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Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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4

Evaluation of Health Conditions

Veterans who were deployed to the Persian Gulf region in 1990–1991 have consistently reported having poorer health and quality of life than veterans who served in the military during the war but were not deployed or were deployed elsewhere. This increase in adverse health effects has been seen not only in U.S. veterans, but also in veterans of the coalition forces, including Australia, Canada, Denmark, and the United Kingdom (UK). As noted in Chapter 1, these service members were exposed to a multitude of chemicals, vaccinations, and adverse environmental conditions that individually or in concert may be harmful to a few or many service members.

In this chapter, each health condition section starts with an overview of the condition, then a brief summary of Volumes 4 and 8 findings and conclusions, followed by a review of the new literature where available, and then a summary of the Volume 10 committee’s findings and conclusions. Each section ends with a summary table of the primary studies from Volumes 4 and 8 as well as any new primary studies. All health conditions addressed in Volume 8 are covered here; if new literature was not identified, this is indicated. In the last section of this chapter, the committee describes the only veteran studies that had objective exposure measures, that is, to depleted uranium (DU); no summary table is included for these primary studies, although they are described in the text.

Some health conditions discussed individually in Volume 8 were combined in this volume. The section on women’s health from Volume 8 is not mirrored in this volume; if information specific to women’s health conditions was identified it was included in the relevant health condition section. Fibromyalgia, chronic widespread pain, chronic fatigue syndrome (CFS), and conditions of the musculoskeletal system are all now discussed in the section on pain-related conditions. Although, the health conditions generally are presented in the same order as Volume 8, the names of some of the sections have been slightly modified and the terminology of the International Statistical Classification of Diseases and Related Health Problems (ICD), 9th or 10th edition, is no longer used. Finally the section on chronic multisymptom illness is now called Gulf War illness in keeping with the suggestion of prior Institute of Medicine (IOM) committees (IOM, 2010, 2014a). All cancers, regardless of the affected organ system, are discussed in the section on cancer rather than in the section on the organ system affected. Similarly,

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

all studies on mortality, whether from external causes or from disease, are now discussed in the section on causes of mortality.

Information on the committee’s process and criteria for identifying, reviewing, and categorizing the literature, as well as description of the categories of association the committee used, may be found in Chapter 2. It should be noted that not all studies were classified the same way for each health condition. A study may be classified as a primary study for one health condition because of the method used to obtain the data, but the same study may be classified as secondary for another health condition if less rigorous methods were used to assess that condition. The committee indicates in each section why a particular study was classified as primary, secondary, or was best described in the subsection “Other Related Studies.”

The Volume 10 committee relied on human epidemiologic studies to draw its conclusions about the strength of evidence regarding associations between deployment to the Gulf War and health conditions seen in Gulf War veterans. A major problem with comparing rates of health conditions in deployed cohorts vs nondeployed cohorts or versus the general public is the so-called healthy-warrior effect (see Chapter 2 for a description), which may underestimate effects on veterans. Inasmuch as military personnel must meet physical-health criteria when they enter the military and while they are on active duty, particularly when deployed, the group’s health status is usually better than that of their nondeployed counterparts or the general population of the same age and sex.

Further complicating the assessment of Gulf War veterans’ health is that in recent years, the diagnostic criteria or definitions for several of the health conditions discussed in this volume have been revised to reflect the evolving understanding of these conditions brought on by scientific and other advances. These types of changes are normal in medical science, and it is likely that the diagnostic criteria for these conditions will further change in the future as knowledge about them grows.

Among those health outcomes with recently changed criteria are mental health disorders, fibromyalgia, CFS, and Gulf War illness. Although none of the studies discussed in this report have used the revised diagnostic criteria for mental health disorders, fibromyalgia, and CFS, there are research implications as the new criteria are adopted and implemented. As future bodies review and compare studies using the old criteria and new diagnostic criteria, there may be differences in the incidence or prevalence of a condition that may result from the use of the revised criteria. For example, the new diagnostic criteria for autism resulted in a lower prevalence estimate of the condition than the old criteria (Maenner et al., 2014). The revised criteria for these conditions are briefly discussed in the relevant sections below.

GULF WAR ILLNESS

Shortly after Gulf War veterans returned from their deployments to the Persian Gulf region, many of them began complaining of a broad range of symptoms that did not have an obvious, documentable etiology and pathophysiology. This reporting of symptoms was seen not only in U.S. veterans who had been exposed to many chemicals, including possibly nerve agents from the demolition at Khamisiyah, but Gulf War veterans from coalition countries, including Australia, Canada, Denmark, and the United Kingdom, also reported an increase in numerous symptoms. Many of the coalition forces were in the Persian Gulf region after Khamisiyah or were otherwise unlikely to have been exposed to nerve agents. Since the mid-1990s, numerous studies have documented that deployment to the Gulf War in 1990–1991 entailed an increased risk of developing a multitude of symptoms that veterans themselves called “Gulf War illness” or “Gulf War syndrome.” Although exact numbers are not available, it has been estimated that as many as one-third of the Gulf War deployed veterans may have Gulf War illness (RAC, 2014) and in the recent survey of the National Cohort of Gulf War and Gulf Era Veterans, Dursa et al. (2016) esti-

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

mated that as of 2013 approximately 44% of deployed veterans reported having chronic multisymptom illness compared with 20% of the era veterans (weighted estimates). Studies have consistently shown that deployed Gulf War veterans have a higher number and greater severity of symptoms compared with nondeployed and era veterans (IOM, 2010). The cause of and treatment interventions for Gulf War illness have been addressed by several previous IOM committees (IOM, 2000, 2006b, 2010, 2014b), by the Department of Veterans Affairs (VA) Research Advisory Committee on Gulf War Veterans’ Illnesses (RAC), and by numerous researchers. Several difficulties persist in studying this illness, including the many different methods used for identifying cases and the variable presentations and complex manifestations. All primary studies of Gulf War illness are summarized in Table 4-1 at the end of this section.

Definitions of Gulf War Illness

The proper term to use when describing the complex set of symptoms experienced by Gulf War veterans has been the subject of considerable discussion. This conglomeration of symptom clusters linked to various organ systems has been called chronic multisymptom illness by VA (Kang et al., 2009). However, several alternate definitions and suggestions for classifying these syndromes have been proposed, including those of the Centers for Disease Control and Prevention (CDC) (Fukuda et al., 1998) and a definition proposed by Lea Steele on the basis of her work with Gulf War veterans in Kansas (Steele, 2000) (see Table 4-2). Other definitions include the Gulf War illness syndromes proposed by Robert Haley and colleagues based on factor analysis and clinical assessments (Haley et al., 1997b); three categories of symptoms identified in veterans living near Portland, Oregon (Bourdette et al., 2001; Spencer et al., 1998); and symptom reporting by veterans in the National Health Survey of Gulf War Veterans and Their Families begun by VA in 1995 (Kang et al., 2000, 2009). This multiplicity of definitions makes it difficult to compare results across studies of Gulf War illness.

Prior IOM committees and other organizations have struggled with choosing a name or label to exactly delineate the complex set of symptoms that Gulf War veterans present with. A variety of terms have been used to refer to what was initially labelled “Gulf War illness,” and this proliferation of definitions has resulted in a lack of clarity and inconsistency in the research literature as to what symptoms or conditions are actually being studied. VA has traditionally used the term “unexplained illnesses” for the symptoms experienced by Gulf War veterans. “Gulf War syndrome” was used shortly after the war, but in general most groups, including the RAC, have used the term “Gulf War illness,” although there is no ICD code for such an array of symptoms. The Volume 4 committee approached the issue of multisymptom illnesses from the perspective of “unexplained illness,” focusing on symptoms reported by Gulf War deployed veterans in efforts to determine whether the presenting symptoms defined a unique illness complex. The Volume 8 committee did not attempt to make such a determination, but rather accepted that “multisymptom illness” was in itself a diagnostic entity and assessed the literature regarding the association between symptom reporting indicative of “multisymptom illness” and deployment to the Gulf War.

Recently, the IOM report Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined (IOM, 2014a) reconsidered chronic multisymptom illness in Gulf War veterans. After carefully examining the existing definitions (Bourdette et al., 2001; Fukuda et al., 1998; Haley et al., 1997b; Kang et al., 2009; Spencer et al., 1998; Steele, 2000) that committee concluded that two of those definitions—the CDC and the Kansas definitions—appeared to capture the most salient and commonly identified arrays of symptoms presented by deployed veterans, although neither definition captured all aspects of a case definition. All of the studies reviewed by that committee included reports of fatigue, pain, and neurocognitive symptoms. The committee recommended that VA use those two case definitions,

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

TABLE 4-2 Case Definitions of Gulf War Illness* Used in Gulf War Veteran Studies

Definition Symptoms
CDC
(Fukuda et al., 1998)
One or more from at least two of the following categories:
  1. Fatigue
  2. Mood and cognition (symptoms 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) Duration: ≥ 6 months; severity: mild, moderate, or severe by self-report
Kansas
(Steele, 2000)
Three of six domains:
  1. Fatigue and sleep problems
  2. Pain symptoms
  3. Neurologic, cognitive, or mood symptoms
  4. Gastrointestinal symptoms
  5. Respiratory symptoms
  6. Skin symptoms
Exclusions: Symptom reporting must be in the absence of diagnosed exclusionary conditions; only respondents who have at least one moderately severe symptom or two or more symptoms within a group were considered to have a high level of symptoms in the group
Duration: chronic; onset: since 1990; severity: mild, moderate, or severe by self-report
Haley
(Haley et al., 1997b)
Cases are defined mathematically by using factor scores calculated with weights; cases with factor scores > 1.5 are identified as having a syndrome (a factor derived with the same factor analysis); cases may have multiple syndromes.
Three major syndromes:
  1. Impaired cognition characterized by problems with attention, memory, and reasoning, as well as insomnia, depression, daytime sleepiness, and headaches
  2. Confusion-ataxia characterized by problems with thinking, disorientation, balance disturbances, vertigo, and impotence
  3. Arthromyoneuropathy characterized by joint and muscle pains, muscle fatigue, difficulty lifting, and extremity paresthesias

*Gulf War illness is called chronic multisymptom illness in the IOM report.

SOURCE: Adapted from IOM, 2014a.

pointing out that each of the definitions could serve specific needs. The CDC definition was considered to be less suitable for research that would require a more narrowly defined study population; whereas, the Kansas definition, which is more rigorous, might identify too few cases, thus, compromising the needed statistical power for studying various outcomes of interest. From a practical perspective, adapting the definitions for use in clinical settings was another priority. Besides recommending that VA use both definitions, the committee also recommended that VA systematically monitor data to identify and further refine additional features of chronic multisymptom illness, such as onset, duration, severity, frequency of symptoms, and exclusionary criteria in order to produce a more robust case definition. The committee also recommended that VA use the term “Gulf War illness” rather than “chronic multisymptom illness” for symptomatic Gulf War veterans. The Volume 10 committee uses the term “Gulf War illness” in its discussion of this constellation of symptoms but uses the terms cited by a study’s authors in summaries of the studies.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

Summary of Volumes 4 and 8

The Volume 4 committee noted that findings from factor and cluster analyses for symptoms of Gulf War illness (the committee used the term “unexplained illness”) seem quite similar despite methodologic differences. Similar symptom clusters include neurocognitive symptoms, musculoskeletal symptoms, and peripheral nervous system symptoms. Less commonly reported are symptom clusters involving gastrointestinal and respiratory symptoms. Among the five primary studies of veterans from Iowa (Doebbeling et al., 2000), Australia (Forbes et al., 2004), two UK cohorts (Cherry et al., 2001a; Ismail et al., 1999), and a large national cohort studied by VA (Kang et al., 2002), factor analysis started with representative, generalizable populations and high participation rates. These primary studies found that in general deployed veterans reported more symptoms or more severe symptoms than their nondeployed counterparts. There were seven secondary studies (Bourdette et al., 2001; Fukuda et al., 1998; Haley et al., 1997b, 2001; Hallman et al., 2003; Knoke et al., 2000; Shapiro et al., 2002) that fell short on either the criteria of having high participation rates or having representative samples, that is, the studies included members of only one branch of the service, had small samples of veterans, or used only symptomatic groups of veterans, thus lacking a nonsymptomatic comparison group. Nevertheless, the results of the secondary studies are valuable and add detail to the epidemiologic literature on Gulf War veterans. Although the committee did not find a unique syndrome, illness, or symptom complex in deployed Gulf War veterans, it did report that Gulf War veterans had higher rates of nearly all symptoms or sets of symptoms than their nondeployed counterparts.

The Volume 8 committee considered new information on factor analyses and cluster analyses. That committee found no new studies using factor or cluster analyses on veterans with symptoms of Gulf War illness and discussed only one new primary study focused on prevalence of chronic multisymptom illness (Blanchard et al., 2006). The large and nationally representative National Health Survey of Gulf War Era Veterans and Their Families conducted by VA in 1993–1995, found that nearly 30% of deployed veterans met the CDC case definition of “multisymptom illness” compared with 16% of nondeployed veterans. The Volume 8 committee agreed with the Volume 4 committee in that there was increased reporting of symptoms indicative of multisymptom illness among those deployed to the Gulf War. Furthermore, this increased symptom reporting was also found for deployed veterans from several coalition countries, including Australia, Canada, Denmark, and the United Kingdom, thus adding credence to the findings. The findings across all the studies considered in Volume 8 were similar, broadly describing neurologic, psychologic, cognitive, fatigue, and musculoskeletal symptoms. Even though some studies that compared the most representative samples found symptom patterns that were similar between the deployed and nondeployed groups, symptoms were more severe or more frequent in the deployed than in the nondeployed groups. The Volume 8 committee concluded that there was sufficient evidence of association between deployment to Gulf War and chronic multisymptom illness.

New Literature

This committee reviewed epidemiologic, clinical, and physiologic studies related to Gulf War illness. A major limitation with many of these studies, in particular the epidemiologic ones, is the use of retrospective information (recalled exposures) not clearly verifiable as well as the length of time that has elapsed since the original exposure—that is, deployment to the Persian Gulf region—and the numerous voluntary and involuntary exposures to environmental and other agents that the veterans may have experienced since deployment. In a comparison of symptoms reported by U.S. and UK troops in earlier surveys, Ismail et al. (2011) found that deployed troops from both countries reported more symptoms

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

than nondeployed troops from either country. The most frequently reported symptoms were similar across all four groups (that is, unrefreshed sleep, headaches, irritability, fatigue, and pain).

The Volume 10 committee identified two primary studies and one secondary study that provided new information on Gulf War illness published after the Volume 8 report.

Primary Study

In 2000–2002, Kelsall et al. (2009) conducted a longitudinal assessment of 1,381 of the 1,871 eligible Australian male veterans who had deployed to the Gulf War and a comparison group of 1,085 veterans who had been on active service during the war but had not deployed, as well as 292 veterans who had deployed elsewhere during the war. All the veterans completed a 63-item symptom questionnaire, as well as the 12-item General Health Questionnaire (a measure of psychological distress), the 12-item Short-Form Health Survey (a measure of health-related quality of life), and the Alcohol Use Disorders Identification Test (AUDIT). Veterans also received an in-person health assessment that included a full physical examination, with lung function and fitness tests, and a mental health assessment using the psychologist-administered, computer-assisted Composite International Diagnostic Interview (CIDI). Multisymptom illness was defined using a modification of the CDC operational definition that required one or more symptoms in the past month rated as at least of moderate severity from at least three of four categories (fatigue, “psycho-physiological,” cognitive, and arthroneuromuscular).

The prevalence of multisymptom illness was 25.6% in the Gulf War veterans and 16.0% in the total comparison group. The odds ratio (OR) of having multisymptom illness in the deployed veterans was statistically significant (OR = 1.80, 95% CI 1.48–2.19); models were adjusted for age, military service, rank, education, marital status, other medical conditions, AUDIT score, smoking, health, weight, atopy, and history of diabetes. The odds ratio of multisymptom illness was greatest when deployed veterans were compared with veterans who had not deployed at all (OR = 1.91, 95% CI 1.55–2.36) vs veterans who had deployed elsewhere (OR = 1.45, 95% CI 1.03–2.04). Multisymptom illness was associated with functional and occupational impairment, increased health care utilization, unexplained chronic fatigue, slightly elevated neuropathy score, and increased waist circumference, but not with reduced spirometry performance, lung function, or elevated blood pressure. In particular, multisymptom illness was strongly associated with affective disorder, major depression, any anxiety disorder (but not posttraumatic stress disorder [PTSD]), somatoform disorder, and alcohol use or dependence disorder, in the Gulf War deployed and nondeployed veterans but not in the deployed elsewhere comparison group (Kelsall et al., 2009).

Laboratory values for Gulf War veterans with multisymptom illness were significantly elevated for inflammation (erythrocyte sedimentation rate > 10 mm/hour or > 15 mm/hour if > 50 years of age; C-reactive protein > 10 mg/L or leukocyte count > 11.0 × 109/L) and elevated random plasma glucose compared with deployed veterans who did not have multisymptom illness. Deployed elsewhere veterans with multisymptom illness also showed an elevated plasma glucose compared with their healthy counterparts; these veterans also had more markers of liver disease as determined by alanine aminotransferase > 55 U/L and aspartate aminotransferase > 45 U/L (OR = 6.20, 95% CI 1.61– 23.93; adjusted for military service, age, rank, education, and marital status). Nondeployed veterans with multisymptom illness had more markers of obstructive liver disease than their counterparts without multisymptom illness. There were no other significant differences in laboratory values between veteran groups with multisymptom illness and those without it (Kelsall et al., 2009).

In a follow-up to Kelsall et al. (2009), Sim et al. (2015) reported on the Australian Gulf War Veterans’ Follow Up Health Study, conducted between 2011 and 2013. This study is an assessment

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

of the entire 1,871 Australian Gulf War cohort, 10 years after the 2000–2002 baseline study (Kelsall et al., 2006) and 20 years after the war. Because only about 2% of the participants were women, only results pertaining to males were reported. Results were adjusted for age, rank category, and service branch. Of the 1,456 eligible deployed veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans provided the comparison group. As with the earlier study, veterans completed a 63-item general health symptom questionnaire (sent via mail) and an over-the-phone CIDI, and gave consent for their Department of Defence health records and Medicare claims to be accessed. In-person health assessment or physical examinations were not performed. Gulf War deployed veterans reported a greater prevalence of all 63 symptoms and the difference was statistically significant for 47 of them. Results showed a greater increase in the number of symptoms reported for deployed vs nondeployed veteran. Among the 20 most prevalent symptoms, half were significantly more persistent and/or more incident in the deployed group. The follow-up survey used the same criteria for multisymptom illness as the 2000–2002 baseline study. The prevalence in Gulf War veterans was 29% in veterans who met the criteria for multisymptom illness compared with 18% in nondeployed veterans (these percentages dropped to 26% and 16%, respectively when cases with explanatory conditions were excluded). Gulf War veterans were significantly more likely to have multisymptom illness at follow-up (OR = 1.60, 95% CI 1.31–1.95) than their nondeployed counterparts.

Secondary Study

The wave 3 survey of the cross-sectional National Health Study of Persian Gulf War Era Veterans (discussed in greater detail in Chapter 3), conducted in 2012–2013 via mail, website, or a computer-assisted telephone interview, asked 8,104 deployed and 6,148 Gulf War era veterans to indicate whether they had experienced a number of physical and mental health symptoms (Dursa et al., 2016). The survey also asked veterans about the presence and occurrence of any unexplained multisymptom illnesses. The weighted prevalence of reporting of multisymptom illness increased from just over 36% in 2005 to 43.9% in 2013 for deployed veterans and from about 12% in 2005 to 20.3% in 2013 for era veterans (Dursa et al., 2016; Kang et al., 2009). There was a significant difference in the prevalence of chronic multisymptom illness between deployed and era veterans (OR = 3.06, 95% CI 2.78–3.83); adjusted for age, race, sex, body mass index (BMI), smoking status, service branch, and unit component. The presentation by VA on the preliminary results of this survey noted that among deployed and era veterans with self-reported lifetime chronic multisymptom illness, there was a statistically significant difference in symptom reporting in the past 12 months only for unrefreshing sleep, headaches, and trouble finding words (Bossarte, 2014).

Other Related Studies

Since publication of Volume 8, there have been several new studies focusing on the association of Gulf War illness symptoms with potential exposures and biological mechanisms that may be responsible for the symptoms. During its review of the published literature, the committee identified studies on Gulf War illness that, while they did not meet the criteria for being considered as primary or secondary studies, provided information that the committee believes may be useful in addressing future research questions related to Gulf War illness. The studies focus on three main areas: the effect of Gulf War illness on other health conditions and vice versa; new efforts to link Gulf War illness with particular exposures prior to or during deployment, and neuroimaging and brain metabolism studies that attempt to identify biomarkers of Gulf War illness in brain or other tissues. Investigators for these studies used a variety of

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

definitions of Gulf War illness (or chronic multisymptom illness), including the CDC definition (Fukuda et al., 1998), the Kansas definition (Steele, 2000), and Haley’s Gulf War illness syndromes (defined by 3–6 symptom clusters) (Haley et al., 1997b).

VA provided a health care use report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories; no statistical testing was performed. A veteran can have multiple diagnoses with each health care encounter, and therefore, may be counted in multiple categories, but the person is counted only once in any single diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period. These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans. Of these users, 176,541 (61.5%) of the deployed Gulf War veterans and 157,051 (58.2%) of the nondeployed veterans presented with symptoms, signs, and ill-defined conditions (ICD-9-CM 780-799). The most commonly reported of these were general symptoms (> 50% of veterans in both groups reported having them), respiratory (> 39%), and skin (> 26%) (VA, 2014a,b).

Comorbidities

Gulf War illness is not only characterized by a broad range of symptoms, but it has also been associated with other more clearly defined health conditions. Several researchers have attempted to determine whether having Gulf War illness puts a veteran at risk for developing another disease or whether having any particular medical diagnosis or symptoms makes a veteran more susceptible to having Gulf War illness. In this section, the committee considers some of the recent literature on Gulf War illness and its possible comorbidities.

Wallin et al. (2009) assessed neuropsychologic performance in Gulf War deployed veterans with Gulf War illness (n = 25) and without (n = 16), obtained from the 1995 population-based National Health Survey of Gulf War Era Veterans and Their Families. Cases were defined as meeting the CDC criteria for Gulf War illness. The neuropsychological testing battery included assessment of verbal abilities, attention, memory and learning, problem solving, and motor skills. There were no significant differences between cases and controls for any of the cognitive domains, and the composite test scores for both groups were within normal limits. However, there were statistically significant differences in Personality Assessment Inventory scores used to assess psychiatric symptoms; cases were significantly more impaired than controls on 8 of 11 clinical scales such as somatic complaints, anxiety, depression, mania, and paranoia. Responses to the 36-Item Short Form Health Survey indicated that cases also had poorer self-reported general physical and mental health.

Two new studies have assessed autonomic dysfunction in veterans who have Gulf War illness. In a nested case-control study, Haley et al. (2013) used the Autonomic Symptom Profile questionnaire (a self-administered questionnaire), the Composite Autonomic Severity score, and high-frequency heart rate variability data from a 24-hour electrocardiogram to assess whether some of the symptoms of Gulf War illness are due to autonomic dysfunction. Veterans were selected from the U.S. Military Health Survey (Iannacchione et al., 2011). Sixty-six veterans met Haley’s definitions for one of three syndromes of Gulf War illness (21 with syndrome 1, 24 with syndrome 2, and 21 with syndrome 3), 16 veterans were not ill and had deployed to the Kuwaiti theater during the war, and 15 veterans were in the military but did not deploy. All veterans with Gulf War illness reported significantly more autonomic symptoms (p < 0.001) and had elevated Composite Autonomic Symptom Scale scores (scores were most elevated for syndrome 2 primarily due to a reduction in sudomotor function in the foot), compared with controls.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

Ill veterans also lacked the normal increase in high-frequency heart rate variability at night compared with controls.

In the second study, Li et al. (2014) also studied autonomic dysfunction in 16 veterans with Gulf War illness and 12 era controls. Ill veterans were those who self-reported CFS-like multisymptoms in the 2005 survey titled Health of U.S. Veterans of 1991 Gulf War: A Follow-up Survey in 10 Years. Veterans responded to autonomic nervous system questionnaires and received physical examinations, including large fiber nerve conduction studies, quantitative sensory testing, autonomic testing, a quantitative sudomotor axon reflex test, and a diagnostic tilt-table test. Five veterans in the ill group had impaired cardiovascular function, whereas none of the control group had any impairment. The ill group also had significantly higher baseline heart rate and higher scores on a compound autonomic scoring scale compared with controls. The authors suggest that objective autonomic testing should be carried out on veterans with Gulf War illness who complain of unexplained postexertional fatigue.

In a 2003–2005 follow-up to the 1995 National Health Survey of Gulf War Veterans and Their Families, Coughlin et al. (2011b) assessed alcohol consumption in 9,970 respondents and found that veterans who were problem drinkers (defined as answering yes to any of five questions about problem drinking or hazardous driving in the past 6 months) were more likely to have unexplained multisymptom illness (defined as having unexplained physical symptoms and illnesses that persisted for 6 months or longer and were not explained by other diagnoses) with an odds ratio of 1.56 (95% CI 1.37–1.77, p < 0.001), adjusted for age, sex, race/ethnicity, branch of service, rank, and deployment status. These authors used the same survey results to assess the association between BMI and various health conditions. Multisymptom illness was more prevalent in Gulf War deployed veterans who were obese than in normal weight deployed veterans, but this increase was not evident in a multivariate analysis (Coughlin, 2011a).

Many veterans with Gulf War illness report problems with sleep. In a small study of 18 male veterans with Gulf War illness and 11 asymptomatic control veterans, Amin et al. (2011) found that veterans with the illness had a statistically significant increase in the frequency of sleep arousals from apneas or hypoapneas (p = 0.006), and flow-limited breaths (p < 0.0001); differences in other sleep parameters were not significant between the two groups. The samples were matched for age and BMI. Compared with 36% of control veterans, 96% of veterans with Gulf War illness had their breathing flow limited.

Many veterans with Gulf War illness complain of having headaches. Rayhan et al. (2013b) examined the presence of headache that accompanied Gulf War illness in a small study of 50 veterans with the illness based on the CDC definition (Fukuda et al., 1998), 39 subjects with CFS based on the 1994 CDC criteria, and 45 control subjects (veteran status was not reported for the latter two groups). Compared with 13% of controls, migraines were endorsed in 64% of the veterans with Gulf War illness (OR = 22.5, 95% CI 7.8–64.8). Migraines were frequently comorbid with tension headaches (20 of 32 veterans: OR not reported); tension headaches without migraines occurred in about 20% of the veterans with Gulf War illness and 26% of the controls. Most of the migraines associated with Gulf War illness were with aura (24 of 32); only 8 of 32 did not have aura.

Deployment Exposures and Gulf War Illness

Steele et al. (2012) conducted a case-control study in 2000 that compared Gulf War veterans’ exposures in a population-based sample of 304 deployed veterans, 144 with Gulf War illness and 160 healthy controls. Case status was determined based on screening using the CDC definition, and subsequent inclusion in the study was based on the Kansas definition for Gulf War illness. Study participants were asked about their deployment locations and duration and whether they had any of 19 specific exposures or experiences during deployment. Among veterans in Iraq or Kuwait, Gulf War illness was most

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

strongly associated with the use of pyridostigmine bromide (PB) tablets (OR = 3.5, 95% CI 1.7–7.4), being within 1 mile of an exploding Scud missile (OR = 3.1, 95% CI 1.5–6.1), using pesticides on the skin (OR = 2.07, 95% CI 1.06–4.05, and being exposed to smoke from oil-well fires (OR = 2.78, 95% CI 1.01–7.66). For veterans who were in support areas, Gulf War illness was most closely associated with wearing pesticide-treated uniforms (OR = 12.7, 95% CI 2.6–61.5). For all veterans combined, Gulf War illness was also significantly associated with frequently getting less than 4 hours sleep in 24 hours (OR = 2.91, 95% CI 1.41–6.01).

Haley and colleagues have published a number of studies looking at the epidemiology of the syndromes they have elicited from veterans, as well as using purposive subsamples of subjects meeting criteria for the various syndromes, and performing mechanistic and etiologic experiments in efforts to identify the underlying pathophysiology for each of the three primary Gulf War illness syndrome variants Haley et al. have defined. The publications of this research group have been criticized for restricting their subjects to a pool of 249 out of 606 original veterans of the Twenty-Fourth Reserve Naval Mobile Construction Battalion (Seabees), thus making it difficult to generalize the findings to the entire Gulf War veteran cohort. In a recent publication, Iannacchione et al. (2011) conducted a validation study among a stratified random sample of more than 8,000 deployed and deployable-but-nondeployed veterans selected from all Gulf War active duty and ready reserve veterans. Termed the U.S. Military Health Survey, this study was conducted by telephone between May 2007 and April 2009; the response rate was 60%. Iannacchione et al. report validating, through factor analysis and related techniques, their original three major and three minor Gulf War illness syndromes. The authors also collected information on whether veterans in the validation study met the CDC’s criteria for multisymptom illness, but these data were not reported. Results from the survey indicated that the overall case definition of Gulf War illness was more prevalent in the deployed than nondeployed veterans (OR = 3.87, 95% CI 2.61–5.74); veterans were considered to have met the overall factor case definition if they met any of the six dichotomized component definitions. Each of the Gulf War illness variants was also more prevalent in the deployed veterans than the nondeployed veterans (OR = 3.33, 95% CI 1.10–10.10, for syndrome variant 1; OR = 5.11, 95% CI 2.43–10.75, for variant 2; and OR = 4.25, 95% CI 2.33–7.74, for variant 3).

Haley and Tuite (2013) examined the relationship between the cohort identified in Iannacchione et al. (2011), the prevalence of Gulf War illness (based on both the CDC and the factor analysis case definitions), and the two dependent variables of chemical alarm awareness and unit location with respect to the Khamisiyah explosions. They estimated that 13.6% of the veterans deployed to the Kuwaiti theater of operations had Gulf War illness using the factor-analysis case definition, whereas 41.7% had it on the basis of the CDC definition (95% of veterans classified as having Gulf War illness by the factor analysis met the CDC case definition as well). It was further estimated that 39% of veterans in the theater had exposure to low levels of nerve agents based on responses to the survey question about hearing chemical alarms, and 16% may have been located in the plume of nerve agent from the Khamisiyah demolition based on Department of Defense (DoD) exposure models. The risk of having Gulf War illness (Haley overall factor case definition) was strongly associated with hearing chemical alarms (OR = 4.13, 95% CI 2.51–6.80), and the authors found a dose–response relationship between the relative risk of having Gulf War illness and the number of alarms heard. The risk of Gulf War illness and being in the nerve agent plume was not statistically significant (OR = 1.21, 95% CI 0.86–1.69). The authors suggest that factor analysis syndrome 1 is less likely to be related to nerve agent exposure than the other two major syndromes. A strong role for recall bias to produce the relationships with recalled chemical alarms cannot be excluded (the survey was conducted from 2007 to 2010). The two epidemiologic studies by Haley and colleagues do not appear to shed much light on the etiology or mechanism of Gulf War illness,

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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however, they do advance the stature of the factor analysis case definitions of the illness into apparently representative national samples.

The committee recognizes that association is not causation, but felt it was important to look for consistency of associations across studies. One study reports that exposures for which there were significant associations with Gulf War illness include self-reported PB use, proximity to Scud missile explosions, pesticides on skin, wearing permethrin-treated uniforms, and smoke from oil-well fires (Steele et al., 2015), whereas the studies by Haley and Tuite (2013) and Iannacchione et al. (2011) indicated that hearing chemical alarms—but not the nerve agent plume—was associated with the development of Gulf War illness. Together these studies suggest the possibility that chemical exposures—PB, pesticides, insecticide treatment, and alarms—may play a role in Gulf War illness. Nevertheless, the committee cautions that a substantial limitation to this potential association is the lack of any measure that clearly documents the actual chemicals or doses to which the veterans were exposed. Gulf War veterans from the coalition forces also reported increased symptoms indicative of Gulf War illness, but their exposures may have differed from those of U.S. service members. For example, Danish troops were in the Persian Gulf region after the war as peacekeepers and were not exposed to sarin (Ishoy et al., 1999b). There are no reliable or validated biomarkers to indicate that a particular veteran with or without Gulf War illness had a specific chemical exposure during deployment. Also, there is little biologic plausibility for the concept that exposure to PB concentrations that did not cause acute effects would result in long-term effects (IOM, 2004). The committee concludes that, on the basis of the studies of deployment exposures and Gulf War illness (e.g., Haley and Tuite, 2013; Iannacchione et al., 2011; Steele et al., 2015), there is little new information that sheds light on the etiology of or mechanisms for Gulf War illness.

Genetic Factors and Gulf War Illness

There is considerable evidence that a set of genes that is important in metabolizing toxicants is involved in the development of some diseases such as amyotrophic lateral sclerosis (ALS). To explore the etiology of Gulf War illness, several researchers have sought to identify genetic mutations that would affect the body’s ability to metabolize certain toxicants associated with Gulf War deployment, with a particular focus on genes that encode proteins that metabolize cholinesterase inhibitors. PB, some pesticides, and sarin and cyclosarin are potentially toxic exposures that are known to inhibit cholinesterase. Without cholinesterase to inactivate acetylcholine (a neurotransmitter), overstimulation of organs and muscles controlled by acetylcholine may occur.

The most relevant proteins are paraoxonases1 (PON) 1, 2, and 3; butyrylcholinesterase2 (BChE); acetylcholinesterase (AChE); and cytochrome P450-2D6 (CYP2D6). PON and BChE have received the most study in Gulf War illness and so are reviewed here briefly.

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1 The paraoxonases (PON) 1, 2, and 3 are esterases, encoded by genes on chromosome 7, which metabolize oxidized lipids as well as a range of cholinesterase inhibitors (sarin, soman, diazinon, chlorphyrifos). They also oxidize some clinically approved compounds, such as the statins. PON1 has upward of 200 genetic variants in normal individuals. The most common are the variants glutamine-192-arginine and leucine-55-methionine. Also of interest are two regulatory polymorphisms within the PON1 promoter. The impact of these variants on PON1 hydrolase activity varies with the substrate. For example, at codon 192, variant Q has higher activity for sarin, soman, and diazinon, while variant R has higher activity for parathion and paraxon. Studies of the C-108T promoter polymorphism show that the C allele has higher promoter activity (Brophy et al., 2001; Costa et al., 2005; Davies et al., 1996).

2 BChE (pseudocholinesterase, plasma cholinesterase, chromosome 3q) hydrolyzes many choline esters, including butyrylcholine, a synthetic substance. BChE inactivates organophosphates by both binding and hydrolyzing them. BChE has been studied extensively because of its role in metabolizing succinylcholine. There are several allelic variants in the BChE gene, identified as BChE-U, which has high enzyme activity, and allelic vairants K, A, and F, which are less common and have less activity. The lower activity alleles are sometimes lumped in one category (Jensen et al., 1995).

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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The Volume 10 committee reviewed studies described in Volume 8 as well as new studies of genetic associations to interpret the evidence as a whole. The Volume 8 committee reviewed several studies that sought to positively link PON1 genotype (Haley et al., 1999; Hotopf et al., 2003b; Mackness et al., 2000) or BChE genotypes (Lockridge, 1999; Sastre and Cook, 2004) to Gulf War illness; these were generally underpowered and inconsistent. The Volume 8 committee recommended that well-designed studies be undertaken and replicated to robustly test the hypothesis that variants in genes that code for detoxifying enzymes for cholinesterase inhibitors may be a susceptibility factor for development of Gulf War illness.

As described in Volume 8, a genetic association between cholinesterase inhibitors and PON1 was first proposed by Haley et al. (1999) who studied 25 symptomatic Gulf War veterans. The authors suggested that PON1 variants are overrepresented in Gulf War illness; however, this study did not reach statistical significance (p = 0.08 before correction for multiple comparisons). Mackness et al. (2000) initially reported an association of Gulf War illness with reduced PON1 enzyme activity; however, Hotopf et al. (2003b) reported that PON1 levels are low in both symptomatic and asymptomatic Gulf War veterans.

Lockridge et al. (1999) reported that rare, low-activity variants of BChE are overrepresented in symptomatic Gulf War veterans, but Sastre and Cook (2004) could not replicate this. They found an association between multisymptom illness and carriers of rare BChE genotypes who also self-reported PB exposure. A caveat is that the numbers of carriers of rare genotype were small in these studies (11/226 in Lockridge; 28/304 in Sastre and Cook).

Four new studies investigating the role of certain genes in Gulf War illness were identified and reviewed by the Volume 10 committee (Craddock et al., 2015; Georgopoulos et al., 2015; Haley et al., 2010; Steele et al., 2015). Steele et al. (2015) examined Gulf War illness (using Kansas and CDC definitions) in relation to BChE activity and genotype, and examined deployment exposures to pesticides and PB use in 144 Gulf War veterans with symptoms of the illness and 160 asymptomatic veterans. While cases and controls did not differ by BChE activity or genotype, BChE activity did differ by genotype. The 276 veterans with the more common genotypes (designated BChE-U; including U/U and U/K genotypes) had significantly higher BChE activity than the 28 veterans with the less common variants (designated BChE-LCV; including K/K, U/AK, U/A, A/F, and AK/F genotypes). There were no differences between veterans with and without Gulf War illness in regard to associations between BChE activity (low vs high activity measured by benzocholine in serum) and self-reported exposures to PB and pesticides. However, when the veterans were stratified by BChE genotype (BChE-U vs BChE-LCV), those who reported taking PB pills were more likely to have Gulf War illness than those who did not (OR = 40.00, p = 0.0005). The same association existed for the BChE-U group, but the magnitude of the association was less (OR = 2.68, p = 0.0001). The difference between those two associations was significant (p = 0.019), thus the authors suggest an interaction between BChE genotype and PB that affects the risk of Gulf War illness such that Gulf War veterans who have BChE-LCV genotypes and took PB are at greatest risk comparatively in this study. The committee notes that the number of cases in these groups was small; there were only 28 veterans in the BChE-LCV group—14 with Gulf War illness (of whom 13 had PB exposure) and 14 without (of whom only 3 had PB exposure). By contrast, members of the BCHE-LCV group did not have a higher risk of Gulf War illness if they reported chemical weapons exposure. Lastly, when the authors re-sorted the cases not using the CDC case definition for Gulf War illness (a broader definition than the Kansas definition), the result was the same but less pronounced.

Another analysis suggests that in veterans with Gulf War illness, altered immune function may be related to human leukocyte antigen (HLA) genes (Georgopoulos et al., 2015). Like Steele et al. (2015), this investigation used a sample of Gulf War veterans (66 with Gulf War illness, using either the CDC criteria or the Kansas case definition, and 16 without the illness) who had participated in the earlier study described in Steele (2000). Nine HLA genes were compared between the two groups and 144 unique al-

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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leles of Class I and II HLA genes were found. Six Class II alleles were found to correctly classify veterans as either cases or controls 84% of the time (sensitivity = 84.8%; specificity = 81.2%) and results were statistically significant. The frequency of the six alleles appeared to be protective in the control group such that allele frequencies were significantly lower among cases (p < 0.002) and there was a negative correlation between overall symptom severity and frequency of the six alleles (p < 0.0001). Two of the six alleles were completely absent among veterans with Gulf War illness. The authors interpret their findings as indicating that veterans with Gulf War illness might have a genetic susceptibility by which certain exposures (possibly vaccination or chemical exposures) result in immune dysfunction and the symptoms of Gulf War illness.

In a subset of Gulf War veterans, Haley et al. (2010) further analyzed levels of Q192 vs R192 serum PON1 activities and investigated the relationship between enzyme activity, the PON1 Q192R genotype, and exposure to nerve agents. Using a history of an alarm sounding as a marker for early exposure to these agents, the authors concluded that early exposure was strongly associated with Gulf War illness and the risk was highest in individuals with the lowest quartile of Q isozyme activity.

Craddock et al. (2015) examined the association between gene expression patterns in male veterans with Gulf War illness to gene expression patterns associated with some human conditions and to genes targeted by known pharmaceuticals. The study collected data and specimens from 17 veterans with Gulf War illness (using the CDC case definition) and 22 healthy but sedentary Gulf War era veterans between 2006 and 2008. Nineteen gene expression patterns were significantly associated with Gulf War illness; these patterns were correlated to 18 conditions that share features of Gulf War illness.3 Eight of the 19 modules of genes associated with Gulf War illness had known drug targets. Rheumatoid arthritis was found to be correlated with the same eight modules. The authors interpreted their work to support previous studies that suggested that Gulf War illness is associated with dysregulation in some genetic pathway and to hypothesize potentially useful drug treatments.

Immune Function and Cytokines in Gulf War Illness

Eight studies examined immune function and cytokines in veterans with Gulf War illness. Five are from one group that tested the hypothesis that Gulf War illness involves a dysfunction in the immune system. One looked for abnormal patterns of pro-inflammatory immune markers, one study reported a comparison of cytokine expression in patients with either Gulf War illness or myalgic encephalomyelitis, and the final study looked at immune function in veterans with Gulf War illness. Each is discussed below.

Five papers on the immune system (Broderick et al., 2011, 2012, 2013; Smylie et al., 2013; Whistler et al., 2009) all used a similar exercise protocol to stimulate the immune system and tested responses. The initial pilot study (Whistler et al., 2009) tested the hypothesis that physiological responses to stress might differ in veterans with Gulf War illness. Nine veterans with Gulf War illness and 11 sedentary, nondeployed veterans were tested for stress-related biomarkers before, during, and after a standard bicycle ergometer exercise test. Endpoints measured included blood cell counts, natural killer (NK)-cell cytotoxicity, cytokines, expression levels of 20,000 genes, and salivary cortisol. As expected, exercise increased blood lymphocyte levels in the controls, but this response was muted in veterans with Gulf War illness. Compared with control veterans, Gulf War illness veterans had the following: decreased

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3 In order from most correlated to least correlated: Frontotemporal lobar degeneration (FTLD) sporadic frontal; cerebral palsy semitendinous muscle; schizophrenia; FTLD progranulin mutation frontal; benzene exposure; autism; bipolar disorder; chronic stress; adenocarcinoma of the esophagus; acute quadriplegic myopathy; spastic paraplegia; mixed hyperlipidemia; glaucoma; nonsevere asthma CD8 T cells; multiple sclerosis; Crohn’s disease; Becker muscular dystrophy; and sickle cell disease.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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NK cell cytotoxicity, altered gene expression associated with NK-cell function, decreased blood concentrations of pro-inflammatory cytokines, T-cell ratios (CD4/CD8), and mediators of the stress response, including decreased salivary cortisol. The authors concluded that Gulf War illness involved impaired immune function. The authors suggested an overlap in symptomology and clinical findings with persons who have CFS.

A later study published by the same group (Broderick et al., 2011) appears to be from the same cohort and with similar samples as reported by Whistler et al. (2009), but the samples are analyzed in a different way. Instead of making comparisons between individual cytokines, the authors used multivariate statistical models to determine patterns of change shared by various cytokines, cortisol, and neuropeptide Y, to analyze the “fight or flight” response to exercise. The method used a form of graph theoretical methods and complex mathematical systems to identify significant trends shared by pairs of biomarkers and then constructed association networks linking immune and endocrine biomarkers in each study group (Broderick et al., 2011). The results reported differ from those reported by Whistler et al. (2009), but the authors mention several times that their method of analysis can detect altered patterns in the immune system that would not be detected by standard analyses. The authors concluded that the study showed that “the potential heightened lymphocyte and hypothalamic-pituitary-adrenal axis (HPA) responsiveness to IL-1 stimulation in the context of a mixed Th1:Th2 immune signature supports an autoimmune component to Gulf War illness.”

In Broderick et al. (2012), the authors sought to determine if the expression of immune biomarkers can be used to diagnose Gulf War illness. The results indicate that such biomarkers are not adequate for the diagnosis of Gulf War illness in individuals, but they could offer insight into the physiological basis for the disease. In a later paper (Broderick et al., 2013), the same protocol was used to test the difference in immune response to exercise in patients with Gulf War illness (n = 20) compared with those with CFS/myalgic encephalomyelitis (CFS/ME) (n = 7) and with healthy veterans (n = 22). Earlier studies (Barbier et al., 2009) had indicated that gene expression in stressed mice exposed to PB showed increases in hippocampal expression of three genes involved in memory development: brain-derived neurotrophic factor, tropomyosin-related kinase B, and calcium/calmodulin protein kinase II alpha. These studies could not be conducted in humans, but the investigators used circulating lymphocytes to reflect changes in the brains of veterans. The hypothesis was the NF-kappa beta activity was altered in circulating lymphocytes of Gulf War illness subjects as a lasting result of exposure to acetylcholinesterase inhibitors in the field. The authors performed an analysis of gene expression using a novel methodology (Efroni et al., 2007, 2008) for estimating the activity level of more than 400 pathways described in the National Cancer Institute databases. The authors point out that this is a significant departure from conventional analysis, where no estimate of pathway activation is produced. Using the alternative approach, pathway activation from gene expression in peripheral blood monocytes before, during, and after exercise in Gulf War illness and in healthy veterans was estimated. A statistical association of baseline Gulf War illness symptom burden with increased activation at peak exercise time in pathways was found, supporting neuronal development along with down regulation of apoptotic signaling. This was accompanied by prolactin-mediated increases in NF-kappa beta activation, a shift in T- and NK-cell populations, and the expression of IL-10 and IL-1 alpha.

Finally, the same group (Smylie et al., 2013) compared cytokines in peripheral blood of 20 male and 10 female Gulf War illness veterans with 12 male and 10 female CFS patients and 21 male and 9 female healthy veterans before, during, and after exercise. Analysis was performed as in the earlier studies. Linear classification models were constructed using stepwise variable selection to identify cytokine coexpression patterns characteristic of each group. Common to the signature of both Gulf War illness and CFS were IL-10 and IL-23 accompanied by NK and Th1 markers in males and Th2 markers in fe-

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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males. Exercise response differed between sexes. Male Gulf War illness veterans presented characteristic signatures at rest, but not at peak exercise effort. The opposite was true for females.

The data analyses that were used in the last four of the above five studies testing the immune network response in veterans groups before, during, and following exercise stress, were nonconventional and hard to interpret. Even the authors discuss the limitations of their approach saying, “it must be emphasized that our analysis was constrained to a specific set of documented pathways and was by no means comprehensive” (Broderick et al., 2013). In addition to the limited scope of pathways examined, the authors point out that they found the mathematical method of Efroni et al. (2007, 2008), which they used, was conservative and unable to detect the loss of more subtle signaling mechanisms. Also, the number of subjects is small, and the panel of cellular and molecular markers used is relatively narrow and does not represent a complete survey of immune response (Broderick et al., 2011). Therefore the data from these researchers must be considered preliminary until more information is obtained.

In a small study, Parkitny et al. (2015) tested to see if Gulf War illness was associated either with abnormal concentrations or abnormal fluctuations in pro-inflammatory immune markers in sera. Three hypotheses were tested: First, that serum pro-inflammatory cytokines would be higher in Gulf War illness veterans than in healthy veterans; second, that daily cytokine fluctuations would be greater in Gulf War illness veterans than in healthy veterans; and third, that daily self-reported fatigue in Gulf War illness veterans would covary with the concentrations of pro-inflammatory cytokines. Seven Gulf War illness veterans and eight healthy veterans had daily blood draws and gave daily self-reports on fatigue symptoms for 25 consecutive days. Among the 21 pro-inflammatory cytokines measured, only eotaixn-1 was found to be elevated in the blood of Gulf War illness veterans compared with healthy veterans. Higher self-reported fatigue days were associated with greater concentrations of IL-1b and IL-15. The small size of the study plus the fact that fatigue was self-reported diminished the potential significance of the study.

One study compared cytokines in sera in veterans with Gulf War illness and CFS/ME. Khaiboullina et al. (2015) tested the hypothesis that Gulf War illness resembles CFS/ME and might be a subset of that disease. For the study, 77 cytokines were measured in sera from Gulf War illness veterans (37), patients with CFS/ME (67) and healthy controls (42). The profile of cytokines could be used to delineate Gulf War illness and ME from controls, but the Gulf War illness values resembled control values more than the CFS/ME values. The authors concluded that the two conditions have distinct immune profiles despite their overlapping symptomology.

British physicians have tested the hypothesis that Gulf War illness results from an imbalance in the Th1/Th2 immune system (Skowera et al., 2004). Their subjects consisted of 80 nonsymptomatic Gulf War veterans, 40 symptomatic veterans, 20 symptomatic veterans of peacekeeping duties in Bosnia, and 39 symptomatic veterans in service at the time of the Gulf War but not deployed. The latter two groups were combined (total = 59) to form a control group who had multisymptom illness but had not been in the Gulf War. Peripheral blood CD4+ lymphocytes were stained using appropriate PE-conjugated anti-cytokines and were analyzed by flow cytometry for IL-2, IFN-gamma, IL-4 and IL-10 in the absence of activators. There was considerable overlap in the data but symptomatic Gulf War veterans had significantly higher mean levels of non-stimulated IL-4+ and IL-2+ cells compared to well Gulf War veterans and the control group. After short-term polyclonal stimulation, the cultured cells were found to secrete more IL-10 in the symptomatic Gulf War group than in the nonsymptomatic group. The IL-10 levels were also higher in the control group compared with the nonsymptomatic group. Again, there was considerable overlap in the data. The authors conclude that, even several years after the Gulf War, symptomatic veterans showed evidence of ongoing immune activation which is predominately Th1 and an expansion of IL-10 producing memory cells. The considerable overlap of the data in all three groups

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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indicates that these immune markers could not be used as biomarkers in diagnosis of Gulf War illness. While significant differences were observed, the biological significance is uncertain. Earlier reviews did not find that immunological responses were abnormal in symptomatic Gulf War veterans (Everson et al., 2002).

While several investigators have attempted to define a cytokine profile unique to Gulf War illness, their studies have not been successful. The committee notes that the findings of Broderick et al. (2013) are intriguing but preliminary and their significance is uncertain. Nonetheless, the committee observes that there is potential merit in the methodology. It would likely be productive to repeat these transcriptomic studies with several protocol enhancements including expansion of the study cohorts for sufficient power; use of appropriately chosen controls; use of distinct discovery and replication cohorts, each appropriately powered; use of RNAseq methods to analyze the sequences and numbers of all coding and noncoding RNA transcripts in an unbiased manner; and appropriate use of bioinformatics tools to discern specific disease pathways.

Other Studies of Possible Relevance

In a search for persistent enteroviruses, Urnovitz and colleagues (1999) compared levels of circulating RNA in sera from 24 deployed Gulf War veterans and 50 nonmilitary controls. RNA was isolated and amplified with primers from untranslated domains of the enterovirus, longer species of circulating RNAs in sera of Gulf War veterans were detected. Two of these were sequenced and found to map to human chromosome 2q11; they were not enteroviral sequences.

In a series of genes proposed to be relevant to susceptibility to chronic fatigue, Vladutiu and Natelson (2004) studied CFS/idiopathic chronic fatigue in two case-control sets: 49 veterans with CFS and 30 veterans without CFS, and in 61 nonveterans with CFS and 45 nonveterans without CFS. They examined the frequency of gene variants for three proteins: angiotensin converting enzyme, myoadenylate deaminase, and carnitine palmitoyltransferase II. The authors reported that an insertion allele (“I”) in intron 16 of the gene encoding angiotensin-converting enzyme (otherwise designated DCP1) is reduced in frequency in Gulf War veterans (0.15) with CFS compared with asymptomatic vets (0.48). Reciprocally, the alternate deletion “D” allele was overrepresented in symptomatic Gulf War veterans (0.85), as was the DD allele (0.78). However, the frequency of the I-allele in symptomatic and asymptomatic nonveterans was the same as the asymptomatic veterans (0.48–0.50). The reduced I-allele was predicted to enhance angiotensin-converting enzyme activity and promote higher angiotensin II levels, a profile that has been associated with adverse outcomes (more coronary artery disease).

Conclusions

Gulf War illness continues to be the signature health concern of veterans who served in the Persian Gulf region in 1990–1991. A variety of studies in U.S. and the coalition forces veterans who served during and even after the conflict continue to show that veterans who were deployed to the Gulf War experience more symptoms, signs, and ill-defined conditions and that their symptoms are more severe than their nondeployed counterparts; furthermore, these symptoms have persisted for more than 25 years after the war. In spite of concerted efforts to identify a cause or physiologic mechanism for Gulf War illness, no clear answer has been established, and the committee finds that Gulf War illness is not a mental health condition. Several new studies report associations between several exposures, particularly to chemicals, and the presence of Gulf War illness, but to date, there are no reliable or validated biomarkers of exposure or symptoms to substantiate the etiology or mechanisms of the illness. Animal

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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toxicology studies of Gulf War illness are discussed in Chapter 5. As noted earlier in this section, one of the difficulties in studying Gulf War illness is the several case definitions and the variable presentations of this condition.

Studies looking for biomarkers of Gulf War illness or other health conditions face many methodological problems irrespective of the approach or technology used (neuroimaging, genetics, cytokines). In general, such studies are small and often not adequately powered, suffer from multiple comparisons, and focus on nonspecific pathology that may indicate, or be involved in, many different disease pathways, known and unknown. Furthermore, researchers interpret their results as demonstrating positive findings without consideration of the high possibility of type I errors (false positive). Biomarkers, in general, are indicators of current pathology and are not useful or reliable measures of an exposure or an effect occurring many years earlier. They are, however, good for discovering clinically latent or subclinical disease.

Therefore, the Volume 10 committee concludes that there is sufficient evidence of association between deployment to the Gulf War and the constellation of chronic symptoms (including fatigue, musculoskeletal pain, sleep disturbances, cognitive dysfunction, alterations of mood) known as Gulf War illness.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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TABLE 4-1 Primary Studies of Gulf War Illness

Study Design Population Outcomes Results Adjustments Comments
Volumes 4 and 8 Primary Studies
Factor Analyses and Surveys
Haley et al., 1997b (Vol. 4) Exploratory factor analysis of 52 symptoms Active-duty and retired Navy GWVs (n = 249) Factor-analysis derived syndromes Impaired cognition Confusion-ataxia Arthromyoneuropathy Phobia-apraxia Fever-adenopathy Weakness-incontinence Small cohort size, no nondeployed control group Syndromes accounted for 71% of observed variance
Fukuda et al., 1998 (Vol. 4) Cross-sectional population survey; factor analysis of 35 symptoms to identify symptom categories in combination with clinical reasoning 3,675 members of the Air Force, including National Guard, reserve, and active-duty components (1,155 GWVs and 2,520 NDVs) Factor analysis: n = 3,255 Cases defined as having one or more symptoms from at least two of the three identified symptom categories: Fatigue Mood-cognition Musculoskeletal GWV vs NDV: Mild-to-moderate cases (449 vs 354) OR = 4.08 (95% CI 3.39–4.93) Severe cases (68 vs 18) OR = 16.18 (95% CI 8.99–29.14) Rank, sex, age, smoking status Symptom categories accounted for 39% of common variance
Nisenbaum et al., 2000 (Vol. 8) Cross-sectional survey 1,002 Air Force GWVs selected from the population described by Fukuda et al. (1998) Association of self-reported exposures with severe cases (n = 58) and mild-to-moderate (n = 401), as defined by Fukuda et al. (1998) Belief that biological or chemical weapons were used, severe OR = 3.5 (95% CI 1.7–6.9) and mild/moderate OR = 2.3 (95% CI 1.5–3.3);
PB, severe OR = 2.9 (95% CI 1.4–6.1) and mild/moderate OR = 1.6 (95% CI 1.1–2.2); Insect repellent, severe OR = 2.4 (95% CI 1.3–4.5) and mild/moderate OR = 1.7 (95% CI 1.2–2.3);
Injuries requiring medical attention, severe cases only OR = 2.1 (95% CI 1.1–4.3)
Age, sex, smoking status, current rank All exposures self-reported
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Ismail et al., 1999 (Vol. 4) Exploratory factor analysis of 52 symptoms (based on survey conducted by Unwin et al., 1999) 3,214 male UK GWVs compared to 1,770 Bosnia veterans and 2,384 nondeployed era veterans Symptom categories Mood-cognition Respiratory symptoms Peripheral nervous system symptoms Frequency of symptom reporting higher in GWVs compared to Bosnia and era cohorts, but similar correlations between symptoms for all cohorts Response rates: GWVs (76%), Bosnia veterans (42%), era veterans (56%) Factor categories accounted for 20% of the common variance
Kang et al., 2002 (Vol. 4) Exploratory factor analysis of 47 symptoms 10,423 GWVs compared to 8,960 nondeployed era veterans Symptom clusters; association of symptom clusters with self-reported exposures Five similar symptom clusters were found in both groups: Fatigue or depression Musculoskeletal/rheumatologic Gastrointestinal Pulmonary Upper respiratory Four symptoms comprised a neurologic cluster that appeared to be unique to GWVs: blurred vision, loss of balance/dizziness, tremors/shaking, and speech difficulty. 277 (2.4%) GWVs reported mild or severe problems with these symptoms vs 43 (0.45%) nondeployed. At least 3 out of 4 of these symptoms were observed in 877 (7.7%) GWVs vs 175 (1.8%) nondeployed veterans Exposures associated with four-symptom cases (n = 277) vs nonsymptomatic controls (n = 6,730), p < 0.0001: Contaminated food (73% vs 21%); nerve gas (42% vs 5%); DU (29% vs 7%); toxic paint (51% vs 16%); bathed in or drank contaminated water (60% vs 19%); sexual assault (3.3% vs 0.4%); sexual harassment (15% vs 3%); botulism vaccine (26% vs 9%) 69% response rate in GWVs and 60% in era controls 69% of the GWVs suffering all four symptoms also met criteria for PTSD
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Study Design Population Outcomes Results Adjustments Comments
Ishoy et al., 1999b (Vol. 4) Cross-sectional 686 Danish peacekeepers deployed to gulf in 1990–1997 vs 231 age- and sex-matched nondeployed controls Health examination by physician, including lung function and self-report questionnaire of symptoms Deployed veterans reported higher prevalence (p < 0.05) of 17 out of 22 neuropsychological symptoms, 8 out of 14 gastrointestinal symptoms, and 8 out of 19 skin symptoms 81% of deployed veterans vs 71% of controls had one or more ICD-10 diagnoses at examination (p = 0.002) Participation rate: 83.6% deployed, 57.8% nondeployed
Blanchard et al., 2006 (Vol. 8) Cross-sectional 1,035 GWVs vs 1,116 NDVs CMI determined by medical examination in 1999–2001 Deployed vs nondeployed: CMI (all cases), 29% vs 16% (OR = 2.16, 95% CI 1.61–2.90) Mild to moderate cases, 25% vs 15% (OR = 1.92, 95% CI 1.41–2.63) Severe cases, 7% vs 1.6% (OR = 4.65, 95% CI 2.27–9.52) Age, sex, race, education, duty type, service branch, rank, income, combat exposure score, Khamisiyah exposure, psychiatric and other diagnoses prior to GW Participation rate: 53% deployed, 39% nondeployed
Nisenbaum et al., 2004 (Vol. 4) Dichotomous factor analysis (reanalysis of survey results from Fukuda et al., 1998, and Ismail et al., 1999) 3,454 male UK GWVs compared to 1,979 Bosnia veterans and 2,577 nondeployed era veterans 1,163 deployed U.S. Air Force veterans Symptom clusters UK cohort: Identified a cluster of gastrointestinal/urogenital symptoms that loaded to deployed veterans but not to either control group Confirmed factors identified by Ismail et al. (1999) were very similar across all three cohorts U.S. cohort: Gastrointestinal/respiratory Allergies Mood-cognition Musculoskeletal No control group in U.S. cohort
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Hospitalization Studies
Gray et al., 1996 (Vol. 8) Retrospective cohort, hospitalizations from August 1991 through September 1993 547,076 active-duty U.S. GWVs, 618,335 NDVs Hospital-discharge diagnoses of circulatory system disease in DoD hospital system (ICD-9 classification) No increase in any-cause hospitalization among deployed GWVs Prewar hospitalization, sex, age, race, service branch, marital status, rank, length of service, salary, occupation Very short follow-up period; no outpatient data; restricted to DoD hospitals, and thus to persons remaining on active duty after the war; no adjustment for potential confounders such as smoking status
Knoke et al., 1998 (Vol. 8) 552,111 deployed vs 1,479,751 nondeployed U.S. service members in service during Gulf War and remaining there through 1996 Hospitalization records: DoD only, 1991–1996, ICD 799.9 (unexplained illness) No excess in hospitalizations in this period when effect of CCEP was eliminated Race, rank, salary, military branch, occupation, prewar hospitalization, sex Active duty only, no assessment of outpatient treatment, respiratory findings removed after adjustment for VA screening-program attendance
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Study Design Population Outcomes Results Adjustments Comments
Gray et al., 2000 (Vol. 8) Retrospective cohort, hospitalizations from August 1991 through December 1994 652,979 GWVs, 652,922 randomly selected NDVs: 182,164 DoD hospitalizations; 16,030 VA hospitalizations; 5,185 COSHPD hospitalizations Hospital-discharge diagnoses in DoD, VA, and COSHPD hospital systems Similar rates of hospitalization between deployed and nondeployed veterans Age, sex, race (only for DoD PMR) Able to assess only illnesses that resulted in hospitalization; possible undetected confounders PMR has lower sensitivity than a comparison of hospitalization rates
Smith et al., 2006 (Vol. 8) Retrospective cohort study (cohort data from the DMDC) Active-duty personnel with a single deployment to: Gulf War theater (n = 455,465); southwest Asia peacekeeping mission, 1991–1998 (n = 249,047); Bosnia, 1995–1998 (n = 44,341) Postdeployment hospitalization events (1991–2000) Veterans of southwest Asia had slightly higher rate of hospitalization compared to deployed GWVs, while veterans of Bosnia had slightly lower rate of hospitalizations Sex, age, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalization; time-dependent covariate to account for changing hospitalization methods, diagnostic criteria, and procedures Lower hazard ratio observed in veterans of Bosnia may be partially explained by shorter followup period Limitations: active-duty personnel only; hospitalizations at DoD facilities only
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Volume 10 Primary Studies
Kelsall, et al., 2009 Cross-sectional study to compare physiological and psychological outcomes in GW deployed and nondeployed Questionnaire, including the CIDI, and medical assessment conducted between 2000–2002 Male Australian veterans randomly sampled: 1,456 GWVs and 1,588 NDVs Questionnaire included hospitalizations, medications, functional impairment, Alcohol Use Disorders Test, GHQ-12, SF-12, 63-symptom checklist, deployment information. Full medical exam included fitness test, heart rate, blood tests, and evaluation for psychiatric disorders; Gulf War illness defined using the CDC definition 26% of GWVs and 16% of NDVs had Gulf War illness (OR = 1.8, 95% CI 1.5–2.2) Gulf War illness in GWVs was associated with stopping the fitness test early (OR = 2.1, 95% CI 1.2–3.8), but not heart rate recovery; increased functional impairment (OR = 4.9, 95% CI 3.7–6.5); occupational impairment (OR = 2.7, 95% CI 1.6–4.5); increased health care utilization (OR = 1.7, 95% CI 1.2–2.4); unexplained chronic fatigue (OR = 13.3, 95% CI 7.7–23.1); elevated neuropathy score (mean difference = 2.4, 95% CI 1.5–3.8); increased waist circumference (OR = 1.5, 95% CI 1.1–2.0); poorer SF-12 physical health quality of life scores (mean difference = –9.5, 95% CI –10.5–8.5); SF-12 mental health scores (mean difference = –11.1, 95% CI –12.4–9.9); any current psychiatric disorder (OR = 5.0, 95% CI 3.8–6.7) including affective disorders, major depression, anxiety, PTSD, somatoform disorders, and alcohol use/dependence (all ORs > 2 and p < 0.05); inflammation (OR = 1.6, 95% CI 1.1–2.3); and elevated random glucose (OR = 6.9, 95% CI 1.5–41.9) compared to healthy controls. Gulf War illness in GWVs not associated with spirometry performance, lung function, blood pressure, anemia, renal impairment, obstructive or inflammatory liver disease, or prior exposure to EBV or CMV compared to healthy controls Frequency matched on service branch and 3-year age bands Derivative of Kelsall et al., 2004a Women excluded Response rate: 80.5% in GWVs and 56.8% in NDVs 21% of NDVs had been actively deployed elsewhere This study shows importance of psychiatric disorders for classification of those who meet definitions of Gulf War illness and lack of routine physiologic signs
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Study Design Population Outcomes Results Adjustments Comments
Sim et al., 2015 (Australian Veterans Study) Cohort study Longitudinal health survey conducted in 2011; mortality and cancer registry studies All Australian Gulf War veterans eligible Health survey: 715 GWVs and 675 NDVs; mortality and cancer registry study: 1,871 GWVs and 2,922 NDVs Self-reported symptoms based on 63-item checklist Gulf War illness diagnosed using CDC definition GWVs had a sig higher prevalence of 47 symptoms than NDVs Both groups reported sig more symptoms at follow-up than baseline Risk of Gulf War illness increased in both groups from baseline to follow-up: GWVs RR = 1.27 (95% CI 1.11–1.44) and NDVs RR = 1.19 (95% CI 0.97–1.47) Gulf War illness at follow-up in GWVs vs NDVs RR = 1.6 (95% CI 1.31–1.95) Participation rate: 54% in GWVs and 47% in NDVs First survey conducted in 2003 Derivative of Kelsall et al. (2009)

NOTE: CCEP = Comprehensive Clinical Evaluation Program; CDC = Centers for Disease Control and Prevention; CI = confidence interval; CIDI = Composite International Diagnostic Interview; CMI = chronic multisymptom illness; CMV = cytomegalovirus; COSHPD = California Office of Statewide Health Planning and Development; DMDC = Defense Manpower Data Center; DoD = Department of Defense; DU = depleted uranium; EBV = Epstein-Barr virus; GHQ = General Health Questionnaire; GW = Gulf War; GWV = Gulf War veteran; ICD = International Classification of Diseases; NDV = nondeployed veteran; OR = odds ratio; PB = pyridostigmine bromide; PMR = proportional morbidity ratio; PTSD = posttraumatic stress disorder; RR = risk ratio; SF-12 = 12-item short form health survey; UK = United Kingdom; U.S. = United States; VA = Department of Veterans Affairs.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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CANCER

Cancer can develop at any age, but the median age for any type of cancer diagnosis is 65 years (National Cancer Institute, 2015). The National Cancer Institute’s Surveillance, Epidemiology, and End Results Program estimates incidence, prevalence, and deaths from all cancers and site-specific cancers using age-adjusted rates and actual cases and deaths from 2008–2012. The overall incidence rate for all cancer sites in 2015 was estimated to be 454.8 per 100,000 people per year, or a total of 1,658,370 new cases that year (National Cancer Institute, 2015). Based on 2010–2012 data, approximately 40% of U.S. men and women will be diagnosed with cancer (that is, a malignant neoplasm) at some point during their lifetime (National Cancer Institute, 2015). As of January 1, 2014, approximately 14.5 million people in the United States had a history of a cancer diagnosis (American Cancer Society, 2015). Cancer usually has a long latency period (≥ 20 years) (Cogliano et al., 2004), and, therefore, many Gulf War veterans are still young for cancer diagnoses (the mean age of military personnel during the Gulf War in 1991 was 28 years). However, some forms of cancers—such as testicular cancer, skin cancer, leukemia, lymphoma, and brain cancer—may also develop in younger people or may have shorter latency periods.

Relatively few studies of Gulf War veterans have focused on cancer incidence or prevalence; rather, the majority of studies on the association between overall or cause-specific cancers and Gulf War deployment are mortality studies, which are discussed in the section on causes of mortality. All primary studies of cancer morbidity are summarized in Table 4-3 at the end of this section.

Summary of Volumes 4 and 8

The Volume 4 committee reviewed four cancer studies and found no consistent evidence of a higher overall incidence of cancer in Gulf War veterans than in nondeployed veterans. However, the committee also noted that many veterans were young for a cancer diagnosis and, for most cancers, the follow-up period after the Gulf War was probably too short to expect the onset of most cancers. The incidence of cancer in general, and testicular cancer in particular, have been assessed in cohort studies. Two studies focused on the risk of developing testicular cancer, but results were inconsistent: one study concluded that there was no evidence of an excess risk (Knoke et al., 1998), and the other, a small registry-based study, suggested there may be an increased risk but no definitive conclusions could be made because few cases were identified (Levine et al., 2005). One study examined cancer of all sites. The first study examined incident cases of all cancer in UK Gulf War deployed and nondeployed veterans in the 10 years following the conflict, but after adjusting for sex, age group, service branch, and rank found no evidence of an association between deployment to the gulf and development of cancer (Macfarlane et al., 2003). The Volume 4 committee concluded that additional follow-up time was needed to assess the association between deployment and development of site-specific cancers.

The Volume 8 committee reviewed three primary studies and 10 secondary studies. No consistent evidence of a higher overall incidence of cancer was found in veterans who were deployed to the Gulf War vs nondeployed veterans. Two primary studies found no statistically significant increase in hospitalizations from neoplasms in Gulf War veterans compared with their nondeployed counterparts. A third primary study found no association between deployment and any cancer, including brain, testicular, and digestive tract, among Canadian Gulf War veterans. The Volume 8 committee concluded that there was insufficient/inadequate evidence of an association between Gulf War exposures and brain cancer. Mixed results for testicular cancer were reported by the Volume 4 committee, and the Volume 8 committee did not identify any new studies of this cancer site. The Volume 8 committee agreed with the Volume 4 committee in that many veterans were still too young for cancer diagnoses, and the follow-up period

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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was too short for most cancers. Therefore, the Volume 8 committee found that further follow-up was necessary to be able to make a conclusion about whether there is an association between deployment during the Gulf War and any cancer outcomes. The Volume 8 committee concluded that there was insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and any cancer. The committee also recommended that due to the long latency period for cancer, there needed to be continued follow-up of Gulf War veterans and an appropriate comparison group to adequately determine any association.

New Literature

The Volume 10 committee identified three new studies of cancer in Gulf War veterans; two were deemed primary studies, one was considered a secondary study.

Primary Studies

The first primary study was the Australian Gulf War Veterans’ Follow Up Health Study (Sim et al., 2015) that examined cancer incidence rates through 2008 in the entire cohort of 1,871 Australian Gulf War veterans and a comparison group of 2,922 veterans frequency matched based on age, sex, rank category, and service branch. Incident cancers were identified and linked to the cohort using the Australian Cancer Database, which collects data on all primary, malignant cancers diagnosed in Australia since 1982, but does not include basal cell or squamous cell carcinomas of the skin, cancer recurrences, or metastases. Data includes date of cancer diagnosis, site, histology, the Austrialian state in which the cancer was diagnosed, date of death (if applicable), and the ICD-10 codes for the type of cancer. Cancer diagnoses were presented as all malignant neoplasms; lip cancer; colorectal; other digestive organs; lung, trachea, and bronchus; melanoma; prostate; testis; kidney; brain and other central nervous system cancers; thyroid; all lymphomas; and leukemia. Hazard ratios (HRs) were used to make comparisons between the two veteran groups and standardized incidence ratios were used to make comparisons between each veteran group and the Australian population.

Because women veterans composed only 2% of the Australian deployed cohort, and no deployed women developed cancer in the 18-year follow-up, women were excluded from the cancer incidence analyses. A total of 115 cancers were observed among the male veterans, affecting about 2.5% of the total male cohort. No significant differences between the deployed and the comparison group were found for all malignant cancers (adjusted HR = 1.20, 95% CI 0.83–1.73) or any type of cancer. For site-specific cancers, there were fewer than five cases observed for deployed or comparison groups for several sites including colorectal; brain and other parts of the central nervous system; testis; lung, trachea, and bronchus; kidney; thyroid; lip; and leukemia. No significant differences were observed between deployed veterans and the Australian male population for site-specific cancers; however, few incident cancers were available for analysis and the power of this study to identify rare cancers was low. There was a statistically significant risk for thyroid cancer calculated on the basis of standardized incidence ratios (SIR = 2.89, 95% CI 1.20–6.93), although this estimate was based on only five cases of thyroid cancer observed in the comparison veterans, which limits the conclusions that can be drawn. The number of brain cancer cases, while not statistically significant and based on less than five cases, was higher than expected among Gulf War veterans compared to the general Australian population (SIR = 2.38, 95% CI 0.89–6.35). The authors concluded “In the 18 year period since the Gulf War, there have been no statistically significant differences in cancer incidence of any type between the male Gulf War veterans, the male comparison group members, and the same-aged Australian male population.”

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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The committee notes that while the Australian study adjusted for some factors—such as age, service branch, and rank—the study did not adjust for other important potential confounders such as smoking, body mass index, and alcohol use.

The second primary study examined proportional cancer incidence among all 621,902 U.S. veterans deployed to the Gulf War and 746,248 era veterans (Young et al., 2010). Era veterans were a stratified random sample of veterans from all military personnel who served during the conflict but were not deployed to the Persian Gulf region. Veterans diagnosed with cancer between 1991 and 2006 were identified using data from the Defense Manpower Data Center (DMDC), which was linked to central cancer registries in 28 states and the VA Central Cancer Registry. The 28 state registries captured 84% of the U.S. population, based on the 2000 Census; cancer cases were grouped into 30 categories. Logistic regression models that controlled for age, race, and sex were used to determine whether the proportion of veterans with a diagnosed cancer differed between deployed and era veterans. Crude and adjusted proportional incidence ratios (PIRs) were calculated to determine differences by specific cancer type; adjustment was made for sex, diagnosis age, diagnosis age squared, diagnosis year, race, branch of service, unit type, and registry group. For cancer types with statistically significant adjusted PIRs, SIRs were calculated. The SIRs compared the Gulf War veterans and era veterans with the general population, adjusted for sex, race, and age.

A total of 21,075 incident cancer diagnoses were identified—8,211 among the deployed veterans and 12,864 among the era veterans—of these, 2,796 were identified from the VA Central Cancer Registry. No statistically significant association was found between deployment status and the proportion of veterans diagnosed with cancer (OR = 0.99, 95% CI 0.96–1.02). No difference in proportional incidence between deployed and era veterans was found for brain cancer (PIR = 0.86, 95% CI 0.73–1.01), melanoma (PIR = 0.98, 95% CI 0.89–1.09), other skin cancers (PIR = 0.82, 95% CI 0.53–1.28), digestive system cancers (PIR = 1.07, 95% CI 0.97–1.18), or leukemia (PIR = 0.93, 95% CI 0.78–1.12). Lung cancer was the only site-specific cancer found to have a significantly higher proportion among deployed veterans compared with era veterans (PIR = 1.15, 95% CI 1.03–1.29). It remained significant when further analysis compared proportional incidence of lung cancer in Army and Marine veterans with era veterans (PIR = 1.21, 95% CI 1.07–1.38). Two types of cancers had statistically significant decreased proportional incidence ratios in deployed veterans compared with nondeployed veterans: testicular cancer (PIR = 0.85, 95% CI 0.75–0.98) and Kaposi sarcoma (PIR = 0.54, 95% CI 0.37–0.79). SIRs comparing deployed and era veterans with the general U.S. population were calculated for lung cancer, testicular cancer, and Kaposi sarcoma. Neither deployed nor era veterans showed significantly increased risks of lung or testicular cancer compared to the general population. Both of these veteran groups had significantly decreased risks of Kaposi sarcoma when compared with the general population (SIR deployed = 0.08, 95% CI 0.05–0.12; SIR era = 0.18, 95% CI 0.13–0.24).

The committee notes that as with the Australian cohort study, Young and colleagues (2010) were able to adjust for some demographic, diagnostic, or military factors, but no data on smoking status were available, and therefore, this factor was not included in the adjusted effect models. The length of follow-up was, at most, 15 years, which may not be enough time for certain cancers such as lung cancer to develop if there were a Gulf War etiologic factor. Additionally, the numbers of incident cancer diagnoses are likely to be underestimated because 22 states were not represented, which may alter the PIR as it is affected by the relative frequencies of other cancer types. Also, of the 28 state registries that were included, not all covered the full time period. Major strengths of the study are that it used the entire population of deployed Gulf War veterans and a large and representative sample of era veterans, and that it used cancer registry data—as opposed to mortality, hospitalization, or self-reported diagnoses—to assess cancer incidence outcomes. For more frequently occurring cancers such as lung, prostate, and melanoma, the sample sizes were large enough to provide adequate statistical power to

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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detect relatively small differences between veteran groups and between each veteran cohort and the general U.S. population.

Secondary Studies

The wave 3 survey of the cross-sectional National Health Study of Persian Gulf War Era Veterans was conducted in 2012–2013 and asked 8,104 deployed and 6,148 Gulf War era veterans four questions pertaining to cancer: whether a doctor ever told the veteran that they had skin cancer (other than melanoma), melanoma, brain cancer, or any other cancer, with space to write in what that cancer was (Dursa et al., 2016). If the veteran responded yes, they were asked whether the condition had been present in the past 4 weeks.

Weighted prevalence and adjusted odds ratios (models were adjusted for age, race, sex, BMI, smoking status, service branch, and unit component) were presented for the four self-reported cancer questions among deployed and era veterans. No statistically significant differences between deployed and era veterans were observed for weighted reports (cases) of skin cancer (4.4% [488 cases] vs 5.4% [418 cases]; OR = 1.06, 95% CI 0.88–1.29), melanoma (2.5% [230 cases] vs 2.7% [183 cases]; OR = 1.15, 95% CI 0.87–1.52), or other cancers (5.2% [505 cases] vs 5.6% [399 cases]; OR = 1.12, 95% CI 0.91–1.37). The number of brain cancer cases was small: 30 among the deployed and 19 among the era veterans (0.3% each; OR = 1.02, 95% CI 0.47–2.21) (Dursa et al., 2016). Bossarte (2014) presented additional results to the committee on weighted cases of self-reported brain cancer among deployed and era veterans by service branch, but no significance testing was performed.

Other Related Studies

VA provided a health care use report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories, including the top 10 malignant cancers (ICD-9-CM 140–209) (see Table 4-4); no statistical testing was performed. A veteran can have multiple diagnoses with each health care encounter, and therefore, may be counted in multiple categories, but the person is counted only once in any single diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period (VA, 2014a,b). These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans. In addition to the malignant neoplasms in Table 4-4, a total of 43,337 benign neoplasms were diagnosed among deployed veterans, and 43,757 benign neoplasms were diagnosed among nondeployed veterans.

Conclusions

Given the lack of new evidence on the effect of deployment to the Gulf War and incidence of overall or site-specific cancers from two primary studies, the committee concurs with the conclusions of the Volume 8 committee that there is insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and the incidence or prevalence of any cancer. (Cancer mortality is discussed in the section on causes of mortality.) However, the committee also concurs with the Volume 8 committee’s recommendation that because many cancers have long latency periods, follow-up of deployed Gulf War veterans and an appropriate comparison group of era veterans should be continued to adequately determine whether there is an association.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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TABLE 4-4 10 Most Frequent Malignant Neoplasm Diagnoses for Deployed and Nondeployed Gulf War Veterans Seeking Health Care in VA Between 2002 and 2013

Diagnosis Deployed N = 14,572 (%) Nondeployed N = 17,105 (%)
Other malignant neoplasm of skin 23.6 23.8
Malignant neoplasm of prostate 22.1 24.4
Malignant melanoma of colon 6.2 5.7
Malignant neoplasm of trachea, bronchus, and lung 6.0 6.3
Malignant neoplasm of skin 5.3 5.1
Other malignant neoplasms of lymphoid, histiocytic tissue 5.2 5.0
Secondary malignant neoplasm of other specified sites 4.4 4.1
Malignant neoplasm of kidney and other unspecified urinary organs 4.1 3.8
Malignant neoplasm without specification of site 4.0 3.8
Malignant neoplasm of female breast 3.8 5.9

SOURCES: VA, 2014a,b.

Brain and lung cancer have been of particular concern to Gulf War veterans (see statement of task in Chapter 1). Both of the new primary studies reported on these cancers, but neither provided evidence of an increased risk for these cancers among Gulf War veterans. Young et al. (2010) found a higher proportion of lung cancer in Gulf War veterans compared with era veterans, but there was no difference when compared to the general population. Moreover, Young et al. (2010) made no adjustment for smoking status in their analyses. CDC (2014) estimates that cigarette smoking is linked to 90% of lung cancers. No statistically significant differences for brain cancer were identified in either of the primary studies. Volumes 4 and 8 described studies (Barth et al., 2009; Bullman et al., 2005) that reported an increased risk of brain cancer mortality potentially associated with demolition of chemical munitions at Khamisiyah, however these authors based exposure on a plume model for which there is considerable uncertainty (GAO, 2004). The committee thus concurs with the Volume 4 and 8 committees that there is insufficient/inadequate evidence of an association between demolitions at Khamisiyah and an increased risk of brain cancer. The committee finds that follow-up of cancer prevalence and incidence has only been conducted through 2006 (15 years since the Gulf War), which may not account for latency periods of 25 years or longer. Because cancer incidence in the past 10 years has not been reported, additional follow-up is needed.

Therefore, the Volume 10 committee concludes that there is insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and any form of cancer, including lung cancer and brain cancer.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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TABLE 4-3 Cancer

Study Design Population Outcomes Results Adjustments Comments
Volumes 4 and 8 Primary Studies
Testicular Cancer
Knoke et al., 1998 (Vol. 4) Cohort study (follow-up of Gray et al., 1996) 517,223 active-duty male U.S. GWVs and 1,291,323 NDVs First diagnosis of testicular cancer at U.S. military hospitals worldwide (7/31/1991–3/31/1996) GWVs (134 cases) vs NDVs (371 cases) RR = 1.05 (95% CI 0.86–1.29) Race or ethnicity, age, occupation Short follow-up time, but right age range; no specific exposures evaluated; military hospitals only
Levine et al., 2005 (Vol. 4) Population based survey—pilot study All U.S. GWVs (incl. reserves) and random sample of NDVs; 621,902 GWVs and 746,248 NDVs Testicular cancers diagnosed 1991–1999 and registered by DC or NJ cancer registries GWVs (cases = 17) vs NDVs (cases = 11) (358 males with cancer) PIR = 2.33 (95% CI 0.95–5.70) Age, state of residence, deployment status, race
Gray et al., 1996 (Vol. 4) Hospitalizations from August 1991 through September 1993 547,076 active-duty GWVs, 618,335 NDVs Hospital-discharge diagnoses of testicular cancer (ICD-9-CM Code 186) GWVs vs NCV Last 5 months of 1991: 29 cases vs 14 cases, SRR = 2.12 (95% CI 1.11–4.02) 1992: SRR = 1.39 (95% CI 0.91–2.11) 1993: SRR = 0.89 (95% CI 0.54–1.44) Prewar hospitalization, sex, age, race, service branch, marital status, rank, length of service, salary, occupation Limitations: restricted to persons remaining on active duty after the war, and thus does not include veterans who may have left the service due to poor health; no adjustment for other potential confounders
All Cancers
Macfarlane et al., 2003 (Vol. 4) Cohort (follow-up of Macfarlane et al., 2000) 51,721 UK GWVs, 50,755 NDVs; random samples Subgroup of 28,518 GWVs and 20,829 NDVs veterans with records of smoking and alcohol use Cancers identified from National Health Service Central Register; first diagnosis 4/1/1991–7/31/2002 GWVs (cases = 270) vs NDVs (cases = 269) Main study: RR = 0.99 (95% CI 0.83–1.17) Subgroup: RR = 1.12 (95% CI 0.86–1.45) Main analysis: sex, age group, service branch, rank Subgroup: smoking, alcohol use Follow-up period shorter than expected latency for most cancers; low age; grouped all cancer sites due to low numbers of occurrences
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Gray et al., 2000 (Vol. 8) Retrospective cohort, hospitalizations from August 1991 through December 1994 652,979 GWVs, 652,922 randomly selected NDVs 182,164 DoD hospitalizations; 16,030 VA hospitalizations; 5,185 COSHPD hospitalizations Hospital-discharge diagnoses of neoplasms in DoD, VA, and COSHPD hospital systems DoD PMR = 0.98 (95% CI 0.94–1.01) VA PMR = 0.88 (95% CI 0.78–0.98) COSHPD = PMR 0.86 (95% CI 0.61–1.1) Age, sex, race Able to assess only illnesses that resulted in hospitalization; possible undetected confounders
Statistics Canada, 2005 (Vol. 8) Retrospective cohort study (based on Goss Gilroy Inc., 1998) Approximately 2,200 deployed Canadians in region during combat 5,117 Canadian GWVs; 6,093 NDVs, frequency matched for age, sex, and military duty status Cancer incidences determined from CCD through 1999 Incidence of any cancer (HR = 0.86, 95% CI 0.54–1.39); cancer of the digestive system (HR = 2.00, 95% CI 0.62–6.12); testicular cancer (HR = 0.76, 95% CI 0.18–3.24); cancer of the lymph nodes (HR = 0.65, 95% CI 0.16–2.62) Age, rank Small sample size with low statistical power; young age of cohort; short follow-up period; no information on confounding factors
Smith et al., 2006 (Vol. 8) Hospitalizations cohort study (cohort data from the DMDC) Active-duty personnel with a single deployment to: Gulf War theater (n = 455,465); Southwest Asia peacekeeping mission, 1991–1998 (n = 249,047); Bosnia, 1995–1998 (n = 44,341) Postdeployment hospitalization events (1991–2000) for an ICD-9-CM diagnosis of malignant neoplasm, and for testicular cancer specifically Veterans of Bosnia and of SW Asia compared to GWVs Any neoplasm: Bosnia HR = 0.61 (95% CI 0.50–0.76) SW Asia HR = 1.03 (95% CI 0.93–1.15) Testicular cancer: Bosnia HR = 0.80 (95% CI 0.27–2.39) SW Asia HR = 0.64 (95% CI 0.32–1.28) Sex, age, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalization; time-dependent covariate to account for changing hospitalization methods, diagnostic criteria, and procedures Active-duty personnel only; hospitalizations at DoD facilities only
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Study Design Population Outcomes Results Adjustments Comments
Volume 10 Primary Studies
Sim et al., 2015 Cohort study Longitudinal health survey conducted in 2011; mortality and cancer registry studies All Australian Gulf War veterans eligible to deploy Mortality and cancer registry study: 1,871 GWVs and 2,922 NDVs Self-reported doctor-diagnosed disorders Cancer incidence and mortality (SIR, SMR, and HR) based on Australian Cancer database GWVs vs NDVs Other skin cancer: RR = 0.98 (95% CI 0.8–1.2); Malignant melanoma: RR = 1.25 (95% CI 0.62–2.52) All malignant cancer: HR = 1.2 (95% CI 0.83–1.73) Brain cancer: SIR = 2.38 (95% CI 0.89–6.35) GWVs vs Australian general male population Cancer incidence and mortality (SIR and SMR) were not elevated for any cancer type, nor were there more cancers in GWVs compared with NDVs No female cancer deaths identified, 4 cases of breast cancer, reported results limited to men No smoking adjustment Follow-up to Sim et al., 2003
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Young et al., 2010 Cohort study. Cancer cases diagnosed between 1991 and 2006 from SEER and the VA Central Cancer Registry 8,211 cancer cases among 621,902 GWVs and 12,864 cancer cases among 746,848 NDVs Incident cancer cases and proportional incidence ratios Only lung cancer had an increased proportional incidence ratio in GWVs vs NDVs (620 vs 966 cases; PIR = 1.15, 95% CI 1.03–1.29) Decreased PIRs were found for testicular cancer (496 vs 590 cases, PIR = 0.85, 95% CI 0.75–0.98) and Kaposi sarcoma (46 vs 85 cases, PIR = 0.54, 95% CI 0.37–0.79) Compared to the general population, SIRs for lung cancer were not elevated in either GWVs or NDVs; SIR for testicular cancer in NDVs was 1.1 (95% CI 1.0–1.2); and SIRs for Kaposi sarcoma showed sig decreased risk in both GWVs and NDVs All other comparisons and sites were not significant Analyses controlled for age, race, and sex SIRs adjusted for age and included white males only Record linkage only represents VA data and SEER data from 28 states; other states are unknown, thus these results may represent an underestimate of the 15-year incidence No smoking data available (GWVs reported to smoke more than NDVs) Follow-up to Levine et al., 2005 (reported in Volume 8) PIR of a cancer site is affected by the relative frequencies of other cancer types

NOTE: BIRLS = Beneficiary Identification Records Locator System; CCD = Canadian Cancer Database; CI = confidence interval; COSHPD = California Office of Statewide Health Planning and Development; DC = District of Columbia; DMDC = Defense Manpower Data Center; DoD = Department of Defense; GW = Gulf War; GWV = Gulf War veteran; HR = hazard ratio; ICD = International Classification of Diseases; NDI = National Death Index; NDV = nondeployed veteran; NJ = New Jersey; PIR = proportional incidence ratio; PMR = proportional morbidity ratio; RR = risk ratio; SEER = Surveillance, Epidemiology, and End Results; SIR = standardized incidence ratio; SMR = standardized mortality ratio; SRR = standardized rate ratio; UK = United Kingdom; U.S. = United States; VA = Department of Veterans Affairs.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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BLOOD AND CIRCULATORY SYSTEM CONDITIONS

Cardiovascular disease is a broad term for any disorder of the heart or the blood vessels, such as atherosclerosis and hypertension. Cardiovascular disease, which includes coronary heart disease and stroke, is the leading cause of death for both women and men in the United States.

Conditions of the blood and blood-forming organs include conditions affecting blood cells (erythrocytes, leukocytes, platelets) as well as the organs where these cells are produced (bone marrow, lymph nodes, spleen). The etiology of these disorders is varied, and can include genetic conditions, exposure to toxins and medications, infections, and nutritional deficiencies. All primary studies of conditions of the blood and circulatory system are summarized in Table 4-5 at the end of this section.

Summary of Volumes 4 and 8

As reported in Volume 4, two primary studies (Eisen et al., 2005; Smith et al., 2003) found no statistically significant differences in the prevalence of cardiovascular disease between deployed and nondeployed Gulf War veterans. In the secondary studies, which included hospitalization studies, deployed veterans were generally more likely to self-report hypertension and palpitations, but those reports were not confirmed by medical evaluations. Thus, the Volume 4 committee concluded that there was no difference in the prevalence of cardiovascular disease between deployed and nondeployed Gulf War veterans.

Primary studies of hospitalizations for cardiovascular conditions reviewed in Volume 8 (Gray et al., 1996, 2000; Smith et al., 2002, 2006) did not find an increased risk in deployed vs nondeployed veterans during the first 10–15 years after the Gulf War. The few studies measuring blood pressure in deployed and nondeployed veterans also found no differences between the two groups (Ishoy et al., 1999b; Kelsall et al., 2004a). The only study that found an increase in cardiovascular disease assessed cardiac dysrhythmia in deployed veterans who were possibly exposed to the Khamisiyah plume compared with those who were not exposed (Smith et al., 2003). No studies confirmed this association in other populations, nor was there an increase in hospitalizations for cardiac disease in veterans exposed to smoke from oil-well fires (Smith et al., 2002).

Seven secondary studies provided self-reported prevalence of different cardiovascular conditions, including high blood pressure, palpitations, stroke, heart attacks, and unspecified heart problems by deployment status (Goss Gilroy Inc., 1998; Kang et al., 2000, 2009; Kelsall et al., 2004a; Page et al., 2005a; Proctor et al., 1998; Simmons et al., 2004; Steele, 2000; Stretch et al., 1995). In these studies, deployed veterans were generally more likely to self-report hypertension, palpitations, and other cardiovascular disease, but those reports were not confirmed by clinical evaluations.

Conditions of the blood were not considered as distinct health conditions in Volume 4; however, the Volume 8 committee identified five primary studies that examined hospitalization rates for blood disorders in deployed and nondeployed veterans (Gray et al., 1996, 2000; Smith et al., 2002, 2003, 2006). Overall, these studies did not show that the prevalence of blood disorders was different in deployed Gulf War veterans vs nondeployed veterans. However, these studies precluded any firm conclusions being drawn because hospitalizations were mostly restricted to DoD hospitals, the studies lacked information on outpatient visits where patients with mild disorders are most likely to be seen, most studies lacked information on potential confounders, and none of them differentiated between specific hematologic disorders. Two other primary studies measured hematologic parameters in Danish and Australian Gulf War veterans compared with nondeployed veterans, but neither showed any major difference by deployment status (Ishoy et al., 1999b; Sim et al., 2003). The two studies were limited by different participation rates for deployed and nondeployed veterans—suggesting a bias—and lacked adjustment for confounding

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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variables. Additionally, studies of blood disorders are limited by the nature of the disease; some blood disorders typically have a long latency, and hospitalization and mortality studies are poor approaches to detect their prevalence and incidence. The Volume 8 committee concluded that there was inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and cardiovascular disorders or disorders of the blood and blood-forming organs.

New Literature

The Volume 10 committee did not identify any new primary studies on the risk of Gulf War veterans having conditions of the cardiovascular system.

Secondary Studies

Three secondary studies were identified. One study assessed cardiovascular outcomes in deployed and nondeployed Australian veterans and two studies assessed them in U.S. Gulf War veterans.

The Australian Gulf War Veterans’ Follow Up Health Study, conducted between 2011 and 2013, assessed the entire Australian Gulf War cohort 10 years after the 2000–2002 baseline study and 20 years after the war (Sim et al., 2015). This study was a follow-up to the Kelsall et al. (2004b) baseline study discussed in Volumes 4 and 8. Results were adjusted for age, rank category, and service branch, but not for smoking. Of the 1,456 eligible deployed veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans provided the comparison group. Health outcomes were based on self-reports and on self-reports of doctor-diagnosed conditions. Deployed veterans were slightly but not significantly more likely to report high blood pressure (RR = 1.14, 95% CI 0.95–1.37) and angina (RR = 1.26, 95% CI 0.51–3.10) but less likely to report having had a heart attack or myocardial infarction (RR = 0.91, 95% CI 0.51–1.63). High cholesterol was the most prevalent medical condition reported by both groups; 35.4% of deployed veterans and 33.2% of nondeployed veterans reported having this diagnosis, but no statistically significant difference between groups was found (RR = 1.13, 95% CI 0.98–1.32).

In 2005, Li et al. (2011a) reported on findings from the 10-year follow-up survey of U.S. Gulf War deployed (n = 5,469) and nondeployed veterans (n = 3,353) who had also participated in the 1995 National Health Survey of Gulf War Veterans and Their Families. Compared with nondeployed veterans, deployed veterans were less likely to report having hypertension (RR = 0.85, 95% CI 0.76–0.96), although they were more likely to report a new incidence of it (RR = 1.15, 95% CI 1.02–1.29). Deployed veterans were also more likely to report the persistence of coronary heart disease, but not significantly so (RR = 1.14, 95% CI 0.70–1.86), and they had a statistically significantly increased risk of new onset of coronary heart disease (RR = 1.61, 95% CI 1.17–2.23). The risk ratios were adjusted in 2005 for age, gender, race, rank, service branch, service type, BMI, and current cigarette smoking.

The wave 3 survey of the cross-sectional National Health Study of Persian Gulf War Era Veterans was conducted in 2012–2013 and asked 8,104 deployed and 6,148 Gulf War era veterans to indicate whether a doctor had ever told them they had a medical condition and then whether the condition had been present in the previous 4 weeks. There was a significant difference between the deployed and era veterans in self-reports of tachycardia (8.1% vs 5.9%; OR = 1.47, 95% CI 1.20–1.79), coronary heart disease (5.6% vs 5.3%; OR = 1.32, 95% CI 1.09–1.59), and hypertension (43.0% vs 40.0%; OR = 1.22, 95% CI 1.10–1.35); the prevalence of stroke was not significantly different between the two groups (2.2% vs 2.4%; OR = 0.99, 95% CI 0.75–1.32) (Dursa et al., 2016). The ORs were adjusted for age, race, sex, BMI, smoking status, service branch, and unit component.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Other Related Studies

VA provided a health care utilization report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories, including diseases of the blood and blood-forming organs (ICD-9-CM 280–289) and diseases of the circulatory system (ICD-9-CM 390–459) (see Table 4-6). A veteran can have multiple diagnoses with each health care encounter, and therefore, may be counted in multiple categories, but the person is counted only once in any single diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period (VA, 2014a,b). These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans.

Other studies have assessed the effect of a co-occurring health condition on the prevalence of coronary heart disease, hypertension, and tachycardia. Based on responses to the Patient Health Questionnaire component of the second wave of the VA National Health Survey of Gulf War Era Veterans, Coughlin and colleagues (2011a) found that among 6,111 Gulf War deployed and 3,859 era veterans, deployed veterans, regardless of their weight status (underweight, normal weight, overweight, or obese), self-reported more coronary heart disease and hypertension than nondeployed veterans. No information on diet or physical activity was provided. Further assessment of these veterans found that self-reported

TABLE 4-6 10 Most Frequent Diagnoses of Diseases of the Circulatory and Blood and Blood-Forming Organ Systems for Deployed and Nondeployed Gulf War Veterans Seeking Health Care in VA Between 2002 and 2013

Diagnosis Deployed (%) Nondeployed (%)
Diseases of the Circulatory System N = 138,489 N = 131,363
Essential hypertension 81.2 81.0
Hemorrhoids 16.8 17.0
Cardiac dysrhythmias 12.7 13.4
Other forms of chronic ischemic heart disease 11.6 13.5
Ill-defined descriptions, complications of heart disease 4.0 4.3
Other peripheral vascular disease 3.2 4.0
Heart failure 2.9 3.4
Other disorders of circulatory system 2.8 3.2
Orthostatic hypotension 2.8 Not reported
Other diseases of the endocardium 2.7 3.2
Diseases of Blood and Blood-Forming Organs N = 28,305 N = 28,307
Other, unspecified anemias 55.7 57.7
Diseases of white blood cells 21.0 19.5
Iron deficiency anemias 18.8 21.4
Other diseases of blood, blood-forming organs 10.8 9.8
Purpura, other hemorrhagic conditions 9.8 9.4
Other deficiency anemias 6.9 6.9
Hereditary hemolytic anemias 6.2 6.0
Coagulation defects 4.0 4.3
Aplastic anemia, other bone marrow failure syndromes 2.2 2.4
Acquired hemolytic anemias 0.6 0.4

SOURCES: VA, 2014a,b.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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hypertension was more prevalent in both deployed and nondeployed veterans with problem drinking (33.4% vs 33.5%) than in deployed and nondeployed veterans without problem drinking (29.4% vs 27.5%). Similar results were also seen for self-reported tachycardia, where deployed veterans with and without problem drinking had an increased prevalence compared with nondeployed veterans (16.6% vs 11.4% and 13.7% vs 9.9%, respectively) (Coughlin et al., 2011b). Heavy drinking was defined as ≥ 15 drinks/week.

Abouzeid et al. (2012) assessed the co-occurrence of PTSD and hypertension in Australian veterans who had deployed to the Gulf War. They found that in 2000–2002, among the 1,381 veterans for whom medical information and results of the CIDI for diagnosing PTSD were available, 100 veterans were considered to have probable hypertension. The ORs for hypertension were 2.90 (95% CI 1.19–7.09) for veterans with PTSD in the past 12 months (n = 71) and 2.27 (95% CI 1.01–5.10) for lifetime prevalence (n = 91), compared with veterans without PTSD (n = 1,290 and 1,310, respectively). The ORs were adjusted for age, occupation, education, marital status, service branch, military service experience, questionnaire score, military rank, BMI, waist circumference, pack-years of smoking, AUDIT case status, and the presence of affective disorders or anxiety disorders other than PTSD.

Conclusions

The new secondary studies of Gulf War veterans that compared cardiovascular disease in deployed veterans vs nondeployed veterans had mixed results. One study found that U.S. deployed veterans had a significantly increased risk of having tachycardia but a second study, using the same cohort, found no significant increase in the risk of having hypertension or of having coronary heart disease, although there was a moderate increase in the risk of developing both conditions. A study of Australian Gulf War veterans found no significantly increased risk of having high cholesterol, high blood pressure, heart attacks or myocardial infarction, or angina in deployed vs nondeployed veterans.

The committee finds that given the aging of the population of Gulf War veterans and the unlikelihood that new blood and circulatory conditions will develop 25 years after the Gulf war that are attributable to their Gulf War service, it is doubtful that further assessments will show increased risk of these conditions.

Therefore, the Volume 10 committee concludes that there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and cardiovascular conditions or conditions of the blood organs.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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TABLE 4-5 Conditions of the Blood and Circulatory System

Study Design Population Outcomes Results Adjustments Comments
Volume 4 and 8 Primary Studies
Cardiovascular System
Eisen et al., 2005 (Vol. 4) Population-based; cross-sectional; prevalence; medical evaluation; 1999–2001 1,061 U.S. GWVs, 1,128 NDVs Hypertension = blood pressure > 140/90 mmHg or history of hypertension and use of antihypertensive medications Hypertension: OR = 0.90 (95% CI 0.60–1.33) Age, sex, race, years of education, smoking, duty type, service branch, rank Low response rates, especially in control group (53% in GWVs, 39% in era controls), but analysis of nonparticipants and participants reveals no differences in hypertension or diabetes
Smith et al., 2003 (Vol. 4) DoD hospitalization study (1991–2000); analysis of health outcomes and exposure to nerve agents 99,614 active-duty military considered exposed vs 318,458 nonexposed, according to revised DoD exposure model First hospitalization for any disease of the circulatory system (ICD-9-CM codes 390–459); hospitalization for cardiac dysrhythmia Circulatory system diseases: RR = 1.07 (95% CI 1.01–1.13); Cardiac dysrhythmia: RR = 1.23 (95% CI 1.04–1.44) Sex, age, status, prewar hospitalization, pay grade, race, branch, days deployed, marital status, occupation Restricted to DoD hospitals; restricted to hospitalizations for only Gulf War veterans who remained on active duty after the war; no adjustment for confounding exposures
Gray et al., 1996 (Vol. 8) Retrospective cohort, hospitalizations from August 1991 through September 1993 547,076 active-duty GWVs, 618,335 NDVs Hospital-discharge diagnoses of circulatory system disease in DoD hospital system (ICD-9 classification) ORs about 0.90–0.95 (95% CI 0.85–1.05) across all 3 years, 1991–1993 Exact values not given Prewar hospitalization, sex, age, race, service branch, marital status, rank, length of service, salary, occupation Very short follow-up period; no outpatient data; restriction to DoD hospitals, and thus to persons remaining on active duty after the war; no adjustment for potential confounders such as smoking
Gray et al., 2000 (Vol. 8) Retrospective cohort, hospitalizations from August 1991 through December 1994 652,979 GWVs, 652,922 randomly selected NDVs 182,164 DoD hospitalizations; 16,030 VA hospitalizations; 5,185 COSHPD hospitalizations Hospital-discharge diagnoses of circulatory system disease in DoD, VA, and COSHPD hospital systems Circulatory system disease: DoD PMR = 0.94 (95% CI 0.91–0.98); VA PMR = 0.85 (95% CI 0.76–0.93); COSHPD PMR = 0.98 (95% CI 0.82–1.14) Age, sex, race (only for DoD PMR) Age, sex (for VA and COSHPD PMR) Able to assess only illnesses that resulted in hospitalization; possible undetected confounders PMR has lower sensitivity than a comparison of hospitalization rates
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Smith et al., 2002 (Vol. 8) DoD hospitalizations 1991–1999; exposure modeling for oil-well fire smoke 405,142 active-duty GWVs who were in theater during the time of Kuwaiti oil-well fires Hospitalization for diseases of the circulatory system and for ischemic heart disease specifically Significant decrease in risk ratio for exposed to oil-well fire smoke vs nonexposed in 3 of 5 exposure categories Lower risk of ischemic heart disease in all exposed vs nonexposed (RR = 0.82, 95% CI 0.68–0.99) Adjusted for “influential covariates,†defined as demographic or deployment variables with p values less than 0.15 Objective measure of disease not subject to recall bias; no issues with self-selection; however, only DoD hospitals, only active duty, no adjustment for potential confounders such as smoking status
Smith et al., 2006 (Vol. 8) Retrospective cohort study (cohort data from the DMDC) Active-duty personnel with a single deployment to: Gulf War theater (n = 455,465); Southwest Asia peacekeeping mission, 1991–1998 (n = 249,047); Bosnia, 1995–1998 (n = 44,341) Postdeployment hospitalization events (1991–2000) for an ICD-9-CM diagnosis of a disease of the circulatory system (390–459) Compared to GWVs, veterans of Bosnia showed reduced risk (HR = 0.70, 95% CI 0.59–0.83), and veterans of Southwest Asia showed similar risk (HR = 1.06, 95% CI 0.97–1.16) Sex, age, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalization; time-dependent covariate to account for changing hospitalization methods, diagnostic criteria, and procedures Lower hazard ratio observed in veterans of Bosnia may be partially explained by shorter follow-up period Limitations: active-duty personnel only; hospitalizations at DoD facilities only
Ishoy et al., 1999b (Vol. 8) Cross-sectional 686 Danish peacekeepers deployed to gulf in 1990–1997 vs 231 age- and sex-matched nondeployed controls Blood pressure measured by physician Deployed vs nondeployed: Systolic: 127 (sd = 12) vs 126 (sd = 11) mmHg Diastolic: 78 (sd = 9) vs 76 (sd = 10) mmHg Participation rate: 83.6% deployed, 57.8% nondeployed
Sim et al., 2003 (Vol. 8) Cross-sectional, mailed questionnaire and clinical examination 1,371 male and 30 female Australian GWVs; 1,368 male and 32 female NDVs Blood pressure measured by a physician High-normal blood pressure, males: OR = 1.1 (95% CI 0.9–1.3) Hypertension, males: OR = 1.1 (95% CI 0.9–1.4); females: similar prevalence (3%) in both groups Service type, rank, age, education, marital status High participation in deployed veterans (male 81%, female 79%), but low participation in control group (male 57%, female 44%) possibly leading to participation bias
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Study Design Population Outcomes Results Adjustments Comments
Blood and Blood-Forming Organs
Gray et al., 1996 (Vol. 8) Retrospective cohort, hospitalizations from August 1991 through September 1993 547,076 active-duty GWVs, 618,335 NDVs Hospital-discharge diagnoses of blood disease in DoD hospital system Exact values not given 1991: OR about 0.9 (95% CI 0.8–1.05); 1992: OR about 1.1 (95% CI 1.0–1.2); 1993, OR about 1.05 (95% CI 0.9–1.15) Prewar hospitalization, sex, age, race, service branch, marital status, rank, length of service, salary, occupation Short follow-up period; no outpatient data; restriction to DoD hospitals and thus to persons remaining on active duty after the war; no adjustment for other potential confounders
Gray et al., 2000 (Vol. 8) Retrospective cohort, hospitalizations from August 1991 through December 1994 652,979 GWVs, 652,922 randomly selected NDVs 182,164 DoD hospitalizations; 16,030 VA hospitalizations; 5,185 COSHPD hospitalizations Hospital-discharge diagnoses of blood disease in DoD, VA, and COSHPD hospital systems DoD PMR = 1.08 (95% CI 0.97–1.19) VA PMR = 0.77 (95% CI 0.54–1.01) COSHPD PMR = 1.09 (95% CI 0.22–1.96) Age, sex, race (only for DoD PMR) Able to assess only illnesses that resulted in hospitalization; possible undetected confounders; PMR has lower sensitivity than a comparison of hospitalization rates
Smith et al., 2006 (Vol. 8) Retrospective cohort study (cohort data from the DMDC) Active-duty personnel with a single deployment to: Gulf War theatre (n = 455,465); Southwest Asia peacekeeping mission, 1991–1998 (n = 249,047); Bosnia, 1995–1998 (n = 44,341) Postdeployment hospitalization events (1991–2000) for an ICD-9-CM diagnosis of a disease of the blood (280–289) Compared to GW veterans, veterans of Bosnia showed similar risk (HR = 0.93, 95% CI 0.80–1.07), as did veterans of Southwest Asia (HR = 0.93, 95% CI 0.75–1.15) Sex, age, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalization; time-dependent covariate to account for changing hospitalization methods, diagnostic criteria, and procedures Limitations: active-duty personnel only; hospitalizations at DoD facilities only
Smith et al., 2002 (Vol. 4) DoD hospitalizations 1991–1999; exposure modeling for oil-well fire smoke 405,142 active-duty GWVs who were in theater during the time of Kuwaiti oil-well fires Hospitalization for diseases of the blood (ICD-9-CM codes 280–289) No clear association between exposure and blood disease across all exposure levels Adjusted for “influential covariates,†defined as demographic or deployment variables with p values less than 0.15 Objective measure of disease not subject to recall bias; no issues with self-selection; however, only DoD hospitals, only active duty, no adjustment for potential confounders such as smoking
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×
Smith et al., 2003 (Vol. 4) DoD hospitalization study (1991–2000); analysis of health outcomes and exposure to nerve agents (follow-up of Gray et al., 1999b) 99,614 active-duty military considered exposed vs 318,458 nonexposed, according to revised DoD exposure model First hospitalization for any blood disorder (ICD-9-CM codes 280–289) Exposed vs unexposed: RR = 0.96 (95% CI 0.89–1.03) Sex, age, status, prewar hospitalization, pay grade, race, branch, days deployed, marital status, occupation Restricted to DoD hospitals; restricted to hospitalizations for only Gulf War veterans who remained on active duty after the war; no adjustment for confounding exposures
Ishoy et al., 1999b (Vol. 8) Cross-sectional 686 Danish peacekeepers deployed to gulf in 1990–1997 vs 231 age- and sex-matched nondeployed controls Blood hemoglobin, erythrocyte count, hematocrit, mean corpuscular volume, leukocyte count, and platelet count Hemoglobin (mmol/L): 9.3 (sd = 0.5) vs 9.3 (sd = 0.6); erythrocytes (million/L): 4.8 (sd = 0.3) vs 4.8 (sd = 0.3); hematocrit 0.44 (sd = 0.25) vs 0.44 (sd = 0.26); corpuscular volume (10–15 L): 91 (sd = 3.6) vs 91 (sd = 3.8); leukocytes (109/L): 5.8 (1.7) vs 5.9 (sd = 1.8); platelets (109/L): 205 (sd = 45) vs 211 (sd = 43), p < 0.05 None Participation rate: 83.6% deployed, 57.8% nondeployed; no adjustment for possible confounding factors
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Study Design Population Outcomes Results Adjustments Comments
Sim et al., 2003 (Vol. 8) Cross-sectional, mailed questionnaire and clinical examination 1,355 male and 30 female Australian GWVs; 1,361 male and 32 female nondeployed veterans Hemoglobin, MCV, MCH, lymphocyte count, platelet count Hemoglobin (g/L), men: 153.4 (sd = 9.5) vs 153.1 (sd = 9.1); women: 131.8 vs 134.3 MCV (fl), men: 91.6 (sd = 4.7) vs 91.5 (sd = 4.5); women: 92.8 vs 93.4 MCH (pg), men: 30.4 (sd = 1.4) vs 30.5 (sd = 1.3); women: 29.8 vs 30.3 Lymphocyte count (109/L), men: 1.9 (sd = 0.5) vs 1.9 (sd = 0.6); women: 2.0 vs 2.1 Platelets (109/L), men: 227.8 (sd = 44.4) vs 231.3 (sd = 48.5); women: 263.6 vs 269.6 Service type, rank, age, education, marital status High participation in deployed veterans (male 81%, female 79%), but low participation in control group (male 57%, female 44%) possibly leading to participation bias

NOTE: CI = confidence interval; COSHPD = California Office of Statewide Health Planning and Development; DMDC = Defense Manpower Data Center; DoD = Department of Defense; GW = Gulf War; GWV = Gulf War veteran; HR = hazard ratio; ICD = International Classification of Diseases; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; mmHg = millimeters of mercury; mmol = millimoles; NDV = nondeployed veteran; OR = odds ratio; pg = picogram; PMR = proportional morbidity ratio; RR = risk ratio; sd = standard deviation; VA = Department of Veterans Affairs.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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ENDOCRINE AND METABOLIC CONDITIONS

Among the general U.S. population, the most frequent conditions in this category are diabetes, thyroid disease, and obesity. It is estimated that 29 million people in the United States (9.3%) have diabetes; 1.7 million people aged 20 years or older were newly diagnosed with diabetes in 2012, and another 86 million adults—more than one in three U.S. adults—have prediabetes, where their blood sugar levels are higher than normal but not high enough to be classified as type 2 diabetes (CDC, 2015a). The CDC also estimates that more than one-third (34.9% or 78.6 million) of U.S. adults are obese (CDC, 2015b), a risk factor for diabetes. Although the Volume 10 committee attempted to identify other specific endocrine or metabolic conditions in Gulf War veterans, no new literature on those outcomes was found to have been published since Volume 8. Primary studies for Volumes 4 and 8 are detailed in Table 4-7 at the end of this section.

Summary of Volumes 4 and 8

Volume 4 included diabetes under diseases of the circulatory system. Two primary studies were identified; one study (Eisen et al., 2005) included medical evaluations for diabetes, and the other (Smith et al., 2003), a hospitalization study, used a dispersion model to determine exposure status to nerve agents at the Khamisiyah demolition site. Neither study found a statistically significant increase in the prevalence of diabetes in deployed veterans or in hospital diagnoses for endocrine, nutritional, and metabolic diseases. None of the four secondary studies found a statistically significant increase in diabetes in any of the Gulf War veteran populations they studied; however, most of the studies relied on self-reported diagnoses.

Two primary studies reviewed by the Volume 8 committee reported on risk factors of diabetes, insulin levels, and blood glucose in Gulf War veterans from Denmark (Ishoy et al., 1999b) and Australia (Sim et al., 2003), but neither reported differences between deployed and nondeployed veterans. The five secondary studies of self-reported outcomes in four military cohorts indicated comparable risks of diabetes between deployed and nondeployed veterans (Kang et al., 2009; Page et al., 2005a; Proctor et al., 2001a; Simmons et al., 2004; Smith et al., 2006).

Thyroid disease was not specifically described in Volume 4. The Volume 8 committee reviewed one primary study (Eisen et al., 2005) that reported elevated but not statistically significant risks for hyperthyroidism and for hypothyroidism in deployed veterans compared with nondeployed veterans based on medical examinations.

Obesity was also not studied separately in Volume 4. Studies reviewed by the Volume 8 committee used measures of BMI, weight, and waist circumference to measure obesity in veterans. One primary study, conducted in 1997, found a slightly higher weight and waist circumference in Danish deployed veterans compared with nondeployed veterans (Ishoy et al., 1999b), whereas an Australian study found that BMI and waist circumference measures were comparable between deployed and nondeployed male and female veterans in 2002 (Sim et al., 2003). A secondary study found no differences in BMI, glycemia, or blood levels of thyroxine-stimulating hormone between deployed and nondeployed UK veterans (Ismail et al., 2008).

The Volume 8 committee reported that primary studies showed no clinically relevant differences between deployed and nondeployed veterans in prevalence of different endocrine and metabolic conditions, including diabetes, thyroid disease, and obesity. Five of the eight primary studies relied on hospital discharge data; thus, conditions that did not require hospitalization were not evaluated. The existing studies, however, did not indicate any increased risk of these conditions among deployed veterans. Results

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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from secondary studies were similarly inconclusive: deployment status was unrelated to self-reported diabetes but observed findings were less consistent for “other endocrine disorders.” The Volume 8 committee concluded that there was inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and endocrine, nutritional, and metabolic conditions.

New Literature

No new primary studies were identified by the Volume 10 committee.

Secondary Studies

The Volume 10 committee identified three studies that met its criteria for secondary studies. These studies assessed the prevalence of diabetes on the basis of self-reports.

Li et al. (2011a) conducted a 10-year follow-up survey of U.S. Gulf War deployed (n = 5,469) and nondeployed veterans (n = 3,353) who had participated in the 1995 VA National Health Survey. Compared with nondeployed veterans, deployed veterans in 2005 were at decreased risk of having diabetes (RR = 0.8, 95% CI 0.7–1.0) or having new onset of the disease (RR = 0.9, 95% CI 0.8–1.2). The risk ratios were adjusted for age in 2005, gender, race, rank, service branch, service type, BMI, and current cigarette smoking.

Sim et al. (2015) conducted the Australian Gulf War Veterans’ Follow Up Health Study between 2011 and 2013 to assess the entire Australian Gulf War cohort 10 years after the 2000–2002 baseline study and 20 years after the war. Results were adjusted for age, rank category, and service branch, but not for smoking. Of the 1,456 eligible deployed veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans provided the comparison group. Health outcomes were based on self-reports and on self-reports of doctor-diagnosed diseases. Deployed veterans had a nonsignificant decreased risk of having diabetes compared with nondeployed veterans (RR = 0.76, 95% CI 0.51–1.14).

Dursa et al. (2016) reported results from the third wave of the cross-sectional National Health Study of Persian Gulf War Era Veterans that was conducted in 2012–2013 and asked 8,104 deployed and 6,148 Gulf War era veterans whether a doctor ever told the veteran that they had diabetes or some other endocrine disorder. The weighted prevalence for diabetes was the same in deployed and era veterans—13.2%, but the OR was not statistically significant. Era veterans had a slightly higher weighted prevalence (8.0%) of other endocrine disorders compared with deployed veterans (7.4%), but the OR of 1.09 was not statistically significant (95% CI 0.87–1.33).

Other Related Studies

Other studies have assessed the effect of a co-occurring health condition on the prevalence of diabetes and other endocrine and metabolic conditions. In a 2003–2005 follow-up to the 1995 National Health Survey of Gulf War Veterans and Their Families, Coughlin and colleagues (2011a) investigated self-reported health outcomes among 6,111 Gulf War deployed and 3,859 era veterans stratified by weight. The percentage of normal weight, overweight, and obese deployed veterans who reported a diagnosis of diabetes was 9%, 10.8%, and17.5%, respectively. The corresponding percentages for nondeployed veterans were 7.8%, 10.1%, and 15.6%, respectively. Underweight deployed and nondeployed veterans had a greater percentage of diabetes than normal weight veterans (15.4% and 16.7%, respectively). These data were not adjusted for age and no information on diet or physical activity was provided in this study.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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VA provided a health care use report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories, including for diseases of the endocrine, nutritional, and metabolic systems (ICD-9-CM 240-279) (see Table 4-8); no statistical analyses were performed. A veteran can have multiple diagnoses with each health care encounter, and therefore, may be counted in multiple categories, but the veteran is counted only once in any single diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period (VA, 2014a,b). These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans.

Conclusions

The Volumes 4 and 8 committees found no evidence of an increase in the prevalence of endocrine disorders such as diabetes and thyroid disease or disorders such as obesity in veterans who were deployed to the Gulf War. The several hospitalization studies also found no increased risk of these conditions, although the Volume 8 committee noted that most of these conditions do not require hospitalization and therefore, the prevalence may be underreported.

The new literature reviewed by the Volume 10 committee, much of which was follow-up of previously discussed Gulf War veteran cohorts, also found no evidence of an increased risk of having or developing diabetes or other endocrine or metabolic conditions.

The committee finds that given the aging of the population of Gulf War veterans and the unlikelihood that new endocrine and metabolic conditions will develop 25 years after the Gulf War that are attributable to their Gulf War service, it is doubtful that further assessments will show an increased risk of these conditions.

Therefore, the Volume 10 committee concludes that there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and endocrine and metabolic conditions.

TABLE 4-8 10 Most Frequent Diagnoses of Diseases of the Endocrine, Nutritional, and Metabolic Systems for Deployed and Nondeployed Gulf War Veterans Seeking Health Care in VA Between 2002 and 2013

Diagnosis Deployed N = 28,305 (%) Nondeployed N = 28,307 (%)
Disorders of lipid metabolism 76.8 76.4
Overweight, obesity, other hyperalimentation 45.1 46.1
Diabetes mellitus 25.9 24.6
Vitamin D deficiency 9.0 9.0
Disorders of fluid, electrolyte, acid–base balance 8.5 8.0
Acquired hypothyroidism 8.4 7.1
Gout 6.6 6.6
Testicular dysfunction 4.7 5.1
Deficiency of B-complex components 2.7 2.6
Disorders of mineral metabolism 2.4 2.3

SOURCES: VA, 2014a,b.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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TABLE 4-7 Conditions of the Endocrine and Metabolic Systems

Study Design Population Outcomes Results Adjustments Comments
Eisen et al., 2005 (Vol. 4) Cross-sectional, prevalence, population-based (derived from Kang et al., 2000) 1,061 GWVs and 1,128 NDVs Diabetes, hypothyroidism, hyperthyroidism Diabetes (OR = 1.52, 95% CI 0.81–2.85); hypothyroidism (OR = 1.70, 95% CI 0.75–3.87); hyperthyroidism (OR = 4.86, 95% CI 0.68–34.58); no outcomes tested were significant Age, sex, race, smoking, duty type, service branch, education, rank (hyperthyroidism not adjusted for service branch or rank) Low participation rates, deployed (53%), nondeployed (39%)
Smith et al., 2003 (Vol. 4) DoD hospitalization study (1991–2000) of those potentially exposed to nerve agent 99,614 active-duty military considered exposed vs 318,458 nonexposed, according to revised DoD exposure model Hospitalization due to endocrine, nutritional, and metabolic diseases (ICD-9 classification) RR = 1.00 (95% CI 0.94–1.06) One or more hospitalizations in a specific diagnostic category Diagnoses not requiring hospitalization not captured; no outpatient data; DoD hospitals and active duty only; not possible to adjust for confounding exposures
Ishoy et al., 1999b (Vol. 8) Cross-sectional 686 Danish peacekeepers deployed to gulf in 1990–1997 vs 231 age- and sex-matched nondeployed controls Plasma insulin levels Avg. weight and waist circumference No significant difference in insulin levels between deployed (48 pmol/L) and nondeployed (52 pmol/L) Weight and waistline were higher (p < 0.05) for deployed (84.2 kg, 90.2 cm) than for nondeployed (81.9 kg, 88.3 cm) Participation rate: 83.6% deployed, 57.8% nondeployed
Sim et al., 2003 (Vol. 8) Cross-sectional, mailed questionnaire and clinical examination 1,384 male and 30 female Australian GWVs; 1,379 male and 32 female NDVs (Only 1,365 GWVs and 1,365 NDVs for plasma glucose analysis) Plasma glucose; BMI; waist circumference Plasma glucose, men: 85 mg/dL in both groups; women: 90 mg/dL vs 81 mg/dL BMI, men: 28.1 kg/m2 (sd = 4.1) vs 28.3 kg/m2 (sd = 4.1), OR = –0.3 (95% CI –0.6–0.02); women: 26 kg/m2 in both groups Waist circumference, men: 97.7 cm (sd = 10.7) vs 98.2 cm (sd = 10.7), OR = –0.6 (95% CI –1.4–0.2); women: 86.3 cm vs 83.4 cm Service type, rank, age (< 20, 20–24, 25 to 34, ≥ 35 years), education and marital status High participation in deployed veterans (male 81%, female 79%), but low participation in control group (male 57%, female 44%) possibly leading to participation bias
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Smith et al., 2003 (Vol. 4) DoD hospitalization study (1991–2000); analysis of health outcomes and exposure to nerve agents (follow-up of Gray et al., 1999b) 99,614 active-duty military considered exposed vs 318,458 nonexposed, according to revised DoD exposure model First hospitalization for any endocrine, nutritional, and metabolic diseases (ICD-9-CM codes 240–279) Exposed vs unexposed: RR = 1.00 (95% CI 0.94–1.06) Restricted to DoD hospitals; restricted to hospitalizations for only GWVs who remained on active duty after the war; no adjustment for confounding exposures; diagnoses not severe enough to require hospitalizations are not captured
Gray et al., 1996 (Vol. 8) Retrospective cohort, hospitalizations from August 1991 through September 1993 547,076 active-duty GWVs, 618,335 NDVs Hospital-discharge diagnoses of endocrine, metabolic, or nutritional system diseases in the DoD hospital system (ICD-9 classification) OR about 0.85–0.90 (95% CI 0.80–0.95) across all 3 years, 1991–1993, exact values not given Prewar hospitalization, sex, age, race, branch of service, marital status, rank, length of service, salary, occupation Very short follow-up period; no outpatient data; restriction to DoD hospitals, and thus to persons remaining on active duty after the war; no adjustment for potential confounders
Gray et al., 2000 (Vol. 8) Retrospective cohort, hospitalizations from August 1991 through December 1994 652,979 GWVs, 652,922 randomly selected NDVs 182,164 DoD hospitalizations; 16,030 VA hospitalizations; 5,185 COSHPD hospitalizations Hospital-discharge diagnoses for endocrine, nutritional, and metabolic disease in three hospital systems: DoD, VA, COSHPD DoD PMR = 0.99 (95% CI 0.93–1.06) VA PMR = 1.08 (95% CI 0.92–1.24) COSHPD PMR = 0.81 (95% CI 0.48–1.14) Age, sex, race (only for DoD PMR) Able to assess only illnesses that resulted in hospitalization; possible undetected confounders PMR has lower sensitivity than a comparison of hospitalization rates
Smith et al., 2002 (Vol. 8) DoD hospitalizations 1991–1999; exposure modeling for oil-well fire smoke 405,142 active-duty GWVs who were in theater during the time of Kuwaiti oil-well fires Association of exposure level with hospitalizations for endocrine, nutritional, and metabolic disease (ICD-9 classification) No significant difference between RR for exposure at any level vs nonexposed Adjusted for “influential covariates,†defined as demographic or deployment variables with p values less than 0.15 Objective measure of disease not subject to recall bias; no issues with self-selection; however, only DoD hospitals, only active duty, no adjustment for potential confounders such as smoking
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Study Design Population Outcomes Results Adjustments Comments
Smith et al., 2006 (Vol. 8) Retrospective cohort study Active-duty personnel with a single deployment to: Gulf War theater (n = 455,465); Southwest Asia peacekeeping mission, 1991–1998 (n = 249,047); Bosnia, 1995–1998 (n = 44,341) Postdeployment hospitalization events (1991–2000) for an ICD-9-CM diagnosis of an endocrine disease (240–279) Veterans of Bosnia, HR = 0.69 (95% CI 0.57–0.84) Veterans of SW Asia, HR = 1.02 (95% CI 0.92–1.13) Sex, age, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalization; time-dependent covariate to account for changing hospitalization methods, diagnostic criteria, and procedures Limitations: active-duty personnel only; hospitalizations at DoD facilities only

NOTE: BMI = body mass index; CI = confidence interval; COSHPD = California Office of Statewide Health Planning and Development; DoD = Department of Defense; GWV = Gulf War veteran; HR = hazard ratio; ICD = International Classification of Diseases; NDV = nondeployed veterans; OR = odds ratio; pmol = picomoles; PMR = proportional morbidity ratio; RR = risk ratio; VA = Department of Veterans Affairs.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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MENTAL AND BEHAVIORAL HEALTH CONDITIONS

Mental health disorders are among the most disabling and costly health conditions globally. Notwithstanding their high prevalence and their impact on cost and disability, appropriate interventions for mental health conditions remain one of the most neglected areas in health care worldwide, a reality that may be related to stigma as well as diagnostic issues. The latter may result in ambiguous definitions that may affect the proper characterization of those in need of services.

Mental health conditions are well-known sequelae of war (Pizarro et al., 2006; Wessely, 2005). These conditions have been an important focus of studies of military populations, and each large cohort study of Gulf War veterans has included at least some psychological assessments. Mental health conditions most commonly studied in the Gulf War veteran population include major depressive disorder (MDD), PTSD, and substance use disorders. In general, for most of the studies discussed in this section, the American Psychiatric Association’s (APA’s) Diagnostic and Statistical Manual of Mental Health Disorders, fourth edition (DSM-IV), was the basis for the assessment of mental health disorders in veterans and others (APA, 2000). In 2013, the APA released a revised fifth edition of the DSM, which substantially changed many of the criteria that are used to diagnose mental health disorders.

For example, the DSM-5 diagnostic criteria for PTSD may affect the incidence and prevalence of PTSD in both military and civilian populations. Part of the difficulty in assessing and treating for PTSD is the inherent heterogeneity in presentation. For example, Galatzer-Levy and Bryant (2013) found that the DSM-5 criteria could result in 636,120 PTSD symptom combinations. The new criteria for PTSD are summarized in Box 4-1. None of the studies considered in this report used the new criteria.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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General population estimates of prevalence of mental health conditions show that in general, about one-third of the U.S. adult population may, at some time in their lives, meet criteria for a mental health disorder. The National Comorbidity Survey–Replication, a large epidemiologic study in the United States, found a 12-month prevalence estimate of 3.1% for alcohol abuse, 2.4% for bipolar disorder, 1.4% for drug abuse, 2.7% for generalized anxiety disorder, 3.6% for PTSD, 8.9% for MDD, 3.7% for panic disorder, 7.2% for social phobia, and 9.2% for specific phobia (Gadermann et al., 2012). Lifetime prevalence for the same mental health disorders in the general U.S. population tends to be higher (Kessler et al., 2005). The rates of mental disorders in the general population based on the above estimates tend to be higher than those reported in deployed veterans and much higher than in the nondeployed veteran populations (IOM, 2010), a finding that has been interpreted as due to a “healthy-warrior effect,” but these rates may not be comparable as they have been obtained through different research strategies. It is likely that both military screening and self-selection contribute to the belief that individuals entering the military, and being eligible for deployment, may have a better mental and physical health status than similar individuals in the general population. However, it is well recognized that deployment and exposure to combat result in an increased incidence of certain mental health disorders such as PTSD.

The proper examination of mental health conditions among veterans serving in the Gulf War has been complicated by the passage of time, the stigma that mental health disorders may convey on veterans and their families, and the rejection of these diagnoses by many veterans who vigorously advocate against their symptoms and disorders being called “mental” or “psychiatric.” Indeed, many Gulf War veterans fear that discussion of the psychological aspects of their symptoms would question the legitimacy of their health problems.

All primary studies of mental and behavioral health conditions are summarized in Table 4-9 at the end of this section.

Summary of Volumes 4 and 8

In Volume 4, eight primary studies were reviewed that used direct interviews of large Gulf War cohorts. Across those studies, publications from three U.S. cohorts, one Australian cohort, and one Canadian cohort reported a two- to three-fold increased prevalence of mental health conditions including generalized anxiety disorder, panic disorder, PTSD, any anxiety disorder, and substance abuse in deployed vs nondeployed veterans (Barrett et al., 2002; Black et al., 2004a,b; Brailey et al., 1998; Kang et al., 2003; Proctor et al., 1998; Wolfe et al., 1999a,b). Analyses also indicated reduced functioning and quality of life in deployed veterans with mental health conditions. Two of those studies indicated that symptoms of depression and PTSD could worsen over time (Brailey et al., 1998; Wolfe et al., 1999a). The primary studies and most of the secondary studies, regardless of their techniques of ascertainment or their target population, reported almost identical conclusions regarding the psychiatric outcomes of Gulf War deployment for veterans. Depression, substance abuse or dependence, and anxiety disorders, especially PTSD, were increased in Gulf War deployed veterans compared with nondeployed veterans. Symptom severity was associated with the perceived level of deployment stress, even if veterans did not have direct combat exposure.

The Volume 8 committee identified four new primary studies (Fiedler et al., 2006; Ismail et al., 2002; Kang et al., 2009; Toomey et al., 2007) and five new secondary studies (Al-Turkait and Ohaeri, 2008; Axelrod et al., 2005; Black et al., 2006; Kang et al., 2005; Rona et al., 2007) that further supported the Volume 4 committee conclusions on the relationship between deployment to the Gulf War and mental health disorders. First, that committee found that combat exposure in the Gulf War was causally related to PTSD. The primary studies were in Kuwaiti, UK, and U.S. veterans. The available evidence from

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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these studies is sufficient to support the conclusion that the causal relationship of combat exposure to PTSD shown for other wars, such as Vietnam and the conflicts in Iraq and Afghanistan, also pertains to combat exposure and the development of PTSD in the 1990–1991 Gulf War. Second, there is sufficient evidence of an association between deployment to the Gulf War and several other psychiatric disorders. These include generalized anxiety disorder, depression, and substance abuse, particularly alcohol abuse. Third, the associations between Gulf War deployment and psychiatric disorders were still evident 10 years after deployment. For many of the psychiatric disorders that were measured in long-term followup studies, their prevalence even 10 years after the war was more than two-fold higher in veterans who had been deployed compared with nondeployed veterans.

In particular, the Volume 8 committee found that the high prevalence of medically unexplained disability in Gulf War veterans could not be completely explained by specific psychiatric causes or disorders. Somatization disorder, which is rare, requires eight symptoms that are not caused by a medical illness. Somatoform disorders in DSM-IV included separate diagnoses such as somatization disorder, hypochondriasis, pain disorder, and undifferentiated somatoform disorder. The latter is a disorder with little specificity and is by far the most commonly found; it requires only one symptom that cannot be attributed to known medical causes. In the study by Ismail et al. (2002), “undifferentiated somatoform disorder” was more commonly seen in deployed than in nondeployed Gulf War veterans and in disabled Gulf War veterans compared with disabled veterans from other wars, but the diagnosis was present in only a small minority of disabled Gulf War veterans, and medical evaluations were not sufficiently comprehensive to rule out medical explanations for the symptoms in those given the undifferentiated somatoform disorder diagnosis. Fiedler et al. (2006) and Toomey et al. (2007) found almost no cases of somatization disorder among Gulf War veterans, nor was there a significant elevation in somatization disorder among deployed vs nondeployed veterans. They and other researchers (Al-Turkait and Ohaeri, 2008; Toomey et al., 2007) found a statistically significant increase in the prevalence of psychiatric disorders, notably PTSD, MDD, and substance dependence, in deployed vs nondeployed Gulf War veterans. Thus, based on available evidence that used the DSM-IV for diagnoses, the high prevalence of medically unexplained disability in Gulf War veterans cannot be explained by DSM-IV somatoform disorders.

On the basis of available evidence, the Volume 8 committee concluded that there was sufficient evidence of a causal relationship between traumatic war exposures experienced during deployment to the Gulf War and PTSD. The committee also concluded that there was sufficient evidence of an association between deployment to the Gulf War and other psychiatric disorders, including generalized anxiety disorder, depression, and substance abuse, particularly alcohol abuse. Furthermore, these disorders persist for at least 10 years after deployment. Finally, the excess of unexplained medical symptoms reported by deployed Gulf War veterans cannot be fully explained by any DSM-IV psychiatric disorder.

New Literature

Primary Studies

During its review of the scientific literature on mental health disorders in Gulf War veterans published since 2008, the committee identified only one new study that met its criteria for a primary study (Sim et al., 2015). The Australian-based Gulf War Veterans’ Follow Up Health Study, conducted between 2011 and 2013, is an assessment of the entire 1,871 Australian Gulf War cohort 10 years after the 2000–2002 baseline study and 20 years after the war (Sim et al., 2015). Because only about 2% of the participants were women, only males were recruited for the study. Results were adjusted for age, rank category, and service branch. Of the deployed cohort of 1,456 eligible veterans, 715 participated in

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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the study and 675 of the 1,449 nondeployed veterans provided the comparison group. There were four survey components (see Chapter 3), one of which—the CIDI administered via telephone—was used to assess the presence of mental health disorders. Based on the CIDI interviews, as well as responses to the PTSD Checklist (PCL) and self-reports of doctor-diagnosed and treated PTSD in the past 12 months, 7.3% (PCL) and 8.2% (CIDI) of the deployed veterans met the criteria for PTSD compared with 2.7% (PCL) and 4.8% (CIDI) of the nondeployed veterans. Compared with the prevalence of PTSD in the baseline study, deployed veterans were more likely to have PTSD in the follow-up (RR = 1.96, 95% CI 1.29–2.97). Furthermore, Gulf War veterans were more likely to develop incident PTSD than nondeployed veterans (RR = 2.29, 95% CI 1.24–4.24). The authors report that excess PTSD in Gulf War veterans appears to persist even 20 years after the war, and it appears to be increasing with time compared with the nondeployed veterans.

Sim et al. (2015) also used the CIDI to assess for other mental health disorders in the Australian veterans between 2011 and 2013. Compared with nondeployed veterans, deployed veterans had a greater risk for 12-month alcohol use disorder at follow-up (RR = 1.93, 95% CI 1.10–3.38) or the AUDIT (RR = 1.26, 95% CI 1.05–1.52), but not self-reported doctor diagnosis and treatment (RR = 1.55, 95% CI 0.64–2.81). The prevalence of alcohol use disorder had about doubled in deployed veterans since the baseline study (RR = 2.0, 95% CI 1.25–3.20); a similar increase in nondeployed veterans was not statistically significant (RR = 1.78, 95% CI 0.84–3.76). The number of substance use disorders was too small to allow for statistical analysis and was not assessed. There were no statistically significant differences between the Gulf War and era veterans in the prevalence of other 12-month mental health disorders (as measured by the CIDI) including dysthymia, bipolar disorder, generalized anxiety disorder, obsessive compulsive disorder, social phobia, specific phobia, panic disorder, drug dependence or abuse, and any somatic disorder (i.e., somatization, conversion disorder, pain disorder, and hypochondriasis).

Compared with PTSD and alcohol use disorders, the prevalence of MDD did not differ between the two groups at follow-up (RR = 1.2, 95% CI 0.8–1.7), although it had increased by about 2% in each group since the baseline assessment (from 7.8% to 9.6% in deployed and from 5.0% to 7.2% in nondeployed veterans) (Sim et al., 2015). In a separate analysis of the depression data, it was noted that deployed veterans reported slightly more severe symptoms and were more likely to have been prescribed antidepressants (RR = 1.56, 95% CI 1.05–2.32). There was also a dose–response relationship between depression and self-reports of war-related stressors (Ikin et al., 2015).

Sim et al. (2015) also reported that one out of four Gulf War veterans and one out of six comparison group participants met the criteria for at least one CIDI-defined 12-month psychiatric disorder at followup. This difference between groups was statistically significant.

Secondary Studies

The committee identified only two studies published in the peer-reviewed literature that met its criteria for a secondary study. In 1997, Ishoy et al. (2004) examined psychological symptoms in 686 Danish Gulf War veterans and 231 nondeployed military controls who were matched to the deployed veterans on age, gender, and profession. Subjects completed the Symptom Checklist, revised edition (SCL-90-R), that measures self-reports of symptoms of psychological distress in nine dimensions: somatization, obsessive-compulsive symptoms, interpersonal sensitivity, depression, anxiety, hostility, phobia, paranoid ideation, and psychoticism. Being a Gulf War veteran was statistically significantly associated with six of the nine dimensions—somatization, interpersonal sensitivity, anxiety, hostility; the strongest associations were with obsessive-compulsive and depression. The associations with phobia, paranoid ideation, and psychoticism were not significant.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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In addition to the published study by Ishoy et al. (2004), Dursa et al. (2016) published on the most recent results of the third survey wave of the cross-sectional National Health Study of Persian Gulf War Era Veterans. The wave 3 survey (discussed in greater detail in Chapter 3), conducted in 2012–2013, asked 8,104 deployed and 6,148 Gulf War era veterans to indicate whether a doctor had ever told them they had a medical condition and then whether the condition had been present in the previous 4 weeks. Depression and alcohol use are included in the survey, and participants were also asked about the effect of a variety of emotional problems on their daily lives. The 17-question PCL was used to screen for PTSD. After adjustment for age, race, sex, service branch, and unit component, the adjusted OR for a positive screen for a mental health condition for deployed vs era veterans was 1.93 (95% CI 1.67–2.24) for PTSD, 1.56 (95% CI 1.41–1.73) for MDD, 1.24 (95% CI 1.08–1.38) for other depressive disorders, and 1.34 (95% CI 1.17–1.54) for other anxiety disorders.

Other Related Studies

Blore et al. (2015) reviewed 14 studies that compared the presence of depression and dysthymia or chronic dysphoria in Gulf War veterans with nondeployed veterans (11 of the studies were discussed in Volumes 4 or 8). The authors concluded that although PTSD has been the focus of attention in past studies, depression and dysthymia were twice as common among Gulf War veterans compared to nondeployed military personnel (OR = 2.28, 95% CI 1.88–2.76 and OR = 2.39, 95% CI 2.0–2.86, respectively), regardless of the method used to screen for or diagnose the disorders.

VA provided a health care use report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories, including mental health diagnoses (ICD-9-CM 290–319) (see Table 4-10). A veteran can have multiple diagnoses with each health care encounter, and therefore, may be counted in multiple categories, but the veteran is counted only once in any single diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period (VA, 2014a,b). These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans.

The prevalence of PTSD specifically in U.S. Gulf War veterans has been the subject of a systematic review and meta-analysis by Magruder and Yeager (2009). Using quality adjusted Forrest plots of 12

TABLE 4-10 10 Most Frequent Mental Health Diagnoses for Deployed and Nondeployed Gulf War Veterans Seeking Health Care in VA Between 2002 and 2013

Diagnosis Deployed N = 157,277 (%) Nondeployed N = 129,561 (%)
Adjustment reaction 52.4 39.5
Nondependent abuse of drugs 51.0 49.5
Depressive disorder NEC 48.5 46.1
Anxiety, dissociative, somatoform disorders 37.9 35.3
Episodic mood disorder 30.6 29.6
Alcohol dependence syndrome 16.8 14.7
Sexual, gender identity disorders 15.5 16.7
Drug dependence 9.8 8.8
Special symptoms or syndromes, NEC 8.9 8.1
Personality disorders 5.3 Not reported

NOTE: NEC = not elsewhere classified.

SOURCES: VA, 2014a,b.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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papers published between 1993 and 2003 that assessed PTSD in deployed and nondeployed veterans (one paper was on women veterans only), the authors found that deployed veterans were twice as likely to develop PTSD as were nondeployed veterans (overall OR = 2.03, 95% CI 1.32–3.15; OR range for the 12 papers was 0.74–5.98). Studies were adjusted for sampling methods, sampling frame and study population, PTSD diagnostic criteria, time since exposure, survey methods, exposure assessment, participation rate, analytic strategy, and interviewer training. A similar meta-analysis was done by Kelsall et al. (2015) looking at literature published on Gulf War veterans between 1990 and 2014. They found seven studies that looked at alcohol use disorders in deployed and nondeployed Gulf War veterans and determined a summary OR of 1.33 (95% CI 1.22–1.46). The three studies that assessed substance use disorders in Gulf War veterans yielded an OR of 2.13 (95% CI 1.11–1.66). Kelsall et al. derived ORs for any studies that did not include them. All of the studies in these meta-analyses had been reviewed by the Volume 8 committee.

Although there were few papers that provided any evidence on which to reconsider the conclusions of the Volume 8 committee, this committee did identify several papers that contained findings that may inform future research efforts. For example, in a study of 1,197 male Royal Australian Navy veterans who had served in Gulf War, McKenzie et al. (2010) found that in veterans with no prewar history of mental health diagnoses, postdeployment diagnoses of alcohol abuse or dependence, anxiety disorders, and affective disorders peaked in the first 2 years after deployment, but then decreased in subsequent years. Alcohol abuse and dependence was the most prevalent diagnosis, and was greatest in veterans reporting the most psychological stressors, but anxiety disorders were the first to be evident. Although the onset of affective disorders also peaked at 1–2 years after the war, the effect of time phase was not significant.

In a 2003–2005 follow-up to the 1995 National Health Survey of Gulf War Veterans and Their Families, Coughlin et al. (2011a) found that PTSD was more prevalent in both deployed and era Gulf War veterans who were obese or overweight compared with Gulf War veterans who were of normal weight (OR = 1.5, 95% CI 1.2–1.8 and OR = 1.2, 95% CI 1.0–1.5, respectively). These same researchers also found that when deployed veterans who had drinking problems were compared with deployed veterans who did not have drinking problems, the former were more likely to have PTSD (OR = 2.72, 95% CI 2.33–3.16) and MDD (OR = 2.32, 95% CI 1.99–2.70). PTSD and MDD were also more prevalent in nondeployed veterans with drinking problems (Coughlin et al., 2011b). Heavy drinking was defined as ≥ 15 drinks per week.

Previous IOM Gulf War and Health committees have found that veterans exposed to traumatic war experiences show higher rates of mental health disorders, particularly of PTSD, than those with low or no exposure or nondeployed veterans (IOM, 2008b). The Gulf War and Health, Volume 6 report on deployment-related stress (IOM, 2008b) found a dose–response relationship between the degree of traumatic war exposure and PTSD, but deployment to a war zone even without direct combat exposure could be considered to be a risk factor for the development of PTSD and other mental health disorders such as anxiety and depressive disorders (Ikin et al., 2004). Recent studies of Gulf War veterans continue to show that being in combat and exposed to dead, wounded, and dying people adversely affects mental health (Gade and Wenger, 2011); increases the likelihood of developing PTSD but not depression (Maguen et al., 2011); and leads to a higher level of postdeployment substance abuse, particularly alcohol use (Kelsall et al., 2015; Maguen et al., 2011). One large study that assessed Gulf War veterans over time found that between 1995 and 2005, the number of deployed veterans with PTSD increased significantly (p < 0.05) from 12.01% to 14.4%, and this rate was three times that of nondeployed veterans (3.9% and 4.0%, respectively) (Li et al., 2011a).

Other studies have found that the presence of PTSD increases the risk of having other psychiatric and physical conditions (IOM, 2012).

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Conclusions

A well-accepted reality in today’s medical practice is the frequent co-occurrence of chronic physical conditions such as diabetes, hypertension, and cancer, with mental health conditions such as depression, anxiety, and PTSD. This co-occurrence of health conditions can make it difficult to disentangle the physical from the psychological components of these conditions.

The Volume 10 committee identified only one new primary study and two secondary studies that provided new information on the mental health status of Gulf War veterans. The primary study found that even 20 years after the war, deployed Australian veterans continued to have a greater prevalence of PTSD and were more likely to develop PTSD than nondeployed veterans. Two secondary studies also supported the finding that even many years after the war, U.S. and Danish Gulf War veterans experience more PTSD, depression, and other mental health conditions than nondeployed veterans.

The committee finds that associations between Gulf War service and PTSD, generalized anxiety disorder, substance abuse, and depressive disorders are well established. Furthermore, the committee finds that monitoring and treating these issues and the mental and physical problems that may have caused them deserves greater attention than additional studies that seek to examine their relationship to Gulf War deployment.

The committee recognizes that comparing combat-related PTSD in deployed and nondeployed veterans is not necessarily the best approach for determining the risk of PTSD in either group. Nondeployed veterans cannot have PTSD related to non-existent combat experiences. However, as noted in the Summary of Volumes 4 and 8 section, some of the studies reviewed in the earlier volumes reported that increased levels of combat exposure may result in an increase in PTSD among the deployed veterans, that is, the greater the exposure the more likely the development of PTSD and the more severe its symptoms. Interestingly, even years after the war, deployed veterans continue to show a greater prevalence of PTSD (combat related or otherwise was not specified) and a greater risk for new incidence of it than nondeployed veterans (Sim et al., 2015). Whether the cause of the PTSD in later years is deployment or a post-war exposure was not stated in the study of Australian veterans. As noted in the IOM reports on PTSD (IOM, 2012, 2014c), although delayed onset PTSD can occur it is not common. Furthermore, some veterans may have many of the symptoms of PTSD for years, but initially may not have met the full criteria for such a diagnosis. Future long-term studies of PTSD in Gulf War veterans or other veteran groups would be enhanced by providing information on the traumatic event that precipitated the development of PTSD in both deployed and nondeployed veterans. For the most part, the studies reviewed by Gulf War and Health committees, including this one, have not adequately determined the cause of PTSD in any of the veterans. The use of screening measures, without subsequent diagnostic assessments, is inadequate to make this determination.

Therefore, the Volume 10 committee concludes that there is sufficient evidence of a causal relationship between traumatic experiences during deployment to the Gulf War and PTSD. The committee also concludes that there is sufficient evidence of an association between deployment to the Gulf War and generalized anxiety disorder, depression, and substance abuse (particularly alcohol abuse).

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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TABLE 4-9 Mental and Behavioral Health Conditions

Study Design Population Outcomes Results Adjustments Comments
Volumes 4 and 8 Primary Studies
Black et al., 2004b (Vol. 4) Population-based interview study, by telephone; stratified random sample with proportional allocation (cohort from Iowa Persian Gulf Study Group, 1997) 1,896 GWVs vs 1,799 NDVs listing Iowa as home state at time of enlistment PRIME-MD (MDD, panic disorder, GAD) PCL-M, combat exposure assessed in basic demographic questionnaire CAGE questionnaire (alcohol abuse) Panic disorder (OR = 2.2, 95% CI 1.2–3.8); GAD (OR = 2.5, 95% CI 1.5–4.1); PTSD (OR = 2.5, 95% CI 1.2–5.0); any anxiety disorder (OR = 2.3, 95% CI 1.5–3.5) Age, sex, race, branch of military, rank, military status, prior mental health condition Large, population-based sample
Barrett et al., 2002 (Vol. 4) Population-based survey; completed telephone survey about their health status (same population as Black et al., 2004b) 3,682 GWVs and control subjects PCL-M, SF-36 Persons screened positive for PTSD more likely to have been deployed to Gulf War (OR = 2.02, 95% CI 0.97–4.23) PTSD associated with: current smoking status (OR = 3.83, 95% CI 1.40–10.46); number of self-reported symptoms (19.83 symptoms with PTSD vs 3.64 with no PTSD, p < 0.0001); number of medical conditions (1.73 conditions with PTSD vs 10.18 with no PTSD) Lower SF-36 scores for physical functioning (93 vs 66, p < 0.0001) and general health (80 vs 33, p < 0.0001) Deployment status, age, sex, race, rank, branch, military status, and smoking status Brief PTSD screen used; used 50 as the cutoff score with the PCL-M; low number of subjects who screened positive for PTSD; the sample from Iowa might not be representative of all U.S. military personnel
Black et al., 2004a (Vol. 4) Nested case-comparison; face-to-face interviews 602 veterans and controls SCID (face-to-face interviews); SNAP; SF-36; Whitely Index PTSD (27% vs 5% in deployed vs controls, OR = 7.1, 95% CI 2.1–24.2); anxiety disorders (52% vs 25%, OR = 3.2, 95% CI 1.6–6.3); any disorder (68% vs 52%, OR = 2.0, 95% CI 1.0–3.7) Validated PTSD checklist against SCID (70.4% sensitivity and 86.2% specificity of questionnaire for the 192/602 subjects who met the criteria for depression)
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Kang et al., 2003 (Vol. 4) Cross-sectional; population-based stratified random sample of GWVs deployed compared with those deployed elsewhere 11,441 deployed vs 9,476 deployed elsewhere Mail survey and telephone-based survey of PTSD symptoms GWV (12.1%) compared to deployed elsewhere veterans (4.3%); OR = 3.1 (95% CI 2.7–3.4) Sex, age, marital status, rank, and unit component Nationally representative sample, questionnaire only
Proctor et al., 1998 (Vol. 4); Wolfe et al., 1999a,b Cross-sectional survey and interviews from larger cohorts followed longitudinally 220 Ft. Devens vs 73 New Orleans vs 48 Germany; New Orleans and Germany cohorts only studied at time 2 Health Symptom Checklist, Mississippi PTSD Scale (time 1 [day of arrival home] and time 2 [2 yrs later]), SCID, CAPS (clinician diagnostic interviews, time 2 only) Risk factors for PTSD were being female (time 1 OR = 3.2, 95% CI 1.9–5.5; time 2 OR = 2.3, 95% CI 1.5–3.5) and having high combat exposure (time 1 OR = 1.22, time 2 OR = 1.12, p < 0.05 for both); PTSD also highly correlated with current major depression (r = 0.35, p < 0.001) Lifetime occurrence of PTSD more prevalent in Ft. Devens (8.1%) and New Orleans (7.6%) vs Germany (0%), no p value reported Prevalence of PTSD increased from time 1 (3%) to time 2 (8%) in Ft. Devens group, 2% of the study group had PTSD at both time 1 and time 2, 1% had PTSD at time 1 but not time 2, and 6% had PTSD at time 2 but not time 1 Sex, reported health symptoms Small sample deployed to Germany, 78% participation rate; Wolfe, 1999b, used direct interviews
Brailey et al., 1998 (Vol. 4) Longitudinal; psychological interviews 9 months after war, and subgroup follow-up at 16 months; Louisiana National Guard and Reserve troops 876 deployed (349 at time 2, 16 months later) vs 396 nondeployed BDI-II, State Anger; State Anxiety; BSI Depression; BSI Anxiety; BSI Hostility, the HSC, PCL, and the Mississippi Scale Prevalence of depression increased over time in deployed veterans from time 1 (6.9%) to time 2 (13.8%), as did prevalence of PTSD (2.3% to 10.6%) and hostility (4.9% to 13.8%); no p values reported Age, education Large attrition by time 2 (39.8% response rate at follow-up)
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Study Design Population Outcomes Results Adjustments Comments
Ikin et al., 2004 (Vol. 4) Cross-sectional survey of all Australian deployed veterans 1,381 GWVs vs 1,377 comparison veterans CIDI Prevalence of any disorder: 31% in GWVs vs 21% in comparison group; PTSD: OR = 3.9 (95% CI 2.3–6.5); MDD: OR = 1.6 (95% CI 1.3–2.0); alcohol abuse: OR = 1.5 (95% CI 1.2–2.0) Service type, rank, age, education, marital status GWVs younger, more likely in the Navy, and lower ranked than comparison group Large sample, well-validated psychological interview tool; low participation bias
Dlugosz et al., 1999 (Vol. 4) Post-war hospitalizations June 1991–September 1993 Active-duty men (1,775,236) and women (209,760) June 1991–September 1993; GWVs vs NDVs ICD-9 CM categories for 10 mental health disorders GWVs had increased risk of hospitalizations due to: acute reactions to stress (RR = 1.45, 95% CI 1.08–1.94); drug-related disorders (RR = 1.29, 95% CI 1.10–1.52) No general increase in alcohol-related diagnoses, but serving in ground war in Iraq associated with alcohol-related hospitalizations in men (RR = 1.13, 95% CI 1.04–1.23) Age, sex, service-branch adjusted rates Active duty only; no assessment of outpatient treatment
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Ismail et al., 2002 (Vol. 8) Two-phase cohort study Random sample of UK GWVs with reported disability (n = 111) and no disability (n = 98) and era and Bosnia veterans with disability (n = 54) and no disability (n = 79); Disability defined as score < 72.2 on SF-36 DSM-IV disorders assessed during clinician-administered interview Disabled GWVs compared to disabled controls: No increase in prevalence of any mental health disorder except undifferentiated somatoform disorder (OR = 3.1, 95% CI 1.0–9.6) Response rate good in GWV (67% disabled and 62% nondisabled), but low in controls (55% and 43%) Strength: clinician-administered interview
Fiedler et al., 2006 (Vol. 8) Cross-sectional, random sampling of all U.S. GWVs vs NDVs; assessment by computer-assisted telephone interview 967 GWVs vs 784 NDVs CIDI Deployed veterans had significantly higher 12-month prevalence of any psychiatric disorder compared to nondeployed (26.1% vs. 16.1%, p < 0.05) Increase in MDD (14.2% vs 7.2% for males and 25.3% vs 11.8% for females) and PTSD (3.4% vs 0.7% for males and 4.0% vs 2.2% for females), no p value reported All deployed vs all controls: Any anxiety disorder (OR = 1.81, 95% CI 1.34–2.45); depression (OR = 2.07, 95% CI 1.50–2.85) Males: alcohol dependence (4.8% vs 3.3%, NS); drug dependence (1.2% vs 0.0% p < 0.05) Response rate 59% for GWVs, 51% for NDVs Female gender, divorced, and lower rank were significant independent risk factors
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Study Design Population Outcomes Results Adjustments Comments
Toomey et al., 2007 (Vol. 8) Cross-sectional survey; stratified random sample of U.S. deployed vs nondeployed veterans; structured interview, self-report of symptoms 1,061 GWVs vs 1,128 NDVs (same cohort as Eisen et al., 2005) CAPS; CIDI; PTSD Checklist; BDI-II; BAI; SF-36; QoLI; CES Gulf War era onset: PTSD (6.2% GWVs vs 1.1%, NDVs), (OR = 5.78, 95% CI 2.6–12.7); non-PTSD anxiety disorders (4.3% GWVs vs 1.4% NDVs), (OR = 3.79, 95% CI 1.8–8.0); major depression (7.1% GWVs vs 4.1% NDVs), (OR = 1.81, 95% CI 1.0–3.2) 10 years post-Gulf War era: PTSD (1.8% vs 0.06% GWVs vs NDVs, p = 0.12); non-PTSD anxiety disorders (2.8% vs 1.2% GWVs vs NDVs, p = 0.01); major depression (3.2% GWVs vs 0.8% NDVs, p = 0.01) Symptom self report: GWVs reported more severe symptoms of PTSD, depression, anxiety; lower-level quality of life; SF-36 scores significantly lower Age, sex, ethnicity, years of education, duty type (active vs reserve/guard), service branch, rank Response rate: 53% for GWVs; 39% for NDVs Prevalence of non-PTSD anxiety disorders with onset prior to war was significantly higher in GWVs (12.5%) vs NDVs (9.2%), p = 0.02
Al-Turkait and Ohaeri, 2008 (Vol. 8) Retrospective cohort; stratified random sampling of four groups of veterans: retired from military prior to war; active duty with no combat; active duty with combat; POW 200 Kuwaiti Gulf War veterans, 50 from each group PTSD, determined by CAPS POWs: 48.4% Combat: 32% No combat: 22% Retired: 24% Higher rates of anxiety, depression, and low self-esteem in those with PTSD compared to those without PTSD (p = 0.0001) Potential bias resulting from application of questionnaire to a foreign population
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Volume 10 Primary Study
Sim et al., 2015 Cohort study Longitudinal health survey conducted in 2011–2012 as follow-up to baseline 2000–2002 Australian Gulf War Veterans’ Health Study All 1,456 male Australian Gulf War veterans and 1,588 NDVs in comparison group; 715 GWVs and 675 NDVs participated in follow-up study Mental health status based on SF12 and GHQ-12 CIDI via phone interview used to measure 12-month PTSD, alcohol disorder, MDD, specific phobia, social phobia, bipolar disorder, and obsessive compulsive disorder Included Australian Department of Veterans Affairs health data and data from Medicare, Pharmaceutical Benefits Scheme and Repatriation Pharmaceutical Benefits Scheme claims PTSD also based on self-reported symptoms and PCL, and report of doctor-diagnosed PTSD in the past 12 months Alcohol and substance use disorders based on self-reports using CIDI, AUDIT, and doctor-diagnosed disorders in the past 12 months GWVs had significantly worse physical (adj mean diff = –1.34) and mental health (–3.32) than NDVs. Both groups reported sig worse physical and mental health from baseline to follow-up No significant difference in groups reporting depression, but GWVs were more likely to have mild or moderate symptoms No significant changes from baseline to follow-up GWVs (approx. 7.3–8.2% vs 2.7–4.8%) reported significantly more PTSD by all 3 methods (RRs = 1.56 to 2.94) than NDVs, and greater prevalence from baseline to follow-up (RR = 1.96, 95% CI 1.29–2.97) but not in NDVs Significantly more GWVs had current alcohol use disorder per CIDI and AUDIT (RRs = 1.93 and 1.26) Significantly higher prevalence in GWVs from baseline to follow-up (RR = 2.0, 95% CI 1.25–3.2) but not in NDVs (RR = 1.78, 95% CI 0.84–3.76) Age, rank category, and service branch Participation rate: 54% in GWVs and 47% in NDVs First survey conducted in 2003 Derivative of Kelsall et al., 2009

NOTE: AUDIT = Alcohol Use Disorders Identification Test; BAI = Beck Anxiety Inventory; BDI-II = Beck Depression Inventory; BSI = Brief Symptom Inventory; CAPS = Clinician Administered PTSD Scale; CES = Combat Exposure Scale; CI = confidence interval; CIDI = Composite International Diagnostic Interview; DSM-IV = Diagnostic and Statistical Manual of Mental Health Disorders, fourth edition; GAD = generalized anxiety disorder; GHQ-12 = 12-Item General Health Questionnaire; GWV = Gulf War veteran; ICD = International Classification of Diseases; MDD = major depressive disorder; NDV = nondeployed veteran; NS = not significant; OR = odds ratio; PCL = PTSD Checklist; PCL-M = PTSD Checklist–Military Version; POW = prisoner of war; PRIME-MD = Primary Care Evaluation of Mental Disorders; PTSD = posttraumatic stress disorder; QoLI = Quality of Life Inventory; RR = risk ratio; SCID = Structured Clinical Interview for DSM Disorders; SF-12 = 12-Item Short Form Health Survey; SF-36 = 36-Item Short Form Health Survey; SNAP = Special Needs Assessment Profile; UK = United Kingdom; U.S. = United States.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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NEUROLOGIC CONDITIONS

Neurologic conditions have been associated with a variety of environmental exposures, such as those experienced by Gulf War veterans while deployed. In addition to exposures to nerve agents, organophosphate pesticides, and prophylactic agents such as pyridostigmine bromide, exposure to combat with its inherent and immediate risk of traumatic brain injury (TBI) and traumatic peripheral nerve injury can also result in the subsequent development of posttraumatic neurologic conditions including localization-related epilepsy and cognitive disorders related to focal and diffuse TBI. Other risk factors for the development of specific neurologic disorders include age and family history. Among the neurologic problems that have been studied following deployment to the Gulf War are peripheral nerve pain, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), immune-mediated neuropathies (including Guillain Barré syndrome), and migraines. In this section, the committee considers previous Gulf War and Health reports and new literature on neurologic conditions, specifically peripheral neuropathy, MS, ALS, and other neurodegenerative conditions in Gulf War veterans. In each section, the committee summarizes the findings and conclusions from Gulf War and Health Volume 4 and Volume 8, reviews the new literature published since Volume 8, and discusses any other studies that do not meet the criteria of a primary or secondary study but that nonetheless provide further information to assess neurological conditions in Gulf War veterans. All primary studies of neurologic conditions are summarized in Table 4-11 at the end of this section.

Peripheral Neurologic Disorders

Peripheral neuropathy may be defined as weakness, numbness, and pain in the nerves, typically, but not exclusively, in the hands and feet. Peripheral neuropathy can result from traumatic injuries, diabetes, alcohol abuse, infections, metabolic problems, inherited factors, and exposure to toxicants, including chemotherapeutic agents. This section reviews studies of peripheral mononeuropathy, polyneuropathy, or neuromuscular symptoms, as identified by the investigators conducting the studies.

Types of peripheral neurologic conditions and their diagnoses were characterized in Volumes 4 and 8 of the Gulf War and Health series and are not repeated here. This committee agreed with prior Gulf War and Health committees in that neurophysiologic studies with objective measures are especially helpful in determining the presence of neuropathy and are used in conjunction with clinical evaluations including diminished or absent distal deep tendon reflexes, distal or symmetric leg and foot weakness and atrophy, and change in sensation in toes and feet. Studies that include objective and quantitative measures, such as nerve conduction tests or more sophisticated neurophysiological tests, and even nerve biopsies, are optimal and considered to be primary studies. Studies that relied solely on self-reports of neuropathic symptoms (including numbness, neuropathic pain, weakness, among other related symptoms) were considered to be secondary.

Summary of Volumes 4 and 8

In Volume 4, two primary studies were identified. One was a large, well-designed population-based study of a VA cohort that looked at the presence of distal symmetric polyneuropathy in 1,047 deployed and 1,121 nondeployed Gulf War veterans (Davis et al., 2004). The neuropathy was evaluated based on history, physical examination, and standardized electrophysiological assessment of motor and sensory nerves. Spouses of each group of veterans and 240 Khamisiyah-exposed veterans were also studied. That committee found that the distal symmetric polyneuropathy identified by nerve conduction was the

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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best, most reliable measure of peripheral neuropathy. There were no significant differences between the deployed and nondeployed veterans in term of distal symmetric neuropathy, nor were there differences upon physical examination or self-reported peripheral neuropathy, although more deployed veterans reported numbness and tingling. The other primary study was a smaller evaluation of UK troops deployed to the Gulf War who handled pesticides and nerve agent prophylaxis (Rose et al., 2004; Sharief et al., 2002). Objective neurologic and myopathic testing showed no significant differences between deployed and nondeployed veterans who had neuromuscular symptoms of Gulf War illness with the exception of greater effort on the bicycle exercise test.

The four secondary studies reviewed in Volume 4 also showed a lack of association between deployment and peripheral neuropathy on the basis of objective measures or were inconclusive. Some studies reported higher rates of peripheral neuropathy, but they used self-reports, which the committee did not accept as a reliable measure of peripheral neuropathy. The different case definitions of peripheral neuropathies used by researchers led to problems with ascertainment, and thus, it was difficult to make comparisons among studies.

The Volume 8 committee identified one additional primary study of Australian Gulf War veterans (Kelsall et al., 2005). On the basis of self-report, the deployed veterans had more lower-extremity symptoms that were considered to be possibly indicative of neuropathy but they did not differ from nondeployed veterans on the basis of neurologic examinations. The increased self-reports of neurological symptoms were associated with self-reports of immunizations and exposure to chemical agents including PB and pesticides. The authors found no clinical evidence of an increased risk of myopathy or muscle weakness across the entire cohort. Therefore, the Volume 8 committee concluded that there was limited/suggestive evidence of no association between deployment to the Gulf War and peripheral neuropathy.

New Literature

The Volume 10 committee did not identify any new primary studies that assessed the association between deployment to the Gulf War and peripheral neurologic disorders.

Secondary Studies

The committee found two studies that met its criteria for secondary studies because they were based on self-reports of health conditions. Sim et al. (2015) reported on the Australian Gulf War Veterans’ Follow Up Health Study, conducted between 2011 and 2013. This study is an assessment of the entire 1,871 Australian Gulf War cohort 10 years after the 2000–2002 baseline study and 20 years after the war. Results were adjusted for age, rank category, and service branch. Of the 1,456 eligible deployed veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans provided the comparison group. Neuropathic symptoms were based on self-reports for 17 symptoms. Deployed veterans were significantly more likely to report at least one neuropathic symptom in the previous month than nondeployed veterans (60% vs 52%; RR = 1.13, 95% CI 1.03–1.25) and more likely to report at least four neuropathic symptoms (24% vs 18%; RR = 1.32, 95% CI 1.07–1.64). Among the symptoms of muscle weakness, the most significant differences were found for difficulty lifting object above head (RR = 1.42, 95% CI 1.13–1.79), difficulty getting up from sitting in a chair (RR = 1.25, 95% CI 1.06–1.48), and problems with tripping or feet slapping while walking (RR = 1.54, 95% CI 1.07–2.22); the symptoms of sensory disturbance with the greatest differences were difficulty feeling pain, cuts, or injuries (RR = 3.25, 95% CI 1.45–7.30), and unusual sensitivity or tenderness of skin when clothes or bedclothes rub against the

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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person (RR = 2.07 95% CI 1.23–3.46); the difference in the one symptom of autonomic dysfunction (feeling faint when standing up from lying or sitting) was not significant.

The wave 3 survey of the cross-sectional National Health Study of Persian Gulf War Era Veterans was conducted in 2012–2013 and asked 8,104 deployed and 6,148 Gulf War era veterans to indicate whether a doctor had ever told them they had a medical condition and then whether the condition had been present in the previous 4 weeks (Dursa et al., 2016). There was a significant difference in the self-reports of neuralgia between the deployed and era veterans (9.4% vs 6.3%; OR = 1.65, 95% CI 1.40–1.95). The OR was adjusted for age, race, sex, BMI, smoking status, service branch, and unit component.

Other Related Studies

VA provided a health care use report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories, including diseases of the nervous system and sense organs (ICD-9 codes 320–389). A veteran can have multiple diagnoses with each health care encounter, and therefore, may be counted in multiple categories, but the person is counted only once in any single diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period (VA, 2014a,b). These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans. Of these veterans, 166,396 (58.0%) deployed veterans and 156,772 (58.1%) nondeployed veterans had any diagnosis for ICD-9 codes 320–389. Of these, 11.9% of deployed veterans and 11.8% of nondeployed veterans had a diagnosis of mononeuritis of the upper limb or mononeuritis multiplex (VA, 2014a,b).

Conclusions

The primary studies that assessed peripheral neuropathy used objective measures, clinical examinations, or both to diagnose the damage. These studies uniformly found no association between deployment to the Gulf War and peripheral neuropathy in the veterans. However, several of the secondary studies that relied on self-reports of neurological problems did find increased reporting of those problems among veterans who had deployed to the Gulf War when compared with nondeployed veterans. The committee believes that objective measures are a more reliable diagnostic tool than self-reports.

It is reasonable to consider polyneuropathy to have two phases of expression. The first is related to proximate exposure in the field due to some hypothesized toxic factor (e.g., pesticide exposure), and the second is late in life with deployment to the Gulf War serving as a modifying factor. That is, perhaps some exposure experienced during the Gulf War would make a veteran more likely to express polyneuropathy in later life, whether as an idiopathic entity or even in a veteran with a known causal factor, such as a nutritional or diabetic neuropathy, or even Charcot-Marie-Tooth disease (one of the most common genetic neurologic conditions). Although the committee recognizes that these phases are speculative, they do argue for peripheral neuropathy as a continuing area of study in aging Gulf War veterans; however, the committee also emphasizes that age itself is one of the stronger factors associated with symmetric loss of ankle jerk reflexes, which is often asymptomatic, but is nonetheless an objective evidence of polyneuropathy.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Therefore, the Volume 10 committee concludes that there is limited/suggestive evidence of no association between deployment to the Gulf War and objective measures of peripheral neurologic conditions.

Multiple Sclerosis and Related Neuroinflammatory Conditions

MS is a chronic inflammatory disease of the brain and spinal cord caused by an immune-mediated attack primarily on the myelin membrane that surrounds and insulates nerve fibers (axons) that are responsible for normal transmission of electrical and chemical information in the nervous system. MS can vary from a relatively benign illness to a rapidly evolving and incapacitating disease. Symptoms of MS—such as weakness of the limbs, numbness, vision loss or blurring, pain, imbalance, fatigue, slowed thinking, and bladder/bowel/sexual dysfunction—reflect the loss of neural connections required for normal function.

MS affects about 400,000 people in the United States and is approximately three times more common in women than men (Multiple Sclerosis Association of America, 2015). The age of onset is typically between 18 and 40 years of age, but the disease can present across the life span. MS also appears to be increasing in frequency in multiple populations, especially in women. The environmental factors that influence MS are not known; however, several risk factors have been implicated in the development of MS, including infection with Epstein-Barr virus, ultraviolet light exposure and vitamin D status, and cigarette smoking (Wingerchuk, 2011).

Summary of Volumes 4 and 8

No literature on MS was available for review in Volume 4, but one secondary study was reviewed in Volume 8 (a primary study on mortality from MS is discussed in the section “Causes of Mortality”). The small secondary study (Kelsall et al., 2005) did not show any increased risk for MS in the deployed Australian Gulf War cohort. Therefore, the Volume 8 committee concluded that there was inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and MS. The Volume 8 committee recommended that additional well-designed, adequately powered studies of MS incidence following deployment are needed.

New Literature

Primary Study

The committee identified one new primary study that assessed the association between deployment to the Gulf War and MS. Wallin et al. (2014) assembled an incident cohort of veterans of the Gulf War who had been on active-duty military service during the 1990–1991 war. Cases of MS were identified based on VA Compensation and Pension files for service connection for MS for 17 years after the war. Service connection for MS requires definitive evidence of clinical signs of MS upon examination during or within 7 years after military service. The authors found 330 cases of MS among the 696,118 deployed veterans (250 in males and 80 in females) and 1,230 cases among the 1,780,215 nondeployed veterans (837 in males and 393 in females), resulting in a total relative risk of 0.69 (95% CI 0.61–0.78) for MS in deployed vs nondeployed. The RR for men was 0.72 (95% CI 0.62–0.83) and 0.96 for women (95% CI 0.75–1.22).

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Wallin et al. (2014) also assessed the association between deployment to the Gulf War and neuromyelitis optica and other neurologic conditions that the authors grouped under the term “other demyelinating disease” (ODD), that is demyelinating conditions other than MS. ODD also included possible MS (compared with definite MS), transverse myelitis, optic neuritis, and other clinically isolated syndromes. An incident cohort of 57 deployed veterans of the Gulf War who had an ODD diagnosis was compared with 224 nondeployed ODD-diagnosed veterans of the same era. Possible MS was the most common ODD, followed by optic neuritis. The absolute risk (17-year cumulative risk) for any ODD was 8.19 for deployed personnel (57 cases in 696,118 service members) and 12.54 for nondeployed personnel (224 cases in 1,786,215 service members). Further analysis comparing deployed with nondeployed veterans was not conducted.

Secondary Studies

The committee found two studies that met its criteria for secondary studies. In the Sim et al. (2015) Australian Gulf War Veterans’ Follow Up Health Study discussed in the previous section on peripheral neurologic disorders, only 1 of the 697 deployed male Australian Gulf War veterans and 1 of the 659 nondeployed veterans reported a doctor-diagnosed case of MS.

Dursa et al. (2016) reported results from the third wave of the cross-sectional National Health Study of Persian Gulf War Era Veterans that was conducted in 2012–2013 and asked 8,104 deployed and 6,148 Gulf War era veterans whether a doctor ever told the veteran that they had multiple sclerosis. The adjusted OR for self-reported MS in the deployed vs nondeployed veterans was 1.35 (95% CI 0.72–2.51) and the prevalence was 0.6% and 0.5%, respectively.

Conclusions

Together the new primary study and the two additional secondary studies, combined with the study in Volume 8, indicate that Gulf War veterans do not have an increased risk of developing MS.

Therefore, the Volume 10 committee concludes that there is limited/suggestive evidence of no association between deployment to the Gulf War and multiple sclerosis.

Amyotrophic Lateral Sclerosis

ALS, often referred to as Lou Gehrig’s disease, motor neuron disease, or Charcot’s disease, is a neuromuscular disease that affects approximately 20,000 to 30,000 people in the United States (ALS Association, 2008; National Institute of Neurological Disorders and Stroke, 2006, 2009). ALS affects all races and ethnic backgrounds, and the risk is higher in men than women of the same age (Annegers et al., 1991). The disease is almost always fatal, although the rate of progression varies from patient to patient.

ALS causes degeneration of the motor neurons in the cerebral motor cortex, the brain stem, and the spinal cord (Rowland, 2000). The motor neurons are nerve cells that provide communication between the highest levels of the nervous system and the voluntary muscles of the body (National Institute of Neurological Disorders and Stroke, 2006). When the upper motor neurons degenerate, their connections to the lower motor neurons and spinal interneurons are disrupted, leading to muscle weakness and spasticity. Lower motor neuron degeneration disrupts nerve contact to the muscles resulting in muscle atrophy. Eventually, affected people are unable to move their arms and legs and cannot speak or swallow. When the connection between the neurons and the muscles responsible for breathing is disrupted,

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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patients either die from respiratory failure or require mechanical ventilation to continue to breathe. The majority of persons with ALS die from respiratory failure within 5 years from the onset of symptoms. To be diagnosed with ALS, patients must have signs and symptoms of both upper and lower motor neuron damage that cannot be attributed to other causes.

While most cases of ALS are sporadic, about 10% of cases are transmitted through families as a dominant trait (Sreedharan and Brown, 2013). These inherited forms of ALS have provided a powerful opportunity to dissect pathological events that trigger motor neuron disease. The gene most commonly mutated in ALS (about 40–45% of familial cases and 5–8% of sporadic cases in the United States) is also implicated in frontotemporal dementia; it is designated C9orf72 (DeJesus-Hernandez et al., 2011; Gijselnck et al., 2012; Renton et al., 2011). Some variability in C9orf72 prevalence by race/ethnicity and country of origin exists in both sporadic and familial ALS (Majounie et al., 2012). The defect is expansion of intronic hexanucleotide repeats. The second most common ALS gene is superoxide dismutase, whose mutations (usually missense changes) account for approximately 20% of ALS cases. Mutations in the RNA binding proteins FUS/TLS and TDP43 each account for approximately 5% of cases. All told, there are upward of 50 ALS genes with clear Mendelian inheritance and more than 120 that may bear on the genetic risk of ALS.

Several hypotheses purport to explain why these mutations are pathogenic (Ling et al., 2013; Peters et al., 2015). Many mutations, like SOD1, lead to protein instability and aggregation with multiple adverse effects on cellular metabolism. Others, like FUS/TLS (Kwiatkowski et al., 2009) and TDP43 (Sreedharan et al., 2008), perturb RNA metabolism both within the cell body and in dendrites and axons. Toxicity of the C9orf72 expansions probably arises in part from deposition of RNA foci in cell nuclei, which sequesters intranuclear proteins, disturbances of nuclear membrane transport, and in part via expression of toxic dipeptides through atypical protein translation.

The causes of sporadic ALS are not well defined, but may include complex interactions of multiple gene variants, exposure to environmental toxins, and activation of endogenous retroviruses, as well as occupational, socioeconomic, demographic, and life style risk factors (Li et al., 2015; Mayo Clinic, 2014). Despite a number of epidemiologic studies examining environmental, occupational, socioeconomic, demographic, and life style risk factors for ALS, to date no consistently identified nongenetic risk factors have been reported (Armon, 2003, 2004; Armon et al., 1991; Cermelli et al., 2003; Chio et al., 2005; Kamel et al., 2002; McGuire et al., 1996, 1997; Nicolson et al., 2002; Rowland, 2000; Valenti et al., 2005).

Summary of Volumes 4 and 8

In Volume 4, two primary studies (Coffman et al., 2005; Horner et al., 2003) and one secondary study (Haley, 2003) found that deployed veterans appear to be at increased risk for ALS. In the nationwide epidemiologic case ascertainment study, Horner et al. (2003) found an almost two-fold increase in the risk of ALS for the deployed Gulf War veterans compared with nondeployed (RR = 1.92, 95% CI 1.29–2.84). In a further study of the same data using capture–recapture analysis, Coffman et al. (2005) confirmed the nearly doubled risk. A secondary study found a slightly higher relative risk but within the same overall range when Gulf War veterans were compared to the general U.S. population. Other U.S. and UK mortality studies and a hospitalization study have not found an excess risk of ALS in Gulf War veterans (see the section on causes of mortality in this chapter). The Volume 4 committee concluded that further follow-up was warranted.

In Volume 8, one new primary study (Horner et al., 2008) extended the follow-up of the author’s earlier study through 2001 and described a short-term increase in ALS risk in the deployed Gulf War

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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veterans during the decade after the war. These analyses together support an estimate of a near doubling in risk among deployed veterans compared with nondeployed veterans. The Volume 8 committee concluded that there was limited/suggestive evidence of an association between deployment to the Gulf War and ALS; however, further follow-up was warranted.

New Literature

Primary Study

The committee identified one new primary study of ALS in Gulf War veterans by Kasarskis et al. (2009). This extension of the earlier epidemiologic studies by Horner et al. (2003, 2008) included an additional 28 veterans identified during the 2001–2002 follow-up surveillance period for a total of 43 deployed and 66 nondeployed veterans with ALS (deployment status was based on designation by the Defense Manpower Data Center [DMDC]). Median ventilator-free survival time for deployed veterans was significantly less than that of nondeployed veterans (40.2 vs 57.0 months, HR = 0.62, 95% CI 0.40–0.96, p = 0.03) when adjusted for age and neuroanatomical region of onset of clinical disease.

Secondary Studies

Only two studies met the committee’s criteria for a secondary study. In the Australian Gulf War Veterans’ Follow Up Health Study discussed in the previous sections, Sim et al. (2015) found that only 2 of the 697 deployed male Australian Gulf War veterans had ALS and none of the 659 nondeployed veterans reported having ALS. Given the few cases of ALS, statistical analyses could not be conducted.

The committee also considered the results from Dursa et al. (2016) on the third wave of the National Health Study of Persian Gulf War Era Veterans (discussed in the previous section). The adjusted OR for self-reported ALS in the deployed (0.1% of 8,104) vs era (0.05% of 6,148) veterans was 4.32 (95% CI 0.82–21.74; adjusted for age, race, sex, BMI, smoking status, service branch, and unit component).

Other Related Studies

Miranda et al. (2008) attempted to link the risk of developing ALS in deployed military personnel to specific geographic areas in the Gulf War region using geographic information system modeling. They found that the estimated ALS risk was greatest, although not statistically significant, for troop units with a potential exposure to nerve agents resulting from the munitions destruction at Khamisiyah (RR = 1.7, 95% credible interval4 0.7–3.7). The authors cautioned, however, that there may have been other unknown exposures in the plume that may account for the increased risk.

Conclusions

The one new primary study and the two new secondary studies provided further information on the association between ALS and deployment to the Gulf War. Only one of the studies indicated an increase in ALS among the deployed veterans compared with nondeployed veterans. One study suggested that deployed veterans had a more rapid decline than nondeployed veterans although no explanation for

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4 “Essentially a Bayesian version of a confidence interval” (Miranda et al., 2008).

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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this outcome was suggested. Thus, the new literature does not substantially alter the Volume 8 conclusion, including the need for further follow-up of veterans with and without ALS and both deployed and nondeployed. Since the publication of Volume 8, a substantial growth of knowledge has occurred regarding genetic risk alleles as well as highly penetrant genes associated with ALS. The absence of this information in prior studies is an important limitation in fully understanding the scope of risk of ALS and Gulf War deployment.

Therefore, the Volume 10 committee concludes that there is limited/suggestive evidence of an association between deployment to the Gulf War and amyotrophic lateral sclerosis; however, further follow-up continues to be warranted.

Other Neurodegenerative Conditions

Alzheimer’s disease is the most common neurodegenerative disorder and a cause of dementia in elderly populations. Parkinson’s disease—primarily considered a movement disorder—is the second most common neurodegenerative disorder. Both have progressive courses and no known cure. The neurodegeneration in Parkinson’s disease has been associated with a combination of repeated, prolonged, or chronic exposures to toxicants (particularly pesticides), genetic factors, gene–toxicants interactions, and aging-related effects. In contrast with the Parkinson’s disease literature, the associations, if any, between Alzheimer’s disease and related disorders and environmental toxicants, or their interactions with age or genetic factors, are not as well established.

Summary of Volumes 4 and 8

The committee was unable to identify any studies of dementia or Alzheimer’s disease in Gulf War veterans for Volumes 4 and 8, or for the current study. This committee did not identify any new literature on Parkinson’s disease in Gulf War veterans. The Volume 8 committee noted that Parkinson’s and Alzheimer’s diseases generally present later in life (usually after age 60) and thus, it is unlikely that Gulf War veterans would manifest symptoms or signs of these neurodegenerative disorders until they reach at least the sixth decade of life. Therefore, the Volume 8 committee concluded that there is insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and other neurodegenerative conditions.

New Literature

The committee only identified one new study that met the criteria for a secondary study of other neurodegenerative conditions in Gulf War veterans. Dursa et al. (2016) reported results from the third wave of the cross-sectional National Health Study of Persian Gulf War Era Veterans that was conducted in 2012–2013 and asked 8,104 deployed and 6,148 Gulf War era veterans whether a doctor ever told the veteran that they had Parkinson’s disease. The weighted prevalence was 0.5% in both deployed and era veterans and the OR was not statistically significant (OR = 1.15, 95% CI 0.59–2.24). However, the committee noted that given the long latency of Alzheimer’s disease, Parkinson’s disease, and related disorders, associations may not be evident without longitudinal prospective monitoring of an aging Gulf War veteran population.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Conclusions

This committee concurs with the determination of the Volume 8 committee that a very long latency period for these health outcomes is a possibility, and that current studies have inadequate follow-up time to assess whether risk for these disorders is increased among Gulf War veterans. Given the lack of new information on the prevalence or incidence of neurodegenerative disease among Gulf War veterans, the Volume 10 committee had no evidence on which to modify the Volume 8 conclusions.

Therefore, the Volume 10 committee concludes that there is insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and other neurodegenerative conditions; further follow-up is warranted.

Neurocognitive and Neurobehavioral Outcomes

This section contains an overview and update on neurocognitive and neurobehavioral performance in Gulf War deployed veterans compared with nondeployed veterans.

Summary of Volumes 4 and 8

In Volumes 4 and 8, the committees defined primary studies as those “studies that used neurobehavioral tests that had previously been used to detect adverse effects in population-based research on occupational groups.” In Volume 4, two primary studies found significant differences in neurobehavioral performance—specifically the Purdue Pegboard Test, the California Verbal Learning Test, and the Wisconsin Card Sorting Test—when deployed Gulf War veterans were compared with nondeployed veterans or those deployed elsewhere (David et al., 2002; Proctor et al., 2003). Only one of the three secondary studies found a difference in neurocognition between the two groups. The Volume 8 committee identified two additional secondary studies. One study (Proctor et al., 2006) did not compare deployed with nondeployed veterans but rather looked at neurocognition with respect to putative level of exposure to sarin during deployment. The second study of participants from the National Health Study of Gulf War Era Veterans and Their Families Study, assessed veterans 10 years after the war. Deployed veterans scored poorly compared with nondeployed veterans on two of eight factors (Toomey et al., 2009). The study authors and the committee found that the results did not suggest overall impaired neuropsychological functioning.

In conclusion, primary studies of Gulf War deployed vs nondeployed veterans failed to demonstrate differences in cognitive and motor measures as determined through neurobehavioral testing. Therefore, the Volume 8 committee concluded that there was inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and neurocognitive and neurobehavioral performance.

New Literature

Primary Study

The committee identified one new study that met its criteria for a primary study. The committee did not identify any new secondary studies of neurocognitive or neurobehavioral performance in Gulf War veterans.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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In 1997, Ishoy et al. (2004) examined neurobehavioral symptoms in 686 Danish Gulf War veterans and 231 nondeployed military controls that were matched to the deployed veterans on age, gender, and profession. Subjects performed the Coordination Ability Test System (CATSYS) tests including its extensions, the tremor test and the sway test. Physicians administered a questionnaire on cognitive and psychological symptoms the veteran had experienced in the prior 12 months. Results indicated that compared with nondeployed veterans, deployed veterans reported statistically significant increases (p ≤ 0.001) in concentration or memory problems, repeated fits of headache, balance disturbances or fits of dizziness, abnormal fatigue (not caused by physical activity), and problems sleeping all night. However, the CATSYS tests showed that for 23 of the 26 tests results there were no significant differences between the two groups; for the 3 tests for which the difference was significant (p = 0.05: hand supination/pronation test standard deviation, reaction time test standard deviation, and mean sway velocity), the differences between the two groups were small.

Other Related Studies

Wallin et al. (2009) assessed neuropsychologic performance in a sample of 41 veterans from the National Health Survey of Gulf War Era Veterans conducted in 1995. Twenty-five of the participants met the CDC definition of Gulf War illness, and the 16 controls did not. There were no statistically significant differences between the two groups for composite scores on the traditional and computerized neuropsychologic testing battery, which included verbal abilities, vigilance, processing speed, reading level, memory and learning, problem solving and reasoning, motor coordination, speed, and strength, and effort on testing (all p ≥ 0.1). The veterans with Gulf War illness, however, did have significantly more impairment on the Personality Assessment Inventory for somatic complaints, anxiety, anxiety-related disorders, depression, mania, paranoia, and borderline personality disorders (all p < 0.01) but not for schizophrenia, antisocial features, or alcohol or drug problems.

Chao et al. (2010) studied the cognitive effects of possible exposure to sarin and cyclosarin on 40 exposed and 40 unexposed Gulf War veterans who were participating in a study of Gulf War illness at the San Francisco Veterans Affairs Medical Center between 2002–2007. Fifty-four percent of the exposed veterans and 59% of the unexposed veterans met the Fukuda et al. (1998) definition for chronic multisymptom illness. Study participants underwent a neuropsychological test battery. Test results showed no significant differences between the exposed and unexposed groups on measures of general verbal intelligence, attention, executive function, manual dexterity, visuospatial abilities, or memory. When subjects who failed the Test of Memory Malingering were removed from the analysis, there were no statistical differences between the groups for neurobehavioral functioning.

In a cross-sectional, follow-up study of 64 exposed and 64 “matched” unexposed veterans who underwent neuropsychological and magnetic resonance imaging (MRI) assessment, Chao et al. (2011) found exposed veterans committed more errors of omission and had slower responses on the Continuous Performance Test than unexposed veterans, but these were reported without correction for multiple comparisons. Regression analysis found that exposure to the nerve agents predicted the number of continuous performance test omission errors (β = 0.22, p = 0.02).

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Conclusions

The one new primary study found only a very small association between deployment to the Gulf War and a few adverse neurobehavioral outcomes in Danish veterans. There were no new secondary studies. These results echo those of the Volume 8 committee.

Therefore, the Volume 10 committee concludes that there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and neurocognitive and neurobehavioral performance.

Migraines

This section contains an overview and update on migraines in Gulf War veterans compared with nondeployed veterans. Many studies have included headaches as part of multiple item, self-reported symptom checklists or clustered them with other symptoms related to a specific condition, such as CFS and Gulf War illness. For both CFS and Gulf War illness, as well as in general, more headaches are reported among deployed vs nondeployed veterans (Doebbeling et al., 2000; Haley et al., 1997b; Ishoy et al., 1999b; Kang et al., 2000, 2009; Kelsall et al., 2004a; Pierce, 1997; Proctor et al., 1998; Stretch et al., 1995; Unwin et al., 1999). Fewer studies have focused on migraine among Gulf War deployed and era veterans or looked at sex differences in prevalence. The latter point is important as three out of four people with migraines are women.

Summary of Volumes 4 and 8

Volumes 4 and 8 did not include any studies of migraine, and headaches were only considered within the symptom complex of Gulf War illness and CFS. The Volume 8 report also included one study under a section on female veterans’ health that assessed the health of 525 women who had been on active duty or in the reserve or National Guard during the Gulf War, of whom 160 served in the Persian Gulf region (Pierce, 1997). The women were asked about their physical and emotional health 2 years after the war (time 1) and 4 years after the war (time 2). At time 2, deployed women were more likely than nondeployed women to report headaches (p = 0.001), regardless of the length of their deployment. Reported health problems were not related to whether the woman was on active duty, in the reserves, or a member of the National Guard. The Volume 8 committee did not make any conclusions regarding an association between deployment to the Gulf War and migraines or headaches.

New Literature

The Volume 10 committee did not identify any new literature that met its criteria for a primary study, but two secondary studies and one other related study were identified for migraine and other headache disorders in Gulf War veterans.

Secondary Studies

The Australian Gulf War Veterans’ Follow Up Health Study, conducted between 2011 and 2013, assessed the entire Australian Gulf War cohort 10 years after the 2000–2002 baseline study and 20 years after the war (Sim et al., 2015). This study was a follow-up to the Kelsall et al. (2004b), baseline study discussed in Volumes 4 and 8. Results were adjusted for age, rank category, and service branch, but not

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

for smoking. Of the 1,456 eligible deployed veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans provided the comparison group; women were not included in the analysis. Health outcomes were based on self-reports and on self-reports of doctor-diagnosed conditions. Deployed veterans were slightly but not statistically significantly more likely to report doctor-diagnosed migraines (RR = 1.06, 95% CI 0.66–1.70). Using a 63-item symptom checklist, 60.2% of deployed veterans and 49.2% of era veterans reported headaches in the last month. Deployed veterans were statistically significantly more likely to report headaches compared with era veterans (RR = 1.19, 95% CI 1.08–1.31). The change in the prevalence of headaches reported between deployed and era veterans was not statistically different. The incidence of headaches (not reported at baseline but reported 10 years later at follow-up)—43% of deployed and 29% of comparison veterans—was statistically significantly higher among deployed than era veterans (RR = 1.43, 95% CI 1.14–1.78).

The second study reviewed by the committee was results from the third wave of the National Health Study of Persian Gulf War Era Veterans, conducted in 2012–2013 (Dursa et al., 2016). The wave 3 survey asked 8,104 deployed and 6,148 Gulf War era veterans to indicate whether a doctor had ever told them they had migraine headaches. If the person answered yes, the next question was whether it had been present in the past 4 weeks. Further in the survey, the same two headache questions that were asked in wave 2 of the survey were repeated. The first asked whether the person had “persistent or recurring problems with” any headaches in the past 12 months. If yes, the person was to indicate whether the headaches were mild or severe (defined at the beginning of the survey section) and whether they had been present for 6 months or longer. Survey respondents were asked to indicate how much they had been bothered by headaches in the past 4 weeks. Questions elucidating potential confounders and risk factors such as experiencing head injury or TBI were not included. The weighted prevalence of migraine headache was 20.3% in the deployed and 16.1% in the era veterans. The odds of migraine headache were statistically significantly increased for self-reported migraine headaches among the deployed compared with the era veterans (OR = 1.30, 95% CI 1.15–1.47; adjusted for age, race, sex, BMI, smoking status, service branch, and unit component). Weighted prevalence of headache was limited to study participants who self-reported having lifetime chronic multisymptom illness.

Other Related Studies

In the VA utilization reports discussed in the section on peripheral neuropathy earlier, 166,396 (58.0%) deployed veterans and 156,772 (58.1%) nondeployed veterans received any diagnosis for ICD-9 codes 320–389. Of these 20,473 (12.3%) deployed veterans and 17,599 (11.2%) nondeployed veterans had a diagnosis of migraine (VA, 2014a,b).

Conclusions

Migraines were not considered independently of symptom complexes of other conditions in Volumes 4 and 8. Two secondary studies were reviewed, but findings were not consistent. Among Australian veterans, the odds of migraine headache were statistically significantly increased for self-reported migraine for deployed compared with era veterans. Among U.S. veterans, deployed veterans did not report statistically significantly more doctor-diagnosed migraines compared with era veterans, but deployed veterans were statistically significantly more likely to report headaches compared with era veterans; over 13 years of follow-up, incident headaches were statistically significantly higher among deployed than comparison veterans.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Therefore, the Volume 10 committee concludes that there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and migraines and related headache conditions.

Other Neurologic Outcomes

Haley and colleagues performed detailed neurologic assessments in several case-control studies of Seabee reservists to investigate any possible neurologic underpinning of Gulf War illness. The cases were veterans who had met criteria for factor-derived syndromes defined by Haley et al. (see Chapter 3). Under the hypothesis that those veterans were ill from neurotoxic exposures, especially to organophosphates, the assessments covered broad neurologic function (Haley et al., 1997b), autonomic function (Haley et al., 2004), vestibular function (Roland et al., 2000), basal ganglia injury (Haley et al., 2000a,b), normalized regional cerebral blood flow (Haley et al., 2009), and paraoxonase (PON) genotype and serum concentrations (Haley et al., 1999). Separate groups of investigators also studied PON genotype or activity (Hotopf et al., 2003b; Mackness et al., 1997) and neuropsychologic functioning (Hom et al., 1997).

Summary of Volumes 4 and 8

The Volume 8 committee regarded the Seabee case-control studies as secondary studies primarily because of their lack of generalizability, strong potential for selection bias, and small sample sizes. Although their study design was characterized as nested case-control, the studies of Haley et al. are not true nested case-control studies. Cases were, appropriately, selected from the original cohort, but controls were not. With regard to the lack of generalizability, the authors selected as cases the most severely affected veterans—that is, those who scored highest on factor analysis-derived syndromes—whereas the Volume 8 committee thought that a random sample of those who met a particular case definition would be more appropriate.

The Volume 8 committee concluded that there is insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and other neurologic outcomes.

New Literature

The committee did not identify any new literature that met the criteria for a primary or a secondary study of other neurological outcomes in Gulf War veterans.

Conclusions

There was no new literature to supplement or contradict the conclusions of the Volume 8 committee.

Therefore, the Volume 10 committee concludes that there is insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and other neurologic outcomes.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Neuroimaging Studies of Gulf War Veterans

Overview of Studies

A number of studies using MRI of the brain have been published on veterans who have Gulf War illness. Veterans who participate in these studies usually have a diagnosis that meets the definition of Gulf War illness as established by Haley et al. (1997b) or by the CDC (Fukuda et al., 1998). These studies span the gamut of different MRI modalities—structural MRI, task activation functional MRI (fMRI), 1H MR spectroscopy, diffusion MRI, and perfusion MRI. Many of these studies attempt to identify correlations between imaging and clinical or psychological findings, while others seek to identify a unique imaging biomarker for Gulf War illness. In this section, the committee considers the limitations of using MRI technology to identify, distinguish, and characterize neurologic conditions in veterans who have or do not have Gulf War illness.

The first limitation is that none of the MRI modalities themselves are specific for any disease or disorder. The small brain volume or reduced cortical thickness (i.e., atrophy) seen on structural MRI, response patterns on task fMRI, spectroscopic metabolite levels, spin diffusion metrics, and tissue perfusion of Gulf War veterans may also be seen in many other disease conditions (Fotuhi et al., 2012). For example, decreased brain volume—especially hippocampal atrophy—figures prominently in many structural MRI studies of Gulf War veterans. However, atrophy of various brain regions, particularly the hippocampus, is seen in many other conditions such as epilepsy; neurodegenerative disorders such as frontotemporal lobar degeneration syndromes and Alzheimer’s disease; sleep disorders; developmental disorders; chronic stress; mental health disorders such as depression, anorexia and PTSD; head trauma; and ischemic cerebrovascular disease. Apfel et al. (2011) and Chao et al. (2014a) both found reduced hippocampal volume to be associated with PTSD in Gulf War veterans, but Chao (2014b) also found reduced brain volume to be associated with disturbed sleep efficiency in Gulf War veterans. Thus, brain atrophy, especially hippocampal atrophy, is not specific for, nor predictive of, Gulf War illness or Gulf War deployment, and any reported imaging findings are potentially attributable to other factors such as PTSD.

Other studies have analyzed N-acetyl aspartate (NAA), a brain metabolite visible on 1H MR spectroscopy, which reflects neuron number and health; it is often referenced as a ratio to creatinine (Cr). Decreased NAA/Cr levels in basal ganglia have been reported in veterans with Gulf War illness compared with veterans without Gulf War illness (Haley et al., 2000a; Menon et al., 2004), but as with atrophy, decreased NAA/Cr is seen in a variety of other conditions and a direct relationship with Gulf War illness cannot be inferred.

Decreased NAA/Cr levels in basal ganglia have been reported in veterans who have Gulf War illness compared with veterans who do not have Gulf War illness (Haley et al., 2000b; Menon et al., 2004). In contrast, Weiner et al. (2011) found no evidence of reduced NAA/Cr in Gulf War veterans with Gulf War illness compared with veterans without Gulf War illness using both the CDC and Haley syndrome 2 definitions of Gulf War illness.

Task fMRI activation is a complex measure that reflects changes from the resting (control) state for both local blood flow and brain oxygen extraction in response to mental tasks. Differences in task activation patterns were found in various groups of veterans with Gulf War illness (Calley et al., 2010; Gopinath et al., 2012; Moffet et al., 2015; Rayhan et al., 2013d; Tillman et al., 2010), but altered task fMRI activation properties have been reported in many neurodegenerative, developmental, psychiatric, and other conditions.

Diffusion MRI is a measure of the magnitude and directionality of the diffusion of water in tissue. Intact tissue microstructure (e.g., white matter tracts, cell membranes, cell processes) impedes the ran-

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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dom motion (diffusion) of water to a greater extent than tissue with disrupted microstructure. Diffusion MRI uses two common measures, mean diffusivity (MD) and fractional anisotropy (FA), to determine the integrity of tissue microstructure. MD is a scalar quantity, and the lower the MD value the more intact the tissue microstructure. FA is a vector quantity and the greater the FA value the more intact is the white matter tract myelination. The component measures that contribute to FA (radial vs axial diffusivity) are sometimes analyzed separately; however, detailed modeling studies have called into question the validity of this approach (Wheeler-Kingshott and Cercignani, 2009). Perfusion MRI measures tissue perfusion—that is, the delivery of blood via the microvascular system to tissue. Abnormalities in both diffusion and perfusion MRI are seen in many different neurodegenerative and psychiatric conditions such as those mentioned above. In summary the committee recognizes that some of the imaging findings described could mediate symptoms associated with combat exposure (e.g., medical temporal lobe atrophy and PTSD). However, these MRI modalities are not disease-specific biomarkers in contrast to an imaging modality such as amyloid PET imaging (Clark et al., 2011; Ikonomovic et al., 2008; Klunk et al., 2004), which is specific for β-amyloid deposition in Alzheimer’s disease.

The second limitation to attempting to identify imaging biomarkers for Gulf War illness is that specific environmental exposures were not habitually or reliably documented for every unit or for every veteran while deployed to the Persian Gulf region. To date, no imaging studies have identified a specific neuroimaging finding that might serve as a biomarker of exposure for a particular toxicant relevant to Gulf War illness (e.g., sarin, PB, or N,N-diethyl-meta-toluamide [DEET]). Some imaging studies have sought to identify an imaging signature of stress or of other mental health conditions such as PTSD. Although much work is being done in this area, it would be difficult many years after deployment to be sure that any neuroimaging anomalies were the result of deployment-related or combat-related stress rather than a subsequent stressful situation More importantly, exposure to the stress of combat and putative exposure to environmental toxins are often comingled within study cohorts. This makes cause-and-effect inferences between environmental toxin exposure and specific imaging findings suspect.

The third limitation concerns methodological features of many imaging studies in this area. While structural MRI results are highly reproducible over time, derived MRI metrics (perfusion, diffusion, functional activation) are less so. Furthermore, voxel-based or multiple regions of interest-based analyses using atlases for anatomic labeling of brain regions can result in numerous comparisons in a given analysis. Large samples are needed to avoid statistical errors. Unfortunately, the sample sizes in many studies are small, which undermines the reliability of the results, particularly those for the more “noisy” imaging modalities. Another methodological issue is that participants in imaging studies are selected from larger cohorts. The criteria used to select participants for the imaging studies are rarely mentioned, which raises the question of participation bias. Moreover, participant selection biases likely differ from imaging study to study, thus contributing to interstudy inconsistencies. Because of these limitations, results within and across the neuroimaging studies are often conflicting and not reproducible, thereby calling into question any specific imaging signature or consequence of Gulf War illness.

Bierer et al. (2015) found decreased MD and increased FA in the right (but not left) cingulum bundle in Gulf War veterans with PTSD (n = 12) compared to those without PTSD (n = 8). Decreased MD and increased FA imply greater myelination and thus increased anatomic connectivity between brain areas served by these tracts. Bierer et al. also found that the presence of Gulf War illness in those with PTSD diminished these effects. The authors concluded that Gulf War illness is a distinct entity from PTSD, but unlike PTSD, Gulf War illness is associated with decreased central nervous system plasticity. The difficulty with this interpretation is that the inference about a specific effect of Gulf War illness on diffusion measures was based on comparing nine PTSD subjects with Gulf War illness against three PTSD subjects without Gulf War illness. Much larger samples and evidence of independent replication of results

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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would be needed to draw firm conclusions about pathophysiology. Rayhan and colleagues published a series of papers in 2013 comparing subsets of the same groups of Gulf War veterans with and without Gulf War illness (determined by the Haley criteria). The groups were compared across many regions of interest on measures of diffusion MRI (Rayhan et al., 2013a) and task fMRI (Rayhan et al., 2013c,d). Various associations were found among the different Gulf War illness syndrome groups, but group sizes in some cases were less than 10 subjects. Small sample sizes coupled with failure to correct for multiple comparisons make it difficult to draw any conclusions.

Chao et al. (2015) compared diffusion MRI measures in 59 Gulf War veterans with predicted exposure to sarin/cyclosarin with 59 nonexposed veterans. Although prior research has linked FA changes to documented sarin exposure from the Tokyo subway sarin attack (Yamasue et al., 2007), the authors did not find FA changes in white matter in their predicted sarin-exposed group. They did report increased axial diffusivity among veterans with predicted exposure, but the interpretability of axial/radial diffusivity measures has been called into question (Wheeler-Kingshott and Cercignani, 2009), and Chao et al. (2015) did not correct for multiple comparisons.

Moffet et al. (2015) found fMRI activation differences between Gulf War veterans who met criteria for Haley’s Gulf War illness syndrome 2 compared with controls during a verbal fluency task. The authors infer that the fMRI data provides support for the hypothesis that Gulf War illness syndrome is attributable to unique toxicant exposures during the Gulf War. However, the subjects performed worse on verbal fluency than the controls when the testing occurred outside the scanner. The fMRI findings are not a biomarker for a particular syndrome attributable to toxin exposure but are simply a manifestation of the fact that the control group performed better on verbal fluency tasks than the subject group. The same fMRI result would be expected when any two groups of subjects are compared where one group outperforms the other on the cognitive task of interest. Hubbard et al. (2014) found fMRI activation differences between Gulf War veterans with and without Gulf War illness (Gulf War illness was determined using the Haley criteria). It is noteworthy though that the same research group (Odegard et al., 2013) using a similar functional activation paradigm did not find fMRI differences among the three Gulf War illness syndrome groups.

Chao et al. (2010, 2011) examined brain volume and cognitive performance measures in a group of Gulf War veterans who may have been exposed to sarin or cyclosarin in comparison to matched Gulf War veterans who were not exposed. They found that grey and white matter brain volumes were reduced in the exposed group; however, there was no dose–response relationship between exposure and brain volume (which would be expected if the association were reliable). The exposed group performed worse on some psychometric tests but performed better on other tests. The results overall were inconsistent and do not conclusively support a relationship between exposure and either cognitive performance or reduced brain volumes. Li et al. (2011b) and Liu et al. (2011) published results of cerebral perfusion measured with arterial spin labeling MRI in response to physostigmine challenge in Gulf War veterans who met Haley’s criteria for Gulf War illness syndromes 1, 2, or 3 and controls. Syndrome 2 and 3 subjects displayed reduced physostigmine effect on perfusion compared to controls, but syndrome 1 exhibited an increased physostigmine effect. The results were thus inconsistent among those who met the criteria for Gulf War illness. Moreover, it might be expected that syndromes 1 (impaired cognition) and 2 (confusion-ataxia) would be more similar than 2 and 3 (central neuropathic pain) because 1 and 2 both include impaired mental function, but the opposite was seen.

Other functional modalities in addition to imaging have been used. Tillman et al. (2010, 2012, 2013) assessed functional response by event-related potentials in groups of Gulf War illness syndromes. Various findings were reported, but sample sizes in some of the Gulf War illness syndrome groups were less than 10 subjects.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Summary

The imaging literature generally supports the established concept that MRI findings, such as evidence of brain atrophy, may be associated with chronic stress. But, the literature does not support the conclusion that any type of imaging signature is consistently associated with Gulf War illness, deployment to the Gulf War, or any specific Gulf War exposure. Thus, the committee does not find MRI abnormalities to be a valid biomarker of Gulf War illness.

The committee emphasizes that environmental exposures at the individual veteran level cannot be determined and therefore finds that conducting studies that seek or propose a cause-and-effect relationship between environmental exposures unique to Gulf War veterans (sarin, cyclosarin) and neuroimaging results is not advisable. Any studies of Gulf War veterans that use neuroimaging techniques should be adequately powered and should contain independent replication samples that are also adequately powered. This would help address the current state of the imaging literature, which is characterized by conflicting and nonreplicable results that make it difficult to draw coherent conclusions.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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TABLE 4-11 Neurologic Conditions

Study Design Population Outcomes Results Adjustments Comments
Volumes 4 and 8 Primary Studies
Peripheral Neuropathy and Myopathy
Davis et al., 2004 (Vol. 4) Cross-sectional, prevalence, medical evaluation, exposure-specific component 1,047 GWVs vs 1,121 NDVs; 240 Khamisiyah-exposed GWVs vs 807 non-Khamisiyah-exposed GWVs Distal symmetric polyneuropathy identified by nerve-conduction studya GWVs vs NDVs: OR = 0.65 (95% CI 0.33–1.28); Khamisiyah-exposed GWVs vs non-Khamisiyah-exposed GWVs: OR = 1.04 (95% CI 0.25–4.37) Excludes coexisting conditionsb Low participation rate: 53% in deployed veterans, 39% in nondeployed veterans
Rose et al., 2004; Sharief et al., 2002 (Vol. 4) Case-control 49 symptomatic deployed UK veterans vs 26 healthy deployed UK veterans, 13 symptomatic Bosnia deployed veterans, 22 symptomatic NDVs Nerve-conduction studies, quantitative sensory and autonomic testing, concentric needle and single-fiber, electromyography, ischemic forearm exercise test, subanaerobic bicycle exercise test, muscle biopsy No significant differences between symptomatic deployed and nondeployed veterans, except deployed veterans had increased lactate production in bicycle exercise test
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Study Design Population Outcomes Results Adjustments Comments
Kelsall et al., 2005 (Vol. 8) Cross-sectional survey 1,382 Australian male GWVs, 1,376 male NDVs frequency matched by age and service type (Same study population as Kelsall et al., 2004a,b) Self-reported neurologic symptoms corroborated during neurological examination; SF-12; modified NIS Lower limb neurological type symptoms and signs: OR = 1.6 (95% CI 1.0–2.7) Neuropathy Score: GWV (2.0, sd = 4.3) vs NDVs (2.0, sd = 4.7) RoM = 1.1 (95% CI 0.9–1.3) Association of neurological symptoms in self-reported nonexposed compared to exposed: PB (RoM = 1.5, 95% CI 1.2–1.8) Antibiological warfare tablets (RoM = 1.8, 95% CI 1.3–2.5) Solvents (RoM = 1.8, 95% CI 1.4–2.2) Pesticides (RoM = 1.7, 95% CI 1.4–2.0) Insect repellents (RoM = 1.3, 95% CI 1.1–1.5) No association with self-reports of immunizations or chemical exposure Age, rank, service type, current marital status, highest level of education, alcohol consumption, and history of diabetes Exposure data self-reported; response rate 80.5% for GWVs, 56.8% for NDVs
Amyotrophic Lateral Sclerosis
Horner et al., 2003 (Vol. 4) Retrospective cohort All active, GWVs (1990–1991) compared with NDVs ALS All deployed forces, significant increased risk of ALS (RR = 1.92, 95% CI –1.29–2.84) Age-adjusted average, annual 10-year incidence; attributable risk Case ascertainment through screening of VA and DoD medical databases and benefit files (and TriCare) by ICD-9 code for ALS or riluzole use; extensive recruitment efforts
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Coffman et al., 2005 (Vol. 4) Capture–recapture reanalysis of Horner et al. (2003), cohort See Horner et al., 2003 ALS Found no under-ascertainment of ALS cases among deployed Log-linear models; sample coverage; ecologic models Possible undercounts not likely to substantively affect results
Horner et al., 2008 (Vol. 8) Retrospective cohort, follow-up from 1991–2001 (follow-up of Horner et al., 2003) All active, Gulf War deployed military personnel (n = 696,118), compared with NDVs ALS Deployed (48 cases) vs nondeployed (76 cases), no significant difference in SIR during additional follow-up period Similar percentage of young onset between deployed (69%) and controls (64%) Age-adjusted average, annual 10-year incidence; attributable risk Small number of cases and short follow-up period limit the ability of the study to determine long-term trends
Neurobehavioral and Neurocognitive Studies
David et al., 2002 (Vol. 4) Case-control, clinical evaluations 200 male UK GWVs, 54 Bosnia-deployed, 78 era nondeployed veterans randomly selected from larger cohort of UK veterans who participated in earlier postal survey (see Unwin et al., 1999) WAIS-R scaled scores: Vocabulary, Digit span, Arithmetic, Similarities, Picture arrangement, Block design, Object assembly, Digit symbol, PASAT, Sustained attention to response task, Stroop, Trail-making test, A & B WMS: Logical memory, Verbal paired associates, Camden recognition memory test, Purdue pegboard GWVs had significantly lower scores on five cognitive tests: Digit symbol Trail-making Stroop PASAT Verbal associates After final Bonferroni adjustments for multiple comparisons and BDI, only the results of the Purdue pegboard remained significantly different ANCOVA adjusted for education, age, NART, BDI; multiple comparison adjustment for least significant difference procedure and Bonferroni adjustments Careful treatment of potential confounders, such as depression, mood, intelligence quotient, education, demographics Examiners were blinded
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Study Design Population Outcomes Results Adjustments Comments
Proctor et al., 2003 (Vol. 4) Cross-sectional 143 male Danish GWVs, 72 male NDVs randomly selected from 84% and 58% of total Danish armed forces deployed and nondeployed, respectively, at time of Gulf War WAIS-R Information subscale, continuous performance test, trail making, WCST, Purdue pegboard, WAIS-R block design, CVLT, WMS visual reproductions, TOMM; individually administered tests except in computer-based NES; blinded examiners No overall differences in neuropsychologic domains, significant test differences in domains (p ≤ 0.05) for CVLT and WCST MANCOVA by neuropsychologic domain, adjusted for age Response rate 75%
Storzbach et al., 2001 (Vol. 4) Case-control 239 randomly selected male and female GWVs with symptoms vs 112 deployed with no symptoms; case = one of memory loss, confusion, inability to concentrate, mood swings, somnolence, gastrointestinal distress, fatigue, muscle and joint pain, skin or mucous membrane lesions lasting 1 month or longer, starting during or after service in gulf, and present during 3 months before questionnaire received Symbol digit Serial digit learning ODTP Selective attention test Digit span Simple reaction time BARS computer-based testing system Blinded examiners Cases significantly worse than controls on: Digit span backward Simple reaction time ODTP Errors Latency (including a slow group of 13% of sample with scores > 2 sd slower than control mean latency) PCA showed the slow ODTP (slow case in 1999) were responsible for group differences in neurobehavioral performance; 2 of 354 excluded for possible poor motivation because of excess errors in ODTP ANCOVA, adjusted for age, sex, and AFQT, but effect was small so t-tests were used; Bonferroni correction for multiple comparisons
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Volume 10 Primary Studies
Amyotrophic Lateral Sclerosis
Kasarkis et al., 2009 Cohort study; medical records review All veterans on active duty between 1990–1991 (GWVs = 696,118; NDVs = 1,786,215) 109 ALS/motor neuron disease cases diagnosed 1990–2002 ALS/motor neuron disease verified by medical records, World Federation of Neurology case definition used Disease characteristics abstracted from medical records 43 cases GWVs; 66 cases NDVs by the DMDC records (55 cases deployed; 53 nondeployed by self-report) Age of disease onset, race, site of onset, family history not different by deployment group Median survival time less in deployed cases (40 vs 57 months, HR = 0.62, 95% CI 0.4–0.96) Survival analyses adjusted for age and site of onset Derivative of Horner et al., 2003 (28 additional cases) Active and passive case ascertainment methods used All cases were male Discrepancy between DMDC recorded and self-reported deployment (43 vs 55)
Multiple Sclerosis
Wallin et al., 2014 Cohort study 387 GWV cases and 1,454 NDV cases of MS and clinically isolated syndromes among veterans on active duty 1990–1991 (GWVs = 696,118; NDVs = 1,786,215) MS incidence rates MS diagnosed using 2005 McDonald criteria (McDonald et al., 2001); neuromyelitis diagnosed with Wingerchuk et al., 2006 criteria; other demyelinating disease includes clinically isolated syndromes and possible MS Sarin and cyclosarin exposure provided by DoD Khamisiyah plume modeling Deployment was protective of MS risk and all demyelinating disorders (RR = 0.7, 95% CI 0.6–0.8) Risk associated with Khamisiyah exposure was not significant (RR = 1.1, 95% CI 0.8–1.5; 65 exposed cases) Age, race, sex, or service branch Derivative of Wallin et al., 2012 Explores possibility of healthy warrior/soldier effect on explaining protective effect of seemingly adverse set of exposures
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Study Design Population Outcomes Results Adjustments Comments
Neurobehavioral and Neurocognitive Studies
Ishoy et al., 2004 Cross-sectional; clinical examination in 1997 686 Danish GWVs (83.6% of all deployed); 231 NDVs Physician-administered neuropsychological questionnaire; CATSYS Test System: hand pronation/supination; finger tapping; reaction time; tremor test; and sway test Statistically significant difference between GWVs and NDVs for concentration, headache, balance disturbance or dizziness, abnormal fatigue, and problems sleeping all night CATSYS test system results were not statistically significant between the two groups for 23 of 26 test results (p ≤ 0.05); 3 significant ones represented only small differences Adjusted for age, gender, and occupation 84% participation rate among GWVs, 58% among NDVs

NOTE: AFQT = Armed Forces Qualifying Test; ALS = amyotrophic lateral sclerosis; ANCOVA = analysis of covariance; BARS = Behavioral Assessment and Research System; BDI = Beck Depression Inventory; CATSYS = Coordination Ability Test System; CI = confidence interval; CVLT = California Verbal Learning Test; DMDC = Defense Manpower Data Center; DoD = Department of Defense; GWV = Gulf War veteran; HR = hazard ratio; ICD = International Classification of Diseases; MANCOVA = multivariate analysis of variance; MS = multiple sclerosis; NART = National Adult Reading Test; NDV = nondeployed veteran; NIS = Neuropathy Impairment Score (Mayo Clinic version); ODTP = Oregon Dual Task Procedure; OR = odds ratio; PASAT = Paced Auditory Serial Addition Test; PB = pyridostigmine bromide; PCA = principal components analysis; RR = risk ratio; sd = standard deviation; SF-12 = 12-item Short Form Health Survey; SF-36 = 36-Item Short Form Health Survey; SIR = standardized incidence ratio; TOMM = Test of Memory Malingering; UK = United Kingdom; VA = Department of Veterans Affairs; WAIS-R = Wechsler Adult Intelligence Scale-Revised; WCST = Wisconsin Card Sorting Test; WMS = Wechsler Memory Scale.

aAlthough the study defined distal symmetric polyneuropathy as distal sensory or motor neuropathy identified on basis of neurologic examination, nerve conduction study, or both, the committee defined it by nerve-conduction study alone.

bAlcohol dependence, diabetes mellitus, renal insufficiency, hypothyroidism, AIDS/HIV, collagen vascular disease, and neurotoxic medications.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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RESPIRATORY SYSTEM CONDITIONS

As noted in previous Gulf War and Health reports (IOM 2006b, 2010), respiratory conditions such as asthma, bronchitis, chronic obstructive pulmonary disease (COPD), and various symptoms consistent with respiratory disease, such as wheezing and shortness of breath, have consistently been self-reported more frequently by deployed Gulf War veterans than era veterans. Exposures of concern during deployment include smoke from oil-well fires, high levels of ambient dust, pesticide sprays, and nerve gas exposure. Lung cancer is discussed in the section on cancer. All primary studies of conditions of the respiratory system are summarized in Table 4-12 at the end of this section.

Summary of Volumes 4 and 8

Volume 4 presented five primary studies (Eisen et al., 2005; Gray et al., 1999a; Ishoy et al., 1999b; Karlinsky et al., 2004; Kelsall et al., 2004b) that represented four cohorts from three countries. Those studies examined associations of respiratory outcomes with deployment to the Gulf War region. Outcomes were, in part, determined on the basis of pulmonary function measures or respiratory disease diagnoses. None of those studies reported any positive associations with Gulf War Service. Numerous secondary studies were reviewed that relied on self-reported respiratory symptoms, and the overwhelming majority of these studies found that deployed veterans report higher levels of respiratory symptoms and respiratory illnesses than nondeployed veterans.

The Volume 4 committee also reviewed objective measures of respiratory conditions associated with specific exposures experienced by Gulf war veterans during their deployment. Three studies used the same objective exposure measure and methods to estimate exposure to smoke from oil-well fires, but no associations were detected for doctor-assigned diagnoses of asthma, respiratory health outcomes, and hospitalization for asthma, acute bronchitis, chronic bronchitis, or emphysema. One study (Gray et al., 1999b) found an association between modeled exposure to nerve agents at Khamisiyah and a small increase in postwar hospitalization for respiratory system disease. However, that study had several limitations, including likely exposure misclassification, failure to control for tobacco smoking, lack of a clear dose–response pattern, and there appeared to be little biologic plausibility for effects on the respiratory system. A second study of nerve agent exposure and pulmonary function measures found no association between the two (Karlinsky et al., 2004). The Volume 4 committee noted that, with respect to nerve agents at Khamisiyah, no study that used valid objective estimates of exposure found statistically significant associations with pulmonary function measures or physician-diagnosed respiratory disease.

Based on one additional primary (Smith et al., 2006) and four secondary studies (including one study that assessed Khamisiyah-exposed veterans specifically), the Volume 8 committee also found that studies of Gulf War veterans based on self-reported symptoms and self-reported diagnoses have frequently, but inconsistently, shown an excess of respiratory conditions. However, there appears to be no increase in respiratory disease among Gulf War veterans when examined with objective measures of disease. Pulmonary function studies have shown no significant excess of lung function abnormalities among Gulf War veterans. Therefore, the Volume 8 committee concluded that there was insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and respiratory disease. The committee also concluded that there was limited/suggestive evidence of no association between deployment to the Gulf War and decreased lung function in the first 10 years after the war.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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New Literature

The Volume 10 committee did not identify any new primary studies of Gulf War veterans that assessed respiratory conditions.

Secondary Studies

The Volume 10 committee identified three secondary studies. Sim et al. (2015) reported on the Australian Gulf War Veterans’ Follow Up Health Study, conducted between 2011 and 2013 (this study was a follow-up to the Kelsall et al., 2004b, baseline study discussed in Volumes 4 and 8). This study assessed the entire Australian Gulf War cohort 10 years after the 2000–2002 baseline study and 20 years after the war. Results were adjusted for age, rank category, and service branch, but not for smoking. Of the 1,456 eligible deployed veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans formed the comparison group. Respiratory symptoms were based on self-reports and on self-reports of doctor-diagnosed respiratory symptoms. Deployed veterans were significantly more likely to report morning cough (RR = 1.67, 95% CI 1.26–2.23), wheeze (RR = 1.44, 95% CI 1.15–1.80), morning sputum (RR = 1.38, 95% CI 1.10–1.74), and daytime or nighttime cough (RR = 1.36, 95% CI 1.09–1.70). They were also more likely to report a doctor-diagnosis or treatment for sinus problems (RR = 1.51, 95% CI 1.07–2.15) and pneumonia (RR = 1.87, 95% CI 1.03–3.39). Deployed veterans were also more likely to report, although not significantly so, a doctor-confirmed diagnosis of asthma, chronic bronchitis, emphysema, or COPD.

Li et al. (2011a) conducted a 10-year follow-up survey of U.S. Gulf War deployed (n = 5,469) and nondeployed veterans (n = 3,353) who had also participated in a 1995 VA National Health Survey. Compared with nondeployed veterans, deployed veterans in 2005 were less likely to report the persistence of chronic asthma (RR = 0.76, 95% CI 0.59–0.97), although they did have a nonstatistically significant increased risk of a new onset of it (RR = 1.26, 95% CI 0.94–1.68). The risk ratios were adjusted for age in 2005, gender, race, rank, service branch, service type, BMI, and current cigarette smoking.

Dursa et al. (2016) reported results of the third survey wave of the cross-sectional National Health Study of Persian Gulf War Era Veterans. The wave 3 survey (discussed in greater detail in Chapter 3), conducted in 2012–2013 via mail, website, or a computer-assisted telephone interview, asked 8,104 Gulf War deployed and 6,148 era veterans to indicate whether a doctor had ever told them they had a medical condition and then whether the condition had been present in the previous 4 weeks. There was a statistically significant difference between the deployed and era veterans in self-reports of asthma (10.2% vs 9.0%; OR = 1.22, 95% CI 1.04–1.44) and COPD (8.4% vs 6.3%; OR = 1.48, 95% CI 1.23–1.78). The OR was adjusted for age, race, sex, BMI, smoking status, service branch, and unit component.

Other Related Studies

VA provided a health care use report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories, including diseases of the respiratory system (ICD-9 categories 460–519) (see Table 4-13). A veteran can have multiple diagnoses with each health care encounter, and therefore, may be counted in multiple categories, but the person is counted only once in any single

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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TABLE 4-13 10 Most Frequent Respiratory Disease Diagnoses for Deployed and Nondeployed Gulf War Veterans Seeking Health Care in VA Between 2002 and 2013

Diagnosis Deployed N = 105,481 (%) Nondeployed N = 97,539 (%)
Allergic rhinitis 39.1 39.2
Acute upper respiratory infections of multiple or unspecified sites 28.8 29.6
Chronic sinusitis 22.6 22.6
Asthma 16.7 16.5
Acute bronchitis, bronchiolitis 13.6 13.9
Acute sinusitis 13.6 14.1
Pharyngitis, acute 13.2 13.3
Chronic airway obstruction, not elsewhere classified 12.4 12.6
Bronchitis, not specified as acute or chronic 12.2 12.4
Chronic pharyngitis, nasopharyngitis 8.8 8.8

SOURCES: VA, 2014a,b.

diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period (VA, 2014a,b). These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans.

Conclusions

The three new secondary studies provide mixed results. In the Australian study, there was a significant increase in self-reported respiratory symptoms such as cough in deployed compared with nondeployed Gulf War veterans. However, two of the three studies showed no increase in the risk of asthma or COPD (Li et al., 2011a; Sim et al., 2015); whereas, the VA survey found a slight increase in the risk of asthma and a slightly greater risk of having COPD (Dursa et al., 2016). All of these studies relied on self-reports of diagnoses.

Because the respiratory system is a common portal for exposure, the committee finds that should surveillance of respiratory conditions in Gulf War veterans continue to be conducted, the studies need to adjust for smoking status if the data are to be informative.

Therefore, the Volume 10 committee concludes that there is insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and respiratory disease. The committee concludes that there is limited/suggestive evidence of no association between deployment to the Gulf War and decreased lung function.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

TABLE 4-12 Conditions of the Respiratory System

Study Design Population Outcomes Results Adjustments Comments
Eisen et al., 2005 (Vol. 4) Population-based, cross-sectional, prevalence, medical evaluation 1,061 U.S. GWVs vs 1,128 NDVs Self-reported asthma, bronchitis, or emphysema; obstructive lung disease (history of disease or symptoms plus use of bronchodilators or 15% improvement in FEV1 after bronchodilator use) Asthma, bronchitis, or emphysema: OR = 1.07 (95% CI 0.65–1.77) Obstructive lung disease: OR = 0.91 (95% CI 0.52–1.59) Age, sex, race, years of education, smoking, duty type, service branch, rank Low participation rates, especially among nondeployed
Karlinsky et al., 2004 (Vol. 4) Cross-sectional, medical evaluation 1,036 U.S. GWVs vs 1,103 NDVs PFT results classified into five categories: normal, nonreversible obstruction, reversible obstruction, restrictive, small-airways obstruction No association of PFT-based classifications with deployment status, nor with exposure to nerve agents at Khamisiyah based on 2002 DoD exposure models No adjustment for smoking or other confounders Description of sampling strategy inadequate to evaluate bias; no explanation of “matching†or control of matching in analysis
Gray et al., 1999a (Vol. 4) Cross-sectional, medical evaluation 527 GWVs vs 970 NDVs from 14 U.S. Navy Seabees commands Cough; shortness of breath; FVC (L); FEV1 (L) Cough: OR = 1.8 (95% CI 1.2–2.8) Shortness of breath: OR = 4.0 (95% CI 2.2–7.3) FVC (L): 4.96 vs 4.99, p = 0.77 FEV1 (L): 4.05 vs 4.04, p = 0.81 Age, height, race, smoking status No use of modeled oil-fire exposures
Kelsall et al., 2004b (Vol. 4) Cross-sectional, medical evaluation 1,456 Australian GWVs vs 1588 NDVs Asthma; bronchitis; FEV1/FVC < 70% Asthma: OR = 1.2 (95% CI 0.8–1.8); Bronchitis: OR = 1.9 (95% CI 1.2–3.1); FEV1/FVC < 70%: OR = 0.8 (95% CI 0.5–1.1); FVC, but not FEV1, associated with self-report of oil-well fire exposure Service type, rank, age, education, marital status Generally well done; substantial potential for selection bias (response rates: GWVs 81% vs NDVs 57%); no use of modeled oil-well fire exposures
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×
Ishoy et al., 1999b (Vol. 4) Cross-sectional, population-based, medical evaluation 686 peacekeeping Danish GWVs vs 231 NDVs Shortness of breath; FVC; FEV1; peak flow 14% vs 3.5% Percent of predicted: FVC 100.7 vs 100.7, NS FEV1 95.6 vs 96.4, NS peak flow 94.0 vs 92.8, NS None Appropriate population-based controls but differential participation: 84% deployed vs 58% nondeployed; smoking histories similar in deployed and nondeployed
Smith et al., 2006 (Vol. 8) Hospitalizations cohort study (cohort data from the DMDC) Active-duty personnel with a single deployment to: Gulf War theater (n = 455,465); Southwest Asia peacekeeping mission, 1991–1998 (n = 249,047); Bosnia, 1995–1998 (n = 44,341) Postdeployment hospitalization events (1991–2000) for an ICD-9-CM diagnosis of respiratory disease (140–208) Veterans of Bosnia compared to GWV: HR = 0.73 (95% CI 0.63–0.84) Veterans of Southwest Asia compared to GWV: HR = 1.08 (95% CI 1.00–1.16) Sex, age, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalization; time-dependent covariate to account for changing hospitalization methods, diagnostic criteria, and procedures Active-duty personnel only; hospitalizations at DoD facilities only
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×
Study Design Population Outcomes Results Adjustments Comments
Studies of Respiratory Outcomes Specifically Associated with Modeled Exposure to Oil-Well Fires
Cowan et al., 2002 (Vol. 4) Case-control study of exposure to smoke from oil-well fires; DoD registry, Army only 873 GWVs with asthma vs 2,464 controls Physician-assigned diagnosis of asthma 3–6 years after war Self-reported exposure: OR = 1.56 (95% CI 1.23–1.97) Cumulative modeled exposure: OR = 1.24 (95% CI 1.00–1.55) for intermediate cumulative modeled exposure; OR = 1.40 (95% CI 1.11–1.75) for high exposure Number of days at > 65 μg/m3: OR = 1.22 (95% CI 0.99–1.51) for 1–5 days; OR = 1.41 (95% CI 1.12–1.77) for 6–30 days Sex, age, race, military rank, smoking history, self-reported exposure Effect seen in former smokers and never-smokers, but not current smokers. Modeled exposure rather than only self-reported exposure; however, self-selected population; no specified criteria for asthma diagnosis and no pulmonary function data; pre-exposure asthma status unknown
Lange et al., 2002 (Vol. 4) Cross-sectional study of exposure to smoke from oil-well fires; derived from cohort study 1,560 Iowa veterans Asthma symptoms; bronchitis symptoms; structured interviews conducted 5 years after the war For modeled exposure, ORs for quartiles of exposure, 0.77–1.26 with no dose–response relationship; for self-reported exposure, asthma ORs = 1.77–2.83, bronchitis ORs = 2.14–4.78 Sex, age, race, military rank, smoking history, military service, level of preparedness for war Modeled exposure rather than only self-reported exposure, population-based sample Symptom-based case definition of bronchitis and asthma
Smith et al., 2002 (Vol. 4) DoD hospitalizations 1991–1999; exposure modeling for oil-well fire smoke 405,142 active-duty GWVs ICD-9-CM codes for: Asthma Acute bronchitis Chronic bronchitis Emphysema Respiratory conditions due to chemical fumes and vapors Other respiratory diseases Exposed vs nonexposed: OR = 0.90 (95% CI 0.74–1.10) OR = 1.09 (95% CI 0.62–1.90) OR = 0.78 (95% CI 0.38–1.57) OR = 1.36 (95% CI 0.62–2.98) OR = 0.71 (95% CI 0.23–2.17) OR = 1.45 (95% CI 0.86–2.46) “Influential predictors†of p < 0.15 included in analyses Objective measure of disease not subject to recall bias; no issues with self-selection; however, only DoD hospitals, only active duty, no information on smoking or other confounders related to respiratory symptoms Asthma and chronic bronchitis do not often require hospitalization
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×
Study of Respiratory Outcomes Specifically Associated with Exposure to Khamisiyah Nerve Agent
Gray et al., 1999b (Vol. 4) DoD hospitalizations 1991–1995, exposure to nerve agents at Khamisiyah based on 1997 DoD exposure models Not exposed (n = 224,804), uncertain low-dose exposure (n = 75,717), exposed (n = 48,770) Respiratory system disease (vs not exposed): Uncertain low dose < 0.013 mg-min/m3 0.013–0.097 mg-min/m3 0.097–0.514 mg-min/m3 OR = 0.92 (95% CI 0.85–0.99) OR = 0.90 (95% CI 0.77–1.04) OR = 0.89 (95% CI 0.79–1.02) OR = 1.26 (95% CI 1.05–1.51) Sex, age group, prewar hospitalization, race, service type, marital status, pay grade, occupation Probable substantial exposure misclassification as models were revised, lack of a clear dose–response pattern, little biologic plausibility given that no effect was seen for nervous system conditions

NOTE: CI = confidence interval; DMDC = Defense Manpower Data Center; DoD = Department of Defense; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; GWV = Gulf War veteran; HR = hazard ratio; ICD = International Classification of Diseases; MRR = mortality rate ratio; NS = not significant; OR = odds ratio; PFT = pulmonary function test; UK = United Kingdom; U.S. = United States.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

GASTROINTESTINAL SYSTEM CONDITIONS

Digestive disorders may be functional, structural, or in some cases combinations of both (see Gulf War and Health, Volume 6, for a description of functional and structural digestive disorders). The functional gastrointestinal (GI) disorders, such as irritable bowel syndrome (IBS) or functional dyspepsia, are conditions without pathology or clear structural change—that is, recurrent or prolonged clusters of symptoms that occur together. GI conditions, sometimes called “organic” or structural conditions, such as peptic ulcer and inflammatory bowel disease (that is, ulcerative colitis and Crohn’s disease), are characterized by morphological abnormalities seen on X-ray, endoscopy, or through laboratory tests. All primary studies for conditions of the gastrointestinal system are summarized in Table 4-14 at the end of this section.

Summary of Volumes 4 and 8

The Volume 4 committee reviewed three primary studies of digestive system disorders, two of which analyzed hospitalization data. In one report (Eisen et al., 2005), dyspepsia was diagnosed on the basis of in-person interviews and was statistically significantly associated with deployment; however, the Volume 8 committee noted that some cases of dyspepsia may have been misdiagnosed given the terminology used by the authors. One study by Gray et al. (1996) found no excess hospitalizations for conditions of the digestive system for deployed or nondeployed veterans, although in a later study they found an increase in hospitalizations for digestive system conditions at VA hospitals but not in other hospital systems for deployed vs nondeployed veterans (Gray et al., 2000). Two secondary studies showed that deployed veterans more frequently reported gastrointestinal symptoms than nondeployed veterans (Ishoy et al., 1999a,b; Sostek et al., 1996). The Volume 4 committee noted that gastrointestinal disturbances in Gulf War deployed veterans seem to be linked to contaminated water and burning of animal waste.

The Volume 8 committee found in numerous studies that Gulf War veterans self-reported more GI symptoms than nondeployed veterans (Kang et al., 2000; Kelsall et al., 2004a; Proctor et al., 1998; Simmons et al., 2004; Sostek et al., 1996; Unwin et al., 1999). The primary study by Sostek et al. (1996) used survey questions that were highly specific for functional GI disorders and that met the Rome III criteria for IBS. The study found statistically significant increases in the reporting of symptoms consistent with IBS and other functional GI disorders in deployed veterans compared with nondeployed veterans. All of the secondary studies identified by the committee found that deployed veterans reported more GI symptoms than their nondeployed counterparts, but the studies were limited because their methods are insufficient to determine a clear association between deployment and the onset of a functional disorder—diagnosed by standard Rome criteria—or of a structural disorder. The committee noted that the diagnosis of structural GI conditions should be validated by medical records because physicians may place an organic label on a patient’s symptoms (e.g., gastritis or peptic ulcer) without performing the necessary diagnostic studies.

The Volume 8 committee found limitations in the epidemiologic body of evidence for GI disorders, mostly related to methods of effect assessment. These limitations included self-reporting of GI symptoms that did not fulfill the criteria for diagnosing a functional GI disorder; inability to determine the degree to which the gastrointestinal symptoms are specific to IBS and other functional GI disorders, or are part of a larger spectrum of illness (specifically, Gulf War illness); lack of determination of the presence of medical and psychosocial comorbidities; and a lack of adequate medical diagnostic testing to identify a GI structural disease. Nevertheless, taken together, the Volume 8 committee found that the overall pattern of symptoms reported in the few primary and numerous secondary studies confirmed

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

an association between deployment to the Gulf War and functional GI symptoms, including abdominal pain, diarrhea, nausea, and vomiting, and a few studies exist that provide presumptive data to allow standardized diagnosis of functional GI disorders. These studies were strengthened by physiologic and mechanistic data for veterans with IBS, with particular reference to new evidence for preexisting acute gastroenteritis as a predictive factor in postinfectious IBS and dyspepsia. The Volume 8 committee recommended that further studies be conducted to determine the role of prior acute gastroenteritis among deployed service members in the development of functional GI disorders. Therefore, the Volume 8 committee concluded that there was sufficient evidence for an association between deployment to the Gulf War and GI symptoms consistent with functional GI disorders such as IBS and functional dyspepsia. The committee also concluded that there was inadequate/insufficient evidence to determine whether an association exists between deployment to a war zone and the development of structural GI conditions.

New Literature

The Volume 10 committee did not identify any new studies that met its criteria for a primary study. One study of Australian veterans and preliminary results on VA’s follow-up survey of U.S. Gulf War veterans were considered to be secondary studies.

Secondary Studies

Sim et al. (2015) conducted the Australian Gulf War Veterans’ Follow Up Health Study between 2011 and 2013 to assess the entire Australian Gulf War cohort 10 years after the 2000–2002 baseline study and 20 years after the war. Results were adjusted for age, rank category, and service branch, but not for smoking. Of the 1,456 eligible deployed veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans made up the comparison group. The prevalence of GI conditions was based on self-reports and on self-reports of doctor-diagnosed conditions. There were no statistically significant differences in reporting of doctor-diagnosed GI conditions. More deployed than nondeployed veterans reported having polyps in the bowel (RR = 1.34, 95% CI 0.96–1.88). There were statistically significantly more deployed veterans who met the Rome III criteria for IBS based on self-reported symptoms than nondeployed veterans (13% vs 8%; RR = 1.64, 95% CI 1.18–2.27).

The committee also considered the results from Dursa et al. (2016) on the third wave of the National Health Study of Persian Gulf War Era Veterans The wave 3 survey (discussed in greater detail in Chapter 3), conducted in 2012–2013 via mail, website, or a computer-assisted telephone interview, asked 8,104 deployed and 6,148 Gulf War era veterans to indicate whether a doctor had ever told them they had a medical condition and then whether the condition had been present in the previous 4 weeks. There were statistically significant differences between the deployed and era veterans in the weighted prevalence of self-reports of IBS (24.4% vs 14.3%; OR = 2.1, 95% CI 1.79–2.45), gastritis (20.2% vs 14.3%; OR = 1.59, 95% CI 1.35–1.73), and functional dyspepsia based on the ROME criteria (27.7% vs 15.9%; OR = 1.94, 95% CI 1.75–2.17). The ORs were adjusted for age, race, sex, BMI, smoking status, service branch, and unit component. Self-reports of hepatitis and cirrhosis were also included in the survey, but the odds of either condition were not statistically different between deployed and era veterans (Dursa et al., 2016).

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

TABLE 4-15 10 Most Frequent Diagnoses of Diseases of the Digestive System for Deployed and Nondeployed Gulf War Veterans Seeking Health Care in VA Between 2002 and 2013

Diagnosis Deployed N = 127,786 (%) Nondeployed N = 117,565 (%)
Diseases of esophagus 50.4 49.1
Other diseases of the teeth, supporting structures 32.3 33.0
Diseases of hard tissues of teeth 28.1 28.5
Gingival and periodontal diseases 25.6 26.2
Functional digestive disorders, not elsewhere classified 15.7 13.8
Other hernia of abdominal cavity without obstruction or gangrene 10.4 9.8
Other disorders of intestine 10 9.8
Gastrointestinal hemorrhage 9.5 9.2
Diverticula of intestine 8.8 10.1
Diseases of pulp, periapical tissues 7.9 8.0

SOURCES: VA, 2014a,b.

Other Related Studies

VA provided a health care use report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories, including diseases of the digestive system (ICD-9 categories 520–579) (see Table 4-15). A veteran can have multiple diagnoses with each health care encounter, and therefore, may be counted in multiple categories, but the person is counted only once in any single diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period (VA, 2014a,b). These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans.

In another analysis of the second wave of VA’s National Health Survey of Gulf War Veterans, Coughlin and colleagues (2011a) found that among 6,111 Gulf War deployed and 3,859 era veterans, deployed veterans, regardless of their weight status (underweight, normal weight, overweight, or obese), self-reported more physician-diagnosed cirrhosis of the liver, hepatitis, and gastritis than nondeployed veterans. No information was provided on diet or physical activity. Further assessment of these veterans found that self-reported GI outcomes were more prevalent in both deployed and nondeployed veterans with problem drinking. Unadjusted percentages of veterans reporting cirrhosis, hepatitis, and gastritis are presented in Table 4-16 (Coughlin et al., 2011b). Problem drinking was determined based on affirmative answers to questions about problem or hazardous drinking in the previous 6 months. No modeling or statistical testing was reported pertaining to these outcomes.

TABLE 4-16 Unadjusted Percentages of Self-Reported Physician-Diagnosed Outcomes Reported in Deployed vs Nondeployed Gulf War Veterans

Without Problem Drinking Problem Drinking
Cirrhosis of the liver 8.1% vs 6.3% 9.9% vs 6.9%
Hepatitis 10.4% vs 8.9% 13.3% vs 9.8%
Gastritis 26.8% vs 17.6% 30.3% vs 21.7%

SOURCE: Coughlin et al., 2011b.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

Conclusions

The Volume 8 committee found there was sufficient evidence for an association between deployment to the Gulf War and gastrointestinal symptoms consistent with functional GI disorders such as IBS and functional dyspepsia. Two new secondary studies provide additional support for this conclusion by reporting increased rates of IBS among deployed veterans; however, they are based on self-reported information.

The Volume 8 committee also concluded that there was inadequate/insufficient evidence to determine whether an association exists between deployment to a war zone and the development of structural gastrointestinal conditions. Little new literature was available to assess the risks of structural gastrointestinal disease, but the literature did not suggest increased risks among deployed veterans. The committee finds that given the aging of the population of Gulf War veterans and the unlikelihood that new gastrointestinal conditions will develop 25 years after the Gulf war that are attributable to their Gulf War service, it is doubtful that further assessments will show increased risk of these conditions.

Therefore, the Volume 10 committee concludes that there is sufficient evidence for an association between deployment to the Gulf War and gastrointestinal symptoms consistent with functional gastrointestinal disorders such as IBS and functional dyspepsia.

The committee also concludes that there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and the development of structural gastrointestinal conditions.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

TABLE 4-14 Conditions of the Gastrointestinal System

Study Study Design Population Outcomes Results Adjustments Comments
Eisen et al., 2005 (Vol. 4) Cross-sectional, prevalence 1,061 GWVs vs 1,128 NDVs Physician evaluation, questionnaire for dyspepsia; GI symptoms and medical conditions reported from earlier survey Dyspepsia (OR = 1.87, 95% CI 1.16–2.99); self-reported gastritis (OR = 1.57, 95% CI 0.88–2.78) Age, sex, race, smoking, duty type, service branch, rank, years of education Limited by low participation rate, length of time since war; weak diagnostic criteria
Gray et al., 1996 (Vol. 4) Retrospective cohort study (hospitalization records) DoD hospitals: 547,076 GWVs, 618,335 NDVs Digestive system diseases All ORs < 1.0 Hospitalization rates and rate ratios adjusted for age, sex; multiple logistic-regression models adjusted for all observed demographic differences between groups Data reflect only hospitalization experience of persons who remained on active duty through September 1993
Gray et al., 2000 (Vol. 4) Retrospective cohort study (hospitalization records) 652,979 GWVs (August 1990–July 1992) and 652,922 NDVs, stratified by California residence, service, and service branch of all 2,912,737 NDVs Digestive system diseases VA hospitals: PMR = 1.12 (95% CI 1.05–1.18); DoD hospitals: PMR = 0.98 (95% CI 0.96–0.99); COSHPD hospitals: PMR = 1.11 (95% CI 0.97–1.24) Hospitalization records were matched on sex, age Findings might be influenced by chance or by potential confounders, including health registry participation
Sosteck et al., 1996 (Vol. 8) Cross-sectional, prevalence 57 male GWVs, 44 NDVs of National Guard unit Questionnaire about GI and non-GI symptoms with recall before, during, and after Gulf War period Prevalence of GI symptoms: abdominal pain 70% vs 9%; diarrhea 74% vs 18%; incomplete rectal evacuation 60% vs 7%; gas 74% vs 23%; decreased appetite 42% vs 7% (all p < 0.001) Response rate 74%; limited by small sample (recall before, during, after Gulf War), questionnaire (at time of assessment)
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×
Study Study Design Population Outcomes Results Adjustments Comments
Gray et al., 2002 (Vol. 8) Retrospective, case-control U.S. Navy Seabees: 3,831 GWVs, 4,933 veterans deployed elsewhere, 3,104 NDVs Self-reported physician diagnoses, self-reported symptoms from postal questionnaire Gulf War Seabees vs NDVs: self-reported peptic ulcer disease (OR = 3.11, 95% CI 1.67–5.78); self-reported IBS (OR = 3.57, 95% CI 2.22–5.73); new GI disease diagnosed since September 1990 (OR = 2.10, 95% CI 1.39–3.17); clustering of CFS, PTSD, MCS, IBS: Seabees who had one averaged 13–18 other symptoms; Seabees without one averaged only 6 other symptoms Age, sex, active-duty or reserve status, race or ethnicity, current smoking, current alcohol drinking Study limited by recall bias, IBS not analyzed exclusively, response rate 70%, large sample

NOTE: CFS = chronic fatigue syndrome; CI = confidence interval, COSHPD = California Office of Statewide Health Planning and Development; DoD = Department of Defense; GI = gastrointestinal; GWV = Gulf War veteran; IBS = irritable bowel syndrome; MCS = multiple chemical sensitivity; NDV = nondeployed veteran; OR = odds ratio; PMR = proportional morbidity ratio; PTSD = posttraumatic stress disorder; U.S. = United States.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

CHRONIC SKIN CONDITIONS

Skin conditions are among the most frequent health problems reported by Gulf War veterans. Rash usually refers to dermatitis, an umbrella term covering several subtypes, including atopic dermatitis, contact dermatitis, seborrheic dermatitis, and psoriasis. All primary studies for chronic skin conditions are summarized in Table 4-17 at the end of this section.

Summary of Volumes 4 and 8

On the basis of two primary (Eisen et al., 2005; Higgins et al., 2002) and two secondary studies (Kang et al., 2000; Proctor et al., 1998) of dermatologic conditions, the Volume 4 committee determined that unrelated skin conditions occur more frequently among Gulf War deployed veterans compared with nondeployed veterans, but the findings were not consistent among studies. The Volume 4 committee noted that there is some evidence in deployed veterans of a higher prevalence of two distinct dermatologic conditions—atopic dermatitis and warts.

The Volume 8 committee identified an additional primary study (Ishoy et al., 1999b) that reported significantly greater rates of eczema; retarded wound healing; other skin problems; hair loss or hair disease; and sweaty, clammy, or damp hands in deployed Danish veterans than nondeployed veterans based on medical examination. However, there were no significant differences in the prevalence of psoriasis or nettle rash between deployed and nondeployed troops. Although the examination process used to verify the veteran’s actual skin conditions at the time of the interview by the physician is somewhat unclear in the report, the use of a physician to discuss the veterans’ responses to the questionnaire provided added validity to the study.

Secondary studies were largely consistent with the primary studies, but they lacked specificity regarding dermatologic outcomes or relied only on self-reported symptoms or self-reports of physician-diagnosed dermatologic conditions. Several large cohort studies reported similar findings in Gulf War veterans based on self-reported data collected by questionnaires. These results reflect higher rates of rash and skin irritation; dermatitis; and skin conditions other than dermatitis, skin cancer, eczema, or psoriasis among Gulf War veterans than control groups (Kelsall et al., 2004a; Proctor et al., 1998; Unwin et al., 1999). Additional secondary studies that relied on long lists of self-reported symptoms indicated that the prevalence of generally nonspecified skin conditions or conditions in deployed Gulf War veterans was greater than in nondeployed veterans including skin allergies or other skin conditions, sweating, itching skin, hair loss, boils, or abscesses; physician-diagnosed or treated skin conditions other than skin cancer; moderate or multiple skin symptoms; eczema; skin allergies; and dermatitis (Cherry et al., 2001a; Goss Gilroy Inc., 1998; Gray et al., 1999a; Kang et al., 2000; Proctor et al., 2001a; Simmons et al., 2004; Steele, 2000; Wolfe et al., 1998).

In summary, the Volume 8 committee found a high frequency of self-reports of various types of rash and other skin conditions among deployed vs nondeployed veterans, and, in general, these reports were confirmed by dermatologic examination. Overall, very few studies rigorously assessed the prevalence of skin conditions in Gulf War veterans, and results are mixed, with increases for some skin conditions but not for others. Furthermore, there was no consistency across these studies, which suggests that the findings could have occurred by chance. Finally, most of the studies are weak in design and limited by self-selection and possible reporting bias. The Volume 8 committee concluded that there was insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and skin disorders.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

New Literature

New literature pertaining to skin conditions in Gulf War veterans includes two secondary studies, and one other related study. The committee did not identify any new primary studies.

Secondary Study

Sim et al. (2015) conducted the Australian Gulf War Veterans’ Follow Up Health Study between 2011 and 2013 to assess the entire Australian Gulf War cohort 10 years after the 2000–2002 baseline study and 20 years after the war. Results were adjusted for age, rank category, and service branch, but not for smoking. Of the 1,456 eligible deployed veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans made up the comparison group. Skin conditions were based on self-reports and on self-reports of doctor diagnoses. Statistically significantly more deployed veterans reported having dermatitis (RR = 2.21, 95% CI 1.35–3.59) and eczema (RR = 2.84, 95% CI 1.43–5.65) than nondeployed veterans. There was no significant difference in reporting of doctor-diagnosed psoriasis (RR = 1.11, 95% CI 0.66–1.85).

Dursa et al. (2016) published on the most recent results of the third survey wave of the cross-sectional National Health Study of Persian Gulf War Era Veterans. The wave 3 survey (discussed in greater detail in Chapter 3), conducted in 2012–2013, asked 8,104 deployed and 6,148 Gulf War era veterans to indicate whether a doctor had ever told them they had dermatitis. The weighted prevalence was 27.4% and 21.1% in the deployed and era veterans, respectively, and the odds of dermatitis were statistically significantly increased in the deployed compared with the era veterans (OR = 1.44, 95% CI 1.27–1.63).

Other Related Studies

VA provided a health care use report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories, including diseases of skin (ICD-9 categories 680–709) (see Table 4-18). A veteran can have multiple diagnoses with each health care encounter, and therefore, may

TABLE 4-18 10 Most Frequent Diagnosed Skin Diseases for Deployed and Nondeployed Gulf War Veterans Seeking Health Care in VA Between 2002 and 2013

Diagnosis Deployed N = 88,012 (%) Nondeployed N = 80,617 (%)
Contact dermatitis, other eczema 31.8 29.7
Other disorders of skin, subcutaneous tissue 21.4 22.0
Diseases of sebaceous glands 20.7 20.9
Other cellulitis, abscess 19.0 18.5
Other dermatoses 14.4 17.9
Other hypertropic, atrophic conditions of skin 12.7 13.7
Diseases of hair, hair follicles 11.5 10.6
Diseases of nails 9.5 10.8
Pruritus, related conditions 7.5 7.5
Corns and callosities 7.4 8.5

SOURCES: VA, 2014a,b.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

be counted in multiple categories, but the person is counted only once in any single diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period (VA, 2014a,b). These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans.

Conclusions

Both the Volume 4 and Volume 8 committees noted a high frequency of self-reports of various types of skin conditions among deployed vs nondeployed veterans, but the specific skin conditions found were not consistent across the studies. For the most part, the studies, while occasionally using a dermatologic examination to confirm the skin conditions, did not include adequate assessment of the skin conditions. In Volume 10, the one new secondary study further suggested that while self-reports of some skin conditions such as dermatitis and eczema are more prevalent in deployed Gulf War veterans, others such as psoriasis are not. The committee finds that given the aging of the population of Gulf War veterans and the unlikelihood that new chronic skin conditions will develop 25 years after the Gulf war that are attributable to their Gulf War service, it is doubtful that further assessments will show increased risk of these conditions.

Therefore, the Volume 10 committee concludes that there is insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and skin conditions.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

TABLE 4-17 Chronic Skin Conditions

Study Design Population Outcomes Results Adjustments Comments
Eisen et al., 2005 (Vol. 4) Population-based, cross-sectional, prevalence, medical evaluation 1,061 U.S. GWVs and 1,128 NDVs Atopic dermatitis and verruca vulgaris (warts) Atopic dermatitis: 1.2% vs 0.3% (OR = 8.1, 95% CI 2.4–27.7); verruca vulgaris (warts): 1.6% vs 0.6% (OR = 4.02, 95% CI 1.28–12.6) Age, sex, race, years of education, smoking, duty type, service branch, rank Low participation rates, especially among nondeployed
Higgins et al., 2002 (Vol. 4) Prospective case-comparison study 111 disabled and 98 nondisabled UK GWVs; 133 disabled NDV controls (54 deployed to Bosnia and 79 nondeployed era controls) (population randomly sampled from Ismail et al., 2002, cohort) Skin conditions No significant difference in prevalence of all skin conditions combined: Disabled GWVs: 47.7% Nondisabled GWVs: 36.7% Disabled NDVs: 42.8% Sebhorrheic dermatitis: 8.1% in disabled deployed vs 2.3% in disabled nondeployed (p = 0.06) Age, sex, rank, smoking, and alcohol Response rates: Disabled GWVs: 67% Nondisabled GWVs: 62% Disabled Bosnia: 55% Disabled NDVs: 43%
Ishoy et al., 1999b (Vol. 8) Cross-sectional, prevalence 686 Danish GWV peacekeepers deployed to gulf in 1990–1997 vs 231 age- and sex-matched NDVs Health examination by physician, self-report questionnaire Prevalence of skin conditions with onset after gulf: eczema 15.0% vs 3.0%, p < 0.001; retarded wound healing 6.0% vs 1.7%, p < 0.01; other forms of skin problems 17.1% vs 5.2%, p < 0.001; hair loss or hair disease 4.2% vs 0.9%, p < 0.01; sweaty, clammy, or damp hands 7.9% vs 3.9%, p < 0.05 Lack of information on adjustment for confounders in multivariate analysis Participation rate 83.6% deployed, 57.8% nondeployed

NOTE: CI = confidence interval; GWV = Gulf War veteran; NDV = nondeployed veteran; OR = odds ratio; UK = United Kingdom; U.S. = United States.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

PAIN-RELATED CONDITIONS

This section discusses health conditions that are hard to diagnose and that are typically manifest with multiple symptoms including chronic fatigue, headaches, and muscle and joint pain. These conditions are also associated with impairment of function and increased use of health care. Diagnostic criteria for CFS, fibromyalgia, and rheumatic disorders such as rheumatoid arthritis and osteoarthritis are distinct, but the conditions have overlapping symptoms and in some cases may be difficult to distinguish from each other and from related conditions such as chronic widespread pain (CWP) and Gulf War illness, which are seen in many Gulf War veterans.

In 2010, the American College of Rheumatology (ACR) published new diagnostic criteria for fibromyalgia that updated the 1990 criteria to revise the distribution and intensity of symptoms as essential elements of the diagnosis. The new criteria removed the requirement for a clinician rating and rely solely on subjective information from the patient. The result may be that more people will be diagnosed with fibromyalgia. The new criteria may also shift the demographic profile of people with fibromyalgia to include more men (Bennet et al., 2014), which would significantly affect the rate of fibromyalgia observed in a population of mostly men, such as Gulf War veterans. While all the studies in this report that assessed fibromyalgia used the 1990 criteria, new studies may show different trends or associations based on the new criteria. Additionally, exclusive reliance on self-report in the most recently revised criteria for fibromyalgia contrasts with the importance that this committee assigned to studies based on objective outcomes. It will be important to consider the two sets of criteria if the prevalence of fibromyalgia using the new criteria is compared with studies using the old criteria.

CFS, also known as myalgic encephalomyelitis, was recently assessed by another IOM committee (IOM, 2015). That committee proposed new diagnostic criteria and a new name for the condition, systemic exertion intolerance disease (SEID). The new criteria were based on a systematic review of the evidence. It is not clear what effect the new definition will have on future epidemiologic studies; the studies reviewed in this chapter did not adopt the new name nor use the new diagnostic criteria. In Volumes 4 and 8, pain-related conditions were considered as separate entities as there was considerable literature on each in Gulf War veterans. However, for this volume, there is little new scientific information on the prevalence of these conditions in Gulf War veterans. Many of the studies look at more than one condition. Therefore, this committee has chosen to assess the literature on these conditions in one section to highlight the differences and overlap in the new data. All primary studies of pain-related conditions are summarized in Table 4-19 at the end of this section.

Summary of Volumes 4 and 8

In Volume 4, CFS and fibromyalgia were considered in separate sections as were conditions of the musculoskeletal system such as arthritis and arthralgia. Chronic pain was considered in the section on symptoms, signs, and abnormal laboratory findings (ICD-10 R00–R99). In volume 8, CFS was discussed in the section on multisymptom illnesses and there were separate sections on fibromyalgia and CWP, and on musculoskeletal conditions.

Chronic Fatigue Syndrome

The CDC case definition for CFS requires fatigue and related impairment in function, and the occurrence of four of eight other defining symptoms for at least 6 months (Fukuda et al., 1994). Of the eight symptoms, the most commonly reported are headaches, postexertional malaise, impaired cognition, and

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

muscle pain (Buchwald and Garrity, 1994). This definition is widely used by researchers, although some studies describe a “CFS-like” syndrome. The Volume 4 and Volume 8 committees considered a primary study for CFS to be one in which CFS had been diagnosed according to the CDC criteria and a secondary study to be one in which a CFS-like condition was documented. Self-reports of CFS or self-reports of a physician’s diagnosis of CFS were not included among the primary studies because such self-reports are frequently inaccurate. Neither committee included studies that lacked a control group; estimated the prevalence of symptoms of “chronic fatigue” or multisymptom illness; or used scalar measures of disability and poor quality of life related to health as surrogates for the CDC criteria.

The Volume 4 committee reviewed one primary and four secondary studies and noted that because the diagnosis of CFS depends entirely on symptoms, not on physical or laboratory findings, the prevalence was variable from study to study. The one primary study (Eisen et al., 2005) demonstrated a higher prevalence of CFS in deployed vs nondeployed veterans (1.6% vs 0.1%; OR = 40.6, 95% CI 10.2–161.15). All the secondary studies (Goss Gilroy Inc., 1998; Iowa Persian Gulf Study Group, 1997; Kang et al., 2003; Proctor et al., 2001b) also showed a higher prevalence of CFS or CFS-like illnesses among veterans deployed to the Persian Gulf than among their nondeployed or deployed elsewhere counterparts.

The Volume 8 committee identified two new primary studies (Ismail et al., 2008; Kelsall et al., 2006) and one new secondary study (Lucas et al., 2007). One study in Australian Gulf War veterans showed that CFS and complaints of unexplained chronic fatigue were increased in deployed vs nondeployed veterans (CFS OR = 1.2, 95% CI 0.5–2.9; chronic fatigue lasting more than 6 months OR = 1.9, 95% CI 1.4–2.7) (Kelsall et al., 2006). CFS was also more prevalent in disabled Gulf War veterans from the United Kingdom compared with either nondeployed or deployed elsewhere veterans who had similar levels of disability (OR 7.8, 95% CI 2.5–24.5) (Ismail et al., 2008).

CFS and complaints of unexplained chronic fatigue appear to be increased in deployed Gulf War veterans compared to contemporaneous cohorts (either nondeployed or deployed elsewhere). Those results were also observed in several cross-sectional population-based studies that used self-reports to define CFS or chronic fatigue. However, the absolute prevalence of these symptoms varied considerably from study to study. Associations between fatigue, subjective neurological symptoms, and exposures were also based entirely on retrospective self-reports. Therefore, the Volume 8 committee concluded that there was sufficient evidence for an association between deployment to the Gulf War and CFS.

Fibromyalgia and Chronic Widespread Pain

Fibromyalgia is characterized by widespread muscle and skeletal pain in combination with point tenderness at numerous soft tissue sites. Although a diagnosis of fibromyalgia cannot be confirmed through pathologic or laboratory tests, the ACR (Wolfe et al., 1990) established diagnostic criteria for clinical examinations.5 The case definition requires both widespread pain (pain on both sides of the body, above and below the waist, and including axial skeletal pain) lasting for at least 3 months and pain (not just tenderness) in at least 11 of 18 tender point sites on palpation with an approximate force of 4 kg. Other symptoms of fibromyalgia include fatigue, sleep disturbance, morning stiffness, and cognitive impairment, but those are not sensitive and specific enough to use for classification; fibromyalgia may be considered to be a subset of CWP (Wolfe et al., 1990). The disorder is chronic and varies in intensity (Wolfe et al., 1997). It has been estimated that the prevalence of fibromyalgia in the general U.S. population is about 3% in women and about 0.5% in men, and its prevalence increases with age (Wolfe et al., 1995).

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5 In 2013, the ACR revised the criteria for fibromyalgia. However, no studies reviewed in this section use the revised criteria.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

Among the pain-related disorders, none of the studies reviewed by the current and past Gulf War and Health committees have used the recently changed diagnostic criteria of fibromyalgia that base diagnosis on self-report (Bennett, 2014). These new criteria would likely have the effect of changing the inclusion criteria for fibromyalgia. This change in diagnostic criteria may also increase the diagnosis in males and therefore may increase the proportion of Gulf War veterans meeting criteria for fibromyalgia. Despite the recent change in the diagnostic criteria for fibromyalgia, the complete reliance on self-report may change the results and interpretive value of investigative studies, thus future researchers will have to weigh this in their planning.

The ACR defines CWP as “the presence of pain above and below the waist, or on both the left and right sides of the body, for 3 months or longer.” Prior studies have reported CWP prevalence rates between 11% and 13% in Germany, Sweden, the United Kingdom, and the United States. Several studies have reviewed the presence of chronic pain in Gulf War veterans, but its definition varies by study. Many studies of Gulf War veterans reported increased pain symptoms that could be clustered into CWP, but the terminology used in the studies is not consistent and includes joint pain and general aches and pain; these pain clusters may or may not meet the ACR criteria for CWP. The committee required that primary studies include a physical examination and not rely solely on symptom reporting by patients.

In Volume 4, only one study used the full ACR case definition of fibromyalgia (Eisen et al., 2005), including criteria based on physical examination and found significantly more deployed Gulf War veterans than nondeployed veterans diagnosed with fibromyalgia (OR = 2.32, 95% CI 1.02–5.27). However, another study based on hospitalizations for fibromyalgia assessment found no association between Gulf War deployment and hospitalization for fibromyalgia in active-duty service members. These findings are consistent with other study findings because few cases of fibromyalgia are severe enough to warrant hospitalization. In two large, but secondary, cohort studies, deployed veterans reported significantly increased fibromyalgia symptoms compared with nondeployed veterans but those findings are of limited value as the studies did not include physical examinations. The Volume 4 committee concluded that there was a higher prevalence of fibromyalgia among deployed than nondeployed Gulf War veterans.

The Volume 8 committee reviewed one primary study (Ang et al., 2006) and three secondary studies on Gulf War deployment and CWP. Although each of the studies found a higher prevalence of CWP in deployed than in nondeployed veterans, all of them had considerable limitations. The primary study that looked specifically at CWP was a large random sample of veterans who reported significantly more bodily pain than did nondeployed veterans; a 10-year follow-up study of a subset of these veterans who had not met the classification criteria for CWP at 5 years after the war, found that the prevalence of CWP at 10 years after the war had increased both with combat exposure and with perception of life stress at the time of deployment. Three secondary studies indicated that pain symptoms were reported more frequently in deployed than nondeployed veterans. The Volume 8 committee concluded that there was limited but suggestive evidence of an association between deployment to the Gulf War and both fibromyalgia and chronic widespread pain.

Conditions of the Musculoskeletal System

Arthritis is the most common form of joint disease and is generally related to major trauma, repetitive joint use, heavy manual material handling, and age. Arthralgia, which is a self-reported symptom of arthritis, refers to painful joints. In the absence of other clinical features and radiographic findings, arthralgias are not necessarily diagnostic of arthritis.

The Volume 4 committee found that in the one primary and two secondary studies that examined these outcomes, there was no statistically significant difference in arthralgias for the deployed vs nondeployed Gulf War veterans who underwent a medical examination. The primary study by Eisen

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

et al. (2005) found a nonsignificant increased risk arthralgias in deployed veterans (OR = 1.5, 95% CI 0.70–1.89). The secondary studies also indicated that self-reports of arthritis was more common among those deployed to the gulf.

The Volume 8 committee identified five new primary studies that looked at hospitalization discharge diagnoses of some form of musculoskeletal disease in Gulf War veterans, but specific diagnoses were not provided in any of the studies. Those studies showed no increased risk of hospitalization for musculoskeletal system conditions among Gulf War deployed veterans compared with their nondeployed counterparts. Possible exposure to smoke from oil-well fires and nerve agents from the Khamisiyah demolition also failed to result in increased hospitalizations. The committee notes, however, that many musculoskeletal conditions, such as arthritis, do not typically require hospitalization and are more likely to be treated on an outpatient basis. The Volume 8 committee concluded that there was insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and musculoskeletal system conditions.

New Literature

The committee did not identify any new primary studies for any pain-related disorders in Gulf War veterans. The committee did review four studies that met its criteria for a secondary study (Dursa et al., 2016; Kelsall et al., 2014; Li et al., 2011a; Sim et al., 2015).

Secondary Studies

Li et al. (2011a) conducted a 10-year follow-up survey of 5,469 U.S. Gulf War deployed and 3,353 nondeployed veterans who had also participated in the 1995 VA National Health Survey. Compared with nondeployed veterans, the authors found that in 2005 deployed veterans were no more likely to report the persistence of the most prevalent chronic conditions in the past year including arthritis (RR = 1.10, 95% CI 0.93–1.10) and CFS-like illness (RR = 1.63, 95% CI 0.72–3.72) than nondeployed veterans. However, deployed veterans had a statistically significant increased risk of reporting a new onset of both arthritis (RR = 1.24, 95% CI 1.11–1.39) and CFS-like illness (RR = 2.36, 95% CI 1.90–2.93) since 2005 than nondeployed veterans. The risk ratios were adjusted for age in 2005, gender, race, rank, service branch, service type, BMI, and current cigarette smoking.

In a cross-sectional study, Kelsall et al. (2014) compared 1,381 Australian veterans of the Gulf War with 1,377 veterans who were serving in the military at the time or had previously deployed. The assessment, conducted in 2000–2002, queried veterans about doctor-diagnosed arthritis or rheumatism, back or neck problems, joint problems, and soft tissue disorders. Medical practitioners then rated the self-reported diagnoses as nonmedical, unlikely, possible, or probable; only probable diagnoses were analyzed. This approach, which added a level of medical judgment to the self-reported conditions but did not verify the self-reported diagnoses with a clinical evaluation, showed that the odds of having any musculoskeletal disorder was increased for the deployed veterans (OR = 1.19, 95% CI 1.00–1.43), but the odds of having any specific disorder was not. Depression was significantly associated with having any musculoskeletal disorder (OR = 1.81, 95% CI 1.21–2.69), arthritis or rheumatism (OR = 3.42, 95% CI 1.64–7.14), and back or neck problems (OR = 2.32, 95% CI 1.49–3.60), but not joint problems (OR = 1.51, 95% CI 0.88–2.58) in deployed veterans. However, depression was also significantly associated with the same disorders, including joint problems, in the comparison group. PTSD was significantly associated with arthritis or rheumatism (OR = 2.89, 95% 1.21–6.86) and joint problems (OR = 1.97,

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

95% CI 1.05–3.70) in the deployed veterans and significantly associated with all the musculoskeletal disorders except arthritis or rheumatism in the comparison group.

Sim et al. (2015) reported on the Australian Gulf War Veterans’ Follow Up Health Study, conducted between 2011 and 2013 (this study was a follow-up to the baseline study discussed in Volume 8). This study is an assessment of the entire 1,871 Australian Gulf War cohort 10 years after the 2000–2002 baseline study and 20 years after the war. Because only about 2% of the participants were women, only males were recruited for the study. Results were adjusted for age, rank category, and service branch. Of the 1,456 eligible deployed veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans provided the comparison group. Fatigue and musculoskeletal symptoms were based on responses to questions about the veterans’ experience with fatigue, prolonged fatigue (at least 1 month duration), and chronic fatigue (at least 6 months duration). Deployed veterans (n = 697) were significantly more likely than nondeployed veterans (n = 659) to report extreme tiredness or fatigue (RR = 1.38, 95% CI 1.15–1.65), prolonged fatigue (RR = 1.37, 95% CI 1.04–1.80), or chronic fatigue (RR = 1.41, 95% CI 1.02–1.96). The Chalder Fatigue Scale6 was used to assess fatigue severity, and results indicated that deployed veterans met the standardized diagnostic criteria more frequently than nondeployed veterans (RR = 1.23, 95% CI 1.04–1.45). Furthermore, the prevalence of prolonged fatigue and chronic fatigue more than doubled from baseline to follow-up in both the deployed and nondeployed groups, and these increases were statistically significant.

Veterans were also categorized into one of five chronic pain grades. Although deployed veterans were more likely to report both greater intensity pain and more disability from it than nondeployed veterans, the differences were not statistically significant. Compared with nondeployed veterans, deployed veterans had pain in more body areas in the previous 7 days (based on categories of four to six body areas, OR = 1.47, 95% CI 1.12–1.93, and 11 or more body areas of pain, OR = 2.89, 95% CI 1.01–8.28, but not in 7 to 10 body areas). Gulf War veterans also reported more pain-related health symptoms in the past month, general muscle aches or pains, headaches, and low back pain. More than half of both deployed and nondeployed veterans reported those symptoms. Finally, with regard to musculoskeletal disorders, the follow-up study asked more specific questions than the baseline study, so longitudinal comparisons were not made. In the follow-up study, veterans were asked whether they had a doctor diagnosis of or had been treated for osteoarthritis, rheumatoid arthritis, other inflammatory arthritis, or gout since 2001. There were no statistically significant differences between the deployed and nondeployed groups for any of the musculoskeletal disorders; osteoarthritis was the most common ailment in both groups (Sim et al., 2015).

The third wave of VA’s National Health Study of Persian Gulf War Era Veterans conducted about 20 years after the war, asked 8,104 deployed and 6,148 Gulf War era veterans to indicate whether a doctor had ever told them they had a medical condition and then whether the condition had been present in the previous 4 weeks. Dursa et al. (2016) found a statistically significant difference between the deployed and era veterans in the prevalence of self-reported CFS (11.8% vs 5.3%; OR = 2.36, 95% CI 1.94–2.86), fibromyalgia (3.7% vs 2.9%; OR = 1.48, 95% CI 1.15–1.91), rheumatoid arthritis (9.9% vs 7.9%; OR = 1.40, 95% CI 1.17–1.67), and arthritis not specified (33.9% vs 31.8%; OR = 1.16, 95% CI 1.05–1.29). Self-reported osteoarthritis was not statistically significantly different between deployed and era veterans (OR = 1.06, 95% CI 0.92–1.23). The ORs were adjusted for age, race, sex, BMI, smoking status, service branch, and unit component.

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6 The Chalder fatigue scale is widely used to measure physical and mental fatigue in CFS patients (Chalder et al., 1993).

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

Other Related Studies

VA provided a health care use report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories, including diseases of the musculoskeletal systems and connective tissue (ICD-9 categories 710–739) (see Table 4-20). A veteran can have multiple diagnoses with each health care encounter, and therefore, may be counted in multiple categories, but the person is counted only once in any single diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period (VA, 2014a,b). These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans.

Other studies have assessed the effect of a co-occurring health disorder (e.g., musculoskeletal disorders) on the prevalence of PTSD. Using data from the Patient Health Questionnaire component of the second wave of the VA National Health Survey of Gulf War Era Veterans, Coughlin and colleagues (2011a) found that among 6,111 Gulf War deployed and 3,859 era veterans, CFS, fibromyalgia, or arthritis was more commonly reported by obese veterans compared with normal weight veterans. This was also true for having a CFS-like illness in the past 12 months for obese nondeployed veterans but not for obese deployed veterans. Further assessment of these veterans found that having a self-reported CFS-like illness was also more prevalent among deployed and era Gulf War veterans with problem drinking than those without problem drinking. Gulf war veterans, deployed or era, were at significantly increased risk of having a CFS-like illness if they had problem drinking (OR = 1.48, 95% CI 1.22–1.78, adjusted for age, sex, race/ethnicity, branch of service, rank, and deployment status) (Coughlin et al., 2011b). Heavy drinking was defined as ≥ 15 drinks per week.

Individuals with fibromyalgia typically experience an exacerbation of their symptoms following acute exercise. In an effort to determine whether Gulf War veterans with chronic widespread pain had a similar reaction to exercise, Cook et al. (2010) assessed 27 Gulf War veterans from a VA medical center, 11 of whom had chronic muscle pain and 16 healthy controls. There was no difference between the two groups with regard to heat and pressure pain thresholds either before or after exercise; however, after exercise (submaximal cycling) veterans with chronic muscle pain rated the heat-pain stimuli after exercise as more intense and reported greater leg-muscle pain intensity during exercise compared with the healthy controls.

TABLE 4-20 10 Most Frequent Diagnosed Diseases of the Musculoskeletal System and Connective Tissue for Deployed and Nondeployed Gulf War Veterans Seeking Health Care in VA Between 2002 and 2013

Diagnosis Deployed N = 182,473 (%) Nondeployed N = 168,543 (%)
Other, unspecified disorders of joint 65.4 64.2
Other, unspecified disorders of back 55.8 56.0
Osteoarthrosis, allied disorders 38.0 39.5
Other disorders of soft tissues 27.7 27.3
Peripheral enthesopathies, allied syndromes 22.8 23.6
Other disorders of cervical region 20.4 21.4
Intervertebral disc disorders 17.3 18.2
Disorders of muscle, ligament, fascia 14.4 15.1
Other and unspecified arthropathies 13.4 13.5
Other disorders of synovium, tendon, bursa 11.7 12.6

SOURCES: VA, 2014a,b.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

Two studies tested for differences in synovial fluid in veterans with Gulf War illness complaining of joint pain compared to patients with either osteoarthritis or rheumatoid arthritis (Diaz-Torne et al., 2007; Pessler et al., 2008). Neither found evidence of synovitis in veterans with Gulf War illness using tests that easily detected synovitis in the arthritis patients.

Conclusions

There were no new studies that were of sufficient quality to be considered primary studies for Volume 10. Four secondary studies described inconsistent results for pain-related disorders among deployed veterans.

CFS was assessed in two new secondary studies that reported increased CFS (Dursa et al., 2016) and new onset CFS (Li et al., 2011a). Sim et al. (2015) found increased chronic fatigue and greater severity of it in deployed veterans. These results lend further support to the conclusion reached by the Volume 8 committee. Furthermore, the Volume 10 committee believes that the changes to the CFS case definition discussed at the beginning of this section will not significantly affect its conclusions with regard to the association between CFS and deployment to the Gulf War.

Reports for fibromyalgia and chronic pain are described in two studies. Sim et al. (2015) found that deployed veterans reported greater pain intensity and more disability than nondeployed veterans, but the differences were not statistically significant; however, deployed veterans reported statistically significant more pain in more body areas, and Dursa et al. (2016) reported a statistically significant greater rate of fibromyalgia in deployed veterans compared with era veterans. While these results are suggestive of an association between chronic pain and fibromyalgia and deployment, their reliance on self-reports limits the committee’s confidence in the association.

Evidence for musculoskeletal disorders was less consistent in the three studies that reported this outcome, which supports the Volume 8 conclusion of insufficient/inadequate evidence. Sim et al. (2015) found no statistically significant differences between the deployed and nondeployed groups for any of the musculoskeletal disorders, but deployed veterans reported more general muscle aches or pains and low back pain. Li et al. (2011a) found that rates of arthritis were similar in both groups, but deployed veterans were more likely to report new onset arthritis. Kelsall et al. (2014) found increased rates of any self-reported musculoskeletal disorder in deployed veterans but not for specific conditions, such as arthritis.

Despite the limited number of musculoskeletal disorders studies in this cohort, the aging Gulf War veteran cohort is likely to experience an increase in musculoskeletal disorders studies over time, consistent with the prevalence of musculoskeletal disorders documented in other occupational groups and the general population.

Thus, the committee finds that given the effects of aging and the unlikelihood that new pain-related conditions that are attributable to service in the Gulf War will develop 25 years later, it is doubtful that further assessments will show an increased risk of these conditions. Should these conditions be followed in this cohort, differences in musculoskeletal disorders by gender and race/ethnicity should be reported when data are available.

Therefore, the Volume 10 committee concludes that that there is sufficient evidence for an association between deployment to the Gulf War and CFS; that there is limited/suggestive evidence of an association between deployment and both fibromyalgia and chronic widespread pain; and that there is insufficient/inadequate evidence to determine whether an association exists between deployment and musculoskeletal system conditions.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

TABLE 4-19 Pain-Related Conditions

Study Design Population Outcomes Results Adjustments Comments
Chronic Fatigue Syndrome
Eisen et al., 2005 (Vol. 4) Population-based, cross-sectional, prevalence, in-person medical and psychiatric evaluations 1,061 GWVs vs 1,128 NDVs; selected from among those who had participated in 1995 National Health Survey of Gulf War Era Veterans and Their Families (mail and telephone survey) (Kang et al., 2000) CFS based on in-person interviews according to CDC CFS criteria and exclusionary diagnoses from history, interviews, examinations, laboratory testing OR = 40.6 (95% CI 10.2–161.2) Age, sex, race, smoking, duty type, service branch, rank Low participation rates (53% of GWVs and 39% of NDVs), but analysis of nonparticipants and participants reveals that participants, both GWVs and NDVs, are more likely to report symptoms of CFS
Kelsall et al., 2006 (Vol. 8) Cross-sectional survey 1,424 Australian male GWVs, 1,548 male NDVs frequency matched by age and service type (Same population as Kelsall et al., 2004a,b, 2005) Association of unexplained chronic fatigue and CFS determined in clinical assessment with self-reported exposure to various stressors CFS in deployed veterans vs control groups OR = 1.2 (95% CI 0.5–2.9) Chronic fatigue (≥ 6 months) OR = 1.9 (95% CI 1.4–2.7) 91 (6.6%) GWVs had unexplained chronic fatigue vs 40 (2.9%) of controls (OR = 2.3, 95% CI 1.6–3.4) Unexplained chronic fatigue in GWVs associated with PB (OR = 2.8, 95% CI 1.3–6.1), oil-well fire smoke (OR = 2.0, 95% CI 1.2–3.4), pesticides (OR = 2.4, 95% CI 1.5–3.8), presence in chemical weapons area (OR = 4.6, 95% CI 2.7–7.8), and deployed during air war (OR = 2.3, 95% CI 1.1–4.5) Age, service branch, rank; also education, marital status, smoking, and alcohol use for unexplained chronic fatigue Relatively large study with national ascertainment; response rate 80.5% for deployed, 56.8% for nondeployed Exposures self-reported; possible recall bias
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×
Study Design Population Outcomes Results Adjustments Comments
Ismail et al., 2008 (Vol. 8) Two-phase cohort study; first phase population-based postal survey, second phase random sample of disabled phase 2 responders 111 deployed GWVs; 133 era veterans, including Bosnia peacekeepers; must have physical disability (less than 72.2 on SF-36 physical functioning scale from phase 1 survey) (Population derived from Unwin et al., 1999, and Ismail et al., 2002) CFS determined through clinical assessment using CDC criteria 20 disabled GWVs (18%) and 4 disabled controls (3%), OR = 7.8, 95% CI 2.5–24.5 Age, sex, rank, marital status, alcohol disorders, selection bias via probability weights Phase 1 response rate 70% for GWVs, 60% and 63% for Bosnia and era veterans, respectively. Phase 2 response rate 67% for GWVs, 55% and 43% for Bosnia and era veterans, respectively. 54% of GWVs with CFS had concomitant depression or anxiety disorder
Fibromyalgia and Chronic Widespread Pain
Eisen et al., 2005 (Vol. 4) Population-based, cross-sectional, prevalence, medical evaluation 1,061 U.S. GWVs, 1,128 NDVs Symptoms and physical examination using criteria of American College of Rheumatology Prevalence: 2.0% vs 1.2%, OR = 2.32 (95% CI 1.02–5.27) Age, sex, race, years of education, cigarette smoking, duty type, service branch, rank Uses gold standard for diagnosis of fibromyalgia; low participation rates, especially among nondeployed
Smith et al., 2000 (Vol. 4) Postwar hospitalization study 551,841 GWVs, 1,478,704 NDVs Hospitalization (1991–1997); Cox proportional-hazards models ICD-9 codes for fibromyalgia (729.1) RR = 1.23 (95% CI 1.05–1.43); however, survival curves indicate excess due to hospitalization only for purposes of evaluation during the CCEP; before CCEP: RR = 0.92 (95% CI 0.74–1.13) Sex, age, branch of service No increase after accounting for CCEP effect; limited to active duty; most cases of fibromyalgia are not severe enough to warrant hospitalization
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Ang et al., 2006 (Vol. 8) Cohort of veterans from IPGWSG 370 veterans who were free of CWP at 5 years were examined 10 years after war: 267 GWVs, 103 NDVs Structured telephone interview about 5 years after the war; in-person follow-up medical examination 10 years after war of 370 veterans who did not report chronic widespread pain 5 years after war Neither deployment to nor time in gulf region significantly correlated with CWP: OR = 1.1, 95% CI 0.6–2.0 and OR = 1.0, 95% CI 0.7–13.0, respectively; combat exposure correlated: OR = 1.5, 95% CI 1.1–2.0; perception of stress due to military experience at time of war correlated more significantly with CWP: OR = 1.6, 95% CI 1.1–2.3, p = 0.0084 Controls matched for age, sex, branch of service Potential for recall bias; only veterans who were free of CWP at 5 years were assessed 10 years after war
Conditions of the Musculoskeletal System
Eisen et al., 2005 (Vol. 4) Population-based, cross-sectional, prevalence, medical evaluation 1,061 U.S. GWVs vs 1,128 NDVs Persistent and clinically significant bone or joint symptoms with or without joint effusion, and treatment with anti-inflammatory agents, narcotic pain medications, or nonnarcotic pain medications Prevalence: 6.4% vs 6.8% (OR = 1.15, 95% CI 0.70–1.89) Age, sex, race, years of education, smoking, duty type, service branch, rank Low participation rates, especially among nondeployed
Gray et al., 1996 (Vol. 8) Retrospective cohort, hospitalizations from August 1991 through September 1993 547,076 active-duty GWVs, 618,335 NDVs Hospital-discharge diagnoses of musculoskeletal system diseases in DoD hospital system Exact values not given 1991: OR < 1.0 (95% CI < 1.0); 1992: OR < 1.0 (95% CI < 1.0) 1993, OR about 1.01 (95% CI 0.9–1.15) Prewar hospitalization, sex, age, race, service branch, marital status, rank, length of service, salary, occupation Short follow-up period; no outpatient data; restriction to DoD hospitals, and thus to persons remaining on active duty after the war; no adjustment for other potential confounders
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Study Design Population Outcomes Results Adjustments Comments
Gray et al., 2000 (Vol. 8) Retrospective cohort, hospitalizations from August 1991 through December 1994 652,979 GWVs, 652,922 randomly selected NDVs 182,164 DoD hospitalizations; 16,030 VA hospitalizations; 5,185 COSHPD hospitalizations Hospital-discharge diagnoses of musculoskeletal system diseases in DoD, VA, and COSHPD hospital systems DoD PMR = 1.01 (95% CI 0.99–1.02) VA PMR = 0.86 (95% CI 0.81–0.91) COSHPD PMR = 0.79 (95% CI 0.64–0.93) Age, sex, race (only for DoD PMR) Able to assess only illnesses that resulted in hospitalization; possible undetected confounders PMR has lower sensitivity than a comparison of hospitalization rates
Smith et al., 2006 (Vol. 8) Retrospective cohort study (cohort data from the DMDC) Active-duty personnel with a single deployment to: Gulf War theater (n = 455,465); southwest Asia peacekeeping mission, 1991–1998 (n = 249,047); Bosnia, 1995–1998 (n = 44,341) Postdeployment hospitalization events (1991–2000) for an ICD-9-CM diagnosis of a musculoskeletal system disease (ICD-9 codes 710–739) Compared to GWVs, veterans of Bosnia showed reduced risk (HR = 0.78, 95% CI 0.71–0,86), veterans of southwest Asia at slightly increased risk (HR = 1.06, 95% CI 1.01–1.12) Sex, age, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalization; time-dependent covariate to account for changing hospitalization methods, diagnostic criteria, and procedures Limitations: active-duty personnel only; hospitalizations at DoD facilities only
Smith et al., 2002 (Vol. 8) DoD hospitalizations 1991–1999; exposure modeling for oil-well fire smoke 405,142 active-duty GWVs who were in theater during the time of Kuwaiti oil-well fires Hospitalization for musculoskeletal system diseases (ICD-9-CM codes 710–739) No association between exposure and musculoskeletal system diseases across all exposure levels Adjusted for “influential covariates,†defined as demographic or deployment variables with p values less than 0.15 Objective measure of disease not subject to recall bias; no issues with self-selection; however, only DoD hospitals, only active duty, no adjustment for potential confounders such as smoking
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Gray et al., 1999b (Vol. 4) DoD hospitalizations 1991–1995, exposure to nerve agents at Khamisiyah based on 1997 DoD exposure models Not exposed (n = 224,804), uncertain low-dose exposure (n = 75,717), exposed (n = 48,770) Musculoskeletal system disease (vs not exposed): Uncertain low dose; < 0.013 mg-min/m3; 0.013–0.097 mg-min/m3; 0.097–0.514 mg-min/m3 OR = 0.90 (95% CI 0.86–0.94) OR = 0.90 (95% CI 0.83–0.98) OR = 0.90 (95% CI 0.83–0.96) OR = 0.98 (95% CI 0.87–1.09) Sex, age group, prewar hospitalization, race, service type, marital status, pay grade, occupation See Smith et al. (2002); also, probable substantial exposure misclassification as models were revised, lack of a clear dose–response pattern, little biologic plausibility given that no effect was seen for nervous system diseases
Smith et al., 2003 (Vol. 8) DoD hospitalization study (1991–2000); analysis of health outcomes and exposure to nerve agents (follow-up of Gray et al., 1999b) 99,614 active-duty military considered exposed vs 318,458 nonexposed, according to revised DoD exposure model First hospitalization for any musculoskeletal system disease (ICD-9CM codes 710–739) Exposed vs unexposed: RR = 0.99 (95% CI 0.96–1.02) No adjustment for confounding exposures Restricted to DoD hospitals; restricted to hospitalizations for only Gulf War veterans who remained on active duty after the war

NOTE: CCEP = Comprehensive Clinical Evaluation Program; CDC = Centers for Disease Control and Prevention; CFS = chronic fatigue syndrome; CI = confidence interval; COSHPD = California Office of Statewide Health Planning and Development; CWP = chronic widespread pain; DMDC = Defense Manpower Data Center; DoD = Department of Defense; GWV = Gulf War veteran; HR = hazard ratio; ICD = International Classification of Diseases; IPGWSG = Iowa Persian Gulf War Study Group; NDV = nondeployed veteran; OR = odds ratio; PB = pyridostigmine bromide; PMR = proportional morbidity ratio; RR = risk ratio; UK = United Kingdom; U.S. = United States.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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GENITOURINARY SYSTEM CONDITIONS

Major conditions evaluated in this section include kidney disease, urolithiasis (kidney stones), urinary tract infections, prostatitis, and sexual difficulties. Gynecologic outcomes including abnormal cervical pathology and inflammatory disease of the ovary are also assessed. Cancers of the genitourinary system such as testicular cancer are discussed in the section on cancer. All primary studies of conditions of the genitourinary system are summarized in Table 4-21 at the end of this section.

Summary of Volumes 4 and 8

Genitourinary outcomes were not addressed separately in Volume 4 of the Gulf War and Health series. The Volume 8 committee identified five primary studies of hospitalization for genitourinary system conditions, one other primary study that was not on hospitalization (Frommelt et al., 2000), and 10 secondary studies (mostly large surveys of self-reported outcomes). Frommelt et al. (2000) found that the evidence did not support an association between Gulf War deployment and cervical pathology using clinical confirmation of Pap smear results among female veterans in all age groups except women aged 26–30 who had a slight increase in “other than within normal limits,” but the authors concluded that there was no biologically plausible evidence to support an age-specific association between deployment and abnormal cervical pathology.

In the 10 secondary studies, the prevalence of various self-reported genitourinary conditions was greater among Gulf War deployed veterans compared with nondeployed veterans (Gray et al., 2002; Kang et al., 2000, 2009; Page et al., 2005a; Pierce, 2005; Proctor et al., 1998; Simmons et al., 2004; Steele, 2000; Unwin et al., 1999). In one study of the effects of exposure to nerve agents released by the Khamisiyah demolition, reporting of genitourinary conditions was similar in exposed and unexposed veterans (Page et al., 2005b).

Five hospitalization studies, mostly in DoD hospitals, assessed conditions of the genitourinary system. Gray et al. (1996, 2000) and Smith et al. (2006) assessed the difference between deployed and nondeployed veterans, and two other studies examined the effects of environmental exposures to nerve agents or oil-well fires among Gulf War veterans (Smith et al., 2002, 2003). These studies suggest that excess hospitalization due to conditions of the genitourinary system did not occur among active-duty Gulf War veterans within the 10 years following the war. There is some suggestion that postwar hospitalizations for genitourinary conditions were similar among Gulf War deployed veterans who were and were not exposed to nerve agents or smoke from oil-well fires, but the results are not generalizable to the entire cohort of Gulf War veterans. Furthermore, by limiting such studies of genitourinary outcomes to hospitalizations, conditions that are not severe enough to require inpatient care were not assessed. Combining all genitourinary conditions into a single broad diagnostic category of “diseases of the genitourinary system” would also have limited the ability to detect associations with more specific, but etiologically distinct, outcomes.

The specific conditions being evaluated in surveys of Gulf War veterans have varied across studies, generally addressing frequency of urination, urinary tract infections, sexual problems, or broadly defined “disease of the genital organs.” Secondary studies addressing deployment and genitourinary conditions are limited by self-reported outcomes, lack of clinical confirmation, potential recall bias, and generally poor response rates. The discrepancies between hospitalization studies and survey studies of genitourinary outcomes may reflect variation in the severity and types of genitourinary outcomes ascertained by the different approaches; differences in active-duty, reserve, and former military personnel; the influence of reporting and selection biases; or the role of chance.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

Studies of self-reported sexual dysfunction have included reports of decreased libido, erectile dysfunction, discomfort or pain during intercourse, and a burning sensation after sex. One primary study was discussed in Volume 4 that indicated deployed veterans reported more sexual problems than controls and problems were associated with traumatic events (having seen killed or wounded people, watched a friend or colleague being threatened or shot at, or having been threatened themselves) (Ishoy et al., 2001b).

The Volume 8 committee identified no new primary studies of sexual dysfunction in Gulf War veterans but did consider seven secondary studies (Gray et al., 2002; Iowa Persian Gulf Study Group, 1997; Page et al., 2005a; Proctor et al., 1998; Simmons et al., 2004; Steele, 2000; Unwin et al., 1999). Gulf War veterans consistently reported an increased prevalence of sexual problems when compared with nondeployed veterans. The one study assessing exposures specific to Gulf War service reported no association between nerve agent exposure, and reported sexual problems among veterans deployed to the Gulf War (Page et al., 2005b). With the exception of a single study that incorporated physician interviews to verify symptom reporting, studies of sexual problems have relied exclusively on self-reports. The Volume 8 committee concluded there was inadequate/insufficient evidence to determine whether an association exists between Gulf War deployment and other specific conditions of the genitourinary system. The Volume 8 committee also concluded there was limited/suggestive evidence of an increased prevalence of self-reported sexual difficulties among Gulf War veterans.

New Literature

The committee did not identify any new primary studies on the genitourinary system, including sexual dysfunction. However, Ishoy et al. (2001b) which assessed sexual difficulties in Danish Gulf War veterans, and was included in Volume 4 as a primary study in the section on male fertility problems, has been added to the table in this section.

Secondary Studies

The committee found two studies that met its criteria for a secondary study. Sim et al. (2015) reported on the Australian Gulf War Veterans’ Follow Up Health Study, conducted between 2011 and 2013 (this study was a follow-up to the baseline study discussed in Volume 8). This study is an assessment of the entire 1,871 Australian Gulf War cohort 10 years after the 2000–2002 baseline study and 20 years after the war. Results were adjusted for age, rank category, and service branch. Of the 1,456 eligible deployed male veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans provided the comparison group. Deployed veterans were more likely to report physician-diagnosed kidney disease (RR = 1.83, 95% CI 0.95–3.35) and bladder disease (RR = 1.65, 95% CI 0.74–3.67), but the differences were not statistically significant.

Dursa et al. (2016) reported results from the third wave of VA’s cross-sectional National Health Study of Persian Gulf War Era Veterans that was conducted in 2012–2013 and asked 8,104 deployed and 6,148 Gulf War era veterans whether a doctor ever told the veteran that they had “any disease of the genital organs” or “repeated bladder infections.” The weighted prevalence of genital organ disease was 5.1% in the deployed and 4.6% in the era veterans (OR = 1.17, 95% CI 0.93–1.47); the weighted prevalence of repeated bladder infections was 2.4% and 2.8% in deployed and era veterans, respectively (OR = 1.00, 95% CI 0.76–1.33). ORs were adjusted for age, sex, race, service branch, unit, BMI, and smoking status.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Other Related Studies

VA provided a health care use report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories, including diseases of the genitourinary systems (ICD-9 categories 580–629) (see Table 4-22). A veteran can have multiple diagnoses with each health care encounter, and therefore, may be counted in multiple categories, but the person is counted only once in any single diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period (VA, 2014a,b). These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans.

Conclusions

The studies cited in Volume 8, particularly the secondary studies, found that Gulf War veterans reported more conditions and symptoms of the genitourinary system. The one secondary study identified by the Volume 10 committee indicated that deployed veterans were slightly but not significantly more likely to report having had a disease of the kidney or bladder.

Therefore, the Volume 10 committee concludes that there is inadequate/insufficient evidence to determine whether an association exists between Gulf War deployment and genitourinary conditions.

There was no new evidence to support or refute the association between self-reported sexual dysfunction and deployment in Gulf War veterans. The committee finds that given the aging of the Gulf War veterans and the unlikelihood that new genitourinary conditions will develop 25 years after the Gulf war that are attributable to their Gulf War service, it is doubtful that further assessments will show increased risk of these conditions.

Therefore, the Volume 10 committee concludes there is limited/suggestive evidence of an increased prevalence of self-reported sexual difficulties among Gulf War veterans.

TABLE 4-22 10 Most Frequent Genitourinary Diagnoses for Deployed and Nondeployed Gulf War Veterans Seeking Health Care in VA Between 2002 and 2013

Diagnosis Deployed N = 80,156 (%) Nondeployed N = 82,231 (%)
Disorders of penis 34.0 29.8
Other disorders of urethra, urinary tract 24.9 25.3
Hyperplasia of prostate 20.2 21.9
Calculus of kidney, ureter 10.3 9.5
Chronic kidney disease 8.2 8.2
Other disorders of male genital organs 6.7 Not reported
Menopausal and postmenopausal disorders 6.3 10.3
Other disorders of breast 6.3 8.0
Other disorders of kidney, ureter 6.2 9.5
Disorders of menstruation, other abnormal bleeding from female genital tract 5.7 Not reported

SOURCES: VA, 2014a,b.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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TABLE 4-21 Conditions of the Genitourinary System

Study Design Population Outcomes Results Adjustments Comments
Frommelt et al., 2000 (Vol. 8) Retrospective cohort 1,446 female GWVs and 5,269 female NDVs with routine Pap smears conducted in 1994 Pap smear results Nonnormal diagnosis more frequent in GWVs (11.5%) vs NDVs (6.6%) in 26–30-year-old age group (p = 0.013); no significant difference in occurrence of nonnormal diagnoses detected in any other age group 5-year age groups (20–50, over 50), marital status, race, rank
Gray et al., 1996 (Vol. 8) Retrospective cohort, DoD hospitalizations from August 1991 through September 1993 547,076 active-duty GWVs, 618,335 NDVs Hospital-discharge diagnoses of a disease of the genitourinary system in DoD hospital system (ICD-9 classification) Any genitourinary disease (exact values not given) 1991: OR about 1.1 (95% CI 1.0–1.15); 1992 and 1993: ORs about 1.0 (95% CI 0.95–1.05) Inflammatory disease of ovary, fallopian tube, pelvic cellular tissue, and peritoneum: Rate ratio = 1.35 (95% CI 1.11–1.63) Other disorders of the breast: Rate ratio = 1.30 (95% CI 1.03–1.63) Redundant prepuce and phimosis: OR = 1.59 (95% CI 1.22–2.07) Infertility, female: Rate ratio = 1.59 (95% CI 1.19–2.11) Prewar hospitalization, sex, age, race, service branch, marital status, rank, length of service, salary, occupation Very short followup period; no outpatient data; restriction to DoD hospitals, and thus to persons remaining on active duty after the war; no adjustment for potential confounders such as smoking
Gray et al., 2000 (Vol. 8) Retrospective cohort, hospitalizations from August 1991 through December 1994 652,979 GWVs, 652,922 randomly selected NDVs 182,164 DoD hospitalizations; 16,030 VA hospitalizations; 5,185 COSHPD hospitalizations Hospital-discharge diagnoses of a disease of the genitourinary system in DoD, VA, and COSHPD hospital systems DoD PMR = 1.01 (95% CI 0.98–1.03); VA PMR = 0.96 (95% CI 0.87–0.1.05); COSHPD PMR = 0.80 (95% CI 0.59–1.00) Age, sex, race (only for DoD PMR) Able to assess only illnesses that resulted in hospitalization; possible undetected confounders PMR has lower sensitivity than a comparison of hospitalization rates
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Study Design Population Outcomes Results Adjustments Comments
Ishoy et al., 2001b (Vol. 4) Cross-sectional (elaboration of findings in Ishoy et al., 2001a) Danish Gulf War Study: 661 GWVs, 215 NDVs Self-reported sexual problems Male GWVs vs NDVs: sexual problems (80% decreased libido), 79 vs 8 (OR = 2.9, 95% CI 1.4–6.0) Age Limitations: small study, self-reported soft outcomes and exposures
Smith et al., 2006 (Vol. 8) Retrospective cohort study of DoD hospitalizations (cohort data from the DMDC) Active-duty personnel with a single deployment to: Gulf War theatre (n = 455,465); southwest Asia peacekeeping mission, 1991–1998 (n = 249,047); Bosnia, 1995–1998 (n = 44,341) Postdeployment hospitalization events (1991–2000) for an ICD-9-CM diagnosis of a disease of the genitourinary system (580–629) and nephritis specifically Compared with GWVs, veterans of Bosnia showed reduced risk (HR = 0.60, 95% CI 0.51–0.70), and veterans of southwest Asia showed similar risk (HR = 1.00, 95% CI 0.92–1.09) Nephritis, Bosnia: HR = 0.47 (95% CI 0.20–1.08); Southwest Asia: HR = 1.30 (95% CI 0.84–2.01) Sex, age, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalization; time-dependent covariate to account for changing hospitalization methods, diagnostic criteria, and procedures Lower hazard ratio observed in veterans of Bosnia may be partially explained by better access to care in theater Active-duty personnel only; hospitalizations at DoD facilities only; no outpatient data
Smith et al., 2002 (Vol. 8) Retrospective cohort study of DoD hospitalizations 1991–1999; exposure modeling for oil-well fire smoke 405,142 GWVs who were in theater during the time of Kuwaiti oil-well fires Hospitalization for diseases of the genitourinary system Risk was not increased at any level of smoke plume exposure Adjusted for “influential covariates,†defined as demographic or deployment variables with p values less than 0.15 Objective measure of disease not subject to recall bias; no issues with self-selection; however, only DoD hospitals, only active duty, no adjustment for other potential confounders
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×
Smith et al., 2003 (Vol. 8) Retrospective cohort study of DoD hospitalizations (1991–2000); analysis of health outcomes and exposure to nerve agents (follow-up of Gray et al., 1999b) 99,614 active-duty GWVs considered exposed vs 318,458 nonexposed, according to revised DoD exposure model Hospitalization for any disease of the genitourinary system (ICD-9-CM codes 580–629) RR = 0.96 (95% CI 0.91–1.00) Restricted to DoD hospitals; restricted to hospitalizations for only Gulf War veterans who remained on active duty after the war; no adjustment for confounding exposures

NOTE: CI = confidence interval; COSHPD = California Office of Statewide Health Planning and Development; DMDC = Defense Manpower Data Center; DoD = Department of Defense; DU = depleted uranium; GWV = Gulf War veteran; HR = hazard ratio; MRR = mortality rate ratio; NDV = nondeployed veteran; OR = odds ratio; PHQ = Patient Health Questionnaire; PMR = proportional morbidity ratio; RR = risk ratio; VA = Department of Veterans Affairs.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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ADVERSE REPRODUCTIVE AND PERINATAL OUTCOMES

This section evaluates the findings on birth defects in the offspring of veterans, adverse pregnancy outcomes, and infertility. As appropriate, the major results from each study are addressed by whether the father or the mother served in the Gulf War and by outcome. Sexual dysfunction is discussed in the previous section on conditions of the genitourinary system even though it may affect one’s ability to reproduce. All primary studies of adverse reproductive and perinatal outcomes are summarized in Table 4-23 at the end of this section.

Birth Defects

Birth defects occur in about 3% of live births. The numerous types of serious or disabling birth defects include structural defects, chromosomal abnormalities, and birth defect syndromes (California Birth Defects Monitoring Program, 2009). Because of that diversity, epidemiologists attempting to calculate whether birth defects are increased in a particular group such as deployed veterans, sometimes encounter the problem of making multiple comparisons; that is, the greater the number or the more types of comparisons, the greater the likelihood that one or more of them will appear significant when no true differences exists. Several statistical techniques are used to adjust for, or minimize, the problem of multiple comparisons, but they are not foolproof.

Summary of Volumes 4 and 8

In Volume 4, one primary study (Araneta et al., 2003) and five secondary studies (Cowan et al., 1997; Doyle et al., 2004; Goss Gilroy Inc., 1998; Kang et al., 2001; Penman et al., 1996) were reviewed. Some evidence of increased risk of birth defects among offspring of Gulf War veterans was reported primarily on the basis of two studies (Araneta et al., 2003; Doyle et al., 2004); however, with the possible exception of urinary tract abnormalities, the increased prevalence estimates of specific defects in the two studies were not consistent. The reported association of Gulf War service with Goldenhar syndrome, a rare craniofacial abnormality, was inconclusive (Werler et al., 2005). Thus, the Volume 4 committee concluded that there is no consistent pattern of higher prevalence estimates of birth defects among offspring of male or female Gulf War veterans and that no single defect, except urinary tract abnormalities, had been found in more than one well-designed study.

The Volume 8 committee identified three additional secondary studies (Ishoy et al., 2001a; Kelsall et al., 2007; Verret et al., 2008) that reported data on birth defects in association with the Gulf War; however, no additional support for an association between birth defects and deployment to the Gulf War was reported. Few cases made detection of any differences between birth defect risks in deployed and nondeployed veterans difficult. Overall, studies of Gulf War service and congenital malformations were problematic because specific birth defects are relatively rare, multiple comparisons were performed, and sample sizes were small when divided by timing of exposure (before or after conception) and whether the mother or the father was exposed. Thus, the Volume 8 committee repeated the conclusion of the Volume 4 committee. The Volume 8 committee concluded there was inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and specific birth defects.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Adverse Pregnancy Outcomes

Studies of adverse pregnancy outcomes have evaluated the prevalence of spontaneous abortions, stillbirths, ectopic pregnancies, preterm births, low birth weight, and macrosomia in the pregnancies of Gulf War deployed and nondeployed men and women.

Summary of Volumes 4 and 8

The Volume 4 committee reviewed one primary study of hospital-discharge data suggestive of an increased risk of spontaneous abortions and ectopic pregnancies (Araneta et al., 2004). However, those results may not be generalizable to deployed women who left the service or to pregnancy-related admissions to nonmilitary hospitals. Thus, the Volume 4 committee found it difficult to conclude whether there is a higher prevalence of adverse pregnancy outcomes in Gulf War deployed than in nondeployed veterans. Two secondary studies of self-reported adverse birth outcomes indicated possible increased risks of miscarriage, spontaneous abortions, and stillbirths among pregnancies to fathers deployed to the Gulf War, but results were not consistent between the studies (Doyle et al., 2004; Kang et al., 2001).

Five additional secondary studies evaluating the effect of deployment on adverse pregnancy outcomes were identified by the Volume 8 committee; all of these studies were based on self-reported data (Ishoy et al., 2001a; Kang et al., 2009; Kelsall et al., 2007; Verret et al., 2008; Wells et al., 2006). Findings for spontaneous abortion were not replicated in the four secondary studies of female veterans, which used self-reported outcome data (Ishoy et al., 2001a; Kang et al., 2009; Kelsall et al., 2007; Wells et al., 2006). Similarly, only one secondary study assessed ectopic pregnancies and observed no differences by deployment status among male or female veterans (Wells et al., 2006). Among males, no consistent associations with Gulf War deployment were observed for spontaneous abortion, preterm birth, or low birth weight, although three studies reported modest increases in self-reported miscarriages among partners of deployed males (Kang et al., 2009; Kelsall et al., 2007; Wells et al., 2006). The Volume 8 committee concluded there was inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and adverse pregnancy outcomes such as miscarriage, stillbirth, preterm birth, and low birth weight.

Fertility

Studies of fertility problems have assessed semen parameters, hospitalization for infertility or genitourinary system conditions, self-reported difficulties achieving a pregnancy, and serum concentrations of reproductive hormones in males. Infertility is typically defined as trying to conceive unsuccessfully for 12 months or more after discontinuing contraception, although the quality of the outcome measurement has varied across studies and has included inference from self-reported disorders of infertility or sperm abnormalities, reports of having difficulty getting pregnant, reports of consulting a doctor after trying unsuccessfully for more than 1 year, and seeking treatment for childlessness.

Summary of Volumes 4 and 8

The Volume 4 committee reviewed two primary studies (Ishoy et al., 2001a,b; Maconochie et al., 2004). For the most part, the findings on fertility and sexual problems relied on self-reports. There was no evidence of statistically significant differences in concentrations of male reproductive hormones between Gulf War deployed veterans and nondeployed veterans. While self-reported infertility was

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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increased among deployed veterans vs nondeployed veterans and deployed veterans reported a longer time to conception, few cases could be verified with clinical diagnostic information, and information about partners’ fertility status was lacking. The Volume 4 committee concluded that although it appears that there is no difference in the prevalence of male fertility problems or infertility between the deployed Gulf War veterans and their nondeployed counterparts, it was difficult to draw conclusions from the small number of available studies.

The Volume 8 committee identified three secondary studies (Kang et al., 2009; Kelsall et al., 2007; Verret et al., 2008). It found no evidence of significant differences in concentrations of male reproductive hormones between deployed and nondeployed Gulf War veterans. Although changes in hormonal concentrations and semen characteristics are reproductive outcomes of interest, they are not definitive indicators of infertility (with the exception of azoospermia). The Volume 8 committee concluded there was inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and fertility problems.

New Literature

Only two studies reporting on reproductive outcomes were identified: one primary study of birth defects (Bukowinski et al., 2012) and one secondary study of self-reported pregnancy, fertility, and adverse birth outcomes (Sim et al., 2015).

Primary Study

Bukowinski et al. (2012) identified 178,766 infants in the DoD Birth and Infant Health Registry born between 1998–2004 with at least one parent who was in the military during the Gulf War era (26,617 born to female veterans and 159,446 born to male veterans). Rates of birth defects among infants born to deployed veterans were compared with those among nondeployed veterans. The investigators studied eight specific birth defects: the five most common in the study population (atrial septal defect, ventricular septal defect, patent ductus arteriosus, hypospadias/epispadias, and congenital hip dislocation), and three previously reported to be associated with deployment (aortic valve stenosis, hypoplastic left heart syndrome, and renal agenesis/dysgenesis). Exposure information was collected from DoD databases pertaining to deployment, exposure to nerve agents at Khamisiyah and oil-well fires, and in-theater hospitalizations. Analyses were stratified by which parent was deployed, and regression models were adjusted for effects of infant gender, preterm birth, maternal and paternal age, race/ethnicity, branch of service, pay grade, and occupation. There was no association between being deployed and any of these birth defects (OR = 1.05, 95% CI 0.86–1.28), nor were there any statistically significant increases in specific birth defects for deployed vs era females or males. However, there was a slight increase in birth defects in children born to men who had been deployed for 153–200 days (OR = 1.25, 95% CI 1.05–1.49), but not for a shorter or longer period. Birth defects were not associated with any other exposures. This study may be limited by its use of registry data to identify occurrences of birth defects; use of the DoD registry will miss births to veteran parents who left the military.

Secondary Study

Sim et al. (2015) reported on the Australian Gulf War Veterans’ Follow Up Health Study, conducted between 2011 and 2013 (this study was a follow-up to the Kelsall et al. [2004b] baseline study discussed in Volumes 4 and 8). This study is an assessment of the entire Australian Gulf War cohort 10 years after

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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the 2000–2002 baseline study and 20 years after the war. Results were adjusted for age, rank category, and service branch, but not for smoking. Of the 1,456 eligible deployed veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans provided the comparison group. Based on self-reported pregnancy and fertility information collected since 1992, more deployed veterans reported difficulty fathering a pregnancy (RR = 1.44, 95% CI 1.05–1.99), but they have not sought or undertaken treatment or been less likely to have actually fathered a pregnancy since then. Also, deployed veterans reported more doctor-diagnosed impotence (RR = 2.06, 95% CI 1.30–3.29). No differences in reported live births, miscarriage, stillbirth, termination, premature births, or low birthweight were found.

Conclusions

Very little new information on reproductive and birth effects was available to the Volume 10 committee. The one primary study is limited by its use of registry data, which may not be representative of all Gulf War veterans, and the one secondary study is limited by its use of self-reported information collected more than 20 years after the Gulf War. Regardless of their limitations, the results of those studies are in concurrence with studies described in previous volumes in that no increased risks of birth defects or adverse pregnancy or birth outcomes were reported for deployed male or female Gulf War veterans. Self-reported information indicates possible male infertility, but the evidence is not strong enough to warrant any change to the Volume 8 conclusions. Furthermore, most studies of Gulf War deployment and infertility have relied on self-reports that give rise to a substantial opportunity for recall bias. Few studies have examined the question of fertility among female veterans.

The committee finds that given that female Gulf War veterans are past childbearing age, and the unlikelihood that new birth defects, adverse pregnancy outcomes, and fertility conditions will develop 25 years after the Gulf war that are attributable to their Gulf War service, it is doubtful that further assessments will show increased risk of these conditions.

Therefore, the Volume 10 committee concludes there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and specific birth defects. It further concludes there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and adverse pregnancy outcomes such as miscarriage, stillbirth, preterm birth, and low birth weight.

The Volume 10 committee also concludes there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and fertility problems.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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TABLE 4-23 Birth Defects, Adverse Pregnancy Outcomes, and Fertility

Study Design Population Outcomes Results Adjustments Comments
Volume 4 and 8 Primary Studies
Birth Defects
Araneta et al., 2003 (Vol. 4) Retrospective cohort, using population-based, birth-defect registries (active surveillance all cases identified from birth to 1 year) Infants of military personnel born 1/1/1989–12/31/1993 in Arizona, Hawaii, Iowa, and participating counties of Arkansas, California, Georgia to 450 GWV mothers 3,966 NDV mothers 11,511 GWV fathers 29,086 NDV fathers 48 birth defects identified by CDC as occurring frequently or of public health importance, excluding pulmonary artery anomalies and adding dextrocardia, chromosomal anomalies (other than trisomies 13, 18, and 21), and Goldenhar syndrome Postwar conceptions, GWVs vs NDVs (unadjusted RRs): father: tricuspid valve insufficiency, 10/4,648 vs 9/11,164 (RR = 2.7, 95% CI 1.1–6.6); aortic valve stenosis, 5/4,648 vs 2/11,164 (RR = 6.0, 95% CI 1.2–31.0); coarctation of aorta, 5/4,648 vs 3/11,164 (RR = 4.0, 95% CI 0.96–16.8); renal agenesis or hypoplasia, 5/4,648 vs 5/11,164 (RR = 2.4, 95% CI 0.7–8.3) mother: hypospadias 4/154 vs 4/967 (RR = 6.3, 95% CI 1.5–26.3) GWVs postwar vs prewar conceptions (unadjusted RRs): father: aortic valve stenosis 5/4,648 vs 0/6,863 (RR = 16.3, 95% CI 0.9–294); coarctation of aorta, 5/4,648 vs 1/6,863 (RR = 7.4, 95% CI 0.9–63.3); renal agenesis and hypoplasia, 5/4,648 vs 0/6,863 (RR = 16.3, 95% CI 0.9–294); adjustment did not change results State, maternal and paternal age, race, marital status, education, plurality, parity, prenatal visits, gestational weight gain, branch of service, military rank, prenatal alcohol exposure, intrauterine growth retardation, low birth weight, small for gestational age, preeclampsia California limited to diagnoses in nonmilitary hospitals; relies on availability of unique personal identifiers in military and birth certificate data, limited power to assess individual defects, multiple comparisons, limited to live births Population-based, including reservists, National Guard, former military personnel; includes defects diagnosed through first year, medically confirmed diagnoses, comparisons with prewar experience
Werler et al., 2005 (Vol. 4) Case-control HFM cases £ 3 years old (born 1996–2002) from craniofacial clinics in 24 U.S. cities (n = 232); controls matched by age and pediatrician (n = 832) HFM, facial asymmetry, or Goldenhar syndrome and no evidence of Mendelian inherited or chromosomal anomaly Adjusted ORs: parental army service, OR = 2.4 (95% CI 1.4–4.2); parental GW army service, OR = 2.8 (95% CI 0.8–9.6); any parental GW service, OR = 0.8 (95% CI 0.3–2.3) Family income, race, BMI in early pregnancy, multiple gestation No adjustment for lifestyle factors Included cases diagnosed up to of 3 years age
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Study Design Population Outcomes Results Adjustments Comments
Doyle et al., 2004 (Vol. 8) Retrospective cohort All UK GWVs and randomly selected cohort of NDVs responding to postal questionnaire; conceptions from postdeployment (for NDVs—conceived after 1/1/1991) through 11/8/1997 16,442 GWV fathers 11,517 NDV fathers 484 GWV mothers 377 NDV mothers External comparison populations: (1) NIFS; (2) annual registered stillbirths in England and Wales, 1991–1998 Fetal death: early and late miscarriage, stillbirth; congenital malformations excluding minor abnormalities among live births; self-report with clinical confirmation attempted for fetal deaths and live births with reported abnormalities Adjusted ORs GWVs vs NDVs: fathers: all miscarriages 2,829/15,539 vs 1,525/10,988 (OR = 1.4, 95% CI 1.3–1.5); any congenital malformation, 686/13,191 vs 342/9,758 (OR = 1.5, 95% CI 1.3–1.7); other malformations of digestive system, 69/13,191 vs 31/9,758 (OR = 1.6, 95% CI 1.0–2.5); genital system, 45/13,191 vs 19/9,758 (OR = 1.8, 95% CI 1.0–3.0); urinary system, 103/13,191 vs 48/9,758 (OR = 1.6, 95% CI 1.1–2.3); musculoskeletal system, 194/13,191 vs 78/9,758 (OR = 1.8, 95% CI 1.4–2.4); other nonchromosomal malformations, 45/13,191 vs 19/9,758 (OR = 1.7, 95% CI 1.0–3.0); cranial neural crest, 184/13,191 vs 101/9,758 (OR = 1.3, 95% CI 1.0–1.7); metabolic and single gene defects, 22/13,191 vs 8/9,758 (OR = 2.0, 95% CI 0.9–4.8); mothers: no significant associations Stratum matched on branch of service, sex, age, serving status, rank; ORs adjusted by year of pregnancy end, paternal/maternal pregnancy order, maternal age, service, rank, previous fetal death, multiplicity Response rates: GWVs: men 53%, women 72%; NDVs: men 42%, women 60% Poor response rates among men and response rates lower in NDVs, low numbers of miscarriages in NDVs compared with NIFS population could mean participation and reporting bias; multiple comparisons Medical confirmation for some cases; fetal deaths as well as live births; external comparison groups to evaluate possible biases
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Study Design Population Outcomes Results Adjustments Comments
Adverse Pregnancy Outcomes
Araneta et al., 2004 (Vol. 4) Retrospective cohort Deployed women admitted to military hospitals for pregnancy-related diagnoses (including live births, abortions, ectopic pregnancies, pregnancy-related complications) from 8/2/1990 to 5/31/1992 and who responded to mailed survey: GW-exposed conceptions (n = 415), GW postwar conceptions (n = 298), NDVs (n = 427) Self-reported stillbirths, spontaneous abortions, ectopic pregnancies, pregnancy-related complications (ICD-9-CM codes 640–676); confirmed by discharge diagnostic data Adjusted RRs: mothers: GWV vs NDV postwar conceptions: spontaneous abortions, 68 vs 39 (RR = 2.92, 95% CI 1.87–4.56); ectopic pregnancies, 32 vs 6 (RR = 7.70, 95% CI 3.00–19.8); GWV vs NDV exposed conceptions: spontaneous abortions, 48 vs 39 (RR = 1.44, 95% CI 0.91–2.29); ectopic pregnancies, 10 vs 6 (RR = 1.91, 95% CI 0.67–5.46) Age, race, education, marital status, branch of service, military rank, parity, history of adverse outcome Overall response rate: 50% Low response rate; no information on smoking, alcohol, caffeine, other known risk factors for fetal loss; possible limited generalizability due to restriction to military hospital admissions; recall bias Confirmation with discharge data, assessed GW-exposed and postwar conceptions
Fertility
Ishoy et al., 2001a (Vol. 4) Cross-sectional Danish Gulf War Study, 661 GWVs 215 NDVs Self-reports of sexual problems (including reduced libido); measured male reproductive hormones: serum concentrations of LH, FSH, testosterone, inhibin B Male GWVs vs NDVs: self-reported sexual problems, 12.0% vs 3.7% (p < 0.001); reproductive hormones, no significant difference; suspected oligospermia, FSH ≥ 10 IU/L, inhibin B £ 80 pg/mL, 1.6% vs 1.6%; fertility rates, spontaneous abortion, congenital malformations: no differences Age; BMI available; stratified on deployment organization, duration of deployment Participation rates: GWVs, 83.6%; NDVs, 57.8% Limited control for confounding, small numbers for study of fertility rates, congenital malformations; objective measurement of hormones
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Maconochie et al., 2004 (Vol. 4) Retrospective cohort (same cohort as Doyle et al., 2004) Male UK veterans fathering or trying to father pregnancies after GW and before 8/97 10,465 GWV 7,376 NDV Self-reported fertility problems: tried unsuccessfully for > 1 year and consulted doctor; type I infertility: never achieving pregnancy; type II infertility: never achieving live birth; semen quality; time to conception; attempted clinical confirmation from both partners’ physicians Adjusted ORs GWVs vs NDVs: fertility problems, 732 vs 370: (OR = 1.38, 95% CI 1.20–1.60); type I 259 vs 122 (OR = 1.41, 95% CI 1.05–1.89); type II 356 vs 166 (OR = 1.50, 95% CI 1.18–1.89); time to conception > 1 year for planned pregnancies, 845/9,968 vs 528/7,408 (OR = 1.18, 95% CI 1.04–1.34) (increase in risk stable with time since GW) Maternal and paternal age at first infertility consult or post-GW conception, year of first consult or conception, pre-GW pregnancy history, military service and rank, smoking, alcohol, pregnancy order Response rates: GWVs, 53%; NDVs, 42% Limitations: low response rates, possible recall bias, clinically evaluated only 40% Strengths: attempted clinical evaluation, information on nonresponders available
Volume 10 Primary Study
Bukowinski, et al., 2012 Cross-sectional 178,766 infants in DoD Birth and Infant Health Registry born between 1998–2004 with at least one parent who was GWV (26,617 born to female GWV and 159,446 born to male GWV) Birth defects diagnosed in first year of life: five most prevalent and three reported to be increased in children of deployed GWV No association between being deployed and birth defect (OR = 1.05, 95% CI 0.86–1.28) No statistically significant increases in any birth defects for GWV vs NDV females or males: ventricular septal defect; atrial septal defect; aortic valve stenosis; hypoplastic left heart syndrome; patent ductus arteriosus; renal agenesis/dysgenesis; hypospadias and epispadias; and congenital hip dislocation Slight increase in birth defects in children born to men who had been deployed for 153–200 days (OR = 1.25, 95% CI 1.05–1.49) but not for a shorter or longer period Birth defects were not associated with any other exposures Adjustments for infant gender, parental age at birth, preterm birth, race/ethnicity, branch of service, pay grade, occupational category Assessed for modeled exposure to smoke from oil-well fires and nerve agents from Khamisiyah, in theater hospitalization, and length of deployment, including during major combat period

NOTE: BMI = body mass index; CDC = Centers for Disease Control and Prevention; CI = confidence interval; DU = depleted uranium; FSH = follicle-stimulating hormone; GW = Gulf War; GWV = Gulf War veteran; HFM = hemifacial microsomia; LH = luteinizing hormone; NDV = nondeployed veteran; NIFS = Nuclear Industry Family Study; OR = odds ratio; RR = risk ratio.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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CAUSES OF MORTALITY

This section evaluates the findings on external and disease-related causes of death among Gulf War veterans. External causes of mortality include deaths due to motor vehicle accidents and crashes, and homicides and suicides. Studies of veterans of other wars, such as the Vietnam War, have found increased mortality from external causes, particularly in the years immediately following deployment (IOM, 2006b). Disease-related causes of death include cancers, cardiovascular disease, and conditions of other organ systems.

In Volumes 4 and 8, only external causes of mortality were considered as a separate outcome; information on disease-related mortality was considered for each organ system when available. However, given the small number of new studies that have assessed mortality from any cause, this committee believed that it was reasonable to consider all causes of mortality in one section, the better to determine if deployed Gulf War veterans were at increased risk of dying compared with nondeployed veterans or with the general U.S. population. Therefore, this section begins with a brief description of the three new primary and one new secondary studies of mortality from a variety of outcomes that are cited for external causes and each relevant disease-related outcome later in this section. All primary studies on mortality are summarized in Table 4-24 at the end of this section.

New Mortality Literature

Three new primary studies of mortality were identified by the committee as well as one presentation from VA, which was considered to be a secondary study. Two studies were conducted on UK Gulf War veterans (Knapik et al., 2009; UK Ministry of Defence, 2014) and the third was a follow-up study of Australian Gulf War veterans (Sim et al., 2015). The first study, a statistical report from the UK Ministry of Defence, compared mortality rates for 53,409 deployed and 53,143 nondeployed (era) UK veterans from April 1, 1991, through December 31, 2013. Groups were similar based on age, gender, service component, regular vs reservist status, and rank. Mortality rate ratios (MRRs) and standardized mortality ratios (SMRs) (see Box 2-1 for definitions of statistical terms) were calculated for the two veteran groups and also for each veteran group and the general UK population adjusted for age, sex, and year. Cause of death was provided by the National Health System Information Centre for Health and Social Care and the National Office of Statistics for deaths that occurred in England and Wales, the General Register Office for deaths that occurred in Scotland, and the Northern Ireland Statistics Research Agency for deaths that occurred in Northern Ireland. These data have been used for all calculations where the veteran cohorts are compared to the UK population. Defence Statistics receives quarterly updates from each of these sources.

Over the 22-year follow-up period, a total of 1,506 deaths occurred among deployed veterans and 1,627 deaths occurred among era veterans; the difference in deaths between the groups was not statistically significant (MRR = 0.95, 95% CI 0.88–1.02). Causes of death were presented by total, all-cause coded, disease-related and major subcategories (e.g., neoplasms, infectious and parasitic diseases, conditions of the nervous system, conditions of the circulatory system, conditions of the respiratory system, conditions of the gastrointestinal system, and all other disease-related causes), and external causes including major categories and specific causes when available. Selected categories were compared for the veterans groups and the general UK population. These comparisons were limited to all causes, all disease-related, neoplasms overall, circulatory system conditions as a category, all external causes, suicide and open verdict (deaths where intent could not be definitively proved), and transportation accidents (these include motor vehicle, motorcycle, pedestrian, train, airplane, air and space, water, and other). Specific results are presented below under each category.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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The second primary study examined only external causes of death and was a systematic review of postdeployment mortality from injuries (Knapik et al., 2009). Although no new data were collected, the authors performed a meta-analysis of 20 studies (identified from a database search) of both Vietnam and Gulf War service members. Postdeployment injury mortality was assessed using ICD-9-CM E-codes E800–E999 (external causes of injury). Five of the studies were specific to Gulf War veterans and were retrospective cohort studies.

The third primary study was the Australian Gulf War Veterans’ Follow Up Health Study (Sim et al., 2015). It updated all-cause and cause-specific mortality through 2010 in the entire cohort of 1,871 Australian Gulf War veterans and a comparison group of 2,922 veterans, frequency matched based on age, rank, and branch of service. Mortality data was obtained from the Australian National Death Index and included the date of death and all ICD-9 and ICD-10 coded underlying causes of death. Results were adjusted for age, rank category, and service branch, but not for smoking. A total of 108 deaths (2.3%) were reported for the entire cohort, and because this was such as small percentage of the cohort, categories of mortality were limited to all cause, overall external causes, intentional self-harm, transport accidents, cancer, and cardiovascular disease. Women veterans made up 2% of the deployed cohort, but because no women in either group had died during the 20-year follow-up, they were excluded from the mortality analyses.

The Volume 10 committee also was provided a presentation from VA on the most recent results of third survey wave of the cross-sectional National Health Study of Persian Gulf War Era Veterans (Bossarte, 2014). Although the data are not published and have not been peer reviewed, the committee found the information presented by VA to be useful and therefore discusses it here. The cohort consisted of 621,902 Gulf War veterans who served in the Persian Gulf between August 1, 1990, and March 1, 1991, and 746,248 veterans who served during this time, but were not deployed. The follow-up period spanned 20 years; for deployed veterans, follow-up began the year they left the theater, for nondeployed veterans, follow-up began May 1, 1991. For both groups, follow-up ended on the date of death or December 31, 2011. Cause of death was obtained from the National Death Index. A total of 21,144 deaths occurred in the deployed group and 29,340 deaths in the nondeployed group. Using the U.S. population (1960–2009) as the reference group, both deployed and nondeployed veterans had statistically significantly lower SMRs for all-cause deaths (SMR deployed = 0.53, 95% CI 0.52–0.53; SMR nondeployed = 0.54, 95% CI 0.53–0.54); mortality rates for the deployed and nondeployed veterans were adjusted for age, sex, race, branch of service, and unit component. However, the committee notes that these findings should be interpreted with caution as using a 50-year span of non-age–adjusted mortality in the general U.S. population is not the most appropriate comparison group. The five most frequent causes of death were the same for both groups of veterans: malignant neoplasms, heart disease, transportation injuries, intentional self-harm, and other injury (major).

External Causes

Summary of Literature from Volumes 4 and 8

The Volume 4 committee reviewed four primary and two secondary studies that examined external mortality in Gulf War veterans, but all had numerous limitations. Although there were no statistically significant findings after adjustment for age, sex, race, and year of death, some studies suggested a modest increase in transportation-related deaths among deployed Gulf War veterans compared with nondeployed veterans in the first several years after the war (DASA, 2005; Kang and Bullman, 1996, 2001; Macfarlane et al., 2000; Writer et al., 1996).

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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The Volume 8 committee identified five new primary studies and two secondary studies reporting on external causes of mortality among Canadian, UK, and U.S. veterans. The Canadian and UK studies were small, reflecting the relatively small number of personnel deployed from these countries. In the UK study, a previously reported increase in mortality from external causes had essentially disappeared with an additional 5 years of follow-up (Macfarlane et al., 2005). In the Canadian study, there was an excess of deaths from air and space transportation-related crashes among Gulf War veterans, but the authors suggest that this may have been due to greater employment of veterans in flight-related occupations (Statistics Canada, 2005). New studies concerning fatal motor vehicle accidents in U.S. Gulf War veterans found that younger age, lower education, and not using seatbelts or other restraints were risk factors for these events (Lincoln et al., 2006). The Volume 8 committee found that the studies provided evidence of a modestly higher mortality from all transportation-related causes among Gulf War deployed veterans compared with era veterans. In U.S. veterans, the excess was largely due to motor vehicle accidents specifically, which diminished and perhaps disappeared over time. The Volume 8 committee concluded that there was limited/suggestive evidence of an association between deployment to the Gulf War and an increase in mortality from external causes, primarily motor vehicle accidents, in the early years after deployment.

New Literature

Primary Studies

The UK Ministry of Defence (2014) statistical report listed categories of external causes of mortality including transportation accidents, overall and with additional subcategories of car, pedestrian, motorcycle, air and space, water, and other; accidental injuries including falls, inanimate mechanical forces, poisonings, and exposures; intentional self-harm and events of undetermined intent; assault; and legal interventions and operations of war. No statistically significant difference in mortality rates was found for any of the categories or subcategories of external causes between deployed and nondeployed UK veterans. However, when the overall SMRs7 were calculated that compared deployed and nondeployed veterans to the age- and gender-adjusted UK population from 1991 to 2013, the veterans of both groups had a statistically significant decreased risk of dying overall (SMR deployed = 0.60, 95% CI 0.57–0.63; SMR nondeployed = 0.64, 95% CI 0.61–0.67), but they had increased rates of deaths from transportation accidents (SMR deployed = 1.86, 95% CI 1.63–2.13; SMR nondeployed = 1.61, 95% CI 1.39–1.86). The authors further investigated the increased risk of dying from transport accidents in both veteran cohorts compared with the age- and gender-standardized UK population. SMRs were calculated using 3-year moving averages for each year from 1991 to 2013. The SMR for all causes of death and deaths due to external causes peaked in 1992 and remained elevated in the years immediately following the Gulf War as previously reported in Volumes 4 and 8.

The meta-analysis performed by Knapik et al. (2009) only examined death from external causes, that is, motor vehicle accidents, suicide, homicide, and all other external causes. The authors reported summary mortality rate ratios8 (SMRR). Injury-related mortality was increased for deployed UK veterans vs

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7 Although the UK Ministry of Defence and Sim et al. (2015) both present standardized mortality ratios and hazard ratios multiplied by 100, the committee presents the results on a 1.0 scale to be consistent with the more common practice as well as to make comparisons with the U.S. literature easier.

8 A summary mortality rate ratio is a summary statistic reflecting the comparison of mortality rates of deployed and nondeployed veterans, whereas an SMR represents a ratio of frequencies (observed deaths in either deployed or nondeployed veterans vs expected number of deaths derived from rates occurring in a reference population, usually the general U.S. population).

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×

nondeployed veterans (SMRR = 1.26, 95% CI 1.16–1.37) during the 3 to 8 years of follow-up. Much of the excess mortality among deployed veterans was associated with motor vehicle events (SMRR = 1.39, 95% CI 1.22–1.60). At 7 to 13 years of follow-up, excess mortality appeared to decrease, but mortality rates for all external causes and motor vehicle events remained statistically significantly higher among the deployed veterans (SMRR external causes = 1.09, 95% CI 1.04–1.14 and SMRR motor vehicle = 1.29, 95% CI 1.18–1.40). No statistically significant difference between deployed and nondeployed veterans was found for suicide or homicide. However, two of the studies used in the meta-analysis (Kang and Bullman, 1996, 2001) stratified mortality rates by gender and found that female Gulf War veterans had statistically significantly higher adjusted MRRs for all external causes and the specific subcategories of motor vehicle events, suicide, and homicide, compared with male veterans. The authors did not examine other causes of death included in all external causes, such as falls, firearms, poisoning, or asphyxiation. The committee notes that the authors used the entire range of external cause codes (E800–E999) without eliminating accidental poisoning (E850–E869), adverse effects of therapeutic drugs (E930–949), medical misadventure during surgical and medical care (E870–E876), and injuries resulting from operations of war (E990–E999). Therefore, the individual studies that assessed mortality postdeployment might have contributed to misclassification errors when considered in aggregate in the meta-analysis.

In the Australian Gulf War Veterans’ Follow Up Health Study (Sim et al., 2015) the all-cause mortality and all-external cause mortality were lower for both veterans cohorts compared with the Australian male population, but the differences were statistically significant only for the era veterans (all-cause SMR = 0.59, 95% CI 0.45–0.76; all external causes SMR = 0.61, 95% CI 0.41–0.92), but not the deployed veterans (all cause SMR = 0.77, 95% CI 0.58–1.02; all external causes SMR = 0.70, 95% CI 0.43–1.13). No statistically significant differences between the deployed or era veterans and the Australian male population were found for intentional self-harm or transport accidents, nor were there differences between deployed and era veterans for all external causes (SMR = 1.19, 95% CI 0.63–2.25), intentional self-harm (SMR = 1.12, 95% CI 0.39–3.17), or transportation accidents (SMR = 1.19, 95% CI 0.45–3.16).

Secondary Study

In VA’s presentation to the committee (Bossarte, 2014), mortality rates of deployed and nondeployed veterans were compared to each other and to the U.S. population. No statistically significant difference was found for all-cause mortality (MRR = 0.98, 95% CI 0.97–1.00) or for all external causes of death (MRR = 1.02, 95% CI 0.99–1.05). However, when external causes of death were presented by subcategories of motor vehicle-related, suicide, and homicide, deployed veterans had an increased risk of motor vehicle deaths compared with nondeployed veterans (MRR = 1.09, 95% CI 1.03–1.15). No significant difference in the MRR was found for suicide or homicide among deployed and nondeployed veterans.

The only external cause-specific subcategories using the U.S. population as the reference group were suicide and drivers of motor vehicle crash deaths (Bossarte, 2014). For both the deployed and nondeployed veterans, rates of suicide were statistically significantly lower (SMR deployed and nondeployed = 0.91, 95% CI 0.88–0.95) compared with the U.S. population. The rate of dying as the driver in motor vehicle crashes for deployed veterans was not statistically different from the whole U.S. population (SMR = 0.97, 95% CI 0.91–1.02), but the rate of dying as the driver of motor vehicle crashes for nondeployed veterans was statistically significantly lower compared with the U.S. population (SMR = 0.88, 95% CI 0.83–0.93).

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Conclusions

Both the Volume 4 and Volume 8 committees found that the studies of mortality from external causes provided evidence of a modestly higher mortality from all transportation-related causes, specifically motor vehicle crashes (which diminished but persisted), among Gulf War deployed veterans compared with era veterans. These findings are consistent with the new literature reviewed by the Volume 10 committee. Numerous hypotheses have been proposed to account for this increased risk including an increase in risk-taking behaviors following deployment, which may be due to posttraumatic stress or other mental health factors; increased use of alcohol or substances that may increase risk of injury; or possible combat-zone exposures that may lead to ill-defined syndromes that affect decision making, reaction time, or balance (Bell et al., 2001; Gackstetter et al., 2006; Gray and Kang, 2006; Killgore et al., 2008).

Therefore, the Volume 10 committee concludes that there is limited/suggestive evidence of an association between deployment to the Gulf War and an increase in mortality from external causes, primarily motor vehicle accidents, in the early years after deployment. However, after those first few years, there is limited/suggestive evidence of no association between deployment to the Gulf War and external causes of mortality.

Disease-Specific Mortality

As noted above, the committee decided to consider mortality from conditions of specific organ systems (such as cardiovascular and neurologic) or from specific diseases (such as cancer) in this section. The committee notes that mortality data on Gulf War veterans are available for only a few conditions or organ systems.

First, the committee briefly considers the overall rates of disease-specific mortality based on underlying cause of death. In the UK follow-up study (UK Ministry of Defense, 2014), 911 deployed veterans died of disease-related causes compared with 1,073 nondeployed veterans (MRR = 0.88, 95% CI 0.81–0.97; adjusted for age). In the Australian Gulf War Follow Up Study, all disease-specific mortality was not reported. Cancer and cardiovascular disease were the only specific causes of death reported, and are discussed in those sections below. VA’s presentation to the committee (Bossarte, 2014) included selected mortality risk rates over a 20-year period (1991–2011) for all disease causes as well as selected subcategories for all deployed and nondeployed U.S. veterans. After adjusting for age, sex, race, branch of service, and unit component, deployed veterans had a statistically significantly lower rate of death from all disease-related causes compared with nondeployed veterans (MRR = 0.96, 95% CI 0.94–0.98).

Cancer

Summary of Volumes 4 and 8

Cancer mortality in Volumes 4 and 8 focused on brain cancers, although all other cancers were included if data were available. Two primary studies of cancer mortality were reviewed in Volume 4 and one additional primary study in Volume 8. An association of brain-cancer mortality with possible nerve-agent exposure (based on the 2000 DoD exposure model for the Khamisiyah munitions demolition) was observed in one study discussed in Volume 4 (RR = 1.94, 95% CI 1.12–3.34; adjusted for age at entry to follow-up, race, sex, rank, and unit component) (Bullman et al., 2005). The increased relative risk of dying from brain cancer in veterans exposed to 2 days or more at Khamisiyah vs unexposed deployed veterans was further supported after an additional 4 years of follow-up (MRR = 2.71, 95% CI 1.25–5.87;

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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adjusted for sex, race, type of unit, and age) (Barth et al., 2009). Bullman et al. (2005) also assessed the risk of brain cancer mortality from modeled exposure to smoke from the oil-well fires. They found no statistically significant increase in brain cancer death, however, an association of brain cancer death with exposure to smoke from oil-well fires was seen at the later follow-up (MRR = 1.81, 95% CI 1.0–3.27) (Barth et al., 2009). Sex-specific rate ratios were presented and no difference in brain cancer deaths was observed between deployed and nondeployed women or men. However, the Volume 8 committee noted that the numbers of cases of brain cancer in veterans who had possibly been exposed to nerve agents was small, and there was little previous evidence of an association between exposure to sarin or organophosphate pesticides and brain cancer. Therefore, the Volume 8 committee concluded that there was insufficient/inadequate evidence of an association between Gulf War exposures and brain cancer.

Primary studies that assessed mortality from all types of cancers in Volumes 4 and 8 failed to show an increased risk in deployed vs nondeployed veterans (DASA, 2009; Kang and Bullman, 2001; Macfarlane et al., 2003, 2005; Statistics Canada, 2005). Both committees found that, in general, many veterans were still too young for cancer diagnoses, given the maximum follow-up period of about 10 years, and for most cancers the follow-up period after the Gulf War was probably too short to expect the onset of cancer, let alone death from it. Only the UK statistical report (DASA, 2009) had a follow-up period of 16 years and it found no increase in the number of malignant neoplasms in deployed vs nondeployed UK Gulf War veterans. The Volume 8 committee did not reach any conclusions regarding the association between deployment to the Gulf War and mortality from any cancer.

New Literature

Two of the primary studies described above assessed disease-specific mortality in Gulf War veterans: one in UK veterans and one in Australian Gulf War veterans. The statistical report from UK Ministry of Defence (2014) compared disease-specific mortality rates for deployed and nondeployed UK Gulf War veterans from April 1, 1991, through December 31, 2013. The largest contributor of disease-related deaths was neoplasms: 404 neoplasm deaths out of 911 disease-related deaths in deployed veterans and 455 neoplasm deaths out of 1,035 disease-related deaths in nondeployed veterans. Consistent with previous studies (e.g., Barth et al., 2009; Bullman et al., 2005), no statistically significant difference in the number of deaths due to neoplasms was found between the two groups (MRR = 0.89, 95% CI 0.78–1.02; adjusted for age). Neoplasms were examined by specific sites. The numbers of deaths from malignant neoplasms of the colon and of the bronchus and lung were statistically significantly lower among the deployed veterans than the comparison group (MRR colon = 0.54, 95% CI 0.31–0.96 and MRR lung = 0.60, 95% CI 0.42–0.85). There was no difference in brain cancer mortality (MRR = 0.71, 95% CI 0.46–1.09).

The Australian Gulf War Veterans’ Follow Up Health Study (Sim et al., 2015) compared cancer mortality rates between deployed and nondeployed veterans as well as between each veteran cohort and the age-adjusted Australian male population. Among deployed veterans, observed cancer deaths were slightly higher than expected compared with the age-matched Australian male population, but this difference was not statistically significant. The observed number of cancer deaths in the comparison veteran cohort was lower than expected, but also was not statistically different from the Australian male population. The rate of cancer deaths in deployed veterans was not statistically different from the nondeployed veterans (HR = 1.82, 95% CI 0.88–3.74). Because there were fewer than five brain cancer deaths in both the veteran cohorts, further analyses were not performed.

VA’s presentation to the committee was considered a secondary study and included mortality rates from all cancers and specifically for lung and brain cancers (Bossarte, 2014). No statistically significant

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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difference was observed between both the deployed and nondeployed veterans with regard to death from cancer (MRR = 0.99, 95% CI 0.95–1.03; adjusted for race, sex, age, rank, branch of service, and unit component). Mortality rates for lung cancer were calculated for each veteran group, but only compared with the U.S. population, not to each other. Because the committee was not presented with additional information including specific model covariates, adjustment weights, or the denominator for the U.S. mortality population used, it was not possible for the committee to calculate even a crude mortality risk ratio comparing lung cancer deaths between the veteran groups. The lung cancer mortality rates for both deployed and nondeployed veterans were statistically significantly lower than that for the general U.S. population (SMR deployed = 0.60, 95% CI 0.57–0.64; SMR nondeployed = 0.59, 95% CI 0.56–0.62).

VA also presented more detailed information on mortality from brain cancer (Bossarte, 2014). Despite using a non-age–adjusted, 50-year span of mortality in the general U.S. population as the referent group, deployed veterans had a statistically significant decreased risk of dying from brain cancer (SMR = 0.88, 95% CI 0.78–0.98); but there was no difference for nondeployed veterans (SMR = 0.93, 95% CI 0.85–1.02). The MRR appeared to show lower risk of brain cancer mortality for deployed veterans compared with nondeployed veterans, but this difference was not statistically significant (MRR = 0.92, 95% CI 0.80–1.07).

As a follow-up to Barth et al. (2009) and Bullman et al. (2005), VA also performed additional modeling using the subset of deployed Army veterans who were considered to be exposed to smoke from oil-well fires and nerve gas at Khamisiyah (based on a DoD model that was found to have serious limitations by GAO [2004]) to estimate whether they were at increased risk of brain cancer (Bossarte, 2014). Relative risk models were adjusted for sex, race, age, and unit type; no statistically significant differences were found for veterans exposed to smoke from oil-well fires at Khamisiyah overall (RR = 1.42, 95% CI 0.93–2.19) or for veterans exposed to 2 or more days at Khamisiyah (RR = 1.60, 95% CI 0.80–3.20) compared with nonexposed veterans.

Conclusions

Two new primary studies on mortality from cancer in Gulf War veterans were reviewed. Even after following Gulf War deployed and era veterans for 22 years, no statistically significant differences in mortality were found in either the primary or secondary studies, which is consistent with the findings from Volumes 4 and 8. Furthermore, no differences were found between the mortality rates of the two types of cancers—brain and lung—thought to be of greatest concern for Gulf War veterans.

Therefore, the Volume 10 committee concludes that there is insufficient/inadequate evidence of an association between deployment to the Gulf War and mortality from any form of cancer.

Neurologic Conditions

This section covers conditions and disorders related to the central nervous system (those affecting the brain or spinal cord). The neurologic conditions of interest are primarily degenerative, and include MS, ALS, Parkinson’s disease, and Alzheimer’s disease. Brain cancer is discussed in the section on cancer.

Summary of Volumes 4 and 8

No studies on MS were reviewed in Volume 4. The Volume 8 committee reviewed one primary study (Barth et al., 2009) and one secondary study (Kelsall et al., 2005) on mortality from MS. Barth

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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et al. compared mortality rates from neurologic conditions through 2004 in the entire deployed cohort of 621,902 veterans who served in the Gulf War between August 1, 1990, and March 1, 1991, with 746,248 nondeployed veterans who served concurrently. Records from the VA Beneficiary Identification and Records Locator Subsystem, a database consisting of all veterans eligible for VA benefits, and the Social Security Administration’s Death Masterfile were examined. Death certificates and medical records were reviewed by experts who were blinded to deployment status. A total of 19 deaths due to MS were identified; 6 in the deployed group and 13 in the nondeployed group. There was no increased risk for MS mortality (RR = 0.67, 95% CI 0.24–1.85). Although this was a well-designed study, the authors were unlikely to detect an increased risk of MS associated with deployment because MS mortality is likely to be minimal during the first 15 years of the illness.

ALS was the only neurologic condition of interest reviewed in Volume 4. Two primary studies (Coffman et al., 2005; Horner et al., 2003) and one secondary study (Haley, 2003) found that deployed veterans appear to have an increased risk of developing ALS, but these studies measured ALS incidence, not mortality. Several UK and U.S. mortality studies found no excess risk of dying from ALS among Gulf War veterans, but they were limited by short follow-up periods or their applied methods (DASA, 2005; Kang and Bullman, 1996; Macfarlane et al., 2000). In Volume 8, Barth et al. (2009) updated the original Kang and Bullman (1996) mortality study with data through December 2004. Similar to prior mortality studies, Barth et al. (2009) did not find any increase in ALS mortality in Gulf War veterans compared with nondeployed veterans (MRR = 0.96, 95% CI 0.56–1.62; adjusted for sex, race, type of unit, and age).

Neither the Volume 4 nor Volume 8 committees were able to identify any studies of dementia or Alzheimer’s disease in Gulf War veterans. Barth et al. (2009) compared mortality from Parkinson’s disease in deployed vs nondeployed Gulf War veterans. The adjusted MRR for Parkinson’s disease in male veterans was 0.71 (95% CI 0.17–2.99); three deaths among deployed veterans and eight among nondeployed); there were no cases among female veterans in either group.

New Literature

In the primary report from the UK Ministry of Defence (2014), mortality from diseases of the nervous system conditions as a whole were examined, but because there were so few deaths among the deployed veterans (n = 36) and the era veterans (n = 46), mortality for specific neurologic conditions such as MS, ALS, Alzheimer’s disease, or Parkinson’s disease was not presented. No statistically significant increased risk of mortality was found for neurologic conditions between deployed and nondeployed veterans (MRR = 0.80, 95% CI 0.52–1.24; adjusted for age).

VA’s presentation to the committee (a secondary study) included crude mortality rates and adjusted mortality rate ratios from three specific neurologic conditions: MS, ALS, and Parkinson’s disease (Bossarte, 2014). No statistically significant difference was observed between the deployed and nondeployed veterans with regard to death from MS (MRR = 0.85, 95% CI 0.53–1.34), ALS (MRR = 0.97, 95% CI 0.74–1.28), or Parkinson’s disease (MRR = 0.64, 95% CI 0.34–1.21). SMRs for MS were calculated for each veteran group compared with the U.S. population and the mortality rates for both deployed and nondeployed veterans were statistically significantly lower than in the general U.S. population (SMR deployed = 0.47, 95% CI 0.32–0.66; SMR nondeployed = 0.48, 95% CI 0.36–0.64).

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Conclusions

Relatively few deaths among either Gulf War deployed or era veterans were related to neurologic causes. Consistent with the one primary study on deaths from neurologic diseases reviewed in Volume 8, the new literature also showed few deaths from these causes. In the one secondary study that presented mortality information on conditions of the nervous system, no statistically significant differences were observed between the deployed and nondeployed veterans.

Therefore, the Volume 10 committee concludes that there is insufficient/inadequate evidence of an association between deployment to the Gulf War and mortality from neurologic conditions, specifically multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease.

The committee also concludes that there is insufficient/inadequate evidence of an association between deployment to the Gulf and mortality from amyotrophic lateral sclerosis, but the committee recognizes this occurs in the context of limited/suggestive evidence of increased ALS incidence among deployed veterans (as discussed in further detail in the Neurologic Conditions section).

Circulatory System Conditions

Summary of Volumes 4 and 8

No studies of mortality from circulatory system conditions were reviewed in Volume 4. The Volume 8 committee reviewed five primary reports on mortality from cardiovascular conditions in Gulf War veterans from Canada, the United Kingdom, and the United States (Bullman et al., 2005; DASA, 2009; Kang and Bullman, 2001; Macfarlane et al., 2005; Statistics Canada, 2005). Although each study adjusted for basic demographics, such as sex, age, race, branch of service, and various other military-related factors, none adjusted for potential lifestyle confounders, such as smoking or alcohol consumption. None of the adjusted MRRs for cardiovascular conditions in deployed vs nondeployed veterans was statistically significant. Therefore, the Volume 8 committee concluded that there was limited/suggestive evidence of no association between deployment and mortality from cardiovascular disease in the first 10 years after the war.

New Literature

Two new primary studies assessed mortality from cardiovascular disease. The UK Ministry of Defence mortality report of Gulf War veterans (2014) found no statistically significant differences in deaths since 1991 due to diseases of the circulatory system between deployed and nondeployed veterans (MRR = 0.88, 95% CI 0.75–1.03; adjusted for age). When SMRs for deployed and nondeployed veterans were compared with the age- and gender-adjusted UK population, both groups of veterans had a statistically significant decreased risk of dying from circulatory system diseases (SMR deployed = 0.48, 95% CI 0.43–0.54; SMR nondeployed = 0.53, 95% CI 0.48–0.59).

A total of 16 deaths (5 deployed and 11 nondeployed) from cardiovascular disease were reported in the Australian Gulf War Veterans’ Follow Up Health Survey (Sim et al., 2015). The rates of death from these conditions was not statistically different between the cohorts (HR = 0.79, 95% CI 0.27–2.29; adjusted for age, rank, and branch of service). Mortality from cardiovascular conditions was lower in both veteran cohorts compared with the Australian male population, but neither reached statistical significance (SMR deployed = 0.46, 95% CI 0.19–1.11 and SMR nondeployed = 0.63, 95% CI 0.35–1.14). The authors note that the power of this study to detect excess mortality continues to be limited because

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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the veteran cohort “was still quite young at 30 November 2010, with approximately 40% aged between 35–44 years, and the period of follow up is still relatively short for the purpose of detecting disease-related deaths.”

VA’s presentation to the committee, which was considered to be a secondary study, included mortality rates from circulatory system diseases (Bossarte, 2014). No statistically significant difference was observed between the deployed and nondeployed Gulf War veterans (MRR = 0.98, 95% CI 0.94–1.02; adjusted for race, sex, age, branch of service, and unit component).

Conclusions

Consistent with the findings of mortality from cardiovascular disease presented in Volume 8, the Volume 10 committee also failed to find any statistically significant differences in mortality from these conditions between deployed and nondeployed veterans after 20 or more years of follow-up. However, the committee notes that the models used to compute MRRs for Australian, UK, and U.S. studies adjusted for some basic demographics, but did not adjust for lifestyle factors, such as smoking or alcohol consumption, that are known potential confounders for cardiovascular conditions.

Therefore, the Volume 10 committee concludes that there is limited/suggestive evidence of no association between deployment and mortality from cardiovascular disease.

Respiratory Conditions

Summary of Volumes 4 and 8

No studies of mortality from respiratory conditions were reviewed in Volume 4. The Volume 8 committee identified three primary studies on mortality from respiratory conditions in Gulf War veterans from Canada and the United Kingdom (Macfarlane et al., 2000, 2005; Statistics Canada, 2005). The UK study assessed mortality through March 31, 1999, and found no excess deaths due to conditions of the respiratory system in either deployed or nondeployed veterans (Macfarlane et al., 2000). An update of the same cohort through 2004 (Macfarlane et al., 2005) again found no excess in deaths related to respiratory disease. Bullman et al. (2005) examined cause-specific mortality through December 31, 2000, in deployed U.S. veterans considered to be exposed or not exposed to nerve agents at the Khamisiyah munitions destruction in 1991. No increase in mortality due to respiratory conditions was seen in the exposed veterans (RR = 1.03, 95% CI 0.62–1.72; adjusted for age). Similarly, no increased risk for respiratory disease mortality was observed when the authors divided the exposed group into persons exposed for 1 day only or for 2 days.

Statistics Canada (2005) conducted a mortality follow-up study of Canadian Gulf War veterans and compared them to randomly selected Canadian veterans who were eligible but not deployed to the Gulf War and to the general Canadian population. There were 5,117 members in the deployed cohort and 6,093 members in the nondeployed population. The authors estimated the study power to be 80% to find a 60% increase in total mortality; however, there were insufficient deaths from respiratory disease to make meaningful comparisons between the veteran cohorts or with the general population.

Two secondary respiratory disease mortality studies were considered by the Volume 8 committee. Kang and Bullman (1996) found that through September 1993 Gulf War veterans had a statistically significant decreased risk of death due to respiratory illness (SMR = 0.14, 95% CI 0.07–0.23) compared with the U.S. population, and a slight but statistically insignificant increase when compared with nondeployed veterans. However, there were only 14 respiratory disease-related deaths in both the deployed and nondeployed groups. An updated mortality study of the same cohort through December 31, 1997 (Kang and Bullman, 2001), found no statistically significant differences between the veteran groups for

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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respiratory mortality and both veteran cohorts had statistically significant lower respiratory mortality compared with the general U.S. population. The Volume 8 committee found no statistically significant excess of mortality due to respiratory disease among Gulf War veterans.

New Literature

In a primary study of UK Gulf War veterans, the UK Ministry of Defence (2014) found few deaths due to respiratory diseases (34 of 1,506 total deaths among the deployed veterans and 36 of 1,583 total deaths among the nondeployed veterans). The difference was not statistically significant (MRR = 0.93, 95% CI 0.58–1.49; adjusted for age). Specific types of respiratory system conditions were not presented. Lung and other respiratory system cancers are considered in the Cancer section. Because the number of deaths due to respiratory conditions was few, standardized mortality ratios comparing deployed and nondeployed veterans with the age- and gender-adjusted UK population were not calculated.

VA’s presentation to the committee (Bossarte, 2014) included mortality rates for respiratory conditions for both deployed and nondeployed Gulf War veterans. This secondary study found no statistically significant difference between the two groups (MRR = 0.96, 95% CI 0.86–1.06; adjusted for race, sex, age, branch of service, and unit component).

Conclusions

The new literature reviewed by the Volume 10 committee was consistent with the literature reviewed in Volume 8, where few deaths due to respiratory causes were reported and no evidence of different mortality rates were observed between deployed and nondeployed veterans.

Therefore, the Volume 10 committee concludes that there is limited/suggestive evidence of no association between deployment to the Gulf War and mortality from respiratory disease.

Gastrointestinal System Conditions

Summary of Volumes 4 and 8

No studies of mortality from gastrointestinal conditions were reviewed in Volume 4. The Volume 8 committee reviewed two studies that assessed mortality from gastrointestinal diseases in UK Gulf War veterans. Macfarlane et al. (2005) assessed mortality over a 13-year follow-up period. Based on National Health Service data, Gulf War veterans experienced fewer deaths from gastrointestinal conditions than the era cohort, but after adjusting for age the difference was not statistically significant (MRR = 0.77, 95% CI 0.40–1.46). The UK Defence Analytical Services Agency (DASA, 2009) published summary statistics on causes of deaths in Gulf War deployed and nondeployed veterans through 2007; the age-adjusted MRR for gastrointestinal conditions was 0.71 (95% CI 0.46–1.11).

New Literature

In a primary study, the UK Ministry of Defence (2014) reported 88 deaths in Gulf War deployed veterans and 92 deaths in era veterans that were caused by gastrointestinal conditions other than cancers, since 1991; the difference was not statistically significant (MRR = 0.97, 95% CI 0.73–1.30; adjusted for age). Specific types of gastrointestinal conditions were not presented. Standardized mortality ratios

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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comparing deployed and nondeployed veterans with the age- and gender-adjusted UK population were not calculated.

In a secondary study, VA (Bossarte, 2014) included mortality rates from gastrointestinal conditions for both deployed and era Gulf War veterans. No statistically significant difference was observed between the two groups (MRR = 1.01, 95% CI 0.93–1.11; adjusted for race, sex, age, branch of service, and unit component).

Conclusions

Based on findings from Volume 8 and the new literature, there is no evidence of a statistically significant difference in mortality from gastrointestinal conditions between deployed and era Gulf War veterans.

Therefore, the Volume 10 committee concludes that there is limited/suggestive evidence of no association between deployment to the Gulf War and mortality from gastrointestinal conditions.

Infectious and Parasitic Diseases

Summary of Volumes 4 and 8

The Volume 4 and Volume 8 committees did not review studies of mortality related to or resulting from infectious and parasitic diseases because those outcomes were examined in Gulf War and Health, Volume 5: Infectious Diseases (IOM, 2007). Volume 5 characterized the long-term adverse health outcomes associated with infection by the following pathogens: Brucella species (spp.), the cause of brucellosis; Campylobacter spp., nontyphoidal Salmonella spp. and Shigella spp., which cause diarrheal disease; Coxiella burnetii, the cause of Q fever; Leishmania spp., the cause of leishmaniasis; Mycobacterium tuberculosis, which causes tuberculosis; Plasmodium spp., the cause of malaria; and West Nile virus, the cause of West Nile fever. That report stated, “Among U.S. Gulf War troops, the overall incidence of infectious diseases was low, mostly composed of acute diarrheal and respiratory infections; less than 20 cases each of viscerotropic leishmaniasis and cutaneous leishmaniasis; three cases of Q fever, a case of West Nile fever, and seven cases of malaria (Hyams et al., 1995, 2001)” (IOM, 2007). During Operations Desert Storm and Desert Shield, infectious diseases reportedly caused only one death among U.S. troops—a fatal case of meningococcal meningitis. The Volume 5 committee did not reach any conclusions on the associations between mortality from infection diseases and deployment to the Gulf War. Volume 5 contains a lengthy discussion of the long-term effects of these infectious diseases, when those effects might be evident, and the role of immunizations.

In the two UK studies of Gulf War deployed and era veterans (DASA, 2009; Macfarlane et al., 2005), fewer than 10 deaths in total were reported for this category. Bullman et al. (2005) examined mortality through 2000 from all and specific causes in Gulf War veterans exposed to the nerve-agent plume at Khamisiyah. A total of 29 deaths from infectious and parasitic diseases were reported in the exposed veterans and 56 deaths in the unexposed, but the difference was not statistically significant (MRR = 1.16, 95% CI 0.74–1.82; adjusted for age at entry to follow-up, race, sex, rank, and unit component).

New Literature

The primary UK Ministry of Defence mortality report (2014) listed “certain infectious and parasitic diseases,” but did not provide additional details on which specific diseases were included. A cumulative total of 20 deaths in this category since 1991 were reported: 11 deaths among the deployed veterans

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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and 9 deaths in the nondeployed veterans. The difference was not statistically significant (MRR = 1.23, 95% CI 0.50–3.01; adjusted for age).

In a secondary study, VA (Bossarte, 2014) included mortality rates from infectious diseases for both Gulf War deployed and era veterans. A total of 728 deaths and 1,196 deaths were reported among the deployed and era cohorts, respectively. The deployed veterans had a statistically significant decreased risk of dying from infectious diseases compared with era veterans (MRR = 0.74, 95% CI 0.67–0.81; adjusted for race, sex, age, branch of service, and unit component).

Conclusions

Few studies have presented mortality from infectious diseases. However, the results have consistently shown no statistically significant differences between deployed and era veterans. The VA presentation (Bossarte, 2014) suggests that the Gulf War deployed veterans are at less risk of developing and dying from infectious or parasitic diseases than nondeployed veterans; however, the committee did not have a category of association to indicate such a relationship.

Therefore, the Volume 10 committee concludes that there is limited/suggestive evidence of no association between deployment to the Gulf War and infectious or parasitic disease-related causes of mortality.

Limitations of Mortality Studies

Veterans deployed to the Persian Gulf region and veterans serving in the armed forces but not deployed may offer reasonably comparable groups for examining many health outcomes, including death, but there are considerations in the conduct and use of mortality studies. A major limitation of the mortality studies discussed in this section is the short follow-up period. In general, more time is required before investigators will be able to assess whether deployed veterans are experiencing increased mortality compared with their nondeployed counterparts, particularly for conditions with established risk factors and long latencies, such as cancer, or conditions that have deteriorating and protracted courses, such as cardiovascular diseases or some neurodegenerative disorders such as Parkinson’s disease.

A further limitation to the U.S. and Australian mortality studies is their reliance on the National Death Index for each country. Information in these indexes is taken from death certificates which are completed by different types of health professionals with varying levels of expertise in assessing cause of death. For example, in the United States information in these indexes is taken from death certificates that are completed by coroners, attending physicians, or medical examiners depending on the laws and processes in place to adjudicate deaths, and are generally state or county specific. Furthermore, cause of death is typically determined based on the first listed cause of death or underlying cause of death, and additional contributing causes of death were not taken into account for classification. The most reliable cause of death information is typically provided by medical examiners and those records are less likely to suffer from nondifferential misclassification bias, especially for causes of death that may have links to specific exposures or require knowledge of underlying pathology (IOM, 2003).

Finally, few studies have been published with enough power to assess cause-specific mortality rates among deployed and nondeployed Gulf War veterans from the United States or any coalition country (e.g., Australia, Canada, the United Kingdom). In addition to large cohort studies comparing deployed and nondeployed veterans, nested case-control studies among the deployed may yield efficient and more suitable comparisons between deceased or “sick” veterans (cases) and alive or “non-sick” veterans (controls).

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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TABLE 4-24 Causes of Mortality

Study Design Population Outcomes Results Adjustments Comments
Volumes 4 and 8 Primary Studies
Cancer
DASA, 2009 (Vol. 8) Summary statistics of causes of death from April 1, 1991, to December 31, 2007 53,409 UK GWVs vs 53,143 NDVs Mortality due to malignant neoplasms GWVs (209 cases) compared to NDVs (228 cases) MRR = 0.97 (95% CI 0.81–1.18) No significant difference in mortality rate was found for any of the specific classes of malignant neoplasm included in the study Single years of age structure of the Gulf cohort at January 1, 1991
Statistics Canada, 2005 (Vol. 8) Retrospective cohort study (cohort based on Goss Gilroy Inc., 1998) 5,117 Canadian GWVs; 6,093 Canadian NDVs, frequency matched for age, sex, and military duty status Mortality and cancer incidences determined from the CMD and CCD through 1999 Cancer mortality, (HR = 0.85, 95% CI 0.38–1.90) Incidence of any cancer (HR = 0.86, 95% CI 0.54–1.39); cancer of the gastrointestinal system (HR = 2.00, 95% CI 0.62–6.12); testicular cancer (HR = 0.76, 95% CI 0.18–3.24); cancer of the lymph nodes (HR = 0.65, 95% CI 0.16–2.62) Age, rank Limitations: Small sample; young age of cohort; short follow-up period; no information on other confounding factors
Macfarlane et al., 2005 (Vol. 8) Mortality cohort; 13-year followup 51,753 UK GWVs and 50,808 NDVs, randomly selected, matched by age, sex, service branch, rank; also fitness for active service in the army and Royal Air Force Mortality due to malignant neoplasms GWVs (123 deaths) vs NDVs (130 deaths): MRR = 1.01 (95% CI 0.79–1.30) Complete and long-term follow-up; cohort of moderate size; potentially other uncontrolled confounders
Kang and Bullman, 2001 (Vol. 4) Cohort mortality study; followup from 1991 through 1997 621,902 GWVs vs random sample of 746,248 NDVs Overall cancer mortality ascertained from BIRLS, death certificates, and NDI Males: GWVs (cases = 477) vs NDVs (cases = 860): RR = 0.90 (95% CI 0.81–1.01) Females: GWVs (cases = 49) vs NDVs (cases = 103): RR = 1.11 (95% CI 0.78–1.57) Age, race, branch of service, unit component, marital status Short latency; low age range; mortality ascertained with death certificates
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Study Design Population Outcomes Results Adjustments Comments
Bullman et al., 2005 (Vol. 4) Cohort mortality study (population from same source as Kang and Bullman, 1996, 2001) 100,487 U.S. Army GWVs exposed to chemical warfare agents at Khamisiyah; 224,980 nonexposed Army GWVs; exposure determined from the DoD plume model Brain cancer mortality through December 2000 ascertained from BIRLS and NDI Exposed (25 cases) vs unexposed (27 cases) RR = 1.94 (95% CI 1.12–3.34); Exposed 1 day: RR = 1.72 (95% CI 0.95–3.10) Exposed 2+ days: RR = 3.26 (95% CI 1.33–7.96) Age at entry, race, sex, unit component, and rank 9-year followup likely too short to examine brain cancer risk (increases with time since exposure); exposure assessment dependent on accuracy of the DoD plume model; multiple comparisons; death certificate diagnosis
Barth et al., 2009 (Vol. 8) Mortality cohort study, follow-up through 2004 of Bullman et al. (2005) 621,902 U.S. GWVs and 746,248 nondeployed era veterans; 98,406 GWVs exposed to Khamisiyah nerve agents; 123,478 GWVs exposed to oil-well fire smoke Brain cancer mortality GWVs (144 cases) vs NDVs (228 cases) MRR = 0.90 (95% CI 0.73–1.11) Khamisiyah exposed: MRR = 2.71 (95% CI 1.25–5.87) Oil-well fire smoke exposed: MRR = 1.81 (95% CI 1.00–3.27) Race, service branch, type of unit, age, marital status, and sex Similar results after 19 misclassified cancers removed from analysis; see Bullman et al. (2005)
Conditions of the Nervous System
Barth et al., 2009 (Vol. 8) Mortality cohort study, follow-up through 2004 of same cohort as Kang and Bullman (2001) 621,901 U.S. male GWVs and 746,247 male NDVs Mortality due to MS (McDonald criteria) (McDonald et al., 2001) GWVs (6 cases) vs NDVs (13 cases) MRR = 0.67 (95% CI 0.24–1.85) Race, service branch, type of unit, age, marital status
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×
Cardiovascular Conditions
Kang and Bullman, 2001 (Vol. 8) Cross-sectional, mortality 1991–1997 621,902 GWVs, 746,248 NDVs Mortality and vital status determined with VA BIRLS database and SSA Master Beneficiary Record database Men RR = 0.90 (95% CI 0.81–1.01) Women RR = 0.96 (95% CI 0.55–1.69) Age, race, service branch, type of unit, marital status Study had good power; limited by relying on death certificates rather than medical records; no adjustment for predeployment health status or confounders
Bullman et al., 2005 (Vol. 8) Retrospective cohort; follow-up from March 1991 through 2000 100,487 U.S. Army GWVs exposed to chemical warfare agents at Khamisiyah; 224,980 nonexposed Army GWVs (derived from Kang and Bullman, 2001); exposure determined from the 2000 DoD plume model Association of exposure to chemical warfare agents and mortality due to diseases of the circulatory system, determined through BIRLS, SSA; COD data from NDI 1.76% exposed vs 1.88% nonexposed RR = 0.89 (95% CI 0.74–1.06) Age, race, sex, rank, unit component Possible exposure misclassification, possible bias due to healthy warrior effect
Statistics Canada, 2005 (Vol. 8) Retrospective cohort study (cohort based on Goss Gilroy Inc., 1998) 5,117 Canadian GWVs; 6,093 Canadian NDVs, frequency matched for age, sex, and military duty status Mortality due to diseases of the circulatory system determined from the CMD and CCD MRR = 0.49 (95% CI 0.17–1.40) Age, sex, rank, marital status Small sample; short followup; young age of cohort; no information on smoking
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×
Study Design Population Outcomes Results Adjustments Comments
Macfarlane et al., 2005 (Vol. 8) Cohort; 13-year followup 51,753 UK GWVs and 50,808 NDVs, randomly selected, matched by age, sex, service branch, rank; also fitness for active service in the Army and Royal Air Force Mortality due to diseases of the circulatory system MRR = 0.87 (95% CI 0.66–1.14) Complete and long-term follow-up; cohort of moderate size; no control for confounding variables
DASA, 2009 (Vol. 8) Summary statistics of causes of death from April 1, 1991, to December 31, 2007 53,409 UK GWVs vs 54,143 NDVs Mortality due to diseases of the circulatory system MRR = 0.87 (95% CI 0.70–1.07) Age Roughly the same cohort as Macfarlane et al., 2005
Conditions of the Respiratory System
Macfarlane et al., 2000, 2005 (Vol. 8) Cohort study 2000: 53,462 UK GWVs vs 53,450 NDVs 2005: 51,753 UK GWVs and 50,808 NDVs Mortality (1991–1999/2004) due to diseases of the respiratory system 2000: 3 deaths in GWVs vs 3 deaths in NDVs, MRR = 1.0 (95% CI 0.1–7.5) 2005: 9 deaths in GWVs vs 6 deaths in NDVs, MRR = 1.64 (95% CI 0.58–4.66) Matching by sex, age, branch, fitness for service
Bullman et al., 2005 (Vol. 8) Cohort mortality study; followup from March 1991 through 2000 100,487 U.S. Army GWVs exposed to chemical warfare agents at Khamisiyah; 224,980 nonexposed army GWVs; exposure Association of exposure to chemical warfare agents and respiratory disease mortality, determined through BIRLS, SSA; COD data from NDI Exposed vs unexposed RR = 1.03 (95% CI 0.62–1.72) Age, race, sex, rank, unit component Short duration of followup; possible exposure misclassification
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×
External Causes of Mortality
Kang and Bullman, 1996, 2001 (Vol. 4) Retrospective cohort, 2.4-year follow-up; Retrospective cohort, approximately 7-year follow-up 695,516 GWVs vs 746,291 NDVs Mortality 1991–1997; Cox proportional hazards models Increased deaths from motor vehicle accidents in Kang and Bullman, 1996 (RR = 1.31, 95% CI 1.14–1.49) RRs became nonsignificant in Kang and Bullman, 2001 (RR = 1.17, 95% CI 0.98–1.4) in 1994–1995; Increased HIV deaths in NDVs; no difference in potential nerve gas exposure; no homicide or suicide increase Sex, age, race, marital status, branch of service, type of unit Short duration of followup; healthy-warrior effect may obscure difference
Macfarlane et al., 2000 (Vol. 4) Cohort study 53,462 UK GWVs vs 53,450 UK NDVs Mortality 1991–1999 Higher mortality in GWVs from external causes (MRR = 1.18, 95% CI 0.98–1.42); no increase in homicide or suicide Matching by sex, age, branch, fitness for service
DASA, 2005 (Vol. 4) Summary statistics of causes of death from April 1, 1991, to June 30, 2005 53,409 UK GWVs vs 53,143 UK NDVs Mortality 1991–June 2005 No increase in mortality except small and nonsignificant increase in transport accidents (SMR = 1.21, 95% CI 0.96–1.51); other external causes of accidental injury (SMR = 1.07, 95% CI 0.74–1.54); higher deaths from external causes disappeared about 10 years after Gulf War Matching by sex, age, branch
Lincoln et al., 2006 (Vol. 8) Retrospective cohort and nested case-control; risk factors for motor vehicle crash fatality (cohort derived from Kang and Bullman, 1996) 1,318 cases of motor vehicle crash mortality (1991–1995) identified from VA’s 1991 Gulf War cohort: 765 deployed GWVs, 553 NDVs; COD, demographic, and military records from the DMDC and FARS Annual motor vehicle mortality rate by risk factor Higher motor vehicle annual mortality rate in deployed veterans: 23.56 (95% CI 21.9–25.3) for deployed vs 15.87 (95% CI 14.6–17.3) for nondeployed per 100,000 Deployed population possibly associated with greater risk-taking behavior (younger, less educated, not married)
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×
Study Design Population Outcomes Results Adjustments Comments
Macfarlane et al., 2005 (Vol. 8) Cohort; 13-year followup (follow-up of Macfarlane et al., 2000) 51,753 UK GWVs and 50,808 NDVs, randomly selected, matched by age, sex, service branch, rank; also fitness for active service in the army and Royal Air Force Mortality rates All causes (MRR = 1.03, 95% CI 0.92–1.15); external causes (MRR = 1.19, 95% CI 1.02–1.39); transport accidents (MRR = 1.44, 95% CI 1.13–1.84); intentional self-harm (MRR = 1.04, 95% CI 0.80–1.36) No self-reported Gulf War theater exposure significantly associated with all cause, disease-related, or external mortality Complete and long-term follow-up; cohort of moderate size; potentially uncontrolled confounders
DASA, 2009 (Vol. 8) Summary statistics of causes of death from April 1, 1991, to December 31, 2007 53,409 UK GWVs vs 54,143 NDVs Mortality data, causes of death classified based on ICD-10 All external cause mortality (MRR = 1.09, 95% CI 0.95–1.25) No significant difference in mortality rate was found for any of the specific external causes of mortality included in the study Single years of age structure of the gulf cohort at January 1, 1991
Statistics Canada, 2005 (Vol. 8) Retrospective cohort (cohort based on Goss Gilroy Inc., 1998) 5,117 Canadian GWVs; 6,093 Canadian NDVs, frequency matched for age, sex, and military duty status Mortality and cancer incidences determined from the CMD and CCD, 1991–1999 All external causes (OR = 1.53, 95% CI 0.82–2.86); motor vehicle crash (OR = 0.74, 95% CI 0.18–3.11); air/space crash (OR = 5.50, 95% CI 1.16–26.0); suicide (OR = 1.17, 95% CI 0.46–2.95) Age, rank
Bullman et al., 2005 (Vol. 8) Cohort mortality study; followup from March 1991 through 2000 (population from same source as Kang and Bullman, 1996, 2001) 100,487 U.S. Army GWVs exposed to chemical warfare agents at Khamisiyah; 224,980 nonexposed army GWVs; exposure determined from the 2000 DoD plume model Association of exposure to chemical warfare agents and mortality, determined through BIRLS, SSA; COD data from NDI Exposed vs unexposed Any external cause: relative risk = 1.01 (95% CI 0.92–1.10) Suicide: relative risk = 1.05 (95% CI 0.88–1.25) Motor vehicle fatalities: relative risk = 1.00 (95% CI 0.86–1.17) Age, race, sex, rank, unit component Short duration of followup; possible exposure misclassification
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
×
Volume 10 Primary Studies
UK Ministry of Defence, 2014 Annual mortality report using national death data reported between April 1, 1991, and December 31, 2013 (reported as of February 1, 2014) All 53,409 UK GWVs and 53,143 UK NDVs 1,506 deaths among GWVs; 1,627 deaths among NDVs External cause and disease-related mortality Number of deaths in GWVs vs NDVs All causes: 1,506 vs 1,583 (RR = 0.95, 95% CI 0.88–1.02); Disease related: 999 vs 1,035 (RR = 0.88, 95% CI 0.81–0.97); All cancer: RR = 0.89 (95% CI 0.78–1.02) Colon cancer: RR = 0.54 (95% CI 0.31–0.96) Lung cancer: RR = 0.60 (95% CI 0.42–0.85) Brain cancer: RR = 0.71 (95% CI 0.46–1.09). Neurologic diseases: MRR = 0.80 (95% CI 0.52–1.24) Circulatory system diseases: MRR = 0.88 (95% CI 0.75–1.03) Respiratory diseases: MRR = 0.93 (95% CI 0.58–1.49) Gastrointestinal diseases: MRR = 0.97 (95% CI 0.73–1.30) Infectious diseases: MRR = 1.23 (95% CI 0.50–3.01) Comparison with age- and gender-adjusted UK population: GWV SMR = 0.48 (95% CI 0.43–0.54); NDV SMR = 0.53 (95% CI 0.48–0.59) External causes: 539 vs 505 (RR = 1.06, 95% CI 0.94–1.2); All subcauses were nonsignificant Transportation accidents: 213 vs 183 (RR = 1.16); Other accidental injury: 94 vs 94 (RR = 0.95); Intentional self-harm: 208 vs 190 (RR = 1.09). Comparing veterans to UK population: SMR deployed = 0.60 (95% CI 0.57–0.63); SMR nondeployed = 0.64 (95% CI 0.61–0.67), Deaths from transportation accidents: SMR deployed = 1.86 (95% CI 1.63–2.13); SMR nondeployed = 1.61 (95% CI 1.39–1.86) Age and gender, standardized to the general UK population NDVs are similar to GWVs in age, gender, service, regular/reservist status, and rank
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Study Design Population Outcomes Results Adjustments Comments
Sim et al., 2015 (Australian Follow Up Health Study) Cohort study. Longitudinal health survey conducted in 2011; mortality and cancer registry data obtained from the Australian National Death All Australian Gulf War veterans, follow-up of 1,871 GWVs and 2,922 NDVs External cause and disease-related mortality (SMR and HR) GWVs vs NDVs: 108 deaths (2.3%) total deaths reported All cancer: HR = 1.82 (95% CI 0.88–3.74). Cardiovascular disease HR = 0.79 (95% CI 0.27–2.29) No statistically significant differences were found between GWVs and NDVs for all external causes (SMR = 1.19, 95% CI 0.63–2.25), intentional self-harm (SMR = 1.12, 95% CI 0.39–3.17), and transportation accidents (SMR = 1.19, 95% CI 0.45–3.16) Comparing to general male Australian population: All-cause mortality GWV SMR = 0.77 (95% CI 0.58–1.02) NDV SMR = 0.59 (95% CI 0.45–0.76) All external causes GWV SMR = 0.70 (95% CI 0.43–1.13) NDV SMR = 0.61 (95% CI 0.41–0.92) No differences between GWVs or NDVs and the Australian male population were found for intentional self-harm or transport accidents Cardiovascular diseases: GWV SMR = 0.46 (95% CI 0.19–1.11) NDV SMR = 0.63 (95% CI 0.35–1.14) Hazard ratios adjusted for branch of service, rank, and age group as of August 1990 No female deaths identified thus females were excluded from analyses Because of so few deaths, categories of mortality were limited to all cause, overall external causes, intentional self-harm, transport accidents, cancer, and cardiovascular disease
Knapik et al., 2009 Systematic review Persian Gulf or Vietnam veterans N = 20 studies (5 pertain to GWVs) Meta-analysis of cause of death based on ICD-9 codes Injury-related SMRR = 1.26 (95% CI 1.16–1.37) in GWVs vs era after 3 to 8 years of follow-up and was associated with motor vehicle accidents (SMRR = 1.39, 95% CI 1.22–1.60) Excess mortality decreased with time after deployment except mortality rates for all external causes and motor vehicle events, which remained significantly higher among GWVs compared with NDVs (external causes SMRR = 1.09, 95% CI 1.04–1.14; and motor vehicle SMRR = 1.29, 95% CI 1.18–1.40) No statistically significant difference between GWVs and NDVs was found for suicide or homicide Systematic review; no new data

NOTE: BIRLS = Beneficiary Identification Records Locator System; CCD = Canadian Cancer Database; CI = confidence interval; CMD = Canadian Mortality Database; COD = Cause of Death; DMDC = Defense Manpower Data Center; DoD = Department of Defense; FARS = Fatality Analysis Reporting System; GW = Gulf War; GWV = Gulf War veteran; HIV = human immunodeficiency virus; HR = hazard ratio; ICD = International Classification of Diseases; MRR = mortality rate ratio; MS = multiple sclerosis; NDI = National Death Index; NDV = nondeployed veteran; OR = odds ratio; RR = risk ratio; SMR = standardized mortality ratio; SMRR = summary mortality rate ratio; SSA = Social Security Administration; UK = United Kingdom; U.S. = United States; VA = Department of Veterans Affairs.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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HEALTH CONDITIONS RELATED TO DEPLETED URANIUM EXPOSURE

A small group of U.S. Gulf War veterans who were exposed to DU have been regularly assessed at the Baltimore VA Medical Center since 1993. Most of the veterans experienced inhalation exposure to DU from cleanup operations, fires, or contaminated tanks and munitions, but some continue to have embedded shrapnel in their bodies from friendly fire incidents. Because surgical morbidity precludes further removal of the embedded DU fragments, surveillance of DU toxicity resulting from the chronic, systemic exposure to DU from embedded fragments has been conducted to medically manage any adverse effects. Additionally, there is concern about DU exposure because it has been shown to be carcinogenic in animals (IOM, 2000, 2008a; NRC, 2008). DU is the only Gulf War biomarker of exposure that can be directly monitored in the urine of exposed veterans.

Although up to 80 DU-exposed Gulf War veterans have been evaluated at least once in this cohort over time, at any single time point, only a small subset of individuals are assessed (McDiarmid et al., 2013). Over the years additional members have been added to the cohort. This small group of Gulf War veterans exposed to DU has been followed biennially for 20 years to identify uranium-related changes in health; findings from these cross-sectional assessments have been routinely published (McDiarmid et al., 2001, 2004, 2006, 2007a,b, 2009, 2011a, 2013, 2015).

Veterans were categorized as low exposure (current urinary U concentrations < 0.1 μg U/g creatinine) or high exposure (current urinary U concentrations ≥ 0.1 μg U/g creatinine) (McDiarmid et al., 2000). Comparisons are made based on low vs high DU exposure (Hines et al., 2013) or in some cases small groups of unexposed patients (Shvartsbeyn et al., 2011). Typically, about 35 members undergo clinical evaluation each follow-up session with about 17–18 veterans in each exposure group (McDiarmid et al., 2009, 2011a). Thus, comparisons are based on small numbers.

Investigators have collected a wide range of data including history, clinical laboratory values, urinary uranium measurement, and psychiatric and neurocognitive assessment biennially. The assessments, conducted over 3 days, include a medical examination; blood and urine samples to assess markers of tubular kidney damage (kidney injury marker-1, neutrophil gelatinase-associated lipocalin, and interleukin-18), renal and bone metabolism, hematological markers, and neuroendocrine markers, and lymphocyte response; pulmonary function testing; radiological exams to detect soft tissue reaction to foreign bodies; and tests of neurocognitive performance (McDiarmid et al., 2013). Results have been described by both Volumes 4 and 8 for each assessed health outcome. Some publications focus on particular assessments, such as biomarkers of genotoxicity (Albertini et al., 2015; McDiarmid et al., 2011b), pulmonary effects in registrants with inhalation exposure (Hines et al., 2013), and skin reactivity (Shiu et al., 2015; Shvartsbeyn et al., 2011).

In general, findings have focused on the radioactive and heavy metal toxicity of DU, although adverse DU-related health effects have not been reported (McDiarmid et al., 2013).

At the 16- and 18-year follow-up assessments, there were virtually no statistically significant differences between the high exposure and low exposure groups of veterans for any of the clinical or laboratory parameters measured including

  • endocrine function (i.e., blood glucose, insulin levels, serum concentrations of free thyroxine and thyroid-stimulating hormone as measures of thyroid function, serum follicle-stimulating hormone, lutenizing hormone, prolactin, and total testosterone) (McDiarmid et al., 2000, 2001, 2004, 2006, 2007a,b, 2009, 2011a);
  • blood parameters (i.e., mean number of cells with micronuclei and total number of micronuclei per 2,000 cells; and for frequencies of cells with translocated chromosomes, dicentrics, acentric
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Even though no health condition has been consistently observed, urinary concentrations of DU continue to be high, but stable, more than 20 years later. Because tissue concentrations will accrue with continued mobilization of embedded DU, health effects may still be expected to occur and thus, these veterans will continue to be monitored (McDiarmid et al., 2015).

As a part of the surveillance program for Gulf War veterans exposed to DU, skin reactivity to uranium was examined in 40 deployed Gulf War veterans and 46 controls (patients with no known occupational exposure to DU seen at University of Maryland Dermatology Clinic for evaluation of contact dermatitis who completed a clinical assessment between April–June 2009) (Shvartsbeyn et al., 2011). Patch testing was conducted with an extended metals panel and uranyl acetate in three concentrations (0.25%, 2.5%, and 25%). No patch test allergic reactions to uranyl acetate (0.25%, 2.5%, or 25%) were observed in either the high or the low exposure group, but there were more irritant reactions with 25% uranyl acetate than lower concentrations in both groups. The authors concluded that dermatitis observed in deployed veterans is unrelated to their DU exposure. However, it should be noted that the deployed and control groups differed significantly: 74% of controls were female whereas all of the deployed veterans were male. Shiu et al. (2015) assessed the 35 veterans in the 2013 cohort for dermatologic findings. Fragment retainment and related scarring was significantly increased (p = 0.002) in veterans exposed to high levels of DU (n = 23) compared with the low exposure group (n = 11); other dermatologic findings such as dermatitis and hypertrophic scarring were also increased in the high exposure group but not significantly so.

Conclusions

The Volume 10 committee finds that there is little evidence of adverse health effects from DU in this group of exposed veterans. However, because of the carcinogenic potential of DU, this group of veterans should continue to be followed to determine any long-term adverse health conditions that may occur in the future.

Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Page 96
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Page 97
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Page 98
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Page 99
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Page 100
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Page 101
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Page 102
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Page 103
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Page 104
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Page 105
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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Page 106
Suggested Citation:"4 Evaluation of Health Conditions." National Academies of Sciences, Engineering, and Medicine. 2016. Gulf War and Health: Volume 10: Update of Health Effects of Serving in the Gulf War, 2016. Washington, DC: The National Academies Press. doi: 10.17226/21840.
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