Cluster analysis of inflammatory biomarker expression in the International Severe Asthma Registry (ISAR)

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 (ISAR)

Eve Denton^* (Corresponding Author), 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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

55 Citations (Scopus)

3 Downloads (Pure)

Abstract

Background:
Allergy, eosinophilic inflammation, and epithelial dysregulation are implicated in severe asthma pathogenesis. We aimed to characterize 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 pre-specified thresholds for biomarker positivity (serum IgE ³75kU/L, blood eosinophils ³300 cells/uL, FeNO ³25ppb), 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, post-bronchodilator FEV 1 predicted 74±20%. By pre-specified thresholds, 59% were IgE positive, 57% eosinophil positive, and 58% FeNO positive.
Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation There was substantial overlap; 59% were positive for either two or three 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 sino-nasal 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.

Original language	English
Pages (from-to)	2680-2688.e7
Number of pages	16
Journal	The Journal of Allergy and Clinical Immunology: In Practice
Volume	9
Issue number	7
Early online date	18 Mar 2021
DOIs	https://doi.org/10.1016/j.jaip.2021.02.059
Publication status	Published - Jul 2021

Bibliographical note

Funding Information:
Conflicts of interest: D. B. Price has board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, Thermofisher; consultancy agreements with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals, Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca , Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma, Novartis; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; funding for patient enrollment or completion of research from Novartis; stock/stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp, which develops adherence monitoring technology; is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation Programme programme, and Health Technology Assessment Programme; and was an expert witness for GlaxoSmithKline. T. N. Tran and A. Quinton are employees of AstraZeneca, a cofunder of the International Severe Asthma Registry. M. Sadatsafavi has received honoraria from AstraZeneca for purposes unrelated to the content of this manuscript, and has also received research funding from AstraZeneca directly into his research account from AstraZeneca for unrelated projects. G. W. Canonica has received research grants, as well as lecture or advisory board fees from A. Menarini, Alk-Albello, Allergy Therapeutics, Anallergo, AstraZeneca, MedImmune, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia, Danone, Faes, Genentech, Guidotti Malesci, GlaxoSmithKline, Hal Allergy, Merck, MSD, Mundipharma, Novartis, Orion, Sanofi Aventis, Sanofi, Genzyme/Regeneron, Stallergenes, UCB Pharma, Uriach Pharma, Teva, Thermo Fisher, and Valeas. A. Menzies-Gow has attended advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi, and Teva, and has received speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, Roche, Teva, and Vectura; has participated in research with AstraZeneca for which his institution has been remunerated and has attended international conferences with Teva; had consultancy agreements with AstraZeneca, Sanofi, and Vectura. L. Perez de Llano declares nonfinancial support, personal fees, and grants from Teva ; nonfinancial support and personal fees from Boehringer Ingelheim, Esteve, GlaxoSmithKline, Mundipharma, and Novartis; personal fees and grants from AstraZeneca and Chiesi; personal fees from Sanofi; and nonfinancial support from Menairi outside the submitted work. C. K. Rhee declares consultancy and lecture fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mundipharma, MSD, Novartis, Sandoz, Takeda, and Teva-Handok, and Sanofi. G. Brusselle has received honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Teva; is a member of advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi/Regeneron, and Teva. C. Ulrik reports personal fees from AstraZeneca, GSK, TEVA, Novartis, Chiesi, Boehringer-Ingelheim, Sanofi, ALK-Abello, Orion Pharma, and Actelion, outside the submitted work. N. Lugogo consulted for AstraZeneca and GSK; on protocol committee with AstraZeneca; on advisory board with AstraZeneca, GSK, Sanofi, Novartis, Genentech, and Teva. I. Chaudhry, L. Bulathsinhala, and V. A. Carter are employees of Optimum Patient Care, a cofunder of the International Severe Asthma Registry. M. Hew declares grants and other advisory board fees (made to his institutional employer) from AstraZeneca, GlaxoSmithKline, Novartis, and Seqirus, for unrelated projects. The rest of the authors declare that they have no relevant conflicts of interest.

Funding Information:
Funding: ISAR is conducted by the Observational and Pragmatic Research Institute, and co-funded by Optimum Patient Care Global Ltd and AstraZeneca.Conflicts of interest: D. B. Price has board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, Thermofisher; consultancy agreements with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals, Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma, Novartis; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; funding for patient enrollment or completion of research from Novartis; stock/stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp, which develops adherence monitoring technology; is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation Programme programme, and Health Technology Assessment Programme; and was an expert witness for GlaxoSmithKline. T. N. Tran and A. Quinton are employees of AstraZeneca, a cofunder of the International Severe Asthma Registry. M. Sadatsafavi has received honoraria from AstraZeneca for purposes unrelated to the content of this manuscript, and has also received research funding from AstraZeneca directly into his research account from AstraZeneca for unrelated projects. G. W. Canonica has received research grants, as well as lecture or advisory board fees from A. Menarini, Alk-Albello, Allergy Therapeutics, Anallergo, AstraZeneca, MedImmune, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia, Danone, Faes, Genentech, Guidotti Malesci, GlaxoSmithKline, Hal Allergy, Merck, MSD, Mundipharma, Novartis, Orion, Sanofi Aventis, Sanofi, Genzyme/Regeneron, Stallergenes, UCB Pharma, Uriach Pharma, Teva, Thermo Fisher, and Valeas. A. Menzies-Gow has attended advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi, and Teva, and has received speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, Roche, Teva, and Vectura; has participated in research with AstraZeneca for which his institution has been remunerated and has attended international conferences with Teva; had consultancy agreements with AstraZeneca, Sanofi, and Vectura. L. Perez de Llano declares nonfinancial support, personal fees, and grants from Teva; nonfinancial support and personal fees from Boehringer Ingelheim, Esteve, GlaxoSmithKline, Mundipharma, and Novartis; personal fees and grants from AstraZeneca and Chiesi; personal fees from Sanofi; and nonfinancial support from Menairi outside the submitted work. C. K. Rhee declares consultancy and lecture fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mundipharma, MSD, Novartis, Sandoz, Takeda, and Teva-Handok, and Sanofi. G. Brusselle has received honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Teva; is a member of advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi/Regeneron, and Teva. C. Ulrik reports personal fees from AstraZeneca, GSK, TEVA, Novartis, Chiesi, Boehringer-Ingelheim, Sanofi, ALK-Abello, Orion Pharma, and Actelion, outside the submitted work. N. Lugogo consulted for AstraZeneca and GSK; on protocol committee with AstraZeneca; on advisory board with AstraZeneca, GSK, Sanofi, Novartis, Genentech, and Teva. I. Chaudhry, L. Bulathsinhala, and V. A. Carter are employees of Optimum Patient Care, a cofunder of the International Severe Asthma Registry. M. Hew declares grants and other advisory board fees (made to his institutional employer) from AstraZeneca, GlaxoSmithKline, Novartis, and Seqirus, for unrelated projects. The rest of the authors declare that they have no relevant conflicts of interest.

Publisher Copyright:
© 2021 The Authors

Keywords

Severe asthma
Biomarkers
Immunoglobulin E
Fractional exhaled nitric oxide
Eosinophils

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Denton_et_al_Cluster_analysis_Journal_of_allergyy_and_clinical_immunology_vor
©2021 The Authors. Published by Elsevier Inc. on behalf of the American Academyof Allergy, Asthma & Immunology. This is an open access article under the CCBY license (http://creativecommons.org/licenses/by/4.0/).
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Cite this

Denton, E., Price, D. B., Tran, T. N., Canonica, G. W., Menzies-Gow, A., FitzGerald, J. M., Sadatsafavi, M., Perez de Llano, L., Christoff, G., Quinton, A., Rhee, C. K., Brusselle, G., Ulrik, C., Lugogo, N., Hore-Lacy, F., Chaudhry, I., Bulathsinhala, L., Murray, R. B., Carter, V. A., & Hew, M. (2021). Cluster analysis of inflammatory biomarker expression in the International Severe Asthma Registry (ISAR). The Journal of Allergy and Clinical Immunology: In Practice, 9(7), 2680-2688.e7. https://doi.org/10.1016/j.jaip.2021.02.059

Denton, E, Price, DB, Tran, TN, Canonica, GW, Menzies-Gow, A, FitzGerald, JM, Sadatsafavi, M, Perez de Llano, L, Christoff, G, Quinton, A, Rhee, CK, Brusselle, G, Ulrik, C, Lugogo, N, Hore-Lacy, F, Chaudhry, I, Bulathsinhala, L, Murray, RB, Carter, VA & Hew, M 2021, 'Cluster analysis of inflammatory biomarker expression in the International Severe Asthma Registry (ISAR)', The Journal of Allergy and Clinical Immunology: In Practice, vol. 9, no. 7, pp. 2680-2688.e7. https://doi.org/10.1016/j.jaip.2021.02.059

@article{5967c9f970ab49c2b180ea0562d36763,

title = "Cluster analysis of inflammatory biomarker expression in the International Severe Asthma Registry (ISAR)",

abstract = "Background:Allergy, eosinophilic inflammation, and epithelial dysregulation are implicated in severe asthma pathogenesis. We aimed to characterize 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 pre-specified thresholds for biomarker positivity (serum IgE ³75kU/L, blood eosinophils ³300 cells/uL, FeNO ³25ppb), 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, post-bronchodilator FEV 1 predicted 74±20%. By pre-specified thresholds, 59% were IgE positive, 57% eosinophil positive, and 58% FeNO positive.Powered by Editorial Manager{\textregistered} and ProduXion Manager{\textregistered} from Aries Systems Corporation There was substantial overlap; 59% were positive for either two or three 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 sino-nasal 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 = "Severe asthma, Biomarkers, Immunoglobulin E, Fractional exhaled nitric oxide, Eosinophils",

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

note = "Funding Information: Conflicts of interest: D. B. Price has board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, Thermofisher; consultancy agreements with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals, Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca , Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma, Novartis; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; funding for patient enrollment or completion of research from Novartis; stock/stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp, which develops adherence monitoring technology; is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation Programme programme, and Health Technology Assessment Programme; and was an expert witness for GlaxoSmithKline. T. N. Tran and A. Quinton are employees of AstraZeneca, a cofunder of the International Severe Asthma Registry. M. Sadatsafavi has received honoraria from AstraZeneca for purposes unrelated to the content of this manuscript, and has also received research funding from AstraZeneca directly into his research account from AstraZeneca for unrelated projects. G. W. Canonica has received research grants, as well as lecture or advisory board fees from A. Menarini, Alk-Albello, Allergy Therapeutics, Anallergo, AstraZeneca, MedImmune, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia, Danone, Faes, Genentech, Guidotti Malesci, GlaxoSmithKline, Hal Allergy, Merck, MSD, Mundipharma, Novartis, Orion, Sanofi Aventis, Sanofi, Genzyme/Regeneron, Stallergenes, UCB Pharma, Uriach Pharma, Teva, Thermo Fisher, and Valeas. A. Menzies-Gow has attended advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi, and Teva, and has received speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, Roche, Teva, and Vectura; has participated in research with AstraZeneca for which his institution has been remunerated and has attended international conferences with Teva; had consultancy agreements with AstraZeneca, Sanofi, and Vectura. L. Perez de Llano declares nonfinancial support, personal fees, and grants from Teva ; nonfinancial support and personal fees from Boehringer Ingelheim, Esteve, GlaxoSmithKline, Mundipharma, and Novartis; personal fees and grants from AstraZeneca and Chiesi; personal fees from Sanofi; and nonfinancial support from Menairi outside the submitted work. C. K. Rhee declares consultancy and lecture fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mundipharma, MSD, Novartis, Sandoz, Takeda, and Teva-Handok, and Sanofi. G. Brusselle has received honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Teva; is a member of advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi/Regeneron, and Teva. C. Ulrik reports personal fees from AstraZeneca, GSK, TEVA, Novartis, Chiesi, Boehringer-Ingelheim, Sanofi, ALK-Abello, Orion Pharma, and Actelion, outside the submitted work. N. Lugogo consulted for AstraZeneca and GSK; on protocol committee with AstraZeneca; on advisory board with AstraZeneca, GSK, Sanofi, Novartis, Genentech, and Teva. I. Chaudhry, L. Bulathsinhala, and V. A. Carter are employees of Optimum Patient Care, a cofunder of the International Severe Asthma Registry. M. Hew declares grants and other advisory board fees (made to his institutional employer) from AstraZeneca, GlaxoSmithKline, Novartis, and Seqirus, for unrelated projects. The rest of the authors declare that they have no relevant conflicts of interest. Funding Information: Funding: ISAR is conducted by the Observational and Pragmatic Research Institute, and co-funded by Optimum Patient Care Global Ltd and AstraZeneca.Conflicts of interest: D. B. Price has board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, Thermofisher; consultancy agreements with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals, Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma, Novartis; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; funding for patient enrollment or completion of research from Novartis; stock/stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp, which develops adherence monitoring technology; is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation Programme programme, and Health Technology Assessment Programme; and was an expert witness for GlaxoSmithKline. T. N. Tran and A. Quinton are employees of AstraZeneca, a cofunder of the International Severe Asthma Registry. M. Sadatsafavi has received honoraria from AstraZeneca for purposes unrelated to the content of this manuscript, and has also received research funding from AstraZeneca directly into his research account from AstraZeneca for unrelated projects. G. W. Canonica has received research grants, as well as lecture or advisory board fees from A. Menarini, Alk-Albello, Allergy Therapeutics, Anallergo, AstraZeneca, MedImmune, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia, Danone, Faes, Genentech, Guidotti Malesci, GlaxoSmithKline, Hal Allergy, Merck, MSD, Mundipharma, Novartis, Orion, Sanofi Aventis, Sanofi, Genzyme/Regeneron, Stallergenes, UCB Pharma, Uriach Pharma, Teva, Thermo Fisher, and Valeas. A. Menzies-Gow has attended advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi, and Teva, and has received speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, Roche, Teva, and Vectura; has participated in research with AstraZeneca for which his institution has been remunerated and has attended international conferences with Teva; had consultancy agreements with AstraZeneca, Sanofi, and Vectura. L. Perez de Llano declares nonfinancial support, personal fees, and grants from Teva; nonfinancial support and personal fees from Boehringer Ingelheim, Esteve, GlaxoSmithKline, Mundipharma, and Novartis; personal fees and grants from AstraZeneca and Chiesi; personal fees from Sanofi; and nonfinancial support from Menairi outside the submitted work. C. K. Rhee declares consultancy and lecture fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mundipharma, MSD, Novartis, Sandoz, Takeda, and Teva-Handok, and Sanofi. G. Brusselle has received honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Teva; is a member of advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi/Regeneron, and Teva. C. Ulrik reports personal fees from AstraZeneca, GSK, TEVA, Novartis, Chiesi, Boehringer-Ingelheim, Sanofi, ALK-Abello, Orion Pharma, and Actelion, outside the submitted work. N. Lugogo consulted for AstraZeneca and GSK; on protocol committee with AstraZeneca; on advisory board with AstraZeneca, GSK, Sanofi, Novartis, Genentech, and Teva. I. Chaudhry, L. Bulathsinhala, and V. A. Carter are employees of Optimum Patient Care, a cofunder of the International Severe Asthma Registry. M. Hew declares grants and other advisory board fees (made to his institutional employer) from AstraZeneca, GlaxoSmithKline, Novartis, and Seqirus, for unrelated projects. The rest of the authors declare that they have no relevant conflicts of interest. Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = jul,

doi = "10.1016/j.jaip.2021.02.059",

language = "English",

volume = "9",

pages = "2680--2688.e7",

journal = "The Journal of Allergy and Clinical Immunology: In Practice",

issn = "2213-2198",

publisher = "Elsevier",

number = "7",

}

TY - JOUR

T1 - Cluster analysis of inflammatory biomarker expression in the International Severe Asthma Registry (ISAR)

AU - Denton, Eve

AU - Price, David B

AU - Tran, Trung N

AU - Canonica, G Walter

AU - Menzies-Gow, Andrew

AU - FitzGerald, J Mark

AU - Sadatsafavi, Mohsen

AU - Perez de Llano, Luis

AU - Christoff, George

AU - Quinton, Anna

AU - Rhee, Chin Kook

AU - Brusselle, Guy

AU - Ulrik, Charlotte

AU - Lugogo, Njira

AU - Hore-Lacy, Fiona

AU - Chaudhry, Isha

AU - Bulathsinhala, Lakmini

AU - Murray, Ruth B

AU - Carter, Victoria A

AU - Hew, Mark

N1 - Funding Information: Conflicts of interest: D. B. Price has board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, Thermofisher; consultancy agreements with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals, Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca , Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma, Novartis; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; funding for patient enrollment or completion of research from Novartis; stock/stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp, which develops adherence monitoring technology; is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation Programme programme, and Health Technology Assessment Programme; and was an expert witness for GlaxoSmithKline. T. N. Tran and A. Quinton are employees of AstraZeneca, a cofunder of the International Severe Asthma Registry. M. Sadatsafavi has received honoraria from AstraZeneca for purposes unrelated to the content of this manuscript, and has also received research funding from AstraZeneca directly into his research account from AstraZeneca for unrelated projects. G. W. Canonica has received research grants, as well as lecture or advisory board fees from A. Menarini, Alk-Albello, Allergy Therapeutics, Anallergo, AstraZeneca, MedImmune, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia, Danone, Faes, Genentech, Guidotti Malesci, GlaxoSmithKline, Hal Allergy, Merck, MSD, Mundipharma, Novartis, Orion, Sanofi Aventis, Sanofi, Genzyme/Regeneron, Stallergenes, UCB Pharma, Uriach Pharma, Teva, Thermo Fisher, and Valeas. A. Menzies-Gow has attended advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi, and Teva, and has received speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, Roche, Teva, and Vectura; has participated in research with AstraZeneca for which his institution has been remunerated and has attended international conferences with Teva; had consultancy agreements with AstraZeneca, Sanofi, and Vectura. L. Perez de Llano declares nonfinancial support, personal fees, and grants from Teva ; nonfinancial support and personal fees from Boehringer Ingelheim, Esteve, GlaxoSmithKline, Mundipharma, and Novartis; personal fees and grants from AstraZeneca and Chiesi; personal fees from Sanofi; and nonfinancial support from Menairi outside the submitted work. C. K. Rhee declares consultancy and lecture fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mundipharma, MSD, Novartis, Sandoz, Takeda, and Teva-Handok, and Sanofi. G. Brusselle has received honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Teva; is a member of advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi/Regeneron, and Teva. C. Ulrik reports personal fees from AstraZeneca, GSK, TEVA, Novartis, Chiesi, Boehringer-Ingelheim, Sanofi, ALK-Abello, Orion Pharma, and Actelion, outside the submitted work. N. Lugogo consulted for AstraZeneca and GSK; on protocol committee with AstraZeneca; on advisory board with AstraZeneca, GSK, Sanofi, Novartis, Genentech, and Teva. I. Chaudhry, L. Bulathsinhala, and V. A. Carter are employees of Optimum Patient Care, a cofunder of the International Severe Asthma Registry. M. Hew declares grants and other advisory board fees (made to his institutional employer) from AstraZeneca, GlaxoSmithKline, Novartis, and Seqirus, for unrelated projects. The rest of the authors declare that they have no relevant conflicts of interest. Funding Information: Funding: ISAR is conducted by the Observational and Pragmatic Research Institute, and co-funded by Optimum Patient Care Global Ltd and AstraZeneca.Conflicts of interest: D. B. Price has board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, Thermofisher; consultancy agreements with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals, Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma, Novartis; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; funding for patient enrollment or completion of research from Novartis; stock/stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp, which develops adherence monitoring technology; is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation Programme programme, and Health Technology Assessment Programme; and was an expert witness for GlaxoSmithKline. T. N. Tran and A. Quinton are employees of AstraZeneca, a cofunder of the International Severe Asthma Registry. M. Sadatsafavi has received honoraria from AstraZeneca for purposes unrelated to the content of this manuscript, and has also received research funding from AstraZeneca directly into his research account from AstraZeneca for unrelated projects. G. W. Canonica has received research grants, as well as lecture or advisory board fees from A. Menarini, Alk-Albello, Allergy Therapeutics, Anallergo, AstraZeneca, MedImmune, Boehringer Ingelheim, Chiesi Farmaceutici, Circassia, Danone, Faes, Genentech, Guidotti Malesci, GlaxoSmithKline, Hal Allergy, Merck, MSD, Mundipharma, Novartis, Orion, Sanofi Aventis, Sanofi, Genzyme/Regeneron, Stallergenes, UCB Pharma, Uriach Pharma, Teva, Thermo Fisher, and Valeas. A. Menzies-Gow has attended advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi, and Teva, and has received speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, Roche, Teva, and Vectura; has participated in research with AstraZeneca for which his institution has been remunerated and has attended international conferences with Teva; had consultancy agreements with AstraZeneca, Sanofi, and Vectura. L. Perez de Llano declares nonfinancial support, personal fees, and grants from Teva; nonfinancial support and personal fees from Boehringer Ingelheim, Esteve, GlaxoSmithKline, Mundipharma, and Novartis; personal fees and grants from AstraZeneca and Chiesi; personal fees from Sanofi; and nonfinancial support from Menairi outside the submitted work. C. K. Rhee declares consultancy and lecture fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mundipharma, MSD, Novartis, Sandoz, Takeda, and Teva-Handok, and Sanofi. G. Brusselle has received honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Teva; is a member of advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi/Regeneron, and Teva. C. Ulrik reports personal fees from AstraZeneca, GSK, TEVA, Novartis, Chiesi, Boehringer-Ingelheim, Sanofi, ALK-Abello, Orion Pharma, and Actelion, outside the submitted work. N. Lugogo consulted for AstraZeneca and GSK; on protocol committee with AstraZeneca; on advisory board with AstraZeneca, GSK, Sanofi, Novartis, Genentech, and Teva. I. Chaudhry, L. Bulathsinhala, and V. A. Carter are employees of Optimum Patient Care, a cofunder of the International Severe Asthma Registry. M. Hew declares grants and other advisory board fees (made to his institutional employer) from AstraZeneca, GlaxoSmithKline, Novartis, and Seqirus, for unrelated projects. The rest of the authors declare that they have no relevant conflicts of interest. Publisher Copyright: © 2021 The Authors

PY - 2021/7

Y1 - 2021/7

N2 - Background:Allergy, eosinophilic inflammation, and epithelial dysregulation are implicated in severe asthma pathogenesis. We aimed to characterize 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 pre-specified thresholds for biomarker positivity (serum IgE ³75kU/L, blood eosinophils ³300 cells/uL, FeNO ³25ppb), 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, post-bronchodilator FEV 1 predicted 74±20%. By pre-specified thresholds, 59% were IgE positive, 57% eosinophil positive, and 58% FeNO positive.Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation There was substantial overlap; 59% were positive for either two or three 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 sino-nasal 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.

AB - Background:Allergy, eosinophilic inflammation, and epithelial dysregulation are implicated in severe asthma pathogenesis. We aimed to characterize 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 pre-specified thresholds for biomarker positivity (serum IgE ³75kU/L, blood eosinophils ³300 cells/uL, FeNO ³25ppb), 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, post-bronchodilator FEV 1 predicted 74±20%. By pre-specified thresholds, 59% were IgE positive, 57% eosinophil positive, and 58% FeNO positive.Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation There was substantial overlap; 59% were positive for either two or three 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 sino-nasal 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.

KW - Severe asthma

KW - Biomarkers

KW - Immunoglobulin E

KW - Fractional exhaled nitric oxide

KW - Eosinophils

U2 - 10.1016/j.jaip.2021.02.059

DO - 10.1016/j.jaip.2021.02.059

M3 - Article

C2 - 33744476

SN - 2213-2198

VL - 9

SP - 2680-2688.e7

JO - The Journal of Allergy and Clinical Immunology: In Practice

JF - The Journal of Allergy and Clinical Immunology: In Practice

IS - 7

ER -

Cluster analysis of inflammatory biomarker expression in the International Severe Asthma Registry (ISAR)

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