Lower airway immunophenotyping in severe preschool wheeze reveals distinct clusters described by heterogeneity in neutrophil phenotypes
American Journal of Respiratory and Critical Care Medicine, 2026
Bonner K., Fontanella S., Gore M., Cook J., Hoffland A., Scotney E., Tian K., Hillson K., Shamji M., Layhadi J., Al-Kuwari H., Bush A., Custovic A., Lloyd C., Saglani S.,
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Respiratory Diseases Immunological & Inflammatory Diseases | Patient Stratification | BALF |  Olink Target 96 |
Abstract
Rationale
Recurrent preschool wheeze accounts for most childhood hospitalisations for asthma and often responds poorly to inhaled corticosteroids (ICS).
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 1–5 years underwent clinical phenotyping, bronchoscopy, multi-parameter flow cytometry of blood and bronchoalveolar lavage (BAL) to characterise 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 non-sensitized children. However, significantly more non-sensitized 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; Cluster 3, low infection rate with CD62Lhi neutrophils. The clusters were independent of clinical features, prescribed ICS, antibiotics and allergic sensitization.
Conclusions
Airway inflammation in RSW is heterogeneous. A sub-group have airway neutrophilia, but with distinct neutrophil subtypes. Those with bacterial infection had CD62Llo neutrophils (Cluster 1). Others had CD62Lhi neutrophils (Clusters 2 & 3). Intervention trials stratifying using these clusters may provide a novel management approach.