Impact of allergen sensitization on phenotypes of T2-low asthma: a post-hoc analysis of a nationwide cohort study, NHOM Asthma.

Background: Asthma is a heterogeneous disease influenced by genetic and environmental factors. Type 2 (T2)-high asthma has been extensively studied; however, the pathophysiological mechanisms of T2-low asthma remain unclear.

Objective: The present study aimed to determine the clinical indices contributing to asthma exacerbation and identify the phenotypes of T2-low asthma.

Methods: We used data from the NHOM Asthma Study (N = 1925), a nationwide asthma cohort study conducted in Japan. T2-low asthma was defined by eosinophils < 150/μL and fractional exhaled nitric oxide levels < 25 ppb. The clinical indices associated with asthma exacerbation were identified using univariate and multivariate analyses. Hierarchical cluster analysis was performed to classify the phenotypes of T2-low asthma.

Results: Multivariate analysis revealed that younger age and comorbid allergic diseases contributed to the exacerbation of T2-low asthma. Four phenotypes were identified: Cluster 1 (n = 19, 7.8%, smoking-related T2-low asthma with preserved pulmonary function), Cluster 2 (n = 18, 7.4%, smoking-related T2-low asthma with low pulmonary function), Cluster 3 (n = 99, 40.7%, elderly, female-dominant, late-onset T2-low asthma), and Cluster 4 (n = 107, 44.0%, younger, female-dominant, comorbid with allergic disease T2-low asthma). Clusters 2 and 4 were prone to asthma exacerbation, indicating distinct allergen sensitization.

Conclusions: These findings indicate that antigen-specific IgE profiles may reflect the phenotypic heterogeneity of T2-low asthma and could serve as potential biomarkers for identifying subgroups at increased risk of exacerbations.