Background

As of the end of December 2024, the World Health Organization reported >777 million COVID-19 infections and >7.1 million deaths recorded globally since the first COVID-19 cases were reported in mid-December 2019 [1]. The U.S. still leads the world in total confirmed COVID cases (103 million) and deaths (1.2 million) and, although the number of the most serious COVID-related outcomes (hospitalizations, ICU admissions, and deaths) have declined, COVID-19 remained in the top 10 leading causes of death in the U.S. in 2023 [2].

COVID-19 is a globally recognized disease of disparities, disproportionately impacting older adults, race/ethnic minority and socioeconomically marginalized populations, and with comorbidities such as obesity, immune compromise, neurological and respiratory conditions. Inequities were especially apparent among workers in occupations with elevated SARS-CoV-2 exposure risk during the pre-vaccine period. It is not well-established, however, whether occupational cohorts with known substantial exposure to other health hazardous agents faced further increased health risks with SARS-CoV-2 infection.

One historically highly occupationally exposed cohort includes the almost 700,000 U.S. veterans—about one-quarter of all U.S. military personnel at the time—who deployed to the Persian Gulf (PG) to serve in the 1990–1991 Gulf War (GW) as part of a multinational military response to Iraq’s invasion of Kuwait. These deployed Gulf War veterans (GWVs) are well-recognized for experiencing broad and, in some cases, near unique combination of exposure to potentially multiple health hazards during deployment, including extensive inhalation of smoke from more than 650 oil well fires and harmful-sized and environmentally cross-contaminated blowing desert sand, low-level nerve agent (sarin/cyclosarin) exposure during chemical weapon plant demolition, and wide self-administered use of anti-nerve agent pyridostigmine bromide pills as pre-exposure prophylaxis to prevent harm when concerned about possible chemical weapon exposure [3–7]. Others included experimental vaccines (e.g., anthrax), depleted uranium munitions, high dosage of widely applied military-grade pesticides, as well as hazards also common in later military conflicts including post-9/11 deployments to Afghanistan and Iraq, such as open burn pits, occupational chemicals, psychological and physical stress, heat, traumatic brain injury, multiple vaccinations, and local zoonoses.

Soon after returning from PG deployment, the deployed GWV cohort drew national attention and Congressionally statute mandated expert research advisory panels and on-going follow-up to evaluate potential long-term health effects associated with these deployment-related exposures given early, elevated prevalence of several unusual health conditions. In addition to suggestive small clusters of early onset cases of two rapidly fatal neurological diseases, amyotrophic lateral sclerosis (ALS) and brain cancer that are extremely rare and occur almost exclusively in older adults in the general population, this also included large numbers of young recently returned and previously healthy deployed GWVs reporting onset of persistent, debilitating, and medically-unexplained clinical symptoms. They frequently spanned multiple clinical domains, most prominently neurological (e.g., cognitive impairment, pain, fatigue, sleep, autonomic, mood disturbance) and dermatologic, gastrointestinal, respiratory, with symptoms typically beginning during or shortly after deployment [4,8,9]. Now termed Gulf War Illness (GWI⁺), it is estimated that over 30% of deployed GWVs remain affected even decades after the conflict ended with this high burden disorder [ 3,4,10–13], with emerging experimental and pre-clinical evidence supporting a neuro-immune etiology arising from persistent immune dysregulation following neurotoxic deployment exposures [14–16].

We conducted a retrospective study leveraging the largest nationwide research cohort comprised of >136,000 veterans with military service during the 1990−1991 Gulf War era (GWEVs) enrolled in the U.S. Department of Veterans Affairs (VA) Million Veteran Program (MVP) [17] to assess whether deployment to the Gulf War conflict theater or having GWI⁺ were associated with increased risk of developing SARS-CoV-2 infection or having more severe COVID-19 outcomes (hospitalization, ICU admission, death). We purposively restricted our evaluation to the early pandemic-period of 2020, prior to advent and wide-scale availability of COVID vaccines, effective oral anti-COVID pharmacotherapy, widespread immunity, and viral variant emergence to evaluate potential impact of deployment and GWI⁺ on contemporary GWEV cohort’s baseline susceptibility to this novel respiratory pathogen.

Methods

Results

COVID Testing and health outcomes: Comparison of Deployed vs. Non-Deployed GWVs

COVID-tested cohort description: Our VA COVID Shared Data Resource (CSDR) searches identified 26,141 (>19%) of our COVID-study eligible CSP2006 Gulf War era veteran (GWEV) cohort members had ≥ 1 VA lab-performed PCR or antigen test with confirmed SARS-CoV-2 test findings between 3/1/2020 and 12/31/2020. (Fig 1) Almost 22% (n = 5,707) were deployed GWVs; deployed a few years younger (mean age: 58.0 vs. 60.6 in non-deployed GWEVs), and modestly more likely male (86.9% vs. 79.7%) and African-American (34.2% vs. 29.7%) than non-deployed GWEVs, all p-values<0.001. (S2 Table) Sociodemographic and military characteristics in our never-tested GWEVs (n = 110,727) were broadly similar with those in ever-tested, with again only modest differences in magnitude (e.g., mean age: 58.6 vs. 61.5 years, African-American: 30.1% vs. 24.6% in never-tested deployed vs. non-deployed GWEVs, respectively, p-values<0.001) (S2 Table).

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Fig 1. COVID-19 lab-test status and vital outcomes among CSP2006 Gulf War era veterans (GWEVs) ever tested for COVID in 2020, by deployment status.

(A) Among the N = 26,141 GWEVs with a VA-confirmed PCR/antigen COVID test between 3/1/2020 and 12/31/2020, the figure shows branching by deployment status (Deployed N = 5,707, 22%; Non-Deployed N = 20,434, 78%), COVID test result (COVID⁺ or COVID⁻), and vital outcome (Alive, Died COVID,^d or Died Other Cause). The N = 110,727 GWEVs not lab-tested for COVID are cross-referenced to S5 Fig. Superscript footnote definitions: ^a CSP2006 COVID-study eligible expanded cohort of 136,868 DoD-confirmed GWEVs enrolled in MVP by 2020 and confirmed alive as of 3/1/2020. ^b VA COVID Shared Data Resource (CSDR) identified as VA-confirmed PCR/antigen laboratory test between 3/1/2020 and 12/31/2020. ^c PCR/antigen laboratory test confirmed COVID⁺ if ever tested COVID⁺, and COVID⁻ if all test results confirmed COVID⁻ during the study period. ^d National Death Index (NDI) death-certificate match: COVID listed as underlying or contributing cause of death; otherwise coded other cause of death; no match indicates alive through 12/31/2020.

https://doi.org/10.1371/journal.pone.0348594.g001

COVID-related testing and health outcomes: 1) Test positivity: Overall crude COVID test positivity was higher in deployed GWVs (18.8%) vs. 17.2% in non-deployed GWEVs (p < 0.005). (Table 1) Deployed COVID⁺ (n = 1,072) were ~2.2 years younger (mean age: 57.4 vs. 59.6 non-deployed GWEVs), and modestly but significantly more likely to be male (88.4% vs. 83.6%) and African-American (38.2% vs. 31.6%) vs. non-deployed COVID⁺ GWEVs (n = 3,514). (S2 Table) Deployment was associated with significantly increased COVID test-positivity risk (OR_unadj: 1.11, 95% CI: 1.03–1.20, p = 0.005) in univariable analysis. (Table 2) However, associations were attenuated and non-significant in adjusted tiered-multivariable models (range ORs_adj: 1.04–1.06, N.S.).

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Table 1. COVID-related outcomes across deployment and GWI case-status in COVID-tested Gulf War Era Veterans (GWEVs) in 2020.

https://doi.org/10.1371/journal.pone.0348594.t001

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Table 2. Logistic regression models assessing 1990–1991 Gulf War deployment and Gulf War Illness and COVID-related outcomes in GWEVs in pre-vaccine pandemic period.

https://doi.org/10.1371/journal.pone.0348594.t002

1. 1). COVID-related hospitalization: Unadjusted COVID-related hospitalization prevalence was low and non-significantly different by deployment status (13.5% in deployed GWVs vs. 15.2% in non-deployed GWEVs, p = 0.18). (Table 2) Deployment was similarly not associated with COVID-related hospitalization risk across tiered-multivariable models (ORs_adj range: 0.87–0.90, all p-values≥0.23). (Table 2)
2. 2). COVID-related ICU admission: Crude ICU admission prevalence during COVID-hospitalization was significantly lower in deployed GWVs (25.5% vs. 34.3% in non-deployed GWEVs, p = 0.047, Table 1), with significant reduced relative ICU admission risk in univariable analysis (OR_unadj = 0.66, 95% CI: 0.43–0.99). (Table 2) However, effects were attenuated and non-significant in all tiered-multivariable models (e.g., OR_adj__final = 0.72, 95% CI: 0.47–1.10, p = 0.13).
3. 3). COVID-related 30-day mortality: There were 103 COVID-related deaths among 4,586 lab-confirmed COVID⁺ GWEVs, with 2.2% of both deployed GWVs and non-deployed GWEVs dying within 30 days of test-positivity. (Table 1) Deployment was not significantly associated with COVID-related mortality in univariable (OR_unadj = 0.99, p > 0.99) through final multivariable analysis (OR_{adj_final} = 1.27, 95% CI: 0.79–2.05, p = 0.32). (Table 2)

Post-hoc exploratory evaluation of clinical comorbidities in association between GWI^± and COVID-hospitalization risk

We added a secondary post-hoc hypothesis generating descriptive evaluation to explore if any of the 15 most prevalent individual clinical factors included in Elixhauser comorbidity index [ 30] or among CDC evidence-based review conditions associated with severe COVID risk [26] may be selectively associated with our suggestive preliminary finding of >2-fold potential excess relative COVID-related hospitalization risk among deployed GWVs who were GWI⁺. We employed well-established epidemiological practice including p-value threshold of p < 0.20 [ 34] without further correction for multiple comparisons [ 35,36] to guide descriptive exploratory identification of potential suggestive additional confounders to prioritize for examination in future large sample hypothesis testing research.

We found three conditions suggestively potentially more common in deployed GWI⁺ who were COVID-hospitalized vs. similarly COVID⁺ deployed GWVs also COVID-hospitalized but who were GWI^-; depression (occurred in 13 of 18 [72%] GWI⁺ COVID-hospitalized vs. 3 of 14 [21%] GWI^- COVID-hospitalized, p = 0.01); bronchitis (in 5 of 18 [28%] GWI⁺ but in 0 of 14 GWI^-, p = 0.05); and coronary atherosclerotic heart disease [CAHD] (also in 5 of 18 [28%] GWI⁺ but in 0 of 14 GWI^-, p = 0.05). (Table 3)

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Table 3. Post-hoc descriptive comparison of comorbid risk factors in COVID+ deployed Gulf War Veterans according to COVID-hospitalization and GWI case-status.

https://doi.org/10.1371/journal.pone.0348594.t003

Depression, however, was similarly highly prevalent among COVID⁺ GWI⁺ who were not ultimately hospitalized for COVID (occurring in 62 of 93 [67%] vs. 72% in GWI⁺ who were COVID-hospitalized, N.S.). In contrast, both bronchitis and CAHD were also suggestively potentially differentially more prevalent in deployed COVID⁺ GWI⁺ who were COVID-hospitalized vs. COVID⁺ GWI⁺ who were not ultimately hospitalized for COVID (bronchitis: 28% in GWI⁺ COVID hospitalized vs. 7% GWI⁺ not hospitalized, p = 0.02; and CAHD: 28% GWI⁺ hospitalized vs. 13% GWI⁺ not hospitalized, p = 0.14, respectively). (Table 3) Although we cannot distinguish type of bronchitis based on CSDR-identified bronchitis (which captures both chronic and acute bronchitis diagnostic codes) given inability to perform confirmatory chart review within the VA’s CSDR framework, 4 of 5 also had COPD diagnostic codes, suggesting multiple bronchitis cases may be chronic.

1. 3). COVID-related ICU admission: Only 5 deployed COVID⁺ sub-cohort members hospitalized for COVID were subsequently ICU-admitted, with similar non-significantly different crude ICU prevalence rates (16.6% GWI⁺ vs. 14.3% GWI^-, respectively). (Table 1) Limited numbers precluded modeling.
2. 4). COVID-related mortality: There were only 8 deaths within 30 days of testing lab-confirmed COVID⁺, with non-significantly different low crude COVID-related mortality (1.8% in deployed GWI⁺ vs. 3.1% in GWI^-, p = 0.71). (Table 2) Limited numbers precluded modeling.

National Death Index-determined overall and COVID-related mortality burden in GWVs in 2020

Study flow diagram Fig 1 includes final National Death Index (NDI) death-certificate determined vital status in our COVID-tested GWEV cohort as of the end of the study period, 12/31/2020. See Supplemental Results for documenting excellent concordance between NDI-determined COVID mortality and VA CSR&D 30-day COVID mortality, and comparative impact on overall survival in the 10-month early pandemic period in 2020 vs. year prior. (S4 Text)

COVID mortality burden associated with Deployment:.

There were N = 207 CSP2006 GWEV cohort members who died with COVID as death certificate-recorded cause of death; including n = 100 (48%) among 4,586 lab-confirmed COVID⁺ GWEVs (Fig 1) and n = 96 (46%) among 110,727 GWEVs never COVID-tested in 2020. (S5 Fig)

Of the N = 110,727 GWEVs not lab-tested for COVID (cross-referenced from Fig 1), the figure branches by deployment status (Deployed N = 24,178, 22%; Non-Deployed N = 86,549, 78%) and vital outcome (Alive, Died COVID,^d or Died Other Cause) through 12/31/2020. The ever COVID-tested subcohort (N = 26,141) is cross-referenced to Fig 1. Footnote definitions are as in Fig 1.

Overall deployment to serve in 1990–1991 PG conflict theater zone was not associated with any death-certificate based metric of COVID mortality burden: with extremely low proportions of both deployed GWVs and non-deployed GWEVs who never received a VA-lab confirmed COVID⁺ diagnosis ultimately dying with death certificate-recorded COVID as a cause of death in 2020 (e.g., 0.1% in both never-tested deployed GWVs and non-deployed GWEVs, respectively) (Table 4). Considerably higher though also nearly identical proportions of lab-confirmed COVID⁺ deployed GWVs and non-deployed GWEVs died of COVID (2.2% vs. 2.1%, respectively, N.S.), with COVID accounting for most of all deaths observed in COVID⁺ GWEVs during our 10-month study period (82.1% in deployed, 76.2% in non-deployed, Table 4, N.S.). There were also similar overall age-adjusted COVID mortality rates among deployed GWVs and non-deployed GWEVs (e.g., 24.16/1,000 and 23.98/1,000 in lab-confirmed COVID⁺ deployed and non-deployed, respectively; MRR = 1.01, 95% CI: 0.54–1.47, N.S.) (S3 Table).

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Table 4. National Death Index-determined COVID-related mortality burden in nationwide CSP2006/MVP029 Gulf War Era Veteran Cohort in 2020.

https://doi.org/10.1371/journal.pone.0348594.t004

COVID mortality burden associated with GWI in Deployed COVID-tested subcohort (N = 1,643).

There were only N = 11 death certificate-recorded COVID deaths in our COVID-tested deployed GWV subcohort, n = 8 among 303 confirmed-COVID⁺ and n = 3 among 1,340 confirmed-COVID^- (S6. Fig 3).

Among the N = 1,643 deployed GWVs with a completed 2018 Gulf War survey, the figure branches first by GWI status (GWI⁺ N = 645, 39%; GWI⁻ N = 998, 61%), then by COVID test result (COVID⁺ or COVID⁻), and finally by vital outcome (Alive, Died COVID,^d or Died Other Cause). GWI status was assigned using CDC Severe (Fukuda) criteria^e applied to 2018 survey responses. Footnote definitions are as in Fig 1 except: ^e Deployed GWV in subcohort classified using CDC Severe GWI criteria as GWI⁺ or GWI⁻ based on 2018 Gulf War survey responses.

GWI⁺ was not significantly associated with any metric of death certificate-based COVID-related mortality burden; with same very low proportion (0.2%) of GWI⁺ and GWI^- deployed GWVs who tested only COVID^- ultimately dying of COVID in 2020. (Table 4) In contrast, a non-significantly, slightly higher proportion of GWI^- deployed GWVs lab-confirmed COVID⁺ died from COVID (3.1% vs. 1.8% GWI⁺), with COVID accounting for non-significantly greater proportion of total deaths observed (100% [n = 6] in GWI^- vs. 67% [n = 2 of 3] in GWI⁺, respectively). (Table 4) Similar overall age-adjusted mortality rates (13.1/1,000 GWI^- vs. 11.7/1,000 GWI⁺, N.S.) were also observed, though CIs were imprecise given power constraints. (S3 Table)

Discussion

Our study evaluated COVID-19 related health outcomes in a large nationwide cohort of 1990–1991 U.S. Gulf War veterans (GWVs), an aging group broadly exposed during military deployment to unique toxic exposures and with a high prevalence of Gulf War Illness (GWI⁺), a medically unexplained chronic multi-symptom illness associated with neuro-immune dysfunction and inflammation. We found robust, broadly reassuring results among COVID-tested veterans serving in the Gulf War era (GWEVs) using the VA healthcare system that overall deployment to the Persian Gulf (PG) theater was not associated with increased risks for testing COVID⁺ or experiencing COVID-related hospitalization, ICU admission, or death in the early 2020 pre-vaccine pandemic period.

We found that while GWI⁺ was also not associated with increased COVID test positivity (COVID⁺) among our deployed GWV subcohort, that GWI⁺ was associated with suggestive potential >2-fold significant increase in COVID-related hospitalization among deployed GWVs in both univariable and final multivariable models. These suggestive robust preliminary findings in our deployed GWV subcohort are, however, duly qualified pending replication in other large cohorts given fewer total hospitalizations limited power and confounder adjustment to designated core established COVID risk factors (i.e., age, race/ethnicity, sex, and Elixhauser comorbidity) only. In contrast, we found GWI⁺ was not associated with either strong or significant excess COVID-related ICU admission or mortality risk in deployed GWVs in preliminary unadjusted analyses, though even lower event rates precluded multivariable modeling.

The preliminary suggestive observed association between GWI⁺ and potential significantly increased COVID-related hospitalization in our deployed GWVs is perhaps reflective of a GWI-related vulnerability to more serious sequelae with COVID infection. This is biologically plausible given multiple epidemiological studies reported associations between GWI⁺ as well as overall GW deployment and increased prevalence of diverse chronic health conditions [3,4,8,37–39], with numerous experimental model, pre-clinical and clinical studies incorporating physiologic measures have documented significant neurological/neuropsychological [ 40–43], immunoinflammatory [44–46], metabolic [47–49], microbiome [50–52], and genetic differences associated with GWI⁺ [ 22,53–55]. It is also consistent with findings of increased susceptibility for adverse health effects in association with other exposures [ 56] among deployed GWVs who have GWI and multiple significant findings of long-term substantial increased health symptom burden [13,21] and frailty [57] and persistently reduced health-related quality of life [ 58] among GWI⁺.

Our post-hoc descriptive hypothesis generating bivariable exploration of 15 of most prevalent individual clinical comorbidities from among CDC evidence-based review identified risk factors for severe COVID and in Elixhauser comorbidity scores suggested two, coronary atherosclerotic heart disease (CAHD) and bronchitis, may potentially be differentially elevated among deployed GWI⁺ GWVs who experienced COVID-related hospitalization. The limited total number of hospitalizations, unfortunately, precluded further exploratory evaluation of them as additional potential independent risk factors in multivariable analyses after accounting for our other a priori-specified core COVID risk factors. However, both may warrant further investigation in future larger hypothesis testing cohort studies given: 1) GWI⁺ was recently associated with increased risk of CAHD in another GWV cohort [ 37]; and 2) chronic bronchitis and multiple other respiratory conditions (e.g., post-deployment asthma) are VA-recognized as presumptively military service-related among deployed GWVs given wide-scale exposure to airborne hazards including oil well fires and burn pits and epidemiological findings of increased occurrence of several respiratory diseases in deployed GWVs [ 59], with hazardous environmental airborne exposures also increasingly associated with greater COVID-related health risks in general population studies [ 60].

Another unique study contribution was our assessment of concordance between the VA CSDR-defined 30-day COVID-related mortality algorithmically ascertained using nearer term extracts from extant EHR and linked administrative healthcare databases against gold standard U.S. government official standard NDI death certificate data available only several years later. Excellent observed concordance provides important novel validation of a major VA CSDR-determined COVID outcome used in numerous high-impact published as well as ongoing studies on COVID risks and outcomes including on COVID vaccinations and post-acute long-term sequelae with COVID [ 61–64]. Notably, our NDI-based findings also reaffirmed our primary VA CSDR-determined multivariable relative risk findings of no significant association between deployment and 30-day COVID-related mortality among those testing COVID⁺. This suggests potential unmeasured selection bias was unlikely to have substantively impacted on our VA CSDR-based findings for overall deployment and COVID-related health outcomes.

Our study, which is to the best of our knowledge the first and only study to examine whether a specific veteran cohort deployed to serve in any military conflict (e.g., Vietnam War, 1990–1991 Gulf War, post-9/11 Iraq and Afghanistan conflicts) had potentially increased susceptibility to adverse COVID-related health outcomes had multiple methodological strengths. These include leveraging and expanding upon the well-phenotyped, largest nationwide research cohort of GWEVs, MVP’s CSP2006 Genomics of Gulf War Illness study cohort, which also includes the largest deployed GWV cohort with GWI case-status rigorously defined using National Academy of Sciences (formerly Institute of Medicine, NAS/IOM) recommended CDC criteria and conservative application of the severe phenotype. Additionally, GW survey responses used to determine contemporary GWI⁺ status were obtained from mid-2018 thru 2019, nearly contemporary to the pandemic period and thus a good marker for baseline susceptibility conveyed by GWI⁺, while also obtained long enough before the first U.S. confirmed case in January 2020 to mitigate potential reverse causation bias. Other strengths include utilizing the VA’s well-curated CSDR to comparably identify lab-confirmed COVID-testing/outcomes; our comprehensive methodologically-rigorous tiered multivariable analytic approach evaluating associations between overall deployment and GWI⁺ among deployed GWVs across range of COVID outcomes; and use of gold-standard NDI death certificate data as secondary source allowing us to interrogate age-adjusted COVID mortality cohort-wide (including in substantial number non-COVID tested GWEVs not included in CSDR database).

Importantly, our study is responsive to publicly expressed concerns of deployed GWVs, advocates and clinicians about possible elevated COVID risks given their military service-related toxic exposures and increased risk of several post-deployment exposure-related health conditions [ 65]. GWVs have long reported feelings of betrayal by the government, medical system, and even their country regarding under-recognized and non-redressed post-deployment military exposure-related health risks, burden and unmet healthcare needs [ 66] (including lack of clinical recognition of GWI⁺ both in VA and civilian healthcare settings and effective GWI⁺ tailored healthcare). Our study also aligns with the research and education aims included in The Sergeant First Class (SFC) Heath Robinson Honoring our Promise to Address Comprehensive Toxics (PACT) Act of 2022. The PACT Act has resulted in perhaps the largest expansion of VA healthcare system eligibility and benefits to date to include millions more potentially military service toxic exposed veterans deployed to serve in 1990−1991 GW, Vietnam, and post-9/11 Iraq and Afghanistan conflicts [ 67,68]. Post-deployment susceptibility to novel infectious agents, such as SARS-CoV-2, is not a presumed service-connected condition for any deployed veteran cohort; our findings do not support such a policy change for deployed GWVs.

Our study has several limitations, starting with the retrospective design that precludes causal inferences. Despite this being the largest nationwide research cohort of GWEVs, we had statistical power constraints for analyses of rarer COVID outcomes, particularly in our smaller deployed GWV subcohort analyses and associated power constraints in multivariable confounder adjusted risk modeling. This requires as previously noted qualified interpretation of preliminary findings of association between GWI⁺ and increased COVID-related hospitalization in deployed GWVs as suggestive only pending confirmation in other large external cohorts. Nonetheless, the general consistency in strength, direction and significance of relative risk estimates across unadjusted through all fully adjusted multivariable models, coupled with consistency in findings of no association between deployment or GWI⁺ and age-adjusted COVID-related mortality rates in both VA CSDR and NDI-based mortality analyses is supportive of internal validity of study findings. External generalizability is another important consideration; although earlier research evaluating the original CSP2006 parent cohort of >109,000 GWEVs demonstrated that it, as well as the large subgroup who returned 2018 Gulf War surveys, were generally representative in most sociodemographic and health characteristics to both the broader population of GWEVs using VHA healthcare and the full U.S. population of GWEVs [20]. Additionally, our observed COVID test positivity rates in our expanded CSP2006 cohort, which were similar across deployment and GWI case-status groups, were also aligned with reported COVID⁺ rates in COVID-tested adult males in the general US population in the early pandemic period [ 69]. Caution is still nonetheless warranted in extrapolating our findings to substantial number of GWVs not enrolled in VA healthcare system. VA-users are recognized as having higher rates of chronic illness and health risk factors and there are considerable differences between VA healthcare system (a highly subsidized, needs-based and prioritized equal access healthcare system) and civilian insurance-based healthcare systems with respect to access, utilization, and care delivery that could variably impact clinical outcomes. Our classification of contemporary, pre-pandemic Gulf War Illness (GWI⁺) status relied on a single time-point survey administered decades after the war ended, which may introduce limitations due to reliance on established IOM/NAS endorsed GWI⁺ research case definitions developed in much younger GWVs soon after the Gulf War ended. Despite this, prior analyses demonstrated that our surveyed deployed Gulf War veterans represent the broader national cohort of deployed GWVs in terms of key military service and sociodemographic characteristics [20,21]. Additionally, major risk factors identified for GWI⁺ in them were consistent whether using CDC severe phenotype (used in current COVID research), self-reported physician diagnosis of GWI⁺, or validated measures of multisymptom morbidity, and mirrored findings from previous and also much earlier large-scale studies [21]. This consistency suggests any potential misclassification bias is likely minimal and non-differential.

A further limitation is lack of direct chart review access within the VA COVID Shared Data Resource (CSDR) which prevented further valid characterization of symptomatic disease severity for algorithmically diagnostic code identified clinical comorbidities like bronchitis at time of COVID testing. Additionally, the absence of GWI-specific diagnostic codes precluded identification of GWI⁺ cases outside our deployed sub-cohort survey respondents. The recent introduction of first official diagnostic code for GWI [70], ICD-10 CM code T75.830 for GWI, along with Z77.31 for deployment-related Gulf War exposure (effective October 2025) [71] is expected to significantly enhance future EHR-based research. These codes should enable for the first time reliable, efficient identification of large representative samples of GWVs with comparable clinically documented GWI diagnosis seen across diverse healthcare settings, including importantly also in non-VA community care settings. This should greatly facilitate valid and reliable epidemiological assessment of even rarer outcomes—like COVID-19 related ICU admission and case fatality---within this high-risk population.

In conclusion, our study found overall deployment to the 1990–1991 Gulf War conflict theater was not associated with elevated risk of testing COVID⁺ or experiencing worse COVID-related health outcomes among Gulf War era veterans using the VA healthcare system in the early pre-vaccine pandemic period. Our preliminary suggestive findings of potential association between Gulf War Illness and increased COVID-related hospitalization among deployed Gulf War veterans warrant replication in other large external cohorts. Ongoing follow-up also needed to ascertain implications for our observed early pandemic-era associations with changes in viral variants, introduction of vaccines and effective oral anti-viral medication, and changes in persistence of symptoms associated with COVID infection.

Supporting information

Acknowledgments

The CSP2006 Genomics of Gulf War Illness COVID study team authors would like to acknowledge the support of MVP leadership, especially Suma Muralidhar; support of Karen Block at the VA Gulf War Research Program; administrative assistance from Jason Aguilar and Efthalia Zafeiropoulou at Houston VA Health Services Research Center of Innovations (IQuESt) and from René LaFleur at the Clinical Epidemiology Research Center, and technical assistance on use of the VA’s COVID Shared Data Resource from James Gatsby. The authors also would like to thank the members of the Million Veteran Program (MVP) Core including Nicole Usher for administrative and IRB assistance and Rachel Quaden and Lauren Costa for data acquisition assistance, and especially the Veteran participants in the MVP for their generous contributions. We would also like to acknowledge the vision of the late Dawn Provenzale, former Director of the Cooperative Studies Program Epidemiology Center-Durham and former Co-Study Chair of CSP#2006.