Raised FeNO in optimally-treated severe asthma identifies persistent eosinophilic chemotactic pull towards the airway

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Background: High fractional exhaled nitric oxide (FeNO) predicts asthma attacks, inhaled corticosteroid (ICS) responsiveness and non-adherence. We speculate that raised FeNO in optimally-treated asthma reflects unchecked airway inflammation. Methods: Induced sputum eosinophils (Eos) and supernatant cytokines/chemokines (Eotaxin-3, IL-4,-5,-13,-33, LTE4, PGD2, TSLP, IFN-γ, TNF; measured by MSD/ELISA) in patients with severe asthma were compared to controls. We included only patients on high-dose ICS after biomarker-guided management studies (RASP-UK or FeNO suppression). Analytes were stratified by two strategies: FeNO at cut-offs 25-50 ppb or blood Eos at cut-offs 0.15-0.3×109/L, then compared using Kruskal-Wallis tests adjusted for 12 comparisons. Results: Sputum from 63 patients with severe asthma and 10 controls was analysed. FeNO ≥50 vs <25 ppb was associated with higher median sputum Eos (13 vs 1%, P=0.02), Eotaxin-3 (353 vs 34 pg/mL, P=0.0005), IL-5 (11 vs 1 pg/mL, P=0.01), IL-4 (0.8 vs 0.1 pg/mL, P=0.005) and TSLP (12 vs 2 pg/mL, P=0.03). Spearman correlations were highest between FeNO and sputum eotaxin-3 (r=0.55) and sputum Eos (r=0.52). No differences were found between blood Eos strata (not shown). Results were similar when removing patients on systemic steroids. Conclusion: Raised FeNO in optimally-treated severe asthma identifies eosinophilic chemotactic pull towards the airway.

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