Healthcare utilization and mortality among veterans of the Gulf War

The authors conducted an extensive search for published works concerning healthcare utilization and mortality among Gulf War veterans of the Coalition forces who served during the 1990-1991 Gulf War. Reports concerning the health experience of US, UK, Canadian, Saudi and Australian veterans were reviewed. This report summarizes 15 years of observations and research in four categories: Gulf War veteran healthcare registry studies, hospitalization studies, outpatient studies and mortality studies. A total of 149728 (19.8%) of 756373 US, UK, Canadian and Australian Gulf War veterans received health registry evaluations revealing a vast number of symptoms and clinical conditions but no suggestion that a new unique illness was associated with service during the Gulf War. Additionally, no Gulf War exposure was uniquely implicated as a cause for post-war morbidity. Numerous large, controlled studies of US Gulf War veterans' hospitalizations, often involving more than a million veterans, have been conducted. They revealed an increased post-war risk for mental health diagnoses, multi-symptom conditions and musculoskeletal disorders. Again, these data failed to demonstrate that Gulf War veterans suffered from a unique Gulf War-related illness. The sparsely available ambulatory care reports documented that respiratory and gastrointestinal complaints were quite common during deployment. Using perhaps the most reliable data, controlled mortality studies have revealed that Gulf War veterans were at increased risk of injuries, especially those due to vehicular accidents. In general, healthcare utilization data are now exhausted. These findings have now been incorporated into preventive measures in support of current military forces. With a few diagnostic exceptions such as amyotrophic lateral sclerosis, mental disorders and cancer, it now seems time to cease examining Gulf War veteran morbidity and to direct future research efforts to preventing illness among current and future military personnel.     

Gulf War illness: a view from Australia

Australia sent a small, mostly naval, deployment to the 1991 Gulf War. When papers and media concerns arose about unexplained Gulf War illnesses in Gulf War troops from other countries, Australia decided to undertake its own study of Australian veterans. Undertaking a later study, more than 10 years after the Gulf War, allowed us to incorporate some methodological improvements on previous research, such as the inclusion of a face-to-face health assessment where more objective health data could be collected in addition to using a postal questionnaire. Despite the different Gulf War experience for the mostly naval Australian group, there were remarkable consistencies in the patterns of multiple symptom reporting found in overseas studies, including the fact that no unique symptom clusters were identified. In general, this excess symptom reporting was not found to occur with excesses in more objective measures of physical health. These objective physical measures included a wide range of haematological, biochemical and serological markers, a physical examination, spirometry and a step test of fatigability. In contrast, several psychological disorders, including anxiety, post-traumatic stress disorder, depression and substance abuse, were found to occur in excess in the Australian Gulf War group and were associated with Gulf War psychological stressors. These findings have helped raise awareness in Australia of psychological health problems in deployed military personnel.     

Multi-symptom illnesses, unexplained illness and Gulf War Syndrome

Explanatory models for the increased prevalence of ill health in Gulf veterans compared to those not deployed to the Gulf War 1990-1991 remain elusive. This article addresses whether multi-symptom reporting in Gulf veterans are types of medically unexplained symptoms and whether the alleged Gulf War Syndrome is best understood as a medically unexplained syndrome. A review of the epidemiological studies, overwhelmingly cross-sectional, describing ill health was conducted including those that used factor analysis to search for underlying or latent clinical constructs. The overwhelming evidence was that symptoms in Gulf veterans were either in keeping with currently defined psychiatric disorders such as depression and anxiety or were medically unexplained. The application of factor analysis methods had varied widely with a risk of over interpretation in some studies and limiting the validity of their findings. We concluded that ill health in Gulf veterans and the alleged Gulf War Syndrome is best understood within the medically unexplained symptoms and syndromes constructs. The cause of increased reporting in Gulf veterans are still not clear and requires further inquiry into the interaction between sociological factors and symptomatic distress.     

Long term depleted uranium exposure in Gulf War I veterans does not cause elevated numbers of micronuclei in peripheral blood lymphocytes

Depleted uranium (DU) is a high density heavy metal that has been used in military munitions since the 1991 Gulf War. DU is weakly radioactive and chemically toxic. Long term exposure can cause adverse health effects. This study assessed genotoxic effects in DU exposed Gulf War I veterans as a function of uranium (U) body burden. Levels of urine U were used to categorize the cohort into low and high exposure groups. Exposure to DU occurred during friendly fire incidents in 1991 involving DU munitions resulting in inhalation and ingestion exposure to small particles of DU and soft tissue DU fragments from traumatic injuries. All of these Veterans are enrolled in a long term health surveillance program at the Baltimore Veterans Administration Medical Center. Blood was drawn from 35 exposed male veterans aged 36-59 years, then cultured and evaluated for micronuclei (MN) using the cytokinesis block method. The participants were divided into two exposure groups, low and high, based on their mean urine uranium (uU) concentrations. Poisson regression analyses with mean urine U concentrations, current smoking, X-rays in the past year and donor age as dependent variables revealed no significant relationships with MN frequencies. Our results indicate that on-going systemic exposure to DU occurring in Gulf War I Veterans with DU embedded fragments does not induce significant increases in MN in peripheral blood lymphocytes compared to MN frequencies in Veterans with normal U body burdens.     

Depleted uranium exposure and health effects in Gulf War veterans

Health effects stemming from depleted uranium (DU) exposure in a cohort of Gulf War veterans who were in or on US Army vehicles hit by friendly fire involving DU munitions are being carefully monitored through the Baltimore Veterans Affairs (VA) DU Follow-Up Program initiated in 1993. DU exposure in this cohort has been directly measured using inductively coupled plasma-mass spectrometer (ICP-MS) isotopic analysis for DU in urine specimens. Soldiers with embedded DU fragments continue to excrete elevated concentrations of U in their urine, documenting ongoing systemic exposure to U released from their fragments. Biennial surveillance visits provide a detailed health assessment that includes basic clinical measures and surveillance for early changes in kidney function, an expected target organ for U. Tests also include measurements of genotoxicity and neuroendocrine, neurocognitive and reproductive function. With the exception of the elevated urine U excretion, no clinically significant expected U-related health effects have been identified to date. Subtle changes in renal function and genotoxicity markers in veterans with urine U concentrations greater than 0.1 microg(-1) creatinine, however, indicate the need for continued surveillance of these DU-exposed veterans.     

Gulf War Syndrome: A Reaction to Psychiatry’s Invasion of the Military?

Following the 1991 Gulf War, a number of soldiers who fought there began to complain of various symptoms and disorders, the collection of which came to be known as Gulf War syndrome (GWS). A debate has raged about the nature and cause of this illness, with many suggesting that it is a psychiatric condition. GWS continues to be a contested illness, yet there is no disputing that many Gulf veterans are ill. This article considers the way in which GWS sufferers understand their illness to be physical in nature and the way in which they negotiate and resist psychological theories of their illness. Based on 14 months of ethnographic fieldwork in the United Kingdom, data for this article were collected mainly by in-depth, semistructured interviews with GWS sufferers, their family members, doctors, and scientists, as well as healthy Gulf veterans. A total of 93 informants were interviewed, including 67 UK Gulf veterans, most of whom were ill. The paper argues that despite the increasing presence of psychiatry in military discourse, GWS reveals the way that people are able to transform, negotiate and even negate its power and assumptions.     

The impact of the 1991 Gulf War on the mind and brain: findings from neuropsychological and neuroimaging research

Many veterans of the 1991 Gulf War (GW) have complained of somatic and cognitive symptoms that may be neurological in nature. However, whether or not changes in brain function are associated with GW service continues to be debated. Studies of GW veterans using objective, performance-based neuropsychological measures have yielded inconsistent findings, with those indicating deficits among GW veterans typically revealing only relatively mild levels of neuropsychological impairment. Further, performances on objective neuropsychological tasks show little correspondence to subjective perceptions of cognitive functioning. Although preliminary magnetic resonance spectroscopy (MRS) studies demonstrate reduced N-acetylaspartate-to-creatine (NAA/Cr) ratio in select brain regions among GW veterans who report health concerns, this work requires further replication with larger, more representative samples. There is no evidence from neuroimaging studies of a non-specific effect of GW service or of changes in brain structure or function related to health status when conventional radiological methods are used. Owing to the paucity of objective exposure, baseline health data, and the now significant time elapsed since the GW, aetiological issues may never be fully resolved. Therefore, research addressing clinical management of GW veterans with neuropsychological dysfunction and neuroimaging abnormalities may prove more fruitful than exclusive focus on aetiology.     

Managing future Gulf War Syndromes: international lessons and new models of care

After the 1991 Gulf War, veterans of the conflict from the United States, United Kingdom, Canada, Australia and other nations described chronic idiopathic symptoms that became popularly known as 'Gulf War Syndrome'. Nearly 15 years later, some 250 million dollars in United States medical research has failed to confirm a novel war-related syndrome and controversy over the existence and causes of idiopathic physical symptoms has persisted. Wartime exposures implicated as possible causes of subsequent symptoms include oil well fire smoke, infectious diseases, vaccines, chemical and biological warfare agents, depleted uranium munitions and post-traumatic stress disorder. Recent historical analyses have identified controversial idiopathic symptom syndromes associated with nearly every modern war, suggesting that war typically sets into motion interrelated physical, emotional and fiscal consequences for veterans and for society. We anticipate future controversial war syndromes and maintain that a population-based approach to care can mitigate their impact. This paper delineates essential features of the model, describes its public health and scientific underpinnings and details how several countries are trying to implement it. With troops returning from combat in Afghanistan, Iraq and elsewhere, the model is already getting put to the test.     

The challenges of exposure assessment in health studies of Gulf War veterans

A variety of exposures have been investigated in Gulf War veterans' health studies. These have most commonly been by self-report in a postal questionnaire but modelling and bio-monitoring have also been employed. Exposure assessment is difficult to do well in studies of any workplace environment. It is made more difficult in Gulf War studies where there are a number and variety of possible exposures, no agreed metrics for individual exposures and few contemporary records associating the exposure with an individual. In some studies, the exposure assessment was carried out some years after the war and in the context of media interest. Several studies have examined different ways to test the accuracy of exposure reporting in Gulf War cohorts. There is some evidence from Gulf War studies that self-reported exposures were subject to recall bias but it is difficult to assess the extent. Occupational exposure-assessment methodology can provide insights into the exposure-assessment process and how to do it well. This is discussed in the context of the Gulf War studies. Alternative exposure-assessment methodologies are presented, although these may not be suitable for widespread use in veteran studies. Due to the poor quality of and accessibility of objective military exposure records, self-assessed exposure questionnaires are likely to remain the main instrument for assessing the exposure for a large number of veterans. If this is to be the case, then validation methods with more objective methods need to be included in future study designs.     

Stress and stressors of the early phases of the Persian Gulf War

Soldiers who deployed to Saudi Arabia in support of Operation Desert Shield were exposed to a wide variety of stressors. These stressors from the pre-combat phase of the deployment undoubtedly affect the current health of Gulf War veterans, but the exact mechanisms and linkages are not known. This article examines the nature of those stressors and possible effects on later health of veterans.     

Interaction of static and extremely low frequency electric and magnetic fields with living systems: health effects and research needs

An international seminar was held June 4-6, 1997, on the biological effects and related health hazards of ambient or environmental static and extremely low frequency (ELF) electric and magnetic fields (0-300 Hz). It was cosponsored by the World Health Organization (WHO), the International Commission on Non-Ionizing Radiation Protection (ICNIRP), the German, Japanese, and Swiss governments. Speakers provided overviews of the scientific literature that were discussed by participants of the meeting. Subsequently, expert working groups formulated this report, which evaluates possible health effects from exposure to static and ELF electric and magnetic fields and identifies gaps in knowledge requiring more research to improve health risk assessments. The working groups concluded that, although health hazards exist from exposure to ELF fields at high field strengths, the literature does not establish that health hazards are associated with exposure to low-level fields, including environmental levels. Similarly, exposure to static electric fields at levels currently found in the living and working environment or acute exposure to static magnetic fields at flux densities below 2 T, were not found to have demonstrated adverse health consequences. However, reports of biological effects from low-level ELF-field exposure and chronic exposure to static magnetic fields were identified that need replication and further study for WHO to assess any possible health consequences. Ambient static electric fields have not been reported to cause any direct adverse health effects, and so no further research in this area was deemed necessary.     

Infertility among male UK veterans of the 1990-1 Gulf war: reproductive cohort study

Objectives To examine the hypothesis that, theoretically at least, exposure to toxicants of the type present in the Gulf war could affect spermatogenesis, which might be observed as increased levels of infertility.Design Retrospective reproductive cohort analysis.Setting Male UK Gulf war veterans and matched comparison group of non-deployed servicemen, surveyed by postal questionnaire.Participants 42 818 completed questionnaires were returned, representing response rates of 53% for Gulf veterans and 42% for non-Gulf veterans; 10 465 Gulf veterans and 7376 non-Gulf veterans reported fathering or trying to father pregnancies after the Gulf war.Main outcome measures Failure to achieve conceptions (type I infertility) or live births (type II infertility) after the Gulf war, having tried for at least a year and consulted a doctor; time to conception among pregnancies fathered by men not reporting fertility problems.Results Risk of reported infertility was higher among Gulf war veterans than among non-Gulf veterans (odds ratio for type I infertility 1.41, 95% confidence interval 1.05 to 1.89; type II 1.50, 1.18 to 1.89). This small effect was constant over time since the war and was observed whether or not the men had fathered pregnancies before the war. Results were similar when analyses were restricted to clinically confirmed diagnoses. Pregnancies fathered by Gulf veterans not reporting fertility problems also took longer to conceive (odds ratio for > 1 year 1.18, 1.04 to 1.34).Conclusions We found some evidence of an association between Gulf war service and reported infertility. Pregnancies fathered by Gulf veterans with no fertility problems also reportedly took longer to conceive.     

Organophosphates dysregulate dopamine signaling, glutamatergic neurotransmission, and induce neuronal injury markers in striatum

The neurological effects of organophosphate (OP) pesticides, commonly used on foods and in households, are an important public health concern. Furthermore, subclinical exposure to combinations of organophosphates is implicated in Gulf War illness. Here, we characterized the effects of the broadly used insecticide chlorpyrifos (CPF) on dopamine and glutamatergic neurotransmission effectors in corticostriatal motor/reward circuitry. CPF potentiated protein kinase A (PKA)-dependent phosphorylation of the striatal protein dopamine- and cAMP-regulated phosphoprotein of M(r) 32 kDa (DARPP-32) and the glutamate receptor 1 (GluR1) subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in mouse brain slices. It also increased GluR1 phosphorylation by PKA when administered systemically. This correlated with enhanced glutamate release from cortical projections in rat striatum. Similar effects were induced by the sarin congener, diisopropyl fluorophosphate, alone or in combination with the putative neuroprotectant, pyridostigmine bromide and the pesticide N,N-diethyl-meta-toluamide (DEET). This combination, meant to mimic the neurotoxicant exposure encountered by veterans of the 1991 Persian Gulf War, also induced hyperphosphorylation of the neurofibrillary tangle-associated protein tau. Diisopropyl fluorophosphate and pyrodostigmine bromide, alone or in combination, also increased the aberrant activity of the protein kinase, Cdk5, as indicated by conversion of its activating cofactor p35 to p25. Thus, consistent with recent findings in humans and animals, organophosphate exposure causes dysregulation in the motor/reward circuitry and invokes mechanisms associated with neurological disorders and neurodegeneration.     

Neurological disorders in Gulf War veterans

We present a review of neurological function in Gulf War veterans (GWV). Twenty-two studies were reviewed, including large hospitalization and registry studies, large population-based epidemiological studies, investigations of a single military unit, small uncontrolled studies of ill veterans and small controlled studies of veterans. In nearly all studies, neurological function was normal in most GWVs, except for a small proportion who were diagnosed with compression neuropathies (carpal tunnel syndrome or ulnar neuropathy). In the great majority of controlled studies, there were no differences in the rates of neurological abnormalities in GWVs and controls. In a national US study, the incidence of amyotrophic lateral sclerosis (ALS) seems to be significantly increased in GWVs, compared to the rate in controls. However, it is possible that military service, in general, might be associated with an increased risk of ALS, rather than Gulf War service in particular. Taken together, the conclusion is that if a neurological examination in a GWV is within normal limits, then extensive neurological testing is unlikely to diagnose occult neurological disorders.     

The Use of Epidemiology in Risk Assessment: Challenges and Opportunities

The assessment of risk from environmental and occupational exposures incorporates and synthesizes data from a variety of scientific disciplines including toxicology and epidemiology. Epidemiological data have offered valuable contributions to the identification of human health hazards, estimation of human exposures, quantification of the exposure–response relation, and characterization of risks to specific target populations including sensitive populations. As with any scientific discipline, there are some uncertainties inherent in these data; however, the best human health risk assessments utilize all available information, characterizing strengths and limitations as appropriate. Human health risk assessors evaluating environmental and occupational exposures have raised concerns about the validity of using epidemiological data for risk assessment due to actual or perceived study limitations. This article highlights three concerns commonly raised during the development of human health risk assessments of environmental and occupational exposures: (a) error in the measurement of exposure, (b) potential confounding, and (c) the interpretation of non-linear or non-monotonic exposure–response data. These issues are often the content of scientific disagreement and debate among the human health risk assessment community, and we explore how these concerns may be contextualized, addressed, and often ameliorated.     

On being a Gulf veteran: an anthropological perspective

There is no doubt that Gulf service has affected the well-being of some of the members of the UK armed forces who served in that conflict, yet the reason for this remain unclear. At present, the debate surrounding Gulf War Syndrome (GWS) has become stagnant and highly polarized. This paper argues that a new perspective is needed to further improve our understanding of the problem and suggests that the methods and theories of anthropology, with its focus on nuances and subtleties, can provide new insights. Data were generated from 14 months of ethnographic fieldwork in the UK including participant observation, semi-structured interviews and document analysis. Anthropology provides a unique way of approaching and understanding somatic symptoms and suggests that GWS symptom reporting can be seen as a form of communication. The work focuses on the sufferers' accounts, the symptoms themselves and the context within which we find them in order to better understand what was being expressed and commented upon. Although necessary to contextualize GWS through situating it among other emergent illnesses and widespread health beliefs, this paper shows there is a need to bring back the particular. This work seeks to make sense of the cultural circumstances, specific and general, which gave rise to the illness.     

Pharmacologically increasing microtubule acetylation corrects stress‐exacerbated effects of organophosphates on neurons

Many veterans of the 1990‐1991 Gulf War contracted Gulf War Illness (GWI), a multisymptom disease that primarily affects the nervous system. Here, we treated cultures of human or rat neurons with diisopropyl fluorophosphate (DFP), an analog of sarin, one of the organophosphate (OP) toxicants to which the military veterans were exposed. All observed cellular defects produced by DFP were exacerbated by pretreatment with corticosterone or cortisol, which, in rat and human neurons, respectively, serves in our experiments to mimic the physical stress endured by soldiers during the war. To best mimic the disease, DFP was used below the level needed to inhibit acetylcholinesterase. We observed a diminution in the ratio of acetylated to total tubulin that was correctable by treatment with tubacin, a drug that inhibits HDAC6, the tubulin deacetylase. The reduction in microtubule acetylation was coupled with deficits in microtubule dynamics, which were correctable by HDAC6 inhibition. Deficits in mitochondrial transport and dopamine release were also improved by tubacin. Thus, various negative effects of the toxicant/stress exposures were at least partially correctable by restoring microtubule acetylation to a more normal status. Such an approach may have therapeutic benefit for individuals suffering from GWI or other neurological disorders linked to OP exposure.      

Chemical sensitivity: Risks in schools

Congressional interest in the health and safety of school children led to a request for the Congressional Office of Technology Assessment (OTA) to assess the available data on hazards to children in schools in the United States. In this report, OTA identified the major hazards thought to pose a risk of illness in schools. Illnesses were limited to those arising from environmental hazards, which were grouped in this report as school materials and indoor air. Few data have been collected on any of these hazards in school. OTA could not identify a functional national reporting system for environmental ?hazards in schools. The absence of studies documenting in‐school illnesses or exposure in school presents fundamental gaps in the data needed to assess risks nationwide.     

Gulf War veterans and hemifacial microsomia

BACKGROUND: Concerns have been raised that more infants with Goldenhar syndrome were born to U.S. Gulf War veterans than expected. Goldenhar syndrome is considered a variant of the malformation hemifacial microsomia (HFM). We used data collected from a case-control study of HFM to estimate risk in relation to parental military service and, in particular, Gulf War service. METHODS: Cases with HFM who were three years old or younger were identified at craniofacial clinics in 24 U.S. cities and matched to controls by age and pediatrician. The mothers of 232 cases and 832 controls were interviewed between April 1996 and November 2002 about pregnancy events and exposures, including military service before the child was born and Gulf War deployment five to 11 years before the child was born. Odds ratios were adjusted for family income, race, and body mass index in early pregnancy. RESULTS: Four (1.7%) case mothers and 10 (1.2%) control mothers served in the military. Among fathers, 30 (12.9%) cases and 100 (12.0%) controls served in the military. The parents of four (1.7%) cases and 23 (2.8%) controls served in the Gulf War (multivariate adjusted odds ratio [MVOR], 0.8; 95% confidence interval [CI], 0.3-2.3). All four case parents with Gulf War service were in the Army compared to 9 of 23 control parents. The MVOR for parental Gulf War service in the Army was 2.8 (95% CI, 0.8-9.6). The corresponding MVOR for any parental service in the Army was 2.4 (95% CI, 1.4-4.2), based on 22 cases and 45 controls. CONCLUSIONS: The risk of HFM in offspring was not associated with parental service in the Gulf War five to 11 years before birth. The odds ratio for service in the Army was independent of Gulf War service and was associated with a modest increase in risk. Our findings for service in the Army may be confounded by unmeasured lifestyle factors.     

Dysbiosis in gastrointestinal pathophysiology: Role of the gut microbiome in Gulf War Illness

Gulf War Illness (GWI) has been reported in 25%–35% of veterans returned from the Gulf war. Symptoms of GWI are varied and include both neurological and gastrointestinal symptoms as well as chronic fatigue. Development of GWI has been associated with chemical exposure particularly with exposure to pyridostigmine bromide (PB) and permethrin. Recent studies have found that the pathology of GWI is connected to changes in the gut microbiota, that is the gut dysbiosis. In studies using animal models, the exposure to PB and permethrin resulted in similar changes in the gut microbiome as these found in GW veterans with GWI. Studies using animal models have also shown that phytochemicals like curcumin are beneficial in reducing the symptoms and that the extracellular vesicles (EV) released from gut bacteria and from the intestinal epithelium can both promote diseases and suppress diseases through the intercellular communication mechanisms. The intestinal epithelium cells produce EVs and these EVs of intestinal epithelium origin are found to suppress inflammatory bowel disease severity, suggesting the benefits of utilizing EV in treatments. On the contrary, EV from the plasma of septic mice enhanced the level of proinflammatory cytokines in vitro and neutrophils and macrophages in vivo, suggesting differences in the EV depending on the types of cells they were originated and/or influences of environmental changes. These studies suggest that targeting the EV that specifically have positive influences may become a new therapeutic strategy in the treatment of veterans with GWI.