Bibliografisk note

Funding Information:
FUNDING/SUPPORT: This study was conducted by the Observational and Pragmatic Research Institute (OPRI) Pte Ltd and was partially funded by Optimum Patient Care Global and AstraZeneca Ltd. No funding was received by the OPRI for its contribution.Author contributions: D. B. P. agrees to be accountable for all content and aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors were involved in data acquisition or analysis and interpretation, as well as the critical revision of the manuscript for important intellectual content. L. G. H. L. P. d. L. M. A.-A. V. B. J. B. G. W. C. G. C. C. B. G. C. J. M. F. E. H. T. I. D. J. J. A. N. M.-G. N. G. P. A. I. P. P. E. P. T. A. P. C. M. P. C. K. R. M. S. Y. T. E. W. M. E. W. M. A. A. A. L. B. U. S. B. A. B. G. G. B. R. B. R. W. C. M. H. M. K. S. S. L. L. L. M. P. C. Taill?, C. Taube, T. N. T. J. Z. and D. B. P. were involved in the conception and design of the study and in reaching consensus on the eosinophil gradient algorithm. L. G. H. L. B. V. A. C. I. C. N. E. N. H. M. K. R. B. M. C. A. P. and D. B. P. were responsible for drafting the manuscript. I. C. N. E. and L. B. provided additional administrative, technical, and material support. The study was supervised by D. B. P. All authors approved the final version of this manuscript and agree to be accountable for all aspects of the work. Financial/nonfinancial disclosures: The authors have reported to CHEST the following: L. G. H. declares he has received grant funding, participated in advisory boards, and given lectures at meetings supported by Amgen, AstraZeneca, Boehringer Ingelheim, Circassia, Hoffmann la Roche, GlaxoSmithKline, Novartis, and Teva; he has taken part in asthma clinical trials sponsored by Boehringer Ingelheim, Hoffmann la Roche, and GlaxoSmithKline for which his institution received remuneration; he is the academic lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma, which involves industrial partnerships with a number of pharmaceutical companies including Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann la Roche, and Janssen. L. P. d. L. 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. M. A.-A. has received advisory board and speaker fees from AstraZeneca, Sanofi, Novartis, and GlaxoSmithKline. G. W. C. has received research grants as well as lecture or advisory board fees from A. Menarini, Alk-Abello, 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. B. G. C. declares grants from Chiesi; personal fees for advisory board activities from Chiesi and AstraZeneca; and payment for lectures or speaking engagements from Chiesi, Novartis, Menarini, and AstraZeneca, outside the submitted work. E. H. participates in speaking activities and industry advisory committees for AstraZeneca, Sanofi-Genzyme, GSK, Novartis, TEVA, Circassia, and Nestl? Purina. T. I. declares grants from Astellas, Boehringer Ingelheim, Daiichi-Sankyo, Kyorin, MeijiSeika Pharma, and Teijin Pharma and lecture fees from Kyorin. D. J. J. has received advisory board and speaker fees from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Teva, Napp, Chiesi, and Novartis and research grant funding from AstraZeneca. A. N. M.-G. 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. He has participated in research with AstraZeneca for which his institution has been remunerated and has attended international conferences with Teva. He has had consultancy agreements with AstraZeneca, Sanofi, and Vectura. N. G. P. declares research support from Gerolymatos, Menarini, Nutricia, and Vian and consultancy or speaker fees from ASIT, AZ, Boehringer Ingelheim, GSK, HAL Allergy, Medscape, Menarini, MSD, Mylan, Novartis, Nutricia, OM Pharma, Sanofi, and Takeda. A. I. P. has received fees and honoraria from Menarini, GSK, Novartis, Elpen, Boehringer Ingelheim, AstraZeneca, and Chiesi. P. E. P. has attended advisory boards for Novartis; has given lectures at meetings supported by AstraZeneca and GlaxoSmithKline; has taken part in clinical trials sponsored by AstraZeneca, GlaxoSmithKline, and Novartis, for which his institution received remuneration; and has a current research grant funded by GlaxoSmithKline. T. A. P. declares relevant research support from Novartis and Chiesi Pharma. C. M. P. has attended advisory boards for AstraZeneca, Novartis, TEVA, and Sanofi-Genzyme; has given lectures at meetings supported by AstraZeneca, Novartis, TEVA, Sanofi-Genzyme, and GlaxoSmithKline; has taken part in clinical trials sponsored by AstraZeneca, Novartis, MSD, Sanofi-Genzyme, GlaxoSmithKline, and Novartis; and has received educational and research grants from AstraZeneca, Novartis, TEVA, GlaxoSmithKline, ALK, and Sanofi-Genzyme. C. K. R. declares consultancy and lecture fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mundipharma, MSD, Novartis, Sandoz, Takeda, and Teva-Handok. M. S. has received honoraria from AstraZeneca. He has also received research funding into his research account at The University of British Columbia. Y. T. declares honoraria from Kyorin Pharma and Teijin Pharma and research funding from Kyorin Pharma and Meiji Seika Pharma. E. W. has received honoraria from AstraZeneca and Clinical Care Options. She has been an investigator on clinical trials sponsored by AstraZeneca, GlaxoSmithKline, Genentech, Novartis, Teva, and National Institute of Allergy and Infectious Diseases (NIAID) for which her institution has received funding. M. E. W. reports receiving consulting honoraria from AstraZeneca, Boehringer Ingelheim, Genentech, GSK, Novartis, Regeneron, Sanofi, and Teva. M. A. is an employee of AstraZeneca, a co-funder of the International Severe Asthma Registry. A. A. has received lecture fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, MSD, Norameda, Novartis, and Orion; sponsorships from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, MSD, Norameda, Sanofi, and Novartis; and has been a member of advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi, and Teva. L. B. has (in the last 3 years) received lecture or advisory board fees from Alk-Abello, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mundipharma, Novartis, Sanofi, Genzyme/Regeneron, and Teva. U. S. B. receives gratuities for lectures or presentations from AstraZeneca, Sanofi, and Novartis. A. B. has received industry-sponsored grants from AstraZeneca/MedImmune, Boehringer Ingelheim, Cephalon/Teva, GlaxoSmithKline, Novartis, and Sanofi-Regeneron and has consultancies with AstraZeneca/MedImmune, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Regeneron-Sanofi, Med-in-Cell, Actelion, Merck, Roche, and Chiesi; and is an investigator or coinvestigator for trials promoted by AstraZeneca/MedImmune, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Regeneron- Sanofi, Chiesi, Actelion, Merck, Roche, Vertex, and Galapagos. G. G. B. has received honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Teva. He is a member of advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sanofi/Regeneron, and Teva. R. B. reports grants to Mainz University and personal fees from Boehringer Ingelheim, GSK, Novartis, and Roche, as well as personal fees from AstraZeneca, Chiesi, Cipla, Sanofi, and Teva, outside the submitted work. R. W. C. has received honoraria for lectures from Aerogen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Teva. He is a member of advisory boards for GlaxoSmithKline and Novartis, has received grant support from GlaxoSmithKline and Aerogen, and has patents in the use of acoustics in the diagnosis of lung disease, assessment of adherence, and prediction of exacerbations. M. H. declares grants and other advisory board fees (made to his institutional employer) from AstraZeneca, GlaxoSmithKline, Novartis, and Seqirus, for unrelated projects. M. S. K. reports grant support from AstraZeneca and honoraria for lectures and advisory board meetings paid to her hospital (Singapore General Hospital) from GlaxoSmithKline, AstraZeneca, Sanofi, and Boehringer Ingelheim, outside the submitted work. S. L. declares receipt of lecture (personal) and advisory board (to employer) fees from AstraZeneca, Boehringer Ingelheim, and Novartis. L. L. declares personal fees for consultancy, lectures, and attending advisory boards from ALK, AstraZeneca, Boehringer Ingelheim, Circassia, Chiesi, GlaxoSmithKline, Mundipharma, Novartis, Orion Pharma, Sanofi, and Teva. M. P. declares personal fees and nonfinancial support from AstraZeneca and GlaxoSmithKline. C. Taill? has received lecture or advisory board fees and grants to her institution from AstraZeneca, Sanofi, GlaxoSmithKline, Chiesi, and Novartis, for unrelated projects. T. N. T. is an employee of AstraZeneca, a co-funder of the International Severe Asthma Registry. J. Z. was an employee of AstraZeneca at the time this analysis was conducted. L. B. V. A. C. I. C. N. E. N. H. M. K. and C. A. P. are employees of Optimum Patient Care, a cofunder of the International Severe Asthma Registry. D. B. P. declares advisory board membership with Aerocrine, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Mundipharma, Napp Pharmaceuticals, Novartis, and Teva; consultancy agreements with Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Napp Pharmaceuticals, Novartis, Pfizer, Teva, and Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from Aerocrine, AKL Research and Development Ltd, AstraZeneca, Boehringer Ingelheim, British Lung Foundation, Chiesi, Mylan, Mundipharma, Napp Pharmaceuticals, Novartis, Pfizer, Respiratory Effectiveness Group, Teva, Theravance, UK National Health Service, and Zentiva; payment for lectures or speaking engagements from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Merck, Mundipharma, Novartis, Pfizer, Skyepharma, and Teva; payment for manuscript preparation from Mundipharma and Teva; payment for the development of educational materials from Mundipharma and Novartis; payment for travel, accommodation, and meeting expenses from Aerocrine, AstraZeneca, Boehringer Ingelheim, Mundipharma, Napp Pharmaceuticals, Novartis, and Teva; funding for patient enrolment or completion of research from Chiesi, Novartis, Teva, and Zentiva; stock and stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals, owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and United Kingdom) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); has a 5% shareholding in Timestamp, which develops adherence monitoring technology; is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation programme and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. None declared (V. B. J. B. G. C. C. J. M. F. R. B. M. C. Taube). Role of sponsors: This ISAR research study was cofunded by AstraZeneca and Optimum Patient Care (OPC) Global Limited and overseen by the ISAR Steering Committee, the Respiratory Effectiveness Group, the Anonymised Data Ethics and Protocol Transparency Committee, and the ISAR Operational Committee. The ISAR Steering Committee includes one member from OPC and three medical experts from AstraZeneca, as well as 45 clinicians and researchers across 29 countries. OPC and AstraZeneca members of the ISAR Steering Committee had input into study design, data analysis and interpretation, and manuscript writing and are authors of this article in line with International Committee of Medical Journal Editors authorship criteria. Other Contributions: The authors thank Bassam Mahboub, Carlos A. Torres-Duque, D?sir?e Larenas Linnemann, Diahn-Warng Perng (Steve), Esther Garcia Gil, Jorge Maspero, Peter G. Gibson, Piotr Kuna, Riyad Al-Lehebi, Rupert C. Jones, and Sundeep Salvi, members of the ISAR Steering Committee, for their valued contributions during the planning, analysis, and drafting of this article; and the following individuals, who contributed substantially to the International Severe Asthma Registry: Bulgaria - Cvetanka Odjakova, Darina Petrova Dimova, Diana X. Hristova, Eleonara M. Stamenova, Katya Vasileva Noleva, Nadezda K. Takovska, Plamen Hristov Yakovliev, Sonya Metodieva Genova, and Violina Milchova Vasileva; Canada - Andreanne Cote, Celine Bergeron, Dloui-Philippe Boulet, Louis Phillipe Boulet, Mohit Bhutani, and Kenneth Chapman; Denmark - Anders Christiansen, Charlotte Ulrik, Johannes Schmid, Karin Dahl Assing, Kirsten Rasmussen, Linda Rasmussen, and Ole Hilberg; Greece - Giannis Paraskevopoulos, Konstantinos Kostikas, and Stelios Loukides; Italy - Alessandro Farsi, Andrea Vianello, Angelo Guido Corsico, Antonio Spanevello, Barbaro Maria Pia Foschino, Carlo Lombardi, Caterina Bucca, Cecilia Calabrese, Concetta Sirena, Cristiano Caruso, Daniela Morrone, Eleonora Nucera, Elisabetta Favero, Erminia Ridolo, Fabio Luigi Massimo Ricciardolo, Francesco Blasi, Francesco Mazza, Francesco Menzella, Gabriella Guarnieri, Gianenrico Senna, Gianna Camiciottoli, Giovanni Passalacqua, Giovanni Rolla, Girolamo Pelaia, Giuseppe Guida, Giuseppe Spadaro, Laura Pini, Lorenzo Cosmi, Luca Richeldi, Luigi Macchia, Luisa Ricciardi, Manlio Milanese, Marcello Montagni, Marco Bonavia, Maria Cristina Zappa, Maria D'Amato, Maria Elisabetta Conte, Maria Filomena Caiaffa, Maria Teresa Costantino, Mona-Rita Yacoub, Nicola Scichilone, Nunzio Crimi, Paolo Montuschi, Paolo Solidoro, Pierachille Santus, Pierluigi Paggiaro, Roberta Parente, Salvatore Lo Cicero, Simona D'Al?, Stefano Centanni, Stefano Del Giacco, Vincenzo Patella, and Vittorio Viviano; Japan - Hiroshi Tanaka, Soichiro Hozawa, and Takahiko Horiguchi; Kuwait - Ahmed Maher and Jasmina Nurkic; South Korea - Jae Ha Lee, Ji-yong Moon, Youlim, Kim, Seung Won Ra, and Kwang Ha Yoo; Spain - Vicente Plaza; United Kingdom - the clinical staff and data entry teams at participating UK Severe Asthma Registry centers; and the United States - Joy Zimmer and Pearlanne Zelarney. Additional information: The e-Appendix, e-Figures, and e-Tables can be found in the Supplemental Materials section of the online article.

Funding Information:
FUNDING/SUPPORT: This study was conducted by the Observational and Pragmatic Research Institute (OPRI) Pte Ltd and was partially funded by Optimum Patient Care Global and AstraZeneca Ltd. No funding was received by the OPRI for its contribution.

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