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Sanna Toppila-Salmi,1,2 Leif Bjermer,3 Lars-Olaf Cardell,4,5 Anders Cervin,6,7 Tuuli Heinikari,2 Lauri Lehtimäki,8,9 Marie Lundberg,10 Jens C Richter,11 Saara Sillanpää9,12 1Department of Otorhinolaryngology, Kuopio University Hospital and School of Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland; 2Skin and Allergy Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; 3Department of Clinical Sciences, Respiratory Medicine and Allergology, Lund University, Lund, Sweden; 4Division of ENT Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; 5Department of Otorhinolaryngology, Karolinska University Hospital, Stockholm, Sweden; 6Centre for Clinical Research, University of Queensland, Brisbane, Australia; 7Faculty of Medicine, Lund University, Lund, Sweden; 8Allergy Centre, Tampere University Hospital, Tampere, Finland; 9Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; 10Department of Otorhinolaryngology – Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; 11Department of Asthma and Allergology, Clinic of Lung Medicine, Skåne University Hospital and Lund University, Lund, Sweden; 12Department of Otorhinolaryngology and Head and Neck Surgery, Tampere University Hospital, Tampere, FinlandCorrespondence: Sanna Toppila-Salmi, Haartmaninkatu 3, Haartman Institute, University of Helsinki, Helsinki, 00014, Finland, Email sanna.salmi@helsinki.fiAbstract: Severe chronic rhinosinusitis with nasal polyposis (CRSwNP) is a disabling airway disease that significantly impacts patients’ lives through the severity of symptoms, the need for long-term medical treatment and the high risk of recurrence post-surgery. Biological agents targeting type 2 immune responses underlying the pathogenesis of CRSwNP have shown effectiveness in reducing polyp size and eosinophilic infiltrate, and in decreasing the need for additional sinus surgeries. However, despite recent progress in understanding and treating the disease, type 2 inflammation-driven severe CRSwNP continues to pose challenges to clinical management due to several factors such as persistent inflammation, polyp recurrence, heterogeneity of disease, and comorbidities. This article presents the findings of a scientific discussion involving a panel of ear, nose and throat (ENT) specialists and pulmonologists across Sweden and Finland. The discussion aimed to explore current management practices for type 2 inflammation-driven severe CRSwNP in the Nordic region. The main topics examined encompassed screening and referral, measurements of disease control, treatment goals, and future perspectives. The experts emphasized the importance of a collaborative approach in the management of this challenging patient population. The discussion also revealed a need to broaden treatment options for patients with type 2 inflammation-driven CRSwNP and comorbid conditions with shared type 2 pathophysiology. In light of the supporting evidence, a shift in the disease model from the presence of polyps to that of type 2 inflammation may be warranted. Overall, this discussion provides valuable insights for the scientific community and can potentially guide the future management of CRSwNP.Keywords: chronic rhinosinusitis, type 2 immunity, surgery, biological therapy, Nordic countries, collaboration

Martin Garcia-Ryde,1 Nicole MD van der Burg,1 Carin E Larsson,1 Anna-Karin Larsson-Callerfelt,2 Gunilla Westergren-Thorsson,2 Leif Bjermer,1 Ellen Tufvesson1 1Department of Clinical Sciences Lund, Respiratory Medicine, Allergology and Palliative Medicine, Lund University, Lund, Sweden; 2Department of Experimental Medical Science, Lung Biology, Lund University, Lund, SwedenCorrespondence: Ellen Tufvesson, Department of Clinical Sciences Lund, Respiratory Medicine, Allergology and Palliative Medicine, Lund University, BMC, D12, 221 84, Lund, Sweden, Email Ellen.Tufvesson@med.lu.seBackground and aim: Cigarette smoking is the most common cause of chronic obstructive pulmonary disease (COPD) but more mechanistic studies are needed. Cigarette smoke extract (CSE) can elicit a strong response in many COPD-related cell types, but no studies have been performed in lung fibroblasts. Therefore, we aimed to investigate the effect of CSE on gene expression in lung fibroblasts from healthy and COPD subjects.Patients and methods: Primary lung fibroblasts, derived from six healthy and six COPD subjects (all current or ex-smokers), were either unstimulated (baseline) or stimulated with 30% CSE for 4 h prior to RNA isolation. The mRNA expression levels were measured using the NanoString nCounter Human Fibrosis V2 panel (760 genes). Pathway enrichment was assessed for unique gene ontology terms of healthy and COPD.Results: At baseline, a difference in the expression of 17 genes was found in healthy and COPD subjects. Differential expression of genes after CSE stimulation resulted in significantly less changes in COPD lung fibroblasts (70 genes) than in healthy (207 genes), with 51 genes changed in both. COPD maintained low NOTCH signaling throughout and upregulated JUN > 80%, indicating an increase in apoptosis. Healthy downregulated the Mitogen-activated protein kinase (MAPK) signaling cascade, including a ≥ 50% reduction in FGF2, CRK, TGFBR1 and MEF2A. Healthy also downregulated KAT6A and genes related to cell proliferation, all together indicating possible cell senescence signaling.Conclusion: Overall, COPD lung fibroblasts responded to CSE stimulation with a very different and deficient expression profile compared to healthy. Highlighting that stimulated healthy cells are not an appropriate substitute for COPD cells which is important when investigating the mechanisms of COPD.Plain Language Summary: We investigated, for the first time, the effect of cigarette smoke extract (CSE) on gene expression in lung fibroblasts from healthy subjects and subjects with COPD. We found that fibroblasts from subjects with COPD respond very differently than from healthy subjects by changing fewer gene expressions after CSE. Pathway enrichment suggested that fibroblasts from subjects with COPD respond to CSE by affecting genes involved in apoptosis pathways, while fibroblasts from healthy subjects respond by affecting genes involved in cell senescence. This study highlights the importance of assessing stimulated COPD cells in mechanistic studies.Keywords: COPD, lung fibroblast, gene expression, cigarette smoke extract, GO term, signaling pathways

Breda Cushen,1,* Mariko Siyue Koh,2,* Trung N Tran,3 Neil Martin,3,4 Ruth Murray,5 Thendral Uthaman,6 Celine Yun Yi Goh,5,6 Rebecca Vella,7 Neva Eleangovan,5,6 Lakmini Bulathsinhala,5,6 Jorge F Maspero,8,9 Matthew J Peters,10 Florence Schleich,11 Paulo Pitrez,12 George Christoff,13 Mohsen Sadatsafavi,14 Carlos A Torres-Duque,15,16 Celeste Porsbjerg,17 Alan Altraja,18 Lauri Lehtimäki,19 Arnaud Bourdin,20 Christian Taube,21 Nikolaos G Papadopoulos,22,23 Csoma Zsuzsanna,24 Unnur Björnsdóttir,25 Sundeep Salvi,26 Enrico Heffler,27 Takashi Iwanaga,28 Mona al-Ahmad,29 Désirée Larenas-Linnemann,30 Job FM van Boven,31 Bernt Bøgvald Aarli,32,33 Piotr Kuna,34 Cláudia Chaves Loureiro,35,36 Riyad Al-lehebi,37 Jae Ha Lee,38 Nuria Marina,39 Leif Bjermer,40 Chau-Chyun Sheu,41,42 Bassam Mahboub,43 John Busby,44 Andrew Menzies-Gow,45 Eileen Wang,46 David B Price5,6,47 On behalf of ISAR Inventory Study Group1Department of Respiratory Medicine, Beaumont Hospital, Dublin, Ireland; 2Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore, Singapore; 3AstraZeneca, Gaithersburg, MD, USA; 4Department of Respiratory Medicine, University of Leicester, Leicester, UK; 5Optimum Patient Care Global, Cambridge, UK; 6Observational Pragmatic Research Institute, Singapore, Singapore; 7Optimum Patient Care, Brisbane, Queensland, Australia; 8Clinical Research for Allergy and Respiratory Medicine, CIDEA Foundation, Buenos Aires, Argentina; 9University Career of Specialists in Allergy and Clinical Immunology at the Buenos Aires University School of Medicine, Buenos Aires, Argentina; 10Department of Thoracic Medicine, Concord Hospital, Sydney, Australia; 11CHU Sart-Tilman, GIGA I3, University of Liege, Liège, Wallonia, Belgium; 12Pulmonology Division, Hospital Santa Casa de Porto Alegre, Porto Alegre, Brazil; 13Faculty of Public Health, Medical University, Sofia, Bulgaria; 14Respiratory Evaluation Sciences Program, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, Canada; 15CINEUMO, Respiratory Research Center, Fundación Neumológica Colombiana, Bogotá, Colombia; 16Universidad de La Sabana, Chia, Colombia; 17Department of Respiratory Medicine and Infectious Diseases, Research Unit, Bispebjerg Hospital, Copenhagen, Denmark; 18Department of Pulmonology, University of Tartu and Lung Clinic, Tartu University Hospital, Tartu, Estonia; 19Allergy Centre, Tampere University Hospital, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; 20PhyMedExp, Univ Montpellier, CNRS, INSERM, CHU Montpellier, Montpellier, France; 21Department of Pulmonary Medicine, University Medical Center Essen-Ruhrlandklinik, Essen, Germany; 22Division of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester, UK; 23Allergy Department, 2nd Pediatric Clinic, University of Athens, Athens, Greece; 24Asthma Outpatient Clinic, National Koranyi Institute for Pulmonology, Budapest, Hungary; 25Department of Allergy and Respiratory Medicine, University Hospital, Reykjavik, Iceland; 26Pulmocare Research and Education Foundation, Pune, India; 27Personalized Medicine, Asthma and Allergy, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; 28Kindai University Hospital, Osakasayama, Japan; 29Microbiology Department, College of Medicine, Kuwait University, Kuwait, Al-Rashed Allergy Center, Ministry of Health, Kuwait City, Kuwait; 30Centro de Excelencia en Asma y Alergia, Hospital Médica Sur, Ciudad de México, Mexico; 31University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Department of Clinical Pharmacy & Pharmacology, Groningen, the Netherlands; 32Department of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway; 33Department of Clinical Science, University of Bergen, Bergen, Norway; 34Division of Internal Medicine Asthma and Allergy, Medical University of Lodz, Lodz, Poland; 35Pneumology Unit, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; 36Centre of Pneumology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; 37Department of Pulmonology, King Fahad Medical City, Riyadh, Saudi Arabia, Alfaisal University, Riyadh, Saudi Arabia; 38Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea; 39Pneumology Service, Biocruces, Cruces University Hospital, Barakaldo, Spain; 40Respiratory Medicine and Allergology, Department of Clinical Sciences, Skåne University Hospital, Lund University, Lund, Sweden; 41Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 42Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 43Rashid Hospital, Dubai Health Authority (DHA), Dubai, United Arab Emirates; 44Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, Northern Ireland, UK; 45Lung Division, Royal Brompton & Harefield Hospital, London, UK; 46Division of Allergy and Clinical Immunology, Department of Medicine, National Jewish Health and University of Colorado School of Medicine, Denver and Aurora, CO, USA; 47Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, Scotland, UK*These authors contributed equally to this workCorrespondence: David B Price, Observational and Pragmatic Research Institute (OPRI) Pte Ltd, 22 Sin Ming Lane, #06-76, Midview City, 573969, Singapore, Tel +65 3105 1489, Email dprice@opri.sgAim: The International Severe Asthma Registry (ISAR; http://isaregistries.org/) uses standardised variables to enable multi-country and adequately powered research in severe asthma. This study aims to look at the data countries within ISAR and non-ISAR countries reported collecting that enable global research that support individual country interests.Methods: Registries were identified by online searches and approaching severe asthma experts. Participating registries provided data collection specifications or confirmed variables collected. Core variables (results from ISAR’s Delphi study), steroid-related comorbidity variables, biologic safety variables (serious infection, anaphylaxis, and cancer), COVID-19 variables and additional variables (not belonging to the aforementioned categories) that registries reported collecting were summarised.Results: Of the 37 registries identified, 26 were ISAR affiliates and 11 non-ISAR affiliates. Twenty-five ISAR-registries and 4 non-ISAR registries reported collecting > 90% of the 65 core variables. Twenty-three registries reported collecting all optional steroid-related comorbidity variables. Twenty-nine registries reported collecting all optional safety variables. Ten registries reported collecting COVID-19 variables. Twenty-four registries reported collecting additional variables including data from asthma questionnaires (10 Asthma Control Questionnaire, 20 Asthma Control Test, 11 Asthma Quality of Life Questionnaire, and 4 EuroQol 5-dimension 5-level Questionnaire). Eight registries are linked to databases such as electronic medical records and national claims or disease databases.Conclusion: Standardised data collection has enabled individual severe asthma registries to collect unified data and increase statistical power for severe asthma research irrespective of ISAR affiliations.Keywords: Asia-Pacific, biologics, COVID-19, Europe, ISAR, International Severe Asthma Registry, oral corticosteroids, Registry, Middle East, Severe Asthma, Latin America, USA

Wenjia Chen,1 Mohsen Sadatsafavi,2 Trung N Tran,3 Ruth B Murray,4 Chong Boon Nigel Wong,1 Nasloon Ali,4,5 Cono Ariti,4,5 Esther Garcia Gil,6 Anthony Newell,5,7 Marianna Alacqua,8 Mona Al-Ahmad,9 Alan Altraja,10 Riyad Al-Lehebi,11,12 Mohit Bhutani,13 Leif Bjermer,14 Anne Sofie Bjerrum,15 Arnaud Bourdin,16 Lakmini Bulathsinhala,4,5 Anna von Bülow,17 John Busby,18 Giorgio Walter Canonica,19,20 Victoria Carter,4,5 George C Christoff,21 Borja G Cosio,22 Richard W Costello,23 J Mark FitzGerald,24 João A Fonseca,25 Kwang Ha Yoo,26 Liam G Heaney,27 Enrico Heffler,19,20 Mark Hew,28,29 Ole Hilberg,30 Flavia Hoyte,31,32 Takashi Iwanaga,33 David J Jackson,34,35 Rupert C Jones,36 Mariko Siyue Koh,37,38 Piotr Kuna,39 Désirée Larenas-Linnemann,40 Sverre Lehmann,41 Lauri A Lehtimäki,42,43 Juntao Lyu,5,7 Bassam Mahboub,44,45 Jorge Maspero,46,47 Andrew N Menzies-Gow,48 Concetta Sirena,49 Nikolaos Papadopoulos,50,51 Andriana I Papaioannou,52 Luis Pérez de Llano,53,54 Diahn-Warng Perng,55,56 Matthew Peters,57 Paul E Pfeffer,58,59 Celeste M Porsbjerg,17 Todor A Popov,60 Chin Kook Rhee,61 Sundeep Salvi,62 Camille Taillé,63 Christian Taube,64 Carlos A Torres-Duque,65 Charlotte S Ulrik,66 Seung Won Ra,67 Eileen Wang,31,32 Michael E Wechsler,68 David B Price4,5,69 1Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore; 2Respiratory Evaluation Sciences Program, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada; 3AstraZeneca, Gaithersburg, MD, USA; 4Optimum Patient Care, Cambridge, UK; 5Observational and Pragmatic Research Institute, Singapore, Singapore; 6AstraZeneca, Barcelona, Spain; 7Optimum Patient Care, Queensland, VIC, Australia; 8AstraZeneca, Cambridge, UK; 9Microbiology Department, Faculty of Medicine, Kuwait University, Al-Rashed Allergy Center, Ministry of Health, Kuwait City, Kuwait; 10Department of Pulmonology, University of Tartu and Lung Clinic, Tartu University Hospital, Tartu, Estonia; 11Department of Pulmonology, King Fahad Medical City, Riyadh, Saudi Arabia; 12College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; 13Department of Medicine, Division of Pulmonary Medicine, University of Alberta, Western Canada, AB, Canada; 14Department of Clinical Sciences, Respiratory Medicine and Allergology, Skåne University Hospital, Lund University, Lund, Sweden; 15Department of Respiratory Medicine and Allergy, Aarhus University Hospital, Jutland, Aarhus, Denmark; 16PhyMedExp, Univ Montpellier, CNRS, INSERM, CHU Montpellier, Montpellier, France; 17Respiratory Research Unit, Bispebjerg University Hospital, Copenhagen, Denmark; 18Centre for Public Health, Queen’s University Belfast, Belfast, Northern Ireland; 19Personalized Medicine, Asthma and Allergy, Humanitas Clinical and Research Center IRCCS, Milan, Italy; 20Department of Biomedical Sciences, Humanitas University, Milan, Italy; 21Medical University-Sofia, Faculty of Public Health, Sofia, Bulgaria; 22Son Espases University Hospital-IdISBa-Ciberes, Mallorca, Spain; 23Department of Respiratory Medicine, Clinical Research Centre, Smurfit Building Beaumont Hospital, RCSI, Dublin, Ireland; 24Department of Medicine, the University of British Columbia, Vancouver, BC, Canada; 25Comunity Health, Information and Decision Sciences Department (MEDCIDS) & Center for Health Technology and Services Research (CINTESIS), Faculty of Medicine of University of Porto, Porto, Portugal; 26KonKuk University School of Medicine in Seoul, Seoul, Korea; 27Wellcome-Wolfson Centre for Experimental Medicine, Queen’s University Belfast, Belfast, Northern Ireland; 28Allergy, Asthma & Clinical Immunology Service, Alfred Health, Melbourne, VIC, Australia; 29Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia; 30Medical Department, Vejle University Hospital, Jutland, Vejle, Denmark; 31Department of Medicine, Division of Allergy and Clinical Immunology, National Jewish Health, Denver, CO, USA; 32Department of Internal Medicine, Division of Allergy & Clinical Immunology, University of Colorado School of Medicine, Aurora, CO, USA; 33Center for General Medical Education and Clinical Training, Kindai University Hospital, Osakasayama, Japan; 34UK Severe Asthma Network and National Registry, Guy’s and St Thomas’ NHS Trust, London, UK; 35School of Immunology & Microbial Sciences, King’s College London, London, UK; 36Research and Knowledge Exchange, Plymouth Marjon University, Plymouth, UK; 37Respiratory & Critical Care Medicine, Singapore General Hospital, Singapore, Singapore; 38SingHealth Duke-NUS Lung Centre, Singapore, Singapore; 39Division of Internal Medicine, Asthma and Allergy Medical University of &Lstrok;ód&zacute;, &Lstrok;ód&zacute;, Poland; 40Directora Centro de Excelencia en Asma y Alergia, Hospital Médica Sur, Ciudad de México, Mexico; 41Section of Thoracic Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway; 42Allergy Centre, Tampere University Hospital, Tampere, Finland; 43Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; 44College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; 45Rashid Hospital, Dubai Health Authority, Dubai, United Arab Emirates; 46Clinical Research for Allergy and Respiratory Medicine, CIDEA Foundation, Buenos Aires, Argentina; 47University Career of Specialists in Allergy and Clinical Immunology at the Buenos Aires University School of Medicine, Buenos Aires, Argentina; 48Royal Brompton & Harefield Hospitals, London, UK; 49Severe Asthma Network in Italy (SANI), Milano, Italy; 50Division of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester, UK; 51Allergy Department, 2nd Pediatric Clinic, University of Athens, Athens, Greece; 52 2nd Respiratory Medicine Department, National and Kapodistrian University of Athens Medical School, Attikon University Hospital, Athens, Greece; 53Pneumology Service, Lucus Augusti University Hospital, EOXI Lugo, Lugo, Spain; 54Biodiscovery Research Group, Health Research Institute of Santiago de Compostela, Santiago de Compostela, Spain; 55Division of Clinical Respiratory Physiology Chest Department, Taipei Veterans General Hospital, Taipei, Taiwan; 56COPD Assembly of the Asian Pacific Society of Respirology Hongo, Bunkyo-ku, Tokyo, Japan; 57Department of Thoracic Medicine, Concord Hospital, Sydney, NSW, Australia; 58Department of Respiratory Medicine, Barts Health NHS Trust, London, UK; 59Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 60University Hospital ”sv. Ivan Rilski”, Sofia, Bulgaria; 61Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul, South Korea; 62Pulmocare Research and Education Foundation, Pune, India; 63Department of Respiratory Diseases, Bichat Hospital, AP-HP Nord-Université de Paris, Paris, France; 64Department of Pulmonary Medicine, University Medical Center Essen-Ruhrlandklinik, Essen, Germany; 65CINEUMO, Respiratory Research Center, Fundación Neumológica Colombiana, Bogotá, Colombia; 66Department of Respiratory Medicine, Copenhagen University Hospital-Hvidovre, Hvidovre, Denmark; 67Department of Internal Medicine, Division of Pulmonology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea; 68Department of Medicine, NJH Cohen Family Asthma Institute, National Jewish Health, Denver, CO, USA; 69Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UKCorrespondence: David B Price, Observational and Pragmatic Research Institute, 22 Sin Ming Lane, &num;06 Midview City, Singapore, Singapore, 573969, Tel +65 3105 1489, Email dprice@opri.sgBackground: Many severe asthma patients with high oral corticosteroid exposure (HOCS) often do not initiate biologics despite being eligible. This study aimed to compare the characteristics of severe asthma patients with HOCS who did and did not initiate biologics.Methods: Baseline characteristics of patients with HOCS (long-term maintenance OCS therapy for at least 1 year, or ≥ 4 courses of steroid bursts in a year) from the International Severe Asthma Registry (ISAR; https://isaregistries.org/), who initiated or did not initiate biologics (anti-lgE, anti-IL5/5R or anti-IL4R), were described at the time of biologic initiation or registry enrolment. Statistical relationships were tested using Pearson’s chi-squared tests for categorical variables, and t-tests for continuous variables, adjusting for potential errors in multiple comparisons.Results: Between January 2015 and February 2021, we identified 1412 adult patients with severe asthma from 19 countries that met our inclusion criteria of HOCS, of whom 996 (70.5%) initiated a biologic and 416 (29.5%) did not. The frequency of biologic initiation varied across geographical regions. Those who initiated a biologic were more likely to have higher blood eosinophil count (483 vs 399 cells/μL, p=0.003), serious infections (49.0% vs 13.3%, p< 0.001), nasal polyps (35.2% vs 23.6%, p< 0.001), airflow limitation (56.8% vs 51.8%, p=0.013), and uncontrolled asthma (80.8% vs 73.2%, p=0.004) despite greater conventional treatment adherence than those who did not start a biologic. Both groups had similar annual asthma exacerbation rates in the previous 12 months (5.7 vs 5.3, p=0.147).Conclusion: Around one third of severe HOCS asthma patients did not receive biologics despite a similar high burden of asthma exacerbations as those who initiated a biologic therapy. Other disease characteristics such as eosinophilic phenotype, serious infectious events, nasal polyps, airflow limitation and lack of asthma control appear to dictate biologic use.Keywords: severe asthma, biologics, real-world, treatment pattern, patient characteristics

Soham Shukla,1 Dhvani Shah,2 Alan Martin,3 Nancy A Risebrough,4 Robyn Kendall,5 Claus F Vogelmeier,6 Isabelle Boucot,3 Lee Tombs,7 Leif Bjermer,8 Paul W Jones,3 Edward Kerwin,9 Chris Compton,3 François Maltais,10 David A Lipson,11,12 Afisi S Ismaila1,13 1Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 2ICON, New York, NY, USA; 3Value Evidence and Outcomes, GSK, Brentford, Middlesex, UK; 4Global Health Economics, and Outcomes Research and Epidemiology, ICON, Toronto, ON, Canada; 5Global Health Economics, and Outcomes Research and Epidemiology, ICON, Vancouver, BC, Canada; 6Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany; 7Precise Approach Ltd, Contingent Worker on Assignment at GSK, Brentford, Middlesex, UK; 8Respiratory Medicine and Allergology, Lund University, Lund, Sweden; 9Altitude Clinical Consulting and Clinical Research Institute of Southern Oregon, Medford, OR, USA; 10Centre de Pneumologie, Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Québec, QC, Canada; 11Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 12Respiratory Clinical Sciences, GSK, Collegeville, PA, USA; 13Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, CanadaCorrespondence: Afisi S IsmailaValue Evidence and Outcomes, GlaxoSmithKline 1250 South Collegeville Road, Collegeville, PA, 19426-0989, USATel +1 919 315 8229Email afisi.s.ismaila@gsk.comIntroduction: Dual bronchodilators are recommended as maintenance treatment for patients with symptomatic COPD in the UK; further evidence is needed to evaluate cost-effectiveness versus monotherapy. Cost-effectiveness of umeclidinium/vilanterol versus umeclidinium and salmeterol from a UK healthcare perspective in patients without exacerbations in the previous year was assessed using post hoc EMAX trial data.Methods: The validated GALAXY model was populated with baseline characteristics and treatment effects from the non-exacerbating subgroup of the symptomatic EMAX population (COPD assessment test score ≥ 10) and 2020 UK healthcare and drug costs. Outputs included estimated exacerbation rates, costs, life-years (LYs), and quality-adjusted LYs (QALYs); incremental cost-effectiveness ratio (ICER) was calculated as incremental cost/QALY gained. The base case (probabilistic model) used a 10-year time horizon, assumed no treatment discontinuation, and discounted future costs and QALYs by 3.5% annually. Sensitivity and scenario analyses assessed robustness of model results.Results: Umeclidinium/vilanterol treatment was dominant versus umeclidinium and salmeterol, providing an additional 0.090 LYs (95% range: 0.035, 0.158) and 0.055 QALYs (− 0.059, 0.168) with total cost savings of £ 690 (£ 231, £ 1306) versus umeclidinium, and 0.174 LYs (0.076, 0.286) and 0.204 QALYs (0.079, 0.326) with savings of £ 1336 (£ 1006, £ 2032) versus salmeterol. In scenario and sensitivity analyses, umeclidinium/vilanterol was dominant versus umeclidinium except over a 5-year time horizon (more QALYs at higher total cost; ICER=£ 4/QALY gained) and at the lowest estimate of the St George’s Respiratory Questionnaire treatment effect (fewer QALYs at lower total cost; ICER=£ 12,284/QALY gained); umeclidinium/vilanterol was consistently dominant versus salmeterol. At willingness-to-pay threshold of £ 20,000/QALY, probability that umeclidinium/vilanterol was cost-effective in this non-exacerbating subgroup was 95% versus umeclidinium and 100% versus salmeterol.Conclusion: Based on model predictions from a UK perspective, symptomatic patients with COPD and no exacerbations in the prior year receiving umeclidinium/vilanterol are expected to have better outcomes at lower costs versus umeclidinium and salmeterol.Keywords: COPD treatment, cost-effectiveness, umeclidinium, salmeterol, umeclidinium/vilanterol

Claus F Vogelmeier,1 Ian P Naya,2,3 François Maltais,4 Leif Bjermer,5 Edward M Kerwin,6 Lee Tombs,7 Paul W Jones,2 Chris Compton,2 David A Lipson,8,9 Isabelle H Boucot2,10 1Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany; 2Global Specialty & Primary Care, GSK, Brentford, Middlesex, UK; 3RAMAX Ltd, Bramhall, Cheshire, UK; 4Centre De Pneumologie, Institut Universitaire De Cardiologie Et De Pneumologie De Québec, Université Laval, Québec, Canada; 5Respiratory Medicine and Allergology, Lund University, Lund, Sweden; 6Altitude Clinical Consulting and Clinical Research Institute of Southern Oregon, Medford, OR, USA; 7Precise Approach Ltd, Contingent Worker on Assignment at GSK, Brentford, Middlesex, UK; 8Respiratory Clinical Sciences, GSK, Collegeville, PA, USA; 9Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 10Medical Emerging Markets, GSK, Brentford, Middlesex, UKCorrespondence: Claus F VogelmeierUniversity Medical Center Giessen and Marburg, Philipps-Universität Marburg, Member of the German Center for Lung Research (DZL), Baldingerstraße, Marburg, 35043, GermanyTel +49 6421/58-66451Email claus.vogelmeier@med.uni-marburg.deIntroduction: This post hoc analysis of the “Early MAXimization of bronchodilation for improving COPD stability” (EMAX) trial investigated whether patients achieving early clinically important improvement (CII) sustained longer-term improvements and lower risk of clinically important deterioration (CID).Methods: Patients were randomized to umeclidinium/vilanterol, umeclidinium, or salmeterol for 24 weeks. The patient-reported outcomes (PROs) Transition Dyspnea Index (TDI), Evaluating Respiratory Symptoms, St George’s Respiratory Questionnaire (SGRQ) and COPD Assessment Test (CAT) were assessed. CII, defined as attaining minimum clinically important differences (MCID) in ≥ 2 PROs, was assessed at Weeks 4, 12 and 24. CID was defined as a deterioration in CAT, SGRQ, TDI by the MCID and/or a moderate/severe exacerbation from Day 30.Results: Of 2425 patients, 50%, 53% and 51% achieved a CII at Weeks 4, 12 and 24, respectively. Patients with a CII at Week 4 versus those without had significantly greater odds of achieving a CII at Weeks 12 and 24 (odds ratio: 5.57 [95% CI: 4.66, 6.66]; 4.09 [95% CI: 3.44, 4.86]). The risk of a CID was higher in patients who did not achieve a CII at Week 4 compared with patients who did (hazard ratio [95% CI]: 2.09 [1.86, 2.34]). Patients treated with umeclidinium/vilanterol versus either monotherapy had significantly greater odds of achieving CII at Weeks 4, 12 and 24.Conclusion: Achieving a CII at Week 4 was associated with longer-term improvement in PROs and a reduced risk of deterioration. Further research is required to investigate the importance of an early response to treatment on the long-term disease course.Keywords: bronchodilator, clinically important improvement, clinically important deterioration, COPD symptoms, early improvement, patient-reported outcomes

Ellen Tufvesson,1 Finn Radner,1 Georgia Papapostolou,1 Linnea Jarenbäck,1 Saga Jönsson,1 Ulf Nihlén,1 Jaro Ankerst,1 Alf Tunsäter,1 Stefan Peterson,2 Leif Bjermer,1 Göran Eriksson1 1Department of Clinical Sciences Lund, Respiratory Medicine and Allergology, Lund University, Skane University Hospital, Lund, Sweden; 2Regional Cancer Centre South, Region Skane, Lund, SwedenCorrespondence: Ellen TufvessonDepartment of Clinical Sciences Lund, Respiratory Medicine and Allergology, Lund University, Skane University Hospital, Lund 22185, SwedenTel +46 73 640 19 16Email ellen.tufvesson@med.lu.sePurpose: For exercise testing of COPD patients, a standard endurance test (ET) with constant workload is recommended. The test suffers from large inter-individual variability and need for large sample sizes in order to evaluate treatment effects.Methods: A new protocol for ET in COPD was designed. In contrast to the standard ET, the new ET involved an increasing workload in order to reduce the standard deviation of endurance time. Two new ETs were compared with the standard ET. In Study A, the new ET started at 75% of the patient’s maximum workload (WMAX) and increased stepwise with 3%/2 min until exhaustion. Study B started at 70% of WMAX and increased linearly with 1%/min.Results: In Study A, that included 15 patients, the standard deviation and range for endurance time and work capacity were narrower for the new versus the standard ET. However, the higher mean workload at end and the low mean work capacity relative to the standard ET indicated that the stepwise increase was too aggressive. In Study B, that included 18 patients, with a modified protocol, the averages for endurance time, workload at end and work capacity were similar for new and standard ET, while the standard deviations and ranges for endurance time and work capacity were kept more narrow in the new ET. The variances for endurance time were not equal between the standard ET and the two new ETs (p< 0.05 for both according to Levene’s test).Conclusion: The new ET reduced the number of patients with extreme endurance times (short and long) compared to the standard test. The new test showed a significant lower variance for endurance time, which potentially can lead to fewer patients needed in comparative studies. The overall best results were observed with a low linear increase during endurance.Keywords: COPD, exercise testing, constant endurance test, endurance time

Ellen Tufvesson, Henning Stenberg, Jaro Ankerst, Leif Bjermer Respiratory Medicine and Allergology, Department of Clinical Sciences Lund, Lund University, Lund, SwedenCorrespondence: Ellen Tufvesson Respiratory Medicine and Allergology, Department of Clinical Sciences LundLund University, Lund 221 84, SwedenTel +46 736 401916Email Ellen.Tufvesson@med.lu.seIntroduction: Exercise-induced bronchoconstriction is due to osmotic stimulus of the airway epithelium and leads to a cascade of biomarker release from several inflammatory cells. Several type 2 (T2) mediators have been linked to exercise-induced bronchoconstriction, but the T2 response per se has not been described during exercise. The aim of this study was therefore to investigate T2 biomarkers in plasma and urine from subjects with asthma and healthy controls before and after an exercise challenge.Methods: Twenty-two subjects with mild asthma and 18 healthy controls performed an exercise challenge test on a treadmill, and fractional exhaled NO (FeNO) was measured at baseline. Blood and urine samples were collected repeatedly during 60 min after the test and Interleukin-13 (IL-13), thymus and activation-related chemokine (TARC), periostin and leukotrienes were measured.Results: Asthmatics and controls showed similar levels of IL-13, TARC, periostin and Cys-LT in plasma at baseline, and there were no differences in baseline levels between subjects with a negative and positive exercise challenge. After exercise, there was an overall increase in interleukin-13 (IL-13) in plasma in all subjects (p< 0.001), with a peak at 10 min after the exercise challenge in both the asthmatic and control group. An increase in TARC in plasma was also seen (p< 0.001), but only in the control subjects. In contrast, Cys-LT in plasma showed an overall decrease in all subjects (p< 0.001), while periostin in plasma did not change. In conjunction with plasma, the level of IL-13 was increased in urine 30 min after the exercise challenge (p=0.002) and decreased again at 60 min (p=0.004). Similarly, leukotriene E4 (LTE4) was increased in urine samples, with a peak at 60 min and most pronounced in asthmatic subjects (p< 0.001) but was seen also in controls (p=0.008).Discussion: In conclusion, circulating levels of IL-13 are increased after exercise to the same extent in asthmatics and healthy control subjects, which indicates a physiological rather than a pathophysiological response. Also, the levels of TARC and leukotrienes were affected after exercise.Keywords: asthma, biomarkers, exercise, inflammation

Fernando J Martinez,1 Roger A Abrahams,2,3 Gary T Ferguson,4 Leif Bjermer,5 Lars Grönke,6 Florian Voß,7 Dave Singh8 1Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, NY, USA; 2Morgantown Pulmonary Clinical Research, Morgantown, WV, USA; 3Department of Pulmonary & Critical Care, Mon Health Care, Morgantown, WV, USA; 4Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 5Department of Respiratory Medicine and Allergology, Lund University, Lund, Sweden; 6Biotechnology, CSL Behring, Wiesbaden, Germany; 7Biostatistics + Data Sciences Corp., Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; 8Medicines Evaluation Unit, University of Manchester, Manchester, UK Rationale: In symptomatic patients with COPD, the decision whether to initiate maintenance treatment with a single agent or a combination of long-acting bronchodilators remains unclear. Objective: To investigate whether baseline symptomatic status influences response to tiotropium/olodaterol treatment. Materials and methods: Post hoc analysis of the randomized OTEMTO® studies (NCT01964352; NCT02006732), in which patients with moderate-to-severe COPD received placebo, tiotropium 5 µg, tiotropium/olodaterol 2.5/5 µg, or tiotropium/olodaterol 5/5 µg once daily for 12 weeks via the Respimat® inhaler (Boehringer Ingelheim, Ingelheim am Rhein, Germany). Impact of baseline symptomatic status (modified Medical Research Council [mMRC] score) on response to treatment with tiotropium/olodaterol 5/5 µg, tiotropium 5 µg, or placebo at Week 12 was assessed by St George’s Respiratory Questionnaire (SGRQ) total score and response rate, transition dyspnea index (TDI) focal score and response rate, and trough forced expiratory volume in 1 second response. Results: Tiotropium/olodaterol improved SGRQ total scores and response rates compared with placebo and tiotropium for patients with baseline mMRC scores 0–1 and ≥2. For tiotropium/olodaterol vs tiotropium, greater improvements were observed for patients with mMRC ≥2 (SGRQ score adjusted mean treatment difference -3.44 [95% CI: -5.43, -1.46]; P=0.0007; SGRQ response rate ORs 2.09 [95% CI: 1.41, 3.10]; P=0.0002). Dyspnea, measured by TDI score, was consistently improved with tiotropium/olodaterol vs placebo for patients with mMRC scores 0–1 and ≥2 (adjusted mean treatment difference 1.63 [95% CI: 1.06, 2.20]; P

Tufvesson E, Radner F, Papapostolou G, et al. Int J Chron Obstruct Pulmon Dis. 2020;15:3003–3012. Page 3004, left column, line 2 from the bottom, the sentence “The study also included a new WMAX test where the participants started biking with a 3-min warm-up at 40% of their predicted WMAX, followed by an instant increase to 70% and then a linear increase in workload to achieve the predicted WMAX within 8 min” should read “The study also included a new WMAX test where the participants started biking with a 3-min warm-up at 40% of their predicted WMAX, followed by a linear increase in workload to achieve the predicted WMAX within 8 min”. Page 3005, left column, line 4 from the bottom, the sentence “The new maximum test included an initial phase of pedalling for 3 min at 40% (Study A) or 30% (Study B) of the predicted WMAX, followed by an instant increase to 75% (Study A) or 70% (Study B), followed by a stepwise (Study A) or linear (Study B) increase in workload until exhaustion” should read “The new maximum test included an initial phase of pedalling for 3 min at 40% (Study A) or 30% (Study B) of the predicted WMAX, followed by a linear increase in workload to achieve the predicted WMAX within 8 min”. The authors apologize for these errors. Read the original article

Linnea Jarenbäck,1 Ellen Tufvesson,1 Jaro Ankerst,1 Leif Bjermer,1 Björn Jonson2 1Respiratory Medicine and Allergology, Department of Clinical Sciences, Skåne University Hospital, Lund University, Lund, Sweden; 2Clinical Physiology, Department of Clinical Sciences, Skåne University Hospital, Lund University, Lund, Sweden Background: Spirometry, the main tool for diagnosis and follow-up of COPD, incompletely describes the disease. Based on volumetric capnography (VCap), an index was developed for the diagnosis and grading of COPD, aimed as a complement or alternative to spirometry.Methods: Nine non-smokers, 10 smokers/former smokers without COPD and 54 smokers/former smokers with COPD were included in the study. Multiple breath washout of N2 and VCap were studied with Exhalyzer D during tidal breathing. VCap was based on signals for flow rate and CO2 and was recorded during one breath preceding N2 washout. Efficiency Index (EFFi) is the quotient between exhaled CO2 volume and the hypothetical CO2 volume exhaled from a completely homogeneous lung over a volume interval equal to 15% of predicted total lung capacity.Results: EFFi increased with increased Global initiative for chronic Obstructive Lung Disease (GOLD) stage and the majority of subjects in GOLD 2 and all subjects in GOLD 3 and 4 could be diagnosed as having COPD using the lower 95% confidence interval of the healthy group. EFFi also correlated with N2 washout (r=–0.73; p

Ellen Tufvesson,1 Hanna Markstad,2 Gracijela Bozovic,2 Marie Ekberg,1 Leif Bjermer1 1Respiratory Medicine and Allergology, 2Radiology, Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden Abstract: The presence of bacteria in the lower airways in COPD results in inflammation, further airway structural damage, and might lead to repeated exacerbations. We have previously shown that chronic colonization of Haemophilus influenzae during stable disease is related to increased inflammation, and we now aimed to relate previous findings of bacterial colonization and inflammation to the degree of radiological findings of bronchiectasis and emphysema. Thirty-nine patients with COPD were included in their stable state, and a high-resolution computed tomography of the lung was performed. They were followed-up monthly for up to a maximum of 6 months or until exacerbation, and they answered questionnaires, performed spirometry, and induced sputum at every visit. Thirty-five patients had emphysema with an emphysema degree of median 20% (interquartile range 10–50), and five patients had bronchiectasis, of which only four could expectorate sputum. The degree of emphysema correlated with several inflammatory mediators in sputum, such as interleukin-8 concentration, myeloperoxidase activity, and Leukotriene B4 concentration. Ten patients were chronically colonized with H. influenzae (ie, had a positive culture for H. influenzae at all visits). The four sputum patients with bronchiectasis were chronically colonized with H. influenzae and showed higher degree of H. influenzae growth compared to patients without bronchiectasis. During exacerbation, there was no longer any correlation between emphysema degree and inflammation, but patients with bronchiectasis showed higher sputum purulence score than patients without bronchiectasis. Emphysema and bronchiectasis in COPD patients show different clinical features. The presence of emphysema is more related to inflammation, while bronchiectasis is associated with bacterial colonization. We believe that both emphysema and bronchiectasis are therefore COPD phenotypes of highest impact and need evaluation to prevent further disease progression. Keywords: bronchiectasis, emphysema, COPD, chronic colonization, inflammation, pathogenic bacteria

Kerstin Romberg,1,2 Ellen Tufvesson,1 Leif Bjermer1 1Respiratory Medicine and Allergology, Department of Clinical Sciences, Lund, Lund University, Lund, 2Health Care Center, Näsets Läkargrupp, Höllviken, Sweden Background: Strenuous physical activity at an elite level is associated with an increased risk for asthma and, in some sports, also prevalence of allergies. The aim of this study was to investigate the prevalence of asthma and allergy among elite swimmers and tennis players and compare airway hyperreactivity to mannitol and exercise.Materials and methods: One hundred and one adolescent swimmers and 86 tennis players answered a questionnaire about respiratory symptoms and allergy and performed mannitol challenge and sport-specific exercise challenge. Atopy was assessed and fractional exhaled nitric oxide was measured. Mannitol positivity was defined as drop in FEV1 ≥15% (ordinary criteria) and/or β2-reversibility (≥15%) after provocation (extended criteria). A positive exercise test was defined as a drop in FEV1 ≥10% (ordinary criteria) and/or β2-reversibility (≥15%) after provocation (extended criteria). Club cell protein (CC16) was measured in urine before and after the challenges.Results: Asthma symptoms were common in both groups. More swimmers had exercise-induced symptoms (77% versus 50%) and current asthma symptoms (56% versus 38%), compared to the tennis players. More swimmers also had a positive mannitol challenge test both using ordinary (26% versus 6%) and extended criteria (43% versus 17%), while the number of positive exercise tests did not differ. After exercise (but not mannitol) challenge, CC16 level was increased in both groups, but to a higher extent in tennis players. There were no differences in atopy, rhinitis or fractional exhaled nitric oxide.Conclusion: We found a high prevalence of asthma among elite swimmers and tennis players and a higher frequency of current asthma and positive mannitol challenge tests among the swimmers. This indicates an unfavorable exercise environment. Keywords: asthma, sport, swimming, tennis, mannitol, exercise, CC16 bronchial hyperreactivity, bronchial hyperreactivity test

David Price,1,2 Leif Bjermer,3 David A Bergin,4 Rafael Martinez5 1Centre of Academic Primary Care, University of Aberdeen, Aberdeen, UK; 2Observational and Pragmatic Research Institute, Singapore; 3Department of Respiratory Medicine and Allergology, Lund University, Lund, Sweden; 4Novartis Ireland Limited, Dublin, Ireland; 5Novartis Pharma AG, Basel, Switzerland Abstract: Heterogeneity of asthma and difficulty in achieving optimal control are the major challenges in the management of asthma. To help attain the best possible clinical outcomes in patients with asthma, several guidelines provide recommendations for patients who will require a referral to a specialist. Such referrals can help in clearing the uncertainty from the initial diagnosis, provide tailored treatment options to patients with persistent symptoms and offer the patients access to health care providers with expertise in the management of the asthma; thus, specialist referrals have a substantial impact on disease prognosis and the patient’s health status. Hurdles in implementing these recommendations include lack of their dissemination among health care providers and nonadherence to these guidelines; these hurdles considerably limit the implementation of specialist referrals, eventually affecting the rate of referrals. In this review, recommendations for specialist referrals from several key international and national asthma guidelines and other relevant published literature are evaluated. Furthermore, we highlight why referrals are not happening, how this can be improved, and ultimately, what should be done in the specialist setting, based on existing evidence in published literature. Keywords: asthma, disease management, specialization, primary care physicians, referral

Linnea Jarenbäck,1 Göran Eriksson,1 Stefan Peterson,2 Jaro Ankerst,1 Leif Bjermer,1 Ellen Tufvesson1 1Respiratory Medicine and Allergology, Department of Clinical Sciences Lund, Lund University, 2Regional Cancer Center South, Skåne University Hospital, Lund, Sweden Background: COPD is defined as partly irreversible airflow obstruction. The response pattern of bronchodilators has not been followed in advanced lung function parameters. Purpose: The aim of this study was to investigate bronchodilator response pattern in advanced lung function parameters in a continuous fashion along forced expiratory volume in 1 second (FEV1) percent predicted (%p) in COPD patients and controls. Patients and methods: Eighty-one smokers/ex-smokers (41 controls and 40 COPD) performed spirometry, body plethysmography, impulse oscillometry and single-breath helium dilution carbon monoxide diffusion at baseline, after salbutamol inhalation and then after an additional inhalation of ipratropium. Results: Most pulmonary function parameters showed a linear increase in response to decreased FEV1%p. The subjects were divided into groups of FEV1%p 65, and the findings from continuous analysis were verified. The exceptions to this linear response were inspiratory capacity (IC), forced vital capacity (FVC), FEV1/FVC and expiratory resistance (Rex), which showed a segmented response relationship to FEV1%p. IC and FVC, with break points (BP) of 57 and 58 FEV1%p respectively, showed no response above, but an incresed slope below the BP. In addition, in patients with FEV1%p 65, response of FEV1%p did not correlate to response of volume parameters. Conclusion: Response of several advanced lung function parameters differs depending on patients’ baseline FEV1%p, and specifically response of volume parameters is most pronounced in COPD patients with FEV1%p

Piotr Kuna,1 Leif Bjermer,2 Göran Tornling3,4 1Department of Internal Medicine, Asthma and Allergy, Barlicki University Hospital, Medical University of Łódz, Łódz, Poland; 2Department of Respiratory Medicine and Allergology, Skane University Hospital, Lund University, 3AstraZeneca Research and Development, Molndal, 4Respiratory Medicine Unit, Department of Medicine Solna and CMM, Karolinska Institute and Karolinska University Hospital, Solna, Sweden Background: Chemoattractant receptor-homologous molecule expressed on T helper type 2 (Th2) cell (CRTh2) receptor antagonists is being investigated for asthma.Objectives: The aim of this study was to assess the effects of the CRTh2 receptor antagonist, AZD1981 (with/without inhaled corticosteroids [ICSs]), on lung function and asthma control.Patients and methods: Adults aged 18–60 years were enrolled in two randomized, placebo-controlled, parallel-group trials (protocol number: D9830C00003 [study 1, n=209] and protocol number: D9830C00004 [study 2, n=510]). In study 1, patients with stable asthma (forced expiratory volume in 1 second [FEV1]: 65%-110%) were withdrawn from ICS (

Kai-Michael Beeh,1 Eric Derom,2 José Echave-Sustaeta,3 Lars Grönke,4 Alan Hamilton,5 Dongmei Zhai,6 Leif Bjermer71Insaf GmbH Institut für Atemwegsforschung, Wiesbaden, Germany; 2Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium; 3Servicio de Neumología, Hospital Universitario Quirón, Madrid, Spain; 4Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; 5Boehringer Ingelheim, Burlington, ON, Canada; 6InVentiv Health Clinical, Wilmington, DE, USA; 7Department of Respiratory Medicine and Allergology, Lund University, Lund, SwedenBackground: Tiotropium + olodaterol has demonstrated improvements beyond lung function benefits in a large Phase III clinical program as a once-daily maintenance treatment for COPD and may be a potential option for the initiation of maintenance treatment in COPD. Despite guideline recommendations that combined long-acting β2-agonists and inhaled corticosteroids should only be used in individuals at high risk of exacerbation, there is substantial use in individuals at lower risk. This raises the question of the comparative effectiveness of this combination as maintenance treatment in this group compared to other combination regimens.Objective: The study aimed to assess the effect on lung function of once-daily tiotropium + olodaterol versus twice-daily salmeterol + fluticasone propionate in all participants with Global initiative for chronic Obstructive Lung Disease 2 or 3 (moderate to severe) COPD.Methods: This was a randomized, double-blind, double-dummy, four-treatment, complete crossover study in which participants received once-daily tiotropium + olodaterol (5/5 µg and 2.5/5 µg) via Respimat® and twice-daily salmeterol + fluticasone propionate (50/500 µg and 50/250 µg) via Accuhaler® for 6 weeks. The primary end point was change in forced expiratory volume in 1 second (FEV1) area under the curve from 0 hour to 12 hours (AUC0–12) relative to the baseline after 6 weeks.Results: Tiotropium + olodaterol 5/5 µg and 2.5/5 µg demonstrated statistically significant improvements in FEV1 AUC0–12 compared to salmeterol + fluticasone propionate (improvements from baseline were 317 mL and 295 mL with tiotropium + olodaterol 5/5 µg and 2.5/5 µg, and 188 mL and 192 mL with salmeterol + fluticasone propionate 50/500 µg and 50/250 µg, respectively). Tiotropium + olodaterol was superior to salmeterol + fluticasone propionate in lung function secondary end points, including FEV1 area under the curve from 0 hour to 24 hours (AUC0–24).Conclusion: Once-daily tiotropium + olodaterol in participants with moderate-to-severe COPD provided superior lung function improvements to twice-daily salmeterol + fluticasone propionate. Dual bronchodilation can be considered to optimize lung function in individuals requiring maintenance treatment for COPD. Keywords: COPD, maintenance treatment, lung function, tiotropium, FEV1, inhaled corticosteroid

Göran Eriksson,1,* Linnea Jarenbäck,1,* Stefan Peterson,2 Jaro Ankerst,1 Leif Bjermer,1 Ellen Tufvesson11Respiratory Medicine and Allergology, Department of Clinical Sciences, Lund University, 2Regional Cancer Center South, Skåne University Hospital, Lund, Sweden*These authors contributed equally to this workPurpose: COPD is a progressive disease, which can take different routes, leading to great heterogeneity. The aim of the post-hoc analysis reported here was to perform continuous analyses of advanced lung function measurements, using linear and nonlinear regressions.Patients and methods: Fifty-one COPD patients with mild to very severe disease (Global Initiative for Chronic Obstructive Lung Disease [GOLD] Stages I–IV) and 41 healthy smokers were investigated post-bronchodilation by flow-volume spirometry, body plethysmography, diffusion capacity testing, and impulse oscillometry. The relationship between COPD severity, based on forced expiratory volume in 1 second (FEV1), and different lung function parameters was analyzed by flexible nonparametric method, linear regression, and segmented linear regression with break-points.Results: Most lung function parameters were nonlinear in relation to spirometric severity. Parameters related to volume (residual volume, functional residual capacity, total lung capacity, diffusion capacity [diffusion capacity of the lung for carbon monoxide], diffusion capacity of the lung for carbon monoxide/alveolar volume) and reactance (reactance area and reactance at 5Hz) were segmented with break-points at 60%–70% of FEV1. FEV1/forced vital capacity (FVC) and resonance frequency had break-points around 80% of FEV1, while many resistance parameters had break-points below 40%. The slopes in percent predicted differed; resistance at 5 Hz minus resistance at 20 Hz had a linear slope change of -5.3 per unit FEV1, while residual volume had no slope change above and -3.3 change per unit FEV1 below its break-point of 61%.Conclusion: Continuous analyses of different lung function parameters over the spirometric COPD severity range gave valuable information additional to categorical analyses. Parameters related to volume, diffusion capacity, and reactance showed break-points around 65% of FEV1, indicating that air trapping starts to dominate in moderate COPD (FEV1 =50%–80%). This may have an impact on the patient’s management plan and selection of patients and/or outcomes in clinical research.Keywords: spirometry, severity, body plethysmography, single-breath carbon-monoxide diffusion test, impulse oscillometry, break-point

Ellen Tufvesson, Leif Bjermer, Marie Ekberg Respiratory Medicine and Allergology, Department of Clinical Sciences, Lund University, Lund, Sweden Background: Some patients with chronic obstructive pulmonary disease (COPD) show increased airway inflammation and bacterial colonization during stable phase. The aim of this study was to follow COPD patients and investigate chronic colonization with pathogenic bacteria during stable disease phase, and relate these findings to clinical parameters, inflammatory pattern, lung function, and exacerbations. Methods: Forty-three patients with COPD were included while in a stable state and followed up monthly until exacerbation or for a maximum of 6 months. The patients completed the Clinical COPD Questionnaire and Medical Research Council dyspnea scale questionnaires, and exhaled breath condensate was collected, followed by spirometry, impulse oscillometry, and sputum induction. Results: Ten patients were chronically colonized (ie, colonized at all visits) with Haemophilus influenzae during stable phase. These patients had higher sputum levels of leukotriene B4 (P

Leif Bjermer,1 Piotr Kuna,2 Carin Jorup,3 Thomas Bengtsson,4 Johan Rosenborg4 1Department of Respiratory Medicine and Allergology, University Hospital, Lund, Sweden; 2Department of Internal Medicine, Asthma and Allergy, Barlicki University Hospital, Medical University of Lodz, Lodz, Poland; 3AstraZeneca R&D, Mölndal, Sweden; 4StatMind, Lund, Sweden Objective: The clinical pharmacokinetics of AZD3199, an ultra-long-acting β2-agonist, were investigated in healthy volunteers and patients with asthma or chronic obstructive pulmonary disease (COPD). Materials and methods: Five studies are presented: one single ascending dose study in healthy Caucasian males; two multiple ascending dose studies in healthy males, one in Caucasians and one in Japanese; a Phase IIA asthma study; and a Phase IIB COPD study. Subjects received AZD3199 via a Spira nebulizer (Turbuhaler; equivalent delivered doses 5–3200 µg) or Turbuhaler (single delivered doses of 120–1920 µg or repeated delivered once-daily doses 240–1,680 µg). AZD3199 pharmacokinetics were assessed using total plasma concentration and urinary excretion, and tolerability using adverse events, clinical laboratory tests, and physical examinations. Results: AZD3199 appeared rapidly in the systemic circulation following single and multiple dosing in healthy volunteers and patients (maximum plasma concentration within 30 minutes), with dose-proportional time-independent pharmacokinetics. Plasma exposure to unmetabolized drug was similar in healthy volunteers and patients with asthma, but relatively lower in patients with COPD. Estimated terminal half-life was up to 142 hours in healthy Caucasian males. AZD3199 was well tolerated and showed no or at most mild systemic effects. Conclusion: AZD3199 plasma exposure in healthy volunteers and patients suggested linear pharmacokinetics and a long half-life. Systemic availability was similar in healthy subjects and patients with asthma, but was lower in patients with COPD. These clinical trials suggest that AZD3199 is well-tolerated in healthy male volunteers and patients, with no safety concerns identified to preclude further evaluation. Keywords: AZD3199, uLABA, COPD, asthma, pharmacokinetics, tolerability

Jonas Jögi,1 Hanna Markstad,2 Ellen Tufvesson,3 Leif Bjermer,3 Marika Bajc1 1Department of Clinical Physiology and Nuclear Medicine, 2Department of Radiology, 3Department of Respiratory Medicine and Allergology, Skåne University Hospital and Lund University, Lund, Sweden Abstract: Ventilation/perfusion (V/P) single-photon emission computed tomography (SPECT) is recognized as a diagnostic method with potential beyond the diagnosis of pulmonary embolism. V/P SPECT identifies functional impairment in diseases such as heart failure (HF), pneumonia, and chronic obstructive pulmonary disease (COPD). The development of hybrid SPECT/computed tomography (CT) systems, combining functional with morphological imaging through the addition of low-dose CT (LDCT), may be useful in COPD, as these patients are prone to lung cancer and other comorbidities. The aim of this study was to investigate the added value of LDCT among healthy smokers and patients with stable COPD, when examined with V/P SPECT/CT hybrid imaging. Sixty-nine subjects, 55 with COPD (GOLD I–IV) and 14 apparently healthy smokers, were examined with V/P SPECT and LDCT hybrid imaging. Spirometry was used to verify COPD grade. Only one apparently healthy smoker and three COPD patients had a normal or nearly normal V/P SPECT. All other patients showed various degrees of airway obstruction, even when spirometry was normal. The same interpretation was reached on both modalities in 39% of the patients. LDCT made V/P SPECT interpretation more certain in 9% of the patients and, in 52%, LDCT provided additional diagnoses. LDCT better characterized the type of emphysema in 12 patients. In 19 cases, tumor-suspected changes were reported. Three of these 19 patients (ie, 4.3% of all subjects) were in the end confirmed to have lung cancer. The majority of LDCT findings were not regarded as clinically significant. V/P SPECT identified perfusion patterns consistent with decompensated left ventricular HF in 14 COPD patients. In 16 patients (23%), perfusion defects were observed. HF and perfusion defects were not recognized with LDCT. In COPD patients and long-time smokers, hybrid imaging had added value compared to V/P SPECT alone, by identifying patients with lung malignancy and more clearly identifying emphysema. V/P SPECT visualizes comorbidities to COPD not seen with LDCT, such as pulmonary embolism and left ventricular HF. Keywords: lung, lung cancer, V/P SPECT, ventilation/perfusion, single-photon emission computed tomography, computed tomography

Introduction: Limited prospective evidence is available to guide selection of first-line maintenance therapy in patients with COPD. This pre-specified analysis of the EMAX trial explored the efficacy and safety of dual- versus mono-bronchodilator therapy in maintenance-naïve and maintenance-treated patients., Methods: The 24-week EMAX trial evaluated lung function, symptoms (including rescue medication use), exacerbations, and safety with umeclidinium/vilanterol, umeclidinium, and salmeterol in symptomatic patients at low exacerbation risk who were not receiving inhaled corticosteroids. Maintenance-naïve and maintenance-treated subgroups were defined by maintenance bronchodilator use 30 days before screening., Results: The analysis included 749 (31%) maintenance-naïve and 1676 (69%) maintenance-treated patients. For both subgroups, improvements from baseline in trough FEV 1 at Week 24 (primary endpoint) were greater with umeclidinium/vilanterol versus umeclidinium (mean difference [95% CI]; maintenance-naïve: 44 mL [1, 87]; maintenance-treated: 77 mL [50, 104]), and salmeterol (maintenance-naïve: 128 mL [85, 171]; maintenance-treated: 145 mL [118, 172]), and in rescue medication inhalations/day over 24 weeks versus umeclidinium (maintenance-naïve: -0.44 [-0.73, -0.16]; maintenance-treated: -0.28 [-0.45, -0.12]) and salmeterol (maintenance-naïve: -0.37 [-0.66, -0.09]; maintenance-treated: -0.25 [-0.41, -0.08]). In maintenance-naïve patients, umeclidinium/vilanterol numerically improved scores at Week 24 for Transition Dyspnea Index versus umeclidinium (0.37 [-0.21, 0.96]) and versus salmeterol (0.47 [-0.10, 1.05]) and Evaluating Respiratory Symptoms-COPD versus umeclidinium (-0.26 [-1.04, 0.53]) and versus salmeterol (-0.58 [-1.36, 0.20]), with similar improvements seen in maintenance-treated patients. All treatments were well tolerated across both subgroups., Conclusion: Similar to maintenance-treated patients, maintenance-naïve patients receiving umeclidinium/vilanterol showed greater improvements in lung function and symptoms compared with patients receiving umeclidinium or salmeterol. These findings provide support for the consideration of dual bronchodilator treatment in symptomatic maintenance-naïve patients with COPD., Competing Interests: IHB, DAL, CC, and PWJ are employees of GSK and hold stocks and shares in GSK. IHB’s current affiliation is Medical Emerging Markets, GSK, Brentford, Middlesex, UK. IPN was an employee of GSK at the time of the study, holds stocks and shares in GSK, and was a contingent worker on assignment at AstraZeneca. IPN’s current affiliation is RAMAX Ltd, Bramhall, Cheshire, UK. LT is a contingent worker on assignment at GSK. FM has received research grants for participating in multicenter trials for AstraZeneca, Boehringer Ingelheim, GSK, Sanofi, and Novartis, and has received unrestricted research grants and personal fees from Boehringer Ingelheim, Grifols, and Novartis. LB has received honoraria for giving a lecture or attending an advisory board for Airsonett, ALK-Abello, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Meda, Novartis and Teva. EMK has served on advisory boards, speaker panels or received travel reimbursement from for Amphastar, AstraZeneca, Boehringer Ingelheim, Connect Biopharma, GSK, Mylan, Novartis, Pearl, Sunovion, Teva, and Theravance and has received consulting fees from Cipla and GSK. CFV has received grants from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Grifols, Novartis, and the German Federal Ministry of Education and Research (BMBF) Competence Network Asthma and COPD (ASCONET), and has received personal fees from AstraZeneca, Boehringer Ingelheim, Berlin Chemie/Menarini, Chiesi, CSL Behring, GSK, Grifols, MedUpdate, Novartis, Nuvaira, and Teva. The authors report no other conflicts of interest in this work., (© 2021 Bjermer et al.)

Background: The design of inhaler devices may potentially influence adherence/persistence and outcomes in asthma. Objective: The primary objective was to assess asthma control and any change in the quality of life in patients using an intuitive dry powder inhaler containing fluticasone propionate/salmeterol (AirFluSal ® Forspiro ® ) for the treatment of asthma in everyday practice. Methods: ASSURE was a multicenter, noninterventional, open-label, prospective study in patients with asthma, aged ≥12 years and treated with the Forspiro device in Denmark, Sweden and Norway. Patients' opinions of their asthma control were assessed by the Asthma Control Test (ACT) questionnaire and asthma-related quality of life by the Mini Asthma Quality of Life Questionnaire (miniAQLQ) at baseline and at two follow-up visits (approximately 4-8-week intervals). Results: Of 321 patients enrolled in the study, 299 received at least one dose of fluticasone propionate/salmeterol via the Forspiro device and 204 had evaluable data at the baseline visit and at least one later visit. Patients showed improvements in asthma control and quality of life during the study. The mean sum score of ACT increased from 18.0 (SD 4.5) at visit 1 to 19.9 (4.2) at visit 2 and 20.5 (4.3) at visit 3. Overall, 38.2% of patients improved by the minimal clinically important difference (MCID) of ≥3 points (45.6% among those with a baseline score below 23 [ie, not already well controlled]). The mean score on the miniAQLQ increased from 5.16 (SD 1.24) at visit 1 to 5.58 (SD 1.20) at visit 2 and 5.82 (SD 1.04) at visit 3. Overall, 42.6% of patients improved by the MCID of ≥0.5. Conclusion: This real-life study suggests that treatment with fluticasone propionate/salmeterol via the Forspiro device can improve asthma symptom control and quality of life., Competing Interests: Andreas Søderman is an employee of Sandoz AS. Spencer Jones is an employee of Sandoz International GmbH and holds stock in Novartis. Leif Bjermer reports honoraria from ALK, Airsonette, AstraZeneca, Boehringer, Chiesi, GlaxoSmithKline, Novartis, Teva, outside the submitted work. Olav Kåre Refvem reports personal fees from Boehringer-Ingelheim, outside the submitted work, and is the owner of Lungepraksis AS. The authors report no other conflicts of interest in this work.