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Published on: August 7, 2017
Lower airway immunophenotyping in severe preschool wheeze reveals distinct clusters described by heterogeneity in
Katie L Bonner1, Sara Fontanella1,2, Mindy Gore1,2
1Inflammation Repair and Development Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Insights
Recurrent severe wheeze (RSW) in children shows varied airway inflammation. Bacterial infection links to specific neutrophil types, suggesting new treatment strategies for childhood asthma.
Area of Science:
- Pediatric Pulmonology
- Immunology
- Asthma Research
Background:
- Recurrent preschool wheeze is a major cause of childhood asthma hospitalizations.
- Current treatments, including inhaled corticosteroids (ICS), are often ineffective for this condition.
Purpose of the Study:
- To investigate the lower airway immune cell composition in children with recurrent severe wheeze (RSW).
- To correlate immune cell profiles with infection status, allergic sensitization, and treatment regimens.
Main Methods:
- Clinical phenotyping and bronchoscopy were performed on 106 children (aged 1-5 years) with RSW.
- Multi-parameter flow cytometry analyzed blood and bronchoalveolar lavage (BAL) leukocytes.
- Unsupervised analysis identified distinct clusters of airway inflammation.
Main Results:
- Immune cell composition was similar between sensitized and non-sensitized children.
- Non-sensitized children showed higher rates of positive BAL bacterial cultures.
- Bacterial infection correlated with neutrophils expressing low CD62L and CXCR2; absence of infection showed high expression.
- Three inflammation clusters emerged: Cluster 1 (infection, CD62Llo neutrophils), Cluster 2 (eosinophil/lymphocyte-rich, CD62Lhi neutrophils), Cluster 3 (low infection, CD62Lhi neutrophils).
Conclusions:
- Airway inflammation in RSW is heterogeneous, characterized by distinct neutrophil subtypes.
- Bacterial infection is associated with CD62Llo neutrophils, while other clusters have CD62Lhi neutrophils.
- Stratifying RSW patients by these identified clusters could lead to novel therapeutic approaches.
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.
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