Abstract Rationale Understanding molecular heterogeneity and exacerbation mechanisms in severe asthma (SA) is critical for achieving true precision medicine. While transcriptomic profiling has revealed asthma heterogeneity, whole-blood transcriptome analysis aimed at identifying molecular subtypes and exacerbation predictors in the current biological agent era remains unexplored. This gap limits our ability to stratify patients and optimize treatment selection. Objective To identify molecular subtypes specific to SA patients and discover transcriptomic signatures and clinical characteristics that predict future exacerbations in patients with poor prognosis. Methods We performed RNA sequencing on whole-blood samples from 171 SA patients, 259 healthy controls, and 15 mild-to-moderate asthma patients to identify differentially expressed genes distinctive to SA. Unsupervised clustering was used to classify SA patients into distinct molecular clusters. We conducted prospective 12-month follow-up for 169 SA patients to assess the predictive value of baseline patient characteristics and transcriptomic signatures for future exacerbation events. Results We identified 17 genes significantly upregulated in SA patients, predominantly enriched in neutrophil degranulation pathways. These genes showed positive correlations with clinical parameters including BMI, smoking pack-years, maintenance oral corticosteroid dose, history of exacerbations in the previous year, and peripheral blood total leukocyte and neutrophil counts (all p 0.05). Based on distinctive gene expression profiles, three molecular clusters with distinct inflammatory profiles and corticosteroid requirements were identified. Cluster 1 demonstrated the highest proportion of male patients (53.3%, p = 0.012) and significantly greater use of maintenance oral corticosteroids (66.7%, p 0.001). Cluster 2 represented an intermediate phenotype with balanced clinical and inflammatory features. Cluster 3 showed the highest proportion of female patients (79.1%, p = 0.012) and significantly lower peripheral inflammatory markers. In the prospective follow-up study, multivariate analysis revealed that allergic rhinitis (adjusted risk ratio RR 1.82), prior exacerbation history (adjusted RR 1.87), and assignment to cluster 1 or 3 (adjusted RR 2.43 or 1.69 vs. cluster 2) were independently associated with increased future exacerbation risk. Among patients who experienced exacerbations during follow-up, differential gene expression analysis identified upregulated genes predominantly enriched in neutrophil degranulation pathways. Notably, Immunoglobulin Lambda Variable 7-46 (IGLV7-46) showed consistent prognostic value across the overall cohort and among the biologic treatment subgroup, representing a novel exacerbation biomarker. Conclusions Whole-blood transcriptomics reveals neutrophil-associated molecular signatures in SA and enables clinically relevant molecular subtyping. IGLV7-46 emerges as a novel exacerbation biomarker. This integrated approach provides a molecular framework for risk stratification and precision medicine in SA management. This abstract is funded by: the Japan Agency for Medical Research and Development AMED; JP23ek0410084, the Japan Society for the Promotion of Science JSPS; Grant-in-Aid for Science Research, 23K07594, and Takara Bio Inc.
Suzuki et al. (Fri,) studied this question.