTH transportation accidents in the years immediately after the war and possibly were at increased risk for amyotrophic lateral sclerosis (ALS), and in one study deployed veterans’ offspring were more likely to have birth defects. Objective measures failed to show an increased prevalence of hospitalizations, cancer (results for testicular cancer were inconsistent), peripheral neuropathy, cardiovascular disease, diabetes, or pulmonary function in active-duty Gulf War veterans. The committee noted that few studies attempted to link specific exposures, such as exposure to oil- well fire smoke and possibly nerve agents released at Khamisiyah, to health outcomes. Only self- reports of exposure to oil-well fires were linked to an increase in self-reported respiratory symptoms that were suggestive of asthma and bronchitis. CONSIDERATIONS IN IDENTIFYING AND EVALUATING THE LITERATURE The Update committee sought to characterize and weigh the strengths and limitations of the available evidence presented in the studies that it reviewed. For Volume 4 of the Gulf War and Health series, numerous cohort studies and case control studies were objectively reviewed without preconceptions about health outcomes that might be seen in Gulf War veterans. The Volume 4 committee developed criteria to determine which studies to include in its review. The Update committee reviewed and used those criteria to evaluate the studies that have been published since Volume 4 and also uses categories of association to determine the strength of associations between deployment to the Gulf War and health outcomes. The categories of association have been used by the other reports in the Gulf War and Health series. Primary and Secondary Studies To be a primary study, which would be used by the committee to support its conclusions, a study needed to demonstrate rigorous methods (for example, to be published in a peer- reviewed journal, to include details of methods, to have a control or reference group, and to include adjustments for confounders if needed), needed to include information regarding a persistent health outcome, needed to have a medical evaluation conducted by a health professional, and needed to use laboratory testing as appropriate. Those types of studies constituted the committee’s primary literature. The committee did not evaluate studies of acute trauma, rehabilitation, medical treatment, or transient illness. Studies reviewed by the committee that did not necessarily meet all the criteria of a primary study were considered secondary studies. Secondary studies are typically not as methodologically rigorous as primary studies and might present subclinical findings; that is, they are studies of altered functioning consistent with later development of a diagnosis but without clear predictive value. The present report excludes studies of participants in Gulf War registries established by VA or the Department of Defense (DoD), such as DoD’s Comprehensive Clinical Evaluation Program. Registry participants cannot be considered representative of all Gulf War veterans in that they are self-selected subjects, many of whom have joined the registries because they believe that they have symptoms of a new medical syndrome; in addition, they were not randomly selected from all Gulf War military personnel, and there is no nondeployed control group.

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SUMMARY 5 Categories of Association The committee attempted to express its judgment of the available data clearly and precisely. It agreed to use the categories of association that have been established and used by previous Committees on Gulf War and Health and other IOM committees that have evaluated vaccine safety, effects of herbicides used in Vietnam, and indoor pollutants related to asthma. Those categories of association have gained wide acceptance over more than a decade by Congress, government agencies (particularly VA), researchers, and veterans groups. The five categories below describe different levels of association and present a common message: the validity of an observed association is likely to vary with the extent to which common sources of spurious associations could be ruled out as the reason for the association. Accordingly, the criteria for each category express a degree of confidence based on the extent to which sources of error were reduced. The committee members read each of each the studies carefully, noted the studies’ findings and limitations, and discussed the classification of each study (primary or secondary) in plenary session. The committee then discussed the weight of the evidence and reached consensus on the categorization of association to be assigned for each health outcome considered in this report. Sufficient Evidence of a Causal Relationship Evidence is sufficient to conclude that a causal relationship exists between being deployed to the Gulf War and a health outcome. The evidence fulfills the criteria for sufficient evidence of a causal association in which chance, bias, and confounding can be ruled out with reasonable confidence. The association is supported by several of the other considerations used to assess causality: strength of association, dose-response relationship, consistency of association, temporal relationship, specificity of association, and biologic plausibility. Sufficient Evidence of an Association Evidence suggests an association, in that a positive association has been observed between deployment to the Gulf War and a health outcome in humans; however, there is some doubt as to the influence of chance, bias, and confounding. Limited/Suggestive Evidence of an Association Some evidence of an association between deployment to the Gulf War and a health outcome in humans exists, but this is limited by the presence of substantial doubt regarding chance, bias, and confounding. Inadequate/Insufficient Evidence to Determine Whether an Association Exists The available studies are of insufficient quality, validity, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association between deployment to the Gulf War and a health outcome in humans. Limited/Suggestive Evidence of No Association There are several adequate studies, covering the full range of levels of exposure that humans are known to encounter, that are consistent in not showing an association between exposure to a specific agent and a health outcome at any level of exposure. A conclusion of no

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6 GULF WAR AND HEALTH association is inevitably limited to the conditions, levels of exposure, and length of observation covered by the available studies. In addition, the possibility of a very small increase in risk at the levels of exposure studied can never be excluded. MAJOR COHORT STUDIES Another step that the committee took in organizing its literature was to determine how all the study cohorts were related to one another. Numerous Gulf War cohorts have been assembled from several countries, and it is on the basis of those original cohorts that many derivative studies have been conducted and published. The committee organized the literature into the major cohorts and derivative studies because it did not want to interpret the findings of the same cohorts as though they were results of studies of unique groups. The largest studies of Gulf War veterans have been conducted in countries that were members of the Gulf War coalition, including the United States, the United Kingdom, Canada, Denmark, and Australia. Most major cohorts, once established, led to numerous studies that examined more detailed questions about Gulf War veterans’ health; the committee refers to these as derivative studies. The cohort studies of Gulf War veterans and the derivative studies have contributed greatly to our understanding of veterans’ health, but they are beset by limitations that are commonly encountered in epidemiologic studies, including lack of representativeness, selection bias, lack of control for potential confounding factors, self-reporting of health outcomes, outcome misclassification, and self-reporting of exposure. The committee considered studies that used both population-based cohorts and military- unit–based cohorts. Population-based studies of particular importance included the large nationally representative study of Gulf War deployed and nondeployed veterans conducted by VA to address congressional mandates, a study of Iowa veterans initiated by the Iowa Persian Gulf Study Group, a study of all Canadian Gulf War veterans, studies of Oregon and Washington veterans conducted by the Portland Environmental Hazards Research Center, and a study of Kansas veterans. Two teams of researchers in the United Kingdom studied separate, nonoverlapping samples of the over 53,000 UK military personnel sent to the Gulf War. The first team was from the University of London (Guy’s, King’s, and St. Thomas Medical Schools), and the second was from the University of Manchester. A third team of researchers from the London School of Hygiene and Tropical Medicine surveyed the entire cohort of 53,000 veterans for birth defects and other reproductive outcomes. Peacekeepers from Denmark were also studied for a variety of health outcomes, as was the entire Australian military contingent deployed to the Gulf War. Military-unit–based studies have been conducted on Air Force National Guard members from Pennsylvania; Fort Devens, MA; and New Orleans, LA; and Seabees, members of a naval reserve unit of a mobile construction battalion. In addition, several studies have looked at hospitalizations and mortality of Gulf War veterans since the war. HEALTH OUTCOMES The Update committee reviewed numerous new studies from the epidemiologic literature on Gulf War veterans and identified about 400 studies for in-depth evaluation. The latter studies and those described in Volume 4 formed the basis of the committee’s conclusions regarding associations between deployment to the Gulf War and long-term health outcomes. Most of the

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SUMMARY 7 studies compared the prevalence of a given medical condition or symptom in the deployed veterans with the prevalence in nondeployed veterans. If the prevalence of a symptom or condition was linked by the study authors to any specific exposures experienced during deployment—such as vaccines, oil-well fire smoke, anti-nerve-gas agents, or combat—the committee reviewed those associations as well. Although for the most part the Update committee considered the same health outcomes as did the Volume 4 committee, there were several differences: the Update committee added two new health outcomes: genitourinary diseases and diseases of the blood and blood-forming organs. The committee also used the term multisymptom illness to refer to a health outcome rather than the International Classification of Diseases, 9th revision, category of “signs, symptoms, and abnormal clinical and laboratory findings.” Chronic fatigue syndrome and multiple chemical sensitivity were included in the section on multisymptom illnesses; hospitalization and mortality studies were discussed in the relevant health-outcome sections; and chronic widespread pain was included in the section on fibromyalgia. All studies of each health outcome, including those originally cited in Volume 4, were reviewed and categorized as primary or secondary by the entire committee in plenary session before it came to a consensus on the appropriate category of association to be assigned to each health outcome. As in previous volumes of the Gulf War and Health series, the primary studies on which the committee based its conclusions are detailed in the evidence table at the end of each health-outcome section. Using the weight-of-the-evidence approach required that the Update committee be more rigorous in its review of the studies in Volume 4; as a result, some studies considered to be primary in Volume 4 were recategorized as secondary for the present report and vice versa. Thus, the Update committee summarizes de novo the information from both Volume 4 and any new publications to arrive at its conclusions on the strength of associations between deployment to the Gulf War and health outcomes. Box S-1 summaries the health outcomes assigned to each category of association by the Update committee. QUALITY OF THE STUDIES Many studies of Gulf War veterans have been conducted, but their quality is varied, and many have substantial limitations. As a result, there is still uncertainty about the relationship between deployment to the Gulf War and health outcomes. The limitations include • Lack of representativeness of the entire Gulf War population in some studies, which affects external validity in such a way that what we learn from the population studied cannot be easily extrapolated to all Gulf War veterans. • Low participation rates and differential participation rates in many studies, which affect internal validity because of selection bias (for example, significantly higher rate of response of deployed veterans than of nondeployed control groups and the possibility that deployed troops participated because they already experienced health problems). • Narrowness of assessment of health status (for example, self-reported outcomes, such as hypertension, diabetes, and cardiovascular disease), or insufficient sensitivity or validity of instruments to detect abnormalities in deployed veterans (for example, death certificates or hospital discharge diagnoses); there is a particular problem with self-reported exposures, especially if respondents are aware of mass-media reports that link outcomes with putative exposures.

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8 GULF WAR AND HEALTH BOX S-1 Summary of Findings Regarding Associations Between Deployment to the Gulf War and Specific Health Outcomes Sufficient Evidence of a Causal Relatioonship • PTSD. Sufficient Evidence of an Association • Other psychiatric disorders, including generalized anxiety disorder, depression, and substance abuse, particularly alcohol abuse. These psychiatric disorders persist for at least 10 years after deployment. • Gastrointestinal symptoms consistent with functional gastrointestinal disorders such as irritable bowel syndrome and functional dyspepsia. • Multisymptom illness. • Chronic fatigue syndrome. Limited/Suggestive Evidence of an Association • ALS. • Fibromyalgia and chronic widespread pain. • Self-reported sexual difficulties. • Mortality from external causes, primarily motor-vehicle accidents, in the early years after deployment. Inadequate/Insufficient Evidence to Determine Whether an Association Exists • Any cancer. • Diseases of the blood and blood-forming organs. • Endocrine, nutritional, and metabolic diseases. • Neurocognitive and neurobehavioral performance. • Multiple sclerosis. • Other neurologic outcomes, such as Parkinson’s disease, dementia, and Alzheimer’s disease. • Incidence of cardiovascular diseases. • Respiratory diseases. • Structural gastrointestinal diseases. • Skin diseases. • Musculoskeletal system diseases. • Specific conditions of the genitourinary system. • Specific birth defects. • Adverse pregnancy outcomes such as miscarriage, stillbirth, preterm birth, and low birth weight. • Fertility problems. Limited/Suggestive Evidence of No Association • Peripheral neuropathy. • Mortality from cardiovascular disease in the first 10 years after the war. • Decreased lung function in the first 10 years after the war. • Hospitalization for genitourinary diseases. • Timing of investigations relative to the latency of some health outcomes (for example, cancer and some neurologic outcomes, such as multiple sclerosis [MS], ALS, and Parkinson’s disease).

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SUMMARY 9 • Use of cross-sections, which limits assessment of symptom duration and chronicity, latency of onset, severity, and prognosis. Virtually all the reports in the Gulf War and Health series have called for improved studies of Gulf War and other veterans. The Update committee reiterates that need but notes that it is difficult if not impossible 20 years after the war to reconstruct the exposures to which the veterans were subjected in theater or to establish years after deployment the predeployment physical and mental health status of the veterans for comparison purposes. Therefore, the committee believes that future studies of Gulf War veterans—and indeed any veteran population—need to be adequately designed to • Provide sufficient statistical power (precision). • Ensure validity, including the avoidance of such bias as response bias and recall bias, which lead deployed and nondeployed veterans to participate unequally, depending on general health and symptom presence and severity, or to report symptoms differently according to perceived exposures and health status. • Improve disease measurement to avoid misclassification; for example, including information collected from non-DoD hospitals in studies of hospitalization, obtaining cancer incidence data from existing cancer registries, validating self-reports of health outcomes, and using the least error-prone measures of these outcomes. • Characterize deployment and potential related adverse environmental influences better by, for example, collecting information on the length and location of deployment and on jobs and tasks. • Measure and adjust for possible confounding factors by, for example, measuring and adjusting for lifestyle factors (such as smoking and risk-taking behaviors) and predeployment physical and psychologic health status. RECOMMENDATIONS After almost two decades of research on Gulf War veterans, important questions about their health remain unanswered. In particular, the nature and extent of the multisymptom illness reported in the veterans warrant further research to refine its diagnosis and develop effective treatments. The committee believes that the path forward for veterans has two branches. The first is continued surveillance of deployed and nondeployed Gulf War veterans. • Although further investigations based solely on self-reporting are not likely to contribute substantially to the understanding of Gulf War illness, well-designed follow-up studies of mortality, cancer, neurologic, and psychiatric outcomes will continue to be valuable. Well- designed, adequately powered studies of MS and ALS incidence after deployment are also needed. • Methodologically robust cohorts need to be assembled and followed carefully to track the development of ALS, MS, brain cancer, psychiatric conditions, and health problems that occur at a later age, such as other cancers, cardiovascular disease, and neurodegenerative diseases. Several well-characterized cohorts that could form the basis of future studies have already been established, such as the US cohort studied by VA, the two UK cohorts, and the

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10 GULF WAR AND HEALTH Canadian, Danish, and Australian cohorts. Relatively small cohorts, such as the Canadian and Australian veterans, might not be useful for outcomes of low incidence (for example, ALS and brain cancer), but they might be very useful for tracking frequent outcomes, for example, multisymptom illness, cardiovascular and respiratory diseases, other cancer types, such neurodegenerative conditions as dementia, and some psychiatric disorders. • With regard to functional gastrointestinal disorders (irritable bowel syndrome and functional dyspepsia), recent evidence supports the need for two types of studies: to determine the role of prior acute gastroenteritis in the development of these disorders in deployed soldiers and to use symptom-specific criteria (for example, Rome criteria) to clarify the association of medical and psychosocial comorbidities with functional gastrointestinal disorders and their severity. • Uncommon genetic variants and rare environmental events may not be recognized as associated with outcomes of interest unless very large numbers of people are studied or sophisticated capture methods are used to explore them. For example, new and objective information related to exposures that becomes available in the future might improve our ability to estimate individual exposures and to stratify groups of Gulf War veterans. A second branch of inquiry is also important. It consists of a renewed research effort to identify and treat multisymptom illness in Gulf War veterans. Given the high prevalence of persistent symptoms and the steady advances in our understanding of genetics, molecular diagnostics, and imaging, it is now possible to plan and carry out adequately powered studies to identify inherited genetic variants, molecular profiles of gene expression, other epigenetic markers (for example, modifications of DNA structure related to environmental exposures), specific viral exposures, signatures of immune activation, and brain changes identified by sensitive imaging measures that distinguish Gulf War veterans who have persistent medical symptoms from healthy deployed or nondeployed veterans. The committee is optimistic that a rigorous, adequately powered study could identify useful biomarkers that are helpful for symptomatic veterans of the Gulf War and for nondeployed veterans and civilians who have a variety of medically unexplained symptoms, including chronic fatigue, muscle and joint pain, sleep disturbance, difficulty with concentration, and depression. Finally, the committee notes that inadequate numbers of clinical trials have been undertaken to develop more effective and evidence-based treatments for multisystem illness. Aligned with efforts to improve care pathways for veterans suffering from multisymptom illness, a focused effort should be undertaken to support high-quality clinical trials informed by the best available biologic information related to the cause of multisystem illness. The committee believes that a continued and targeted research program is the most likely path to assist VA and other health-care providers in diagnosing and treating the health problems of Gulf War veterans and preventing illness in future veterans.