Air pollution levels drive inflammatory epithelial responses in the pathogenesis of non-viral asthma exacerbations in urban children

Rationale: Exposure to outdoor air pollution has been associated with adverse respiratory effects in children with asthma including an increased risk of exacerbations. The mechanisms by which air pollutant exposure may lead to exacerbations, and how these mechanisms are similar or distinct from virus-associated exacerbations, are incompletely understood. Methods: This is a prospective case-control study of outcomes from upper respiratory illnesses (URIs) among 106 children ages 6-17 years with exacerbation-prone asthma. Daily cold and asthma symptom diaries were completed to identify both the initiation of URI symptoms and worsening of lower respiratory asthma symptoms. Daily longitudinal air pollution data was obtained from epa.gov and geographically matched by core-based-statistical-areas. Serial nasal lavage samples were collected at the initiation of URI symptoms. Nasal gene expression was assessed by RNA sequencing and viral infection by multiplex PCR. Longitudinal differences in air pollution levels among illness subgroups and relationships among pulmonary function, gene expression, and pollution levels were determined by mixed-effects modeling. Results: 154 URIs were utilized for analysis. These illnesses were subgrouped as virus positive colds that resulted in an asthma exacerbation (V+Ex+; n=33), virus positive colds that resolved without exacerbation (V+Ex- n=69), virus negative colds that resulted in exacerbation (V-Ex+; n=14) and virus negative colds that resolved (V-Ex-; n=38). Air quality index (AQI) scores were significantly higher in the V-Ex+ illness subgroup compared to the other 3 groups on the day of exacerbation onset and in the 6 preceding days (Figure; p-values\u3c0.05). The responsible pollutants driving the elevated AQI scores in this group were PM2.5, NO2, and O3. Correspondingly, the mean levels of each of these 3 pollutants were significantly higher in the V-Ex+ group on multiple days in this window Furthermore, the AQI values showed a significant negative Pearson correlation with FEV1%- predicted measured during V-Ex+ illnesses (R=-0.81 p\u3c0.001) and also a significant association with elevated expression of 3 gene-modules related to epithelial barrier functions and inflammation annotated as Keratinization/Epithelial-development/Cell-cell-adhesion/Tightjunctions Tissue kallikrein induction, and Squamous epithelium inflammation (effect sizes 0.9- 1.7, FDRs\u3c0.05) prior to exacerbation onset. Conclusions: Acute periods of exposure to elevated regional air pollutants, specifically PM2.5, NO2, and O3 were associated with elevated expression of multiple inflammatory airway epithelial responses and to a decline in FEV1%- predicted in the lead up to clinical asthma exacerbations that occur in the absence of a viral trigger. These results provide important mechanistic insights into a distinct exacerbation subtype particularly important to asthma in urban populations (Figure Presented)