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 randomised controlled clinical trials of biologic therapies for the treatment of severe, uncontrolled asthma that enrolled comparable patient populations. Annualised asthma exacerbation rates (AAERs) for patients randomised 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 exhaled nitric oxide fraction (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 IgE 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.
Abstract
A pooled analysis of placebo data from seven randomised controlled trials identified exacerbation risk factors in patients with severe, uncontrolled asthma and revealed a prognostic role for persistence of elevations in type 2 inflammation biomarkers https://bit.ly/3sWCKVd
Footnotes
This article has supplementary material available from erj.ersjournals.com
This article has an editorial commentary: https://doi.org/10.1183/13993003.01702-2021
Data sharing: Data underlying the findings described in this article may be requested in accordance with AstraZeneca's data-sharing policy described at https://astrazenecagroup-dt.pharmacm.com/DT/Home.
Author contributions: M. Kraft, M. Fagerås, E. Garcia Gil, I. Hirsch, M. Goldman and G. Colice were involved in the conception and design of the analysis. M. Kraft, G. Brusselle, J.M. FitzGerald, I.D. Pavord, M. Keith, M. Fagerås, E. Garcia Gil, I. Hirsch, M. Goldman and G. Colice were involved in the interpretation of data, reviewed and revised manuscript drafts, and approved the version submitted for publication. All authors had full access to the data and take responsibility for the accuracy and integrity of the work.
Conflict of interest: M. Kraft reports grants from the National Institutes of Health, grants and consulting fees from Sanofi, grants from ALA, grants from Chiesi Farmaceutici, personal fees from Elsevier, grants and consulting fees from AstraZeneca.
Conflict of interest: G. Brusselle has received honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Pfizer and Teva; and is a member of advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi/Regeneron and Teva.
Conflict of interest: J.M. FitzGerald is an advisory board member for AstraZeneca, Boehringer Ingelheim, Novartis, Sanofi-Regeneron and Teva, and has received honoraria for lectures from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Novartis.
Conflict of interest: 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 GlaxoSmithKline, and payments for organising educational events from AstraZeneca, GlaxoSmithKline, Sanofi/Regeneron and Teva; he has received honoraria for attending advisory panels with Genentech, Sanofi/Regeneron, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Teva, Merck, Circassia, Chiesi and Knopp, and payments to support FDA approval meetings from GlaxoSmithKline; he has received sponsorship to attend international scientific meetings from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Teva and Chiesi; he has received a grant from Chiesi to support a phase II 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 2014–2015 he was an expert witness for a patent dispute involving AstraZeneca and Teva.
Conflict of interest: M. Keith is an employee of AstraZeneca.
Conflict of interest: M. Fagerås is an employee of AstraZeneca.
Conflict of interest: E. Garcia Gil is an employee of AstraZeneca.
Conflict of interest: I. Hirsch is an employee of AstraZeneca.
Conflict of interest: M. Goldman is a former employee of AstraZeneca.
Conflict of interest: G. Colice is an employee of AstraZeneca.
Support statement: This work was supported by AstraZeneca. AstraZeneca was involved in study design; in the collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the article for publication. AstraZeneca and Amgen jointly funded the PATHWAY study for tezepelumab, which contributed placebo results data that were pooled with placebo data from other trials in this analysis. Writing and editing support, including preparation of the draft manuscript under the direction and guidance of the authors, incorporating author feedback, and manuscript submission, was also funded by AstraZeneca (Gaithersburg, MD, USA). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received February 9, 2021.
- Accepted April 21, 2021.
- Copyright ©The authors 2021. For reproduction rights and permissions contact permissions{at}ersnet.org
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