5
CONCLUSIONS AND RECOMMENDATIONS

The Update committee was asked to review, evaluate, and summarize the literature on the health outcomes identified in Gulf War and Health, Volume 4: Health Effects of Serving in the Gulf War (IOM, 2006), with an emphasis on those outcomes that appeared to occur at higher incidence or prevalence in veterans deployed to the Gulf War, in particular: cancer, amyotrophic lateral sclerosis (ALS) and other neurologic diseases, birth defects and other adverse pregnancy outcomes, and postdeployment psychiatric conditions. The committee also was asked to review studies on cause-specific mortality in Gulf War veterans as recommended in the 2006 report and to identify any emerging health outcomes seen in Gulf War veterans. In preparing this report, the Update committee modified the health outcomes that were reviewed in Volume 4. For example, the Update committee included genitourinary outcomes, considered multisymptom illness as a separate entity rather than using the ICD category of “symptoms, signs, and abnormal clinical and laboratory findings,” and did not include multiple chemical sensitivity or chronic fatigue syndrome as separate outcomes, but rather considered them as multisymptom illnesses. Furthermore, the Update committee included the diseases and disorders identified in the several hospitalization and mortality studies in the discussion of each relevant health outcome, rather than as a separate outcome.

The approaches used by the Volume 4 committee and the Update committee for reviewing the literature differed and are reflected in the separate conclusions reached by the two committees. Because the task of the Volume 4 committee was to catalog the health outcomes that appeared to have greater prevalence in veterans who had been deployed to the Gulf War compared with veterans who served in the military at the same time but were not deployed to the Persian Gulf area, the Volume 4 committee did not specifically evaluate the strength of association between deployment to the Gulf War and individual health outcomes. Rather it categorized studies on whether the health outcomes seen in veterans were based on self-reports (including self-reports of physician diagnoses) or on objective measures such as a physical examination by a health-care provider and/or laboratory tests. Using that approach, the Volume 4 committee found that deployed veterans more frequently reported symptoms indicative of multisymptom illness (although the symptoms did not appear to constitute a unique syndrome, illness, or symptom complex), psychiatric disorders such 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, the results were different. Deployed veterans were more likely to experience injury or death from motor vehicle accidents in the years immediately after the war, to possibly be at increased risk of ALS, and one study showed more birth defects in offspring of



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5 CONCLUSIONS AND RECOMMENDATIONS The Update committee was asked to review, evaluate, and summarize the literature on the health outcomes identified in Gulf War and Health, Volume 4: Health Effects of Serving in the Gulf War (IOM, 2006), with an emphasis on those outcomes that appeared to occur at higher incidence or prevalence in veterans deployed to the Gulf War, in particular: cancer, amyotrophic lateral sclerosis (ALS) and other neurologic diseases, birth defects and other adverse pregnancy outcomes, and postdeployment psychiatric conditions. The committee also was asked to review studies on cause-specific mortality in Gulf War veterans as recommended in the 2006 report and to identify any emerging health outcomes seen in Gulf War veterans. In preparing this report, the Update committee modified the health outcomes that were reviewed in Volume 4. For example, the Update committee included genitourinary outcomes, considered multisymptom illness as a separate entity rather than using the ICD category of “symptoms, signs, and abnormal clinical and laboratory findings,” and did not include multiple chemical sensitivity or chronic fatigue syndrome as separate outcomes, but rather considered them as multisymptom illnesses. Furthermore, the Update committee included the diseases and disorders identified in the several hospitalization and mortality studies in the discussion of each relevant health outcome, rather than as a separate outcome. The approaches used by the Volume 4 committee and the Update committee for reviewing the literature differed and are reflected in the separate conclusions reached by the two committees. Because the task of the Volume 4 committee was to catalog the health outcomes that appeared to have greater prevalence in veterans who had been deployed to the Gulf War compared with veterans who served in the military at the same time but were not deployed to the Persian Gulf area, the Volume 4 committee did not specifically evaluate the strength of association between deployment to the Gulf War and individual health outcomes. Rather it categorized studies on whether the health outcomes seen in veterans were based on self-reports (including self-reports of physician diagnoses) or on objective measures such as a physical examination by a health-care provider and/or laboratory tests. Using that approach, the Volume 4 committee found that deployed veterans more frequently reported symptoms indicative of multisymptom illness (although the symptoms did not appear to constitute a unique syndrome, illness, or symptom complex), psychiatric disorders such 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, the results were different. Deployed veterans were more likely to experience injury or death from motor vehicle accidents in the years immediately after the war, to possibly be at increased risk of ALS, and one study showed more birth defects in offspring of 255

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256 GULF WAR AND HEALTH deployed veterans. Objective measures failed to show an increased prevalence of hospitalizations among active-duty Gulf War veterans, cancer (results for testicular cancer were inconsistent), peripheral neuropathy, cardiovascular disease, diabetes, or pulmonary function. The committee noted the few studies that attempted to link specific exposures, such as oil-well fire smoke and possible 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. As described in Chapter 4, the Update committee used a different approach for reviewing the literature. It considered studies that used only self-reports by Gulf War veterans to be secondary studies for most health outcomes; the major exception to this rule was multisymptom illness. However, some health outcomes, such as fibromyalgia or irritable bowel syndrome, lack objective diagnostic tests and are diagnosed based on symptom reporting that meet accepted criteria (for example, the Centers for Disease Control and Prevention criteria for chronic fatigue syndrome and the Rome criteria for irritable bowel syndrome). When the symptom reporting was sufficiently descriptive to meet the diagnostic criteria for that outcome, those studies were considered to be primary if the other evaluation criteria for a primary study (described in Chapter 4) were met. Studies that used objective measures to diagnose a health outcome were also considered to be primary if they met the other evaluation criteria. The conclusions reached by the committee regarding the strength of the association between deployment to the Gulf War and each health outcome are summarized below. The committee notes that the majority of studies that it reviewed were conducted on both men and women, but for most studies, results for women were not presented separately as the number of women was relatively small. Results specific for women were presented in Chapter 4. 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, and 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 biological plausibility. • PTSD. 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 chance, bias, and confounding. • Other psychiatric disorders, including generalized anxiety disorder, depression, and substance abuse, particularly alcohol abuse. Furthermore 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.

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CONCLUSIONS AND RECOMMENDATIONS 257 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 in that substantial doubt exists regarding chance, bias, and confounding. • 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 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. • Any cancers. • Disorders 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. • Cardiovascular disorders. • Respiratory diseases. • Structural gastrointestinal diseases. • Skin diseases. • Musculoskeletal disorders. • Other 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 There are several adequate studies, covering the full range of levels of exposure that humans are known to encounter, that are mutually 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 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 elevation in risk at the levels of exposure studied can never be excluded. • Peripheral neuropathy. • Mortality from cardiovascular disease in the first 10 years after the war.

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258 GULF WAR AND HEALTH • Decreased lung function in the first 10 years after the war. • Hospitalization for genitourinary diseases. QUALITY OF THE STUDIES Virtually all the reports in the Gulf War and Health series have called for improved studies of Gulf War and other veterans. This committee reiterates that need but notes that at almost 20 years after the war, it is difficult, if not impossible, to reconstruct the exposures to which the veterans were subjected in theater. It is similarly difficult after so many years to establish the predeployment physical and mental health status of these veterans for comparison purposes. Nevertheless, • To date, while many studies have been conducted on Gulf War veterans, their quality is varied and many of them have substantial methodological limitations. As a result uncertainty remains concerning the relationship between deployment to the Gulf War and health outcomes. These limitations include: ° Lack of representativeness of the Gulf War population in some studies, affecting external validity such that what we have learned from the samples studied cannot be easily extrapolated to all Gulf War veterans. ° Low participation rates and, indeed, differential participation rates in many studies, affecting internal validity due to selection bias. For example, the significantly higher response rate among deployed veterans compared with nondeployed control groups observed in many studies may result from greater participation of deployed troops because they were already experiencing health problems. ° Studies that may have been too narrow in their assessment of health status (for example, self-reported outcomes such as hypertension, diabetes, or cardiovascular disease), or use of data collection instruments that might have been too insensitive (or invalid) to detect abnormalities in deployed veterans (for example, death certificates or hospital-discharge diagnoses). ° There is a particular problem with self-reported exposures, especially when respondents are aware of media reports linking outcomes with putative exposures. ° Timing of the investigation relative to the latent period for some health outcomes (for example, cancer, and some neurologic outcomes, such as MS, ALS, or Parkinson’s disease, for which there might be a long time between exposure and disease onset). ° Use of cross-sectional studies that limit assessment of temporality, symptom duration and chronicity, latency of onset, severity, and prognosis. • Future studies of Gulf War veterans, and indeed any veteran population, need to be adequately designed in order to: ° Provide sufficient statistical power (precision). ° Ensure validity, including the avoidance of bias, such as recall and response bias, meaning that efforts should be made to encourage equal participation among deployed and nondeployed individuals with the goal of avoiding participation rates linked to general health and symptom presence, and to ensure comparable assessment of the severity and frequency of reported symptoms.

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CONCLUSIONS AND RECOMMENDATIONS 259 ° 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. ° Better characterize deployment and potentially related adverse environmental influences; for example, collect information on the length and location of deployment or job and task descriptions. ° Measure and adjust for possible confounding factors; for example, lifestyle factors (such as smoking and risk-taking behaviors) or predeployment physical and psychological health status. POSSIBLE CAUSES OF MULTISYMPTOM ILLNESS IN VETERANS During its deliberations, the Update committee held two public sessions at which it heard from numerous interested parties including representatives of veterans’ service organizations and individual Gulf War veterans. The committee was also asked by VA secretary Gen. Shinseki to invite representatives of the VA Research Advisory Committee on Gulf War Veterans’ Illnesses (RAC) to make presentations to the committee on the findings and conclusions in its report, Gulf War Illness and the Health of Gulf War Veterans, released in November 2008, to “ensure that the basis for any differences between these reports can be efficiently and accurately communicated and considered by the latest IOM committee.” The Update committee concluded, based on a comprehensive review of the human epidemiologic literature, that there is sufficient evidence of an association between deployment to the Gulf War and multisymptom illness (see Chapter 4). The RAC, however, had concluded that the constellation of symptoms called Gulf War illness was caused by exposure to pyridostigmine bromide (PB) and to pesticides during the Gulf War, and that other exposures might also be implicated in Gulf War illness. The Update committee felt it was important to consider this major RAC conclusion regarding the cause of Gulf War illness and the evidence used to support that conclusion in order to respond to Gen. Shinseki’s request. A comprehensive assessment of all the evidence on PB and pesticides exposures in the Gulf War was beyond the Update committee’s formal scope of work. The committee, therefore, limited its assessment to those studies used by the RAC to support its conclusion on the cause of Gulf War illness. The committee believed that its assessment of those RAC studies was best presented in an appendix. Although the Update committee did not assess the biological plausibility of the link between PB and pesticides and Gulf War illness, in keeping with its charge to examine the strength of association between deployment to the Gulf War and various human health outcomes, the committee critically examined the human exposure studies cited by the RAC as evidence that PB and pesticides are causally associated with Gulf War illness (see Appendix A). However, in contrast to the RAC report, the Update committee found that human epidemiologic evidence was not sufficient to establish a causative relationship between any specific drug, toxin, plume, or other agent, either alone or in combination, and Gulf War illness. Given this important issue, the Update committee also undertook an assessment of the key experimental research studies that were cited in the RAC report as supporting the plausibility of this association. This focused assessment of the experimental literature, summarized in Appendix A, did not meet, in the committee’s opinion, a threshold that would lead to the conclusion that any Gulf War illness-

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260 GULF WAR AND HEALTH related problems could reasonably be expected to result from these putative exposures. Indeed, the committee concludes that many key questions remain unanswered. This is true both with respect to the underlying cause or causes of the multisystem illness complex experienced by so many of the Gulf War soldiers, and also with respect to the adequacy of the experimental studies that have addressed the potential contribution of any external agent to the development, course, or persistence of this perplexing disorder. The committee concludes that it is essential to keep in mind that other etiologic factors may also play a role, and research into this matter must continue. The committee also concludes that it is possible that the specific cause(s) of the many and diverse symptoms reported by the veterans may never be determined given the limitations of the available data. To not acknowledge the uncertainty of what we know and the real possibility of not being able to identify a cause of the veterans’ illnesses would be a disservice to medical science and more importantly to the men and women who served so courageously in this battleground. There are other areas of research that might be conducted on the etiology of Gulf War illness. The constellation of unexplained symptoms associated with the Gulf War illness complex could result from interplay between both biological and psychological factors. However, it is important to remember that there are a number of different causes for a disease, but due to the paucity of data it will be difficult to disentangle these for Gulf War illness. The symptoms of Gulf War illness could have a single cause, different causes in different individuals, or require multiple factors operating in combination. Studies that lead to a better understanding of how biological and psychological factors give rise to variety of symptoms are needed as they may be the key to understanding and treating the Gulf War illness complex. For example, certain exposures may lead to alterations in blood– brain barrier permeability, neural pathways or transmitters, or neuroendocrine systems. It is also important to consider the effects of chronic stress, and, given the physical environment in the Persian Gulf, thermal dysregulation, an area that has received little attention to date. THE PATH FORWARD After almost two decades of research on Gulf War veterans, important questions remain unanswered. What are the causes of the multisymptom illness experienced by veterans? How does predeployment health status influence the risk of developing Gulf War illness? Why do some veterans suffer a constellation of many symptoms whereas others experience isolated symptoms or only some components of the illness, and still others who served in the same battleground seemingly with similar exposures remain entirely without symptoms? Why do some veterans who were not on the ground in the Persian Gulf area (for example, Australian troops at sea), or others who arrived after the conclusion of the battle (for example, Danish forces), also experience symptoms of Gulf War illness? How severe and disabling are residual Gulf War symptoms? What are the most effective treatments for veterans who do suffer from multisymptom illness, and should the treatments vary depending on specific symptoms? Beyond the perplexing problem of Gulf War illness, what are the overall long-term physical and mental health consequences of serving in the Gulf War? The committee believes that the path forward for veterans has two branches. The first is continued surveillance of Gulf War veterans. Such surveillance might include the following:

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CONCLUSIONS AND RECOMMENDATIONS 261 • Although further investigations based solely on self-reports are not likely to contribute significantly to increased understanding of Gulf War illness, well-designed follow-up studies of mortality, cancer, and neurologic and psychiatric outcomes will continue to be valuable. Well-designed, adequately powered studies of MS and ALS incidence following deployment are also needed. • Methodologically robust cohorts need to be assembled now and followed carefully to track the development of ALS, MS, brain cancer, and psychiatric conditions, as well as the appearance of additional health issues that occur at a later age, such as other cancers, cardiovascular disease, and neurodegenerative diseases. Several well-characterized cohorts have already been established that could form the basis of future studies. For example, the US cohort studied by the VA; the two UK cohorts; and the Canadian, Danish, and Australian cohorts. Relatively small cohorts, such as the Canadian or Australian veterans, might not be useful for outcomes with low incidence (for example, ALS or brain cancer), but they might be very useful for tracking frequently seen health outcomes such as Gulf War illness, cardiovascular and respiratory diseases, other cancer types, neurodegenerative conditions such 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: one type will determine the role of prior acute gastroenteritis among deployed soldiers in the development of these disorders, and the second type will 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 or rare environmental events may not be recognized as associated with an outcome of interest unless very large numbers of individuals are studied or sophisticated capture methods are used to explore specific hypotheses. It is possible, for example, that new and objective information related to exposures might become available in the future that could improve our ability to estimate individual exposures and to assess health effects in groups of Gulf War veterans according to specific exposures. In addition to epidemiologic studies, the committee believes that a second branch of inquiry is important. This consists of a renewed research effort with substantial commitment to well-organized efforts to better identify and treat multisymptom illness in Gulf War veterans. Given the high reported prevalence of persistent symptoms, plus the steady advances in understanding genetics, molecular diagnostics, and imaging, it is possible now to plan and carry out adequately powered studies to identify inherited genetic variants, molecular profiles of gene expression, other epigenetic markers (such as modifications of DNA structure related to environmental exposures), specific viral exposures, signatures of immune activation, or brain changes identified by sensitive imaging measures—all these are traits that distinguish Gulf War veterans with persistent medical symptoms from healthy deployed or nondeployed veterans. The committee is optimistic that a rigorous, adequately powered analysis would identify useful biomarkers that might not only be helpful for symptomatic veterans of the Gulf War but also for nondeployed veterans and for civilians with a range of medically unexplained symptoms including chronic fatigue, muscle and joint pains, sleep disturbances, difficulty with concentration, and depression. As with many other disorders, it is likely that Gulf War illness results from an interplay of genetic and environmental factors; genetics may play a larger role for some affected

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262 GULF WAR AND HEALTH individuals, whereas the environment is predominant for others. In general, the more complex and heterogeneous a disorder, the larger the number of subjects needed to unravel its etiology. The value of identifying even minor genetic contributors to an unknown disease cannot be overstated, as such discoveries can reveal previously unknown causative pathways that can also clarify potential environmental agents as well as potential therapeutic targets. Subsequent investigations should also explore the biology of Gulf War illness in the context of identifying targets for therapies. These studies might include, but are not limited to, the following goals: • Determine whether inflammation is associated with Gulf War illness. • Evaluate the status of genetic variation in genes that respond to environmental toxicants, such as paraoxonase 1 (PON1). Variants of these genes could be present differentially in sufferers of Gulf War illness. • Improve understanding of the basic symptom complex of Gulf War illness. For example, what is the nature of specific complaints, their severity, and the resulting disability? • Enhance understanding of the objective correlates of Gulf War illness. For example, can sleep disturbances or potential dysfunction of the autonomic nervous system be better understood? • Validate reported biomarkers of Gulf War illness, including anatomic and functional imaging findings and published immune associations. • There is a dearth of organized clinical trials to examine potential treatments for the observed symptoms experienced by Gulf War veterans. Aligned with the effort to improve care pathways for Gulf War illness sufferers, there should be a focused effort to consider the development of clinical trials informed by the best biological data related to the cause of Gulf War illness. Answers to these questions will help to address the issue of possible causes of Gulf War illness and, more importantly, are essential for the development of effective treatments. Detailed planning with access to the very best expertise in medicine, epidemiology, toxicology, imaging, molecular biology, and clinical trials will maximize the chances of success. Careful clinical ascertainment and development of unbiased assembled samples of adequate size are additional prerequisites. For example, given the likely small effect size of any genetic variant that might contribute to multisymptom illness, DNA samples from a cohort of 10,000 affected and an equal number of unaffected individuals might be required for a genome-wide exploration of susceptibility for modifier genes contributing to multisymptom illness. Patient cohorts of this size are now routinely collected for modern investigations of complex illnesses. Given current estimates that more than 250,000 US Gulf War veterans have persistent unexplained medical symptoms, it is feasible to collect two such cohorts for genetic analysis (the first for identification of associated variants and the second for replication). The funding needs to support a study of this magnitude would be substantial but could also present a new opportunity to promote cooperation among different funding sources and provide high-level coordination for an important health problem. A new consortium among the VA, DoD, and National Institutes for Health (NIH) could be established for this purpose, perhaps with participation by the private sector for drug development and clinical trials. The participation and perhaps leadership of the Clinical Translational Sciences Consortium at the NIH would also be worth exploration. The overall goal would be to provide a centrally coordinated but facile organization capable of

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CONCLUSIONS AND RECOMMENDATIONS 263 creating an adequately powered dataset and then encouraging practical and innovative science aimed at understanding the basis of unexplained symptoms in Gulf War veterans and developing effective treatments in order to alleviate their suffering as rapidly and completely as possible.

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