BACKGROUND: Preschool wheeze is heterogeneous and only a subset of children progresses to persistent asthma. We hypothesized that early-life wheeze reflects divergent airway epithelial maturation trajectories associated with distinct mucosal immune programs. METHODS: Nasal epithelial transcriptomes from 265 children and young adults (79 healthy, 81 wheezers, 105 asthmatics; median age 10.4 [1.1-20.3] years) from the All Age Asthma Cohort (ALLIANCE) cohort were analyzed using a hypothesis-driven candidate approach based on predefined cytokine axes. Transcriptional signatures were mapped to epithelial cells by scRNA-sequencing. Asthma-outcome associations were assessed in age- and sensitization-adjusted multivariate models. RESULTS: The candidate approach identified three antagonistic epithelial immune programs: an interferon-associated (E1; IDO1, CSF3, CCL20), a type-2-associated (E2; POSTN, CCL26, CST1), and a type-17-associated program (E3; IL36G, KLK7, KRTDAP). These programs were detected across basal, ciliated, and secretory epithelial cells. In early childhood (1-3 years), wheezers predominantly exhibited E1/E3-dominant epithelial profiles (n = 36). Age-group-specific comparisons showed higher E2 and lower E1/E3 expression in wheezers aged 4-6 years (n = 38) than in those aged 1-3 years (n = 36). E2 dominance correlated with IgE, FeNO, and eosinophilia (p < 0.01). In multivariate models assessing asthma outcome at age 6, E1 expression was inversely associated with asthma persistence (OR = 0.15, p < 0.05), whereas E3 expression was associated with disease progression (OR = 4.93, p < 0.05). The combined epithelial signature discriminated asthma outcomes with high accuracy (AUC = 0.90), independent of allergic sensitization. CONCLUSION: Early-life wheeze reflects distinct airway epithelial immune programs characterized by age-associated patterns in epithelial immune activity. Nasal epithelial transcriptional signatures capture molecular trajectories associated with asthma persistence and may enable early risk stratification. TRIAL REGISTRATION: All-Age-Asthma (ALLIANCE) cohort: clinicaltrials.gov: NCT02496468; adult arm: NCT02419274.
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