IL-17–high asthma with features of a psoriasis immunophenotype

Jörgen Östling; Marleen van Geest; James P.R. Schofield; Zala Jevnikar; Susan Wilson; Jonathan Ward; Rene Lutter; Dominick E. Shaw; Per S. Bakke; Massimo Caruso; Sven Erik Dahlen; Stephen J. Fowler; Ildikó Horváth; Norbert Krug; Paolo Montuschi; Marek Sanak; Thomas Sandström; Kai Sun; Ioannis Pandis; Charles Auffray; Ana R. Sousa; Yi-Ke GUO; Ian M. Adcock; Peter Howarth; Kian Fan Chung; Jeanette Bigler; Peter J. Sterk; Paul J. Skipp; Ratko Djukanović; Outi Vaarala; H. Ahmed; P. Bakke; A. T. Bansal; F. Baribaud; S. Bates; E. H. Bel; H. Bisgaard; M. J. Boedigheimer; K. Bønnelykke; J. Brandsma; P. Brinkman; E. Bucchioni; D. Burg; A. Bush; A. Chaiboonchoe; P. Chanez; C. H. Compton; J. Corfield; A. D'Amico; Xian YANG; U-BIOPRED study group

doi:10.1016/j.jaci.2019.03.027

IL-17–high asthma with features of a psoriasis immunophenotype

Jörgen Östling, Marleen van Geest, James P.R. Schofield, Zala Jevnikar, Susan Wilson, Jonathan Ward, Rene Lutter, Dominick E. Shaw, Per S. Bakke, Massimo Caruso, Sven Erik Dahlen, Stephen J. Fowler, Ildikó Horváth, Norbert Krug, Paolo Montuschi, Marek Sanak, Thomas Sandström, Kai Sun, Ioannis Pandis, Charles AuffrayAna R. Sousa, Yi-Ke GUO, Ian M. Adcock, Peter Howarth, Kian Fan Chung, Jeanette Bigler, Peter J. Sterk, Paul J. Skipp, Ratko Djukanović, Outi Vaarala, H. Ahmed, P. Bakke, A. T. Bansal, F. Baribaud, S. Bates, E. H. Bel, H. Bisgaard, M. J. Boedigheimer, K. Bønnelykke, J. Brandsma, P. Brinkman, E. Bucchioni, D. Burg, A. Bush, A. Chaiboonchoe, P. Chanez, C. H. Compton, J. Corfield, A. D'Amico, Xian YANG, U-BIOPRED study group

Department of Computer Science

Research output: Contribution to journal › Journal article › peer-review

92 Citations (Scopus)

Abstract

Background: The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required. Objective: We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity. Methods: Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17–high and IL-13–high asthma phenotypes. Results: Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17–high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and β-defensin. Conclusion: The IL-17–high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.

Original language	English
Pages (from-to)	1198-1213
Number of pages	16
Journal	Journal of Allergy and Clinical Immunology
Volume	144
Issue number	5
DOIs	https://doi.org/10.1016/j.jaci.2019.03.027
Publication status	Published - 1 Nov 2019

Scopus Subject Areas

Immunology and Allergy
Immunology

User-Defined Keywords

asthma
biomarkers
bronchial biopsies
bronchial brushings
IL-17
psoriasis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.jaci.2019.03.027

Cite this

Östling, J., van Geest, M., Schofield, J. P. R., Jevnikar, Z., Wilson, S., Ward, J., Lutter, R., Shaw, D. E., Bakke, P. S., Caruso, M., Dahlen, S. E., Fowler, S. J., Horváth, I., Krug, N., Montuschi, P., Sanak, M., Sandström, T., Sun, K., Pandis, I., ... U-BIOPRED study group (2019). IL-17–high asthma with features of a psoriasis immunophenotype. Journal of Allergy and Clinical Immunology, 144(5), 1198-1213. https://doi.org/10.1016/j.jaci.2019.03.027

@article{b680b8928046448aa39a44cf2d59c155,

title = "IL-17–high asthma with features of a psoriasis immunophenotype",

abstract = "Background: The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required. Objective: We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity. Methods: Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17–high and IL-13–high asthma phenotypes. Results: Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17–high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and β-defensin. Conclusion: The IL-17–high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.",

keywords = "asthma, biomarkers, bronchial biopsies, bronchial brushings, IL-17, psoriasis",

author = "J{\"o}rgen {\"O}stling and {van Geest}, Marleen and Schofield, {James P.R.} and Zala Jevnikar and Susan Wilson and Jonathan Ward and Rene Lutter and Shaw, {Dominick E.} and Bakke, {Per S.} and Massimo Caruso and Dahlen, {Sven Erik} and Fowler, {Stephen J.} and Ildik{\'o} Horv{\'a}th and Norbert Krug and Paolo Montuschi and Marek Sanak and Thomas Sandstr{\"o}m and Kai Sun and Ioannis Pandis and Charles Auffray and Sousa, {Ana R.} and Yi-Ke GUO and Adcock, {Ian M.} and Peter Howarth and Chung, {Kian Fan} and Jeanette Bigler and Sterk, {Peter J.} and Skipp, {Paul J.} and Ratko Djukanovi{\'c} and Outi Vaarala and H. Ahmed and P. Bakke and Bansal, {A. T.} and F. Baribaud and S. Bates and Bel, {E. H.} and H. Bisgaard and Boedigheimer, {M. J.} and K. B{\o}nnelykke and J. Brandsma and P. Brinkman and E. Bucchioni and D. Burg and A. Bush and A. Chaiboonchoe and P. Chanez and Compton, {C. H.} and J. Corfield and A. D'Amico and Xian YANG and {U-BIOPRED study group}",

note = "Funding Information: The Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes Consortium receives funding from the European Union and the European Federation of Pharmaceutical Industries and Associations as an IMI JU?funded project (no. 115010).Disclosure of potential conflict of interest: Z. Jevnikar reports personal fees from AstraZeneca outside the submitted work. R. Lutter reports personal fees from Boehringer Ingelheim and grants from MedImmune and GlaxoSmithKline outside the submitted work. D. E. Shaw reports personal fees from Novartis, GlaxoSmithKline, and TEVA. S. J. Fowler reports personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, and TEVA outside the submitted work. I. Horv?th reports personal fees from TEVA, Novartis, Chiesi, AstraZeneca, GlaxoSmithKline, Boehringer-Ingelheim, Berlin-Chemie, CSL Behring, Roche, Orion Pharma, and Sager Pharma outside the submitted work. N. Krug reports grants from several pharmaceutical companies outside the submitted work. T. Sandstr?m reports fees from Boehringer Ingelheim outside the submitted work. C. Auffray reports grants from the Innovative Medicines Initiative during the conduct of the study and personal fees from TEVA, Novartis, Synairgen, and GlaxoSmithKline, outside the submitted work. P. Howarth reports personal fees from GlaxoSmithKline and grants from Boehringer Ingelheim outside the submitted work. K. Fan Chung has received honoraria for participating in advisory board meetings of the pharmaceutical industry regarding treatments for asthma and chronic obstructive pulmonary disease and has also been renumerated for speaking engagements. J. Bigler reports that she owns stock in Amgen. P. J. Sterk reports grants from the Innovative Medicines Initiative during the conduct of the study. R. Djukanovi? has consulted and presented at symposia organized by TEVA, Novartis, GlaxoSmithKline, and AstraZeneca and has shares in and consults for Synairgen. O. Vaarala reports others from AstraZeneca and other support from MedImmune during the conduct of the study. The rest of the authors declare that they have no relevant conflicts of interest. Funding Information: The Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes Consortium receives funding from the European Union and the European Federation of Pharmaceutical Industries and Associations as an IMI JU–funded project (no. 115010).Disclosure of potential conflict of interest: Z. Jevnikar reports personal fees from AstraZeneca outside the submitted work. R. Lutter reports personal fees from Boehringer Ingelheim and grants from MedImmune and GlaxoSmithKline outside the submitted work. D. E. Shaw reports personal fees from Novartis, GlaxoSmithKline, and TEVA. S. J. Fowler reports personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, and TEVA outside the submitted work. I. Horv{\'a}th reports personal fees from TEVA, Novartis, Chiesi, AstraZeneca, GlaxoSmithKline, Boehringer-Ingelheim, Berlin-Chemie, CSL Behring, Roche, Orion Pharma, and Sager Pharma outside the submitted work. N. Krug reports grants from several pharmaceutical companies outside the submitted work. T. Sandstr{\"o}m reports fees from Boehringer Ingelheim outside the submitted work. C. Auffray reports grants from the Innovative Medicines Initiative during the conduct of the study and personal fees from TEVA, Novartis, Synairgen, and GlaxoSmithKline, outside the submitted work. P. Howarth reports personal fees from GlaxoSmithKline and grants from Boehringer Ingelheim outside the submitted work. K. Fan Chung has received honoraria for participating in advisory board meetings of the pharmaceutical industry regarding treatments for asthma and chronic obstructive pulmonary disease and has also been renumerated for speaking engagements. J. Bigler reports that she owns stock in Amgen. P. J. Sterk reports grants from the Innovative Medicines Initiative during the conduct of the study. R. Djukanovi{\'c} has consulted and presented at symposia organized by TEVA, Novartis, GlaxoSmithKline, and AstraZeneca and has shares in and consults for Synairgen. O. Vaarala reports others from AstraZeneca and other support from MedImmune during the conduct of the study. The rest of the authors declare that they have no relevant conflicts of interest. We thank Ayasdi, Menlo Park, California, for making available on a collaborative basis their platform for TDA. The U-BIOPRED consortium wishes to acknowledge the help and expertise of the following individuals and groups without whom the study would not have been possible: I. M. Adcock, National Heart and Lung Institute, Imperial College, London, United Kingdom; H. Ahmed, European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France; C. Auffray, European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France; P. Bakke, Department of Clinical Science, University of Bergen, Bergen, Norway; A. T. Bansal, Acclarogen, St John's Innovation Centre, Cambridge, United Kingdom; F. Baribaud, Janssen R&D, Malvern, Pennsylvania; S. Bates, Respiratory Therapeutic Unit, GlaxoSmithKline, London, United Kingdom; E. H. Bel, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; J. Bigler, previously Amgen; H. Bisgaard, COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; M.J. Boedigheimer, Amgen, Thousand Oaks, California; K. B{\o}nnelykke, COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; J. Brandsma, University of Southampton, Southampton, United Kingdom; P. Brinkman, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; E. Bucchioni, Chiesi Pharmaceuticals SPA, Parma, Italy; D. Burg, Centre for Proteomic Research, Institute for Life Sciences, University of Southampton, Southampton, United Kingdom; A. Bush, National Heart and Lung Institute, Imperial College, London, United Kingdom, and Royal Brompton and Harefield NHS trust, United Kingdom; M. Caruso, Department Clinical and Experimental Medicine, University of Catania, Catania, Italy; A. Chaiboonchoe, European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France; P. Chanez, Assistance publique des H{\^o}pitaux de Marseille–Clinique des bronches, allergies et sommeil, Aix Marseille Universit{\'e}, Marseille, France; K. F. Chung, National Heart and Lung Institute, Imperial College, London, United Kingdom; C. H. Compton, Respiratory Therapeutic Unit, GlaxoSmithKline, London, United Kingdom; J. Corfield, Areteva R&D, Nottingham, United Kingdom; A. D'Amico, University of Rome “Tor Vergata,” Rome Italy; S. E. Dahlen, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; B. De Meulder, European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France; R. Djukanovic, NIHR Southampton Respiratory Biomedical Research Unit and Clinical and Experimental Sciences, Southampton, United Kingdom; V. J. Erpenbeck, Translational Medicine, Respiratory Profiling, Novartis Institutes for Biomedical Research, Basel, Switzerland; D. Erzen, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; K. Fichtner, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; N. Fitch, BioSci Consulting, Maasmechelen, Belgium; L. J. Fleming, National Heart and Lung Institute, Imperial College, London, United Kingdom, and Royal Brompton and Harefield NHS trust, United Kingdom; E. Formaggio, previously CROMSOURCE, Verona, Italy; S. J. Fowler, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom; U. Frey, University Children's Hospital, Basel, Switzerland; M. Gahlemann, Boehringer Ingelheim (Schweiz)GmbH, Basel, Switzerland; T. Geiser, Department of Respiratory Medicine, University Hospital Bern, Switzerland; Y. Guo, Data Science Institute, Imperial College, London, United Kingdom; S. Hashimoto, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; J. Haughney, International Primary Care Respiratory Group, Aberdeen, United Kingdom; G. Hedlin, Department of Women's and Children's Health & Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; P. W. Hekking, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; T. Higenbottam, Allergy Therapeutics, West Sussex, United Kingdom; J. M. Hohlfeld, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany; C. Holweg, Respiratory and Allergy Diseases, Genentech, San Francisco, California; I. Horv{\'a}th, Semmelweis University, Budapest, Hungary; P. Howarth, NIHR Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences and Human Development and Health, Southampton, United Kingdom; A. J. James, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; R. Knowles, Arachos Pharma, Stevenge, United Kingdom; A. J. Knox, Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom; N. Krug, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany; D. Lefaudeux, European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France; M. J. Loza, Janssen R&D, Malvern, Pennsylvania; R. Lutter, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; A. Manta, Roche Diagnostics GmbH, Mannheim, Germany; S. Masefield, European Lung Foundation, Sheffield, United Kingdom; J. G. Matthews, Respiratory and Allergy Diseases, Genentech, San Francisco, California; A. Mazein, European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France; A. Meiser, Data Science Institute, Imperial College, London, United Kingdom; R. J. M. Middelveld, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; M. Miralpeix, Almirall, Barcelona, Spain; P. Montuschi, Universit{\`a} Cattolica del Sacro Cuore, Milan, Italy; N. Mores, Universit{\`a} Cattolica del Sacro Cuore, Milan, Italy; C. S. Murray, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom; J. Musial, Department of Medicine, Jagiellonian University Medical College, Krakow, Poland; D. Myles, Respiratory Therapeutic Unit, GlaxoSmithKline, London, United Kingdom; L. Pahus, Assistance publique des H{\^o}pitaux de Marseille, Clinique des bronches, allergies et sommeil, Espace {\'E}thique M{\'e}diterran{\'e}en, Aix-Marseille Universit{\'e}, Marseille, France; I. Pandis, Data Science Institute, Imperial College, London, United Kingdom; S. Pavlidis, National Heart and Lung Institute, Imperial College, London, United Kingdom; P. Powell, European Lung Foundation, Sheffield, United Kingdom; G. Pratic{\`o}, CROMSOURCE, Verona, Italy; M. Puig Valls, CROMSOURCE, Barcelona, Spain; N. Rao, Janssen R&D, Malvern, Pennsylvania; J. Riley, Respiratory Therapeutic Unit, GlaxoSmithKline, London, United Kingdom; A. Roberts, Asthma UK, London, United Kingdom; G. Roberts, NIHR Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences and Human Development and Health, Southampton, United Kingdom; A. Rowe, Janssen R&D UK, High Wycombe, United Kingdom; T. Sandstr{\"o}m, Department of Public Health and Clinical Medicine, Ume{\aa} University, Ume{\aa}, Sweden; W. Seibold, Boehringer Ingelheim Pharma GmbH, Biberach, Germany; A. Selby, NIHR Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences and Human Development and Health, Southampton, United Kingdom; D. E. Shaw, Respiratory Research Unit, University of Nottingham, United Kingdom; R. Sigmund, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; F. Singer, University Children's Hospital, Zurich, Switzerland; P. J. Skipp, Centre for Proteomic Research, Institute for Life Sciences, University of Southampton, Southampton, United Kingdom; A. R. Sousa, Respiratory Therapeutic Unit, GlaxoSmithKline, London, United Kingdom; P. J. Sterk, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; K. Sun, Data Science Institute, Imperial College, London, United Kingdom; B. Thornton, MSD, Kenilworth, NJ; W. M. van Aalderen, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; M. van Geest, AstraZeneca, M{\"o}lndal, Sweden; J. Vestbo, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom; N. H. Vissing, COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; A. H. Wagener, Academic Medical Center Amsterdam, Amsterdam, The Netherlands; S. S. Wagers, BioSci Consulting, Maasmechelen, Belgium; Z. Weiszhart, Semmelweis University, Budapest, Hungary; C. E. Wheelock, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; and S. J. Wilson, Histochemistry Research Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. Additional contributors: Antonios Aliprantis, Merck Research Laboratories, Boston, Massachusetts; David Allen, North West Severe Asthma Network, Pennine Acute Hospital NHS Trust, United Kingdom; Kjell Alving, Dept Women's & Children's Health, Uppsala University, Uppsala, Sweden; P. Badorrek, Fraunhofer ITEM, Hannover, Germany; David Balgoma, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; S. Ballereau, European institute for Systems Biology and Medicine, University of Lyon, France; Clair Barber, NIHR Southampton Respiratory Biomedical Research Unit and Clinical and Experimental Sciences, Southampton, UK; Manohara Kanangana Batuwitage, Data Science Institute, Imperial College, London, United Kingdom; A. Bautmans, MSD, Brussels, Belgium; A. Bedding, Roche Diagnostics GmbH, Mannheim, Germany; A. F. Behndig, Ume{\aa} University, Umea, Sweden; Jorge Beleta, Almirall S.A. Barcelona, Spain; A. Berglind, MSD, Brussels, Belgium; A. Berton, AstraZeneca, M{\"o}lndal, Sweden; Grazyna Bochenek, II Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland; Armin Braun, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany; D. Campagna, Dept of Clinical and Experimental Medicine, University of Catania, Catania, Italy; Leon Carayannopoulos, previously at MSD, Kenilworth, NJ; C. Casaulta, University Children's Hospital of Bern, Switzerland; Romanas Chaleckis, Centre of Allergy Research, Karolinska Institutet, Stockholm, Sweden; B. Dahl{\'e}n, Karolinska University Hospital & Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Timothy Davison, Janssen R&D, Malvern, Pennsylvania; Jorge De Alba, Almirall S.A. Barcelona, Spain; Inge De Lepeleire, MSD, Brussels, Belgium; Tamara Dekker, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; Ingrid Delin, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; P. Dennison, NIHR Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences, NIHR-Wellcome Trust Clinical Research Facility, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; Annemiek Dijkhuis, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; Paul Dodson, AstraZeneca, M{\"o}lndal, Sweden; Aleksandra Draper, BioSci Consulting, Maasmechelen, Belgium; K. Dyson, CROMSOURCE, Stirling, United Kingdom; Jessica Edwards, Asthma UK, London, United Kingdom; L. El Hadjam, European Institute for Systems Biology and Medicine, University of Lyon, France; Rosalia Emma, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy; Magnus Ericsson, Karolinska University Hospital, Stockholm, Sweden; C. Faulenbach, Fraunhofer ITEM, Hannover, Germany; Breda Flood, European Federation of Allergy and Airways Diseases Patient's Associations, Brussels, Belgium; G. Galffy, Semmelweis University, Budapest, Hungary; Hector Gallart, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; D. Garissi, Global Head Clinical Research Division, CROMSOURCE, Italy; J. Gent, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom; M. Gerhardsson de Verdier, AstraZeneca, M{\"o}lndal, Sweden; D. Gibeon, National Heart and Lung Institute, Imperial College, London, United Kingdom; Cristina Gomez, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Kerry Gove, NIHR Southampton Respiratory Biomedical Research Unit and Clinical and Experimental Sciences, Southampton, United Kingdom; Neil Gozzard, UCB, Slough, United Kingdom; E. Guillmant-Farry, Royal Brompton Hospital, London, United Kingdom; E. Henriksson, Karolinska University Hospital & Karolinska Institutet, Stockholm, Sweden; Lorraine Hewitt, NIHR Southampton Respiratory Biomedical Research Unit, Southampton, United Kingdom; U. Hoda, Imperial College, London, United Kingdom; Richard Hu, Amgen, Thousand Oaks, California; Sile Hu, National Heart and Lung Institute, Imperial College, London, United Kingdom; X. Hu, Amgen, Thousand Oaks, California; E. Jeyasingham, UK Clinical Operations, GlaxoSmithKline, Stockley Park, United Kingdom; K. Johnson, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and repair, University Hospital of South Manchester, NHS Foundation Trust, Manchester, United Kingdom; N. Jullian, European Institute for Systems Biology and Medicine, University of Lyon, France; Juliette Kamphuis, Longfonds, Amersfoort, The Netherlands; Erika J. Kennington, Asthma UK, London, United Kingdom; Dyson Kerry, CromSource, Stirling, United Kingdom; G. Kerry, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University Hospital of South Manchester, NHS Foundation Trust, Manchester, United Kingdom; M. Kl{\"u}glich, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; Hugo Knobel, Philips Research Laboratories, Eindhoven, The Netherlands; Johan Kolmert, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; J. R. Konradsen, Dept Women's and Children's Health & Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Maxim Kots, Chiesi Pharmaceuticals, SPA, Parma, Italy; Kosmas Kretsos, UCB, Slough, United Kingdom; L. Krueger, University Children's Hospital Bern, Switzerland; Scott Kuo, National Heart and Lung Institute, Imperial College, London, United Kingdom; Maciej Kupczyk, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Bart Lambrecht, University of Gent, Gent, Belgium; A.-S. Lantz, Karolinska University Hospital & Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Christopher Larminie, GlaxoSmithKline, London, United Kingdom; L. X. Larsson, AstraZeneca, M{\"o}lndal, Sweden; P. Latzin, University Children's Hospital of Bern, Bern, Switzerland; N. Lazarinis, Karolinska University Hospital & Karolinska Institutet, Stockholm, Sweden; N. Lemonnier, European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France; Saeeda Lone-Latif, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; L. A. Lowe, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University Hospital of South Manchester, NHS Foundation Trust, Manchester, United Kingdom; Alexander Manta, Roche Diagnostics GmbH, Mannheim, Germany; Lisa Marouzet, NIHR Southampton Respiratory Biomedical Research Unit, Southampton, United Kingdom; Jane Martin, NIHR Southampton Respiratory Biomedical Research Unit, Southampton, United Kingdom; Caroline Mathon, Centre of Allergy Research, Karolinska Institutet, Stockholm, Sweden; L. McEvoy, University Hospital, Department of Pulmonary Medicine, Bern, Switzerland; Sally Meah, National Heart and Lung Institute, Imperial College, London, United Kingdom; A. Menzies-Gow, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom; Leanne Metcalf, previously at Asthma UK, London, United Kingdom; Maria Mikus, Science for Life Laboratory & The Royal Institute of Technology, Stockholm, Sweden; Philip Monk, Synairgen Research, Southampton, United Kingdom; Shama Naz, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; K. Nething, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; Ben Nicholas, University of Southampton, Southampton, United Kingdom; U. Nihl{\'e}n, previously at AstraZeneca, M{\"o}lndal, Sweden; Peter Nilsson, Science for Life Laboratory & The Royal Institute of Technology, Stockholm, Sweden; R. Niven, North West Severe Asthma Network, University Hospital South Manchester, United Kingdom; B. Nordlund, Department of Women's and Children's Health & Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; S. Nsubuga, Royal Brompton Hospital, London, United Kingdom; J{\"o}rgen {\"O}stling, AstraZeneca, M{\"o}lndal, Sweden; Antonio Pacino, Lega Italiano Anti Fumo, Catania, Italy; Susanna Palkonen, European Federation of Allergy and Airways Diseases Patient's Associations, Brussels, Belgium; J. Pellet, European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France; Giorgio Pennazza, University of Rome “Tor Vergata,” Rome Italy; Anne Petr{\'e}n, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Sandy Pink, NIHR Southampton Respiratory Biomedical Research Unit, Southampton, United Kingdom; C. Pison, European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France; Anthony Postle, University of Southampton, United Kingdom; Malayka Rahman-Amin, previously at Asthma UK, London, United Kingdom; Lara Ravanetti, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; Emma Ray, NIHR Southampton Respiratory Biomedical Research Unit, Southampton, United Kingdom; Stacey Reinke, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Leanne Reynolds, previously at Asthma UK, London, United Kingdom; K. Riemann, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; Martine Robberechts, MSD, Brussels, Belgium; J. P. Rocha, Royal Brompton and Harefield NHS Foundation Trust, United Kingdom; C. Rossios, National Heart and Lung Institute, Imperial College, London, United Kingdom; Kirsty Russell, National Heart and Lung Institute, Imperial College, London, United Kingdom; Michael Rutgers, Longfonds, Amersfoort, The Netherlands; G. Santini, Universit{\`a} Cattolica del Sacro Cuore, Milan, Italy; Marco Santoninco, University of Rome “Tor Vergata,” Rome, Italy; M. Saqi, European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France; Corinna Schoelch, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; James P. R. Schofield, Centre for Proteomic Research, Institute for Life Sciences, University of Southampton, Southampton, United Kingdom; S. Scott, North West Severe Asthma Network, Countess of Chester Hospital, United Kingdom; N. Sehgal, North West Severe Asthma Network, Pennine Acute Hospital NHS Trust; Marcus Sj{\"o}din, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Barbara Smids, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; Caroline Smith, NIHR Southampton Respiratory Biomedical Research Unit, Southampton, United Kingdom; Jessica Smith, Asthma UK, London, United Kingdom; Katherine M. Smith, University of Nottingham, United Kingdom; P. S{\"o}derman, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; A. Sogbessan, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom; F. Spycher, University Hospital Department of Pulmonary Medicine, Bern, Switzerland; Doroteya Staykova, University of Southampton, Southampton, United Kingdom; S. Stephan, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University Hospital of South Manchester, NHS Foundation Trust, Manchester, United Kingdom; J. Stokholm, University of Copenhagen and Danish Pediatric Asthma Centre Denmark; K. Strandberg, Karolinska University Hospital & Karolinska Institutet, Stockholm, Sweden; M. Sunther, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University Hospital of South Manchester, NHS Foundation Trust, Manchester, United Kingdom; M. Szentkereszty, Semmelweis University, Budapest, Hungary; L. Tamasi, Semmelweis University, Budapest, Hungary; K. Tariq, NIHR Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences, NIHR-Wellcome Trust Clinical Research Facility, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; John-Olof Th{\"o}rngren, Karolinska University Hospital, Stockholm, Sweden; Jonathan Thorsen, COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; S. Valente, Universit{\`a} Cattolica del Sacro Cuore, Milan, Italy; Marianne van de Pol, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; C. M. van Drunen, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; Jonathan Van Eyll, UCB, Slough, United Kingdom; Jenny Versnel, previously at Asthma UK, London, United Kingdom; Anton Vink, Philips Research Laboratories, Eindhoven, The Netherlands; C. von Garnier, University Hospital Bern, Switzerland; A. Vyas, North West Severe Asthma Network, Lancashire Teaching Hospitals NHS Trust, United Kingdom; Frans Wald, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; Samantha Walker, Asthma UK, London, United Kingdom; Jonathan Ward, Histochemistry Research Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; Kristiane Wetzel, Boehringer Ingelheim Pharma GmbH, Biberach, Germany; Coen Wiegman, National Heart and Lung Institute, Imperial College, London, United Kingdom; Si{\^a}n Williams, International Primary Care Respiratory Group, Aberdeen, United Kingdom; Xian Yang, Data Science Institute, Imperial College, London, United Kingdom; Elizabeth Yeyasingham, UK Clinical Operations, GlaxoSmithKline, Stockley Park, United Kingdom; W. Yu, Amgen, Thousand Oaks, California; W. Zetterquist, Department of Women's and Children's Health & Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Z. Zolkipli, NIHR Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences and Human Development and Health, Southampton, United Kingdom; and A. H. Zwinderman, Academic Medical Centre, University of Amsterdam, The Netherlands. Partner organizations: Novartis Pharma AG; University of Southampton, Southampton, UK; Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; Imperial College London, London, United Kingdom; University of Catania, Catania, Italy; University of Rome “Tor Vergata,” Rome, Italy; Hvidore Hospital, Hvidore, Denmark; Jagiellonian University Medical College, Krakow, Poland; University Hospital, Inselspital, Bern, Switzerland; Semmelweis University, Budapest, Hungary; University of Manchester, Manchester, United Kingdom; Universit{\'e} d'Aix-Marseille, Marseille, France; Fraunhofer Institute, Hannover, Germany; University Hospital, Umea, Sweden; Ghent University, Ghent, Belgium; Centre Naturale Recherche Scientifique, Lyon, France; Universit{\`a} Cattolica del Sacro Cuore, Rome, Italy; University Hospital, Copenhagen, Denmark; Karolinska Institutet, Stockholm, Sweden; Nottingham University Hospital, Nottingham, United Kingdom; University of Bergen, Bergen, Norway; Netherlands Asthma Foundation, Leusden, The Netherlands; European Lung Foundation, Sheffield, United Kingdom; Asthma UK, London, United Kingdom; European Federation of Allergy and Airways Diseases Patients' Associations, Brussels, Belgium; Lega Italiano Anti Fumo, Catania, Italy; International Primary Care Respiratory Group, Aberdeen, United Kingdom; Philips Research Laboratories, Eindhoven, The Netherlands; Synairgen Research, Southampton, United Kingdom; Aerocrine AB, Stockholm, Sweden; BioSci Consulting, Maasmechelen, Belgium; Almirall; AstraZeneca; Boehringer Ingelheim; Chiesi; GlaxoSmithKline; Roche; UCB; Janssen Biologics BV; Amgen NV; and Merck Sharp & Dome. Members of the ethics board: Jan-Bas Prins, biomedical research, LUMC, The Netherlands; Martina Gahlemann, clinical care, BI, Germany; Luigi Visintin, legal affairs, LIAF, Italy; Hazel Evans, pediatric care, Southampton, United Kingdom; Martine Puhl, patient representation (cochair), NAF, The Netherlands; Lina Buzermaniene, patient representation, EFA, Lithuania; Val Hudson, patient representation, Asthma UK; Laura Bond, patient representation, Asthma UK; Pim de Boer, patient representation and pathobiology, IND; Guy Widdershoven, research ethics, VUMC, The Netherlands; and Ralf Sigmund, research methodology and biostatistics, BI, Germany. Patient input platform: Amanda Roberts, United Kingdom; David Supple (chair), United Kingdom; Dominique Hamerlijnck, The Netherlands; Jenny Negus, United Kingdom; Juli{\"e}tte Kamphuis, The Netherlands; Lehanne Sergison, United Kingdom; Luigi Visintin, Italy; Pim de Boer (cochair), The Netherlands; and Susanne Onstein, The Netherlands. Members of the safety monitoring board: William MacNee, clinical care; Renato Bernardini, clinical pharmacology; Louis Bont, pediatric care and infectious diseases; Per-Ake Wecksell, patient representation; Pim de Boer, patient representation and pathobiology (chair); Martina Gahlemann, patient safety advice and clinical care (cochair); and Ralf Sigmund, bioinformatician.",

year = "2019",

month = nov,

day = "1",

doi = "10.1016/j.jaci.2019.03.027",

language = "English",

volume = "144",

pages = "1198--1213",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "5",

}

Östling, J, van Geest, M, Schofield, JPR, Jevnikar, Z, Wilson, S, Ward, J, Lutter, R, Shaw, DE, Bakke, PS, Caruso, M, Dahlen, SE, Fowler, SJ, Horváth, I, Krug, N, Montuschi, P, Sanak, M, Sandström, T, Sun, K, Pandis, I, Auffray, C, Sousa, AR, GUO, Y-K, Adcock, IM, Howarth, P, Chung, KF, Bigler, J, Sterk, PJ, Skipp, PJ, Djukanović, R, Vaarala, O, Ahmed, H, Bakke, P, Bansal, AT, Baribaud, F, Bates, S, Bel, EH, Bisgaard, H, Boedigheimer, MJ, Bønnelykke, K, Brandsma, J, Brinkman, P, Bucchioni, E, Burg, D, Bush, A, Chaiboonchoe, A, Chanez, P, Compton, CH, Corfield, J, D'Amico, A, YANG, X & U-BIOPRED study group 2019, 'IL-17–high asthma with features of a psoriasis immunophenotype', Journal of Allergy and Clinical Immunology, vol. 144, no. 5, pp. 1198-1213. https://doi.org/10.1016/j.jaci.2019.03.027

TY - JOUR

T1 - IL-17–high asthma with features of a psoriasis immunophenotype

AU - Östling, Jörgen

AU - van Geest, Marleen

AU - Schofield, James P.R.

AU - Jevnikar, Zala

AU - Wilson, Susan

AU - Ward, Jonathan

AU - Lutter, Rene

AU - Shaw, Dominick E.

AU - Bakke, Per S.

AU - Caruso, Massimo

AU - Dahlen, Sven Erik

AU - Fowler, Stephen J.

AU - Horváth, Ildikó

AU - Krug, Norbert

AU - Montuschi, Paolo

AU - Sanak, Marek

AU - Sandström, Thomas

AU - Sun, Kai

AU - Pandis, Ioannis

AU - Auffray, Charles

AU - Sousa, Ana R.

AU - GUO, Yi-Ke

AU - Adcock, Ian M.

AU - Howarth, Peter

AU - Chung, Kian Fan

AU - Bigler, Jeanette

AU - Sterk, Peter J.

AU - Skipp, Paul J.

AU - Djukanović, Ratko

AU - Vaarala, Outi

AU - Ahmed, H.

AU - Bakke, P.

AU - Bansal, A. T.

AU - Baribaud, F.

AU - Bates, S.

AU - Bel, E. H.

AU - Bisgaard, H.

AU - Boedigheimer, M. J.

AU - Bønnelykke, K.

AU - Brandsma, J.

AU - Brinkman, P.

AU - Bucchioni, E.

AU - Burg, D.

AU - Bush, A.

AU - Chaiboonchoe, A.

AU - Chanez, P.

AU - Compton, C. H.

AU - Corfield, J.

AU - D'Amico, A.

AU - YANG, Xian

AU - U-BIOPRED study group

N1 - Funding Information: The Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes Consortium receives funding from the European Union and the European Federation of Pharmaceutical Industries and Associations as an IMI JU?funded project (no. 115010).Disclosure of potential conflict of interest: Z. Jevnikar reports personal fees from AstraZeneca outside the submitted work. R. Lutter reports personal fees from Boehringer Ingelheim and grants from MedImmune and GlaxoSmithKline outside the submitted work. D. E. Shaw reports personal fees from Novartis, GlaxoSmithKline, and TEVA. S. J. Fowler reports personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, and TEVA outside the submitted work. I. Horv?th reports personal fees from TEVA, Novartis, Chiesi, AstraZeneca, GlaxoSmithKline, Boehringer-Ingelheim, Berlin-Chemie, CSL Behring, Roche, Orion Pharma, and Sager Pharma outside the submitted work. N. Krug reports grants from several pharmaceutical companies outside the submitted work. T. Sandstr?m reports fees from Boehringer Ingelheim outside the submitted work. C. Auffray reports grants from the Innovative Medicines Initiative during the conduct of the study and personal fees from TEVA, Novartis, Synairgen, and GlaxoSmithKline, outside the submitted work. P. Howarth reports personal fees from GlaxoSmithKline and grants from Boehringer Ingelheim outside the submitted work. K. Fan Chung has received honoraria for participating in advisory board meetings of the pharmaceutical industry regarding treatments for asthma and chronic obstructive pulmonary disease and has also been renumerated for speaking engagements. J. Bigler reports that she owns stock in Amgen. P. J. Sterk reports grants from the Innovative Medicines Initiative during the conduct of the study. R. Djukanovi? has consulted and presented at symposia organized by TEVA, Novartis, GlaxoSmithKline, and AstraZeneca and has shares in and consults for Synairgen. O. Vaarala reports others from AstraZeneca and other support from MedImmune during the conduct of the study. The rest of the authors declare that they have no relevant conflicts of interest. Funding Information: The Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes Consortium receives funding from the European Union and the European Federation of Pharmaceutical Industries and Associations as an IMI JU–funded project (no. 115010).Disclosure of potential conflict of interest: Z. Jevnikar reports personal fees from AstraZeneca outside the submitted work. R. Lutter reports personal fees from Boehringer Ingelheim and grants from MedImmune and GlaxoSmithKline outside the submitted work. D. E. Shaw reports personal fees from Novartis, GlaxoSmithKline, and TEVA. S. J. Fowler reports personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, and TEVA outside the submitted work. I. Horváth reports personal fees from TEVA, Novartis, Chiesi, AstraZeneca, GlaxoSmithKline, Boehringer-Ingelheim, Berlin-Chemie, CSL Behring, Roche, Orion Pharma, and Sager Pharma outside the submitted work. N. Krug reports grants from several pharmaceutical companies outside the submitted work. T. Sandström reports fees from Boehringer Ingelheim outside the submitted work. C. Auffray reports grants from the Innovative Medicines Initiative during the conduct of the study and personal fees from TEVA, Novartis, Synairgen, and GlaxoSmithKline, outside the submitted work. P. Howarth reports personal fees from GlaxoSmithKline and grants from Boehringer Ingelheim outside the submitted work. K. Fan Chung has received honoraria for participating in advisory board meetings of the pharmaceutical industry regarding treatments for asthma and chronic obstructive pulmonary disease and has also been renumerated for speaking engagements. J. Bigler reports that she owns stock in Amgen. P. J. Sterk reports grants from the Innovative Medicines Initiative during the conduct of the study. R. Djukanović has consulted and presented at symposia organized by TEVA, Novartis, GlaxoSmithKline, and AstraZeneca and has shares in and consults for Synairgen. O. Vaarala reports others from AstraZeneca and other support from MedImmune during the conduct of the study. The rest of the authors declare that they have no relevant conflicts of interest. We thank Ayasdi, Menlo Park, California, for making available on a collaborative basis their platform for TDA. The U-BIOPRED consortium wishes to acknowledge the help and expertise of the following individuals and groups without whom the study would not have been possible: I. M. Adcock, National Heart and Lung Institute, Imperial College, London, United Kingdom; H. Ahmed, European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France; C. Auffray, European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France; P. Bakke, Department of Clinical Science, University of Bergen, Bergen, Norway; A. T. Bansal, Acclarogen, St John's Innovation Centre, Cambridge, United Kingdom; F. Baribaud, Janssen R&D, Malvern, Pennsylvania; S. Bates, Respiratory Therapeutic Unit, GlaxoSmithKline, London, United Kingdom; E. H. Bel, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; J. Bigler, previously Amgen; H. Bisgaard, COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; M.J. Boedigheimer, Amgen, Thousand Oaks, California; K. Bønnelykke, COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; J. Brandsma, University of Southampton, Southampton, United Kingdom; P. Brinkman, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; E. Bucchioni, Chiesi Pharmaceuticals SPA, Parma, Italy; D. Burg, Centre for Proteomic Research, Institute for Life Sciences, University of Southampton, Southampton, United Kingdom; A. Bush, National Heart and Lung Institute, Imperial College, London, United Kingdom, and Royal Brompton and Harefield NHS trust, United Kingdom; M. Caruso, Department Clinical and Experimental Medicine, University of Catania, Catania, Italy; A. Chaiboonchoe, European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France; P. Chanez, Assistance publique des Hôpitaux de Marseille–Clinique des bronches, allergies et sommeil, Aix Marseille Université, Marseille, France; K. F. Chung, National Heart and Lung Institute, Imperial College, London, United Kingdom; C. H. Compton, Respiratory Therapeutic Unit, GlaxoSmithKline, London, United Kingdom; J. Corfield, Areteva R&D, Nottingham, United Kingdom; A. D'Amico, University of Rome “Tor Vergata,” Rome Italy; S. E. Dahlen, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; B. De Meulder, European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France; R. Djukanovic, NIHR Southampton Respiratory Biomedical Research Unit and Clinical and Experimental Sciences, Southampton, United Kingdom; V. J. Erpenbeck, Translational Medicine, Respiratory Profiling, Novartis Institutes for Biomedical Research, Basel, Switzerland; D. Erzen, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; K. Fichtner, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; N. Fitch, BioSci Consulting, Maasmechelen, Belgium; L. J. Fleming, National Heart and Lung Institute, Imperial College, London, United Kingdom, and Royal Brompton and Harefield NHS trust, United Kingdom; E. Formaggio, previously CROMSOURCE, Verona, Italy; S. J. Fowler, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom; U. Frey, University Children's Hospital, Basel, Switzerland; M. Gahlemann, Boehringer Ingelheim (Schweiz)GmbH, Basel, Switzerland; T. Geiser, Department of Respiratory Medicine, University Hospital Bern, Switzerland; Y. Guo, Data Science Institute, Imperial College, London, United Kingdom; S. Hashimoto, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; J. Haughney, International Primary Care Respiratory Group, Aberdeen, United Kingdom; G. Hedlin, Department of Women's and Children's Health & Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; P. W. Hekking, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; T. Higenbottam, Allergy Therapeutics, West Sussex, United Kingdom; J. M. Hohlfeld, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany; C. Holweg, Respiratory and Allergy Diseases, Genentech, San Francisco, California; I. Horváth, Semmelweis University, Budapest, Hungary; P. Howarth, NIHR Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences and Human Development and Health, Southampton, United Kingdom; A. J. James, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; R. Knowles, Arachos Pharma, Stevenge, United Kingdom; A. J. Knox, Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom; N. Krug, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany; D. Lefaudeux, European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France; M. J. Loza, Janssen R&D, Malvern, Pennsylvania; R. Lutter, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; A. Manta, Roche Diagnostics GmbH, Mannheim, Germany; S. Masefield, European Lung Foundation, Sheffield, United Kingdom; J. G. Matthews, Respiratory and Allergy Diseases, Genentech, San Francisco, California; A. Mazein, European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France; A. Meiser, Data Science Institute, Imperial College, London, United Kingdom; R. J. M. Middelveld, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; M. Miralpeix, Almirall, Barcelona, Spain; P. Montuschi, Università Cattolica del Sacro Cuore, Milan, Italy; N. Mores, Università Cattolica del Sacro Cuore, Milan, Italy; C. S. Murray, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom; J. Musial, Department of Medicine, Jagiellonian University Medical College, Krakow, Poland; D. Myles, Respiratory Therapeutic Unit, GlaxoSmithKline, London, United Kingdom; L. Pahus, Assistance publique des Hôpitaux de Marseille, Clinique des bronches, allergies et sommeil, Espace Éthique Méditerranéen, Aix-Marseille Université, Marseille, France; I. Pandis, Data Science Institute, Imperial College, London, United Kingdom; S. Pavlidis, National Heart and Lung Institute, Imperial College, London, United Kingdom; P. Powell, European Lung Foundation, Sheffield, United Kingdom; G. Praticò, CROMSOURCE, Verona, Italy; M. Puig Valls, CROMSOURCE, Barcelona, Spain; N. Rao, Janssen R&D, Malvern, Pennsylvania; J. Riley, Respiratory Therapeutic Unit, GlaxoSmithKline, London, United Kingdom; A. Roberts, Asthma UK, London, United Kingdom; G. Roberts, NIHR Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences and Human Development and Health, Southampton, United Kingdom; A. Rowe, Janssen R&D UK, High Wycombe, United Kingdom; T. Sandström, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden; W. Seibold, Boehringer Ingelheim Pharma GmbH, Biberach, Germany; A. Selby, NIHR Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences and Human Development and Health, Southampton, United Kingdom; D. E. Shaw, Respiratory Research Unit, University of Nottingham, United Kingdom; R. Sigmund, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; F. Singer, University Children's Hospital, Zurich, Switzerland; P. J. Skipp, Centre for Proteomic Research, Institute for Life Sciences, University of Southampton, Southampton, United Kingdom; A. R. Sousa, Respiratory Therapeutic Unit, GlaxoSmithKline, London, United Kingdom; P. J. Sterk, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; K. Sun, Data Science Institute, Imperial College, London, United Kingdom; B. Thornton, MSD, Kenilworth, NJ; W. M. van Aalderen, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; M. van Geest, AstraZeneca, Mölndal, Sweden; J. Vestbo, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom; N. H. Vissing, COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; A. H. Wagener, Academic Medical Center Amsterdam, Amsterdam, The Netherlands; S. S. Wagers, BioSci Consulting, Maasmechelen, Belgium; Z. Weiszhart, Semmelweis University, Budapest, Hungary; C. E. Wheelock, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; and S. J. Wilson, Histochemistry Research Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. Additional contributors: Antonios Aliprantis, Merck Research Laboratories, Boston, Massachusetts; David Allen, North West Severe Asthma Network, Pennine Acute Hospital NHS Trust, United Kingdom; Kjell Alving, Dept Women's & Children's Health, Uppsala University, Uppsala, Sweden; P. Badorrek, Fraunhofer ITEM, Hannover, Germany; David Balgoma, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; S. Ballereau, European institute for Systems Biology and Medicine, University of Lyon, France; Clair Barber, NIHR Southampton Respiratory Biomedical Research Unit and Clinical and Experimental Sciences, Southampton, UK; Manohara Kanangana Batuwitage, Data Science Institute, Imperial College, London, United Kingdom; A. Bautmans, MSD, Brussels, Belgium; A. Bedding, Roche Diagnostics GmbH, Mannheim, Germany; A. F. Behndig, Umeå University, Umea, Sweden; Jorge Beleta, Almirall S.A. Barcelona, Spain; A. Berglind, MSD, Brussels, Belgium; A. Berton, AstraZeneca, Mölndal, Sweden; Grazyna Bochenek, II Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland; Armin Braun, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany; D. Campagna, Dept of Clinical and Experimental Medicine, University of Catania, Catania, Italy; Leon Carayannopoulos, previously at MSD, Kenilworth, NJ; C. Casaulta, University Children's Hospital of Bern, Switzerland; Romanas Chaleckis, Centre of Allergy Research, Karolinska Institutet, Stockholm, Sweden; B. Dahlén, Karolinska University Hospital & Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Timothy Davison, Janssen R&D, Malvern, Pennsylvania; Jorge De Alba, Almirall S.A. Barcelona, Spain; Inge De Lepeleire, MSD, Brussels, Belgium; Tamara Dekker, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; Ingrid Delin, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; P. Dennison, NIHR Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences, NIHR-Wellcome Trust Clinical Research Facility, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; Annemiek Dijkhuis, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; Paul Dodson, AstraZeneca, Mölndal, Sweden; Aleksandra Draper, BioSci Consulting, Maasmechelen, Belgium; K. Dyson, CROMSOURCE, Stirling, United Kingdom; Jessica Edwards, Asthma UK, London, United Kingdom; L. El Hadjam, European Institute for Systems Biology and Medicine, University of Lyon, France; Rosalia Emma, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy; Magnus Ericsson, Karolinska University Hospital, Stockholm, Sweden; C. Faulenbach, Fraunhofer ITEM, Hannover, Germany; Breda Flood, European Federation of Allergy and Airways Diseases Patient's Associations, Brussels, Belgium; G. Galffy, Semmelweis University, Budapest, Hungary; Hector Gallart, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; D. Garissi, Global Head Clinical Research Division, CROMSOURCE, Italy; J. Gent, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom; M. Gerhardsson de Verdier, AstraZeneca, Mölndal, Sweden; D. Gibeon, National Heart and Lung Institute, Imperial College, London, United Kingdom; Cristina Gomez, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Kerry Gove, NIHR Southampton Respiratory Biomedical Research Unit and Clinical and Experimental Sciences, Southampton, United Kingdom; Neil Gozzard, UCB, Slough, United Kingdom; E. Guillmant-Farry, Royal Brompton Hospital, London, United Kingdom; E. Henriksson, Karolinska University Hospital & Karolinska Institutet, Stockholm, Sweden; Lorraine Hewitt, NIHR Southampton Respiratory Biomedical Research Unit, Southampton, United Kingdom; U. Hoda, Imperial College, London, United Kingdom; Richard Hu, Amgen, Thousand Oaks, California; Sile Hu, National Heart and Lung Institute, Imperial College, London, United Kingdom; X. Hu, Amgen, Thousand Oaks, California; E. Jeyasingham, UK Clinical Operations, GlaxoSmithKline, Stockley Park, United Kingdom; K. Johnson, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and repair, University Hospital of South Manchester, NHS Foundation Trust, Manchester, United Kingdom; N. Jullian, European Institute for Systems Biology and Medicine, University of Lyon, France; Juliette Kamphuis, Longfonds, Amersfoort, The Netherlands; Erika J. Kennington, Asthma UK, London, United Kingdom; Dyson Kerry, CromSource, Stirling, United Kingdom; G. Kerry, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University Hospital of South Manchester, NHS Foundation Trust, Manchester, United Kingdom; M. Klüglich, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; Hugo Knobel, Philips Research Laboratories, Eindhoven, The Netherlands; Johan Kolmert, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; J. R. Konradsen, Dept Women's and Children's Health & Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Maxim Kots, Chiesi Pharmaceuticals, SPA, Parma, Italy; Kosmas Kretsos, UCB, Slough, United Kingdom; L. Krueger, University Children's Hospital Bern, Switzerland; Scott Kuo, National Heart and Lung Institute, Imperial College, London, United Kingdom; Maciej Kupczyk, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Bart Lambrecht, University of Gent, Gent, Belgium; A.-S. Lantz, Karolinska University Hospital & Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Christopher Larminie, GlaxoSmithKline, London, United Kingdom; L. X. Larsson, AstraZeneca, Mölndal, Sweden; P. Latzin, University Children's Hospital of Bern, Bern, Switzerland; N. Lazarinis, Karolinska University Hospital & Karolinska Institutet, Stockholm, Sweden; N. Lemonnier, European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France; Saeeda Lone-Latif, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; L. A. Lowe, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University Hospital of South Manchester, NHS Foundation Trust, Manchester, United Kingdom; Alexander Manta, Roche Diagnostics GmbH, Mannheim, Germany; Lisa Marouzet, NIHR Southampton Respiratory Biomedical Research Unit, Southampton, United Kingdom; Jane Martin, NIHR Southampton Respiratory Biomedical Research Unit, Southampton, United Kingdom; Caroline Mathon, Centre of Allergy Research, Karolinska Institutet, Stockholm, Sweden; L. McEvoy, University Hospital, Department of Pulmonary Medicine, Bern, Switzerland; Sally Meah, National Heart and Lung Institute, Imperial College, London, United Kingdom; A. Menzies-Gow, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom; Leanne Metcalf, previously at Asthma UK, London, United Kingdom; Maria Mikus, Science for Life Laboratory & The Royal Institute of Technology, Stockholm, Sweden; Philip Monk, Synairgen Research, Southampton, United Kingdom; Shama Naz, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; K. Nething, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; Ben Nicholas, University of Southampton, Southampton, United Kingdom; U. Nihlén, previously at AstraZeneca, Mölndal, Sweden; Peter Nilsson, Science for Life Laboratory & The Royal Institute of Technology, Stockholm, Sweden; R. Niven, North West Severe Asthma Network, University Hospital South Manchester, United Kingdom; B. Nordlund, Department of Women's and Children's Health & Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; S. Nsubuga, Royal Brompton Hospital, London, United Kingdom; Jörgen Östling, AstraZeneca, Mölndal, Sweden; Antonio Pacino, Lega Italiano Anti Fumo, Catania, Italy; Susanna Palkonen, European Federation of Allergy and Airways Diseases Patient's Associations, Brussels, Belgium; J. Pellet, European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France; Giorgio Pennazza, University of Rome “Tor Vergata,” Rome Italy; Anne Petrén, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Sandy Pink, NIHR Southampton Respiratory Biomedical Research Unit, Southampton, United Kingdom; C. Pison, European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France; Anthony Postle, University of Southampton, United Kingdom; Malayka Rahman-Amin, previously at Asthma UK, London, United Kingdom; Lara Ravanetti, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; Emma Ray, NIHR Southampton Respiratory Biomedical Research Unit, Southampton, United Kingdom; Stacey Reinke, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Leanne Reynolds, previously at Asthma UK, London, United Kingdom; K. Riemann, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; Martine Robberechts, MSD, Brussels, Belgium; J. P. Rocha, Royal Brompton and Harefield NHS Foundation Trust, United Kingdom; C. Rossios, National Heart and Lung Institute, Imperial College, London, United Kingdom; Kirsty Russell, National Heart and Lung Institute, Imperial College, London, United Kingdom; Michael Rutgers, Longfonds, Amersfoort, The Netherlands; G. Santini, Università Cattolica del Sacro Cuore, Milan, Italy; Marco Santoninco, University of Rome “Tor Vergata,” Rome, Italy; M. Saqi, European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France; Corinna Schoelch, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; James P. R. Schofield, Centre for Proteomic Research, Institute for Life Sciences, University of Southampton, Southampton, United Kingdom; S. Scott, North West Severe Asthma Network, Countess of Chester Hospital, United Kingdom; N. Sehgal, North West Severe Asthma Network, Pennine Acute Hospital NHS Trust; Marcus Sjödin, Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Barbara Smids, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; Caroline Smith, NIHR Southampton Respiratory Biomedical Research Unit, Southampton, United Kingdom; Jessica Smith, Asthma UK, London, United Kingdom; Katherine M. Smith, University of Nottingham, United Kingdom; P. Söderman, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; A. Sogbessan, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom; F. Spycher, University Hospital Department of Pulmonary Medicine, Bern, Switzerland; Doroteya Staykova, University of Southampton, Southampton, United Kingdom; S. Stephan, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University Hospital of South Manchester, NHS Foundation Trust, Manchester, United Kingdom; J. Stokholm, University of Copenhagen and Danish Pediatric Asthma Centre Denmark; K. Strandberg, Karolinska University Hospital & Karolinska Institutet, Stockholm, Sweden; M. Sunther, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University Hospital of South Manchester, NHS Foundation Trust, Manchester, United Kingdom; M. Szentkereszty, Semmelweis University, Budapest, Hungary; L. Tamasi, Semmelweis University, Budapest, Hungary; K. Tariq, NIHR Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences, NIHR-Wellcome Trust Clinical Research Facility, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; John-Olof Thörngren, Karolinska University Hospital, Stockholm, Sweden; Jonathan Thorsen, COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; S. Valente, Università Cattolica del Sacro Cuore, Milan, Italy; Marianne van de Pol, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; C. M. van Drunen, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; Jonathan Van Eyll, UCB, Slough, United Kingdom; Jenny Versnel, previously at Asthma UK, London, United Kingdom; Anton Vink, Philips Research Laboratories, Eindhoven, The Netherlands; C. von Garnier, University Hospital Bern, Switzerland; A. Vyas, North West Severe Asthma Network, Lancashire Teaching Hospitals NHS Trust, United Kingdom; Frans Wald, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; Samantha Walker, Asthma UK, London, United Kingdom; Jonathan Ward, Histochemistry Research Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; Kristiane Wetzel, Boehringer Ingelheim Pharma GmbH, Biberach, Germany; Coen Wiegman, National Heart and Lung Institute, Imperial College, London, United Kingdom; Siân Williams, International Primary Care Respiratory Group, Aberdeen, United Kingdom; Xian Yang, Data Science Institute, Imperial College, London, United Kingdom; Elizabeth Yeyasingham, UK Clinical Operations, GlaxoSmithKline, Stockley Park, United Kingdom; W. Yu, Amgen, Thousand Oaks, California; W. Zetterquist, Department of Women's and Children's Health & Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Z. Zolkipli, NIHR Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences and Human Development and Health, Southampton, United Kingdom; and A. H. Zwinderman, Academic Medical Centre, University of Amsterdam, The Netherlands. Partner organizations: Novartis Pharma AG; University of Southampton, Southampton, UK; Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; Imperial College London, London, United Kingdom; University of Catania, Catania, Italy; University of Rome “Tor Vergata,” Rome, Italy; Hvidore Hospital, Hvidore, Denmark; Jagiellonian University Medical College, Krakow, Poland; University Hospital, Inselspital, Bern, Switzerland; Semmelweis University, Budapest, Hungary; University of Manchester, Manchester, United Kingdom; Université d'Aix-Marseille, Marseille, France; Fraunhofer Institute, Hannover, Germany; University Hospital, Umea, Sweden; Ghent University, Ghent, Belgium; Centre Naturale Recherche Scientifique, Lyon, France; Università Cattolica del Sacro Cuore, Rome, Italy; University Hospital, Copenhagen, Denmark; Karolinska Institutet, Stockholm, Sweden; Nottingham University Hospital, Nottingham, United Kingdom; University of Bergen, Bergen, Norway; Netherlands Asthma Foundation, Leusden, The Netherlands; European Lung Foundation, Sheffield, United Kingdom; Asthma UK, London, United Kingdom; European Federation of Allergy and Airways Diseases Patients' Associations, Brussels, Belgium; Lega Italiano Anti Fumo, Catania, Italy; International Primary Care Respiratory Group, Aberdeen, United Kingdom; Philips Research Laboratories, Eindhoven, The Netherlands; Synairgen Research, Southampton, United Kingdom; Aerocrine AB, Stockholm, Sweden; BioSci Consulting, Maasmechelen, Belgium; Almirall; AstraZeneca; Boehringer Ingelheim; Chiesi; GlaxoSmithKline; Roche; UCB; Janssen Biologics BV; Amgen NV; and Merck Sharp & Dome. Members of the ethics board: Jan-Bas Prins, biomedical research, LUMC, The Netherlands; Martina Gahlemann, clinical care, BI, Germany; Luigi Visintin, legal affairs, LIAF, Italy; Hazel Evans, pediatric care, Southampton, United Kingdom; Martine Puhl, patient representation (cochair), NAF, The Netherlands; Lina Buzermaniene, patient representation, EFA, Lithuania; Val Hudson, patient representation, Asthma UK; Laura Bond, patient representation, Asthma UK; Pim de Boer, patient representation and pathobiology, IND; Guy Widdershoven, research ethics, VUMC, The Netherlands; and Ralf Sigmund, research methodology and biostatistics, BI, Germany. Patient input platform: Amanda Roberts, United Kingdom; David Supple (chair), United Kingdom; Dominique Hamerlijnck, The Netherlands; Jenny Negus, United Kingdom; Juliëtte Kamphuis, The Netherlands; Lehanne Sergison, United Kingdom; Luigi Visintin, Italy; Pim de Boer (cochair), The Netherlands; and Susanne Onstein, The Netherlands. Members of the safety monitoring board: William MacNee, clinical care; Renato Bernardini, clinical pharmacology; Louis Bont, pediatric care and infectious diseases; Per-Ake Wecksell, patient representation; Pim de Boer, patient representation and pathobiology (chair); Martina Gahlemann, patient safety advice and clinical care (cochair); and Ralf Sigmund, bioinformatician.

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Background: The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required. Objective: We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity. Methods: Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17–high and IL-13–high asthma phenotypes. Results: Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17–high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and β-defensin. Conclusion: The IL-17–high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.

AB - Background: The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required. Objective: We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity. Methods: Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17–high and IL-13–high asthma phenotypes. Results: Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17–high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and β-defensin. Conclusion: The IL-17–high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.

KW - asthma

KW - biomarkers

KW - bronchial biopsies

KW - bronchial brushings

KW - IL-17

KW - psoriasis

UR - http://www.scopus.com/inward/record.url?scp=85065197283&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2019.03.027

DO - 10.1016/j.jaci.2019.03.027

M3 - Journal article

C2 - 30998987

AN - SCOPUS:85065197283

SN - 0091-6749

VL - 144

SP - 1198

EP - 1213

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 5

ER -

IL-17–high asthma with features of a psoriasis immunophenotype

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