Prognostic Interaction Between Inflammatory and Clinical Risk Factors for Asthma Attacks: Findings from the ORACLE2 Patient-level Meta-analysis
American Journal of Respiratory and Critical Care Medicine, vol. 211, pp. A7065
Abstract
Abstract INTRODUCTION: Preventing attacks is a key goal in asthma management. The type-2 inflammatory biomarkers blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO) are established and modifiable risk factors. Given the complexity and multifaceted nature of asthma, we hypothesized that their prognostic value might vary based on interactions with clinical risk factors. METHODS: We analyzed data from the OxfoRd Asthma attaCk risk scaLE (ORACLE2) patient-level meta-analysis, which includes placebo participants from 22 randomized controlled trials (RCTs) investigating the effects of fixed treatment regimens on severe asthma attack rates over a minimum of 24 weeks. Multiple imputation by chained equations was used for missing values in 10 iterations. Multivariable negative binomial models were fit to assess interactions between inflammatory biomarkers (FeNO and BEC) and other key risk factors, such as the Global Initiative for Asthma (GINA) treatment step, Asthma Control Questionnaire (ACQ)-5 score, attack history, and forced expiratory volume in 1 second (FEV1). A Benjamini-Hochberg procedure adjusted for multiplicity of testing (false discovery rate (FDR)<0.05 significant). Spline curves were plotted to visualize significant interactions. As an exploratory analysis, other potential interactions between asthma attacks risk factors and baseline characteristics were evaluated (FDR<0.05). RESULTS: The 6,513 analysed participants experienced 4615 attacks over 5482 person·years. BEC (per 10-fold increase) was found to interact with FEV1 (per 10% decrease) (interaction term: 1.11 [1.03; 1.21], p-value = 0.01). FeNO (per 10-fold increase) negatively interact with a low treatment step (GINA step 1-2 versus GINA step 3-5) (0.28 [0.11; 0.68], p-value = 0.005) and positively interact with a history of severe attacks in the last 12 months (2.42 [1.51; 3.87], p-value = 2×10⁻⁴). The spline curves illustrated the prognostic value of these inflammatory biomarkers according to subgroups based on the identified interactions (Figure A-C). In an exploratory analysis, a strong positive interaction between Immunoglobulin E (IgE) (per 10-fold increase) and a positive history of nasal polyposis was identified (1.58 [1.25; 1.98], p-value = 9×10⁻⁵). The spline curve illustrated the dichotomous prognostic value of IgE on asthma attack risk according to the presence (n=584) or absence (n=3522) of nasal polyposis (Figure D). CONCLUSIONS: This analysis underscores the complex interactions between inflammatory biomarkers and other asthma attack risk factors. The prognostic value of BEC is stronger in those with reduced lung function, while FeNO's prognostic value depends on recent attack history and treatment step. A potential prognostic interaction between IgE and nasal polyposis was also identified. Registration:PROSPERO-CRD42021245337
Authors 27
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Affiliation as printed
Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, QC, Canada
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Leiden University · Leiden University Medical Center
Affiliation as printed
Biomedical Data Sciences, Leiden University Medical Centre, Leiden, Netherlands
Biomedical Data Sciences, Leiden University Medical Centre, Leiden, Netherlands
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Affiliation as printed
Respirology, University of Sherbrooke, Sherbrooke, QC, Canada
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Affiliation as printed
Pulmonology, Hôpital Fleurimont (CHUS), Sherbrooke, QC, Canada
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Affiliation as printed
Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, QC, Canada
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The University of Western Australia · Institute for Respiratory Health
Affiliation as printed
Institute for Respiratory Health, University of Western Australia, Nedlands, Australia
Institute for Respiratory Health, University of Western Australia, Nedlands, Australia
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Affiliation as printed
National Jewish Health, Denver, CO, United States
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Affiliation as printed
Respiratory Medicine, Ghent University Hospital, Gent, Belgium
Respiratory Medicine, Ghent University Hospital, Gent, Belgium
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University of California, Los Angeles
Affiliation as printed
UCLA, Los Angeles, CA, United States
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Medical Research Institute of New Zealand
Affiliation as printed
Medical Research Institute of New Zealand, Wellington, New Zealand
Medical Research Institute of New Zealand, Wellington, New Zealand
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NIHR Leicester Biomedical Research Centre
Affiliation as printed
Department of Respiratory Sciences, Institute for Lung Health, NIHR Respiratory BRC, Leicester, United Kingdom
Department of Respiratory Sciences, Institute for Lung Health, NIHR Respiratory BRC, Leicester, United Kingdom
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Affiliation as printed
Infection, Immunity, Inflammation, University of Leicester, Maurice Shock Medical School, Leicester, United Kingdom
Infection, Immunity, Inflammation, University of Leicester, Maurice Shock Medical School, Leicester, United Kingdom
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Affiliation as printed
Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, United States
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Guy's Hospital · Guy's and St Thomas' NHS Foundation Trust
Affiliation as printed
Dept of Respiratory Medicine, Guy's & St Thomas’ NHS Trust, London, United Kingdom
Dept of Respiratory Medicine, Guy's & St Thomas' NHS Trust, London, United Kingdom
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Affiliation as printed
AstraZeneca, Cambridge, United Kingdom
AstraZeneca,, Cambridge, United Kingdom
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GlaxoSmithKline (United Kingdom)
Affiliation as printed
Faculté de médecine et des sciences de la santé, Formerly GlaxoSmithKline, London, United Kingdom
Faculté de médecine et des sciences de la santé, Formerly GlaxoSmithKline, London, United Kingdom
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Affiliation as printed
GSK, Epping, United Kingdom
GSK, Epping, United Kingdom
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Affiliation as printed
Sanofi US, Cambridge, MA, United States
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Affiliation as printed
Genentech, South San Francisco, CA, United States
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Affiliation as printed
Formerly Genentech, South San Francisco, CA, United States
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Affiliation as printed
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
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Medical Research Institute of New Zealand
Affiliation as printed
Medical Research Inst of New Zealand, Wellington, New Zealand
Medical Research Inst of New Zealand, Wellington, New Zealand
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Leiden University · Leiden University Medical Center
Affiliation as printed
Biomedical Data Sciences, Leiden University Medical Centre, Leiden, Netherlands
Biomedical Data Sciences, Leiden University Medical Centre, Leiden, Netherlands
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Leiden University · Leiden University Medical Center
Affiliation as printed
Biomedical Data Sciences, Leiden University Medical Centre, Leiden, Netherlands
Biomedical Data Sciences, Leiden University Medical Centre, Leiden, Netherlands
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Affiliation as printed
Respiratory Medicine Unit, University of Oxford, Oxford, United Kingdom
Respiratory Medicine Unit, University of Oxford, Oxford, United Kingdom
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Affiliation as printed
Respirology, Université de Sherbrooke, Sherbrooke, QC, Canada
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