Recurrent wheezing as a mediator between early-life exposures and childhood asthma: a mediation analysis in an Italian primary care paediatric cohort.

Introduction: Asthma represents a significant global public health concern, especially in children, due to its high prevalence and burden on the healthcare system. Early-life exposures, particularly to antibiotics and bronchiolitis, have been independently linked to an increased risk of wheezing and subsequent asthma. Despite extensive research on these risk factors, their interplay and combined impact throughout early childhood remains unclear. This study aims to clarify these relationships by investigating the mediating role of recurrent wheezing in the inception of childhood asthma. Methods: A retrospective birth-cohort study was conducted using data from the Italian Pedianet database, including children followed for at least 5 years. Exposure to antibiotics and bronchiolitis during the first year, episodes of wheezing between ages 1-4, and asthma diagnoses from age 5 onward were identified in outpatient records. Mediation analysis assessed the association between early-life exposures and asthma risk, with recurrent wheezing considered a potential mediator. Results: Among 121 255 children, 2.33% developed asthma after age 5. Our results support the hypothesis that early-life bronchiolitis and antibiotic use increase asthma risk through an indirect pathway mediated by recurrent wheezing, which accounts for the majority of the effect (up to 74%), and a direct pathway, independent of wheezing, which may reflect mechanisms such as immune dysregulation, airway remodelling or microbiome alterations. The strong mediated component underscores recurrent wheezing as a clinically relevant marker and key target for preventive strategies. Nonetheless, the presence of a residual direct effect suggests that interventions focusing exclusively on wheezing may not entirely eliminate asthma risk (up to 70%), even though they could substantially reduce it. Conclusions: Our findings highlight the importance of preventing bronchiolitis and wheezing to reduce asthma incidence, supporting antibiotic stewardship and respiratory syncytial virus immunisation as public health interventions.