Baseline FeNO as a prognostic biomarker for subsequent severe asthma exacerbations in patients with uncontrolled, moderate-to-severe asthma receiving placebo in the LIBERTY ASTHMA QUEST study: a post-hoc analysis
- PMID: 34181876
- DOI: 10.1016/S2213-2600(21)00124-7
Baseline FeNO as a prognostic biomarker for subsequent severe asthma exacerbations in patients with uncontrolled, moderate-to-severe asthma receiving placebo in the LIBERTY ASTHMA QUEST study: a post-hoc analysis
Abstract
Background: Fractional exhaled nitric oxide (FeNO) has potential as a prognostic biomarker in asthma, but its prognostic value among other recognised indicators is unclear. We assessed the added prognostic value of baseline FeNO to blood eosinophil count and prior severe asthma exacerbations for subsequent exacerbations.
Methods: In this post-hoc analysis of the 52-week, double-blind, phase 3 LIBERTY ASTHMA QUEST study, we identified 620 patients with moderate-to-severe asthma who were randomly assigned to placebo; had uncontrolled asthma with inhaled glucocorticoids plus up to two controllers; one or more exacerbations in the previous year; FEV1 percent predicted 40-80%; FEV1 reversibility of 12% or higher and 200 mL; Asthma Control Questionnaire (ACQ-5) score of 1·5 or higher; and complete data on baseline type 2 biomarkers (FeNO, eosinophils, and total IgE) with no baseline minimum requirement. Annualised severe exacerbation rate was assessed by baseline FeNO (<25 ppb, ≥25 to <50 ppb, ≥50 ppb; negative binomial model) and cross-classified by baseline blood eosinophils (<150 cells per μL, ≥150 to <300 cells per μL, ≥300 cells per μL) and prior exacerbations (one, two or more), all adjusted for baseline ACQ-5, postbronchodilator FEV1, and other clinical characteristics. Post-hoc analyses were done in the intention-to-treat population. The LIBERTY ASTHMA QUEST STUDY is registered on ClinicalTrials.gov, NCT02414854, and is complete.
Findings: Patients with baseline FeNO of 50 ppb or higher (n=144) had a 1·54-times higher exacerbation rate than patients with FeNO of less than 25 ppb (n=291; relative risk 1·54 [95% CI 1·11-2·14]; p=0·0097). Patients with baseline FeNO of 25 to <50 ppb (n=185) had a 1·33-times higher exacerbation rate than patients with FeNO of less than 25 ppb (1·33 [0·99-1·78]; p=0·0572). Patients with baseline FeNO of 25 ppb or higher, a blood eosinophil count of 150 cells per μL or higher, and two or more prior exacerbations (n=157) had an exacerbation rate 3·62-times higher than patients with FeNO of less than 25 ppb, a blood eosinophil count of less than 150 cells per μL, and one prior exacerbation (n=116; 3·62 [1·67-7·81]; p=0·0011).
Interpretation: In uncontrolled, moderate-to-severe asthma, higher baseline FeNO levels were associated with greater risk of severe asthma exacerbations, particularly in combination with elevated eosinophil count and prior exacerbations, supporting the added value of FeNO as a prognostic biomarker. Further research is needed to confirm FeNO as an independent predictor for asthma exacerbations.
Funding: Sanofi and Regeneron Pharmaceuticals.
Copyright © 2021 Elsevier Ltd. All rights reserved.
Conflict of interest statement
Declaration of interests WWB declares consultant fees from AstraZeneca, Genentech, GlaxoSmithKline (GSK), Novartis, Regeneron Pharmaceuticals, and Sanofi, and is on the data safety monitoring board (DSMB) for Boston Scientific. SEW reports involvement in industry trials for AstraZeneca, Boehringer Ingelheim, GSK, Novartis, and Sanofi. TBC declares research support provided by American Lung Association, Genentech, Novartis, Patient-Centered Outcomes Research Institute, and Sanofi; was a consultant for AstraZeneca, Boehringer Ingelheim, Genentech, Novartis, and Regeneron Pharmaceuticals; was part of the speaker bureau for Genentech; and is on the DSMB for Novartis. JMF reports being an advisory board member for and receiving personal fees from American Lung Association, Boehringer Ingelheim, GSK, Novartis, Regeneron Pharmaceuticals, Sanofi, and Teva; received peer-review funding from AllerGen NCE, BC Lung Association, and Canadian Institutes of Health Research; had research funding paid directly to the University of British Columbia from AstraZeneca, Boehringer Ingelheim, GSK, Novartis, and Sanofi; and received speaker fees or honoraria from AstraZeneca, Boehringer Ingelheim, GSK, and Novartis. MSR, ND, NP, and PJR are employees of Sanofi. NMHG is a former employee and shareholder of Regeneron Pharmaceuticals. YD and SH are employees and shareholders of Regeneron Pharmaceuticals. TOR was a prior employee of Sanofi. IDP reports receiving speaker fees from Aerocrine, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Regeneron Pharmaceuticals, Sanofi, and Teva; received payments for organisation of educational events from AstraZeneca, GSK, Sanofi, Regeneron Pharmaceuticals, and Teva; received consultant fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Dey Pharma, Genentech, GSK, Knopp Biosciences, Merck, Merck Sharp & Dohme, Napp Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, RespiVert, Sanofi, Schering-Plough, and Teva; received international scientific meeting sponsorship from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Napp Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, and Teva; and reports a research grant from Chiesi.
Comment on
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Increasing utility of FeNO as a biomarker of type-2 inflammation in severe asthma.Lancet Respir Med. 2021 Oct;9(10):1083-1084. doi: 10.1016/S2213-2600(21)00170-3. Epub 2021 Jun 25. Lancet Respir Med. 2021. PMID: 34181878 No abstract available.
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