From the Kansas Commission on Veterans Affairs, Topeka, KS.
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ABSTRACT |
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fatigue syndrome, chronic; Persian Gulf syndrome; risk factors; symptoms and general pathology; veterans
Abbreviations: CI, confidence interval; non-PGW, veterans who did not serve in the Persian Gulf War; OR, odds ratio; PGW, veterans who served in the Persian Gulf War.
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INTRODUCTION |
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Despite a growing body of research on the health problems reported by Gulf War veterans, little is known about their nature or causes. Government review panels (24
) have generally not found that a single "Gulf War syndrome" is likely to explain all of the health problems reported by veterans. At the same time, research studies have consistently documented similar types of symptoms and illnesses in different groups of Gulf War veterans (5
9
) and have invariably found these problems to occur at higher rates in Gulf War veterans than in veterans serving elsewhere (10
15
).
Basic epidemiologic questions regarding the prevalence of these conditions and their association with characteristics of Gulf War service have also remained unanswered. The lack of progress in identifying these parameters is due in part to the difficulty of investigating symptom-based health problems that lack corresponding clinical signs and for which no accepted case definition exists (1, 5
, 8
, 16
, 17
). By December 1997, about 12 percent of eligible veterans who had served in the Persian Gulf War (PGW) had enrolled in one of two voluntary registries offered by the US Departments of Defense and Veterans Affairs (18
). Population-based studies, however, have suggested that a substantially higher proportion of veterans are experiencing health problems (13
15
).
The Kansas Persian Gulf War Veterans Health Initiative Program was developed by the state of Kansas in response to veterans' claims that they had health problems resulting from Gulf War service. The present study was designed to determine if Kansas Gulf War veterans experienced a greater burden of health problems than contemporary veterans who did not serve in the Gulf War and, if so, to describe any excess health problems, their prevalence, and patterns of occurrence.
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MATERIALS AND METHODS |
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Data collection
Interviews were conducted by telephone between February and August of 1998, using a computer-assisted telephone interviewing system. The survey instrument was designed to provide health information, particularly symptom data, comparable with that from other studies of Gulf War veterans. Questionnaires from previous population-based studies were reviewed. A list of representative health questions was generated and pretested in a group of Missouri Gulf War veterans. Veterans were asked if they had ever been diagnosed or treated by a physician for any of 16 specific medical and psychiatric conditions, or for any medical condition in five general areas, and when each reported condition had developed. Veterans were also asked if 37 individual symptoms had been persistent or recurring problems in the prior year, to rate the severity of each symptom endorsed, and when the problem first began. Only limited questions were asked about veterans' military service. Deployed veterans were asked when they arrived in and departed from the Persian Gulf area, the countries to which they deployed, the units with which they served, and whether they had been notified by the Department of Defense that they had been in the area potentially affected by the Khamisiyah munitions demolition in Iraq. Veterans who did not serve in the Persian Gulf War (non-PGW) were asked if they had received any vaccinations or injections from the military between August 1990 and July 1991.
Criteria for "Gulf War illness" symptom complex
The approach used to characterize the health problems reported by Kansas Gulf War veterans relied on two basic premises. First, not all symptoms and conditions experienced by Gulf War veterans were likely to be attributable to their wartime service. Some level of symptomatology and disease would be expected among Gulf War veterans even had they not served in the war (19, 20
). Second, the level of morbidity expected in the absence of Gulf War service could be estimated from an appropriate referent group. Any identified excess or atypical morbidity associated with PGW deployment might then be considered "Gulf War illness." Lacking a gold standard for Gulf War illness, cases were defined by a method similar to that used for another condition defined primarily by symptoms, chronic fatigue syndrome (21
). It involved identification of "exclusionary" conditionsthat is, medical and psychiatric diagnoses not included under the general category of "Gulf War illness" for current research purposesand quantifying the symptoms reported by PGW veterans to define "inclusionary" criteria.
Exclusionary conditions.
Diagnosed medical and psychiatric conditions were not included under the general rubric of Gulf War illness if they: 1) were not elevated among Kansas PGW veterans but might produce symptoms similar to those previously associated with Gulf War service, or 2) might interfere with respondents' perception or reports of their symptoms (i.e., serious psychiatric conditions). Therefore, veterans who reported being diagnosed or treated by a physician for any of the following conditions were excluded from consideration as Gulf War illness cases: cancer, diabetes, heart disease, chronic infectious disease, problems resulting from postwar injuries, liver disease, lupus, multiple sclerosis, stroke, or any serious psychiatric condition (those associated with psychosis and/or for which the respondent had been hospitalized since 1991).
Symptom groups and criteria.
Several approaches to quantifying symptom criteria were considered, including exploratory factor analysis to identify latent constructs that might be used to define symptom groupings or illness subtypes. This approach provided general validation regarding the cooccurrence of symptoms within system-based categories (e.g., respiratory symptoms tended to occur together, as did gastrointestinal symptoms, and so on). The cooccurrence of symptoms in different categories, however, varied in veteran subgroups (e.g., PGW vs. non-PGW veterans, males vs. females, PGW veterans deployed to different areas). This method was therefore not considered a reliable way to define illness subtypes in this population. Instead, a more descriptive approach was taken, defining symptom groups based on measures of correlation and comparisons between PGW and non-PGW veterans. Veterans were asked about symptoms in several general categories (e.g., respiratory, gastrointestinal, neuropsychological, sleep disturbances, pain), as well as symptoms (e.g., fatigue, headache) for which no single category was apparent. Gulf War illness criteria symptoms must have persisted or recurred in the year prior to interview and first have been a problem for respondents in 1990 or later. The correlation of symptom scores was assessed among PGW veterans who did not report exclusionary conditions. The internal reliability of each symptom grouping was determined using Cronbach's alpha (22). Symptom groups were considered reliable constructs if they were associated with an alpha of 0.70 or greater; individual items were retained within symptom groups if they had item-scale correlations of 0.50 or greater. Symptoms not included in a group were iteratively correlated with all symptom groups in order to identify additional associations according to the above criteria. In this manner, five highly reliable symptom groups were identified: 1) fatigue/sleep problems (
= 0.81), 2) pain symptoms (
= 0.78), 3) neurologic/cognitive/mood symptoms (
= 0.89), 4) gastrointestinal symptoms (
= 0.77), and 5) respiratory symptoms (
= 0.76). One additional symptom group, skin symptoms, was identified. Veterans were asked specifically about only one skin symptom (rashes), dis-allowing correlation assessments. This symptom was frequently reported, strongly associated with deployment, and relatively independent of other symptom groups. Veterans also frequently reported other skin problems, about which they had not specifically been asked.
A similar proportion of PGW and non-PGW veterans reported a very low level of symptomatology within most symptom groups (e.g., 9 percent of non-PGW veterans reported a single, mild fatigue/sleep problems symptom, compared with 10 percent of PGW veterans). Greater symptom burdens were significantly associated with PGW deployment in all symptom categories. Therefore, only respondents with at least one moderately severe symptom or two or more symptoms within a group were considered to have an elevated level of symptoms in that group.
Criteria for other symptom-defined outcomes.
Cases of multisymptom illness as defined by the Centers for Disease Control and Prevention were required to have one or more chronic symptoms from at least two of the following three groups: 1) fatigue; 2) mood/cognition (feeling down or depressed, memory problems, difficulty concentrating, trouble finding words, problems falling or staying asleep); and 3) musculoskeletal (joint pain, muscle pain) (14). Cases of chronic fatigue syndrome were defined on the basis of self-reported symptoms, fatigue characteristics, and medical diagnoses, according to established criteria (21
).
Data analyses
Analyses compared the health of PGW veterans with that of non-PGW veterans using several health indicators, including 1) general health status, 2) medical and psychiatric conditions reported to have been diagnosed or treated by a physician since 1990, 3) symptoms persisting over the prior year, and 4) defined symptom complexes (Gulf War illness, Centers for Disease Control and Prevention-defined multisymptom illness, chronic fatigue syndrome). The incidence of physician-diagnosed conditions and the prevalence of symptoms were assessed among veterans who did not have each problem prior to 1990. All outcomes among non-PGW veterans were stratified by veterans' self-reported receipt of vaccines or injections from the military during the index year.
Among both PGW and non-PGW veterans, health outcomes were frequently associated with veterans' sex, age, income level, and education level. Therefore, all analyses controlled for the effects of these variables. Indicators of general health status were compared using Mantel-Haenszel chi-square tests (23). Odds ratios for the association of deployment and vaccine status with conditions diagnosed or treated by a physician and prevalence odds ratios associated with chronic symptoms were determined using logistic regression. Prevalence odds ratios for defined symptom complexes were also determined by logistic regression, controlling for military as well as demographic variables.
Statistical analyses were performed using SAS version 6.12 computer software (24).
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RESULTS |
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Health indicators among PGW and non-PGW veterans
PGW veterans generally reported worse overall health and more symptoms than did non-PGW veterans (table 2). Forty-seven percent of all PGW veterans reported a lower level of health in 1998 than in 1990, compared with 19 percent of non-PGW veterans. Non-PGW veterans who received vaccines during the war were more likely to report a worsened health status since 1990 than were non-PGW veterans who did not receive vaccines, and the former endorsed a greater number of symptoms.
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Table 5 provides estimates of prevalence and prevalence odds ratios for the association of Gulf War illness with deployment and vaccine status. A similar pattern of association between PGW deployment, vaccine status, and illness was observed for Gulf War illness, Centers for Disease Control and Prevention-defined multisymptom illness, and chronic fatigue syndrome.
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Most PGW veterans were present in the Gulf region during the ground and air wars in January and February of 1991. Only 56 (4 percent) left the Gulf area prior to January 1991, and 29 (2 percent) arrived in the area in March 1991 or later. The prevalence of Gulf War illness was lowest among veterans who departed the region prior to the war, higher for those present during the war who left the region by March, and highest for those departing in June or July of 1991.
The association of Gulf War illness with time period differed by location in theater (not shown in table). The prevalence of Gulf War illness was highest among veterans who served in Iraq or Kuwait (42 percent), regardless of when they left the region. For veterans not in Iraq or Kuwait, Gulf War illness occurred in 9 percent of those departing prior to the war (referent), 21 percent of those departing in March (OR = 2.86, 95 percent CI: 1.05, 7.78), 32 percent of those departing in April or May (OR = 3.55, 95 percent CI: 1.28, 9.84), and 41 percent of those departing in June or July (OR = 10.31, 95 percent CI: 2.61, 40.78). This pattern was maintained after adjusting for the number of months veterans spent in the region, with odds ratios ranging from 2.54 for veterans leaving the region in March to 6.04 for those departing in June or July of 1991.
Finally, among non-PGW veterans, Gulf War illness was significantly associated only with self-reported receipt of vaccines (table 5) and being female (OR = 3.19, 95 percent CI: 1.23, 8.29). In multivariable modeling, there was no significant association of Gulf War illness with age, income level, education level, rank, component, or branch of service.
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DISCUSSION |
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Among Gulf War veterans, the prevalence of Gulf War illness was most strongly associated with the time period and location in which they served. Earlier reports have hinted at similar associations. US PGW veterans were least likely to participate in government registries if they were in the Gulf region before the war and most likely to participate if they served during Desert Storm (25). A report on veterans participating in the US Department of Veterans Affairs' registry suggested that veterans exhibit different illness profiles in connection with their location of service during the war (26
). Iowa PGW veterans were found to have more health problems if they served in Iraq, Kuwait, or Saudi Arabia than if they served elsewhere in the region (13
). In addition, Kansas Army veterans, enlisted personnel, and women were disproportionately affected by Gulf War illness, supporting previous indications that ground troops, enlisted personnel, and women may have more health problems than other PGW veterans (7
, 10
, 14
, 27
).
A question of central importance to veterans, government officials, and healthcare providers is, "How many veterans are affected by Gulf War-related health problems?" The answer depends on how such problems are conceptualized and defined, but a surprisingly consistent estimate for the excess burden of symptom-defined illness is emerging from existing population-based studies. Among four Air National Guard units, 45 percent of PGW veterans and 15 percent of non-PGW veterans met criteria for Centers for Disease Control and Prevention-defined multisymptom illness, an excess of 30 percent associated with PGW deployment (14). Among servicemen from the United Kingdom, 62 percent of PGW and 36 percent of non-PGW veterans met similar criteria, an excess of 26 percent among PGW veterans (15
). In the present study, 47 percent of Kansas PGW veterans met criteria for Centers for Disease Control and Prevention-defined multisymptom illness, compared with 20 percent of non-PGW veterans, an excess of 27 percent. In addition, 34 percent of PGW veterans met the more restrictive criteria for Kansas-defined Gulf War illness, compared with 8 percent of non-PGW veterans, an excess of 26 percent among PGW veterans. Thus, using two definitions in three distinct veteran populations, the excess burden of illness associated with deployment to the Gulf War has consistently been between 25 and 30 percent.
Nearly all PGW veterans were likely to have received vaccines prior to or during the war. Inoculations are routinely given in the military prior to overseas duty (28), and about 98 percent of Iowa veterans reported receiving vaccines in association with PGW deployment (13
). The results of the present study suggest that non-PGW veterans who received vaccines during the war may experience some of the same health problems as PGW veterans. The observed association of Gulf War illness with vaccines among non-PGW veterans is based on self-reported receipt of vaccines and so must be considered preliminary in nature. It does not appear to be due to a general overreporting of health problems in this group, however, since only one medical condition (hypertension) and two types of symptoms were significantly associated with receiving vaccines. Additionally, non-PGW veterans who received vaccines were no more likely to attribute health problems to their wartime service than were non-PGW veterans who did not receive vaccines.
A relation between vaccinations and illness has been observed among Gulf War veterans from the United Kingdom and Canada, and a mechanism for an association of illness with multiple vaccinations has been proposed (29). The prevalence of multisymptom illness was associated with reports by veterans from the United Kingdom of receiving vaccines against biologic warfare agents (anthrax, plague, pertussis adjuvant) and with receiving multiple vaccinations during deployment (15
, 30
). A 1998 study of Canadian Gulf War veterans found a significant association between receiving "nonroutine immunizations" (anthrax, plague) and several symptom-defined outcomes (10
).
Patterns associated with where and when a veteran served suggest that multiple factors likely contributed to the excess morbidity experienced by Gulf War-era veterans. Fewer than 4 percent of era veterans with no identified PGW-related exposures experienced symptoms of Gulf War illness. Between 9 and 12 percent of veterans likely to have had the lowest level of Gulf War-related exposures (non-PGW veterans who received vaccines during the war and veterans returning from the Gulf region prior to Desert Storm) had symptoms of Gulf War illness. The highest rate of illness, independent of time period, occurred among veterans who were in Iraq and/or Kuwait, suggesting that the factor or factors contributing to Gulf War illness were most concentrated in battlefield areas. Veterans in those areas might have encountered a greater number or concentration of potentially toxic exposures and experienced more battle-related trauma.
The observation that veterans in support areas who departed the region soon after the war were less likely to be ill than those who departed months later is particularly intriguing. It suggests an association of illness with toxic exposures, since battle-related stressors were reduced in later months. Potential risk factors that would have been more prevalent in support areas in later months might include exposure to contaminants from oil well fires, exposure to toxicants transferred via people or equipment from battlefield areas, and exposures associated with cleanup and refurbishing of equipment.
The results of this study raise methodological issues likely to be important in other Gulf War-related research. Fifteen percent of Gulf War-era veterans whose military records indicated they had not served in the Gulf War reported that they had. If the discrepancies observed here are representative, large studies of Gulf War-era military populations that rely on military personnel databases to compare outcomes between PGW and non-PGW veterans may be seriously affected by inaccurate assessment of deployment status.
Another important methodological issue relates to the use of non-PGW veterans as an "unexposed" referent group in cross-sectional and cohort studies. If vaccines administered to troops are one of the factors contributing to excess morbidity in Gulf War veterans, studies comparing PGW with non-PGW veterans should assess and control for the effects of vaccines received by non-PGW veterans.
There are limitations to consider in interpreting the findings reported here. First, all health and most military information was self-reported. The considerable amount of media attention given to issues surrounding Gulf War-related health problems may have generated an increased awareness of symptoms among PGW veterans and an increased willingness to report them. The possible impact of differential recall or reporting on apparent increases in morbidity among Gulf War veterans is difficult to quantify but has been assessed in previous studies. A large national survey of Gulf War-era veterans found that veteran-reported information relating to clinical encounters was in good agreement with medical records in 93 percent of cases and in partial agreement in 46 percent of cases (31). The Iowa Persian Gulf Study Group, using measures of physical function and veterans' tendency to respond to questions in a socially desirable way, concluded that recall bias may not explain the higher prevalence of health problems observed among PGW veterans (13
). It is also unlikely that increased symptom awareness or reporting among PGW veterans would fully account for the high odds ratios associated with Gulf War illness in the present study. In particular, media influence would not explain the nonrandom distribution of Gulf War illness observed here, since associations of illness with time and place of Gulf War service have not been widely reported.
Limitations generally associated with self-reported exposures in the Gulf War theater were minimized in this study by including only more objective service-related indicatorsrank, branch of service, dates of service, and the countries in which veterans served. The accuracy of self-reported receipt of vaccines by non-PGW veterans is open to question, however, and could have biased the associations observed here in either direction.
Further, it is not known whether the health experience of Kansas veterans is representative of Gulf War veterans nationally. Overall, Kansas Gulf War veterans were similar to their national peers with respect to rank, gender, and age distribution but included fewer non-Caucasians and a lower proportion of Navy and Marine Corps veterans (25). Still, the prevalence of Centers for Disease Control and Prevention-defined multisymptom illness observed in Kansas veterans was similar to that found among Air National Guard units (14
), and the estimated prevalence of chronic fatigue syndrome in Kansas PGW veterans (7 percent) was similar to that reported from a nationwide survey of PGW veterans (5 percent) (27
).
Over a decade after Iraq invaded Kuwait, the health problems reported by Gulf War veterans remain largely an unsolved mystery. These health problems appear to be complex, and their understanding will likely require an approach that considers "clusters of causes" and "combinations of effects" (32). The basic epidemiologic approach taken heredescribing excess health problems reported by veterans and their association with person, place, and timeprovides answers to preliminary questions and suggests areas of follow-up that might produce useful insights regarding etiology and illness subtypes. Such investigations should include comparisons between veteran subgroups with higher and lower rates of illness and among those with different types of symptoms. In this way, as the results of this study and of other recent studies suggest, many of the outstanding questions regarding Gulf War-related health problems may be answerable.
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ACKNOWLEDGMENTS |
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The author gratefully acknowledges members of the Kansas Persian Gulf War Veterans Health Initiative Advisory Board: Jim Bunker, Robert Hayes, Jeff Lawson, Dr. John Neuberger, Dr. Fred Oehme, Sharon Raby, Larry Salmans, and Dan Thimesch, as well as Don Myer for advice and support in project development. The author also thanks Dr. John Neuberger, Jeff Ford, Dr. Walter Schumm, and Dr. Tony Jurich for suggestions regarding questionnaire development; Dr. Robert Poresky, Dr. Minakshi Tikoo, and Jeremy Yorgason for supervising computer-assisted telephone interviewing data collection; the Defense Manpower Data Center for providing data on Kansas veterans; the Information Network of Kansas for assistance with state data; Jay Hemenway, Nicole Charles, and Amy Meier for assistance in locating veterans; Jill Covert and Rebecca Smith for assistance in data management; and Dr. Jeff Levin, Dr. Fred Oehme, Dr. John Neuberger, and Dr. Irving Cohen for helpful suggestions on earlier versions of this manuscript. Special acknowledgment is given to Dan Thimesch, whose persistent efforts made this study possible.
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NOTES |
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REFERENCES |
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