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1 Introduction

Potential health consequences of service in the Gulf War have been a concern since U.S. troops returned home. Research and investigations to date indicate there is no single illness or syndrome common to all ill veterans. Questions have arisen as to whether there are effective treatments for the problems ill veterans are experiencing, and whether these veterans are receiving appropriate care.

In 1998 Congress passed the Veterans Program Enhancement Act (P.L. 105-368). In response to Section 105 of this legislation, the Department of Veterans Affairs (VA) asked the Institute of Medicine (IOM) to convene a committee that would (1) identify and describe approaches for assessing treatment effectiveness; (2) identify illnesses and conditions among veterans of the Gulf War, using data obtained from the VA and the U.S. Department of Defense (DoD) Gulf War registries, as well as information in published articles; and (3) for these identified conditions and illnesses, identify validated models of treatment (to the extent that such treatments exist), or identify new approaches, theories, or research on management of patients with these conditions if validated treatment models are not available. The congressional legislation specifically requested that the IOM study address undiagnosed illnesses as well as any other chronic illness deemed to warrant review. The committee is composed of experts in internal medicine, neurology, gastroenterology, rheumatology, psychiatry, epidemiology, treatment efficacy and effectiveness research, outcomes assessment, and clinical practice guideline development.

Over the course of this study the committee has met and talked with Gulf War veterans and representatives of veterans' organizations, health



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Page 11 1 Introduction Potential health consequences of service in the Gulf War have been a concern since U.S. troops returned home. Research and investigations to date indicate there is no single illness or syndrome common to all ill veterans. Questions have arisen as to whether there are effective treatments for the problems ill veterans are experiencing, and whether these veterans are receiving appropriate care. In 1998 Congress passed the Veterans Program Enhancement Act (P.L. 105-368). In response to Section 105 of this legislation, the Department of Veterans Affairs (VA) asked the Institute of Medicine (IOM) to convene a committee that would (1) identify and describe approaches for assessing treatment effectiveness; (2) identify illnesses and conditions among veterans of the Gulf War, using data obtained from the VA and the U.S. Department of Defense (DoD) Gulf War registries, as well as information in published articles; and (3) for these identified conditions and illnesses, identify validated models of treatment (to the extent that such treatments exist), or identify new approaches, theories, or research on management of patients with these conditions if validated treatment models are not available. The congressional legislation specifically requested that the IOM study address undiagnosed illnesses as well as any other chronic illness deemed to warrant review. The committee is composed of experts in internal medicine, neurology, gastroenterology, rheumatology, psychiatry, epidemiology, treatment efficacy and effectiveness research, outcomes assessment, and clinical practice guideline development. Over the course of this study the committee has met and talked with Gulf War veterans and representatives of veterans' organizations, health

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Page 12researchers, practicing physicians, and representatives of the VA and DoD. During the committee's five meetings, members reviewed and analyzed written material on symptoms, complaints, and diagnoses of Gulf War veterans; approaches to evaluating treatment efficacy, treatment effectiveness, and health outcomes; clinical practice guideline development and assessment; and completed reports of numerous investigations of illnesses of Gulf War veterans. Additionally, the committee held a public meeting and solicited testimony from Gulf War veterans about their illnesses and the treatments they have received. The remainder of this chapter provides the context within which the committee charge was carried out. BACKGROUND Within five days of the August 2, 1990, Iraqi invasion of Kuwait, the United States began to deploy troops to Southwest Asia. Ultimately, in response to United Nations Resolution 678, 41 nations sent nearly a million troops to the area, of which almost 700,000 were U.S. soldiers. (See Appendix A for a list of participating countries and numbers of troops.) From August 1990 through early January 1991, troops settled into position and prepared for war (Operation Desert Shield). Air attacks against the Iraqi forces were begun on January 16, 1991 (Operation Desert Storm), and on February 24 a ground attack was launched. Within four days Iraqi resistance crumbled. Following the fighting, the number of troops in the area declined rapidly. By June 13, 1991, the last U.S. troops who participated in the ground war returned home. U.S. casualties were low during the Gulf War. There were 148 combat deaths and another 145 deaths due to disease or injury. Despite the low number of casualties, U.S. troops were exposed to a large number of stressors. These included a wide range of biological and chemical agents, including sand, smoke from oil well fires, paints, solvents, insecticides, petroleum fuels and their combustion products, organophosphate nerve agents, pyridostigmine bromide, depleted uranium, anthrax and botulinum toxoid vaccinations, and infectious diseases. Additional stressors were the rapid mobilization for military service, with an accompanying disruption of normal patterns; the unfamiliar character of the region; the requirement that U.S. military personnel have virtually no interaction with the indigenous populations; the primitive living conditions of U.S. troops; and the immense destruction visited on the whole nation of Iraq. Following the war, most troops returned home and resumed their normal activities. Within a short time, however, some Gulf War veterans began to report health problems that they were concerned were connected

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Page 13to their service in the Gulf. Commonly reported problems include fatigue, moodiness, memory loss, muscle and joint pain, shortness of breath, and rashes (Fukuda et al. 1998; Iowa Persian Gulf Study Group 1997). A number of efforts have been undertaken by individual veterans, veterans' service organizations, academia, Congress, federal agencies, private-sector organizations, and others to investigate the possible causes of and treatments for the illnesses experienced by Gulf War veterans. This work includes clinical efforts aimed at understanding the nature of the illnesses and the effectiveness of potential treatments, population-based studies on the health status of Gulf War veterans, research on the potential health effects of the agents that were present in the Gulf War, advocacy efforts, and policy efforts on compensation and health care for Gulf War veterans. CLINICAL REGISTRIES In response to concern about possible illnesses, the VA and DoD developed special diagnostic programs. The VA program was begun in 1992 and is divided into two phases—the Persian Gulf Registry and the Uniform Case Assessment Protocol (UCAP). The Registry Exam includes basic laboratory tests and a complete medical history that records time of onset of symptoms or condition, intensity, degree of physical incapacitation, and details of any treatment received through the time of examination. The UCAP provides for additional examination and testing for those veterans who are found to have a disability but no clearly defined diagnosis that explains their health problems. Four Gulf War Referral Centers offer inpatient stays to treat serious health problems not diagnosed in the first two phases. Referral Centers provide multidisciplinary consultations, serial examinations, and treatment that is focused on individual patient needs. The DoD clinical diagnostic program implemented in 1994 is similar to that of the VA and is called the Comprehensive Clinical Evaluation Program (CCEP). The CCEP is also a two-phase process, the first of which is conducted at the primary care level and consists of a medical history, physical examinations, and laboratory tests. Veterans may be referred to Phase II for specialty consultations if the primary care physician determines such referral is indicated. The Specialized Care Center at Walter Reed Army Medical Center provides additional evaluation, treatment, and rehabilitation for patients suffering from chronic debilitating symptoms. As of October 2000, more than 80,000 Gulf War veterans had participated in the VA registry program, while DoD reports having completed examinations on almost 39,000 as of December that year.

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Page 14 SUMMARY OF GULF WAR REPORTS AND EVALUATIONS As reports of illness continued to spread so, too, did criticism of the responsiveness of the VA and DoD, and the media began to talk about a “Gulf War Syndrome.” Numerous efforts were undertaken to understand and solve the health problems of Gulf War veterans. A presidential advisory committee was established to review what was known and being done about veterans' health problems. Congress enacted legislation aimed at providing medical care to veterans experiencing problems and called for investigations into the causes. The General Accounting Office (GAO) undertook several studies. The IOM conducted scientific assessments of different aspects of the problem. The VA and DoD funded more than 120 research projects investigating the health problems of Gulf War veterans. Presidential Advisory Committee on Gulf War Veterans' Illnesses In May 1995, President Clinton established the Presidential Advisory Committee on Gulf War Veterans' Illnesses (PAC) to conduct an independent and comprehensive review of health concerns related to Gulf War service. The 12-member panel produced three reports. Major conclusions were (1) although the government had been somewhat slow to act at the end of the Gulf War, it was now providing appropriate medical care to Gulf War veterans; (2) the government's research portfolio was appropriately weighted toward epidemiological studies and studies on stressrelated disorders; (3) DoD investigations into possible chemical and biological warfare agent exposures had produced an atmosphere of mistrust surrounding every aspect of Gulf War veterans' illnesses, and the government had lost credibility with the public; (4) many veterans have illnesses that are likely connected to their service in the Gulf; (5) there is no evidence of a causal link between reported symptoms and illnesses and specific exposures; and (6) stress is likely to be an important contributing factor in these illnesses (Presidential Advisory Committee, 1996a, b, 1997). General Accounting Office Several studies were conducted by the GAO. In 1993 GAO criticized the Army's preparation for and response to depleted uranium exposure during the Gulf War (GAO 1993). A report on the health concerns of Gulf War veterans from the 123rd Army Reserve Command headquartered in Indianapolis found that veterans were either dissatisfied with the medical services received from DoD and VA or were unaware such services were available (GAO 1995). Additionally, most of these veterans reported health problems they believed were caused by their service in the Gulf

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Page 15and that these problems limited, to some extent, their physical and social activities. A June 1997 GAO report was extremely critical of the DoD and VA efforts to monitor the clinical progress of Gulf War veterans. In an investigation of tumors in Gulf War veterans, GAO reported that the incidence could not be reliably determined from available data (GAO 1998a). A subsequent report observed that “[w]hile the number of Gulf War veterans who participated in the military operations known as Desert Shield and Desert Storm is well established at almost 700,000, the number who actually suffer, or believe they suffer, from illnesses related to their Gulf War service remains uncertain 7 years after the war” (GAO, 1998b:2). This report recommended that the VA provide a case management approach to the care of Gulf War veterans and that the VA work to fully and uniformly implement these systems in its facilities. Institute of Medicine The IOM has completed several studies that focus on the potential health implications of deployment in the Gulf War and on the responses by the DoD and the VA to address veterans' health concerns. The IOM Medical Follow-up Agency examined the health consequences of service in the Gulf and developed recommendations for research and information systems. The first report of this group (IOM 1995:8) recommended that “the VA Persian Gulf Health Registry should be limited and specific to gathering information to determine the types of conditions reported. There should be efforts to implement quality control and standardization of data collected by the registry.” The report also recommended improved outreach to inform veterans about the availability of the registry. A second report focused on findings and recommendations concerning research and information systems needed to assess the health consequences of service during the Gulf War (IOM 1996a). An evaluation of the adequacy of the DoD Comprehensive Clinical Evaluation Program concluded that, while the CCEP was a comprehensive effort to address the clinical needs of those who had served in the Gulf War, specific changes in the protocol would help increase its diagnostic yield (IOM 1996b). The study also concluded that the CCEP was not appropriate as a research tool but that the results could and should be used to educate Gulf War veterans and the physicians caring for them, to improve the medical protocol itself, and to evaluate patient outcomes. IOM continued its evaluation of the CCEP, focusing attention specifically on difficult-to-diagnose problems and ill-defined conditions, the diagnosis and treatment of stress and psychiatric conditions, and the assessment of health problems of those who may have been exposed to low

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Page 16levels of nerve agents. The report addressing the adequacy of the CCEP relative to nerve agents concluded that the CCEP provided an appropriate screening approach to the diagnosis of neurological diseases and conditions but recommended certain refinements to enhance the program (IOM 1997a). In addressing the issues of medically unexplained conditions and stress and psychiatric disorders, the IOM (1997b) emphasized the need to treat veterans' symptoms whether or not a diagnosis had been determined; the need to provide increased screening for depression, traumatic exposure, and substance abuse; the importance of conducting an evaluation across facilities to determine consistency of examination procedures and patterns of referral; and the need for greater coordination between the DoD and the VA, particularly as it relates to the ongoing treatment of patients. A separate IOM committee evaluated the adequacy of the VA medical program for Gulf War veterans (IOM 1998a). This report complimented the VA for its overall provider education and outreach efforts. Recommendations called for the development of clinical practice guidelines for the difficult-to-diagnose or unexplained symptom constellations and for the establishment of a system of feedback and continuous quality improvement to monitor the care received by Gulf War veterans. The IOM Committee on Measuring the Health of Gulf War Veterans was charged with developing a study design and methods for measuring important aspects of the health status of Gulf War veterans. In its published report (IOM 1999a), the committee recommended a prospective cohort study designed to answer four fundamental questions: How healthy are Gulf War veterans? How does the health of Gulf War veterans change over time? How does the health of these veterans compare with others in the general population and the military? What individual and environmental characteristics are associated with observed differences in health between Gulf War veterans and comparison groups? In September 2000 the Committee on Health Effects Associated with Exposures During the Gulf War released the first of several anticipated reports evaluating the published scientific literature regarding the adverse effects of agents to which Gulf War veterans may have been exposed. The report (IOM 2000) placed its conclusions about possible associations between health outcomes and exposures to depleted uranium, sarin, pyridostigmine bromide, and vaccines into five different categories indicating the strength of the evidence. These levels of evidence are: Sufficient evidence of a causal relationship Sufficient evidence of an association Limited/suggestive evidence of an association

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Page 17 Inadequate/insufficient evidence to determine whether an association does or does not exist Limited/suggestive evidence of no association While the committee found sufficient evidence of a causal relationship or of an association between several of the exposures and transient acute effects, there was inadequate or insufficient evidence to determine whether an association does or does not exist between most of the evaluated exposures and long-term adverse health effects. The committee found limited or suggestive evidence of an association between exposure to sarin at doses sufficient to cause acute cholinergic signs and symptoms and subsequent long-term health effects. Additionally, the committee concluded that there is limited evidence of no association between exposure to uranium and kidney disease and between exposure to low levels of uranium and lung cancer. Although the committee was not charged with determining increased risk of illness to veterans due to their potential exposures, the paucity of data regarding the actual agents and doses to which individual Gulf War veterans were exposed meant that the committee could not measure the likelihood that Gulf War veterans' health problems are associated with or caused by these agents. Two other IOM studies were to determine what lessons could be learned from the issues and problems surrounding the health of Gulf War veterans. First, the report, Strategies to Protect the Health of Deployed U.S. Forces: Medical Surveillance, Record Keeping, and Risk Reduction (IOM 1999b), urged that the military health system develop an improved strategy for addressing medically unexplained symptoms that includes education of care providers, detection of veterans developing such symptoms, and treatment of symptoms in the primary care setting if possible. Further, the report recommended study of predisposing, precipitating, and perpetuating factors for medically unexplained symptoms and emphasized the crucial role of risk communication for future deployments. In response to a congressional mandate, an IOM committee was formed to assist the VA in developing a plan for establishing a national center (or centers) for the study of war-related illnesses and postdeployment health issues. The committee's report, National Center for Military Deployment Health Research (IOM 1999c), recommended establishing a national center that is independent of any single federal agency and guided by a board that is representative of all relevant stakeholders (veterans, federal agencies, the community at large, and independent scientists). Further, the report outlined the center's role as one of identifying research gaps and commissioning new research to fill them, fostering effective use of national data sources, and developing policy recommendations from data that emerge from the center's research.

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Page 18 Other Investigations In April 1997 the U.S. Senate Committee on Veterans' Affairs created an expert bipartisan special investigation unit to undertake a comprehensive and detailed review of what may have caused the illnesses of Gulf War veterans. This unit also investigated what should be done to treat these veterans. The unit's report found that “while there does not appear to be any single ‘Gulf War syndrome,' there is a constellation of symptoms and illnesses whose cause or causes eludes explanation at this time” (U.S. Senate Committee on Veterans' Affairs 1998:3). Further, the report said there is a great need to monitor Gulf War veterans to determine whether they are getting better or worse and to define the long-term health effects they may experience. The Executive Office of the President (EOP 1998) issued a report making several recommendations aimed at ensuring that the federal government will be better able to respond promptly and effectively in the future to the health needs of its military, veterans, and their families. When health problems are identified following a military deployment, the report states, plans must be in place to improve and facilitate cooperation and coordination among DoD, VA, and the Department of Health and Human Services. The report recommended (1) creating a Military and Veterans Health Coordinating Board, (2) developing an Information Management/Information Technology Task Force, and (3) implementing strategies aimed at deployment-related health issues, record keeping, health risk communication, and research (EOP 1998). GULF WAR VETERANS' HEALTH: RESEARCH SUMMARY Extensive scientific research has been undertaken on the health of Gulf War veterans. Studies of mortality of Gulf War-deployed veterans compared to similar veterans not deployed to the Gulf (Kang and Bullman 1996; Writer et al. 1996; Kang et al. 2000) found no excess mortality among Gulf War veterans, with the exception of automobile accidents. Several studies have found higher prevalence of self-reported symptoms in Gulf War veterans when compared with nondeployed Gulf War-era veterans or other control groups (Perconte et al. 1993; Southwick et al. 1993; Stretch et al. 1995; Sostek et al., 1996; Stretch et al. 1996a, b; Iowa Persian Gulf Study Group 1997; Pierce 1997; Goss Gilroy 1998; Proctor et al. 1998; Wolfe et al. 1998; Unwin et al., 1999). Some studies have sought to identify a specific illness or illnesses unique to Gulf War veterans (Haley et al. 1997a; Haley and Kurt 1997; Haley et al. 1997b; Fukuda 1998; Ismail et al. 1999). Other studies have focused on the incidence of diagnosed disease in cohorts of Gulf War veterans (Araneta et al. 1997; Cowan et al. 1997; Coker et al. 1999). In

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Page 19evaluating whether Gulf War veterans were more likely to be hospitalized Gray et al. (1996) found that the risk of hospitalization for deployed veterans in the immediate postwar period was no different from that of nondeployed veterans. According to a 1999 IOM report, Gulf War Veterans: Measuring Health, several conclusions can be drawn from results of recent research: Military personnel who served in the Gulf War have had a significantly higher risk of suffering one or more of a set of symptoms that include fatigue, memory loss, difficulty concentrating, pains in muscles and joints, and rashes. Other symptoms are noted with reduced frequency but still may be experienced more often by deployed than nondeployed veterans. The symptoms range in severity from barely detectable to completely debilitating. No single accepted diagnosis or group of diagnoses has been identified that describes and explains this cluster of symptoms. There is no single exposure, or set of exposures, that has been shown conclusively to cause individual symptoms or clusters of symptoms. Although some statistical associations have been seen in some studies, they have not been confirmed in other studies or through laboratory tests that would establish a cause-effect connection in individual patients. No diseases included in the ICD-9-CM or ICD-10 classification systems have been shown to be more frequent in deployed than nondeployed veterans, with the exception of the symptoms of posttraumatic stress disorder. Mortality among deployed veterans is not higher in general than among nondeployed veterans. Health-related quality of life, as measured through instruments such as the SF-36, is lower on average among deployed veterans than among nondeployed veterans. The natural course of symptom experience over time is not known, because no longitudinal studies of symptom experience have been conducted and reported in the literature (IOM 1999a). ONGOING CLINICAL RESEARCH Two federally funded clinical treatment trials are under way. The first is a randomized, multicenter, controlled trial of multi-modal therapy of Gulf War veterans who have unexplained chronic medical symptoms such as pain, fatigue, and/or cognitive difficulties. The treatments studied are cognitive-behavioral therapy and aerobic exercise. Both treatments have shown encouraging results in alleviating symptoms in individuals

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Page 20with similar types of illnesses, such as chronic fatigue syndrome and fibromyalgia. The study is expected to be completed in November 2001. The second federally funded clinical trial (conducted in collaboration with Pfizer Pharmaceuticals, which is donating the antibiotic and matching placebo) is designed to test the hypothesis that antibiotic treatment directed against Mycoplasma species will improve the functional status of patients with Gulf War veterans' illnesses who have tested mycoplasma-positive at baseline. This study is a 30-month prospective randomized double-blind clinical trial in which patients are randomized to either doxycycline (200 mg/day) or placebo treatment groups. The planned completion date is January 2002. A jointly funded VA/DoD study of the occurrence and potential cause or causes of amyotrophic lateral sclerosis (ALS) among Gulf War veterans is also under way. The study is intended to determine if this disease is occurring more often than is reasonably expected among Gulf War veterans and will attempt to identify probable or possible causes of ALS among Gulf War veterans. WAR-RELATED ILLNESSES AND POST DEPLOYMENT HEALTH RESEARCH A large body of research exists on the health effects of military conflict from the U.S. Civil War through the more recent conflicts of the 1991 Gulf War and Bosnia. Elder and colleagues (1997) conducted a longitudinal study of World War II veterans that found, after controlling for age and the effects of self-reported physical health at war's end, exposure to combat predicted that a subject would experience physical decline or death during the postwar period from 1945 to 1960. O'Toole et al. (1996) found, for Australian Vietnam veterans, that combat exposure was significantly related to reports of recent and chronic mental disorders, recent hernia and chronic ulcer, recent eczema and chronic rash, deafness, chronic infective and parasitic disease, and chronic back disorders, as well as symptoms and signs of ill-defined conditions. Hyams and colleagues (1996) summarized reports of poorly understood multisymptom clusters recorded in conflicts dating back to the Civil War and found symptoms of fatigue, shortness of breath, headache, sleep disturbance, forgetfulness, and impaired concentration. Various labels were used to describe clusters of symptoms, including shell shock, combat fatigue, irritable heart, and effort syndrome. No single etiological entity was discovered to account for these symptoms. Thus, concerns about the health of Gulf War veterans and that of veterans of other specific conflicts have slowly broadened to include questions regarding the consequences of service in any major military engage

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Page 21 ment. Further, research is beginning to focus on ways to prevent or treat deployment-related health effects. The remainder of this report presents the committee's deliberations, findings, and recommendations. Chapter 2 summarizes symptom data and describes the process used by the committee to identify health problems on which to focus. Chapter 3 provides a discussion of the study designs that can be used to evaluate the effectiveness and efficacy of interventions in medicine and health care, while Chapter 4 explores general approaches to treating a patient, regardless of diagnosis. Chapter 5 reviews the treatments evaluated for each identified condition and provides the committee's treatment recommendations. Chapter 6 presents concluding observations.

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