PERSISTENT indirect airway hyperresponsiveness (PIAHR) after six weeks of high-dose inhaled corticosteroids (ICS) identified a subgroup of patients with asthma who exhibited greater Type 2 (T2) inflammation and increased airway mast cell burden, according to a post-hoc analysis of the RECONSTRUCT study.
The findings suggest that persistent indirect airway hyperresponsiveness may indicate incomplete suppression of airway inflammation despite intensive corticosteroid treatment. Researchers investigated the clinical, inflammatory, and tissue characteristics associated with persistent responses to mannitol, an osmotic stimulus used to assess airway hyperresponsiveness (AHR).
The analysis included corticosteroid-free patients with asthma and confirmed AHR to mannitol. Participants underwent clinical assessments and bronchoscopy before and after six weeks of treatment with 1600 μg of inhaled budesonide daily. Patients were classified as responders if AHR was abolished, or incomplete responders if AHR persisted following treatment.
Following six weeks of high-dose ICS, 11 of 46 patients (24%) continued to demonstrate indirect AHR to mannitol.
At baseline, incomplete responders exhibited more severe AHR alongside higher T2 inflammatory biomarker levels. These included fractional exhaled nitric oxide (FeNO), blood eosinophils, and sputum eosinophils. Researchers also identified a higher density of chymase-positive mast cells in the airways of incomplete responders.
Baseline AHR severity emerged as the strongest predictor of an incomplete response to corticosteroid treatment, highlighting the potential value of assessing airway responsiveness before initiating intensive treatment.
Although T2 inflammatory markers decreased in both groups following treatment, incomplete responders continued to demonstrate higher blood and sputum eosinophil levels than responders.
Airway mast cell and eosinophil densities decreased similarly across both groups. However, reductions in blood eosinophils were smaller among incomplete responders, suggesting that systemic inflammatory activity remained comparatively elevated despite treatment.
These findings associate persistent indirect airway hyperresponsiveness with incomplete suppression of T2 inflammation and mast cell-associated features.
The findings suggest that indirect AHR to mannitol could provide a repeatable outcome measure for identifying patients with ongoing airway inflammation despite high-dose ICS treatment.
Persistent indirect airway hyperresponsiveness may therefore represent a clinically relevant treatable trait, helping clinicians recognise patients who require closer follow-up.
Further targeted treatment may be appropriate for patients whose airway inflammation remains incompletely controlled with ICS alone. The researchers highlighted the potential of mannitol responsiveness to support the identification of this subgroup and inform more targeted approaches to asthma management.
Reference
Bari EJ et al. Persistent indirect airway hyperresponsiveness after six weeks of high-dose inhaled corticosteroids identifies a subgroup with higher T2 inflammation and mast cell burden. JACI. 2026;DOI:10.1016/j.jaci.2026.09.036.
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