In response to the invasion of Kuwait by Iraq in August 1990, the United States led a coalition of 34 countries in a buildup of forces in the Persian Gulf called Operation Desert Shield. This multinational effort was followed by Operation Desert Storm, which began in January 1991 with an air offensive and a 4-day ground war. The war was over by the end of February, and a ceasefire was signed in April 1991. Of the almost 700,000 U.S. troops deployed to the Persian Gulf region during the height of the buildup, only about 50,000 U.S. troops were still in the region by June 1991. Although brief with relatively few injuries and deaths among the coalition forces, the legacy of the war has been a substantial contingent of veterans who suffer from a number of health problems that have persisted for more than 25 years.
As in any war, the service members who were deployed to the theater of conflict were exposed to many hazardous agents and situations, both known and unknown. These exposures ranged from chemical and biological agents to mandatory vaccines, as well as oil-well fire smoke, dust, high ambient temperatures and heat stress, pesticides, and pyridostigmine bromide (PB), a prophylactic agent against potential nerve agent exposure.
During and after the Gulf War, veterans began reporting a variety of health problems, particularly a constellation of symptoms that have been termed Gulf War illness, and these problems continue to plague many of them to this day. In 1998, in response to the health concerns of the veterans, Congress passed two laws: Public Law (P.L.) 105-277, the Persian Gulf War Veterans Act, and P.L. 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), now part of the National Academies of Sciences, Engineering, and Medicine.
The nine prior reports in the Gulf War and Health series deal with specific deployment exposures or veteran health status:
Volume 1: Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines
Volume 2: Insecticides and Solvents
Volume 3: Fuels, Combustion Products, and Propellants
Volume 4: Review of the Scientific Literature
Volume 5: Infectious Disease
Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress
Volume 7: Long-Term Consequences of Traumatic Brain Injury
Volume 8: Update of Health Effects of Serving in the Gulf War
Volume 9: Long-Term Effects of Blast Exposures
The specific charge to the Volume 10 committee, as requested by the Department of Veterans Affairs (VA), is to
comprehensively review, evaluate, and summarize the available scientific and medical literature regarding health effects in the 1990–1991 Gulf War veterans. The committee will pay particular attention to neurological disorders (e.g., Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and migraines), cancer (especially brain cancer and lung cancer), and chronic multisymptom illness. The proposed study will update earlier IOM reviews on Gulf War and Health, and this volume (Volume 10) will update the literature since the publication of the 2006 (Volume 4) and 2010 (Volume 8) Gulf War and Health reports. The committee will also provide recommendations for future research efforts on Gulf War veterans.
The committee held two public sessions to put its efforts in context and to clarify an approach to its task. The committee heard from representatives of VA and from several Gulf War veterans about their health conditions that have persisted since the war, particularly the symptoms associated with Gulf War illness. The committee also heard presentations from representatives of the VA Research Advisory Committee on Gulf War Veterans’ Illnesses, who discussed that committee’s findings and recommendations, and from several researchers who have been studying Gulf War illness. The committee did not address policy issues, such as service connection, compensation, or the cause of or treatment for Gulf War illness.
Extensive searches of the epidemiologic literature were conducted using the same search strategy as for Volume 8. Literature searches were also conducted to look for studies of Gulf War illness or other toxicologic endpoints using animals, in which the animals were exposed to a mixture of agents that attempted to simulate those experienced by Gulf War veterans during deployment. The committee adopted a policy of using only peer-reviewed publications as the basis of its conclusions except for some government reports and one presentation. Accordingly, committee members read each study 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 Volumes 4 and 8 as primary or secondary studies and the conclusions reached by those committees. The Volume 10 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. The committee 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. Although the majority of the studies considered by the committee for this report were epidemiologic, other types of studies—such as animal toxicology, neuroimaging, and genetics—were assessed in the same manner as other health conditions.
Primary and Secondary Studies
For a study to be included in the committee’s review as primary it had to meet specified criteria. It had to be published in a peer-reviewed journal or other rigorously peer-reviewed publication, such as a government report or monograph; have sufficient detail to demonstrate rigorous methods (e.g., had a control or reference group, and included adjustments for confounders when needed, included necessary level of detail of the methods); include information regarding a persistent health outcome; and use appropriate laboratory testing, if applicable. Furthermore, the sample size needed to suggest that it was generalizable to and representative of the Gulf War veteran population.
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, studies of altered functioning consistent with later development of a diagnosis but without clear predictive value. Many of the secondary studies relied on self-reports of various diagnoses rather than an examination by a health professional or a medical record review.
The Volume 10 committee also included a number of studies that did not meet the criteria for a primary or secondary study, but nonetheless provided information on the health of Gulf War veterans. In an effort to be inclusive, these ancillary studies are discussed in a section called “Other Related Studies” for each health outcome to which they pertain; however, no conclusions were based solely on these ancillary studies.
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 Gulf War and Health and other IOM committees that have evaluated scientific literature. Those categories of association have gained wide acceptance for more than a decade by Congress, government agencies (particularly VA), researchers, and veterans groups.
The committee members read each of 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. 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.
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 such as strength of association, dose–response relationship, temporal relationship, 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. The possibility of a very small increase in risk at the levels of exposure studied can never be excluded.
As noted in earlier volumes, the largest studies of Gulf War veterans have been conducted in countries that were members of the Gulf War coalition, including Australia, Canada, Denmark, the United Kingdom, and the United States. 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 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 for unique groups. The cohort studies of Gulf War veterans and the derivative studies have contributed greatly to our understanding of veterans’ health, but they have some of the limitations that are commonly encountered in epidemiologic studies, such as lack of representativeness, selection bias, lack of control for potential confounding factors, self-reporting of health outcomes, and self-reporting of exposure.
The committee considered studies that used both population-based cohorts and cohorts based on military units. Since Volume 8, few studies have been published on the large veteran cohorts. Several of the new studies reviewed by the Volume 10 committee used data from a large nationally representative study by VA of Gulf War deployed and nondeployed veterans, and further assessments of the entire Australian military contingent deployed to the Gulf War.
The Volume 10 committee reviewed new and old studies from the epidemiologic literature on Gulf War veterans and used those studies to form the basis of the committee’s conclusions regarding associations between deployment to the Gulf War and long-term health outcomes. Most of the studies compared the prevalence of a given medical condition or symptom in the deployed veterans with the prevalence in nondeployed veterans. A small number of studies also looked at the prevalence of health conditions linked to exposure to depleted uranium. For several outcomes only one study, or in some cases no studies, were of sufficient quality to meet the criteria for a primary study. For health outcomes for which new evidence was available, the data tended to support conclusions that generally were in accordance with the findings of prior Gulf War and Health committees.
The committee reviewed more than 50 animal studies that used a variety of protocols to assess multiple chemical and other exposures (e.g., simultaneous or sequential exposure to PB, pesticides, and stress) that attempted to simulate Gulf War exposures. However, the wide variation in the exposure models and in the number and types of outcomes that were assessed (e.g., effects on brain, behavior, reproductive, musculoskeletal, immune, and pain), make comparisons across the animal studies difficult. Most animal studies tended to focus on isolated symptoms of Gulf War illness, again adding to the uncertainty about how representative the effects seen in animals were of veterans’ symptoms. In addition, the observed effects were not usually replicated by other researchers, making it difficult to conclude whether the animal models provide support for linking Gulf War exposures to veterans’ health outcomes, particularly with regard to Gulf War illness. Thus, animal studies have not been successful in suggesting a mechanism by which deployment exposures during the Gulf War might lead to Gulf War illness or its many symptoms.
The committee concludes that although the existence of an animal model would be advantageous for identifying and evaluating treatment strategies for Gulf War illness, it cautions that developing such an animal model is not possible given researchers’ inability to realistically determine the exposures associated with Gulf War service, let alone the frequency, duration, or dose of those exposures, or the effect of multiple exposures.
Between 1994 and 2014, federally funded research on Gulf War veterans has totaled more than $500 million. This large amount of funding has produced many findings, but there has been little substantial progress in our overall understanding of the health effects resulting from deployment to the 1990–1991 Gulf War, particularly Gulf War illness.
Although the committee focused on the epidemiologic literature in making its findings, it also attempted to look at the literature more broadly to identify any information that might provide a more comprehensive picture of the onset, diagnosis, and presentation of the illnesses affecting Gulf War veterans. For example, the committee considered information that might indicate promising areas of research, such as underlying biologic mechanisms of disease, methods for differential diagnoses, or the presence of comorbidities such as obesity or depression, and their potential interactions.
In spite of a thorough literature search, the Volume 10 committee found little evidence to warrant changes to the conclusions made by the Volume 8 committee regarding the strength of the association
between deployment to the Gulf War and adverse health outcomes. For several outcomes only one, or in some cases no, study was of sufficient quality to meet the criteria for a primary study. For health outcomes for which new evidence was available, it tended to support conclusions that were, for the most part, in accordance with the findings of prior Gulf War and Health committees. Veterans who were deployed to the Gulf War do not appear to have an increased risk for many long-term health conditions with the exceptions of posttraumatic stress disorder (PTSD), Gulf War illness, chronic fatigue syndrome, functional gastrointestinal conditions, generalized anxiety disorder, depression, and substance abuse. Indeed, the constellation of symptoms and symptom clusters referred to as Gulf War illness (e.g., fatigue, muscle and joint pain, and cognitive problems) is the signature adverse health outcome of having served in the Persian Gulf region. Multiple studies found that some Gulf War veterans, regardless of their country of origin and their different deployment-related exposures, have persistent, debilitating, and varying symptoms of Gulf War illness. The committee’s conclusions of the association between deployment to the Gulf War and specific health conditions are briefly summarized in Box S-1.
In response to its statement of task, the committee paid special attention to Gulf War illness, neurologic conditions, and lung and brain cancer. The committee’s findings and recommendations on those health conditions and other aspects of Gulf War veteran health are summarized below.
Gulf War Illness
In spite of more than two decades of studies to help define, diagnose, and treat the multitude of symptoms that are characteristic of Gulf War illness, little progress has been made in elucidating the pathophysiologic mechanisms that underlie the condition, the exposures that may have caused it, or treatments that are generally effective for veterans who suffer from it. The committee that worked on Volume 4 of the Gulf War and Health series first indicated that deployed veterans suffer from more signs and symptoms such as headache, joint and back pain, fatigue and sleep problems, and cognitive dysfunction, than do nondeployed veterans. The increased prevalence of numerous symptoms has been seen in Gulf War veterans from the United States as well as several of the coalition countries (e.g., Australia, Denmark, and the United Kingdom).
Gulf War illness is not an easily diagnosed condition. It presents with diverse symptom clusters, many of which overlap with other health conditions such as chronic fatigue syndrome, neurodegenerative disorders, and musculoskeletal problems, and there are multiple definitions of it. Based on available research data, it does not appear that a single mechanism can explain the multitude of symptoms seen in Gulf War illness, and it is unlikely that a single definitive causal agent will be identified this many years after the war.
Although the committee determined that Gulf War illness is not a psychosomatic condition, most studies have excluded the psychological aspects of the illness with regard to both diagnosis and treatment. This is despite the fact that veterans have reported symptoms such as chronic pain and sleep disturbances that may be amenable to psychological therapies, alone or in conjunction with other treatments. Animal studies that attempt to mirror Gulf War illness have been of little use because it is difficult to establish experimental exposures that are representative of those experienced by Gulf War veterans during deployment.
Recommendation: Any future studies of Gulf War illness should recognize the connections and complex relationships between brain and physical functioning and should not exclude any aspect of the illness with regard to improving its diagnosis and treatment.
Emerging diagnostic technologies and personalized approaches to medical care offer promise for allowing sufficiently powered research on the diagnosis and treatment of Gulf War illness.
Recommendation: The Department of Veterans Affairs and the Department of Defense should develop a joint and cohesive strategy on incorporating emerging diagnostic technologies and personalized approaches to medical care into sufficiently powered future research to inform studies of Gulf War illness and related health conditions.
This strategy should ensure that any future studies are scientifically rigorous, adequately powered, and optimize the likelihood of achieving meaningful and replicable findings. It should be informed by recognized subject matter experts and offer an opportunity for broad review and comment. Research support policies should be similarly developed to implement the strategy.
There was little new information pertaining to multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, or migraines. Amyotrophic lateral sclerosis (ALS) is the only neurologic disease for which the committee found limited/suggestive evidence for an association with deployment to the Gulf War. Although Gulf War deployment was associated with increased odds of developing ALS and increased ALS severity, no association with ALS mortality (a uniformly fatal disease) was found. The committee concluded that further follow-up is warranted. The Gulf War veteran population is still young with respect to the development of other neurodegenerative diseases; therefore, the effects of deployment on their incidence and prevalence may not yet be obvious.
Recommendation: The Department of Veterans Affairs should continue to conduct follow-up assessments of Gulf War veterans for neurodegenerative diseases that have long latencies and are associated with aging; these include amyotrophic lateral sclerosis, Alzheimer’s disease, and Parkinson’s disease.
Lung and Brain Cancer
The new studies identified by the committee found no statistically significant increase in the risk of brain cancer in deployed Gulf War veterans compared with their nondeployed counterparts. The studies indicate that the evidence for an association between deployment to the Gulf War and brain cancer is inadequate/insufficient.
Although prior committees found no evidence that Gulf War veterans were at increased risk for lung cancer in the approximately 10–15 years after the war, this committee notes that that time period may not have been adequate to account for the long latency of this disease. One large study of Gulf War veterans found an increased incidence of lung cancer based on state and VA cancer registry data from 1991 to 2006 for deployed vs nondeployed veterans, but neither veteran group had a greater risk when compared with the general population, and the study did not adjust for smoking status.
Thus, the Volume 10 committee finds that there continues to be inadequate/insufficient evidence to determine whether deployed Gulf War veterans are at increased risk of having any cancer, including lung cancer and brain cancer. The relative rarity of cancers such as brain cancer argues for studies with adequate power to detect them. This may require pooling data where feasible and the use of a variety of data sources such as state cancer registries.
Recommendation: The Department of Veterans Affairs should conduct further assessments of cancer incidence, prevalence, and mortality because of the long latency of some cancers. Such studies should maximize the use of cancer registries and other relevant sources, data, and approaches, and should have sufficient sample sizes to account for relatively rare cancers. These studies should also to be able to report sex-specific and race/ethnicity-specific information.
Other Health Conditions
In contrast to cancer, the committee finds that sufficient time has elapsed to determine that Gulf War deployed veterans do not have an increased incidence of circulatory, hematologic, respiratory, musculoskeletal, structural gastrointestinal, genitourinary, reproductive, and chronic skin conditions compared with their nondeployed counterparts. The committee also recognizes that as Gulf War veterans age, it will be more difficult to differentiate the effects of deployment from the natural effects of aging on morbidity and mortality.
The committee finds that the association of deployment to the Gulf War with PTSD, anxiety disorders, substance abuse, and depression is well established, and further studies to assess whether there is an association are not warranted. The committee notes, however, that mental health conditions may be comorbid with other health outcomes such as cancer or neurodegenerative diseases.
There are no data on the delayed effects of Gulf War exposures, such as nerve agents and PB, to indicate that any amount of such toxicants that still remain in the body would be able to cause any adverse health effects this many years after exposure. Thus, the committee finds that, with the exception of diseases with long latency periods such as cancer, it is not reasonable to expect increased risks of these other diseases.
Recommendation: Further studies to assess the incidence and prevalence of circulatory, hematologic, respiratory, musculoskeletal, structural gastrointestinal, genitourinary, reproductive, endocrine and metabolic, chronic skin, and mental health conditions due to deployment in the Gulf War should not be undertaken. Rather, future research related to these conditions should focus on ensuring that Gulf War veterans with them receive timely and effective treatment.
Given the likelihood that recall bias will increase with time, the committee finds that collecting further self-reported exposure information from Gulf War veterans is not necessary. For future conflicts, however, collecting exposure information before, during, and after deployment, preferably using individual environmental monitoring devices and military health and administrative records to capture such information as vaccine administration, troop location, and toxicant concentrations, will permit a more accurate assessment of actual exposures.
The committee also finds that efforts to model or otherwise reconstruct the exposures that Gulf War veterans experienced during deployment are also unlikely to yield useful results. Although animal models of Gulf War illness may be helpful in identifying markers of illness or treatment, the applicability of those laboratory exposures to the real-world exposures of veterans will continue to be unknown. Little credible exposure information currently exists for U.S. Gulf War veterans (except for depleted uranium).
Recommendation: Without definitive and verifiable individual veteran exposure information, further studies to determine cause-and-effect relationships between Gulf War exposures and health conditions in Gulf War veterans should not be undertaken.
Sex, Race, and Ethnicity
An unprecedented number of women deployed to the Gulf War (almost 50,000), but few data are available on the health of those women. Women may have different responses to stress and other exposures and, thus, may have different health effects. Therefore, it is important to assess and report on their health conditions so patterns over time can be understood and used to improve their health and potentially avoid similar problems in the future.
Similarly, health risks for racial/ethnic minority veterans as a result of deployment may also be different. Genetic risks for some diseases vary across race and ethnicities; for example, blacks are at greater risk for developing heart disease than whites.
Notwithstanding well-known differences in disease profiles according to sex and race/ethnicity, few studies on Gulf War veterans specifically report outcomes for women or minorities, although many veteran studies adjust for sex and race/ethnicity in their analyses. This lack of distinction is important and makes it imperative that researchers report sex-specific and race/ethnicity-specific outcomes, particularly in large cohorts and where population subgroups may be oversampled.
Recommendation: Sex-specific and race/ethnicity-specific health conditions should be determined and reported in future studies of Gulf War veterans. In addition, selected prior studies (e.g., large cohort studies) should be reviewed to determine whether reanalysis of the data to assess for possible sex-specific and race/ethnicity-specific health conditions is feasible.
Beginning with Volume 1 of the Gulf War and Health series, numerous IOM committees have reviewed the literature on the health of deployed and nondeployed Gulf War veterans. Although there have been some variations in the strength of the associations between specific exposures (e.g., combustion products, infectious agents, and sarin) and particular health outcomes, in general the results have been remarkably consistent. What is striking about this and prior Gulf War and Health committees’ findings is that the health conditions found to be associated with Gulf War deployment are primarily mental health disorders and functional medical disorders. What links these conditions is that they have no objective medical diagnostic tests and are diagnosed based on subjective symptom reporting. These associations emphasize the interconnectedness of the brain and body.
The committee concludes that it is time research efforts move forward and focus on this interconnectedness when seeking to improve treatment of veterans for Gulf War illness. Further exploration of treatments and management strategies for the symptoms of Gulf War illness, even in the absence of a definitive etiology, is warranted. VA and Department of Defense researchers have already conducted some clinical trials based on therapies that have previously shown benefits for conditions characterized by unexplained symptoms. Gulf War illness research should be realigned to focus on the treatment of the illness’s complex symptomatology rather than causal mechanisms. Such research should recognize the growing evidentiary base demonstrating the intricate and complex brain–body relationship. The acute response to an exposure that causes stress (physiologic or psychologic) involves interactions and effects among multiple organ systems in the body, including the brain, gut, heart, liver, immune system,
thyroid, adrenals, pituitary, gonads, bone, and skin. The multisystem effects may be profound and long lasting. To ignore available treatments that may improve the functioning of any of these organ systems would be to do a disservice to our Gulf War veterans.
Recommendation: Future Gulf War research should place top priority on the identification and development of effective therapeutic interventions and management strategies for Gulf War illness. The Department of Veterans Affairs should support research to determine how such treatments can be widely disseminated and implemented in all health care settings.
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