CONCLUSIONS AND RECOMMENDATIONS
The committee was established to review, evaluate, and summarize the peer-reviewed scientific and medical literature addressing the health status of Persian Gulf War veterans. This chapter summarizes what the literature collectively tells us about the veterans' symptoms and illnesses.
QUALITY OF THE STUDIES
Overall the studies of Gulf War veterans’ health are of varied quality. Although they have provided valuable information, many of them have limitations that hinder accurate assessment of the veterans’ health status. There is a detailed discussion of the limitations of the studies of Gulf War veterans in Chapter 4. The issues under discussion include the lack of representativeness of the entire Gulf War population in some studies, low participation rates in most studies, studies that might be too narrow in their assessment of health status, instruments that might have been too insensitive to detect abnormalities in deployed veterans, and the timing of the investigation relative to the latency for some health outcomes (for example, cancer). In addition, many of the US studies are cross-sectional, and this limits the opportunity to learn about symptom duration and chronicity, latency of onset, and prognosis. Those limitations make it difficult to interpret the results of the findings particularly when several well-conducted studies produce inconsistent results. Furthermore, most of the studies rely on self-reports rather than objective measures of symptoms and exposures.
OVERVIEW OF HEALTH OUTCOMES
In looking at health outcomes in Gulf War-deployed veterans, numerous researchers have attempted to determine whether a set of symptoms reported by veterans could be defined as a unique syndrome or illness. Investigators have attempted, by using factor or cluster analysis, to find a unique outcome, but none has been identified. Veterans of the Gulf War, from the US, the UK, Canada, Australia, and Denmark report higher rates of nearly all symptoms or sets of symptoms than their nondeployed counterparts; that finding was reported consistently in every study reviewed by this committee. Some of the symptoms have been associated with neurobehavioral decrements on neurocognitive tests.
Not surprisingly, given the global excess reporting of symptoms among Gulf War-deployed veterans, the rates of individual symptoms as well as the rates of chronic multisymptom illnesses were higher among deployed veterans than nondeployed in many studies. Multisymptom-based medical conditions reported to occur more frequently among deployed Gulf War veterans include fibromyalgia, chronic fatigue syndrome (CFS), and multiple
chemical sensitivity (MCS). However, the case definitions for those conditions are based on symptom reports, and there are no objective diagnostic criteria that can be used to validate the findings, so it is not clear whether the literature supports a true excess of those conditions or whether the associations are spurious and result from the increased reporting of symptoms across the board. The literature also demonstrates that deployment places veterans at increased risk for symptoms that meet diagnostic criteria for a number of psychiatric illnesses, particularly posttraumatic stress disorder (PTSD), anxiety, depression, and substance abuse. In addition, comorbidities have been reported, for example, veterans reporting symptoms of both PTSD and depression. The committee felt confident that several studies validated the increased risk of psychiatric disorders.
Some studies indicate that Gulf War veterans are at increased risk for amyotrophic lateral sclerosis (ALS). With regard to birth defects, there is weaker evidence that Gulf War veterans’ offspring might be at risk for some birth defects; the findings are inconsistent. Finally, long-term exacerbation of asthma appeared to be associated with oil-well fire smoke, but there were no objective measures of pulmonary function in the studies.
The health outcomes presented above are discussed in some detail in the following pages. They are grouped according to whether the findings were based primarily on self-reporting of symptoms or on objective measures and diagnostic medical tests.
Outcomes Based Primarily on Symptoms and Self-Reports
The largest and most nationally representative survey of US veterans found that nearly 29% of deployed veterans met a case definition of “multisymptom illness”, compared with 16% of nondeployed veterans (Blanchard et al. 2006). Those figures indicate that unexplained illnesses are the most prevalent health outcome of service in the Gulf War. Several researchers, using factor or cluster analyses, have tried to determine whether or not the symptoms that have been reported by Gulf War veterans cluster in such a way as to make up a unique syndrome, such as “Gulf War Illness”.
Numerous studies (Cherry et al. 2001; Doebbeling et al. 2000; Everitt et al. 2002; Forbes et al. 2004; Kang et al. 2002) have used statistical techniques, such as factor and cluster analyses to search for such symptom clusters or syndromes. Those studies have demonstrated that deployed veterans report more symptoms and more severe symptoms than their nondeployed counterparts, but they did not find a unique symptom complex (or syndrome) in deployed Gulf War veterans. What those studies have found is a global increase in symptoms reported by Gulf War-deployed veterans compared to their counterparts—global in that the increased symptom rates occur in every category of health outcome.
Among the many symptoms reported by Gulf War veterans are deficits in neurocognitive ability. Obviously such reports are of concern because of the potential for those deficits to have adverse effects on the lives of the veterans. Primary studies found nonsignificant trends of poorer neurobehavioral performance when Gulf War veterans were compared to nondeployed veterans or veterans deployed to Germany. However, when PTSD (White et al. 2001) or depressed mood (David et al. 2002) was treated as a confounder in the statistical analyses those trends disappeared, but that adjustment might be inappropriate because of the possibility of overcontrolling a variable that might lie on the causal pathway.
One study concluded that Gulf War veterans who reported symptoms associated with the Gulf conflict performed more poorly on neurobehavioral tests than veterans who did not report symptoms (Storzbach et al. 2000); another study found substantial neurobehavioral deficits in
deployed veterans but had intentionally recruited veterans who experienced a high prevalence of post-Gulf War illness (Hom et al. 1997). That study failed to adjust for key confounders and for the large number of statistical comparisons in their study, raising doubt about the validity of their findings.
In conclusion, primary studies of deployed Gulf War veterans vs non-Gulf War deployed do not demonstrate differences in cognitive and motor measures as determined through neurobehavioral testing. However, returning Gulf War veterans with at least one symptom commonly reported by Gulf War veterans (such as, fatigue, memory loss, confusion, inability to concentrate, mood swings, somnolence, GI distress, muscle and joint pain, or skin or mucous membrane complaints) demonstrated poorer performance on cognitive tests when compared to returning veterans who did not report such symptoms.
Several studies focused on multisymptom-based medical conditions: fibromyalgia, CFS, and MCS. Those conditions have several features in common: they do not fit a precise diagnostic category; case definitions are symptom-based; there are no objective criteria for validating the case definitions; and the symptoms among those syndromes overlap to some extent. Gulf War-deployed veterans report higher rates of symptoms that are consistent with case definitions of MCS, CFS, and fibromyalgia.
Several large or population-based studies of Gulf War veterans found, by questionnaire, that prevalence of MCS-like symptoms ranged from 2% to 6% (Black et al. 1999; Black et al. 1999; 2000; Black et al. 2000; Goss Gilroy Inc. 1998; Goss Gilroy Inc. 1998; Goss Gilroy Inc. 1998; Reid et al. 2001; Unwin et al. 1999). Most studies found that the prevalence in Gulf War veterans was about 2-4 times higher than that in nondeployed veterans. However, no two of the primary studies used the same definition of MCS, so it is difficult to compare them, and none performed medical evaluations to exclude other explanations as would be required by the case definition of MCS.
The prevalence of CFS among Gulf War veterans is highly variable from study to study; most studies used the Centers for Disease Control and Prevention case definition. One primary study (Eisen et al. 2005) demonstrated a higher prevalence of CFS in deployed than in nondeployed veterans (odds ratio [OR] 40.6, 95% confidence interval [CI] 10.2-161.15).
Secondary studies also showed a higher prevalence of CFS and CFS-like illnesses among veterans deployed to the Persian Gulf than among their counterparts who were not deployed or who were deployed elsewhere.
The diagnosis of fibromyalgia is based on symptoms and a very limited physical examination that consists of determining whether pain is elicited by pressing on several points on the body; there are no laboratory tests with which to confirm the diagnosis. Only one of the available cross-sectional studies, Eisen and colleagues (2005), included both Gulf War-deployed and nondeployed veterans and used the full American College of Rheumatology (ACR) case definition of fibromyalgia, including the physical-examination criteria (other studies used a case definition based on symptoms alone). That study found a statistically significant difference in the prevalence of fibromyalgia between deployed and nondeployed veterans (2.0% vs 1.2%; adjusted OR1, 2.32; 95% CI, 1.02- 5.27). The study by Smith and colleagues (2000) found no association between Gulf War deployment and hospitalization for fibromyalgia, but the committee did not find this to be inconsistent with the positive findings in the Eisen et al. study because very few cases of fibromyalgia are severe enough to warrant hospitalization (notably,
the prevalence of a diagnosis of fibromyalgia in the Eisen et al. study is about 300 times the prevalence of hospitalization for fibromyalgia in the Smith et al. study). The Iowa study (Iowa Persian Gulf Study Group 1997) and the Canadian study (Goss Gilroy Inc. 1998) both found significantly more fibromyalgia symptoms among deployed veterans than among nondeployed. The findings of those two studies, although generally supportive of the findings of the Eisen et al. study, are of limited value because the lack of a physical examination prohibits the use of the full criteria for diagnosis. The Bourdette study (2001), which did not have a nondeployed-veteran comparison group, estimated a minimum prevalence of 2.47% in the deployed veterans and used the full ACR case definition of fibromyalgia. In conclusion, largely on the basis of the Eisen et al. (2005) study, which used the criteria of the American College of Rheumatology for diagnosis of fibromyalgia but which could have been subject to unrecognized selection bias, there is a higher prevalence of fibromyalgia among deployed Gulf War veterans than among nondeployed veterans.
Other symptoms that are self-reported more often by deployed veterans are gastrointestinal symptoms, particularly dyspepsia; dermatologic conditions, particularly atopic dermatitis and warts; and joint pains.
There were many reports of gastrointestinal symptoms in Gulf War-deployed veterans. Those symptoms seem to be linked to reports of exposures to contaminated water and burning of animal waste in the war theater. The committee notes that several studies (e.g., Eisen et al. 2005) reported a higher rate of self-reported dyspepsia in Gulf War-deployed veterans than in nondeployed veterans. In the context of nearly all symptoms being reported more frequently in Gulf War veterans, it is difficult to interpret these findings.
For dermatologic conditions, a few studies included an examination of the skin and thus were more reliable than self-reports (e.g., Eisen et al. 2005); those have reported that a few unrelated skin conditions occurred more frequently among Gulf War-deployed veterans; however, the findings are not consistent. There is some evidence of a higher prevalence of two distinct dermatologic conditions, atopic dermatitis and verruca vulgaris (warts), in Gulf War-deployed veterans.
Arthralgias (joint pains) were more frequently reported among Gulf War veterans. Likewise, self-reports of arthritis were more common among those deployed to the gulf. Again, in the context of global reporting increases, such data are difficult to interpret. Moreover, studies that included a physical examination did not find evidence of a statistically significant increase in arthritis (Eisen et al. 2005).
Finally, Gulf War veterans consistently have been found to suffer from a variety of psychologic conditions. Two well-designed studies using validated interview-based assessments reported that several psychiatric disorders, most notably PTSD and depression, are 2-3 times more likely in Gulf War-deployed than in nondeployed veterans (Black et al. 2004; Wolfe et al. 1999). Moreover, comorbidities were reported among a number of veterans, with co-occurrence of PTSD, depression, anxiety, or substance abuse. Most of the other studies administered well-validated symptom questionnaires and their findings were remarkably similar: an overall two to three-fold increase in the prevalence of psychiatric disorders. When traumatic war exposures were assessed with symptoms, studies characteristically showed higher rates, particularly of PTSD, in veterans who had more traumatic war experiences than in those with lower levels of traumatic exposure. In other words, studies found a dose-response relationship between the degree of traumatic war exposure and PTSD. The finding of such a dose-response relationship provides increased confidence in the association with deployment.
Outcomes with Objective Measures or Diagnostic Medical Tests
In reviewing the studies of mortality, the committee found numerous limitations. The principal one is the short duration of followup observation. More time must elapse before investigators will be able to assess increased mortality that would result from illnesses with long latency, such as cancer, or that would have a gradually deteriorating course, such as cardiovascular disease. Another potential limitation of comparing deployed with nondeployed personnel is the healthy-warrior effect, which might result in selection bias, insofar as chronically ill or less fit members of the armed forces might be less likely to have been deployed than more fit members.
A number of studies examined rates of injuries in Gulf War veterans (Kang and Bullman 1996; Kang and Bullman 2001; Macfarlane et al. 2000). Those studies provide evidence of a modest increase in transportation-related injuries and mortality among deployed than among nondeployed Gulf War veterans in the decade immediately after deployment. However, studies with longer followup indicate that the increased injury rate was likely to have been restricted to the first several years after the war (Kang and Bullman 2001).
With regard to all causes of hospitalization, studies provide some evidence that excess hospitalizations did not occur among veterans of the Gulf War who remained on active duty through 1994 (Gray et al. 1996). Those studies have certain limitations, however, as they were largely of active-duty personnel and cannot be generalized to the entire cohort of Gulf War veterans; it has been noted that Gulf War veterans who left the military reported worse health outcomes than those who remained (Ismail et al. 2000). It also might be too soon to capture hospitalizations from illnesses that might have longer latency, such as some cancers. In addition, hospitalization data on people separated from the military and admitted to nonmilitary (Department of Veterans Affairs [VA] and civilian) hospitals or on those who used outpatient facilities might be incomplete.
Veterans are understandably concerned about increases in cancer, and the studies reviewed did not demonstrate consistent evidence of increased overall cancer in the Gulf War veterans compared with nondeployed veterans (Kang and Bullman 2001; Macfarlane et al. 2003). However, many veterans are young for cancer diagnoses, and, for most cancers, the time since the Gulf War is probably too short to expect the onset of cancer. Incidence of and mortality from cancer in general, and brain and testicular cancer in particular, have been assessed in cohort studies. An association of brain-cancer mortality with possible nerve-agent exposure (as modeled by the Department of Defense [DOD] exposure model of 2000) was observed in one study (Bullman et al. 2005), but, as discussed in more detail in Chapter 2, there were many uncertainties in the exposure model. Results for testicular cancer were mixed: one study concluded that there was no evidence of an excess risk (Knoke et al. 1998), and another, small, registry-based study (Levine et al. 2005) suggested that there might be an increased risk.
Another concern for veterans has been whether amyotrophic lateral sclerosis (ALS) is increased in Gulf War veterans. Two primary studies and one secondary study found that deployed veterans appear to be at increased risk for ALS. The primary study by Horner et al. (2003), which had the possibility of underascertainment of cases in the nondeployed population, was confirmed by a secondary analysis by Coffman et al. (2005) that documented a nearly 2-fold increase in risk. A secondary study by Haley (2003) used general population estimates as the comparison group and found a slightly higher relative risk.
Peripheral neuropathy has also been studied in Gulf War veterans. One large, well-designed study conducted by VA (Davis et al. 2004), which used a thorough and objective
evaluation and a stringent case definition, did not find statistically significant evidence of excess peripheral neuropathy. Several other secondary studies supported no excess risk. Some studies (e.g., Cherry et al. 2001) do report higher rates of peripheral neuropathy, but they use self-reports, which the committee did not accept as a reliable measure of peripheral neuropathy. Thus, there does not appear to be an increase in the prevalence of peripheral neuropathy in deployed vs nondeployed veterans, as defined by history, physical examination, and electrophysiologic studies.
With regard to cardiovascular disease, primary studies found no statistically significant differences between deployed and nondeployed veterans in rates of hypertension (Fukuda et al. 1998). One study did report a small but significant increase in hospitalizations due to cardiovascular disease among a subset of deployed veterans who were possibly exposed to nerve agents from the Khamisiyah plume compared with Gulf War-deployed veterans who were not in the possible exposure area (Smith et al. 2003). The increased hospitalizations were due entirely to an increase in cardiac dysrhythmias. However, the study suffers from uncertainty about the Khamisiyah plume model. In the secondary studies, deployed veterans were generally more likely to report hypertension and palpitations, but those reports were not confirmed with medical evaluations. Thus, it does not appear that there is a difference in the prevalence of cardiovascular disease or diabetes between deployed Gulf War veterans and nondeployed.
Many veterans are understandably concerned about the possibility of birth defects in their offspring. The Araneta et al. (2003) and Doyle et al. (2004) studies yielded some evidence of increased risk of birth defects among offspring of Gulf War veterans. However, the specific defects with increased prevalence were not consistent. Overall, the studies are difficult to interpret because of the relative rarity of specific birth defects, use of small samples, timing of exposure (before or after conception), and whether the mother or the father was exposed. There was no consistent pattern of one of more birth defects with a higher prevalence in the offspring of male or female Gulf War veterans. Only one set of defects—urinary tract abnormalities—has been found to be increased in more than one well-designed study.
With regard to other adverse reproductive outcomes, the results of the Araneta et al. (2004) study, which had hospital discharge data available, are suggestive of an increased risk of spontaneous abortions and ectopic pregnancies among female Gulf War veterans. Findings specifically related to fertility (Ishoy et al. 2001a; Maconochie et al. 2004) and sexual problems (Ishoy et al. 2001b) relied on self-reports where there is potential for recall bias. In one study, there was no evidence of differences in levels of male reproductive hormones between Gulf War-deployed veterans and nondeployed veterans.
Numerous studies in several countries examined respiratory outcomes related to deployment to the Gulf War Theater. Five studies (Eisen et al. 2005; Gray et al. 1999; Ishoy et al. 1999; Karlinsky et al. 2004; Kelsall et al. 2004) representing four distinct cohorts from three countries (the United States, Australia, and Denmark), examined associations of Gulf War deployment with pulmonary-function measures or respiratory disease diagnoses. In none of those studies were statistically significant associations found. The uniformity of the findings is striking, especially given that the same five studies found that Gulf War deployment status was significantly associated with self-reports of respiratory symptoms among three of the four cohorts. Indeed, the overwhelming majority of studies conducted among Gulf War veterans— whether from the United States (Doebbeling et al. 2000; Gray et al. 1999; Gray et al. 2002; Iowa Persian Gulf Study Group 1997; Kang et al. 2000; Karlinsky et al. 2004; Kroenke et al. 1998; Petruccelli et al. 1999; Steele 2000), the UK (Cherry et al. 2001; Nisenbaum et al. 2004;
Simmons et al. 2004; Simmons et al. 2004; Unwin et al. 1999; Unwin et al. 1999) Canada (Goss Gilroy Inc. 1998), Australia (Kelsall et al. 2004), or Denmark (Ishoy et al. 1999)—have found that several years after deployment those deployed report higher rates of respiratory symptoms and respiratory illnesses than nondeployed troops. Of particular interest is the UK cohort study reported in Nisenbaum et al. (2004) and Unwin et al. (1999), which found substantially higher prevalences of respiratory symptoms and self-reported respiratory disease among those deployed in the Gulf War than among those deployed in another war theater, Bosnia.
Several studies examined respiratory outcomes specifically associated with chemical exposures experienced by Gulf War veterans, whereas the studies discussed above examined respiratory outcomes associated with deployment. The study of Cowan et al. (2002), which used objective exposure measures and methods2, found associations between oil-well fire smoke and doctor-assigned diagnosis of asthma in veterans. A limitation of the study is that the participants were self-selected. The other key Gulf War study of oil-well fire smoke, which was based on the Iowa cohort (Lange et al. 2002), found no relationship between the same objective exposures and respiratory health outcomes; it had the advantage of avoiding the potential selection biases of the Cowan et al. study. However, its definitions of respiratory diseases were based entirely on self-reports of symptoms and cannot be viewed as adequate. The study by Smith et al. (2002) found no statistically significant associations between the same objective measures of exposure to smoke from oil-well fires and later hospitalization for asthma, acute bronchitis, chronic bronchitis, or emphysema. However, the participants were all active-duty veterans; most young adults are seldom hospitalized for those diagnoses, so most cases would not be expected to be captured.
The study by Gray and collaborators (1999) found a small increase in postwar hospitalization for respiratory system disease associated with modeled exposure to nerve agents at Khamisiyah. Limitations of that study probably include substantial exposure misclassification based on DOD exposure estimates that were later revised, lack of control for tobacco-smoking, lack of a clear dose-response pattern, and limited biologic plausibility of effects on the respiratory system in a setting in which no effect on nervous system diseases was seen. Karlinsky et al. (2004) found no statistically significant associations between pulmonary-function measures and exposure to nerve agents at Khamisiyah on the basis of the revised DOD exposure estimates.
In conclusion, as is the case for a number of other organ systems, respiratory symptoms and self-reported health outcomes are strongly associated with Gulf War deployment in most studies addressing this question that use comparison groups of nondeployed veterans. However, studies with objective pulmonary-function measures find no statistically significant association between respiratory illness and disease and Gulf War deployment in the four cohorts in which this has been investigated; thus, the studies leave an uncertain clinical interpretation of the increased symptoms and self-reported diseases.
Among studies that examined pulmonary outcomes in association with specific exposures in the Gulf War Theater, the positive study by Cowan et al. (2002), which used objective measures of oil-well fire smoke and doctor-assigned respiratory diagnoses, is the strongest methodologically. With respect to nerve agents at Khamisiyah, no study using valid objective estimates of exposure has found statistically significant associations with pulmonary-function measures or physician-diagnosed respiratory disease.
The adequacy of the government’s response has been both praised and criticized; VA and DOD have expended enormous effort and resources in attempts to address the numerous health issues related to the Gulf War veterans. The information obtained from those efforts, however, has not been sufficient to determine conclusively the origins, extent, and long-term implications of health problems potentially associated with veterans’ participation in the Gulf War. The difficulty in obtaining meaningful answers, as noted by numerous past Institute of Medicine committees and with which the present committee agrees, is due largely to inadequate predeployment and postdeployment screening and medical examinations, and lack of monitoring of possible exposures of deployed personnel.
Predeployment and Postdeployment Screening
Predeployment and postdeployment data-gathering needs to include physician verification of data obtained from questionnaires so that one could have confidence in baseline and postdeployment health data. Collection and archiving of biologic samples might enable the diagnosis of specific medical conditions and provide a basis of later comparison. Meticulous records of all medications, whether used for treatment or prophylactically, would have improved the data and their interpretation in many of the studies reviewed.
Environmental exposures were usually not assessed directly, and that critically hampers the assessment of the effects of specific exposures on specific health outcomes. There have been detailed and laudable efforts to simulate and model exposures, but those efforts have been hampered by lack of the input data required to link the exposure scenarios to specific people or even to specific units or job categories. Moving beyond the current state requires that more detailed information be gathered during future military deployments. Specifically, working toward the development of a job-task-unit-exposure matrix, in which information on people with specific jobs or tasks or attached to specific units (according to routinely available records) is linked to exposures by expert assessment or simulation studies, would enable quantitative assessment of the effects of specific exposures.
Surveillance for Adverse Outcomes
The committee noted that several health outcomes seemed to be appearing with higher incidence or prevalence in the Gulf War-deployed veterans. For those outcomes, the committee recommends continued surveillance to determine whether there is actually a higher risk in Gulf War veterans. Those outcomes are cancer (particularly brain and testicular), ALS, birth defects
(including Goldenhar syndrome and urinary tract abnormalities) and other adverse pregnancy outcomes (such as spontaneous abortion and ectopic pregnancy), and postdeployment psychiatric conditions. The committee also recommends that cause-specific mortality in Gulf War veterans continue to be monitored. Although there was an increase in mortality in the first few years after the Gulf War, the deaths appear to have been related to transportation injuries.
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