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CHRONIC MULTISYMPTOM ILLNESS CASE DEFINITIONS AND RECOMMENDATIONS

The Department of Veterans Affairs (VA) tasked the committee with determining whether one of several existing case definitions of chronic multisymptom illness (CMI) in Gulf War veterans is adequate, whether an existing case definition needs to be revised, or whether a new case definition needs to be established. At the committee’s first meeting, VA representatives noted that “given the different case-definition criteria and different ways of evaluating symptoms, it has been difficult to compare research results among studies.” They noted further that “consistent use of a case definition is necessary for advancing research.” This chapter examines the current case definitions of CMI and proposes a way forward.

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 it. 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 also 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 veterans who incorrectly receive or do not receive a diagnosis of CMI and the prescribed course of treatments might not be helpful. Inappropriate treatment can have an adverse effect on the health of a veteran in connection with worry 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 treatment is an effective use of limited resources should be cause for 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 recognizes that as the knowledge base changes, a case definition will need to evolve as has occurred in other symptom-based conditions, such as irritable bowel syndrome, chronic fatigue syndrome (CFS), and fibromyalgia.



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5 CHRONIC MULTISYMPTOM ILLNESS CASE DEFINITIONS AND RECOMMENDATIONS The Department of Veterans Affairs (VA) tasked the committee with determining whether one of several existing case definitions of chronic multisymptom illness (CMI) in Gulf War veterans is adequate, whether an existing case definition needs to be revised, or whether a new case definition needs to be established. At the committee’s first meeting, VA representatives noted that “given the different case-definition criteria and different ways of evaluating symptoms, it has been difficult to compare research results among studies.” They noted further that “consistent use of a case definition is necessary for advancing research.” This chapter examines the current case definitions of CMI and proposes a way forward. 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 it. 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 also 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 veterans who incorrectly receive or do not receive a diagnosis of CMI and the prescribed course of treatments might not be helpful. Inappropriate treatment can have an adverse effect on the health of a veteran in connection with worry 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 treatment is an effective use of limited resources should be cause for 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 recognizes that as the knowledge base changes, a case definition will need to evolve as has occurred in other symptom-based conditions, such as irritable bowel syndrome, chronic fatigue syndrome (CFS), and fibromyalgia. 87

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88 CHRONIC MULTISYMPTOM ILLNESS IN GULF WAR VETERANS EXISTING CASE DEFINITIONS This section discusses the studies that have proposed case definitions of CMI in Gulf War veterans. The definitions have been informed by questionnaires and surveys used in cohort studies (see Chapter 3), statistical analyses (see Chapter 4), and clinical observations. Because of the wide array of symptoms found in 1990–1991 Gulf War veterans and the lack of definitive diagnostic tests, several case definitions have been proposed and used by various researchers, but no case definition has been universally accepted. Each definition is described below; details about how the cohorts were assembled can be found in Chapter 3 and are not presented here. Table 5.1 summarizes the definitions and may be found later in this chapter. It should be noted that the authors of the definitions discussed below do not address, nor did they intend to address, all the elements of a typical case definition (see Chapter 2). A standard set of criteria regarding time (a defined period of onset), place, exposures, and clinical and laboratory findings would have been useful; however, 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 not possible to define many of the typical elements associated with a case definition. Haley and Colleagues Haley et al. (1997) defined multisymptom illness in Gulf War veterans on the basis of factor analysis (see Chapter 4) and clinical observation by using two distinct populations. The factor analysis included 249 (41%) of the 606 Gulf War veterans of the Twenty-Fourth Reserve Naval Construction Battalion from five southeastern states. The study was the first to examine groupings of symptoms in Gulf War veterans by using factor analysis. Through standardized symptom questionnaires and a two-stage exploratory factor analysis, the investigators defined what they considered to be either six syndromes or six variants of a single syndrome, which they labeled impaired cognition, confusion–ataxia, arthromyoneuropathy, phobia–apraxia, fever– adenopathy, and weakness–incontinence. One fourth of the veterans in the study (63) were classified as having one of the six syndromes. On the basis of factor analysis and postprocessing decisions, the study defined three syndromes: impaired cognition, confusion–ataxia, and arthromyoneuropathy. The clinical observation included selected cases from a Department of Defense (DOD) military survey and registry. In an effort to compare the factor-analysis–derived syndromes with clinical cases, the veterans in the DOD registry had to meet several criteria—a veteran must have served in the theater of operations during August 8, 1990–July 31, 1991; must not have had a physician’s diagnosis of other medical and psychiatric illnesses that could cause symptoms; and must have experienced at least five of the following eight symptoms: fatigue; arthralgia or low back pain; headache; intermittent diarrhea without bloody stools; neuropsychiatric complaints of forgetfulness, difficulty concentrating, depression, memory loss, or easy irritability; difficulty sleeping; low-grade fever; and weight loss. The degree of association between the factor- analysis–derived syndromes and the clinical case definition was assessed with logistic regression analysis. When the clinical definition was compared with the factor-analysis–derived syndromes, it was found to be strongly associated with syndromes 1 and 3 (impaired cognition and arthromyoneuropathy). The clinical definition proposed by Haley et al. (1997) captured 34% (85) of the veterans, whereas the six-factor derived syndromes identified 25% of the veterans (5% as syndrome 1 and 9% as syndrome 3).

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CHRONIC MULTISYMPTOM ILLNESS CASE DEFINITIONS AND RECOMMENDATIONS 89 Haley et al. (2001) attempted to replicate their factor-analysis findings in a validation cohort, which was separate from their original cohort of Seabees. The validation cohort consisted of 335 veterans who were living in north Texas and had registered with a VA clinic in Dallas or were recruited by advertising. In comparison with the original Seabee cohort, participants in the validation cohort were more likely to have served in the Army and to be representative of those who served in the gulf with regard to racial and ethnic background, age, and wartime military status. The three primary syndrome factors were impaired cognition, confusion–ataxia, and central pain (termed arthromyoneuropathy in the original study); and the four additional variables or secondary symptom factors were chronic watery diarrhea, chronic fatigue involving excessive muscle weakness, chronic fever and night sweats, and middle and terminal insomnia. The higher-order factor was the presence of an underlying single Gulf War syndrome that could explain all variance and covariance among the three first-order factors. Overall, 29% of participants had one or more of the three first-order factors, defined by dichotomizing the syndrome factor scale at 1.5 standard deviations above the mean, as in the original study. The authors found that the apparent three-factor solution, originally demonstrated in the Seabee cohort, was also present in this new cohort (Model 1); that the three syndrome factors probably represented a higher-order syndrome, such as a single Gulf War syndrome (Model 2); and that some additional symptoms (the four secondary symptom factors) appeared in all three syndrome variants. They suggested that syndrome 3 (symptoms related to central pain) may not be a separate syndrome but may reflect a higher-order factor related to overall Gulf War syndrome. The authors concluded that the three-syndrome factor model is the only empirically developed and validated case definition available. The small sample in the study may have limited exploration of less common symptoms, and the nonrandom nature of the sample may have limited to some degree the generalizability of some of the results, such as syndrome prevalence; but the detailed questionnaires and the external validation of the findings through comparison with the Seabee cohort were strengths of the second study. Note that this study, by design, had no comparison group. The authors were seeking to validate the presence of a symptom complex in deployed veterans rather than to examine its prevalence in deployed and nondeployed forces. They concluded by recommending a study of a national randomly selected sample of deployed and nondeployed Gulf War–era military populations with their methods of symptom measurement and syndrome definition. To validate the definition posed by Haley et al. (2001), Iannacchione et al. (2011) conducted a study of a population-based sample of more than 8,000 of Gulf War–deployed and nondeployed (but fit for deployment) service personnel. The questionnaire, conducted in 2007– 2009, contained questions about symptoms used to develop the syndromes found by Haley et al. (2001) and symptoms used for other case definitions—such as that of the Centers for Disease Control and Prevention (CDC)— and similar conditions, for example, CFS and fibromyalgia. The authors did not replicate the exploratory factor analysis. They used the factor weights from the original Haley et al. study to create factor scales and to determine which syndrome fit each person in the study, as was done in both earlier studies of the factor case definition (Haley et al., 1997, 2001). Results showed similar goodness-of-fit statistics for all three studies. Some 14% of the deployed and 4% of the nondeployed fit any of the six syndromes that make up the factor case definition.

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90 CHRONIC MULTISYMPTOM ILLNESS IN GULF WAR VETERANS Centers for Disease Control and Prevention The CMI case definition developed by CDC was derived from clinical data and statistical analyses (Fukuda et al., 1998). The investigators conducted a cross-sectional survey in a Pennsylvania-based Air National Guard unit and three comparison Air Force units. Two case definitions were developed on the basis of clinical data and statistical analyses from a survey of 35 symptoms. To develop the clinical definition, the investigators required that the illness be chronic (6 months or longer) and be present 2.5 times more in deployed than in nondeployed veterans. The method identified symptoms of fatigue, difficulty remembering or concentrating, moodiness, difficulty sleeping, and joint pain or stiffness. The analytic approach included a principal-components analysis followed by a confirmatory factor analysis. The researchers considered the results to identify the same symptoms as in their clinical definition. Two factor- analytic definitions were developed: the factor-score approach, in which participants who had factors scores in the top 25th percentile were cases; and a symptom-category approach—based on the symptom groups identified in the factor analysis (categories of fatigue, mood–cognition, and musculoskeletal)—that specified that a case must have at least one symptom in each of at least two categories. Because there was a high degree of agreement between the two definitions on the basis of prevalence in the study population, the authors endorsed the symptom-category approach as more practical for a clinical setting. The final case definition included an indicator of severity and was used in a clinical study that included clinical evaluation. The definition requires more than one chronic (≥6 months) symptom in each of at least two of three categories: fatigue, mood and cognition, and musculoskeletal. Severe cases were identified if at least one symptom in each of the required categories was rated as severe. Of 1,155 participating Gulf War veterans, 6% had severe CMI, and 39% had mild to moderate CMI; of the 2,520 nondeployed era veterans, 0.7% had severe and 14% had mild to moderate CMI. Risk factors associated with CMI were deployment to the Gulf War, rank, being female, age, and smoking; cases also reported reduced functioning. The definition has been used in numerous studies (discussed below) and fulfills many of the requirements for a case definition (Chapter 2). It also allows subclassification by severity. Several followup studies of Gulf War veterans have used the CDC definition in other study populations, some with modifications. For example, Rayhan et al. (2013) used the CDC criteria in a clinical study of migraines; the researchers required that cases had been deployed to the Persian Gulf for at least 30 days and excluded participants who had chronic diseases that accounted for their CMI symptoms. Among the 50 CMI cases identified and 45 controls, the authors found that 64% of CMI cases had migraines (11 times more likely than controls to suffer from migraines). Kelsall et al. (2009) conducted a study using a questionnaire and medical assessment of 2002 Australian veterans with a modified version of the CDC definition and incorporated results of an Australian factor analysis (Forbes et al., 2004). The Kelsall et al. study required that veterans had one or more symptoms in the preceding month with at least moderate severity from at least three of four categories: fatigue, psychophysiologic, cognitive, and arthroneuromuscular. Of the 1,381 Gulf War veterans who participated in the study, 25.6% met this definition of CMI, as did 16% of the 1,377 nondeployed era veterans. The study found that veterans who had CMI were also significantly more likely to suffer from psychiatric disorders, chronic fatigue, and reduced functional impairment and quality of life, but objective outcomes were similar in the two groups. Gulf War veterans who had CMI had more hospitalizations, obstructive liver disease,

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CHRONIC MULTISYMPTOM ILLNESS CASE DEFINITIONS AND RECOMMENDATIONS 91 and Epstein-Barr virus exposure but were otherwise similar to nondeployed Gulf War–era veterans (Kelsall et al., 2009). Other studies have used the CDC definition to assess cohorts longitudinally and describe potential risk factors. In a 10-year followup of a cross-sectional survey, 1,035 deployed and 1,116 nondeployed veterans who had participated in the 1995–1996 National Health Survey (studied by Fukuda et al., 1998) indicated that CMI was twice as likely in deployed as in nondeployed veterans. Results showed that 28.9% of deployed (7% severe) and 15.8% of nondeployed (1.6% severe) met the criteria for CMI. Both deployed and nondeployed participants who had CMI reported lower quality of life and more symptom-based medical conditions, metabolic syndrome, psychiatric disorders, prewar anxiety, and depression than those who did not have CMI. Deployed CMI veterans reported more nicotine dependence and infectious mononucleosis, but nondeployed CMI veterans reported more headaches and gastritis (Blanchard et al., 2006). Hallman et al. (2003) conducted an exploratory factor analysis and cluster analysis among 1,161 participating veterans who resided in Delaware, Illinois, New Jersey, New York, North Carolina, Ohio, or Pennsylvania and compared results with the CDC case definition of CMI. Four factors were extracted in the factor analysis and were labeled mood/memory/fatigue, musculoskeletal, gastrointestinal, and throat/breathing, and severity was categorized by cluster analysis: group 1, mild or no problems; group 2, moderate to severe symptoms. Some 75% of group 1 and 100% of group 2 (all but one individual) met the CDC case definition. The study was not designed to be representative of US veterans; the investigators sought veterans who believed that they suffered from Gulf War–related illnesses. In a 5-year followup, Ozakinci et al. (2006) surveyed 390 veterans a second time. That study did not use a case definition, but it did distinguish between veterans (60%) reporting good health and no or few symptoms and those (40%) reporting fair or poor health and many symptoms (37 symptoms on the average). Ten years after the Gulf war, those who were highly symptomatic improved less and reported greater symptom severity than those who had had lesser symptomatology initially. Wolfe et al. (2002) assessed 945 respondents from the Ft. Devens cohort in 1997–1998 by using the CDC case definition. Symptom onset must have occurred during or after the Gulf War and symptom frequency and severity were assessed, but a requirement for duration of more than 6 months could not be met, owing to lack of data. About 60% of respondents met the case definition of CMI, including 30% who had severe CMI. Important risk factors for CMI included being female, having less than a college education, being a reservist, and having a variety of deployment-related environmental exposures. The study did not include a comparison group and was composed entirely of Army personnel. Unwin et al. (1999) assessed the health of and symptoms in more than 8,000 Gulf War– deployed, Gulf War–era, and Bosnia-deployed UK veterans who responded to a questionnaire. The authors compared their questionnaire results with the CDC definition of CMI and found that 25.3% of Gulf War veterans, 12.2% of era veterans, and 11.8% of Bosnia-deployed veterans met the criteria. In all three groups of veterans, meeting the CDC case definition was significantly associated with a variety of wartime and environmental exposures (Unwin et al., 1999). In an evaluation of the CDC definition, Smith et al. (2013) conducted a survey of a sample of 495 veterans drawn from the VA Gulf War Health registry about 10 years after the Gulf War. The study included veterans from all branches of the military and was weighted to be

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92 CHRONIC MULTISYMPTOM ILLNESS IN GULF WAR VETERANS representative of the national population. The investigators asked about 35 symptoms but focused on the 10 main symptoms identified by Fukuda et al. and found that 33.8% met the definition of CMI. They also examined symptoms of postwar onset (excluding those with onset during or before the war), which Fukuda et al. did not require. Requiring onset of symptoms after the war did not change the prevalence (33.4%) substantially. Symptoms found to be most characteristic of CMI cases, in descending order of most commonly reported, are fatigue, memory problems, joint pain, joint stiffness, difficulty in sleeping, moodiness, difficulty with words, depression, muscle pain, and anxiety. Symptoms were endorsed by 55.9% of cases. Finally, the investigators examined agreement between the CDC definition and veterans’ beliefs about deployment-related illness: 19.4% met the CMI case definition and believed that they were suffering from CMI, 13.8% of veterans who met the criteria for CMI did not believe that they had CMI, and 14.8% did not meet the CMI criteria but believed that they did have CMI. A similar description of 2,961 UK veterans’ beliefs reported that 17.3% believed that they had CMI, and 90% of those fit the CDC CMI criteria (Chalder et al., 2001). Kansas The Kansas Persian Gulf Veterans Health Initiative in 1998 sponsored a study of deployment-related symptoms (Steele, 2000). The investigator chose to develop a clinically based descriptive definition using correlated symptoms. To be considered in this study, symptom onset must have been in 1990 or later, and symptoms must have been present in the year before interview. Participants were excluded if they had a diagnosis of or were being treated for cancer, diabetes, heart disease, chronic infectious disease, lupus, multiple sclerosis, stroke, or any serious psychiatric condition. Gulf War veterans (2,030) who lived in Kansas participated in a telephone interview. Correlated symptoms of veterans who met the study criteria above resulted in five reliable symptom groups: fatigue and sleep problems, pain, neurologic and mood, gastrointestinal, and respiratory symptoms. One symptom, rashes, was not part of the correlation analysis but was frequently reported and correlated with deployment, so it was also included. In all symptom groups, greater symptom burden was associated with deployment. Gulf War veterans reported worse overall health and more symptoms. The proportion of exclusionary conditions was similar in deployed and nondeployed veterans. Notably, Gulf War veterans were more likely than nondeployed veterans to report moderate or multiple symptoms in three or more symptom groups. The author developed a case definition that required • Symptom onset after 1990. • The presence of symptoms in the year before the interview. • No diagnoses or treatment for exclusionary conditions (cancer, diabetes, heart disease, chronic infectious disease, lupus, multiple sclerosis, stroke, or any serious psychiatric condition). • Symptoms in at least three of six symptom groups: fatigue and sleep problems, pain, neurologic and mood, gastrointestinal, respiratory, and skin symptoms. • At least one moderately severe symptom or two or more symptoms within a symptom group. The Kansas case definition resulted in a prevalence of 34.2% in Gulf War veterans and 8.3% in nondeployed veterans (odds ratio [OR] = 4.68, 95% confidence interval [CI] 3.25–6.75); application of the CDC case definition to the same study population definition resulted in a

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CHRONIC MULTISYMPTOM ILLNESS CASE DEFINITIONS AND RECOMMENDATIONS 93 prevalence of 47.2% in Gulf War veterans and 19.8% in nondeployed veterans (OR = 3.26, 95% CI 2.48–4.28). The Kansas definition found CMI more prevalent in women, those with lower income, those with less education, Army veterans, and enlisted personnel. Portland Population-based studies supported by the Portland Environmental Hazards Research Program have also proposed a definition of CMI (Bourdette et al., 2001; Spencer et al., 1998). A questionnaire and clinical evaluation assessed symptoms in Gulf War veterans by combat period. The study, conducted in 1998, included 244 cases and 113 controls who were deployed to the Persian Gulf. Participants lived in Oregon or Washington state. Veterans who served in other conflicts, such as Vietnam, were excluded from the study. Cases reported (and confirmed) at least one symptom from among three groups: fatigue, cognitive–psychologic, and musculoskeletal symptoms. Symptoms must have persisted or recurred for a month or longer, must have been present in the 3 months before evaluation, and must have begun during or after deployment to the Persian Gulf. After clinical evaluation, a committee composed of neurologists, rheumatologists, internal-medicine specialists, neuropsychologists, and epidemiologists reviewed each participant and excluded those who had exclusionary disorders and diagnostic explanations for reported symptoms. Exclusionary diagnoses included cancer, epileptic seizures, HIV, schizophrenia, hepatitis, hypothyroidism, alcoholism, effects of shift work, mechanical back pain, myofascial pain, bursitis or tendonitis, patellofemoral syndrome, osteoarthritis, diet intolerance, and diabetes mellitus. Skin and gastrointestinal symptoms were not used to define a case, because they were almost always explained by a diagnosable condition or not present at the time of evaluation. Controls did not report symptoms during or after their military service. Stratification by deployment period revealed no differences in symptoms between precombat, combat, and postcombat periods. However, cases were more likely to score lower on the Armed Forces Qualification Tests, to have served more days in theater on the average, and to have been members of the Army (Spencer et al., 1998). In addition, 48% of cases reported symptoms in two or more symptom groups, and 20% reported symptoms in all three groups. Another study of the same population performed a factor analysis of the 69 symptoms reported on the questionnaire to determine whether the symptom groups used for the clinical definition described above could approximate the statistical approach of grouping symptoms and to assess potential misclassification of cases and controls on the basis of the clinical definition (Bourdette et al., 2001). The factor analysis supported the clinically described symptom groups, but its identification of cases and controls differed slightly. The factor analysis–derived case definition was congruent with the clinically derived definition, but the selection of cases differed, identifying 10 of 113 controls as cases and 52 of 241 cases as controls. Department of Veterans Affairs VA sponsored several studies of the health of Gulf War veterans (Kang et al., 2000, 2002). A followup investigation of the same sample assessed “unexplained multisymptom illness” to describe veterans who had such symptoms as fatigue, muscle or joint pain, headache, memory problems, respiratory problems, and skin problems that persist for more than 6 months and were not adequately explained by established, conventional medical or psychiatric disorders. On the basis of that definition, 36.5% of Gulf War veterans and 11.7% of nondeployed veterans met the case definition. About 75% of Gulf War veterans who had CMI reported that symptom

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94 CHRONIC MULTISYMPTOM ILLNESS IN GULF WAR VETERANS onset occurred during 1991–1995. Those who had CMI reported significantly worse physical and mental functioning than nondeployed veterans. This clinically derived definition of unexplained multisymptom illness had the highest adjusted OR among more than 20 conditions but was not unique to Gulf War veterans (Kang et al., 2009). TABLE 5.1 Case Definitions of Multisymptom Illness Used in Gulf War Veteran Studiesa 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 by factor using factor scores calculated with analysis weights; cases with factor scores (Haley et >1.5 are identified as having a al., 1997) 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, al., 1998) 1) fatigue or 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 muscle pain) Kansas 3 of 6 domains: Chronic Since 1990 Symptom reporting Mild, (Steele, 1) fatigue and sleep problems must be in the moderate, 2000) 2) pain symptoms absence of or severe by 3) neurologic, cognitive, and or diagnosed self-report mood symptoms exclusionary 4) gastrointestinal symptoms conditions; only 5) respiratory symptoms respondents who 6) skin symptoms have at least 1

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CHRONIC MULTISYMPTOM ILLNESS CASE DEFINITIONS AND RECOMMENDATIONS 95 Definition Symptoms—must have signs, Duration Onset Exclusions Severity symptoms, or complaints that fit at least 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 and within the after et al., at least 4 of the following: fevers 3 deployment 2001; and chills; new kinds of headache; previous to the Spencer et unrefreshing sleep; tender glands months Persian al., 1998) in the neck, jaw, or groin; changes Gulf War 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, skin conventional problems, or any other unexplained medical or symptoms that may sometimes be psychiatric diagnosed as chronic fatigue diagnoses syndrome, fibromyalgia, irritable bowel syndrome, or multiple chemical sensitivity NOTE: CDC = Centers for Disease Control and Prevention; VA = Department of Veterans Affairs. a Other elements of case definitions (such as laboratory criteria and exposure) not reported.

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96 CHRONIC MULTISYMPTOM ILLNESS IN GULF WAR VETERANS DISCUSSION OF EXISTING CASE DEFINITIONS The committee reviewed the literature that identified the symptoms found in Gulf War veterans through questionnaires and surveys, factor analysis, and clinical observation. After a thorough discussion of that literature, the committee concluded that it was not feasible to develop a new evidence-based definition of CMI. The case-definition studies do not all consistently identify 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. Furthermore, the symptoms of CMI are not unique to Gulf War–deployed veterans although they occur in the deployed at a higher frequency and with greater 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 (see Chapter 3) and depicted in the graph in Appendix B. Thus, the committee has concluded that the available evidence is insufficient to develop a new case definition of CMI inasmuch as the data are lacking for key elements of a case definition of a symptom-defined condition, which might include, for example, onset, duration, and measures of severity. To move the field forward, the committee has developed an approach that is 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 all the case- definition studies summarized in this chapter (albeit not necessarily using the same terminology) that includes symptoms of fatigue, pain, and neurocognitive dysfunction. Furthermore, the different symptoms in the symptom-based studies—as summarized in Chapter 3, Table 4.2, and Appendix B—were regularly reported with higher frequency in Gulf War veterans than in nondeployed era veterans or veterans deployed elsewhere; they include gastrointestinal, respiratory, and dermatologic symptoms in addition to the fatigue, pain, and neurocognitive symptoms already identified. The committee recognized that two existing definitions—the CDC definition and the Kansas definition (see Table 5.1)—capture the array of symptoms most commonly identified. The CDC definition requires one or more symptoms in at least two of the categories of fatigue, pain, and mood and cognition to identify a case. The Kansas definition requires at least three of six symptoms in the domains of fatigue–sleep, pain, neurological– cognitive–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% of the population studied (Kansas Gulf War veterans) (see Table 5.2). The two definitions have important differences. The CDC definition has the greatest concordance with all the other definitions (see Table 5.1) but is less restrictive than the Kansas definition. The CDC definition requires fewer symptoms, does not include any exclusionary criteria, and might identify a case without physical symptoms. 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, 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

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CHRONIC MULTISYMPTOM ILLNESS CASE DEFINITIONS AND RECOMMENDATIONS 97 complexes demonstrated by the Gulf War veterans. The committee recognizes that the definitions were developed in different study populations and that they differ in sensitivity and specificity. However, in the committee’s judgment, those two definitions will provide the VA with a framework that will further research and treatment. TABLE 5.2 Reported Prevalence of CMI Study CMI Rate (%) Definition Period of Data Population GWVs NDVs Collection Fukuda et al. 45% 15% CDC 1995 Air Force units (1998) Wolfe et al. 60% CDC 1997–1998 Ft. Devens cohort (2002) Unwin et al. 62% 36% CDC 1998 UK veterans (1999) Chalder et al. 59% CDC 1998 UK veterans (2001) Kelsall et al. 26% 16% CDC 2000–2002 Australian veterans (2009) Smith et al. 34% CDC ~2001 US national sample of GWVs (2013) Blanchard et al. 29% 16% CDC 2001 US national sample of GWVs (2006) Steele (2000) 34% 8% Kansas 1998 Veterans in Kansas Kang et al. 37% 12% VA 2005 US national sample of GWVs (2009) Haley et al. 25% Haley FA 1994–1995 A Seabee reserve battalion (1997) Haley et al. 34% Haley 1994–1995 A Seabee reserve battalion (1997) clinical Haley et al. 29% Haley FA 1997–1998 US Army veterans living in north (2001) Texas Iannacchione et 14% 4% Haley FA 2007–2009 US national sample of GWVs al. (2011) NOTE: CDC = Centers for Disease Control and Prevention; CMI = chronic multisymptom illness; FA = factor analysis; GWV = Gulf War veteran; NDV = nondeployed veteran; VA = Department of Veterans Affairs. In conclusion, the committee saw merits in both the CDC and Kansas definitions, but the weight of the evidence does not support 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 a definition that is suitable for use in clinical settings.

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98 CHRONIC MULTISYMPTOM ILLNESS IN GULF WAR VETERANS CONCLUSIONS After reviewing the literature on Gulf War veterans’ symptoms the committee came to several conclusions: • The 1990-1991 Gulf War presented a unique set of circumstances and experiences to the Gulf War veterans. • They symptoms complex as described by numerous researchers resembles previous war syndromes. • The evidence to date does not indicate that there is a unique Gulf War syndrome as many of the symptoms experienced by Gulf War veterans are also experienced by the non-deployed and deployed elsewhere. • Gulf War veterans report more symptoms and more severe symptoms than the non- deployed or deployed elsewhere populations. • The symptom reporting is similar in Gulf War veterans from the US, Canada, UK, Denmark, and Australia. • There is no universally accepted case definition and none of the current definitions meet the general criteria of case definitions (e.g., onset, duration, severity, exclusionary criteria). • The available evidence is insufficient to develop a new case definition. 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 (see Appendix B). 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 (see Chapter 3 and Appendix B). 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.

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CHRONIC MULTISYMPTOM ILLNESS CASE DEFINITIONS AND RECOMMENDATIONS 99 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 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. CONSIDERATIONS FOR FUTURE RESEARCH It has been more than 2 decades since the Gulf War, and research has left important questions about the veterans’ health unanswered. The inherent limitations of the research and the lack of data regarding exposures are apparent. Additional new research focused on the definition of CMI is likely to be of little, if any, benefit to the veterans. The veteran population is aging, with an associated increase in comorbidities; with the continued passage of time, recall bias is

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100 CHRONIC MULTISYMPTOM ILLNESS IN GULF WAR VETERANS likely to increase. To inform a case definition, a prospective study design with well-defined cohorts that could be systematically characterized with respect to subjective symptoms would have been needed. Symptoms would be characterized according to standardized scales and measures that would also include severity and time of onset. In addition, baseline and prospective collection of biospecimens, accurate exposure monitoring, and pre-deployment and post-deployment health assessments would add to the knowledge base and possibly enable linkages to be made, for example, regarding exposure. Repeated followup of the cohort would enable the systematic characterization of the natural history of the illness and the documentation of changes in symptoms. However, given the passage of more than 20 years, such a study is no longer possible. More fruitful research efforts might focus on identifying subsets of Gulf War veterans who have distinct symptoms and physiologic characteristics with a view to developing effective treatments to improve function and quality of life. The committee’s review revealed a number of limitations in the data that could be reduced in research on future deployments, such as the following: • Systematic and standardized assessments of frequency, severity, onset, and duration of symptoms in the course of data collection would strengthen the analytic processes. • Early in the evolution of postdeployment studies, when unexpected magnitudes of veteran complaints occur, more attention to in-depth assessment of subsets of veterans would be valuable. • A systematic effort to collect and preserve exposure data (such as data on vaccinations, drugs, and environmental exposures) should increase the ability to analyze and interpret reported symptoms. Successful development of a case definition will depend on accurate information about related exposures. REFERENCES Blanchard, M. S., S. A. Eisen, R. Alpern, J. Karlinsky, R. Toomey, D. J. Reda, F. M. Murphy, L. W. Jackson, and H. K. Kang. 2006. Chronic multisymptom illness complex in Gulf War I veterans 10 years later. American Journal of Epidemiology 163(1):66-75. 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. Chalder, T., M. Hotopf, C. Unwin, L. Hull, K. Ismail, A. David, and S. Wessely. 2001. Prevalence of Gulf War veterans who believe they have Gulf War syndrome: Questionnaire study. British Medical Journal 323(7311):473-476. Forbes, A. B., D. P. McKenzie, A. J. Mackinnon, H. L. Kelsall, A. C. McFarlane, J. F. Ikin, D. C. Glass, and M. R. Sim. 2004. The health of Australian veterans of the 1991 Gulf War: Factor analysis of self- reported symptoms. Journal of Occupational and Environmental Medicine 61(12):1014-1020. 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. 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.]

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CHRONIC MULTISYMPTOM ILLNESS CASE DEFINITIONS AND RECOMMENDATIONS 101 Haley, R. W., G. D. Luk, and F. Petty. 2001. Use of structural equation modeling to test the construct validity of a case definition of Gulf War syndrome: Invariance over developmental and validation samples, service branches and publicity. Psychiatry Research 102(2):175-200. Hallman, W. K., H. M. Kipen, M. Diefenbach, K. Boyd, H. Kang, H. Leventhal, and D. Wartenberg. 2003. Symptom patterns among Gulf War registry veterans. American Journal of Public Health 93(4):624-630. Iannacchione, V. G., J. A. Dever, C. M. Bann, K. A. Considine, D. Creel, C. P. Carson, H. Best, and R. W. Haley. 2011. Validation of a research case definition of Gulf War illness in the 1991 US military population. Neuroepidemiology 37(2):129-140. IOM (Institute of Medicine). 2000. Gulf War and Health, Volume 1: Depleted Uranium, Pyrodostigmine Bromide, Sarin, Vaccines. Washington, DC: National Academy Press. 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. Kang, H. K., C. M. Mahan, L. Y. Lee, C. A. Magee, and F. M. Murphy. 2000. Illnesses among United States veterans of the Gulf War: A population-based survey of 30,000 veterans. Journal of Occupational and Environmental Medicine 42(5):491-501. 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. Kelsall, H. L., D. P. McKenzie, M. R. Sim, K. Leder, A. B. Forbes, and T. Dwyer. 2009. Physical, psychological, and functional comorbidities of multisymptom illness in Australian male veterans of the 1991 Gulf War. American Journal of Epidemiology 170(8):1048-1056. 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. Ozakinci, G., W. K. Hallman, and H. M. Kipen. 2006. Persistence of symptoms in veterans of the first Gulf War: 5-year follow-up. Environmental Health Perspectives 114(10):1553-1557. Rayhan, R. U., M. K. Ravindran, and J. N. Baraniuk. 2013. Migraine in Gulf War illness and chronic fatigue syndrome: Prevalence, potential mechanisms, and evaluation. Frontiers in Physiology 4:181. Smith, B. N., J. M. Wang, D. Vogt, K. Vickers, D. W. King, and L. A. King. 2013. Gulf War illness: Symptomatology among veterans 10 years after deployment. Journal of Occupational and Environmental Medicine 55(1):104-110. 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, and et al. 1999. Health of UK servicemen who served in Persian Gulf War. Lancet 353(9148):169-178. 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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