Cluster Analysis of Inflammatory Biomarker Expression in the International Severe Asthma Registry

Eve Denton; David B Price; Trung N Tran; G Walter Canonica; Andrew Menzies-Gow; J Mark FitzGerald; Mohsen Sadatsafavi; Luis Perez de Llano; George Christoff; Anna Quinton; Chin Kook Rhee; Guy Brusselle; Charlotte Ulrik; Njira Lugogo; Fiona Hore-Lacy; Isha Chaudhry; Lakmini Bulathsinhala; Ruth B Murray; Victoria A Carter; Mark Hew

doi:10.1016/j.jaip.2021.02.059

Cluster Analysis of Inflammatory Biomarker Expression in the International Severe Asthma Registry

J Allergy Clin Immunol Pract. 2021 Jul;9(7):2680-2688.e7. doi: 10.1016/j.jaip.2021.02.059. Epub 2021 Mar 18.

Authors

Eve Denton¹, David B Price², Trung N Tran³, G Walter Canonica⁴, Andrew Menzies-Gow⁵, J Mark FitzGerald⁶, Mohsen Sadatsafavi⁷, Luis Perez de Llano⁸, George Christoff⁹, Anna Quinton¹⁰, Chin Kook Rhee¹¹, Guy Brusselle¹², Charlotte Ulrik¹³, Njira Lugogo¹⁴, Fiona Hore-Lacy¹⁵, Isha Chaudhry¹⁶, Lakmini Bulathsinhala¹⁶, Ruth B Murray¹⁶, Victoria A Carter¹⁶, Mark Hew¹⁵

Affiliations

¹ Allergy, Asthma, and Clinical Immunology, Alfred Health, Melbourne, Australia; Public Health and Preventive Medicine, Monash University, Melbourne, Australia. Electronic address: e.denton@alfred.org.au.
² Optimum Patient Care, Cambridge, UK; Observational and Pragmatic Research Institute, Singapore, Singapore; Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.
³ AstraZeneca, Gaithersburg, Md.
⁴ Personalized Medicine, Asthma and Allergy, Humanitas Clinical and Research Center IRCCS, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
⁵ UK Severe Asthma Network and National Registry, Royal Brompton and Hareﬁeld NHS Foundation Trust, London, UK.
⁶ The Centre for Heart Lung Health, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.
⁷ Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
⁸ Department of Respiratory Medicine, Hospital Universitario Lucus Augusti, Lugo, Spain.
⁹ Faculty of Public Health, Medical University of Sofia, Sofia, Bulgaria.
¹⁰ AstraZeneca, Cambridge, UK.
¹¹ Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
¹² Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium; Department of Epidemiology and Respiratory Medicine, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
¹³ Department of Respiratory Medicine, Hvidovre Hospital, Hvidovre, Denmark.
¹⁴ Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Mich.
¹⁵ Allergy, Asthma, and Clinical Immunology, Alfred Health, Melbourne, Australia; Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
¹⁶ Optimum Patient Care, Cambridge, UK.

PMID: 33744476
DOI: 10.1016/j.jaip.2021.02.059

Abstract

Background: Allergy, eosinophilic inflammation, and epithelial dysregulation are implicated in severe asthma pathogenesis.

Objective: We characterized biomarker expression in adults with severe asthma.

Methods: Within the International Severe Asthma Registry (ISAR), we analyzed data from 10 countries in North America, Europe, and Asia, with prespecified thresholds for biomarker positivity (serum IgE ≥ 75 kU/L, blood eosinophils ≥ 300 cells/μL, and FeNO ≥ 25 ppb), and with hierarchical cluster analysis using biomarkers as continuous variables.

Results: Of 1,175 patients; 64% were female, age (mean ± SD) 53 ± 15 years, body mass index (BMI) 30 ± 8, postbronchodilator forced expiratory volume in 1 second (FEV₁) predicted 72% ± 20%. By prespecified thresholds, 59% were IgE positive, 57% eosinophil positive, and 58% FeNO positive. There was substantial inflammatory biomarker overlap; 59% were positive for either 2 or 3 biomarkers. Five distinct clusters were identified: cluster 1 (61%, low-to-medium biomarkers) comprised highly symptomatic, older females with elevated BMI and frequent exacerbations; cluster 2 (18%, elevated eosinophils and FeNO) older females with lower BMI and frequent exacerbations; cluster 3 (14%, extremely high FeNO) older, highly symptomatic, lower BMI, and preserved lung function; cluster 4 (6%, extremely high IgE) younger, long duration of asthma, elevated BMI, and poor lung function; cluster 5 (1.2%, extremely high eosinophils) younger males with low BMI, poor lung function, and high burden of sinonasal disease and polyposis.

Conclusions: There is significant overlap of biomarker positivity in severe asthma. Distinct clusters according to biomarker expression exhibit unique clinical characteristics, suggesting the occurrence of discrete patterns of underlying inflammatory pathway activation and providing pathogenic insights relevant to the era of monoclonal biologics.

Keywords: Biomarkers; Eosinophils; Fractional exhaled nitric oxide; Immunoglobulin E; Severe asthma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Asthma* / diagnosis
Asthma* / epidemiology
Biomarkers
Cluster Analysis
Eosinophils
Europe
Female
Humans
Male
Middle Aged
Nitric Oxide* / analysis
North America
Registries

Substances

Biomarkers
Nitric Oxide