Illness Among Gulf War Veterans: Title and subTitle BreakRisk Factors, Realities, and Future Research

Although it is now 7 years since the Gulf War ended, research concerning the nature and extent of illnesses reported by returning veterans has yet to define clearly a specific disease entity or etiologic agent to explain these illnesses. Approximately 697000 men and women served in operations Desert Shield and Desert Storm from August 1990 to June 1991. During the war, US troops sustained 148 combat deaths and 145 deaths due to disease or unintentional injuries; 467 individuals were wounded.¹ But shortly after returning from the Persian Gulf, some men and women began to experience debilitating illnesses. The most commonly reported symptoms included fatigue, muscle and joint pain, memory loss, and headaches. In 1992, as the number of veterans reporting these symptoms increased and no obvious explanation for their symptoms had been found, the Department of Veterans Affairs established a registry to identify and treat Gulf War veterans' illnesses. In 1994 the Department of Defense established the Comprehensive Clinical Evaluation Program for active-duty service personnel. Three diagnostic categories (International Classification of Diseases, Ninth Revision, Clinical Modification² )— psychological conditions; musculoskeletal diseases; and symptoms, signs, and ill-defined conditions—accounted for 50% of the diagnoses.^{3 - 4} Other primary diagnoses did not concentrate in any organ system. This strongly parallels the experiences of veterans from previous conflicts.⁵

Several expert committees were asked to examine the various risk factors that Gulf War veterans might have encountered and to determine whether a unique Gulf War illness with a known cause could be established.^{6 - 8} Each of these panels concluded that there was no evidence consistent with the existence of a unique illness and that no single cause could be established. Recommendations for further research regarding individual risk factors, such as stress, pesticides, and Leishmaniasis, were suggested.⁴ Meanwhile, symptomatic veterans and their families continued to push for answers. In response, President Clinton appointed a Presidential Advisory Committee¹ on Gulf War Veterans' Illnesses (PAC) and charged it to review the government response to the concerns of these veterans. This review included an assessment of the most prominent risk factors present during the Gulf conflict and an evaluation of their possible relationship to the symptoms being reported by these ill veterans. Throughout an 18-month period, the PAC heard testimony from veterans, reviewed the available clinical and epidemiological data, and examined the biologic plausibility of a number of suggested causes of illness. These included vaccines, pesticides, pyridostigmine bromide, chemical and biological warfare agents, infectious diseases, depleted uranium, smoke from oil well fires, and petroleum products.

The PAC concluded that although there was indeed excess illness among the troops deployed to the Persian Gulf, the extent and nature of the illness could only be determined by further epidemiological research. Further, the PAC concluded that based on all available research and toxicologic data, it was unlikely that the illnesses were caused by the risk factors listed above and that stress was likely to be an important contributing factor to the broad range of physical and psychological illnesses being reported.¹ A recent review article on the physiologic effects of stress by McEwen⁹ clarifies the mechanisms by which stress influences the pathogenesis of disease and the variability of individual responses and lends support to the PAC conclusion. The PAC recommended that additional epidemiological studies and further research on the physiological effects of stress as well as investigations into the long-term effects of low-level exposure to chemical warfare agents were needed to fill in the gaps. Much of that research is ongoing.

In this issue of THE JOURNAL, Fukuda et al¹⁰ report the results of their investigation of illnesses occurring among active-duty members of a Pennsylvania Air National Guard unit. The authors propose an empirical approach to developing a case definition and suggest that this method might be applied to other epidemiological research studies. Their findings of increased prevalence of chronic multisymptom illness among deployed troops are consistent with other studies of Gulf War veterans.¹¹ However, 15% of the nondeployed study participants also met their case definition and there was no association with risk factors specific to service in the Gulf, suggesting that the clusters of symptoms they identified are not unique to Gulf War veterans. A report of an epidemiological study of Canadian forces who served in the Gulf War came to a similar conclusion.¹² A study of a broader cross-section of deployed and nondeployed personnel is necessary to confirm these findings and is now being carried out by the Department of Veterans Affairs.⁴

To date, $115 million has been committed to fund 121 research projects on the possible causes of illnesses among Gulf War veterans. Of these studies, 39 have been completed, 78 are ongoing, and 4 are pending final approval.⁴ Of this research effort, 42% are clinical studies, 29% are epidemiological investigations, 21% are basic science investigations, and 8% are applied research studies. Twenty-six research projects focus on the brain and nervous system, the majority of which are physiological studies.

Several studies have investigated the overall morbidity associated with service in the Gulf War. For instance, one study of hospitalization data has shown no difference between deployed and nondeployed forces.¹³ A Veterans Affairs study found no differences in mortality rates for active-duty personnel who served in the Gulf vs those who did not, except for a larger number of deaths due to unintentional injuries among those who had been deployed.¹⁴ A study of children of Persian Gulf War veterans born in US military hospitals found no increase in birth defects compared with a control population.¹⁵

Other studies have focused on specific aspects of illness among Gulf War veterans, such as symptoms attributable to neurotoxic exposures. The revelation that the nerve gas sarin was released at Kamisiyah, Iraq, and that 100000 troops may have been exposed to very low levels of sarin has led some to believe that this exposure is one of the causes of Gulf War illnesses.^{16 - 17} Long-term neurologic effects of organophosphate poisoning are well documented, but few data in the medical literature indicate that long-term health effects from short low-level exposure occur in the absence of acute symptoms. For instance, a recent study of rescue workers involved in the sarin incident in Matsumoto, Japan, showed that, among rescuers who were exposed to low levels of sarin and had either minimal or no acute symptoms, none had symptoms when surveyed a year later.¹⁸ Another study of individuals who had sustained acute sarin poisoning in the Tokyo, Japan, subway incident found subtle deficits in the higher cortical and visual nervous systems,¹⁹ and a study of poisoned individuals previously exposed to sarin suggests a potential effect on the vestibulocerebellar system.²⁰ The clinical relevance of these findings and their applicability to Gulf War illness are not clear. Research evaluating the health effects of low-level chemical warfare agents alone, of pyridostigmine bromide alone, and of the interaction of chemical warfare agents with pyridostigmine bromide is ongoing.

Because of the passage of time, inadequate medical recordkeeping, and incomplete environmental exposure data, the controversies surrounding Gulf War illnesses might never completely be resolved. However, the research that has been initiated should clarify a number of issues and also is likely to yield valuable information for the future. The Department of Veterans Affairs, in response to a PAC recommendation, has contracted with the Institute of Medicine of the National Academy of Sciences to conduct a periodic review of the available scientific evidence regarding associations between illnesses and service in the Gulf War. Of paramount importance is the need to acknowledge and validate that Gulf War veterans are experiencing real illnesses and must receive proper care. Despite the absence of a definitive cause of these illnesses, treatment of symptoms can be effective. Clinicians need to help these patients learn to cope better with their chronic symptoms, increase their daily level of functioning, and help them focus on treatment rather than cause.²¹

It is essential that lessons learned from the Gulf War experience are applied to prevent or at least minimize the occurrence of such illnesses in the future. Service personnel should be informed fully about the need for all immunizations and prophylactic medications. Medical records should be complete and accurate. Environmental exposures should be documented thoroughly. Veterans returning from areas of conflict should be monitored carefully, their symptoms or signs should be investigated promptly and comprehensively, and any illnesses discovered should be treated appropriately.