Fractional Exhaled Nitric Oxide Guided-Therapy in Chronic Obstructive Pulmonary Disease: A Stratified, Randomized, Controlled Trial

Abstract

Introduction: Chronic obstructive pulmonary disease (COPD) with eosinophilic airway inflammation represents a distinct phenotype that might respond to treatment with inhaled corticosteroids. Fractional exhaled nitric oxide (FENO) might predict eosinophilic inflammation and guide treatment option. We hypothesized that COPD patients with different baseline levels of FENO might have differentiated response to treatment with salmeterol/fluticasone (SFC) or tiotropium (TIO).

Methods: This open-label, randomized-controlled trial enrolled treatment-naïve COPD patients who were stratified into high- (≥23.5ppb) and low-FENO group, followed by 12-week treatment with SFC or TIO. A linear mixed model with repeated measures was applied to analyze the changes in FENO (primary outcome), COPD assessment test (CAT) score, FEV₁, and parameters in induced sputum and blood after treatment.

Results: 134 patients were divided into 4 subgroups: low-FENO/SFC (n=30), low-FENO/TIO (n=29), high-FENO/SFC (n=37), and high-FENO/TIO (n=38). At baseline, FENO 23.5ppb clearly differentiated between eosinophilic and non-eosinophilic inflammation groups based on the eosinophils in induced sputum and blood. FENO significantly correlated with sputum and blood eosinophils at baseline. High-FENO/SFC (vs. high-FENO/TIO) subgroup had significant reduction in FENO and sputum inflammation profiles (including eosinophils, macrophages, matrix metalloproteinase-9, and interlukin-8) after treatment. These differences were not replicated between low-FENO/SFC and low-FENO/TIO subgroups. The improvement in CAT and FEV₁ after treatment was indiscriminate between SFC and TIO in the low- and high-FENO groups.

Conclusion: High baseline FENO can serve as an indicator of eosinophilic airway inflammation in COPD patients who may respond favorably to treatment with inhaled corticosteroids/long-acting β₂-agonists.

Trial registration number: ClinicalTrials.gov Identifier: NCT02546349.

Keywords: Acute exacerbation; Chronic obstructive pulmonary disease; Eosinophilic airway inflammation; Fractional exhaled nitric oxide; Inhaled corticosteroid.