Longitudinal trajectories of severe wheeze exacerbations from infancy to school age and their association with early-life risk factors and late asthma outcomes

Introduction: Exacerbation-prone asthma subtype has been reported in studies using data-driven methodologies. However, patterns of severe exacerbations have not been studied. Objective: To investigate longitudinal trajectories of severe wheeze exacerbations from infancy to school age. Methods: We applied longitudinal k-means clustering to derive exacerbation trajectories among 887 participants from a population-based birth cohort with severe wheeze exacerbations confirmed in healthcare records. We examined early-life risk factors of the derived trajectories, and their asthma-related outcomes and lung function in adolescence. Results: 498/887 children (56%) had physician-confirmed wheeze by age 8 years, of whom 160 had at least one severe exacerbation. A two-cluster model provided the optimal solution for severe exacerbation trajectories among these 160 children: “Infrequent exacerbations (IE)” (n = 150, 93.7%) and “Early-onset frequent exacerbations (FE)” (n = 10, 6.3%). Shorter duration of breastfeeding was the strongest early-life risk factor for FE (weeks, median [IQR]: FE, 0 [0-1.75] vs. IE, 6 [0-20], P <.001). Specific airway resistance (sR_aw) was significantly higher in FE compared with IE trajectory throughout childhood. We then compared children in the two exacerbation trajectories with those who have never wheezed (NW, n = 389) or have wheezed but had no severe exacerbations (WNE, n = 338). At age 8 years, FEV₁/FVC was significantly lower and FeNO significantly higher among FE children compared with all other groups. By adolescence (age 16), subjects in FE trajectory were significantly more likely to have current asthma (67% FE vs. 30% IE vs. 13% WNE, P <.001) and use inhaled corticosteroids (77% FE vs. 15% IE vs. 18% WNE, P <.001). Lung function was significantly diminished in the FE trajectory (FEV₁/FVC, mean [95%CI]: 89.9% [89.3-90.5] vs. 88.1% [87.3-88.8] vs. 85.1% [83.4-86.7] vs. 74.7% [61.5-87.8], NW, WNE, IE, FE respectively, P <.001). Conclusion: We have identified two distinct trajectories of severe exacerbations during childhood with different early-life risk factors and asthma-related outcomes in adolescence.