Eosinophil Gene Activation in the Upper Airway is a Marker of Asthma Exacerbation Susceptibility in Children

A significant proportion of children in urban populations remain exacerbation prone despite guideline-directed care. Preventing exacerbations in these children remains a major unmet clinical need. Identification of cellular and molecular markers of exacerbation susceptibility that can determine periods of heightened exacerbation risk is important towards improving asthma management. 94 children with exacerbation prone asthma and peripheral blood eosinophils ≥150 /mm3 had nasal lavage samples collected at baseline. Nasal cell differentials were determined by cytospin and nasal gene expression assessed by RNA-sequencing. Participants were monitored for upper respiratory tract infections (URIs) and asthma exacerbations. Differential gene expression was assessed by cell deconvolution and modular analysis coupled with multivariate linear modeling. Baseline nasal samples were compared between children who developed an asthma exacerbation associated with a URI within 2 months of collection versus children who had a URI without asthma exacerbation. Those who developed an exacerbation had 2.7 fold higher nasal eosinophil percentages (p<0.001) and significantly higher expression of 3 eosinophil associated gene sets (fold changes 1.3-1.7) representing multiple functions including cell activation, expression of Th2-type cytokines, and intracellular signaling. These results demonstrate that among children with exacerbation prone asthma with peripheral eosinophilia, the presence of upper respiratory tract tissue eosinophilia and enhanced expression of multiple pathways of eosinophil activation are markers of propensity for disease exacerbation. This profile likely represents a marker of disease instability, and demonstrates molecular mechanisms that may lead to virus-induced exacerbation. These findings could help guide selection and appropriate timing for therapeutic interventions.