2
Illnesses in Gulf War Veterans

Almost a decade after the Gulf War, questions persist about illnesses reported by veterans. A significant number of veterans report having fatigue, skin rash, headache, muscle and joint pain, and loss of memory (Joseph, 1997; Murphy et al., 1999). An increased prevalence of these symptoms has been borne out by large controlled studies of deployed compared to nondeployed military personnel1 from three countries—the United States, the United Kingdom, and Canada. That so many Gulf War veterans have unexplained2 symptoms has prompted concerns about their exposure to potentially hazardous agents during the Gulf War. The U.S. government has made a substantial investment in health research to understand veterans’ illnesses, search for their cause(s), and find effective treatments (CDC, 1999; Research Working Group, 1999).

This chapter describes the research that has addressed three fundamental questions about illnesses in Gulf War veterans:3 (1) what is the nature and prevalence of veterans’ symptoms and illnesses; (2) do their unexplained sym-

1  

Many studies have compared the health of military personnel deployed to the Gulf War with military personnel who were not deployed to the Gulf War but served during the same period (Gulf War era). Some studies have a comparison cohort of military personnel who served in another deployment (e.g., Bosnia).

2  

The terms “unexplained symptoms” or “unexplained illnesses” means that health complaints cannot be accounted for, or explained by, current medical diagnoses.

3  

This chapter employs the term “Gulf War veterans” in the broadest sense. Unless otherwise specified, the term denotes all military personnel who served in the Gulf War theater between August 2, 1990, and June 13, 1991, regardless of whether they later continued on active duty, returned to the reserves or National Guard, or left military service.



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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines 2 Illnesses in Gulf War Veterans Almost a decade after the Gulf War, questions persist about illnesses reported by veterans. A significant number of veterans report having fatigue, skin rash, headache, muscle and joint pain, and loss of memory (Joseph, 1997; Murphy et al., 1999). An increased prevalence of these symptoms has been borne out by large controlled studies of deployed compared to nondeployed military personnel1 from three countries—the United States, the United Kingdom, and Canada. That so many Gulf War veterans have unexplained2 symptoms has prompted concerns about their exposure to potentially hazardous agents during the Gulf War. The U.S. government has made a substantial investment in health research to understand veterans’ illnesses, search for their cause(s), and find effective treatments (CDC, 1999; Research Working Group, 1999). This chapter describes the research that has addressed three fundamental questions about illnesses in Gulf War veterans:3 (1) what is the nature and prevalence of veterans’ symptoms and illnesses; (2) do their unexplained sym- 1   Many studies have compared the health of military personnel deployed to the Gulf War with military personnel who were not deployed to the Gulf War but served during the same period (Gulf War era). Some studies have a comparison cohort of military personnel who served in another deployment (e.g., Bosnia). 2   The terms “unexplained symptoms” or “unexplained illnesses” means that health complaints cannot be accounted for, or explained by, current medical diagnoses. 3   This chapter employs the term “Gulf War veterans” in the broadest sense. Unless otherwise specified, the term denotes all military personnel who served in the Gulf War theater between August 2, 1990, and June 13, 1991, regardless of whether they later continued on active duty, returned to the reserves or National Guard, or left military service.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines toms warrant classification as a new syndrome; and (3) are exposures to specific biological and chemical agents during the Gulf War associated with veterans’ symptoms and illnesses? This chapter’s exclusive focus is on health studies of Gulf War veterans. The questions posed above are designed to guide the reader through a complex body of research. The chapter summarizes studies of veterans’ mortality, hospitalizations, and diagnosable illnesses and provides a brief overview of the Gulf War veterans’ registry programs established by the Department of Veterans Affairs (VA) and the Department of Defense (DoD). The chapter also examines in greater depth the epidemiologic studies that have been conducted to date—on general health status and on specific health endpoints. The information presented here provides background for the reader and the context for committee members as they considered evidence related to health effects of the agents selected for study. Later chapters deal with the specific agents and their health effects in any population, including veterans. REGISTRY PROGRAMS Approximately 697,000 U.S. service men and women were deployed in Operations Desert Shield/Desert Storm in 1990 and 1991 (PAC, 1996). The demographic composition of this deployment was more diverse than in past deployments; there were greater racial and ethnic diversity, more women, and more reserves and National Guard troops (Table 2.1). Soon after the war ended in 1991, veterans began to seek medical treatment for a variety of symptoms and illnesses (PAC, 1996). The Department of Defense and the Department of Veterans Affairs responded to veterans’ health concerns by establishing programs for veterans to voluntarily receive clinical examinations largely for diagnostic purposes. By 1994, these registry programs had been revised and renamed the Comprehensive Clinical Evaluation Program (hereinafter called the DoD registry) and the Persian Gulf Registry and Uniform Case Assessment Protocol (hereinafter called the VA registry), respectively. The programs are similarly structured: they begin with an initial physical examination, including patient and exposure history and screening laboratory tests, followed by the opportunity for referral to more specialized testing and consultation if needed (Joseph, 1997; Murphy et al., 1999).4 About 125,000 Gulf War veterans underwent registry health examinations through March 1999 (IOM, 1999a), the majority conducted under the auspices of the VA. These programs continue to register participants. The most common symptoms reported between 1992 and 1997 from among 52,835 participants of the VA registry were fatigue, skin rash, headache, muscle and joint pain, and loss of memory (Table 2.2) (Murphy et al., 1999). An almost 4   Several independent advisory committees have reviewed these programs and made recommendations for their refinement (NIH, 1994; IOM, 1995–1998; PAC, 1996).

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines TABLE 2.1 Demographic Characteristics of U.S. Gulf War Troops Characteristic Percentage of Troopsa Gender   Male 93 Female 7 Age (mean) in 1991 (years) 27 Race or ethnicity   White 70 African American 23 Hispanic 5 Other 2 Rank   Enlisted 90 Officer 10 Military branch   Army 50 Navy 23 Marines 15 Air Force 12 Military status   Active duty 83 Reserves or National Guard 17 aThere were approximately 697,000 U.S. military personnel. SOURCE: Joseph, 1997. identical set of symptoms was reported most frequently among the approximately 20,000 participants in the DoD registry (CDC, 1999). Veterans classified in the DoD registry as having “signs, symptoms, and ill-defined conditions” most frequently complained of fatigue, headache, and memory loss (Roy et al., 1998). Clinicians were able to arrive at a primary diagnosis for about 82 percent of symptomatic DoD registry participants (Joseph, 1997) and for a similar fraction of VA registry participants (Murphy et al., 1999) (Table 2.2). A registry program established by the United Kingdom Ministry of Defence for U.K. Gulf War veterans found similar types and frequencies of symptoms and diagnoses (Coker et al., 1999). Across the registries, musculoskeletal diseases; mental disorders; and symptoms, signs, and ill-defined conditions5 were the three most 5   “Symptoms, signs, and ill-defined conditions” refers to International Classification of Diseases, Ninth Revision, Classical Modification (ICD-9-CM) codes 780–799, which are reserved for 160 subclassifications of ill-defined, common conditions not

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines common diagnostic categories, together accounting for more than 50 percent of primary diagnoses (CDC, 1999). Registry programs provided an early glimpse into veterans’ symptoms and the difficulties of fitting symptoms into standard diagnoses. As self-selected case series of veterans who presented for care, registries cannot, and were not intended to, be representative of the symptoms and illnesses of the entire group of Gulf War veterans. Nor were registries designed with control groups or with diagnostic standardization across the multiple sites at which examinations took place (Joseph, 1997; Roy et al., 1998). Finally, owing to their reliance on stan- TABLE 2.2 Most Frequent Symptoms and Diagnoses Among 53,835 Participants in the VA Registry (1992–1997) Symptoms or Diagnoses Percentage Self-Reported Symptoms   Fatigue 20.5 Skin rash 18.4 Headache 18.0 Muscle, joint pain 16.8 Loss of memory 14.0 Shortness of breath 7.9 Sleep disturbances 5.9 Diarrhea and other gastrointestinal symptoms 4.6 Other symptoms involving skin 3.6 Chest pain 3.5 No complaint 12.3 Diagnosis (ICD-9-CM)   No medical diagnosis 26.8 Musculoskeletal and connective tissue 25.4 Mental disorders 14.7 Respiratory system 14.0 Skin and subcutaneous tissue 13.4 Digestive system 11.1 Nervous system 8.0 Infectious diseases 7.1 Circulatory system 6.4 Injury and poisoning 5.3 Genitourinary system 3.0 Neoplasm 0.4   SOURCE: Murphy et al., 1999.     coded elsewhere in ICD-9-CM or without a distinct physiological or psychological basis (U.S. DHHS, 1998).

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines dard diagnostic classifications, registries were not designed to probe for novel diagnoses6 or to search for biological correlates. Thus, because of their methodological limitations, registry studies cannot stand alone as a basis for conclusions or for the conduct of research. Registry programs are, however, a valuable resource for information and for generating hypotheses. These hypotheses can be tested in more rigorous epidemiologic studies with control groups in order to estimate the population prevalence of symptoms among Gulf War veterans and to compare these to rates among otherwise similar troops who were not deployed to the Gulf War. EPIDEMIOLOGIC STUDIES OF VETERANS’ SYMPTOMS AND GENERAL HEALTH STATUS A number of epidemiologic studies have been conducted on the health status of Gulf War veterans. The driving issues behind many of these studies are to determine (1) the nature of symptoms and symptom clusters; (2) whether symptom clusters constitute a new, unique syndrome; and/or (3) what types of exposures may have produced the symptoms. The second issue highlighted above—the quest to define a new syndrome—requires some explanation. The question is whether or not these unexplained symptoms constitute a syndrome(s) and, if so, are they best studied and treated as a unique new syndrome(s) or a variant form(s) of an existing syndrome (see Appendix D). The finding of any new set of unexplained symptoms in a group of patients does not automatically qualify as a new syndrome.7 It represents the beginning of a process involving many types of studies to demonstrate that the patients are affected by a unique clinical entity distinct from all other established clinical diagnoses. The process of defining a new syndrome usually begins with a case definition that lists classification criteria to distinguish the potentially new patient population from patients with existing clinical diagnoses. Development of the first case definition is a vital milestone designed to spur research and surveillance. More like a hypothesis than a conclusion, the first case definition is an early step in the process and is often revised as more evidence comes to light. Case definitions usually are a mix of clinical, demographic, and/or laboratory criteria. Clinical criteria refer to signs (physical examination findings) and symptoms (subjective experiences or reports of patients). Demographic criteria refer to age, gender, ethnicity, or other individual characteristics or exposure-related variables. Laboratory criteria are biological measures of either pathology or etiology (e.g., x-ray, blood test). 6   Registries rely on the ICD-9-CM (Joseph, 1997; Murphy et al., 1999). 7   A syndrome is a unique set or cluster of symptoms, signs, and/or laboratory tests without known pathology or etiology (Scadding, 1996).

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines One method of developing an operational case definition is a statistical technique known as factor analysis (Ismail et al., 1999). Factor analysis is useful in identifying a small number of correlated variables from among a much larger number of observed variables, such as the symptoms that are reported in a survey of veterans. Factor analysis aggregates survey responses into statistical groupings of factors that may or may not have biological plausibility or clinical relevance. Several researchers have used factor analysis in their studies (described later in this chapter) on the health of Gulf War veterans. When factor analysis is employed in studies of veterans, the observed variables are measurements of veterans’ symptoms, and the fundamental factors are symptom groupings that may represent a potentially new syndrome. Any new syndrome (defined by factor analysis or other means) may have a distinct, albeit often unknown, etiology and pathogenesis (Taub et al., 1995). It is recognized that factor analysis has the potential to generate syndromes that may not be reproduced when a new population is examined. When evidence is presented that the case definition—defined by factor analysis or other methods—successfully singles out a new patient population from comparison groups, the case definition may gain recognition by the medical establishment as a new syndrome (see Appendix D). There are many advantages to defining and classifying a new syndrome. The foremost advantage is to create a more homogeneous patient population, a crucial step for determining prevalence and ushering in diagnosis and treatment. A potential disadvantage is the mislabeling or misclassification of a condition, which can thwart progress for years, if not decades (Aronowitz, 1991). Classification of a new patient population also stimulates further understanding of the natural history of the disease, risk factors, and ultimately, etiology and pathogenesis. As more knowledge unfolds about etiology and pathogenesis, the classification of an established syndrome can rise to the level of a disease. The renaming of a syndrome as a disease8 implies that the etiology or pathology has been identified. Population-Based Studies This section summarizes findings of population-based studies of Gulf War veterans. The next section summarizes findings from studies using other types of epidemiological designs. A population-based study is a methodologically robust type of epidemiologic study because its goal is to obtain information that is representative of the population of interest, in this case Gulf War veterans. The cohort may be the entire population of interest or a random selection from the population of interest. Population-based studies of Gulf War veterans sample a cohort of veterans by contacting them where they live, as opposed to where they seek treatment or where they serve in the military (e.g., a particular base, a particular branch such as the Air Force). Studies of military units or other military 8   The term “disease” is defined as an abnormality in body structure or function with known etiology (e.g., virus, abnormal gene, toxin) and/or pathology (detectable lesion).

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines subgroups are less representative of the broader Gulf War veteran population than are population-based studies. Large population-based studies of Gulf War veterans have been conducted in each of the three major countries participating in the Gulf War coalition (e.g., the United States, Canada, and the United Kingdom). These studies have shown consistent findings, in both the nature of unexplained symptoms and their deleterious impact on functioning. Summary features of these studies appear in Table 2.3, along with those of other epidemiologic studies. Virtually all epidemiologic studies of Gulf War veterans, regardless of study design, rely on self-reports of both symptoms and exposures. As discussed in Chapter 3, studies based on self-reports have inherent limitations because of potential inaccuracies in recalling past events and difficulty in verifying the reports. Most of the larger epidemiologic studies described here were conducted through mail or telephone surveys, precluding the possibility of clinical examination and diagnosis. Comparison groups were veterans of the same era who were not deployed to the Gulf War. More comprehensive reviews of epidemiologic studies of Gulf War veterans are available elsewhere (CDC, 1999; IOM, 1999a). The Iowa Study The “Iowa study,” a major population-based study of U.S. Gulf War veterans, was a cross-sectional survey of a representative sample of 4,886 military personnel who listed Iowa as their home of record at the time of enlistment (Iowa Persian Gulf Study Group, 1997). The study examined the health of military personnel from all branches of service who either were still serving or had left service. The sample was randomly selected from, and therefore representative of, about 29,000 military personnel. Of the eligible study subjects, 3,695 (76 percent) completed a telephone interview. Study subjects were divided into four groups, two that had been deployed to the Gulf War and two that had not been deployed to the Gulf War. Trained examiners using standardized questions, instruments, and scales interviewed the subjects.9 The two groups of Gulf War military personnel reported roughly twice the prevalence of symptoms suggestive of the following conditions: fibromyalgia, cognitive dysfunction, depression, alcohol abuse, asthma, posttrau- 9   Sources of questions included the National Health Interview Survey, the Behavioral Risk Factor Surveillance Survey, the National Medical Expenditures Survey, the Primary Care Evaluation of Mental Disorders, the Brief Symptom Inventory, the CAGE questionnaire, the PTSD (Posttraumatic Stress Disorder) Checklist—Military, the Centers for Disease Control and Prevention Chronic Fatigue Syndrome Questionnaire, the Chalder Fatigue Scale, the American Thoracic Society questionnaire, the Sickness Impact Profile, and questions to assess fibromyalgia, sexual functioning, and military exposures.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines TABLE 2.3 Major Studies of Gulf War Veterans’ Symptoms and Syndromes Reference Subjects/ Controls (n) Study Design Military Branch and Status Response Rate (%) Major Findings Population-Based Studies Iowa Persian Gulf Study Group, 1997 1,896/1,799 Population-based survey All U.S. branches and duty status 76 Symptoms (subjects vs. controls) Fibromyalgia: 19.2% vs. 9.6% Cognitive dysfunction: 18.7% vs. 7.6% Depression: 17.0% vs. 10.9% Goss Gilroy, 1998 3,113/3,439 Survey All Canadian Gulf War veterans 64.5 Symptoms Chronic fatigue (OR = 5.27) Cognitive dysfunction (OR = 4.36) Multiple chemical sensitivity (OR = 4.01) Unwin et al., 1999; Ismail et al., 1999 2,961/2,620, 2,614a Population-based survey, factor analysis U.K. Gulf War veterans 65.1 Symptoms Fatigue (OR = 2.2) Posttraumatic stress (OR = 2.6) Psychological distress (OR = 1.6) Three factors (mood, respiratory system, peripheral nervous system) not unique to Gulf War veterans

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Other Epidemiologic Studies Haley et al., 1997b 249/no controls Survey, factor analysis Navy reserve 41 25% have one of six syndromes: impaired cognition, confusion–ataxia, arthro-myoneuropathy, phobia–apraxia, fever–adenopathy, weakness–incontinence Fukuda et al., 1998 1,163/2,538 Survey, clinical exam, factor analysis Air Force National Guard and 3 other Air Force units 35–70 31 of 33 symptoms significantly more prevalent in Gulf War veterans; defined case as 1 or more symptoms from 2 of 3 categories: fatigue, mood-cognition, musculoskeletal; case not unique to Gulf War veterans Proctor et al., 1998 300b/48 Survey or clinical interview All U.S. branches and duty status 38–62 PTSD diagnosis: 5–7% vs. 0% Dermatological symptoms (OR = 9.6, 6.9)b Gastrointestinal symptoms (OR = 8.0, 5.8)b Neuropsychological symptoms (OR = 6.4, 5.2)b NOTE: OR = odds ratio; PTSD = posttraumatic stress disorder. aTwo comparison groups (Bosnia, Gulf era). bThe 300 Gulf War veterans came from two study groups—one from Ft. Devens and the other from New Orleans. The control group was deployed to Germany.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines matic stress disorder (PTSD), sexual discomfort, or chronic fatigue (Table 2.4).10 Furthermore, on a standardized instrument for assessing functioning (the Medical Outcome Study’s 36-item questionnaire known as the Short Form-36, or SF-36), Gulf War veterans displayed significantly lower scores across all eight subscales for physical and mental health. These subscales profile different aspects of quality of life. The subscales for bodily pain, general health, and vitality showed the greatest absolute differences between deployed and nondeployed veterans. In short, this large, well-controlled study demonstrated that certain sets of symptoms are more frequent and quality of life is poorer among Gulf War veterans than among nondeployed military controls. Symptom clustering. The Iowa study was the first major population-based study to group together sets of symptoms into categories suggestive of existing syndromes or disorders, such as fibromyalgia or depression. The Iowa study did not search for new syndromes. However, its finding of such higher prevalence of symptom groups suggestive of fibromyalgia, depression, and cognitive dysfunction (see Table 2.4) motivated subsequent researchers to examine the potential for a new syndrome that would group together and classify veterans’ symptoms. Exposure–symptom relationships. The Iowa study assessed exposure– symptom relationships by asking veterans to report on their past exposures. Researchers found that many of the self-reported exposures were significantly associated with many different health conditions. For example, symptoms of cognitive dysfunction were found to have been associated with self-reports of exposure to solvents or petrochemicals, smoke or combustion products, sources of lead from fuels, pesticides, ionizing or nonionizing radiation, chemical warfare agents, use of pyridostigmine, infectious agents, and physical trauma. A similar set of exposures also was associated with symptoms of depression or fibromyalgia. The study concluded that no single exposure to any specific agent was related to the conditions that the authors found to be more prevalent in Gulf War veterans. The Canadian Study The findings of a 1997 survey mailed to the entire cohort of Canadian Gulf War veterans were similar to those from the Iowa study. In this study, Canadian forces deployed to the Gulf War (n = 3,113) were compared with Canadian forces deployed elsewhere (n = 3,439) during the same period (Goss Gilroy, 1998). Of the Gulf War veterans responding, 2,924 were male and 189 were female. Deployed forces had significantly higher rates than controls of self- 10   The conditions listed were not diagnosed because no clinical examinations were performed. Rather, before conducting their telephone survey, researchers grouped together sets of symptoms from their symptom checklists into a priori categories of diseases or disorders. After a veteran identified him- or herself as having the requisite set of symptoms, researchers analyzing responses considered the veteran as having symptoms “suggestive” of or consistent with a particular disorder, but not as having a formal diagnosis of the disorder.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines reported chronic conditions and symptoms of a variety of derived clinical outcomes11 (chronic fatigue, cognitive dysfunction, multiple chemical sensitivities, major depression, PTSD, chronic dysphoria, anxiety, fibromyalgia, and respiratory diseases). The greatest differences between deployed and nondeployed forces were in the first three outcomes. The symptom grouping with the highest overall prevalence was cognitive dysfunction, which occurred in 34–40 percent of Gulf War veterans compared with 10–15 percent of control veterans. Gulf War veterans also reported significantly more visits to health care practitioners, greater dissatisfaction with health, and greater reductions in recent activity because of health than control veterans. Symptom clustering. The Canadian study did not search for potentially new syndromes. Exposure–symptom relationships. In Canadian Gulf War veterans, the greatest number of symptom groupings were associated with self-reported exposures to psychological stressors and physical trauma. Several symptom groupings also were associated with exposure to chemical warfare agents, nonroutine immunizations, sources of infectious diseases, and ionizing or nonionizing radiation. Nevertheless, a subset of Canadian veterans who could not have been exposed to many of the agents, because they were based at sea, reported symptoms as frequently as did land-based veterans in this study. TABLE 2.4 Results of the Iowa Study Symptoms (in order of frequency)a Prevalence in Gulf War Veterans (%) Prevalence in Non-Gulf War Veterans (%) Fibromyalgia 19.2 9.6 Cognitive dysfunction 18.7 7.6 Alcohol abuse 17.4 12.6 Depression 17.0 10.9 Asthma 7.2 4.1 PTSD 1.9 0.8 Sexual discomfort 1.5 1.1 Chronic fatigue 1.3 0.3 aBased on a survey instrument designed by investigators to incorporate structured instruments and standardized questions. SOURCE: Iowa Persian Gulf Study Group, 1997. 11   Several of the reported health conditions or symptoms were combined to form clinically meaningful outcomes (Goss Gilroy, 1998).

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines A study by Engel and colleagues (1999) is one of only a few that used a clinician-administered diagnostic instrument rather than self-reported symptom scales to assess the presence of psychiatric disorders. Researchers compiled diagnoses from among all Gulf War veterans (n = 13,161) who sought health examinations through the DoD registry during its first year of operation (1994–1995). Study authors used the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III-R [SCID-NP]) to explore a range of possible psychiatric disorders and the Clinician-Administered PTSD Scale to explore PTSD. Both of these measures have been psychometrically validated on combat veterans, making this study methodologically stronger than many of the previous investigations. Unfortunately, the study did not employ a control or comparison group and, in using a treatment-seeking population, was not, by design, representative of the Gulf War veteran population. The authors found that 37 percent of the veterans met criteria for at least one psychiatric disorder. About 13 percent of the entire sample met diagnostic criteria for mood disorders, 14 percent met criteria for somatoform disorders,20 and 6 percent met criteria for current PTSD. A study on a subset of this cohort (n = 131) referred for specialty evaluation found significant associations with PTSD and somatoform disorder among those reporting traumatic events (such as handling dead bodies) (Labbate et al., 1998). The authors of this smaller study concluded that at least some veterans with unexplained physical symptoms might be suffering the consequences of combat trauma. The most methodologically rigorous study to have undertaken structured clinical interviews (in addition to PTSD questionnaires) found a current diagnosis of PTSD in 5–7 percent of two groups of deployed veterans (n = 206), compared with none in a control group deployed to Germany (n = 48) (Wolfe et al., 1999).21 Investigators used a stratified random sampling strategy to identify participants from two cohorts of Gulf War veterans from New England and New Orleans. The study also found similarly elevated rates of current major depressive disorder and dysthymia (two distinct types of depression) but did not find elevated rates of somatoform disorders. Yet nearly two-thirds of veterans reporting health symptoms in the moderate to high range had no current diagnosis of a mental disorder such as PTSD or major depressive disorder.22 The authors concluded that, although psychiatric illness is associated with some Gulf War 20   This term encompasses a variety of disorders in which the patients have multiple physical symptoms that are not explained by a known medical disease or condition, by the effects of a substance, or by another mental disorder. The symptoms cause clinically significant distress or impaired functioning (APA, 1994). 21   Four percent of one of the deployed groups (the Ft. Devens cohort) was found to have PTSD symptoms, as measured by psychometric scale within 5 days of returning from the Gulf War, suggesting that PTSD symptoms are chronic (Wolfe et al., 1998), a finding also supported in an uncontrolled study that followed a small cohort for 2 years (Southwick et al., 1995). 22   About 40 percent also had no lifetime history of these disorders (Wolfe et al., 1999).

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines health complaints, such illnesses do not entirely account for the full range and extent of Gulf War veterans’ symptom reporting. Studies of Infectious Disease, Gastrointestinal Symptoms, and Testicular Cancer During the Gulf War, the occurrence of infectious diseases was lower than expected (Hyams et al., 1995). The most common infectious disease among U.S. troops was diarrheal disease caused by the bacterial pathogens Escherichia coli and Shigella sonnei, as detected by stool cultures (Hyams et al., 1991). Almost 60 percent of troops responding to a questionnaire reported at least one episode of diarrheal disease within an average of 2 months in Saudi Arabia (Hyams et al., 1991). Upper respiratory infections also were frequent (Hyams et al., 1995). Finally, 19 cases of cutaneous leishmaniasis and 12 cases of a variant of visceral leishmaniasis have been reported among U.S. Gulf War veterans.23 The latter is an unusual finding because the etiological agent found in veterans’ tissue samples—the protozoan parasite Leishmania tropica, transmitted by sandflies—is not endemic to the Persian Gulf area and is usually associated with cutaneous leishmaniasis (CDC, 1992; Magill et al., 1993; Hyams et al., 1995). Because veterans’ symptoms (e.g., fever, lymphadenopathy, and hepatosplenomegaly) were milder than symptoms of classic visceral leishmaniasis, the condition was given the name viscerotropic leishmaniasis. Even though visceral leishmaniasis and its variants are chronic infectious diseases, the cases were considered too few, and classic signs and symptoms too readily detectable at physical examination, to account for the much more frequent occurrence of unexplained illnesses in veterans (Hyams et al., 1995; PAC, 1996). Further, in the controlled study of Gulf War veterans by Fukuda and colleagues (1998), none of the eight participants who seroreacted to leishmanial antigens met the study’s case definition for a severe case of unexplained illness, which suggests that viscerotropic leishmaniasis is distinct from veterans’ unexplained illnesses. However, some individuals with visceral or viscerotropic leishmaniasis can present with nonspecific symptoms (fatigue, low-grade fever, gastrointestinal symptoms) that are consistent with those seen in veterans with unexplained illnesses. Further research is required (NIH, 1994). Gastrointestinal complaints, as noted earlier, are somewhat common among veterans in the DoD and VA registries (Joseph, 1997; Murphy et al., 1999). In the study reported earlier by Proctor and colleagues (1998), gastrointestinal symptoms were among the symptoms with greatest prevalence differences between deployed and nondeployed veterans. One study investigated a host of gastrointestinal symptoms in a National Guard unit (n = 136). Excessive gas, 23   Leishmaniasis is any variety of diseases affecting the skin (cutaneous leishmaniasis), mucous membranes, and internal organs (visceral leishmaniasis, caused by infection with single-celled parasites called leishmania. It is transmitted from infected animals or people to new hosts by the bites of sand flies (Clayman, 1989).

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines loose stool, incomplete rectal evacuation, and abdominal pain were more prevalent during and after the war in deployed than in nondeployed veterans from the same unit (Sostek et al., 1996). The results were based on a 64-item questionnaire administered after the war. Subjects reported that their gastrointestinal complaints began in the Gulf and persisted after return to the United States. Over the last 5 months of 1991, hospitalizations for testicular cancer were slightly elevated in a large study of active duty deployed versus nondeployed veterans (Gray et al., 1996). In a follow-up study, the investigators extended their analysis through 1996. They replicated their earlier finding, but also found that by 4 years after the war, the cumulative risk of testicular cancer was similar for the two groups of veterans (Knoke et al., 1998). They attributed the transient increase in testicular cancer immediately after the war to regression to the mean because of the healthy-servicemen selection effect and to deferring care during deployment (during which time they would not have had the opportunity for diagnosis and treatment). LIMITATIONS OF PAST STUDIES AND ONGOING STUDIES The epidemiologic studies of Gulf War veterans summarized above have contributed greatly to our understanding of veterans’ symptoms, but they are beset by limitations commonly encountered with epidemiologic studies. A major limitation is representativeness; most studies focus on groups that are not representative of all Gulf War veterans, by virtue of either their military duties and location during deployment; their military status during the war (active duty, reserves or National Guard); their military status after the war (active duty, reserves, discharged); their branch of service (Army, Navy, Air Force, Marines); or ease of ascertainment (IOM, 1999a). The Iowa study, with its population-based design, had the broadest coverage of U.S. Gulf War veterans. Although it is considered the most representative, the cohort contained few members of racial and ethnic minorities (Iowa Persian Gulf Study Group, 1997). The findings from population-based studies from Canada (Goss Gilroy, 1998) and the United Kingdom (Unwin et al., 1999) are generally consistent with U.S. studies. Other limitations of epidemiologic studies include small sample size, low participation rates that could result in selection bias in some studies, and recall bias.24 The potential for recall bias is particularly important because most studies rely on self-reporting of symptoms and exposures years after the event, rather than on biological measures (Joellenbeck et al., 1998). Additionally, studies may be too narrow in their assessment of health status. The measurement instruments may have been too insensitive to have detected abnormalities affecting deployed 24   Selection bias would occur if Gulf War veterans who are symptomatic choose to participate in a study more frequently than those who are not symptomatic. Recall bias would occur if Gulf War veterans who are symptomatic tend to overestimate their previous exposures in comparison with veterans who are not symptomatic (see Chapter 3).

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines veterans. Finally, the period of investigation has, of necessity, been too brief to detect health outcomes that have a long latency period or require many years to progress to the point where disability, hospitalization, or death occurs. Virtually all U.S. studies are cross sectional, which limits the opportunity to learn about symptom duration and chronicity, latency of onset (especially for health conditions with a long-term latency such as cancer), and prognosis. In light of the limitations surrounding studies of veterans’ health, a recent Institute of Medicine (IOM) panel recommended a prospective cohort study of Gulf War veterans (IOM, 1999a). A major study currently in progress by the VA may overcome some of the limitations of past studies. The study, mandated by Public Law 103-446, is a retrospective cohort study. Its purpose is to estimate the prevalence of symptoms and other health outcomes in Gulf War veterans versus non–Gulf War veterans.25 This population-based survey has three phases. The first phase is a questionnaire mailed to a total of 30,000 veterans. The second phase will validate self-reported data with medical record review and analyze characteristics of those who do not respond to the mailed survey. The third phase is a comprehensive medical examination and laboratory testing of a random sample of 2,000 veterans drawn from both the Gulf War and the comparison group (Research Working Group, 1998). The purpose of the third phase is to establish diagnoses that will make it possible to see what proportion of self-reported symptoms are due to established diseases rather than unexplained illnesses.26 A major problem for most epidemiologic studies of Gulf War veterans is the lack of biological measures of exposure to potentially harmful agents. Reliance on self-reported exposures, often taking place years earlier, lacks external verification and is subject to recall bias, a potential problem that affects many retrospective epidemiologic studies. Further, self-reports of exposure may be complicated by recall of perceived—rather than actual—exposures (e.g., because of the sensitivity of the monitors, many false alarms may have been perceived as chemical warfare agent exposure). Enhanced record keeping and monitoring of the environment during and after the Gulf War would have averted this problem. Indeed, many expert panels have recommended efforts to improve record keeping and environmental monitoring in future deployments (e.g., IOM, 1999b; NRC, 2000a,b,c). 25   Health outcomes include reproductive outcomes in spouses and birth defects in children. 26   After the committee completed its deliberations and submitted its report for peer review, the first two phases of the VA study were published (Kang et al., 2000). This study found that Gulf War veterans, in comparison with non-Gulf War veterans, reported higher prevalence of functional impairment, health care utilization, symptoms, and medical conditions. The nature of health concerns and their prevalence were similar to those of U.K. veterans (Unwin et al., 1999). The VA study surveyed veterans about their self-reported exposures in the Gulf War, but did not perform any analyses to determine whether self-reported exposures were related to symptoms and health reporting. The third phase of the VA study has yet to be published.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines CONCLUSIONS This chapter provides an overview of the rapidly growing body of published studies on the health of Gulf War veterans. Many of the studies described in this chapter have been released in the past few years, and the largest U.S. study of veterans’ health has yet to be completed. However, current research demonstrates that Gulf War veterans report more symptoms than their nondeployed counterparts, based on methodologically robust studies from three different countries (Iowa Persian Gulf Study Group, 1997; Goss Gilroy, 1998; Unwin et al., 1999). Symptoms relating to cognition, the musculoskeletal system, and fatigue are more prevalent among Gulf War veterans than controls. Further, many symptoms and their clustering do not appear to fit conventional diagnoses. The conundrum is whether or not these unexplained symptoms constitute a syndrome(s) and, if so, are they best studied and treated as a unique new syndrome(s) or a variant form(s) of an existing syndrome (e.g., chronic fatigue syndrome, fibromyalgia) (see Appendix D). The very lack of definition or classification of veterans’ unexplained illnesses has made it difficult to diagnose and treat many Gulf War veterans. Additionally, the health studies reviewed in this chapter have found little or no excess mortality, hospitalizations, or birth defects in the children of veterans, although these studies have some limitations. Deployment to the Gulf War is associated with stress-related disorders, such as PTSD and depression. Yet a sizable number of veterans with unexplained symptoms do not have any psychiatric diagnoses. Further research is urgently needed to understand the nature of veterans’ unexplained symptoms and their relationship to their experience in the Gulf War. REFERENCES Amato AA, McVey A, Cha C, Matthews EC, Jackson CE, Kleingunther R, Worley L, Cornman E, Kagan-Hallet K. 1997. Evaluation of neuromuscular symptoms in veterans of the Persian Gulf War. Neurology 48(1):4–12. APA (American Psychiatric Association). 1994. Diagnostic and Statistical Manual of Mental Disorders, DSM-IV. 4th edition. Washington, DC: APA. Araneta MR, Moore CA, Olney RS, Edmonds LD, Karcher JA, McDonough C, Hiliopoulos KM, Schlangen KM, Gray GC. 1997. Goldenhar syndrome among infants born in military hospitals to Gulf War veterans. Teratology 56(4):244–251. Araneta MRG, Destiche DA, Schlangen KM, Merz RD, Forrester MB, Gray GC. 1999. Birth defects prevalence among infants of Gulf War veterans born in Hawaii, 1989–1993 [abstract]. Proceedings of the Conference on Federally Sponsored Gulf War Veterans’ Illnesses Research. Pentagon City, VA: Research Working Group, Persian Gulf Veterans Coordinating Board. Aronowitz RA. 1991. Lyme disease: The social construction of a new disease and its social consequences. Millbank Q 69(1):79–112. Axelrod BN, Milner IB. 1997. Neuropsychological findings in a sample of Operation Desert Storm veterans. J Neuropsychiatry Clin Neurosci 9(1):23–28. Baker DG, Mendenhall CL, Simbartl LA, Magan LK, Steinberg JL. 1997. Relationship between posttraumatic stress disorder and self-reported physical symptoms in Persian Gulf War veterans. Arch Intern Med 157(18):2076–2078.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines CDC (Centers for Disease Control and Prevention). 1992. Viscerotropic leishmaniasis in persons returning from Operation Desert Storm, 1990–1991. MMWR 41(8):131–134. CDC (Centers for Disease Control and Prevention). 1999. Background Document on Gulf War-Related Research. The Health Impact of Chemical Exposures During the Gulf War: A Research Planning Conference. Atlanta, GA: CDC. Cherry N, Macfarlane G. 1999. The Manchester Gulf War study: First results [abstract]. Proceedings of the Conference on Federally Sponsored Gulf War Veterans’ Illnesses Research. Pentagon City, VA: Research Working Group, Persian Gulf Veterans Coordinating Board. Clayman CB, ed. 1989. The American Medical Association Encyclopedia of Medicine. New York: Random House. Coker WJ, Bhatt BM, Blatchley NF, Graham JT. 1999. Clinical findings for the first 1000 Gulf war veterans in the Ministry of Defence’s medical assessment programme. BMJ 318(7179):290–294. Cowan DN, DeFraites RF, Gray GC, Goldenbaum MB, Wishik SM. 1997. The risk of birth defects among children of Persian Gulf War veterans. N Engl J Med 336(23): 1650–1656. Doyle P, Maconochie N, Roman E, McMichael A. 1999. Study of the reproductive health of UK Gulf War veterans and the health of their children: An update [abstract]. Proceedings of the Conference on Federally Sponsored Gulf War Veterans’ Illnesses Research. Pentagon City, VA: Research Working Group, Persian Gulf Veterans Coordinating Board. Engel CC Jr, Ursano R, Magruder C, Tartaglione R, Jing Z, Labbate LA, Debakey S. 1999. Psychological conditions diagnosed among veterans seeking Department of Defense care for Gulf War-related health concerns. J Occup Environ Med 41(5): 384–392. Fukuda K, Nisenbaum R, Stewart G, Thompson WW, Robin L, Washko RM, Noah DL, Barrett DH, Randall B, Herwaldt BL, Mawle AC, Reeves WC. 1998. Chronic multisymptom illness affecting Air Force veterans of the Gulf War. JAMA 280(11):981–988. Goldstein G, Beers SR, Morrow LA, Shemansky WJ, Steinhauer SR. 1996. A preliminary neuropsychological study of Persian Gulf veterans. J Int Neuropsychol Soc 2(4):368–371. Goss Gilroy Inc. 1998. Health Study of Canadian Forces Personnel Involved in the 1991 Conflict in the Persian Gulf, Vol. 1. Ottawa, Ontario: Goss Gilroy Inc. Prepared for the Department of National Defence. Gray GC, Coate BD, Anderson CM, Kang HK, Berg SW, Wignall FS, Knoke JD, Barrett-Connor E. 1996. The postwar hospitalization experience of U.S. veterans of the Persian Gulf War. N Engl J Med 335(20):1505–1513. Haley RW. 1998. Point: Bias from the “healthy-warrior effect” and unequal follow-up in three government studies of health effects of the Gulf War. Am J Epidemiol 148(4): 315–323. Haley RW, Kurt TL. 1997. Self-reported exposure to neurotoxic chemical combinations in the Gulf War. A cross-sectional epidemiologic study. JAMA 277(3):231–237. Haley RW, Hom J, Roland PS, Bryan WW, Van Ness PC, Bonte FJ, Devous MDS, Mathews D, Fleckenstein JL, Wians FH Jr, Wolfe GI, Kurt TL. 1997a. Evaluation of neurologic function in Gulf War veterans. A blinded case-control study. JAMA 277(3):223–230.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Haley RW, Kurt TL, Hom J. 1997b. Is there a Gulf War syndrome? Searching for syndromes by factor analysis of symptoms. JAMA 277(3):215–222. Haley RW, Billecke S, La Du BN. 1999. Association of low PON1 type Q (type A) arylesterase activity with neurologic symptom complexes in Gulf War veterans. Toxicol Appl Pharmacol 157(3):227–233. Hotopf M, David A, Hull L, Ismail K, Unwin C, Wessely S. 2000. Role of vaccinations as risk factors for ill health in veterans of the Gulf War: Cross sectional study. BMJ 320:1363–1367. Hyams KC, Bourgeois AL, Merrell BR, Rozmajzl P, Escamilla J, Thorton SA, Wasserman GM, Burke A, Echeverria P, Green KY, Kapikian AZ, Woody JN. 1991. Diarrheal disease during Operation Desert Shield. N Engl J Med 325(20):1423–1428. Hyams KC, Hanson K, Wignall FS, Escamilla J, Oldfield EC III. 1995. The impact of infectious diseases on the health of U.S. troops deployed to the Persian Gulf during Operations Desert Shield and Desert Storm. Clin Infect Dis 20(6):1497–1504. IOM (Institute of Medicine). 1995. Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action. Washington, DC: National Academy Press. IOM (Institute of Medicine). 1996. Health Consequences of Service During the Persian Gulf War: Recommendations for Research and Information Systems. Washington, DC: National Academy Press. IOM (Institute of Medicine). 1997. Adequacy of the Comprehensive Clinical Evaluation Program: Nerve Agents. Washington, DC: National Academy Press. IOM (Institute of Medicine). 1998. Adequacy of the VA Persian Gulf Registry and Uniform Case Assessment Protocol. Washington, DC: National Academy Press. IOM (Institute of Medicine). 1999a. Gulf War Veterans: Measuring Health. Washington, DC: National Academy Press. IOM (Institute of Medicine). 1999b. Strategies to Protect the Health of Deployed U.S. Forces: Medical Surveillance, Record Keeping, and Risk Reduction. Washington, DC: National Academy Press. Iowa Persian Gulf Study Group. 1997. Self-reported illness and health status among Gulf War veterans: A population-based study. JAMA 277(3):238–245. Ismail K, Everitt B, Blatchley N, Hull L, Unwin C, David A, Wessely S. 1999. Is there a Gulf War syndrome? Lancet 353(9148):179–182. Jamal GA, Hansen S, Apartopoulos F, Peden A. 1996. The “Gulf War syndrome.” Is there evidence of dysfunction in the nervous system? J Neurol Neurosurg Psychiatry 60(4):449–451. Joellenbeck LM, Landrigan PJ, Larson EL. 1998. Gulf War veterans’ illnesses: A case study in causal inference. Environ Res 79(2):71–81. Joseph SC. 1997. A comprehensive clinical evaluation of 20,000 Persian Gulf War veterans. Mil Med 162(3):149–155. Kang HK, Bullman TA. 1996. Mortality among U.S. veterans of the Persian Gulf War. N Engl J Med 335(20):1498–1504. Kang HK, Bullman T. 1998. Counterpoint: Negligible “healthy-warrior effect” on Gulf War veterans’ mortality. Am J Epidemiol 148(4):324–325; discussion 334–338. Kang HK, Bullman TA. 1999. Mortality among U.S. veterans of the Gulf War: Update through December 1997 [abstract]. Proceedings of the Conference on Federally Sponsored Gulf War Veterans’ Illnesses Research. Pentagon City, VA: Research Working Group, Persian Gulf Veterans Coordinating Board.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Kang HK, Mahan CM, Lee KY, Magee CA, Murphy FM. 2000. Illnesses among United States veterans of the Gulf war: A population-based survey of 30,000 veterans. J Occup Environ Med 42(5):491–501. Keane TM, Caddell JM, Taylor KL. 1988. Mississippi Scale for combat-related posttraumatic stress disorder: Three studies in reliability and validity. J Consult Clin Psychol 56(1):85–90. Knoke JD, Gray GC. 1998. Hospitalizations for unexplained illnesses among U.S. veterans of the Persian Gulf War. Emerg Infect Dis 4(2):211–219. Knoke JD, Gray GC, Garland FC. 1998. Testicular cancer and Persian Gulf War service. Epidemiology 9(6):648–653. Kulka R, Schlenger W, Fairbank J, Jordan B, Hough R, Marmar C, Weiss D. 1991. Assessment of posttraumatic stress disorder in the community: Prospects and pitfalls from recent studies of Vietnam veterans. J Consul Clin Psychol 3(4):547–560. Labbate LA, Cardena E, Dimitreva J, Roy M, Engel CC. 1998. Psychiatric syndromes in Persian Gulf War veterans: An association of handling dead bodies with somatoform disorders. Psychother Psychosom 67(4–5):275–279. Magill AJ, Grogl M, Gasser RA Jr, Sun W, Oster CN. 1993. Visceral infection caused by Leishmania tropica in veterans of Operation Desert Storm. N Engl J Med 328(19):1383–1387. Murphy FM, Kang H, Dalager NA, Lee KY, Allen RE, Mather SH, Kizer KW. 1999. The health status of Gulf War veterans: Lessons learned from the Department of Veterans Affairs Health Registry. Mil Med 164(5):327–331. NIH (National Institutes of Health) Technology Assessment Workshop Panel. 1994. The Persian Gulf experience and health. JAMA 272(5):391–396. NRC (National Research Council). 2000a. Strategies to Protect the Health of Deployed U.S. Forces: Analytical Framework for Assessing Risks. Washington, DC: National Academy Press. NRC (National Research Council). 2000b. Strategies to Protect the Health of Deployed U.S. Forces: Detecting, Characterizing, and Documenting Exposures. Washington, DC: National Academy Press. NRC (National Research Council). 2000c. Strategies to Protect the Health of Deployed U.S. Forces: Force Protection and Decontamination. Washington, DC: National Academy Press. PAC (Presidential Advisory Committee on Gulf War Veterans’ Illnesses). 1996. Presidential Advisory Committee on Gulf War Veterans’ Illnesses: Final Report. Washington, DC: U.S. Government Printing Office. Penman AD, Currier MM, Tarver RS. 1996. No evidence of increase in birth defects and health problems among children born to Persian Gulf War veterans in Mississippi. Mil Med 161(1):1–6. Perconte ST, Wilson AT, Pontius EB, Dietrick AL, Spiro KJ. 1993a. Psychological and war stress symptoms among deployed and non-deployed reservists following the Persian Gulf War. Mil Med 158(8):516–521. Perconte ST, Wilson A, Pontius E, Dietrick A, Kirsch C, Sparacino C. 1993b. Unit-based intervention for Gulf War soldiers surviving a SCUD missile attack: Program description and preliminary findings. J Traumatic Stress 6(2):225–238. Pierce PF. 1997. Physical and emotional health of Gulf War veteran women. Aviat Space Environ Med 68:317–321. Proctor SP, Heeren T, White RF, Wolfe J, Borgos MS, Davis JD, Pepper L, Clapp R, Sutker PB, Vasterling JJ, Ozonoff D. 1998. Health status of Persian Gulf War veter-

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines ans: Self-reported symptoms, environmental exposures and the effect of stress. Int J Epidemiol 27(6):1000–1010. Research Working Group of the Persian Gulf Veterans Coordinating Group. 1998. Annual Report to Congress: Federally Sponsored Research on Gulf War Veterans’ Illnesses for 1997. Washington, DC: Department of Veterans Affairs. Research Working Group of the Persian Gulf Veterans Coordinating Group. 1999. Annual Report to Congress: Federally Sponsored Research on Gulf War Veterans’ Illnesses for 1998. Washington, DC: Department of Veterans Affairs. Roland PS, Haley RW, Yellin W, Owens K, Shoup AG. 2000. Vestibular dysfunction in Gulf War syndrome. Otolaryngol Head Neck Surg 122:319–329. Roy MJ, Koslowe PA, Kroenke K, Magruder C. 1998. Signs, symptoms, and ill-defined conditions in Persian Gulf War veterans: Findings from the Comprehensive Clinical Evaluation Program. Psychosom Med 60(6):663–668. Scadding JG. 1996. Essentialism and nominalism in medicine: Logic of diagnosis in disease terminology. Lancet 348(9027):594–596. Sostek MB, Jackson S, Linevsky JK, Schimmel EM, Fincke BG. 1996. High prevalence of chronic gastrointestinal symptoms in a National Guard unit of Persian Gulf veterans. Am J Gastroenterol 91(12):2494–2497. Southwick SM, Morgan CA III, Darnell A, Bremner D, Nicolaou AL, Nagy LM, Charney DS. 1995. Trauma-related symptoms in veterans of Operation Desert Storm: A 2-year follow-up. Am J Psychiatry 152(8):1150–1155. Stretch RH, Bliese PD, Marlowe DH, Wright KM, Knudson KH, Hoover CH. 1995. Physical health symptomatology of Gulf War-era service personnel from the states of Pennsylvania and Hawaii. Mil Med 160(3):131–136. Stretch RH, Marlowe DH, Wright KM, Bliese PD, Knudson KH, Hoover CH. 1996. Posttraumatic stress disorder symptoms among Gulf War veterans. Mil Med 161(7):407–410. Sutker PB, Uddo M, Brailey K, Allain AN. 1993. War-zone trauma and stress-related symptoms in Operation Desert Shield/Storm (ODS) returnees. J Social Issues 49(4): 33–49. Sutker PB, Uddo M, Brailey K, Vasterling JJ, Errera P. 1994. Psychopathology in war-zone deployed and nondeployed Operation Desert Storm troops assigned graves registration duties. J Abnorm Psychol 103(2):383–390. Taub E, Cuevas JL, Cook EW, Crowell M, Whitehead WE. 1995. Irritable bowel syndrome defined by factor analysis. Gender and race comparisons. Dig Dis Sci 40(12): 2647–2655. U.K. Ministry of Defence. 2000. Background to the Use of Medical Countermeasures to Protect British Forces During the Gulf War (Operation Granby). [Online]. Available: http://www.mod.uk/policy/gulfwar/info/mcm.htm [Accessed March 2000]. Unwin C, Blatchley N, Coker W, Ferry S, Hotopf M, Hull L, Ismail K, Palmer I, David A, Wessely S. 1999. Health of UK servicemen who served in Persian Gulf War. Lancet 353(9148):169–178. U.S. DHHS (Department of Health and Human Services). 1998. International Classification of Diseases, 9th revision, Clinical Modification. Washington, DC: U.S. Public Health Service. Wolfe J, Brown PJ, Kelley JM. 1993. Reassessing war stress: Exposure and the Persian Gulf War. J Social Issues 49(4):15–31. Wolfe J, Proctor SP, Davis JD, Borgos MS, Friedman MJ. 1998. Health symptoms reported by Persian Gulf War veterans two years after return. Am J Ind Med 33(2): 104–113.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Wolfe J, Proctor S, Erickson D, Heeren T, Friedman MHM, Sutker P, Vasterling J, White R. 1999. Relationship of psychiatric status to Gulf War veterans’ health problems. Psychosom Med 61:532–540. Writer JV, DeFraites RF, Brundage JF. 1996. Comparative mortality among US military personnel in the Persian Gulf region and worldwide during Operations Desert Shield and Desert Storm. JAMA 275(2):118–121.

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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines CONTENTS      METHODS OF GATHERING AND EVALUATING THE EVIDENCE   70      TYPES OF EVIDENCE   71      Animal and Other Nonhuman Studies,   71      Human Studies,   72      Epidemiologic Studies,   72      Experimental Studies,   76      Case Reports and Case Series,   77      CONSIDERATIONS IN ASSESSING THE STRENGTH OF THE EVIDENCE   78      Strength of Association,   78      Dose–Response Relationship,   78      Consistency of Association,   79      Temporal Relationship,   79      Specificity of Association,   79      Biological Plausibility,   80      Other Considerations,   80      SUMMARY OF THE EVIDENCE   81      Understanding Causation and Association,   82      Categories of Association,   83      COMMENTS ON INCREASED RISK OF ADVERSE HEALTH OUTCOMES AMONG GULF WAR VETERANS   84      REFERENCES   85