SUMMARY

More than 2 decades have passed since the 1990–1991 conflict in the Persian Gulf. During the intervening years, many Gulf War veterans have experienced various unexplained symptoms that many associate with service in the gulf region, but no specific exposure has been definitively associated with symptoms. Numerous researchers have described the pattern of signs and symptoms found in deployed Gulf War veterans and noted that they report unexplained symptoms at higher rates than nondeployed veterans or veterans deployed elsewhere during the same period. Gulf War veterans have consistently shown a higher level of morbidity than the nondeployed, in some cases with severe and debilitating consequences. However, efforts to define a unique illness or syndrome in Gulf War veterans have failed, as have attempts to develop a uniformly accepted case definition.

BACKGROUND

On August 2, 1990, Iraqi armed forces invaded Kuwait; within 5 days, the United States had begun to deploy troops to Southwest Asia in Operation Desert Shield. Intense air attacks against the Iraqi armed forces began on January 16, 1991, and opened a phase of the conflict known as Operation Desert Storm. Those two operations, although brief, exposed US and coalition forces to an array of biologic and chemical agents; for example, oil-well fires became visible in satellite images as early as February 9, 1991. The ground war began on February 23; by February 28, the war was over; an official cease-fire was signed in April 1991. The oil-well fires were extinguished by November 1991. The last troops to participate in the ground war returned home on June 13, 1991. In all, about 697,000 US troops had been deployed to the Persian Gulf area during the two operations.1 Although the military operations were considered successful, with few battle injuries and deaths, veterans soon began reporting numerous health problems that they attributed to their participation in the Gulf War. Most of the men and women who served in the Gulf War returned to normal activities without serious health problems, but many experienced an array of unexplained symptoms, such as fatigue, muscle and joint pain, loss of concentration, forgetfulness, headache, respiratory complaints, rashes, sleep disturbances, and gastrointestinal distress.

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1Henceforth, the two operations—Desert Storm and Desert Shield—will be referred to as the Gulf War.



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SUMMARY More than 2 decades have passed since the 1990–1991 conflict in the Persian Gulf. During the intervening years, some Gulf War veterans have experienced various unexplained symptoms that many associate with service in the gulf region, but no specific exposure has been definitively associated with symptoms. Numerous researchers have described the pattern of signs and symptoms found in deployed Gulf War veterans and noted that they report unexplained symptoms at higher rates than nondeployed veterans or veterans deployed elsewhere during the same period. Gulf War veterans have consistently shown a higher level of morbidity than the nondeployed, in some cases with severe and debilitating consequences. However, efforts to define a unique illness or syndrome in Gulf War veterans have failed, as have attempts to develop a uniformly accepted case definition. BACKGROUND On August 2, 1990, Iraqi armed forces invaded Kuwait; within 5 days, the United States had begun to deploy troops to Southwest Asia in Operation Desert Shield. Intense air attacks against the Iraqi armed forces began on January 16, 1991, and opened a phase of the conflict known as Operation Desert Storm. Those two operations, although brief, exposed US and coalition forces to an array of biologic and chemical agents; for example, oil-well fires became visible in satellite images as early as February 9, 1991. The ground war began on February 23; by February 28, the war was over; an official cease-fire was signed in April 1991. The oil-well fires were extinguished by November 1991. The last troops to participate in the ground war returned home on June 13, 1991. In all, about 697,000 US troops had been deployed to the Persian Gulf area during the two operations.1 Although the military operations were considered successful, with few battle injuries and deaths, veterans soon began reporting numerous health problems that they attributed to their participation in the Gulf War. Most of the men and women who served in the Gulf War returned to normal activities without serious health problems, but many experienced an array of unexplained symptoms, such as fatigue, muscle and joint pain, loss of concentration, forgetfulness, headache, respiratory complaints, rashes, sleep disturbances, and gastrointestinal distress. 1 Henceforth, the two operations—Desert Storm and Desert Shield—will be referred to as the Gulf War. 1

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2 CHRONIC MULTISYMPTOM ILLNESS IN GULF WAR VETERANS Charge to the Committee The Department of Veterans Affairs (VA) provided the charge to the committee: An ad hoc committee will develop a case definition for chronic multisymptom illness 2 (CMI) as it pertains to the 1990–1991 Gulf War Veteran population. The committee will comprehensively review, evaluate, and summarize the available scientific and medical literature regarding symptoms for CMI among the 1991 Gulf War Veterans. In addition to reviewing and summarizing the available scientific and medical literature regarding symptoms and case definitions for CMI among Gulf War Veterans, the committee will evaluate the terminology currently used in referring to CMI in Gulf War Veterans and recommend appropriate usage. How the Committee Approached Its Charge The IOM appointed a committee of 16 experts to carry out the task. The committee members have expertise in occupational medicine, biostatistics, psychometrics, epidemiology, basic science, clinical medicine, toxicology, psychiatry, neurology, gastroenterology, and sociology. Some of the committee members treated Gulf War veterans when they came to their clinics or practices, and one committee members’ practice is devoted solely to Gulf War and other veterans. The committee also consulted with an expert in brain imaging because that field was not represented on the committee. The committee members directed the staff to conduct an extensive search of the extant peer-reviewed literature. PubMed was searched for all references related to the 1990–1991 Gulf War. Initially, more than 5,000 papers were retrieved; after elimination of duplicates, 2,033 unique papers remained. The titles and abstracts of those papers were reviewed, and 718 were selected for more rigorous review. The committee members divided the work by reading papers related to their expertise. The papers that were reviewed included all health outcomes that have been noted in Gulf War veterans, for example, mortality, hospitalization, neurologic symptoms, respiratory symptoms, gastrointestinal symptoms, pain, birth defects and fertility, cancer, mental- health conditions, and overlapping syndromes. In an effort to characterize the symptomatology associated with CMI, the focus of the committee’s review is on studies of symptoms not associated with diagnosed medical or psychiatric conditions; the focus is on studies of symptom- reporting in Gulf War veterans. The committee agreed early on that a determination of the etiology of CMI was outside the scope of its charge. Thus, the committee did not consider toxicologic or exposure studies. The committee held one open meeting, in which members heard from veterans, government officials, researchers, clinicians who treat Gulf War veterans, and members of the VA Research Advisory Committee. The meeting increased the committee’s awareness of the variety of symptoms being experienced by the Gulf War veterans. In addition, the vigorous discussions with the veterans and researchers were invaluable for increasing the committee members’ understanding of the complexity of issues involved in its task. 2 The committee uses the term chronic multisymptom illness throughout the report, as defined in the statement of work, when referring to the symptom complex in Gulf War veterans.

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SUMMARY 3 ADDRESSING CHRONIC MULTISYMPTOM ILLNESS IN GULF WAR VETERANS Although many Gulf War veterans suffer from an array of health problems and symptoms (such as fatigue, muscle and joint pain, memory loss, and gastrointestinal disorders), those health issues are not necessarily specific to any identified disease and are not satisfactorily classified by standard diagnostic coding systems. Population-based studies have found a higher prevalence of symptom reporting in Gulf War veterans than in nondeployed Gulf War veterans or other control groups (Goss Gilroy Inc., 1998; Iowa Persian Gulf Study Group, 1997; Unwin et al., 1999). The wide variation in types of symptoms reported by Gulf War veterans has complicated efforts to determine whether there is a unique Gulf War syndrome or whether symptom patterns are consistent with other known symptom-based disorders. Consequently, the array of symptoms suffered by many Gulf War veterans does not often point to an obvious diagnosis, etiology, or specific treatment. The search for a definitive cause of CMI also has been difficult. The veterans of the 1990–1991 Gulf War were exposed to an impressive array of biologic and chemical agents. Numerous studies have been conducted over the past 20 years to determine an etiology based on many possible exposures, such as exposures to pyridostigmine bromide, anthrax vaccination, tent-heater fumes, oil-fire smoke, and chemical odors (Wolfe et al., 2002); jet fuel (Bell et al., 2005); low concentrations of sarin and cyclosarin (Chao et al., 2011); and combinations of organophosphate pesticides, chemical nerve agents, DEET insect repellent, and pyridostigmine bromide (Haley et al., 1997, 1999). However, exposures during the Gulf War were not reliably measured (or necessarily measured at all), and most often exposures have been evaluated through surveys or health examinations some years after they occurred (Gray et al., 2004). The association between retrospective recall of exposures and self-reported health outcomes is subject to recall bias. No coherent mechanism of action or definitive causal relationship between the exposures and the array of symptoms reported has been established (Barrett et al., 2002). Even the terminology used over the years has at times been perplexing. Initially, the term Gulf War syndrome was used, and later numerous other terms appeared in the medical and scientific literature, such as Gulf War illness, unexplained illness, medically unexplained symptoms or medically unexplained physical symptoms, and chronic multisymptom illness. Furthermore, many of the symptoms of CMI overlap with symptoms of other diseases and ill- defined conditions, such as fibromyalgia (FM) and chronic fatigue syndrome (CFS). As noted by Ismail and Lewis (2006), when several symptoms are reported together in the absence of evidence of a physical cause, they are often termed medically unexplained syndromes. To add to the difficulty in defining CMI and finding a common etiology, the literature contains a number of discussions that refer to different postwar syndromes as possible explanations for the illnesses in Gulf War veterans (e.g., Engel, 2004; Hyams et al., 1996). Many similarities between previously identified postwar syndromes and CMI were noted. More generally, all modern wars have been associated with medically unexplained symptoms or syndromes (Jones et al., 2002). After military personnel are deployed to war zones, some of them will have such illnesses when they return. A systematic comparison of UK pension files from previous wars (the Boer War, World War I, and World War II) with clinical files from the Gulf War found that CMI is similar to many postconflict syndromes. During the Boer War, soldiers complained primarily of fatigue, rheumatic pains, weakness, shortness of breath, rapid heart rate, headache, and dizziness. In World War I and World War II, primary symptom complaints were

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4 CHRONIC MULTISYMPTOM ILLNESS IN GULF WAR VETERANS chest pain, breathlessness, dizziness, fatigue, and to a lesser extent headache and anxiety (King’s College London, 2010). Case Definitions of Chronic Multisymptom Illness in Gulf War Veterans One of the tasks of the committee was to examine the peer-reviewed literature specific to deployed Gulf War veterans’ symptomatology in an effort to develop or identify a case definition that will show adequate sensitivity and specificity for research and treatment purposes. In the numerous symptom studies reviewed by the committee, the array of symptoms reported makes it difficult to identify hallmark characteristics of the illness. In addition, the symptoms detailed in Gulf War veterans are shared by other symptom-based disorders such as CFS and FM and are seen in the general adult population. There are no objective diagnostic criteria (such as laboratory abnormalities or characteristic physical signs), so diagnosing symptom-based conditions, such as CMI, often must depend on the exclusion of other causes. Thus, specificity becomes a major limitation in developing a case definition of CMI. As noted by Hyams (1998), specificity requires a low proportion of false positives; however, without diagnostic criteria that exclude well-recognized medical and psychiatric causes of symptoms and distinguish them from other symptom-based conditions, a specific diagnosis has not been possible. The committee recognizes the difficulty of establishing a consensus case definition of CMI, given the lack of uniform symptoms, the variety of symptoms, and the long onset and duration. However, CMI is an important cause of disability in Gulf War veterans and the lack of a consensus case definition poses problems for those who are suffering with this illness. The absence of a consensus case definition is a fundamental weakness of CMI research in that the lack of an agreed on case definition can make it difficult to identify cases and controls. It prevents the accurate estimation of the burden of illness in the veteran population, the use of generalizable results, the accumulation of valid information about the condition, and the effectiveness of treatment. In a clinical setting, the absence of an agreed upon case definition of CMI not only can result in considerable uncertainty about the diagnosis, but might limit the ability to select and administer effective treatments. Practically, that means that there will be some veterans misdiagnosed either as having or not having CMI and the course of treatments might not be helpful. That can have an adverse effect on the health of the veteran with respect to worrying about the lack of improvement, possible side effects of treatment, and the cost of treatment. The impact on health care services may also be considerable, and whether such treatments constitute an effective use of limited resources should be a cause of concern. For those reasons, the committee believes that supporting the development of a case definition or the adoption of a current definition will move the field forward. The committee also recognizes that as the knowledge base changes over time, a case definition will need to evolve as has occurred in other symptom-based conditions, such as irritable bowel syndrome, CFS, and FM. GULF WAR SYMPTOM STUDIES Researchers began to assemble cohorts of Gulf War veterans in the first few years after the war; others were assembled later. Most of the studies compare sizable groups of deployed veterans with groups of veterans who were not deployed during the same period as the Gulf War

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SUMMARY 5 (often referred to as era veterans) or who were deployed to locations other than the Persian Gulf, such as Bosnia (referred to as deployed elsewhere). In addition, a number of volunteer registries were assembled by the US Department of Defense and Department of Veterans Affairs and by governments whose forces were included in the Gulf War coalition to study their veterans’ health. The committee focused on those symptom studies, rather than on studies of well- characterized diagnosed medical and psychiatric conditions, and they provide the foundation for the committee’s understanding of the symptomatology in the Gulf War veterans. A review of all the studies indicates that many Gulf War veterans suffer from an array of health problems and symptoms (for example, fatigue, muscle and joint pain, memory loss, gastrointestinal disorders, and rashes) that are not specific to any disease and are not easily classified with standard diagnostic coding systems. In studies since the mid-1990s, researchers have found a higher prevalence of self-reported and clinically verified symptoms in Gulf War veterans than in nondeployed Gulf War–era veterans or other control groups. Veterans of the Gulf War from Australia, Canada, Danish, the United Kingdom, and the United States report higher rates and increased severity of nearly all symptoms or sets of symptoms than their nondeployed counterparts; that finding was reported consistently in every study that the committee reviewed. However, Gulf War veterans do not all experience the same array of symptoms, and the symptoms reported are also found in the nondeployed. General Limitations of Gulf War Studies The cohort studies of Gulf War veterans have contributed greatly to the understanding of veterans’ health, but limitations are commonly encountered in observational epidemiologic studies. They include selection biases that limit the studies’ control for potential confounding factors, self-reporting of health outcomes and exposures affected by recall bias, outcome misclassification, and reporting bias.3 Other limitations of the body of evidence are that studies might be too narrow in their assessment of health status, the measurement instruments might have been too insensitive to detect abnormalities that affect deployed veterans, and the period of investigation might have been too brief to detect health outcomes that have a long latency or require many years to progress to the point where disability, hospitalization, or death occurs. Finally, research into the health effects of Gulf War deployment is limited by the interval between the war and the conduct of studies. Many studies were conducted years after the war, and this limits the ability to determine when symptoms developed and to detect causal associations; for example, some of the earliest assessments were conducted in 1993 by Pierce (1997) and Wolfe et al. (1998), in 1994 by Gray et al. (1999), and in 1995 by Fukuda et al. (1998). The delay also allows dissemination of speculation by the news media and others that may affect veterans’ recall (Hotopf and Wessely, 2005). 3 Biases previously described by the IOM (2006, 2010).

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6 CHRONIC MULTISYMPTOM ILLNESS IN GULF WAR VETERANS THE USE OF FACTOR ANALYSIS IN STUDIES OF CHRONIC MULTISYMPTOM ILLNESS In an effort to understand the symptomatology in Gulf War veterans, researchers began to use statistical analyses (specifically, factor and cluster analyses) to evaluate whether symptoms found in Gulf War veterans might constitute a unique syndrome. Factor analysis is a statistical method for conducting structural analyses of datasets. The data used in factor-analytic studies can be people’s responses to a set of items or list of symptoms with respect to their presence or absence and their severity. Factor analysis also was used to inform a case definition. In attempting to reduce the amount of data that were gathered (the large and varied number of symptoms), researchers used factor analysis so that a structure that included substantially fewer factors than symptoms could be proposed. Factor Analysis for Case Definition Factor-analytic studies have facilitated and clarified comparisons of symptom prevalence and severity between deployed and nondeployed, but they have been less useful in specifying a case definition of CMI. The results of factor analyses do not differentiate among groups of people and cannot create a case definition. That fact has been obscured because investigators often operationalize a case definition by dichotomizing factor scores obtained from a factor- analytic model. However, people do not have factors; everyone will have a score on each factor, but dichotomization of factor scores to define a “case” is a postprocessing decision made by the investigator and is not a direct result of the factor-analytic model. The studies that have used factor analysis to investigate symptoms in Gulf War veterans have used several strategies. Some studies used statistical testing of the hypothesis that the factor structures of deployed and nondeployed veteran populations are significantly different (that is, testing the null hypothesis that the structures are the same) (Ismail et al., 1999). Others relied exclusively on descriptive statistical techniques, such as correlations among factors, factor scores, or factor loadings (Doebbeling et al., 2000; Haley et al., 1997; Kang et al., 2002). Finally, a number of studies used “visual inspection” to discern differences between the factor structures for deployed and nondeployed groups (Knoke et al., 2000; Nisenbaum et al., 2004; Shapiro et al., 2002). Factor analysis and cluster analysis may be useful for making sense of the large number of symptoms potentially associated with CMI. However, the findings that result from using those methods must be validated against other observed variables. The choice of variables to include in the factor-analytic model is critical, and omission of key symptoms will result in models that do not capture the most salient features of CMI. In addition, the validity of factor analysis or cluster analysis depends on the quality of data. Methodologic flaws in such studies can bias results (Ismail and Lewis, 2006). The committee notes that neither factor analysis nor cluster analysis alone can directly produce a case definition. DISCUSSION OF EXISTING CASE DEFINITIONS The case definition studies do not all consistently identify key elements of a case definition, which might include, for example, period of onset, duration, frequency, severity, exposure, exclusionary criteria, or a uniform set of symptoms. There are no clinically validated tests or measures for diagnosing CMI. And the symptoms of CMI are not unique to Gulf War–

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SUMMARY 7 deployed veterans, although they occur in the deployed at a higher frequency and severity than in nondeployed era veterans or those deployed elsewhere. That is evidenced by higher prevalences of a variety of symptoms, as noted in the cohort studies. Thus, the committee has concluded that the available evidence is insufficient to develop a new case definition of CMI. To move the field forward, however, the committee developed an approach based on its evaluation of the CMI literature and its collective judgment. In its review of CMI symptomatology, factor analyses, and case definitions, the committee noted similarities throughout the body of literature. A common set of symptoms has been identified in the case- definition studies (albeit not necessarily using the same terminology) that includes symptoms of fatigue, pain, and neurocognitive dysfunction (see Table S.1). TABLE S.1 Case Definitions of Chronic Multisymptom Illness Used in Gulf War Veteran Studies Definition Symptoms—must have signs, Duration Onset Exclusions Severity symptoms, or complaints that fit at least Haley— 5 of 8 signs or symptoms: Must be denied a clinical 1) fatigue physician’s (Haley et 2) arthralgia or low back pain diagnosis of other al., 1997) 3) headache medical and 4) intermittent diarrhea without psychiatric bloody stools illnesses that could 5) neuropsychiatric complaints of cause the forgetfulness, difficulty in symptoms concentrating, depression, memory loss, or easy irritability 6) difficulty in sleeping 7) low-grade fever 8) weight loss Haley— Cases are defined mathematically factor by using factor scores calculated analysis with weights; cases with factor (Haley et scores >1.5 are identified as al., 1997) having a syndrome (a factor derived with the same factor analysis); cases may have multiple syndromes CDC 1 or more from at least 2 of the ≥6 Mild, (Fukuda et following categories: months moderate, or al., 1998) 1) fatigue severe by 2) mood and cognition (symptoms self-report of feeling depressed, difficulty in remembering or concentrating, feeling moody, feeling anxious, trouble in finding words, or difficulty in sleeping) 3) musculoskeletal (symptoms of joint pain, joint stiffness, or

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8 CHRONIC MULTISYMPTOM ILLNESS IN GULF WAR VETERANS Definition Symptoms—must have signs, Duration Onset Exclusions Severity symptoms, or complaints that fit at least muscle pain) Kansas 3 of 6 domains: Chronic Since 1990 Symptom Mild, (Steele, 1) fatigue and sleep problems reporting must be moderate, or 2000) 2) pain symptoms in the absence of severe by 3) neurologic, cognitive, or mood diagnosed self-report symptoms exclusionary 4) gastrointestinal symptoms conditions; only 5) respiratory symptoms respondents who 6) skin symptoms have at least 1 moderately severe symptom or 2 or more symptoms within a group were considered to have a high level of symptoms in the group Portland Symptoms in 1 of 3 categories: ≥1 month During or (Bourdette 1) fatigue (unexplained fatigue within the after et al., and at least 4 of the following: 3 deployment 2001; fevers and chills; new kinds of previous to the Spencer et headache; unrefreshing sleep; months Persian al., 1998) tender glands in the neck, jaw, Gulf or groin; changes in memory or difficulty in concentrating; sore throat; painful joints; unexplained weakness in many muscles; persistent muscle aches; prolonged fatigue; and feeling of illness lasting longer than 1 day after mild exercise) 2) cognitive and psychologic symptoms, including memory loss, confusion, inability to concentrate, mood swings, and sleep difficulties 3) musculoskeletal symptoms, including back pain, persistent muscle aches or pains, painful joints, swollen joints, joint stiffness, and pain after exertion VA Might include things like fatigue, ≥6 Must not be (Kang et muscle or joint pain, headache, months adequately al., 2009) memory problems, digestive explained by problems, respiratory problems, conventional skin problems, or any other medical or unexplained symptoms that may psychiatric

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SUMMARY 9 Definition Symptoms—must have signs, Duration Onset Exclusions Severity symptoms, or complaints that fit at least sometimes be diagnosed as diagnoses chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, or multiple chemical sensitivity NOTE: Other elements of case definitions (such as laboratory criteria and exposure) not reported. Furthermore symptoms were regularly reported with higher frequency in Gulf War veterans than in nondeployed era veterans or veterans who were deployed elsewhere; they include gastrointestinal, respiratory, and dermatologic symptoms (those were in addition to the fatigue, pain, and neurocognitive symptoms already identified). The committee recognized that two existing definitions—the Centers for Disease Control and Prevention (CDC) definition and the Kansas definition (see Table S.1)—capture the array of symptoms most commonly identified. The CDC definition requires one or more symptoms in at least two of the fatigue, pain, and mood and cognition categories to identify a case. The Kansas definition requires symptoms in at least three of the domains of fatigue or sleep, pain, neurologic or cognitive or mood, gastrointestinal, respiratory, and skin to identify a case. Thus, both definitions capture the array of symptoms highlighted by the evidence. The CDC case definition, which has been widely used by researchers, identifies 29–60% of US Gulf War–deployed veterans as CMI cases depending on the population studied, whereas the Kansas definition identifies 34% in the population studied (Kansas Gulf War veterans). However, the two definitions have important differences. The CDC definition has the greatest concordance with all the other definitions (see Table S.1) but is less restrictive than the Kansas definition. The CDC definition requires fewer symptoms, does not have any exclusionary criteria, and might identify a case without physical symptoms. In contrast, the Kansas definition will define fewer veterans as cases. The committee also noted particular strengths of each definition, including the CDC definition’s inclusion of severity indicators and the Kansas definition’s exclusionary criteria. In the committee’s judgment, however, neither definition has been sufficiently validated. Given the absence of validators, the committee recommends, with some reticence, the use of two current case definitions. The CDC and Kansas definitions are the best reflection of the symptom complexes demonstrated by the Gulf War veterans. The committee recognizes that the definitions were developed in different study populations and that they differ in their sensitivity and specificity. However, in the committee’s judgment, those two definitions will provide the VA with a framework to further research and treatment. In conclusion, the committee saw merits in both the CDC and Kansas definitions, but the weight of the evidence does not currently support the use of one rather than the other for all purposes. Given the differences, the committee notes the importance of choosing a definition that is based on specific needs. For example, the CDC definition may not be suitable for research that requires a more narrowly defined study population whereas the Kansas definition may identify too few cases and compromise statistical power. Another consideration in choosing a definition is the ability to adapt it for use in clinical settings.

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10 CHRONIC MULTISYMPTOM ILLNESS IN GULF WAR VETERANS RECOMMENDATIONS Evidence is lacking in the studies reviewed to characterize most elements of a case definition (for example, onset, duration, severity, and laboratory findings) with certainty. Without that information, the committee could not develop a new definition for CMI. Furthermore, because that information is lacking, few of the studies that proposed definitions were able to describe many of the elements of a case definition. Although all the studies describe clinical features (symptoms), many of the other criteria are not discussed. Therefore, the committee cannot recommend one specific case definition over another. But it does recommend the consideration of two case definitions on the basis of their concordance with the evidence and their ability to identify specific symptoms commonly reported by Gulf War veterans. There is a set of symptoms (fatigue, pain, neurocognitive) that are reported in all the studies that have been reviewed. The CDC definition captures those three symptoms; the Kansas definition also captures them, but it also includes the symptoms reported most frequently by Gulf War veterans. Other case-definition studies report additional symptoms that are not seen with the same frequency or in all studies. Thus, the committee identified the CDC definition (Fukuda et al., 1998) and the Kansas definition (Steele, 2000) as the two that capture the array of symptoms most frequently reported by veterans as evidenced by the studies reviewed. The committee recommends that the Department of Veterans Affairs consider the use of the Centers for Disease Control and Prevention and Kansas definitions because they capture the most commonly reported symptoms. Neither definition addresses all the key features of a case definition, such as symptom onset, duration, severity, frequency of symptoms, and exclusionary criteria. Identifying those features will contribute to a more accurate case definition. Those features were not regularly reported in the studies considered. It is important to acknowledge that the two definitions, although they cover the most common symptoms, do not reflect the complete array of symptoms reported by Gulf War veterans. Although a standard set of criteria regarding time (a defined period of onset), place, exposures, and clinical and laboratory findings would have been useful; given the lag in time between first reports of illness and epidemiologic study, lack of exposure monitoring, and the absence of validated laboratory tests, it is no longer possible to define many of the typical elements associated with a case definition. However, review of existing data sets might prove useful in detailing some of the needed information. The committee recommends that the Department of Veterans Affairs, to the extent possible, systematically assess existing data to identify additional features of chronic multisymptom illness, such as onset, duration, severity, frequency of symptoms, and exclusionary criteria to produce a more robust case definition. Finally, VA asked the committee to evaluate the terminology used in referring to CMI in 1990–1991 Gulf War veterans and to recommend appropriate terminology. Multiple terms have been used over the past 2 decades. Initially, Gulf War syndrome was used, but syndrome indicates a new group of signs and symptoms not previously seen in medicine (IOM, 2000; King’s College London, 2010). The Gulf War veterans report more symptoms and with greater frequency and severity than nondeployed veterans or veterans who were deployed elsewhere, but

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SUMMARY 11 the types and patterns of symptoms are the same in all groups, and this suggests that no unique syndrome is associated with Gulf War deployment. Although chronic multisymptom illness is descriptive of the heterogeneity of the symptoms, it is not specific to the population and its unique experience. Thus, to capture the population of interest and the symptoms, a preferred term is Gulf War illness. Illnesses are sometimes named after the geographic area or the group in which they were first identified without meaning to convey a sole etiology (for example, the 1918 influenza pandemic referred to as the Spanish flu, the 1968 and 1969 influenza outbreaks referred to as the Hong Kong flu, and pneumonia in legionnaires referred to as Legionnaire’s disease). The committee’s recommendation reflects both the geographic area and the unique experiences of this group of veterans. Gulf War illness has been used by many researchers to identify the array of symptoms expressed by Gulf War veterans. Its consistent use in the literature might reduce confusion. The committee recommends that the Department of Veterans Affairs use the term Gulf War illness rather than chronic multisymptom illness. REFERENCES Barrett, D. H., G. C. Gray, B. N. Doebbeling, D. J. Clauw, and W. C. Reeves. 2002. Prevalence of symptoms and symptom-based conditions among Gulf War veterans: Current status of research findings. Epidemiologic Reviews 24(2):218-227. Bell, I. R., A. J. Brooks, C. M. Baldwin, M. Fernandez, A. J. Figueredo, and M. L. Witten. 2005. JP-8 jet fuel exposure and divided attention test performance in 1991 Gulf War veterans. Aviation Space and Environmental Medicine 76(12):1136-1144. Bourdette, D. N., L. A. McCauley, A. Barkhuizen, W. Johnston, M. Wynn, S. K. Joos, D. Storzbach, T. Shuell, and D. Sticker. 2001. Symptom factor analysis, clinical findings, and functional status in a population-based case control study of Gulf War unexplained illness. Journal of Occupational and Environmental Medicine 43(12):1026-1040. Chao, L. L., L. Abadjian, J. Hlavin, D. J. Meyerhoff, and M. W. Weiner. 2011. Effects of low-level sarin and cyclosarin exposure and Gulf War illness on brain structure and function: A study at 4t. Neurotoxicology 32(6):814-822. Doebbeling, B. N., W. R. Clarke, D. Watson, J. C. Torner, R. F. Woolson, M. D. Voelker, D. H. Barrett, and D. A. Schwartz. 2000. Is there a Persian Gulf War syndrome? Evidence from a large population- based survey of veterans and nondeployed controls. American Journal of Medicine 108(9):695-704. Engel, C. C., Jr. 2004. Post-war syndromes: Illustrating the impact of the social psyche on notions of risk, responsibility, reason, and remedy. Journal of the American Academy of Psychoanalysis and Dynamic Psychiatry 32(2):321-334; discussion 335-343. Fukuda, K., R. Nisenbaum, G. Stewart, W. W. Thompson, L. Robin, R. M. Washko, D. L. Noah, D. H. Barrett, B. Randall, B. L. Herwaldt, A. C. Mawle, and W. C. Reeves. 1998. Chronic multisymptom illness affecting Air Force veterans of the Gulf War. Journal of the American Medical Association 280(11):981-988. Goss Gilroy Inc. 1998. Health study of Canadian Forces Personnel Involved in the 1991 Conflict in the Persian Gulf. Ottawa, Canada: Goss Gilroy Inc. Department of National Defence. Gray, G. C., G. D. Gackstetter, H. K. Kang, J. T. Graham, and K. C. Scott. 2004. After more than 10 years of Gulf War veteran medical evaluations, what have we learned? American Journal of Preventive Medicine 26(5):443-452.

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12 CHRONIC MULTISYMPTOM ILLNESS IN GULF WAR VETERANS Gray, G. C., K. S. Kaiser, A. W. Hawksworth, F. W. Hall, and E. Barrett-Connor. 1999. Increased postwar symptoms and psychological morbidity among U.S. Navy Gulf War veterans. American Journal of Tropical Medicine and Hygiene 60(5):758-766. Haley, R. W., T. L. Kurt, and J. Hom. 1997. Is there a Gulf War syndrome? Searching for syndromes by factor analysis of symptoms. Journal of the American Medical Association 277(3):215-222. [Erratum appears in Journal of the American Medical Association 1997; 278(5):388.] Haley, R. W., S. Billecke, and B. N. La Du. 1999. Association of low PON1 type Q (type A) arylesterase activity with neurologic symptom complexes in Gulf War veterans. Toxicology and Applied Pharmacology 157(3):227-233. Hotopf, M., and S. Wessely. 2005. Can epidemiology clear the fog of war? Lessons from the 1990–91 Gulf War. International Journal of Epidemiology 34(4):791-800. Hyams, K. C. 1998. Developing case definitions for symptom-based conditions: The problem of specificity. Epidemiologic Reviews 20(2):148-156. Hyams, K. C., F. S. Wignall, and R. Roswell. 1996. War syndromes and their evaluation: From the U.S. Civil War to the Persian Gulf War. Annals of Internal Medicine 125(5):398-405. IOM (Institute of Medicine). 2000. Gulf War and Health, Volume 1: Depleted Uranium, Pyrodostigmine Bromide, Sarin, Vaccines. Washington, DC: National Academy Press. IOM. 2006. Gulf War and Health, Volume 4: Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. IOM. 2010. Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. Iowa Persian Gulf Study Group. 1997. Self-reported illness and health status among Gulf War veterans: A population-based study. Journal of the American Medical Association 277(3):238-245. Ismail, K., and G. Lewis. 2006. Multi-symptom illnesses, unexplained illness and Gulf War syndrome. Philosophical Transactions of the Royal Society B: Biological Sciences 361(1468):543-551. Ismail, K., B. Everitt, N. Blatchley, L. Hull, C. Unwin, A. David, and S. Wessely. 1999. Is there a Gulf War syndrome? Lancet 353(9148):179-182. Jones, E., R. Hodgins-Vermaas, H. McCartney, B. Everitt, C. Beech, D. Poynter, I. Palmer, K. Hyams, and S. Wessely. 2002. Post-combat syndromes from the Boer War to the Gulf War: A cluster analysis of their nature and attribution. British Medical Journal 324(7333):321-324. Kang, H. K., C. M. Mahan, K. Y. Lee, F. M. Murphy, S. J. Simmens, H. A. Young, and P. H. Levine. 2002. Evidence for a deployment-related Gulf War syndrome by factor analysis. Archives of Environmental Health 57(1):61-68. Kang, H. K., B. Li, C. M. Mahan, S. A. Eisen, and C. C. Engel. 2009. Health of US veterans of 1991 Gulf War: A follow-up survey in 10 years. Journal of Occupational and Environmental Medicine 51(4):401-410. King’s College London. 2010. King’s Centre for Military Health Research: A Fifteen Year Report. What Has Been Achieved by Fifteen Years of Research into the Health of the UK Armed Forces? University of London. Knoke, J. D., T. C. Smith, G. C. Gray, K. S. Kaiser, and A. W. Hawksworth. 2000. Factor analysis of self-reported symptoms: Does it identify a Gulf War syndrome? American Journal of Epidemiology 152(4):379-388. Nisenbaum, R., K. Ismail, S. Wessely, C. Unwin, L. Hull, and W. C. Reeves. 2004. Dichotomous factor analysis of symptoms reported by UK and US veterans of the 1991 Gulf War. Population Health Metrics 2.

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SUMMARY 13 Pierce, P. F. 1997. Physical and emotional health of Gulf War veteran women. Aviation Space and Environmental Medicine 68(4):317-321. Shapiro, S. E., M. R. Lasarev, and L. McCauley. 2002. Factor analysis of Gulf War illness: What does it add to our understanding of possible health effects of deployment? American Journal of Epidemiology 156(6):578-585. Spencer, P. S., L. A. McCauley, S. K. Joos, M. R. Lasarev, T. Schuell, D. Bourdette, A. Barkhuizen, W. Johnston, D. Storzbach, M. Wynn, and R. Grewenow. 1998. U.S. Gulf War veterans: Service periods in theater, differential exposures, and persistent unexplained illness. Portland Environmental Hazards Research Centre. Toxicology Letters 102-103:515-521. Steele, L. 2000. Prevalence and patterns of Gulf War illness in Kansas veterans: Association of symptoms with characteristics of person, place, and time of military service. American Journal of Epidemiology 152(10):992-1002. Unwin, C., N. Blatchley, W. Coker, S. Ferry, M. Hotopf, L. Hull, K. Ismail, I. Palmer, A. David, and S. Wessely. 1999. Health of UK servicemen who served in Persian Gulf War. Lancet 353(9148):169- 178. Wolfe, J., S. P. Proctor, J. D. Davis, M. S. Borgos, and M. J. Friedman. 1998. Health symptoms reported by Persian Gulf War veterans two years after return. American Journal of Industrial Medicine 33(2):104-113. Wolfe, J., S. P. Proctor, D. J. Erickson, and H. Hu. 2002. Risk factors for multisymptom illness in US Army veterans of the Gulf War. Journal of Occupational and Environmental Medicine 44(3):271- 281.

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