Asthma severity and corticosteroid response depend on variable type 1 and type 2 inflammation in the airway

The prevalence, inter-relationships, and longitudinal behavior of type 1 (T1) and type 2 (T2) immune responses in asthma are uncertain, as is the role of viruses as determinants of these responses. Here, we performed whole transcriptome network analysis on sputum cells collected from Severe Asthma Research Program (SARP)-3 patients before and after treatment with intramuscular corticosteroid and again at 1 and 3-year follow-up visits. We used network analysis to analyze whole-transcriptome gene expression and metagenomic analysis of these RNA-seq data to detect viruses. We identified T1 and T2 airway networks, the expression of which showed that 26% and 44% of patients had T1-high and T2-high asthma at baseline, respectively. Asthma severity outcomes were worse in T2-high asthma than in T1-high asthma and most severe in the subgroup of patients (14%) with combined T1- and T2-high disease. Corticosteroid treatment suppressed T2 but not T1 gene expression, and corticosteroid-associated improvements in FEV1 occurred only in patients with T1-L/T2-H disease and not in T1-H/T2-H patients. Although T1 and T2 inflammation at baseline was a significant predictor of T1 and T2 inflammation at follow-up visits, most patients had variable rather than persistent expression of T1 and T2 network genes. Viral metagenomic analyses uncovered that 24% of asthma sputum samples tested positive for a virus and high viral carriage was associated with an 11-fold increased risk of T1-high disease. Together our results uncover a relatively high burden of T1-high and T1/T2-high disease subtypes in severe asthma, which are corticosteroid-resistant and manifest with sub-clinical viral infection.