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Introduction
Gulf War Illness (GWI) affects approximately 30% of veterans from the 1990-1991 Persian Gulf War. Nasal congestion and fatigue rank among the most prevalent GWI complaints, yet sinonasal cytokine profiles in Gulf War Veterans (GWVs) remain uncharacterized. We hypothesized that deployment-related inhalational exposures, including burn pit emissions and desert particulate matter, drive a distinct sinonasal immunological endotype compared to non-gulf war veteran chronic rhinosinusitis (CRS).
 

Materials and Methods
Sinonasal secretions were collected from 45 GWVs (21 with CRS, 24 without) and 49 non-GWVs (18 with CRS, 31 without) at the VA Greater Los Angeles Healthcare System under an IRB-approved protocol. CRS was defined by 2 or more cardinal symptoms for 12 or more weeks with CT corroboration. Exposure histories, including burn pit emissions, desert particulate matter, organophosphate pesticides, were obtained via structured telephone interviews. Medical history was obtained using chart review. Cytokines and chemokines were quantified via a 38-plex Luminex assay. Disease severity was assessed by SNOT-22 patient-reported outcomes and Lund-Mackay CT scoring. Inflammatory endotype (Type 2 vs. Non-Type 2) was classified using Stevens (90th percentile) threshold applied to IL-4, IL-5, and IL-13. Individual cytokine concentrations were modeled using generalized linear models with a log link and sandwich robust standard errors, with a GWV x CRS interaction term quantifying the differential cytokine signal in veteran-associated CRS relative to non-CRS groups. Group comparisons used multiple variable logistic regression with robust standard errors and controlled for demographics and comorbidities.
 

Results
GWVs and non-GWVs were well-matched on demographics and comorbidities. GWVs reported significantly greater exposure to burn pits and petroleum fires, as well as substantial exposure to pesticides and nerve agents, compared to non-GWVs. GWVs exhibited higher nasal polyp prevalence (52% vs. 33%). SNOT-22 scores and Lund-Mackay CT scores were markedly elevated in GWV-CRS patients relative to NGW-CRS patients (SNOT-22 means, 43.9 vs. 26; Lund-Mackay 9 vs. 6.8), reflecting greater symptom burden and more extensive radiographic disease. GWV-CRS patients had a 1.6 greater odds of being classified as Type 2 endotype. Consistent with this phenotype, Th2 cytokines IL-5 and IL-13 were significantly elevated in GWV-CRS sinonasal secretions, as was the innate immune marker IL-8. In GWVs without CRS, IL-10, IL-6, and MIP-1β were elevated relative to non-Gulf War veterans without CRS, suggesting baseline mucosal immune dysregulation independent of sinusitis (all p<0.05).
 

Conclusions
GWVs with CRS are characterized by a Type 2 eosinophilic endotype with significantly greater symptom burden, more extensive radiographic disease, and elevated Th2 cytokines (IL-5, IL-13) and innate markers (IL-8) compared to non-GWV CRS. Even in the absence of CRS, GWVs demonstrate baseline immune perturbation, suggesting Gulf War toxic exposures may prime Th2-skewed mucosal immunity. Further investigation is needed to clarify the mechanisms linking Gulf War exposures to this distinct sinonasal inflammatory phenotype.