Recurrent Severe Preschool Wheeze: From Prespecified Diagnostic Labels to Underlying Endotypes

Area of Science:

• Pediatric Pulmonology
• Respiratory Medicine
• Microbiology

Background:

• Preschool wheezing is a heterogeneous condition with poorly understood underlying mechanisms.
• Distinguishing between different wheezing phenotypes is crucial for effective management.

Purpose of the Study:

• To investigate lower airway inflammation and infection in preschool children with recurrent severe wheeze (RSW) and nonwheezing respiratory disease (NWRD).
• To identify distinct pathophysiological clusters within preschool wheezing using data-driven analyses.

Main Methods:

• Recruited 136 children (aged 1-5 years) with RSW or NWRD undergoing elective bronchoscopy and bronchoalveolar lavage (BAL).
• Compared lower airway inflammation and infection markers between clinical diagnoses.
• Utilized the Partition around Medoids algorithm to identify pathophysiological clusters.

Main Results:

• Recurrent severe wheeze (RSW) was associated with higher blood eosinophil counts and allergic sensitization compared to NWRD.
• Pathogen distribution differed, with higher rhinovirus in RSW and Moraxella in sensitized RSW.
• Four distinct pathophysiological clusters were identified: atopic, nonatopic with low infection/high ICS use, nonatopic with high infection, and nonatopic with low infection/no ICS use.
• Cluster allocation significantly differed between RSW and NWRD groups, with NWRD predominantly in cluster 4.

Conclusions:

• Four distinct clusters of severe preschool wheeze were identified.
• These clusters are differentiated by sensitization, peripheral eosinophilia, lower airway neutrophilia, and specific bacterial findings.
• The findings provide a framework for understanding the heterogeneity of preschool wheezing.