1 Department of Defense Center for Deployment Health Research, Naval Health Research Center, San Diego, CA.
2 Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA.
3 Deployment Environmental Surveillance Program, US Army Center for Health Promotion and Preventive Medicine, Aberdeen Proving Ground, MD.
Received for publication January 13, 2003; accepted for publication March 20, 2003.
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ABSTRACT |
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exposure, environmental;exposure, occupational; hospitalization; military medicine; morbidity; Persian Gulf syndrome; veterans
Abbreviations: Abbreviations: CI, confidence interval; GIS, geographic information system; GPL, general population limit; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; RR, risk ratio.
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INTRODUCTION |
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Although there is no evidence that Iraq used chemical weapons against coalition forces (17), the Department of Defense announced in June 1996 that the United Nations had found that chemical weapons were destroyed in March 1991 by US forces near Khamisiyah, Iraq. This prompted attempts to identify and notify those Gulf War veterans who might have been exposed to gaseous nerve agents in the hazard areas resulting from the demolition of chemical weapons at Khamisiyah. In a 1999 report (18), we compared the postwar hospitalization experience of these Gulf War veterans with that of other Gulf War veterans who were not likely to have been exposed. We found no evidence that Gulf War veterans, who were possibly exposed to nerve agents in the hazard areas identified by these original models, were suffering increased hospital morbidity through September 1995.
Since our report, exposure estimate models were greatly improved. In December 2000, the Office of the Special Assistant for Gulf War Illnesses released a much more detailed update (19) to its original 1997 case narrative (20). This work was followed by the final report in April 2002, identifying 101,752 Gulf War veterans as having been possibly exposed in the hazard areas created by the destruction of munitions at Khamisiyah (21). The revision of the meteorologic models, reduction in estimates of nerve agent released, combining of toxicity levels of both sarin and cyclosarin instead of only sarin, and inclusion of atmospheric removal mechanisms like deposition and degradation resulted in a greatly improved model of hazard areas. This model determined that a somewhat smaller geographic area of exposure was more likely than originally predicted. These new data, updated unit location and personnel data, and the addition of 5 years of hospitalization data for those veterans continuing in an activated capacity may allow better assessment of illnesses and chronic illnesses of those possibly exposed to chemical warfare agents in the Khamisiyah hazard areas in 1991. In this historical cohort study, we compared the postwar morbidity of 101,752 US military personnel possibly exposed to the revised nerve agent hazard areas at Khamisiyah, Iraq, in March 1991 with that of deployed personnel not likely to have been exposed.
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MATERIALS AND METHODS |
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Demographic and deployment data for Gulf War veterans established in 1997 were provided by the Defense Manpower Data Center, Monterey Bay, California, and reflected military status as of August 1, 1991. These data included age, marital status, gender, race/ethnicity (White, Black, Hispanic non-Black, and other), service branch (Army, Air Force), service type (active duty, National Guard, and Reserve), Department of Defense primary occupational specialties (10 major categories, defined by the DoD Occupational Conversion Manual) (24), rank (enlisted, warrant officer, and commissioned officer), number of days in the Gulf theater (categorized by approximate quartiles as 1107 days, 108161 days, 162202 days, 203572 days), calendar period in the Gulf theater, salary, length of service, and date of separation from military service. The study was approved by the institutional review board of the Naval Health Research Center (San Diego, California), and it was conducted in compliance with all applicable federal regulations governing the protection of human subjects in research.
Hospitalization data
Hospitalization data for each service member included the date of admission and up to eight individual discharge diagnoses, captured from all Department of Defense hospitals during the period from August 1, 1989, through December 31, 2000. These data were linked to deployment and demographic data using a unique identifier. Diagnoses were coded according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) (25). For analyses of major diagnostic categories, the decimal components of the ICD-9-CM diagnoses were not considered. As in previous reports (18, 22, 26, 27), a prewar hospitalization covariate was created and linked to denote hospitalization for any cause during the 12 months prior to August 1, 1990. Hospitalization data available from outside the Department of Defense health care system and outpatient data for the time period of this investigation were not available.
Meteorologic, transport, diffusion, and rocket destruction modeling
Since the 1997 Khamisiyah gaseous hazard area modeling, recommendations from a peer-review panel and the availability of new data and better modeling algorithms have guided the Office of Special Assistant for Gulf War Illnesses to make improvements in the Khamisiyah hazard area modeling (19, 21). The 2000 Khamisiyah gaseous hazard area modeling approach used the composite of four sets of modeling results to define a potential hazard area. Refinement to the modeling included a reduced estimate of 225 destroyed rockets containing nerve agent instead of 500, combined toxicity of sarin and cyclosarin where only sarin toxicity data were available in 1997, integration of atmospheric agent removal mechanisms including deposition (transfer of airborne material to the earths surface) and degradation (decay), and refined meteorologic modeling methodologies.
Hazard area and exposure estimates
Exposure was defined by an existing health standard established by the Centers for Disease Control and Prevention of the Department of Health and Human Services. This standard is referred to as the "general population limit" (GPL). The Centers for Disease Control-recommended GPL is the maximum air concentration that anyone in the general population (including infants and elderly people) could be exposed to continuously for 72 hours with no adverse effect (28). Additionally, the Centers for Disease Control states that even long-term exposure to these concentrations would not create any adverse health effects (19). Because potential Khamisiyah-related exposures were of much briefer duration, the GPL value was adjusted accordingly. Potential hazard areas were generated by the modeling using the 24-hour dosage derived from the adjusted-GPL-based concentration levels of 0.000003 mg/m3 for sarin and 0.00001 mg/m3 for cyclosarin (19).
Geographic information systems data
Geographic information system (GIS) techniques were used to plot revised military unit daily locations in the Gulf War theater. These data were provided by the US Armed Services Center for Unit Records Research, Springfield, Virginia, and were compiled and organized using relational database management system software (Oracle, Redwood Shores, California). Using Arc View GIS software (Environmental Systems Research Institute, Redlands, California), we geo-referenced the four individual gaseous hazard area models to derive daily hazard areas for the period from March 10 to March 13, 1991, by selecting the union of the composite areas. These daily hazard areas were geo-referenced with respective daily troop location data to determine which units were possibly exposed. To associate individual personnel from the units found within the hazard areas, we cross-matched troop unit identification codes to an updated Defense Manpower Data Center Desert Shield/Desert Storm personnel file.
Study outcomes
As in the previous report (18), we chose to examine broad outcomes for our analyses, including hospitalizations for any cause and hospitalizations due to diagnoses in 15 major ICD-9-CM categories (25). In addition to the 15 broad outcomes of hospitalization, specific diagnoses, suggested by an expert panel as possible chronic manifestations of acute subclinical nerve agent exposure, were examined to avoid missing a risk difference due to the possible masking effect of aggregated ICD-9-CM diagnoses (29). Additionally, we planned to investigate the 10 most frequent specific three-digit diagnoses within any broad category for which veterans were at increased risk of hospitalization.
Statistical analyses
Hospitalizations were sorted in chronologic order, and diagnostic fields were scanned in numerical order for ICD-9-CM diagnoses of interest. Univariate analyses were performed to assess possible associations between demographic, exposure, and deployment variables and any-cause hospitalization. An exploratory model analysis was developed to further assess significant risk factor associations, while simultaneously adjusting for all influential predictors of the targeted outcome. These analyses yielded a consistent set of influential covariates, with p values of 0.15 or below, that were then included in subsequent model analyses. Using regression diagnostics, we investigated the collinearity and multiplicative interaction among variables. We used Coxs proportional hazards time-to-event modeling to compare the Department of Defense hospitalization experience of Gulf War veterans, while accounting for separation from military service over the nearly 10-year period. Subjects were classified as having an event if they were hospitalized in any Department of Defense hospital worldwide with any of the targeted outcomes. Follow-up time for the modeling of a single event was calculated from March 10, 1991, until hospitalization, separation from active-duty military service, or December 31, 2000, whichever occurred first. Because no separation data were available for Reserve personnel, they were assumed to have remained in active service until June 10, 1991, at which time most Reservists had returned to civilian careers. Additionally, to investigate rare events occurring among specific diagnoses, we also developed Poisson models to estimate the risk ratio of hospitalization with the rare event.
Modeling multiple hospitalizations within each major ICD-9-CM diagnostic category was accomplished by using a marginal regression model with a conditional method proposed by Prentice et al. (30) and Therneau and Grambsch (31). Follow-up time for multiple hospitalization modeling was calculated from March 10, 1991, and subsequent hospital admission dates to first or subsequent hospitalization, separation from active-duty military service, or December 31, 2000, whichever occurred first.
Using SAS software (version 8.0; SAS Institute, Inc., Cary, North Carolina), we calculated risk ratios and 95 percent confidence intervals for the 418,072 personnel with complete covariate data (32). The time-to-first-event estimates were calculated by exposure status, allowing computation and graphing of the cumulative probability of hospitalization as a function of time.
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RESULTS |
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During the nearly 10-year observation period, 18.4 percent of the exposed personnel were hospitalized, and 18.8 percent of nonexposed personnel were hospitalized. Attrition was approximately equal, with 57.3 percent of the exposed personnel and 57.9 percent of the nonexposed personnel separating from military service over the nearly 10-year period. The adjusted risk of any-cause hospitalization for exposed veterans was not significantly different from the risk for the nonexposed veterans. However, gender, age, military pay grade, Reserve or National Guard status, race/ethnicity, prewar hospitalization, and occupational category remained statistically associated with hospitalization for any cause (table 2). The corresponding cumulative probability of hospitalization plots for exposed personnel versus nonexposed personnel remained very stable and nearly parallel over the 10-year follow-up period (figure 1).
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DISCUSSION |
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As part of our continuing efforts to assess plausible relations among potential Gulf War exposures and health outcomes, we examined the hospitalization experience of US military personnel who were possibly exposed to the refined hazard area estimates after the destruction of chemical munitions at Khamisiyah, Iraq. In this follow-up report, the possibly exposed included more than 35,000 personnel who were not within the GPL hazard areas in the 1997 modeling (21). Furthermore, the additional 5 years of follow-up have allowed development of models to account for multiple hospitalizations or late-occurring diagnoses over the study period.
These exposure-outcome relations were evaluated using updated electronic Department of Defense databases containing deployment history, service, demographic information, hospitalization, daily troop unit location, meteorologic hazard area modeling, and dispersion modeling data. As in previous reports, personnel who were generally older, enlisted, female, persons who were hospitalized before the war, and health care workers were at increased risk of hospitalization for any cause after the war (22).
From the 37 risk-factor models, it is interesting that Gulf War veterans who were possibly exposed to subclinical doses of nerve agent were at slightly increased risk for both single and multiple postwar hospitalizations due to circulatory system diagnoses, specifically cardiac dysrhythmias. Cardiac dysrhythmias are abnormal rates or rhythms of the heart related to a disruption of the normal functioning of the electrical conduction system of the heart. Further investigation showed that the majority of these cases were specific diagnoses of atrial fibrillation (ICD-9-CM code 427.31) and other specified cardiac dysrhythmias (ICD-9-CM code 427.89), including coronary sinus, ectopic, and nodal rhythm disorders. Although a war setting might be conducive to acute disturbances of the rhythm of the heart, there was no evidence of such a deployment effect upon postwar hospitalizations with circulatory disease when all Gulf War veterans were compared with nondeployed veterans using Department of Defense, Department of Veterans Affairs, and California hospitalization data (22, 39). Similarly, Gulf War veterans appear to bear a lower risk for circulatory hospitalizations than do Vietnam veterans (40).
Circulatory system diagnoses, specifically cardiac dysrhythmia, have not been frequent diagnoses in Gulf War veteran health registry evaluations (4143), nor have these diagnoses been the subject of frequent self-report among Gulf War veteran studies (11, 44). However, the Goss Gilroy health study of 3,000 Canadian Gulf War veterans found an increased prevalence (4.7 percent) of self-reported circulatory problems when compared with controls (1.8 percent) (45). Furthermore, the only Gulf War veteran study in which the authors found indications that Gulf War veterans were specifically experiencing irregular heart rates was a modest cross-sectional survey of 300 Gulf War era veterans (8). In this survey, Proctor et al. found that two US Gulf War veteran cohorts were at increased odds of reporting "irregular heart beats" or "heart fluttering" (odds ratios = 2.4 and 4.1) and "racing heart" (odds ratios = 1.8 and 3.0) compared with Germany-deployed US veterans.
Other non-Gulf War-related studies focusing on the effects of organophosphate compounds have reported similar findings. A study of victims of the 1995 Tokyo sarin attack who were followed for 3 years found an initial proportion of 9.5 percent with the symptom "sudden palpitations" that decreased to 8.7 percent and 6.3 percent over subsequent years of observation (46). Jones et al. (47) found that, of 1,856 British servicemen with postcombat syndromes, the sixth most frequent symptom was "rapid or irregular heartbeat" and that functional cardiac disorders were frequent in soldiers fighting in the Boer War and World War I. An animal study investigating organophosphate compounds demonstrated that high concentrations of the compounds, such as sarin, bind to the A1 adenosine receptors in ovine cardiac membranes and suggested that these compounds affect the mechanical responses of the heart (48). Further research, including more animal studies, may be justified in order to establish a biologic mechanism and to better validate these findings.
The present studys findings of an adjusted association between possible exposure to Khamisiyah hazard areas and cardiac dysrhythmias are based on a low magnitude of effect (RR = 1.22, 95 percent CI: 1.02, 1.45) and might be due to chance alone. Our study had a number of important limitations. Acquiring reliable exposure estimates and projecting them on personnel to obtain exposure data at the individual level is very challenging. Ascertainment of quantitative estimates of other potentially confounding behavioral and environmental exposures, such as tobacco use, diesel exhaust, combustion of jet fuel, and other weapons depots that may have contained chemical weapons, was not possible for each individual. The limitations of epidemiologic studies that use group exposure data and individual outcome data without accounting for other possible confounding exposures have been discussed previously (18, 49, 50).
Further limitations include the choice of hospitalization as the measure of health effect. This limited the analyses to morbidity severe enough to require admission to a Department of Defense hospital for inpatient care. Outpatient data and data from personnel who sought private care outside the Department of Defense while on active duty were not available, diminishing the ability for examination of the full spectrum of health effects. However, in an investigation of 3,831 Gulf War Seabees, the authors report no association between Khamisyah hazard area exposure and self-reported symptom morbidity (9). Additionally, hospitalization data were available for only active and Reserve Gulf War veterans who remained on active duty or retired with medical benefits after the end of the war. This limitation may be mitigated by the facts that additional analyses were conducted after removing Reservists from the modeling and the findings remain essentially unchanged, that attritions between exposed and nonexposed veterans were found to be similar over the nearly 10-year follow-up, and that the mean follow-up time for those exposed was 2.9 person-years and for those nonexposed was 3.2 person-years. Furthermore, although the distributions of demographic variables over exposure status were similar, it is possible that those personnel in direct combat roles, as a group, were more physically fit than support personnel and thus less likely to be hospitalized postdeployment. Finally, the observation period of nearly 10 years may not be long enough for all possible long-term sarin and cyclosarin health effects to manifest.
Despite limitations, our study has a number of unique characteristics that may strengthen its conclusions. Sophisticated meteorologic and dispersion modeling techniques were integrated along with testimony by witnesses and GIS unit tracking to identify those possibly exposed to the gaseous hazard areas. Hospitalization outcome data are very complete for active-duty military personnel who seldom seek care outside the Department of Defense health care system (22, 23), and they reflect a more objective measure than self-reported symptoms or illnesses. Additionally, being able to analyze single, uncorrelated events as well as multiple events by using the Cox model permitted the examination of all event information. Finally, our large study population permitted robust risk estimates and considerable statistical power to detect even small differences in hospitalization risk across exposure and demographic groups, making it very likely that if true differences in hospitalization risk existed between exposed and nonexposed veterans, we would have detected them.
In summary, the use of refined exposure estimates to identify those possibly exposed to Khamisiyah nerve agent hazard areas in the Gulf War does not support the hypothesis that such personnel were generally at increased risk of hospitalization after the war. Investigation of both broad and specific outcomes, however, resulted in the finding of a small, increased association with circulatory system disorders, specifically cardiac dysrhythmia, among the possibly exposed personnel. Future work to explore this association may include toxicologic modeling in animals, epidemiologic case-control studies, and prospective evaluations in large military populations such as the Millennium Cohort (51). Our findings of no other increased risk for the remaining 14 categories and specific diagnoses are, however, consistent with the previous report and other studies of health outcomes following military service in the Gulf War. These findings, in addition to a report noting no increase in mortality for the possibly exposed (52), may be reassuring to those veterans concerned about other health effects associated with possible exposure to munitions destruction at Khamisiyah, Iraq.
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ACKNOWLEDGMENTS |
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The authors thank Michael A. Dove and Scott L. Seggerman from the Management Information Division, Defense Manpower Data Center, Seaside, California, for providing Gulf War veteran deployment data. They also thank Jeff Kirkpatrick, Warren Wortman, Veronique Hauschild, and Mark Walter from the Deployment Environmental Surveillance Program of the US Army Center for Health Promotion and Preventive Medicine, Aberdeen Proving Ground, Maryland, and Richard Harrington, Col. Michael Abreu, Larry Sipos, and Dr. Michael Kilpatrick from the Deployment Health Support Directorate (formerly Office of Special Assistant for Gulf War Illnesses), for providing troop location, exposure data, and critical review. The authors appreciate the support of Dr. Gary Gackstetter and Dr. Tomoko Hooper of the Uniformed Services University of Health Sciences, Bethesda, Maryland, and the support of the Henry M. Jackson Foundation for the Advancement of Military Medicine, Rockville, Maryland.
The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of the Army, Department of Defense, or the US Government.
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NOTES |
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REFERENCES |
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