Establishing the PM2.5-associated inflammatory endotype of chronic rhinosinusitis

Background: Chronic rhinosinusitis (CRS) is a complex multifactorial disease characterized by persistent sinonasal inflammation of unknown etiology. A unique inflammatory signature of CRS associated with exposure to particulate matter with a diameter of less than 2.5 μm (PM2.5) has recently been identified, characterized by univariate elevations in mucus IL-2, IL-5, IL-7, IL-12/23p40, and IL-21. Objective: We sought to validate and further define this putative endotype by a joint multivariate cytokine analysis. Methods: Clinical and demographic data for 634 patients undergoing sinus surgery were extracted with a spatiotemporal machine learning model to estimate daily PM2.5 exposure for 12 months before surgery. Inflammatory mucus cytokines were quantified with a cytometric bead assay. Levels of IL-2, IL-5, IL-7, IL-13, IL-12/23p40, and IL-21 were log transformed, scaled, and summed to create a composite measure. Spearman correlation and regression analysis were performed to characterize the relationship between this scaled metric and estimated PM2.5 exposure. Results: Estimated 12-month PM2.5 levels were positively associated with elevations in the composite cytokine score on univariate analysis (β = 1.17, P < .0001). This relationship between the IL-2, IL-5, IL-7, IL-13, IL-12/23p40, and IL-21 composite score and PM2.5 levels was persistent after adjusting for numerous potential clinical and sociodemographic confounders, including age, body mass index, history of asthma/allergic rhinitis, polyps, and income/rurality measures (β = 1.27, P < .0001). Conclusion: PM2.5-associated CRS is characterized by joint multivariate elevations in mucus IL-2, IL-5, IL-7, IL-12/23p40, IL-13, and IL-21, providing key evidence for a putative mixed type 2 and 3 endotype of CRS associated with air pollution.