Early-preschool wheeze trajectories are predominantly nonallergic with distinct biologic and microbiome traits

BACKGROUND: Disentangling preschool wheezing heterogeneity in terms of clinical traits, temporal patterns, and collective health care burden is critical for precise and effective interventions. OBJECTIVE: We aimed to collectively define contributions and distinct characteristics of respiratory phenotypes based on longitudinal wheeze and atopic sensitization patterns in the first 5 years of life. METHODS: Group-based trajectory analysis was performed in the CHILD Cohort Study to identify distinct wheeze and allergic sensitization trajectories. Trajectories were evaluated for associated risk factors, health care utilization, biologic determinants, and clinical outcomes. Stool samples for shotgun metagenomic sequencing profiles of infant microbiomes collected at ages 3 months and 1 year were assessed for phenotype-specific biomarkers. RESULTS: A total of 6 distinct respiratory phenotypes were identified on the basis of samples from 2902 children; the phenotypes differed by temporal wheeze and allergic sensitization patterns. Although allergic wheeze phenotypes (found in 11.6% of participants) carried the highest risk of asthma diagnosis, the more common nonallergic phenotypes (in 88.3% of participants) contributed to the majority of 5-year asthma diagnoses (61.4% of diagnoses). Most importantly, nonallergic phenotypes accounted for more than two-thirds of health care utilization in this age group. Phenotypes differed by lung function, blood eosinophil counts, allergic comorbidities, and weight-for-age z score. Moreover, microbiome profiles developed from 1439 infants revealed that largely nonoverlapping microbial signatures at age 1 year are associated with each phenotype. CONCLUSION: We identified novel early-childhood respiratory phenotypes to disentangle nonoverlapping paths to preschool wheezing. Our findings highlight the continued clinical relevance of nonatopic wheeze phenotypes, which remain undertreated despite accounting for a substantial proportion of health care utilization and asthma diagnoses.