Type 1 Immune Responses Related to Viral Infection Influence Corticosteroid Response in Asthma

This study investigated the prevalence and stability over time of T1 high, T2 high, and mixed T1/T2 high asthma endotypes and assessed the influence of T1 inflammation (potentially driven by subclinical viral infection) on corticosteroid responsiveness in asthma.Adult participants in the Severe Asthma Research Program-3 (SARP-3) cohort (n = 347) and healthy controls (n = 37) contributed sputum samples at baseline, after administration of intramuscular triamcinolone, and at 1- and 3-year follow-up visits. Participants were classified by expression of T-helper type 1 drive (T1) and type 2 (T2)–associated gene networks into T1 high, T2 high, mixed T1/T2 high, or low-expression endotypes.Investigators performed whole-transcriptome RNA sequencing on sputum cells to identify coexpression gene networks associated with T1 and T2 inflammation. Viral metagenomic analysis was conducted to detect respiratory viral RNA. Steroid responsiveness was measured through changes in gene network expression and spirometric response (FEV1) after triamcinolone administration as part of the Systemic Corticosteroid Response Test. The association between viral presence, gene endotype, and corticosteroid response was evaluated.T1 high and T2 high endotypes were observed in 22% and 35% of participants, respectively, while a smaller group (8.5%) displayed elevated expression in both inflammatory pathways. Individuals with a T2 high profile had more severe disease, including significantly higher blood eosinophil counts (median 394 cells/μL vs 195 cells/μL; P < .01). Administration of intramuscular triamcinolone led to marked downregulation of T2 associated gene networks (mean fold change −0.65; P < .001), whereas T1 associated gene activity was largely unchanged (−0.04; P = .45). Functional improvements in lung function, defined by an increase in forced expiratory volume in 1 second (FEV1) of at least 200 mL, occurred in 36% of patients with a T1 low/T2 high endotype compared with just 13% of those with codominant T1 high/T2 high expression. Respiratory viral transcripts were detected in 24% of samples and were strongly correlated with T1 high gene expression (odds ratio, 14.2; 95% CI, 4.1-48.3; P < .001), implicating subclinical viral carriage in shaping this corticosteroid-refractory phenotype.A distinct subset of patients with asthma exhibit T1 dominant or mixed T1/T2 airway inflammation, likely influenced by ongoing viral activity in the airways. Although corticosteroid therapy effectively targets T2 inflammation, it fails to suppress T1-driven gene expression, which may explain the limited treatment response observed in patients with mixed endotypes. These findings reinforce the clinical relevance of inflammatory profiling and suggest that patients with high T1 activity, especially in the context of chronic viral presence, may benefit from nonsteroidal, targeted interventions aimed at antiviral pathways.This study offers compelling evidence that T1 inflammation, often associated with viral exposure, is prevalent in adult asthma and mediates corticosteroid resistance. Its strengths are the inclusion of transcriptomic and viromic data over multiple time points. Clinically, the findings emphasize that not all severe asthma is T2 driven and that mixed endotypes may require novel therapeutic strategies beyond corticosteroids. Limitations include the adult-only population, and the use of intramuscular corticosteroids, which is not typically standard clinical practice. It would be interesting to see whether comparing children with asthma and healthy children, in whom viral infections are very common, would yield similar patterns. In addition, the detection of viral RNA does not necessarily confirm active infection, raising questions about causality. The study supports the advancement of precision medicine in asthma and underscores the potential need to develop and test antiviral and anti-T1 therapies in appropriately selected patients.