Two Distinct Transcriptional Subtypes of Severe Type 2 Asthma in NSAID-Exacerbated Respiratory Disease

Previous studies demonstrated the heterogeneity of the nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) phenotype. Patients with severe asthma and aspirin hypersensitivity may exhibit differences in sputum mRNA gene expression. The aim of the study was to identify distinct transcriptional subtypes of severe asthma with aspirin hypersensitivity using unsupervised cluster analysis.

Sputum induction was performed in 27 patients with severe asthma and aspirin hypersensitivity who met 2022 Global Initiative for Asthma criteria for type 2 (T2) severe asthma. Using the transcriptional signatures of 87 genes, along with clinical characteristics and biomarker measurements, 2 distinct subtypes were identified and compared between study participants.

Two clusters were identified: cluster 1 (n = 10) and cluster 2 (n = 17). In cluster 1, low GATA3 expression was observed, along with several activated inflammatory genes, while cluster 2 was characterised by high GATA3 expression. Cluster 1 was characterised by increased sputum eosinophil count (p = 0.04) and percentage (p = 0.035), and decreased sputum macrophage count (p = 0.003) and percentage (p = 0.003). Patients in cluster 1 had increased sputum supernatant prostaglandin D₂ levels (p = 0.031). Patients in cluster 1 tended to have a higher Lund-Mackay score (p = 0.074) and elevated peripheral blood eosinophilia (p = 0.059).

Patients in cluster 1 exhibited T2 inflammation with low GATA3 expression, while those in cluster 2 showed T2 inflammation with high GATA3 expression. Sputum GATA3 expression may serve as a useful biomarker for differentiating distinct severe asthma subtypes in patients with N-ERD.