Abstract
Background Greater precision in asthma exacerbation risk prediction may improve outcomes. We sought to identify clinical characteristics and biomarkers associated with elevated exacerbation risk in patients with severe, uncontrolled asthma.
Methods Data were pooled from seven similarly designed Phase II and III randomized controlled clinical trials of biologic therapies for the treatment of severe, uncontrolled asthma that enrolled comparable patient populations. Annualized asthma exacerbation rates (AAERs) for patients randomized to placebo were assessed by baseline clinical characteristics and by biomarker concentrations at baseline and over the study duration.
Results The AAER for the 2016 patients in the combined placebo group was 0.91 (95% CI 0.84‒0.98). Baseline characteristics associated with greater AAER were frequent or severe exacerbations within the prior 12 months, nasal polyposis, maintenance oral corticosteroid use, Asian race, and Asian or Western European region. AAER increased with baseline blood eosinophil counts and fractional exhaled nitric oxide (FeNO) concentration, with the greatest AAER occurring for patients with eosinophils ≥300 cells·μL−1 and FeNO ≥50 ppb. No relationship was observed between baseline serum immunoglobulin E concentration and AAER. Combining type 2 inflammation criteria for eosinophils and FeNO had greater prognostic value than either biomarker alone. Persistent eosinophil and FeNO elevations throughout the study period were associated with greater AAER.
Conclusions Exacerbation history, maintenance corticosteroid use, nasal polyposis, Asian race, geographic region, and elevations in blood eosinophil counts and FeNO concentrations (particularly when combined and/or persistently achieving type 2 inflammation criteria) were associated with increased exacerbation risk in patients with severe, uncontrolled asthma.
Footnotes
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Conflict of interest: Dr. Kraft reports grants from National Institutes of Health, grants and consulting fees from Sanofi, grants from ALA, grants from Chiesi Farmaceutici, personal fees from Elsevier, grants and consulting fee from AstraZeneca, outside the submitted work.
Conflict of interest: Dr. Brusselle reports personal fees and Advisory Board Member from AzstraZeneca, personal fees and Advisory Board Member from Boehringer Ingelheim, personal fees from Chiesi, personal fees and Advisory Board Member from GlaxoSmithKline, personal fees and Advisory Board Member from Novartis, personal fees from Pfizer, personal fees and Advisory Board Memberfrom Teva, Advisory Board Member from Sanofi/Regeneron, outside the submitted work.
Conflict of interest: Dr. FitzGerald reports personal fees and advisory board member from AstraZeneca, personal fees and advisory board member from Boehringer Ingelheim, personal fees and advisory board member from Novartis, advisory board member from Sanofi-Regeneron, advisory board member from Teva, personal fees from GSK, outside the submitted work.
Conflict of interest: In the last 5 years I. D. Pavord has received speaker's honoraria for speaking at sponsored meetings from AstraZeneca, Boehringer Ingelheim, Aerocrine AB, Almirall, Novartis, Teva, Chiesi, Sanofi/Regeneron, Menarini, and GSK, and payments for organizing educational events from AstraZeneca, GSK, Sanofi/Regeneron, and Teva. He has received honoraria for attending advisory panels with Genentech, Sanofi/Regeneron, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Teva, Merck, Circassia, Chiesi, and Knopp, and payments to support FDA approval meetings from GSK. He has received sponsorship to attend international scientific meetings from Boehringer Ingelheim, GSK, AstraZeneca, Teva, and Chiesi. He has received a grant from Chiesi to support a phase 2 clinical trial in Oxford. He is co-patent holder of the rights to the Leicester Cough Questionnaire and has received payments for its use in clinical trials from Merck, Bayer, and Insmed. In 2014-5 he was an expert witness for a patent dispute involving AstraZeneca and Teva.
Conflict of interest: Mr. Keith reports as an employee of AstraZeneca, during the conduct of the study.
Conflict of interest: Dr. Fagerås reports as an employee from AstraZeneca, during the conduct of the study.
Conflict of interest: Dr. Garcia Gil reports as an employee from AstraZeneca, during the conduct of the study.
Conflict of interest: Dr. Hirsch reports as an employee from AstraZeneca, during the conduct of the study.
Conflict of interest: Dr. Goldman reports as a former employee of AstraZeneca, during the conduct of the study.
Conflict of interest: Dr. Colice reports as an employee of AstraZeneca, and owns stock in AstraZeneca during the conduct of the study.
- Received February 9, 2021.
- Accepted April 21, 2021.
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