Meta Analysis of Physical and Mental Ailments in US Veterans with Gulf War Illness: Additional Complexity Warrants Deeper Multi-Approach Care

photo by Master Sgt. Bill Thompson/U.S. Army

Abstract

Background:

Few articles have provided a comprehensive look at the total range of physical and mental ailments caused by Gulf War Illness among American veterans. A systematic meta-analysis may help with this description.

Methods:

A bibliography search was conducted on PubMed to compile studies regarding the appropriate subject material, with filters and keywords to find studies regarding post-reconstruction effects. The automatic search results were then manually reviewed to remove irrelevant or duplicate articles. Studies deemed to be relevant to this search were studies that involved direct mental or physical effects on Gulf War-era American veterans who directly deployed to the Persian Gulf and were engaged in operations in Kuwait and Iraq. 

By the end of the results, 33 studies were identified as individually representing a symptom or group of symptoms directly relating to the Gulf War deployment of American veterans.

Results:

All studies within this analysis indicated the definite presence of a chronic multi-symptom illness that significantly impacted deployed Gulf War veterans, completely separate from typical combat-related illnesses that befall servicemen. GWI in particular involves a broad range of primarily neurological and gastrointestinal symptoms, along with additional symptoms relating to pain, fatigue, and dispersed ailments in blood cells and other bodily systems.

Conclusions:

Gulf War Illness is a significant multi-symptom syndrome that has a broad range of observed effects across mental, neurological, somatic, cellular, and overall health. For many Gulf War veterans, this represents a significant decrease in health-related quality of life and health prospects[13][19]. Additionally, the multi-syndrome character that constitutes Gulf War Illness disproves any prevailing thought that it is merely an extension of “normal” post-traumatic stress disorder related to combat deployment. Instead, 

Keywords: Gulf War Illness, Gulf War Syndrome, US Veterans, military medicine, effects of environmental exposure, nerve agent, PB pills, pesticides, Persian Gulf, veteran, post-deployment health, War-Related Injury and Illness Study Center, pesticides, chemical alarms, Military-Ordered Protective Posture Level 4 (MOPP4) gear, pyridostigmine bromide

Introduction

In 1990, Iraq, under the leadership of Saddam Hussein, invaded its neighbor, Kuwait, and fully occupied the nation within two days. The United Nations immediately adopted resolutions condemning the invasion and ordering Iraq to withdraw. When these resolutions expired, President George H. W. Bush authorized the deployment of almost 697,000 American servicemembers to Operation Desert Shield/Storm. Although the land operation only took a hundred hours to complete, the deployment of troops to the region and their continued presence there led to the rise of so-called “Gulf War Illness” (GWI) among the campaign’s veterans. This comprises a multi-symptom disorder that impacts about a third of the 700,000 Americans deployed to Iraq and seems to present the same set of conditions, including fatigue, headaches, cognitive dysfunction, musculoskeletal pain, and respiratory, gastrointestinal, and dermatologic complaints[3][4].

Gulf War Illness is diagnosed through the Centers for Disease Control's CMI GWI criteria or the Kansas GWI criteria. The CDC criteria require that the veteran exhibits at least two of the following chronic symptoms (more than six months): pain, fatigue, mood swings, and alterations to cognition. The Kansas GWI criteria, the stricter of the two, require that the veteran has at least one moderate or severe chronic symptom in three of the following domains: fatigue/sleep problems, pain, neurologic/cognitive/mood symptoms, gastrointestinal symptoms, respiratory symptoms, and skin symptoms.

The most probable causes of GWI are exposure to nerve agents such as sarin, pills containing pyridostigmine bromide, which were meant to be used as anti-nerve agent prophylaxis, and pesticides released in Iraq[1][2][3]. 

American soldiers participating in the invasion of the Persian Gulf were exposed to low levels of nerve agents, including sarin, when Iraqi chemical weapon facilities were bombed by Coalition air support in the weeks leading up to the invasion. After examining the connection between gene-environment interaction of the paraoxonase-1 (PON1) Q192R polymorphism and low-level nerve agent exposure, it can be deduced that this low-level exposure is strongly causal of many neurological symptoms of GWI[1].  

Additionally, exposure among Gulf War veterans (GWV) to pyridostigmine bromide pills (PB pills) can be linked to the symptoms of GWI. Analysis of the gene-toxicant interaction of PB pills with PON1 and the G allele of rs662 points to a strong connection between exposure to PB among American veterans and incidence rates of GWI[2]. 

Lastly, pesticides excessively sprayed in theater were frequently exposed to American troops fighting in Iraq, and can causally be linked to neurological and gastrointestinal symptoms of GWI[3].

These primary factors, along with additional interactions between stressors and environment, lead to a variety of significant long-term symptoms among Gulf War veterans, both in the mental and physical domains.

 This analysis aims to collate and compile studies on the physical and mental symptoms exhibited by Gulf War-era American veterans with Gulf War Illness.

Methods

Search Strategy:

A bibliography search was conducted on PubMed (https://www.ncbi.nlm.nih.gov/pubmed/) to compile studies regarding the appropriate subject material, with filters and keywords to find studies regarding post-reconstruction effects. The keywords used were (Desert Storm OR Gulf War OR U.S. Veteran OR 1991 OR VA OR Veterans Affairs) AND (Gulf War Illness OR Gulf War Syndrome OR PTSD OR Chronic Fatigue Syndrome OR Cognitive Impairment).

The automatic search results were then manually reviewed to remove irrelevant or duplicate articles. The relevant studies were identified by their title, abstract, or text. 

Inclusion Criteria: 

Studies deemed to be relevant to this search were studies that involved direct mental or physical effects on Gulf War-era American veterans who directly deployed to the Persian Gulf and were involved in operations in Kuwait and Iraq. 

There were 6683 results that appeared initially, but the vast majority were revealed to be either studies that were completely unrelated or only tangentially related to the subject matter at hand. After manually reviewing the articles, 6119 articles were removed from consideration, with approximately 5200 articles being unrelated to the Gulf War, 400 articles about military medicine in general, 300 articles about civilians during the Gulf War, and 200 being about PTSD or other combat-involved mental illness unrelated to the Gulf War. These are approximate figures, but they help to show the spread of unrelated subject matter that was discarded for this meta-analysis.

The 564 articles remaining were then manually reviewed to find articles that specifically matched the inclusion criteria. 

By the end of the results, 33 studies were identified as individually representing a symptom or group of symptoms directly relating to the Gulf War deployment of American veterans. The other studies were taken out for being related to causes of Gulf War Illness, symptoms of GWI in foreign or other Coalition soldiers, symptoms of GWI represented by rat or mouse models, corrections to other articles, duplicates, mental illness not directly related to GWI, or articles completely unrelated to GWI.

Results

Overall, the studies selected covered thousands of American servicemembers who were deployed to the Persian Gulf from 1990-1991 during the war, in all areas of the theater and within all service branches. 

All studies within this analysis indicated the definite presence of a chronic multi-symptom illness that significantly impacted deployed Gulf War veterans, completely separate from typical combat-related illnesses that befall servicemen. GWI in particular involves a broad range of primarily neurological and gastrointestinal symptoms, along with additional symptoms relating to pain, fatigue, and dispersed ailments in blood cells and other bodily systems.

Of the 33 studies involved in this meta-analysis, all of them supported the existence of a very significant and distinct multi-symptom illness that involved a broad variety of ailments, both physical and mental. The summaries of the thirty studies are below, primarily with the direct symptoms and effects of deployment-related exposures.

These studies have been broken down into the respective medical fields to which their symptoms relate.

General descriptions of GWI:

Study 1: Within the cohort of 14,103 Gulf War veterans studied, 49% reported their health as fair or poor, and 31% met Centers for Disease Control and Prevention criteria for severe GWI. GWI was most associated with exposure to chemical/biological warfare agents, pyridostigmine bromide pills, and skin pesticides[4].

Study 2: Analysis of 35,902 Gulf War-era veterans (13,107 deployed, 22,795 not deployed) found that deployed GWV had higher percentages for every marker of both the Kansas definition for GWI and the CDC definition[6].

Study 3: A study of the Veterans Affairs Fraility Index (VA-FI) of 703 GWV compared to matched non-GW veterans revealed that GWV that met the criteria for severe Chronic Multisymptom Illness (CMI) at the time of the studies had the highest VA-FI (0.13 ± 0.10, p < 0.001). Additionally, GWV who met CMI criteria had much higher rates of dementia than control GMV. High VA-FI scores were directly related to self-reported environmental exposure attained during the Gulf War, including the use of flea collars[7].

Study 4: In comparison with a matched set of non-deployed veterans, a sample of 15,000 deployed Gulf War veterans found that across all service branches, GWV were more likely to have functional impairment, health care utilization, symptoms, medical conditions, and a higher rate of low general health perceptions[10].

Study 5: A telephone study of 3695 subjects (GWV and non-deployed veterans) were asked about health conditions following their service. Compared to non-deployed veterans, Gulf War veterans had a significantly higher incidence rate of symptoms of depression (17.0% vs 10.9%; Cochran-Mantel-Haenszel test statistic, P<.001), posttraumatic stress disorder (PTSD) (1.9% vs 0.8%, P=.007), chronic fatigue (1.3% vs 0.3%, P<.001), cognitive dysfunction (18.7% vs 7.6%, P<.001), bronchitis (3.7% vs 2.7%, P<.001), asthma (7.2% vs 4.1%, P=.004), fibromyalgia (19.2% vs 9.6%, P<.001), alcohol abuse (17.4% vs 12.6%, P=.02), anxiety (4.0% vs 1.8%, P<.001), and sexual discomfort (respondent, 1.5% vs 1.1%, P=.009; respondent's female partner, 5.1% vs 2.4%, P<.001). Therefore, deployment to the Persian Gulf had direct impacts on veteran health post-service[11].

Study 6: Compared to non-deployed veterans, GWV exhibited significantly greater prevalences of 123 of 137 (90%) symptoms, with none being lower. This directly proves a singular and distinct existence of a multi-symptom GWI[12].

Study 7: Gulf War veterans who exhibit both GWI and PTSD were found to have significantly poorer health outcomes compared to healthy control groups and GWV without PTSD. Additionally, GWV with or without PTSD had higher levels of basophils compared to control groups at peak exercise levels[13]. 

Study 8: A study of 1116 GW veterans showed drastic differences in health-related quality of life (HRQOL) between those with and without GWI. Veterans who met the Kansas GWI definition had worse mental and physical HRQOL outcomes than veterans who did not, and veterans who met the CDC GWI severe criteria had worse mental and physical HRQOL outcomes than those meeting the CDC GWI mild-to-moderate or CDC noncases. Overall, those who met the Kansas GWI definition or the CDC GWI severe definition experienced lower HRQOL and higher rates of depression, PTSD, and severe pain[19].

Study 9: Veterans reporting hearing chemical alarms/donning Military-Ordered Protective Posture Level 4 (MOPP 4) protective gear, pesticide use, and using PB pills as prophylaxis against nerve agents exhibited a high level of moderate-to-severe chronic symptoms in neurocognitive/mood, fatigue/sleep, and pain domains. Specifically, pesticide exposure was directly related to concentration and memory problems, unrefreshing sleep, problems sleeping, and joint pain; PB pill use was related to depression; and MOPP 4 use was related to light sensitivity and unrefreshing sleep. Additionally, the pain symptom severity score was significantly associated with pesticide use and taking PB pills, while overall symptom severity increased with PB pill usage[22].

Cognitive Ability:

Study 1: Testing of 2,189 Gulf War veterans (1,061 deployed, 1,128 non-deployed) at a VA medical center found that the deployed GWV performed significantly worse on motor speed and sustained attention tests than non-deployed veterans. For deployed veterans, exposure to chemical weapons from the Khamisiyah chemical weapons storage facility bombing directly correlated to lower scores on motor speed, while self-reported exposure to toxicants correlated to lower scores on sustained attention tests[5].

Study 2: In a sample of 952 GWV, 17% met the criteria for mild cognitive impairment (MCI). Those veterans classified as having MCI were more likely to have CMI, a history of depression, and prolonged exposures (≥31 days) to smoke from oil well fires and chemical nerve agents compared to veterans with unimpaired and intermediate cognitive status. Therefore, exposure to these deployment-related toxicants is directly related and possibly causal of MCI in Gulf War veterans[9].

Study 3: A study of 411 GW veterans (312 GWI (cases) and 99 healthy veterans) found that those with GWI showed significantly poorer attention, executive functioning, learning, and short- and long-term verbal memory than those without GWI. Additionally, GW veterans with significant exposure to pesticides and nerve agents had worse performance on executive function tasks, while veterans with exposure to oil well fires had worse performance on verbal memory, and those with pyridostigmine bromide anti-nerve gas pill exposures had worse performance on an attention task compared to unexposed veterans[16].

Study 4: Patients with GWI exhibit high levels of dysregulation of immune and endocrine signaling, which is a probable cause of progressive cognitive impairments in Gulf War veterans. This issue is due either to chronic neuroinflammation or disruptions in central cholinergic signaling that only emerge when a stressor is presented[17].

General Neurological Symptoms:

Study 1: A study of 293 GW veterans showed that healthy veterans displayed few Parkinson's disease-like non-motor symptoms,  whereas GW veterans with GWI displayed more PD-like motor and non-motor symptoms, and more GW-related exposures. Compared to healthy GWV, those with GWI also displayed a lower total volume of the basal ganglia, which regulates voluntary movements. Therefore, GWV with GWI display more symptoms related to Parkinson’s disease[15].

Study 2: Veterans with GWI-related chronic headaches and body pain (N = 20, all males) had a significantly higher average resting motor threshold (% ± SD) of 77.2% ± 16.7% compared to age and gender matched military controls (N = 20, all males), whose average was 55.6% ± 8.8%. Veterans with GWI-related diffuse body pain demonstrated a state of diminished corticomotor excitability, suggesting a maladaptive supraspinal pain modulatory state.  Because RMT and diminished motor cortical excitability are known to be associated with chronic pain, GWI can be directly related to the cause of chronic pain in GW veterans, perhaps due to maladaptive supraspinal pain modulation[18].

Study 3: A study using high-density EEG on a group of GW veterans compared to a control group to measure REM and non-REM sleep revealed a broadband reduction in EEG power across all frequency bands in non-REM and REM sleep in a circumscribed region overlying the frontal lobe among GW veterans[23].

Study 4: A study of 621,902 GW veterans versus 746,248 non-GW veterans showed that there was no significant difference in risk of death due to ALS, MS, Parkinson's disease, and brain cancer between the two groups in general. However, prolonged (2 days or more) exposure to nerve agents at Khamisiyah, Iraq, or to oil well fire smoke resulted in a higher risk of mortality due to brain cancer[24].

Study 5: Among 2.5 million eligible military personnel (all active and mobilized reserve military members for the 10 years since August 1990 who served during the Gulf War), 107 confirmed cases of amyotrophic lateral sclerosis were observed, constituting 0.43 persons per 100,000. A significant elevated risk for ALS was observed among all deployed personnel (RR = 1.92; 95% CL = 1.29, 2.84), deployed active duty military (RR = 2.15, 95% CL = 1.38, 3.36), deployed Air Force (RR = 2.68, 95% CL = 1.24, 5.78), and deployed Army (RR = 2.04; 95% CL = 1.10, 3.77) personnel. Therefore, deployment to the Persian Gulf can be directly related to an increase in the risk of ALS[25].

Study 6: US Army veterans possibly exposed to chemical agents at the Kamisiyah chemical weapons storage facility had similar rates of brain cancer mortality to non-exposed veterans, but those possibly exposed had a higher risk of brain cancer in the years following the Gulf War[26].

Study 7: A study of patients afflicted with GWI reveals a substantial (10%) subcortical brain atrophy affecting primarily the brainstem, cerebellum, and thalamus, and, to a lesser extent, basal ganglia, amygdala, and diencephalon. The atrophy is most significant in the brainstem, followed by the left cerebellum and right thalamus, then by the right cerebellum and left thalamus, which indicates atrophy that followed through the brainstem via the crossed superior cerebellar peduncle, which caused this pattern. This distribution most directly resembles the atrophy caused by toxic encephalopathy caused by a variety of substances, including organic solvents. As many GW veterans with GWI were exposed to a great variety of toxic substances, including sand, smoke from oil-well fires, paints, solvents, insecticides, petroleum fuels and their combustion products, organophosphate nerve agents, and pyridostigmine bromide, it is reasonable to assume that this subcortical atrophy is directly caused by these deployment-related exposures[27].

Study 1: 51 GWV were evaluated at the NJ War Related Illness and Injury Study Center, wherein 83% were diagnosed with GWI and 57% had small fiber neuropathy. There was no difference in autonomic nervous system symptoms between veterans with GWI and SFN and veterans with GWI and no SFN. However, of the 24 veterans with both GWI and SFN, 21% did not have an explanation for their SFN, which makes it possible that environmental factors related to their deployment may have caused SFN[8].

Cerebral Blood Flow:

Study 1: In a study of GW veterans in three GWI groups—syndrome 1 (impaired cognition), syndrome 2 (confusion-ataxia), and syndrome 3 (central neuropathic pain)—and a control group, infusions of physostigmine revealed a significant decrease in hippocampal regional cerebral blood flow in the control group and Syndrome 1, but an abnormal increase in Syndrome 2 and 3. This increase progressed to the left hippocampus of the veterans with syndrome 2 and to both hippocampi of the veterans with syndrome 3. This study, conducted nearly 20 years after the conclusion of the Gulf War, proves that GWI causes chronic hippocampal perfusion dysfunction in GW veterans[32].

Study 2: A study of 23 patients with GWI and 9 controls revealed that during orthostatic motion (sitting to standing), those with GWI had significantly lower dynamic cerebral autoregulation along with substantial decreases in cerebral blood velocity after standing and during steady state standing. This reduced cerebral blood flow may indicate significant cognitive difficulties for GWI veterans when standing due to cerebral hypoperfusion[36].

Somatic:

Study 1: Of the five cases with dendriform pulmonary ossification, Cases 4 and 5 were of an Army and a Marine veteran of the Gulf War. Case 4 reported prominent and prolonged exposure to diesel exhaust, burn pits, sandstorms, desert dust, and combat dust during his deployment, while Case 5 reported diesel exhaust, burn pits, oil well fire smoke, sandstorms, desert dust, and combat dust. Both veterans developed DPO after their service and had airway-centric injury, inflammation, and retained particulate matter, suggesting substantial hazardous exposure during military deployment. Therefore, it is probable that exposure to hazardous airborne particles and toxicants sustained during their deployment to the Persian Gulf contributed to the development of DPO[14].

Study 2: Veterans exposed to pyridostigmine bromide pills reported higher dry eye (DE) symptom scores and more intense ocular pain compared to those who were not exposed, differences that remained significant within multi-variable models that took demographics and service history into account. Additionally, those exposed to PB pills had thicker ocular coherence tomography readings, particularly in the outer temporal segment of the macula, than those who were not exposed[20]. 

Study 3: Veterans with GWI exhibit an altered gut microbiome with a significantly different Bray–Curtis beta diversity compared to control veterans. Additionally, a higher self-reported Multidimensional Fatigue Inventory score among GWI veterans was significantly related to an altered gut bacterial diversity[30].

Study 4: Veterans with GWI have higher dry eye symptom scores compared to control veterans (Ocular Surface Disease Index (OSDI) scores: mean 41.20±22.92 vs 27.99±24.03, p=0.01). Additionally, those with GWI had higher eye pain scores than those without (average eye pain over past week: 2.63±2.72 vs 1.22±1.50, p=0.03)[31].

Study 5: A study of the Ft. Devens Cohort (FDC) of GW veterans versus the 2013–2014 National Health and Nutrition Examination Survey (NHANES) cohort shows that FDC males are at an increased risk for seven chronic conditions: high blood pressure, high cholesterol, heart attack, diabetes, stroke, arthritis and chronic bronchitis. Additionally, GW veterans reporting exposure to chemical agents exhibited higher risks of high blood pressure, diabetes, arthritis, and chronic bronchitis, while those reporting exposure to PB pills exhibited higher risks of heart attack and diabetes. Therefore, GW veterans with GWI caused by exposure to chemical agents or PB pills have a higher direct risk for significantly impactful chronic conditions[28].

Cellular Health:

Study 1: Combined exposure to pesticide CPF 71 μM, insect repellants DEET 78 μM, and antitoxins PB 19 μM causes significant mitochondrial dysfunction resulting in decreased mitochondrial respiratory states in neuroblastoma cells[21].

Study 2: A study of 114 GW veterans (80 with and 34 without GWI according to the Kansas definition) revealed that those without GWI had 42% and 47% higher Basal and ATP-linked oxygen consumption, respectively, with no compensatory increase in anaerobic energy generation for those with GWI. This shows that veterans with GWI experience a decrease in mitochondrial respiratory function and glycolytic activity, which causes a decrease in energy availability, in peripheral blood mononuclear cells[29].

Cholinergic System Symptoms:

Study 1: In response to an inhibitory cholinergic challenge, physostigmine infusion, patients with GWI showed significant decreases in cerebral blood flow than control veterans. This indicates that GW veterans with GWI may suffer from variants of a chronic encephalopathic syndrome due to altered cerebral blood flow in deep brain structures[34].

Study 2: Compared to matched controls, GW veterans with GWI showed a significant decrease in performance of the cholinergic system as the task they were completing increased in working memory demand. Imaging shows that patients with GWI used separate processing strategies as working memory workload increased, using the prefrontal cortex for retrieval rather than encoding. Behavioral data suggest that patients with GWI have impaired working memory executive strategies, which is most likely due to the exposure to cholinergic disruptive chemicals during the Gulf War[35].

Conclusions

Gulf War Illness is a significant multi-symptom syndrome that has a broad range of observed effects across mental, neurological, somatic, cellular, and overall health. For many Gulf War veterans, this represents a significant decrease in health-related quality of life and health prospects[13][19].

Some of the common health effects noted among Gulf War veterans with GWI include: depression, post-traumatic stress disorder, chronic fatigue, significant cognitive dysfunction, bronchitis, asthma, fibromyalgia, anxiety, sleeping problems, memory problems, concentration issues, severe risk for chronic life-threatening illness (high blood pressure, high cholesterol, heart attack, diabetes, stroke, arthritis and chronic bronchitis), increased likelihood of severe neurological illnesses (ALS, MS, Parkinson’s, and brain cancer), eye issues, joint pain, fatigue, brain atrophy, chronic pain, alterations to gut microbiome diversity, damage to cholinergic system processes, and changes in cerebral blood flow[3]-[36].

Declarations of Interest

The author declares no competing interests.

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