Treatable traits in the European U‐<scp>BIOPRED</scp> adult asthma cohorts
Authors: Andrew J. Simpson, Pieter‐Paul Hekking, Dominick E. Shaw, Louise J. Fleming, Graham Roberts, John H. Riley, Stewart Bates, Ana R. Sousa, Aruna T. Bansal, Ioannis Pandis, Kai Sun, Per S. Bakke, Massimo Caruso, Barbro Dahlén, Sven‐Erik Dahlén, Ildiko Horvath, Norbert Krug, Paolo Montuschi, Thomas Sandstrom, Florian Singer, Ian M. Adcock, Scott S. Wagers, Ratko Djukanovic, Kian Fan Chung, Peter J. Sterk, Stephen J. Fowler
Journal: Allergy (2018)

To the Editor, Improvements in asthma outcomes have stalled over the past decade,1 which may be attributed to treating patients on the basis of a generic diagnostic label. The taxonomy "Treatable Traits" was proposed by Agusti et al (2016) as a precision medicine approach for the diagnosis and management of chronic airway diseases that is based on the identification of genetic, phenotypic and psychosocial characteristics for which therapeutic interventions are known to improve respiratory health.2 The Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) project was set up to identify multidimensional phenotypes and endotypes in severe asthma.3 Here, we aim to identify and quantify treatable traits within the severe and mild/moderate U-BIOPRED adult asthma cohorts3 and across previously identified phenotypes.4 We hypothesize that treatable traits will be more common in severe asthma and vary significantly across asthma phenotypes. Data from the severe asthma and mild/moderate asthma cohorts of the U-BIOPRED project were included in this study. Full details of the study population and methodology have been presented elsewhere.3 Criteria for treatable traits were based on Agusti et al2 and presented in Table 1. Chi-squared tests were used to examine differences in the prevalence of each treatable trait between groups and independent sample t tests used to determine differences in the total number of traits between cohorts. No adjustment for multiple testing was applied as the analyses were considered exploratory; as this may inflate the type-1 error rate, individual P values are presented for each comparison. A post hoc power calculation shows our sample of 421 (severe smoking/ex-smoking vs severe nonsmoking) and 399 (severe nonsmoking vs mild/moderate) is sufficient to identify a difference in treatable trait prevalence between cohorts with a medium effect size (0.3) and a power close to 1.00. Data analysis was supported by IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY, USA, with significance set at P < 0.05, unless otherwise stated. Twenty-three treatable traits were identified, including seven pulmonary, 11 extra-pulmonary and five behavioural/psychosocial treatable traits (Table 2). Seven out of the ten most prevalent traits in severe asthma were classed as pulmonary treatable traits. The most prevalent extra-pulmonary traits were as follows: atopy, rhinosinusitis, obesity, reflux and obstructive sleep apnoea. Poor adherence to medication, anxiety and depression were the most common behavioural/psychosocial treatable traits in severe asthma. The severe smoking/ex-smoking asthma cohort displayed on average one more treatable trait than the severe nonsmoking asthma cohort (8 ± 3 vs 7 ± 2, P = 0.007). Differences in the prevalence of individual traits, all higher in the smoking/ex-smoking cohort, were seen in bronchodilator reversibility, fixed airflow limitation (P = 0.050), reflux, cardiovascular disease and psychiatric disease. Only atopy was higher in prevalence in the nonsmoking cohort. Nonsmoking individuals with severe asthma have more treatable traits than nonsmoking individuals with mild/moderate asthma (7 ± 2 vs 5 ± 2, P < 0.001). Likewise, individual treatable traits were generally more common in nonsmoking severe asthma compared to the mild/moderate asthma cohort. Only in atopy and poor medication adherence was the prevalence of the treatable trait significantly higher in mild/moderate asthma. The prevalence of treatable traits across previously identified clusters4 is presented and discussed on the Appendix S1. The identification of treatable traits facilitates a precision medicine strategy for the management of airways disease, that is free from the traditional diagnostic labels and based on the identification of pulmonary, extra-pulmonary and psychosocial characteristics, for which there are evidence-based therapeutic choices. This proposal was recently supported by the Lancet commission "After asthma: redefining airways disease"5 and was a favoured strategy to move the field towards precision medicine at a research seminar, held at the European Respiratory Society's annual meeting.6 Ours is the first study to apply the concept to a large asthma cohort, and we have identified a plethora of pulmonary, extra-pulmonary and behavioural / psychosocial treatable traits. The prevalence of treatable traits, both pulmonary and nonpulmonary, was generally higher in individuals with severe asthma compared to mild/moderate asthma. We also identified a difference in the prevalence of pulmonary treatable traits across clinical clusters of patients. Approximately 5%-10% of asthmatics remain poorly controlled, despite being prescribed the maximum dose of therapy.7 Our data suggest individuals with severe asthma, who remain symptomatic despite receiving a high dose ICS, display on average seven treatable traits, and therefore present multiple treatment opportunities beyond the traditional stepwise approach. Perhaps unsurprisingly, pulmonary traits accounted for seven of the ten most prevalent treatable traits in our asthma cohorts and were generally more common in severe asthma. Interestingly, however, we also observed an increased prevalence of extra-pulmonary and behavioural/psychosocial traits in severe asthma suggesting an association with asthma severity, which may reflect the impact of living with severe chronic respiratory conditions. Our data highlight that multiple treatment opportunities exist beyond the pulmonary system, and a holistic management strategy, such as the treatable trait approach, may be beneficial to both physical and mental well-being. This is the first study to apply the concept of treatable traits to a large asthma cohort. Several limitations are worthy of discussion; firstly, we utilized the original paper on treatable traits,2 treatment guidelines and clinical experience to determine the classification criteria for our treatable traits. We acknowledge that our list of traits is not exhaustive and that the selected criteria for some traits could be contentious. Prospective studies would benefit from additional paraclinical investigations to determine the prevalence of additional treatable traits, for example ventilation heterogeneity and small airway disease. Finally, we acknowledge that some traits may not be mutually exclusive and some maybe modified by asthma treatment. Associations between traits were not explored here but have been discussed elsewhere.8 In conclusion, the label-free, precision medicine approach provided by the treatable traits construct allowed for the identification of multiple treatment opportunities for patients with asthma, beyond the traditional stepwise approach. We eagerly await the results of prospective, longitudinal, clinical trials to determine whether this translates to improved clinical outcomes for individuals with respiratory disease. Dr Simpson has nothing to disclose; Dr. Hekking has nothing to disclose; Dr Shaw reports advisory board fees from GSK, Novartis and AZ and travel fees from TEVA and AZ; Dr. Fleming reports personal fees from Vectura, personal fees from Novartis, personal fees from Boehringer Ingelheim, outside the submitted work; Dr. Roberts reports grants to University of Southampton during the conduct of the study; Dr. Riley reports he is employed by and holds shares in GlaxoSmithKline. Dr. Bates reports he is employed by and holds shares in GlaxoSmithKline. Dr. Sousa has nothing to disclose. Dr. Bansal has nothing to disclose. Dr. Pandis has nothing to disclose. Dr. Sun has nothing to disclose. Dr P Bakke has nothing to disclose. Dr. Caruso has nothing to disclose. Dr. B Dahlén reports personal fees from Advisory Board membership, personal fees from Payments for lectures, outside the submitted work; Dr. S-E Dahlén reports personal fees from AZ, GSK, Merck, Novartis, RSPR AB, Teva, outside the submitted work; Dr. Horvath reports personal fees from AstraZeneca, Boehringer-Ingelheim, GSK, Novartis, CSL Behring, Roche, Sandoz, Chiesi, Sager Pharma, Orion, Affidea and Teva, outside the submitted work. Dr. Krug reports grants from IMI, during the conduct of the study; Dr. Montuschi reports personal fees from AstraZeneca, outside the submitted work; Dr. Sandstrom reports personal fees from AstraZeneca, personal fees from GSK, personal fees from Boehringer Ingelheim, personal fees from Novartin, personal fees from Teva, outside the submitted work; Dr. Singer has nothing to disclose; Dr. Adcock reports grants from EU-IMI, during the conduct of the study; Dr. Wagers reports grants from Innovative Medicines Initiative, other from Roche, grants from European respiratory society, during the conduct of the study, other from GSK, other from European Respiratory Society, outside the submitted work; Dr. Chung reports personal fees from Advisory Board membership, grants for research, personal fees from payments for lectures, outside the submitted work; Dr. Sterk reports grants from Innovative Medicines Initiative (IMI), during the conduct of the study; Dr. Fowler has nothing to disclose. The research leading to these results has received support from the Innovative Medicines Initiative (IMI) Joint Undertaking, under grant agreement no. 115010, resources for which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and kind contributions from companies in the European Federation of Pharmaceutical Industries and Associations (EFPIA) (www.imi.europa.eu). I. M. Adcock (National Heart and Lung Institute, Imperial College, London, UK), 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 Ltd, St. John's Innovation Centre, Cambridge, UK), F. Baribaud (Janssen R&D, USA), S. Bates (Respiratory Therapeutic Unit, GSK, London, UK), E. H. Bel (Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands), J. Bigler (previously with Amgen Inc.), H. Bisgaard (COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark), M. J. Boedigheimer (Amgen Inc., Thousand Oaks, CA), 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, UK), 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, UK), A. Bush (National Heart and Lung Institute, Imperial College, London, UK; Royal Brompton and Harefield NHS Trust, UK), M. Caruso (Department of 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), F. K. Chung (National Heart and Lung Institute, Imperial College, London, UK), C. H. Compton (Respiratory Therapeutic Unit, GSK, London, UK), J. Corfield (Areteva R&D, Nottingham, UK), A. D'Amico (University of Rome 'Tor Vergata', Rome Italy), B. Dahlén (Karolinska University Hospital & Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden), S. E. Dahlén (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, UK), V. J. Erpenbeck (Translational Medicine, Respiratory Profiling, Novartis Institutes for Biomedical Research, Basel, Switzerland), D. Erzen and 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, UK; Royal Brompton and Harefield NHS Trust, UK), E. Formaggio (previously of 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, UK), 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), V. Goss (NIHR Respiratory Biomedical Research Unit, University Hospital Southampton NHS Foundation Trust, Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton, UK), Y. Guo (Data Science Institute, Imperial College, London, UK), S. Hashimoto (Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands), J. Haughney (International Primary Care Respiratory Group, Aberdeen, Scotland), 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, UK), J. M. Hohlfeld (Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany), C. Holweg (Respiratory and Allergy Diseases, Genentech, San Francisco, CA), I. Horváth (Semmelweis University, Budapest, Hungary), P. Howarth (NIHR Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences and Human Development and Health, Southampton, UK), A. J. James (Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden), R. Knowles (Arachos Pharma, Stevenge, UK), A. J. Knox (Respiratory Research Unit, University of Nottingham, Nottingham, UK), 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, USA), R. Lutter (Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands), A. Manta (Roche Diagnostics GmbH, Mannheim, Germany), S. Masefield (European Lung Foundation, Sheffield, UK), J. G. Matthews (Respiratory and Allergy Diseases, Genentech, San Francisco, CA), A. Mazein (European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Lyon, France), A. Meiser (Data Science Institute, Imperial College, London, UK), 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, UK), J. Musial (Department of Medicine, Jagiellonian University Medical College, Krakow, Poland), D. Myles (Respiratory Therapeutic Unit, GSK, London, UK), 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, UK), S. Pavlidis (National Heart and Lung Institute, Imperial College, London, UK), A. Postle (University of Southampton, UK), P. Powel (European Lung Foundation, Sheffield, UK), G. Praticò (CROMSOURCE, Verona, Italy), M. Puig Valls (CROMSOURCE, Barcelona, Spain), N. Rao (Janssen R&D, USA), J. Riley (Respiratory Therapeutic Unit, GSK, London, UK), A. Roberts (Asthma UK, London, UK), G. Roberts (NIHR Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences and Human Development and Health, Southampton, UK), A. Rowe (Janssen R&D, UK), T. Sandström (Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden), J. P. R. Schofield (Centre for Proteomic Research, Institute for Life Sciences, University of Southampton, Southampton,UK), 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, UK), D. E. Shaw (Respiratory Research Unit, University of Nottingham, UK), 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, UK), A. R. Sousa (Respiratory Therapeutic Unit, GSK, London, UK), P. J. Sterk (Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands), K. Sun (Data Science Institute, Imperial College, London, UK), B. Thornton (MSD, USA), 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, UK), 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), S. J. Wilson (Histochemistry Research Unit, Faculty of Medicine, University of Southampton, Southampton, UK). 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