Lower airway immunophenotyping in severe preschool wheeze reveals distinct clusters described by heterogeneity in neutrophil phenotypes

RATIONALE: Recurrent preschool wheeze accounts for most childhood hospitalizations for asthma and often responds poorly to inhaled corticosteroids (ICSs). OBJECTIVE: To relate lower airway immune cell composition in children with recurrent severe wheeze (RSW) to infection, allergic sensitization, and prescribed treatments. METHODS: Children with RSW aged 1 to 5 years underwent clinical phenotyping, bronchoscopy, multiparameter flow cytometry of blood and bronchoalveolar lavage (BAL) to characterize leukocytes, and assessments of lower airway bacterial and viral infection. An unsupervised analysis was undertaken to uncover clusters of airway inflammation. MEASUREMENTS AND MAIN RESULTS: Of 106 children (median age 36.5 months), 32% had allergic sensitization. Lower airway immune cells were similar in type and abundance in sensitized and nonsensitized children. However, significantly more nonsensitized wheezers had positive BAL bacterial culture. Bacterial infection was associated with neutrophils with low CD62L and CXCR2 expression. Children without airway bacterial infection also had up to 50% neutrophils but with high CD62L and CXCR2 expression. The data-driven analysis revealed 3 clusters: cluster 1, airway infection predominant with CD62Llo neutrophils; cluster 2, eosinophil/lymphocyte rich with CD62Lhi neutrophils; and cluster 3, low infection rate with CD62Lhi neutrophils. The clusters were independent of clinical features, prescribed ICSs, antibiotics, and allergic sensitization. CONCLUSIONS: Airway inflammation in RSW is heterogeneous. A subgroup had airway neutrophilia but with distinct neutrophil subtypes. Those with bacterial infection had CD62Llo neutrophils (cluster 1). Others had CD62Lhi neutrophils (clusters 2 and 3). Intervention trials stratifying using these clusters may provide a novel management approach.