Airway Hyperresponsiveness Reflects Corticosteroid-Sensitive Mast Cell Involvement Across Asthma Phenotypes.

BACKGROUND: Airway hyperresponsiveness is a hallmark of asthma across asthma phenotypes. Airway hyperresponsiveness to mannitol specifically relates to mast cell infiltration of the airways, suggesting inhaled corticosteroids to be effective in reducing the response to mannitol, despite low levels of type 2 inflammation.

OBJECTIVE: The aim of the RECONSTRUCT study was to investigate the relationship between airway hyperresponsiveness and infiltrating mast cells, and the response to inhaled corticosteroid treatment.

METHODS: In 50 corticosteroid-free patients with airway hyperresponsiveness to mannitol, mucosal cryobiopsies were obtained before and after 6 weeks daily treatment with 1600μg budesonide. Patients were stratified according to baseline FeNO with a cut-off of 25ppb.

RESULTS: Airway hyperresponsiveness was comparable at baseline and improved equally with treatment in both FeNO-high and FeNO-low asthma: doubling dose: 3.98 (95% CI:2.49-6.38, P<0.001) and 3.85 (95% CI: 2.51-5.91, P<0.001), respectively. However, phenotypes and distribution of mast cells differed between the two groups: In FeNO-high asthma, Airway hyperresponsiveness correlated to the density of chymase high mast cells infiltrating the epithelial layer (ρ: -0.42 P= 0.04), and in FeNO-low asthma, to the density in airway smooth muscle (ρ: -0.51, P=0.02). The improvement in airway hyperresponsiveness after inhaled corticosteroids correlated with a reduction in mast cells, as well as in airway TSLP and IL33.

CONCLUSIONS: Airway hyperresponsiveness to mannitol is related to mast cell infiltration across asthma phenotypes, correlating with epithelial mast cells in FeNO-high asthma, and airway smooth muscle mast cells in FeNO-low asthma. Treatment with inhaled corticosteroids was effective in reducing airway hyperresponsiveness in both groups.