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. 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.
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.
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.
Authors: Andrew Menzies-Gow; David J Jackson; Mona Al-Ahmad; Eugene R Bleecker; Francisco de Borja G Cosio Piqueras; Stephen Brunton; Giorgio Walter Canonica; Charles K N Chan; John Haughney; Steve Holmes; Janwillem Kocks; Tonya Winders Journal: Adv Ther Date: 2022-10-17 Impact factor: 4.070