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EVALUATION OF THE U.S. DEPARTMENT OF DEFENSE PERSIAN GULF COMPREHENSIVE CLINICAL EVALUATION PROGRAM 9 patients in the CCEP had one or more psychiatric diagnoses 11% with depression and 5% with posttraumatic stress disorder (PTSD) (DoD, l995d). Since the goal is for most patients to receive a definitive diagnosis in Phase I, but the psychiatric evaluation is mandated only for patients in Phase II, the committee recommends that the DoD develop explicit guidelines for the identification of patients in Phase I who would benefit from a psychiatric evaluation. This will help ensure adequate psychiatric resources for both the initial evaluation and long-term follow-up care. Primary care physicians should be alerted to the relatively high degree of prevalence of these psychiatric disorders in this population. Two methods that have been proposed by RMC physicians to expedite the scheduling of psychiatric evaluations would be (1) the more frequent use of civilian psychiatrists and (2) consideration of using Ph.D.-level psychologists, as well as psychiatrists, when necessary. ANALYSIS AND INTrERPRETATION OF THE RESULTS OF TO CCEP The DoD has released a series of reports that have summarized the results of the medical evaluations of the CCEP patients. The DoD has stated, "The large size of the CCEP cohort and the thoroughness of the CCEP examinations provide considerable clinical insight for understanding the nature of illnesses and health complaints experienced by this group of veterans" (DoD, l995d). The DoD's most recent report, however, recommends caution in the generalization of the interpretation of the CCEP results: "However, self-selection of patients, differential eligibility, recall bias, inability to validate self-reported exposures, and lack of an appropriate control group limit the generalization of these findings to other Gulf War veterans" (DoD, l995d). Four major areas related to the analysis and interpretation of the results of the CCEP deserve attention: (1) the symptoms and diagnoses in the CCEP population; (2) clinical evidence for a new, unique Persian Gulf Syndrome; (3) the potential relationship of illnesses in some CCEP patients to service in the Persian Gulf; and (4) a comparison of the CCEP population with other populations. Symptoms and Diagnoses in the CCEP Population The CCEP patients report a very broad range of symptoms. The most recent DoD report on 10,020 participants summarizes the frequencies of the chief complaints and all complaints for these patients (DoD, l995d). The most common symptoms are fatigue, joint pain, headache, rash/dermatitis, and
10 EVALUATION OF THE U.S. DEPARTMENT OF DEFENSE PERSIAN GULF COMPREHENSIVE CLINICAL EVALUATION PROGRAM memory loss. Only two symptoms were given as the chief complaint by 10% or more of the patients: fatigue (11 %) and joint pain (11 %) (DoD, l995d). The median number of diagnoses per patient is three. The CCEP computer database records seven diagnoses. For a patient with three diagnoses, three different aspects of one organ system could be involved (e.g., three unrelated musculoskeletal problems) or three or more different organ systems (an extreme example would be diabetes, which is only one diagnosis but which affects several organs). The diagnoses in the first 10,020 CCEP patients are stratified by major International Classification of Disease, 9th edition (ICD-9), codes, in the recent DoD report (DoD, 1995d). There are only two major disease groups or organ systems in which 10% or more of the 10,020 patients have a primary diagnosis. The primary diagnosis is the one disease that the CCEP physician judges to be the most important or critical for each patient (DoD, 1995a). These two groups are psychological conditions (19%) and musculoskeletal conditions (16%~. Similarly, there are only two major disease groups or organ systems in which 25% or more of the 10,020 patients have any diagnosis (primary or secondary). These are psychological conditions (37%) and musculoskeletal conditions (45%~. Beyond this, the primary diagnoses among the first 10,020 patients do not appear to be concentrated in any single organ system. Many different combinations of diagnoses exist among the 10,020 patients, and relatively few individuals have the same combinations of diseases. The CCEP physicians presented summaries of several case histories over the course of the three IOM meetings. Most of these individual cases had two or more discrete diagnoses, often in two or more different organ systems. Examples of two typical patient presentations might be (1) PTSD and asthma or (2) migraine headaches, hypothyroidism, and osteoarthritis of the left knee. In most of these cases, it was unlikely that the two or more diseases were different manifestations of the same underlying pathological process. The corn~nittee found no evidence that the DoD has been trying to avoid reaching a single "unifying" diagnosis when a plausible one was available. A "unifying" diagnosis is defined here as a single diagnosis that could explain most or all of a patient's symptoms. One interpretation of the CCEP results is that the signs and symptoms in many patients can be explained by well-recognized conditions that are readily diagnosable and treatable. The committee concludes that this is a more likely interpretation than the interpretation that a high proportion of the CCEP patients are suffering from a unique, previously unknown "mystery disease." By providing more detailed information on specific diagnoses in its future reports, the DoD might help correct the impressions among the general public that exist about the high degree of prevalence of a "mystery disease" or a new, unique "Persian Gulf Syndrome."
EVALUATION OF THE U.S. DEPARTMENT OF DEFENSE PERSIAN 11 GULF COMPREHENSIVE CLINICAL EVALUATION PROGRAM In the medical history, the CCEP patients are asked about how many workdays they have lost because of illness in the last 90 days. Most patients (81 %) reported that they had not missed any days of work because of illness during the 90 days before their initial evaluation. Few patients (7%) reported missing more than 1 week of work because of illness (DoD, l995d). By this measure, most CCEP patients are not seriously impaired by their symptoms. However, it is likely that there are substantial disincentives for taking lengthy sick leave in the military, just as there are in civilian employment. In addition, the reported number of lost workdays may not always reflect more subtle functional impairments. Nonetheless, if these self-reported data on lost workdays are accurate, they can serve a useful sentinel role for significant impairment. It is unlikely that there is a high degree of prevalence of significant impairment among the CCEP population. Disability processing actions in the Services' Physical Disability Processing Systems have been completed for 246 of the 10,020 CCEP patients (DoD, l995c). The DoD has not provided any data about their diagnoses or their reasons for medical separation from the military. The committee recommends that the DoD investigate the diagnoses in this group of patients in future reports, as well as whether or not the disorders could have been caused or exacerbated by service in the Persian Gulf. Many other individuals who served in the Persian Gulf have left active service and, hence, are not eligible for the DoD's CCEP. Some of these veterans may have disabilities related or unrelated to their service in the Persian Gulf, and those with disabilities might be more likely to have left active service. For these reasons, the CCEP results should not be viewed as estimates of the prevalence of disability related to Persian Gulf seNice. Clinical Evidence of a New, Unique Persian Gulf Syndrome In the DoD report on 10,020 CCEP patients, a major conclusion is that "To date, the CCEP has identified no clinical evidence for a new or unique illness or syndrome among Persian Gulf veterans" (DoD, 1995d). The justification for this conclusion is as follows (DoD, 1995d): DoD physicians have diagnosed a wide range of medical conditions commonly seen in general medical practice, but have found no clinical evidence for a unique illness among CCEP participants. The large number of patients participating in the CCEP, the thoroughness of the evaluations, and the clinical impressions of CCEP physicians are the primary basis for forming conclusions regarding the existence of a new or unique condition or syndrome.
12 EVALUATION OF THE U.S. DEPARTMENT OF DEFENSE PERSIAN GULF COMPREHENSIVE CLINICAL EVALUATION PROGRAM The committee agrees that there is currently no clinical evidence in the CCEP of a previously unknown, serious illness among Persian Gulf veterans. If there were a new or unique illness or syndrome among Persian Gulf veterans that could cause serious impairment in a high proportion of veterans at risk, it would probably be detectable in the population of 10,020 CCEP patients. On the other hand, if an unknown illness were mild or affected only a small proportion of veterans at risk, it might not be detectable in a case series, no matter how large. For example, if some particular exposure in the Persian Gulf region could cause a small proportion of veterans to develop mild headaches, this would be difficult to detect. This is because mild headaches are common medical problems, and they are associated with many different risk factors. Sophisticated statistical techniques, including cluster analysis, could be used to identify whether or not there are previously unidentified patterns of symptoms among the CCEP patients. If symptom patterns were identified, the patterns would have to be analyzed to determine whether the affected patients demonstrated characteristic physical abnormalities, lab test abnormalities, and risk factors that might suggest a new, unique syndrome. To be designated as a newly recognized disease, these patterns of physical abnormalities, lab test abnormalities, and risk factors would have to be objectively different from the patterns of well-recognized diseases. If it appears that there is a new, unique syndrome, an investigation of the association between this medical condition and exposure to physical and psychological stressors in the Persian Gulf would then be necessary. The committee encourages the DoD's plan to share the entire CCEP data set with qualified researchers outside of the DoD who might be able to undertake the kind of research with the methodological sophistication that the identification of a new syndrome would require. The DoD and the DVA are sponsoring several large research studies that may provide more definitive answers as to whether there is a new, unique Persian Gulf Syndrome. An outline of the research studies that are relevant to the CCEP appears in a later section of this report. Potential Relationship of Illnesses in CCEP Patients to Service in the Persian Gulf As in previous conflicts, some CCEP patients may have developed illnesses that are directly related to their service in the Persian Gulf, such as (1) acute musculoskeletal injuries that were sustained during the war, (2) infectious diseases such as leishmaniasis that are very rare outside of the Middle East (Hyams et al., 1995), or (3) psychological stress experienced during or after the war that has caused or exacerbated physical or mental illnesses (Sutker et al., 1994a). Some CCEP patients also may have developed illnesses that are
EVALUATION OF THE U.S. DEPARTMENT OF DEFENSE PERSIAN 13 GULF COMPREHENSIVE CLINICAL EVALUATION PROGRAM coincidental with or predate, and that are therefore unrelated to, their service in the Persian Gulf. Physicians involved with the development and the administration of the CCEP have, in various public presentations, acknowledged that some CCEP patients have developed illnesses that are directly related to their service in the Persian Gulf. The recent DoD report on 10,020 CCEP participants, however, only touches on this issue indirectly (DoD, 1995d). The committee encourages the DoD to discuss the issue of causality explicitly and unambiguously in its future reports. Such a discussion might help to alleviate the current climate of confusion and mistrust that exists among some Persian Gulf veterans and the general public. The time of onset of disease is closely related to the potential relationship of an illness and service in the Persian Gulf. The CCEP questionnaire includes an explicit question about the duration of symptoms in weeks; therefore, it would be possible to stratify the onset of each patient's symptoms relative to his or her service in the Persian Gulf. The recent DoD report on 10,020 participants, however, does not address the timing of exposures during Persian Gulf service in relation to the onset of symptoms (DoD, l995d). The committee recommends that the DoD attempt to determine the timing of the onset of disease, especially for patients who have significant impairments. Review of military or civilian medical records that predate enrollment in the CCEP may provide contemporaneous documentation of the onset of symptoms in some patients, especially if the symptoms are serious. In addition, it is important to determine whether service in the Persian Gulf has contributed to the exacerbation of preexisting diseases in some CCEP patients. Comparison of the CCEP Population with Other Populations In its most recent report, the DoD compares the symptoms and diagnoses in the CCEP population with the symptoms and diagnoses in several community- based and clinically based populations (DoD, 1995d). For example, the DoD provides possible explanations for why certain diagnostic categories are more or less common in the CCEP than in the National Ambulatory Medical Care Survey. In the committee's view, interpretations based on comparisons with other populations should be made with great caution and only with the explicit recognition of the limitations of the CCEP as a self-selected case series. The CCEP was not designed to answer epidemiological questions, such as how the frequencies of certain diagnoses compare between the CCEP population and a control population. Instead, it was designed as a medical evaluation and treatment program. Indeed, the research aims of the CCEP do not appear to be stated explicitly, nor does there appear to be a concrete epidemiological study
14 EVALUATION OF THE U.S. DEPARTMENT OF DEFENSE PERSIAN GULF COMPREHENSIVE CLINICAL EVALUATION PROGRAM plan. Without research hypotheses, it is not possible to judge whether any particular comparison group is appropriate. Many different comparison groups are briefly mentioned in the DoD report on 10,020 CCEP participants (DoD, l995d). Each individual population should be described to prevent confusion. Because of the self-selected nature of the CCEP population, a truly comparable reference group may not be available. For example, active-duty military personnel tend to be younger, predominately male, and healthy enough to work full-time. Since the physical requirements to join the military are relatively stringent, active-duty personnel are generally healthier than the average person in the same age group. In contrast, civilian patients who have been evaluated in primary care clinics may be older, may include more females, and may be too sick to work full-time. Because the CCEP population has concerns about chronic symptoms and is actively seeking health care, clinically based groups might be more appropriate for comparison than population-based groups. The CCEP includes a wide variety of data gathered at many sites. Clinical evaluations were performed by different physicians in many locations and who possibly used a variety of diagnostic criteria. This is particularly true for diseases for which the diagnostic methods are not entirely routinize, such as neuropsychological disorders or sleep disorders. These data may not be appropriate for epidemiological purposes beyond the description of a case series because of the potential lack of uniformity in collecting the diagnostic information. For these reasons, it would be extremely difficult to establish causal relationships or to identify and characterize a new "Persian Gulf Syndrome" definitively by relying on data from the CCEP alone. The latitude permitted in the clinical examination program conflicts with the rigor necessary to answer an epidemiological question. The CCEP data do have considerable clinical utility, and they could be used to address many important questions from a descriptive perspective. Many case series could be derived from these data, for example, a case series describing the sleep apneas identified in the CCEP population. In addition, the results of the clinical exams could provide guidance in the selection of research questions and in the design of future epidemiological research. In particular, certain hypotheses could be derived from the clinical exams, which in turn could lead to explicit choices in questionnaire design or laboratory tests. For example, the frequency of serious infectious diseases, such as leishmaniasis or malaria, is very low in the CCEP population; therefore, further epidemiological research should not focus solely on infectious diseases. The CCEP findings could be used to generate epidemiological questions on other types of diseases that are much more frequent in the CCEP population, such as musculoskeletal diseases. An outline of ongoing epidemiological research that is relevant to the CCEP is