Children with neutrophil-predominant severe asthma have pro-inflammatory neutrophils with enhanced survival and impaired clearance

Publication date: Available online 5 September 2018

Source: The Journal of Allergy and Clinical Immunology: In Practice

Author(s): Jocelyn R. Grunwell, Susan T. Stephenson, Rabindra Tirouvanziam, Lou Ann S. Brown, Milton R. Brown, Anne M. Fitzpatrick

Background

Airway neutrophils are abundant in some children with severe asthma, but their functions are poorly understood.

Objective

We hypothesized that the inflammatory airway environment of children with neutrophil-predominant severe asthma promotes neutrophil survival and disrupts neutrophil-associated innate immune defenses.

Methods

Sixty seven children with severe asthma refractory to high-dose inhaled corticosteroid (ICS) treatment undergoing bronchoscopy with bronchoalveolar lavage (BAL) for clinical indications were stratified into neutrophil "high" versus "low" groups based on BAL differential counts. Neutrophil activation markers, functional assays and phenotyping studies were performed as well as airway macrophage functional assays. Results were compared to those from children with moderate asthma treated with ICS.

Results

Children with neutrophil-predominant severe asthma had increased markers of neutrophil activation/degranulation and a greater magnitude of airway pro-inflammatory cytokine and chemokine release. Primary neutrophils exposed to BAL of these children exhibited greater phagocytic capability and greater neutrophil extracellular trap formation, but a more impaired respiratory burst. Despite greater abundance of airway TGF-β1, the neutrophils were not more apoptotic. Instead, neutrophils had a highly pro-inflammatory phenotype associated with a number of surface markers that regulate neutrophil activation, recruitment/migration and granule release. Airway macrophages from children with neutrophil-predominant severe asthma were also more pro-inflammatory with impaired phagocytosis and increased apoptosis.

Conclusions

Children with neutrophil-predominant severe asthma have pro-inflammatory neutrophils with enhanced survival. Airway macrophages are also pro-inflammatory and dysfunctional and may contribute to global innate immune impairment. Therapies that target neutrophils and related inflammation may be warranted in this subset of children.