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Mircea Gabriel Stoleriu,1,2,&ast; Michael Pienn,3,4,&ast; Rudolf A Joerres,5 Peter Alter,6 Tamas Fero,7 Martin Urschler,8 Gabor Kovacs,3,9 Horst Olschewski,3,9 Hans-Ulrich Kauczor,7,10 Mark Wielpütz,7,10 Bertram Jobst,7,10 Tobias Welte,11 Jürgen Behr,2,12 Franziska C Trudzinski,10,13 Robert Bals,14,15 Henrik Watz,16 Claus F Vogelmeier,6 Jürgen Biederer,10,17,18,&ast; Kathrin Kahnert2,12,19,&ast; On behalf of the COSYCONET Study Group1Division for Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich (LMU) and Asklepios Medical Center; Munich-Gauting, Gauting, 82131, Germany; 2Institute for Lung Health and Immunity and Comprehensive Pneumology Center with the CPC-M bioArchive; Helmholtz Center Munich; Member of the German Lung Research Center (DZL), Munich, 81377, Germany; 3Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; 4Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; 5Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Hospital of Ludwig-Maximilians-University Munich (LMU), Munich, 80336, Germany; 6Department of Medicine, Pulmonary and Critical Care Medicine, University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Marburg, 35033, Germany; 7Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany; 8Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria; 9University Clinic for Internal Medicine, Medical University of Graz, Division of Pulmonology, Graz, Austria; 10Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research DZL, Heidelberg, Germany; 11Department of Respiratory Medicine and Infectious Disease, Member of the German Center of Lung Research, Hannover School of Medicine, Hannover, Germany; 12Department of Medicine V, LMU University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany; 13Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Heidelberg, Germany; 14Department of Internal Medicine V-Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg, 66421, Germany; 15Helmholtz Institute for Pharmaceutical Research, Saarbrücken, 66123, Germany; 16Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Centre North, German Centre for Lung Research, Großhansdorf, Germany; 17Faculty of Medicine, Christian-Albrechts-Universität Zu Kiel, Kiel, Germany; 18University of Latvia, Faculty of Medicine, Riga, LV-1586, Latvia; 19MediCenterGermering, Germering, Germany&ast;These authors contributed equally to this workCorrespondence: Mircea Gabriel Stoleriu, Division of Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich (LMU) and Asklepios Lung Clinic Munich-Gauting, Marchioninistr. 15, 81377 Munich and Robert-Koch-Allee 2, Gauting, 82131, Germany, Tel +49 89 85791 4201, Email gabriel.stoleriu@helmholtz-munich.dePurpose: The aim of this study was to evaluate the association between computed tomography (CT) quantitative pulmonary vessel morphology and lung function, disease severity, and mortality risk in patients with chronic obstructive pulmonary disease (COPD).Patients and Methods: Participants of the prospective nationwide COSYCONET cohort study with paired inspiratory-expiratory CT were included. Fully automatic software, developed in-house, segmented arterial and venous pulmonary vessels and quantified volume and tortuosity on inspiratory and expiratory scans. The association between vessel volume normalised to lung volume and tortuosity versus lung function (forced expiratory volume in 1 sec [FEV1]), air trapping (residual volume to total lung capacity ratio [RV/TLC]), transfer factor for carbon monoxide (TLCO), disease severity in terms of Global Initiative for Chronic Obstructive Lung Disease (GOLD) group D, and mortality were analysed by linear, logistic or Cox proportional hazard regression.Results: Complete data were available from 138 patients (39% female, mean age 65 years). FEV1, RV/TLC and TLCO, all as % predicted, were significantly (p < 0.05 each) associated with expiratory vessel characteristics, predominantly venous volume and arterial tortuosity. Associations with inspiratory vessel characteristics were absent or negligible. The patterns were similar for relationships between GOLD D and mortality with vessel characteristics. Expiratory venous volume was an independent predictor of mortality, in addition to FEV1.Conclusion: By using automated software in patients with COPD, clinically relevant information on pulmonary vasculature can be extracted from expiratory CT scans (although not inspiratory scans); in particular, expiratory pulmonary venous volume predicted mortality.Trial Registration: NCT01245933.Keywords: COPD, computed tomography, pulmonary vasculature, vessel volume, vessel tortuosity, lung function

Fernando J Martinez,1 Alberto Papi,2 Tobias Welte3,4 ,† Dave Singh,5 Dmitry V Galkin,6 Alessandro Guasconi,7 Stefania Pirondi,7 George Georges,7 Joseph Imperato,8 Ruben Hermans9 1Weill Cornell Medicine, New York–Presbyterian Hospital, New York, NY, USA; 2Research Center on Asthma and COPD, Department of Medical Sciences, University of Ferrara, Ferrara, Italy; 3Pneumonology and Infectiology, Member of the German Center of Lung Research, Hannover Medical School, Hannover, Germany; 4Biomedical Research in End Stage and Obstructive Lung Disease, German Center for Lung Research, Hannover Medical School, Hannover, Germany; 5Medicines Evaluations Unit, University of Manchester, Manchester University Foundation Hospitals Trust, Manchester, UK; 6Global Clinical Development, Chiesi USA, Cary, NC, USA; 7Global Clinical Development, Chiesi Farmaceutici, S.p.A, Parma, Italy; 8Medical Affairs, IQVIA Inc, New York, NY, USA; 9Medical Affairs, IQVIA Inc, London, UK†Prof. Tobias We 50% in 2020 compared with 2019. The proportions of patients with an exacerbation increased in most countries in 2021. Across each country, seasonal exacerbation increases seen during autumn and winter in pre-pandemic years were absent during the first year of the pandemic. The percentage of patients filling COPD prescriptions across each country increased by 4.53– 22.13% in 2019 to 9.94– 34.17% in 2021.Conclusion: Early, steep declines in exacerbation rates occurred in 2020 versus 2019 across all five countries and were accompanied by a loss of the seasonal pattern of exacerbation.Keywords: COPD exacerbation, chronic obstructive pulmonary disease, COVID-19, electronic health records, real-world study

Peter Alter,1 Cosmina Stoleriu,2 Kathrin Kahnert,3,4 Markus Oliver Henke,5 Robert Bals,6 Franziska C Trudzinski,7 Henrik Watz,8 Tim Speicher,1 Sandra Söhler,1 Tobias Welte,9 Klaus F Rabe,10,11 Emiel FM Wouters,12,13 Claus F Vogelmeier,1 Rudolf A Jörres14 1Department of Medicine, Pulmonary, Critical Care and Sleep Medicine, Philipps University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Marburg, Germany; 2Asklepios Lungenklinik Gauting, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Gauting, Germany; 3Department of Medicine V, LMU University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany; 4MediCenterGermering, Germering, Germany; 5Klinik für Innere Medizin und Pneumologie, Krankenhaus Martha-Maria, Munich, Germany; 6Department of Internal Medicine V, Pulmonology, Allergology, Intensive Care Medicine, Saarland University Hospital, Homburg, Germany; 7Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Member of the Center for Lung Research (DZL), Heidelberg, Germany; 8Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 9Clinic for Pneumology, Hannover Medical School, Member of the German Center for Lung Research (DZL), Hannover, Germany; 10LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 11Department of Medicine, Christian-Albrechts-University, Kiel, Germany; 12Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht, Netherlands; 13Ludwig Boltzmann Institute for Lung Health, Vienna, Austria; 14Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, LMU University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, GermanyCorrespondence: Peter Alter, Department of Medicine, Pulmonary, Critical Care and Sleep Medicine, Philipps University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Baldingerstrasse 1, Marburg, 35033, Germany, Tel +49 6421 5866140, Email Alter@uni-marburg.deBackground: Many patients with chronic obstructive pulmonary disease (COPD) continue smoking. We used data from the “real-life” COSYCONET COPD cohort to evaluate whether these patients differed from patients with COPD who either had ceased smoking prior to inclusion or ceased during the follow-up time of the study.Methods: The analysis was based on data from visits 1– 5 (covering 4.5 years), including all patients with the diagnosis of COPD who were either ex-smokers or smokers and categorized as GOLD 1– 4 or the former GOLD 0 category. We compared the characteristics of smokers and ex-smokers at baseline (visit 1), as well as the course of lung function in the follow-up of permanent ex-smokers, permanent smokers and incident ex-smokers (smokers at visit 1 who ceased smoking before visit 5). We also identified baseline factors associated with subsequent smoking cessation.Results: Among 2500 patients who were ever-smokers, 660 were current smokers and 1840 ex-smokers at baseline. Smokers were younger than ex-smokers (mean 61.5 vs 66.0 y), had a longer duration of smoking but fewer pack-years, a lower frequency of asthma, higher forced expiratory volume in 1 sec (FEV1, 59.4 vs 55.2% predicted) and higher functional residual capacity (FRC, 147.7 vs 144.3% predicted). Similar results were obtained for the longitudinal subpopulation, comprising 713 permanent ex-smokers, 175 permanent smokers, and 55 incident ex-smokers. When analyzing the time course of lung function, higher FRC, lower FEV1 and the presence of asthma (p < 0.05 each) were associated with incident cessation prior to visit 5, while less airway obstruction was associated with smoking continuation.Conclusion: These findings, which were consistent in the cross-sectional and longitudinal analyses, suggest that lung hyperinflation was associated with being or becoming ex-smoker. Possibly, it is perceived by patients as one of the factors motivating their attempts to quit smoking, independent from airway obstruction.Keywords: COPD, smoking, smoking cessation, airway obstruction, lung hyperinflation

Practice guidelines are systematically developed statements and recommendations that assist the physicians and patients in making decisions about appropriate health care measures for specific clinical circumstances taking into account specific national health care structures. The 1st revision of the S-2k guideline of the German Sepsis Society in collaboration with 17 German medical scientific societies and one self-help group provides state-of-the-art information (results of controlled clinical trials and expert knowledge) on the effective and appropriate medical care (prevention, diagnosis, therapy and follow-up care) of critically ill patients with severe sepsis or septic shock. The guideline had been developed according to the “German Instrument for Methodological Guideline Appraisal” of the Association of the Scientific Medical Societies (AWMF). In view of the inevitable advancements in scientific knowledge and technical expertise, revisions, updates and amendments must be periodically initiated. The guideline recommendations may not be applied under all circumstances. It rests with the clinician to decide whether a certain recommendation should be adopted or not, taking into consideration the unique set of clinical facts presented in connection with each individual patient as well as the available resources.

Tanya M Laidlaw1,2 &ast;, Andrew Menzies-Gow3 &ast;, Scott Caveney,4 Joseph K Han,5 Nicole Martin,6,7 Elliot Israel,8 Jason K Lee,9,10 Jean-Pierre Llanos,11 Neil Martin,12,13 Ayman Megally,14 Bhavini Parikh,14 Sylvia Vong,15 Tobias Welte,16 Jonathan Corren17 1Jeff and Penny Vinik Center for Allergic Diseases Research, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital, Boston, MA, USA; 2Department of Medicine, Harvard Medical School, Boston, MA, USA; 3Royal Brompton and Harefield Hospitals, School of Immunology and Microbial Sciences, King’s College London, London, UK; 4Global Development, Inflammation, R&D, Amgen, Thousand Oaks, CA, USA; 5Department of Otolaryngology, Head and Neck Surgery, Eastern Virginia Medical School, Norfolk, VA, USA; 6Biometrics, Late-Stage Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA, USA; 7Cytel Inc, Waltham, MA, USA; 8Divisions of Pulmonary and Critical Care Medicine and Allergy and Clinical Immunology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 9Evidence Based Medical Educator Inc., Toronto, ON, Canada; 10Toronto Allergy and Asthma Clinic, Toronto, ON, Canada; 11Global Medical Affairs, Amgen, Thousand Oaks, CA, USA; 12Respiratory and Immunology, BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK; 13University of Leicester, Leicester, UK; 14Late-Stage Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; 15Translational Science and Experimental Medicine, Early Respiratory and Immunology, AstraZeneca, Gaithersburg, MD, USA; 16Department of Respiratory Medicine and German Center for Lung Research, Hannover Medical School, Hannover, Germany; 17David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA&ast;These authors contributed equally to this workCorrespondence: Tanya M Laidlaw, Jeff and Penny Vinik Center for Allergic Diseases Research, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital, 60 Fenwood Road, Boston, MA, 02115, USA, Email tlaidlaw@bwh.harvard.eduPurpose: Tezepelumab, a human monoclonal antibody, blocks thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab reduced annualized asthma exacerbation rates (AAERs) versus placebo, irrespective of baseline disease characteristics, and improved lung function and symptom control versus placebo in adults and adolescents with severe, uncontrolled asthma. We assessed the efficacy of tezepelumab in patients with severe asthma with or without nasal polyps (NPs) in the 2 years before randomization in NAVIGATOR.Methods: Patients with severe asthma (N=1059) were randomized (1:1) and received tezepelumab 210 mg or placebo every 4 weeks subcutaneously for 52 weeks. Prespecified exploratory analyses included: AAER over 52 weeks and changes from baseline to week 52 in pre-bronchodilator forced expiratory volume in 1 second, Sino-Nasal Outcome Test (SNOT)-22 scores, and asthma control and health-related quality life (HRQoL) outcomes in NP subgroups. Changes from baseline in fractional exhaled nitric oxide (FeNO), blood eosinophil counts, total immunoglobulin E (IgE), eosinophil-derived neurotoxin (EDN), matrix metalloproteinase-10 (MMP-10), and serum interleukin (IL)-5, IL-6, IL-8 and IL-13 were assessed (post hoc).Results: Tezepelumab reduced the AAER over 52 weeks versus placebo by 85% (95% confidence interval [CI]: 72, 92; n=118) and 51% (95% CI: 40, 60; n=941) in patients with and without NPs, respectively. At week 52, tezepelumab improved lung function, asthma control and HRQoL versus placebo in patients with and without NPs. Tezepelumab reduced SNOT-22 total scores (least-squares mean difference versus placebo [95% CI]) in patients with NPs at 28 weeks (– 12.57 points [– 19.40, – 5.73]) and 52 weeks (– 10.58 points [– 17.75, – 3.41]). At week 52, tezepelumab reduced blood eosinophil counts and FeNO, IgE, IL-5, IL-13, EDN and MMP-10 levels versus placebo, irrespective of NP status.Conclusion: Tezepelumab resulted in clinically meaningful improvements in sino-nasal symptoms and asthma outcomes in patients with severe asthma with comorbid NPs.Graphical Abstract: Plain Language Summary: Asthma is a long-term condition caused by ongoing inflammation of the lower airways. The main symptoms are difficulty breathing, coughing, wheezing and shortness of breath. Approximately 41% of patients with severe asthma also have chronic rhinosinusitis with nasal polyps, a condition that affects the upper airways and sinuses. Nasal polyps are painless soft growths inside your nose that can keep growing if not treated. Symptoms include nasal congestion with mucus, facial pain and a reduced sense of smell or taste. People with both severe asthma and nasal polyps often have severe symptoms.Thymic stromal lymphopoietin (TSLP) is a signaling molecule released by cells lining the airways in response to airborne triggers, such as smoke, pollen and viruses. TSLP activates several pathways that cause inflammation in the airways, leading to asthma symptoms. Tezepelumab is a biologic treatment that targets the very start of these inflammatory pathways by blocking TSLP.The 1-year-long clinical trial called “NAVIGATOR” reported that tezepelumab reduced asthma attacks and improved lung function and asthma symptom control compared with placebo in patients with severe asthma that was not controlled with their current medicines. This analysis of data from NAVIGATOR looked at patients with both severe asthma and nasal polyps, showing that tezepelumab treatment improved sino-nasal symptoms compared with placebo. Tezepelumab also reduced asthma attacks and improved asthma symptoms, regardless of a patient’s medical history of nasal polyps. The effects of tezepelumab in patients with severe nasal polyps are being investigated in another clinical trial called “WAYPOINT”.Keywords: chronic rhinosinusitis, nasal polyps, SNOT-22, thymic stromal lymphopoietin

Pia Maria Plank,1,&ast; Christopher Alexander Hinze,2,&ast; Victoria Campbell,3 Stefanie Konwert,4 Tobias Welte,1,4 Nora Drick,1 Moritz Z Kayser,1 Hendrik Suhling,1,4,&ast; Jan Fuge1,4,&ast; 1Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany; 2Department of Respiratory Medicine and Infectious Disease, Hannover Medical School, Hannover, Germany; 3Department of Paediatric Pulmonology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany; 4Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany&ast;These authors contributed equally to this workCorrespondence: Christopher Alexander Hinze, Department of Respiratory Medicine and Infectious Disease, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, 30625, Germany, Tel +49 511-5323531, Email hinze.christopher@mh-hannover.dePurpose: Asthma is associated with a high prevalence of psychopathological disorders, especially depressive disorders or anxiety. In patients with uncontrolled severe asthma, monoclonal antibody (mAb)-therapy positively influenced control of mental disorders. Therefore, we evaluated the impact of antibody therapy on the burden of these mental diseases depending on responder status.Patients and Methods: Data were collected retrospectively in patients with uncontrolled severe asthma (n = 82) prior to mAb-therapy (“baseline”) (omalizumab, dupilumab, benralizumab or mepolizumab). Symptoms of Major Depressive Disorder (MDD) or General Anxiety Disorder (GAD) were detected at baseline using the Hospital Anxiety and Depression Scale (HADS), as well as general sociodemographic data and lung function parameters. At 6-month (± 3 month) follow-up, the burden of psychopathological symptoms under mAb-therapy was assessed using the Patient Health Questionnaire-2 (PHQ-2) and Generalized Anxiety Disorder Scale-2 (GAD-2). Response status was classified using the Biologics Asthma Response Score (BARS), assessing exacerbations, oral corticosteroid usage and asthma control test (ACT) score. Predictors for non-response to mAb-therapy were identified using linear regression analysis.Results: Patients with severe asthma suffered from symptoms of MDD/GAD more often compared to the general population, with a higher prevalence among mAb therapy non-responders. mAb-responders exhibited a declining burden of MDD, better quality of life (QoL), less exacerbations, better lung function and better disease control compared to non-responders. A history of symptoms of depression was identified as a predictor for non-response to mAb-therapy.Conclusion: Asthma symptoms and psychological problems are linked and more prevalent in our cohort of severe asthma patients than in the general population. Patients with signs of MDD/GAD before mAb-therapy show less mAb therapy response suggesting a negative impact of prior psychological problems on treatment response. In some patients, the score on MDD/GAD was caused by severe asthma – here symptoms decreased after effective treatment.Keywords: severe asthma, monoclonal antibody therapy, depression, anxiety, therapy response

Peter Alter,1 Kathrin Kahnert,2 Franziska C Trudzinski,3 Robert Bals,4 Henrik Watz,5 Tim Speicher,1 Sandra Söhler,1 Stefan Andreas,6 Tobias Welte,7 Klaus F Rabe,8 Emiel FM Wouters,9 Antonia Sassmann-Schweda,10 Hubert Wirtz,11 Joachim H Ficker,12,13 Claus F Vogelmeier,1 Rudolf A Jörres14 1Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Germany, Member of the German Center for Lung Research (DZL), Marburg, Germany; 2Department of Internal Medicine V, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany; 3Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; 4Department of Internal Medicine V - Pulmonology, Allergology, Intensive Care Medicine, Saarland University Hospital, Homburg, Germany; 5Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 6LungClinic Immenhausen and Department of Cardiology and Pneumology, University Medical Center Göttingen, Germany, Member of the German Center for Lung Research (DZL), Göttingen, Germany; 7Clinic for Pneumology, Hannover Medical School, Member of the German Center for Lung Research (DZL), Hannover, Germany; 8LungenClinic Grosshansdorf and Department of Medicine, Christian-Albrechts University, Kiel, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 9Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht, Netherlands and Ludwig Boltzmann Institute for Lung Health, Vienna, Austria; 10Center for Clinical Studies, Research Center Borstel, Borstel, Germany; 11Department of Internal Medicine I, Pneumology, University of Leipzig, Leipzig, Germany; 12Department of Respiratory Medicine, Allergology and Sleep Medicine, Klinikum Nuremberg, Nürnberg, Germany; 13Paracelsus Medical University Nuremberg, Nürnberg, Germany; 14Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, GermanyCorrespondence: Peter Alter, Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Baldingerstrasse 1, Marburg, Germany, Email Alter@uni-marburg.deBackground: Multimorbidity plays an important role in chronic obstructive pulmonary disease (COPD) but is also a feature of ageing. We estimated to what extent increases in the prevalence of multimorbidity over time are attributable to COPD progression compared to increasing patient age.Methods: Patients with COPD from the long-term COSYCONET (COPD and Systemic Consequences - Comorbidities Network) cohort with four follow-up visits were included in this analysis. At each visit, symptoms, exacerbation history, quality of life and lung function were assessed, along with the comorbidities heart failure (HF), coronary artery disease (CAD), peripheral arterial disease (PAD), hypertension, sleep apnea, diabetes mellitus, hyperlipidemia, hyperuricemia and osteoporosis. Using longitudinal logistic regression analysis, we determined what proportion of the increase in the prevalence of comorbidities could be attributed to patients’ age or to the progression of COPD over visits.Results: Of 2030 patients at baseline, 878 completed four follow-up visits (up to 4.5 years). CAD prevalence increased over time, with similar effects attributable to the 4.5-year follow-up, used as indicator of COPD progression, and to a 5-year increase in patients’ age. The prevalence of HF, diabetes, hyperlipidemia, hyperuricemia, osteoporosis and sleep apnea showed stronger contributions of COPD progression than of age; in contrast, age dominated for hypertension and PAD. There were different relationships to patients’ characteristics including BMI and sex. The results were not critically dependent on the duration of COPD prior to enrolment, or the inclusion of patients with all four follow-up visits vs those attending only at least one of them.Conclusion: Analyzing the increasing prevalence of multimorbidity in COPD over time, we separated age-independent contributions, probably reflecting intrinsic COPD-related disease progression, from age-dependent contributions. This distinction might be useful for the individual assessment of disease progression in COPD.Keywords: chronic obstructive pulmonary disease, comorbidities, multimorbidity, prognosis, disease progression

Moritz Z Kayser,1 Nora Drick,1 Katrin Milger,2,3 Jan Fuge,1,4 Nikolaus Kneidinger,2,3 Stephanie Korn,5 Roland Buhl,6 Jürgen Behr,2,3 Tobias Welte,1,4 Hendrik Suhling1 1Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany; 2Department of Medicine V, University Hospital, LMU, Munich, Germany; 3Comprehensive Pneumology Center-Munich (CPC‐M), Member of the German Center for Lung Research (DZL), Munich, Germany; 4Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany; 5Clinical Research Centre for Respiratory Medicine, Mainz, Germany; 6Pulmonary Department, Mainz University Hospital, Mainz, GermanyCorrespondence: Moritz Z KayserDepartment of Respiratory Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, 30625, Lower Saxony, GermanyTel +49 0511-532-3531Fax +49 511-532-161108Email kayser.moritz@mh-hannover.dePurpose: Treatment of severe eosinophilic asthma (SEA) has been revolutionized by the development of monoclonal antibodies targeting underlying immunological pathways of eosinophilic asthma. Two of the most frequently used antibodies in clinical practice are mepolizumab, targeting interleukin (IL) 5 and benralizumab, targeting the IL5 receptor alpha. The comparative treatment efficacy of these antibodies remains unclear, particularly regarding long-term outcomes.Patients and Methods: In this multicenter, retrospective study, we included 123 patients treated with mepolizumab and 64 patients treated with benralizumab for 12 months at one of three study sites in Germany. Data were collected at baseline and after 6 and 12 months of therapy. Endpoints were changes in pulmonary function (PF), exacerbation rate, oral corticosteroid (OCS) use and dose, asthma control test (ACT) score and fractional exhaled nitric oxide (FeNO) levels.Results: Both mepolizumab and benralizumab led to significant improvements in PF with an increase in median forced expiratory volume (FEV1) after 12 months from 59% to 74% for mepolizumab and 63% to 72% for benralizumab. Treatment also led to significant improvements in ACT scores after 12 months (mepolizumab: 13 [interquartile range (IQR) 9– 17] to 19 [IQR 15– 23]; benralizumab: 12 [IQR 9– 16] to 22 [IQR 16– 25]) as well as a reduction of mean OCS dose (mepolizumab 8 mg [IQR 5– 12.5 mg] median prednisolone equivalent at baseline to 5 mg [IQR 3– 7.5 mg]; benralizumab 7.5 mg [IQR 5– 15 mg] to 5 mg [IQR 2– 10 mg]). The exacerbation rates were reduced significantly, irrespective of the treatment. Overall, changes were similar after 6 and 12 months of therapy.Conclusion: Both mepolizumab and benralizumab are highly effective in the long-term treatment of SEA, with no clinically relevant differences in outcomes after 12 months of therapy. In both groups, improvements were similar after 6 and 12 months of therapy, underlining the feasibility of early treatment evaluation.Keywords: severe eosinophilic asthma, asthma control, lung, treatment response, interleukin-5, interleukin-5-receptor

Johanna I Lutter,1 Rudolf A Jörres,2 Franziska C Trudzinski,3 Peter Alter,4 Christina Kellerer,2,5 Henrik Watz,6 Tobias Welte,7 Robert Bals,8 Diego Kauffmann-Guerrero,9 Jürgen Behr,9 Rolf Holle,10 Claus F Vogelmeier,4 Kathrin Kahnert9 On behalf of the COSYCONET study group1Institute of Health Economics and Health Care Management, Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research, Munich, Germany; 2Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, LMU Hospital, Comprehensive Pneumology Center Munich (CPC-M), Munich, Germany; 3Department of Pneumology and Critical Care Medicine, Thoraxklinik University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; 4Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-University Marburg (UMR), Germany, Member of the German Center for Lung Research (DZL), Marburg, Germany; 5School of Medicine, Institute of General Practice and Health Services Research, Technical University of Munich (TUM), Munich, Germany; 6Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 7Department of Pneumology, Hannover Medical School, Hannover, Germany; 8Department of Internal Medicine V – Pulmonology, Allergology, Respiratory Intensive Care Medicine, Saarland University Hospital, Homburg, Germany; 9Department of Medicine V, University of Munich (LMU), Comprehensive Pneumology Center, Member of the German Center for Lung Research (DZL), Munich, Germany; 10Institute for Medical Informatics, Biometry and Epidemiology, LMU Hospital, Munich, GermanyCorrespondence: Kathrin KahnertDepartment of Internal Medicine V, University of Munich (LMU), LMU Hospital, Ziemssenstraße 1, Munich, 80336, GermanyEmail Kathrin.Kahnert@med.uni-muenchen.deBackground: In COPD patients of GOLD groups A and B, a high degree of treatment with inhaled corticosteroids (ICS) has been reported, which is regarded as overtreatment according to GOLD recommendations. We investigated which factors predict ICS use and which relationship it has to clinical and functional outcomes, or healthcare costs.Methods: We used pooled data from visits 1 and 3 of the COSYCONET cohort (n=2741, n=2053, interval 1.5 years) including patients categorized as GOLD grades 1– 4 and GOLD group A or B at both visits (n=1080). Comparisons were performed using ANOVA, and regression analyses using propensity matching and inverse probability weighting to adjust for differences between ICS groups. These were defined as having ICS at both visits (always) vs no ICS at both visits (never). Measures were divided into predictors of ICS treatment and outcomes.Results: Among 1080 patients, 608 patients were eligible for ICS groups (n=297 never, n=311 always). Prior to matching, patients with ICS showed significantly (p< 0.05 each) impaired lung function, symptoms and exacerbation history. After matching, the outcomes generic quality of life and CO diffusing capacity were increased in ICS patients (p< 0.05 each). Moreover, costs for respiratory medication, but not total health care costs, were significantly elevated in the ICS group by 780€ per year.Conclusion: ICS therapy in COPD GOLD A/B patients can have small positive and negative effects on clinical outcomes and health care costs, indicating that the clinical evaluation of ICS over-therapy in COPD requires a multi-dimensional approach.Keywords: COPD, inhaled corticosteroids, GOLD groups, overtreatment

Nora Drick,1,* Katrin Milger,2,* Benjamin Seeliger,1 Jan Fuge,1 Stephanie Korn,3 Roland Buhl,3 Maren Schuhmann,4 Felix Herth,4 Benjamin Kendziora,5 Juergen Behr,2 Nikolaus Kneidinger,2 Karl-Christian Bergmann,5 Christian Taube,6 Tobias Welte,1 Hendrik Suhling1 1Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany; 2Department of Internal Medicine V, Ludwig-Maximilians University of Munich (LMU), Munich, Germany; 3Pulmonary Department, Mainz University Hospital, Mainz, Germany; 4Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Heidelberg, Germany; 5Allergy-Centre-Charité, Charité – Universitätsmedizin Berlin, Berlin, Germany; 6Department of Pulmonary Medicine, University Hospital Essen – Ruhrlandklinik, Essen, Germany*These authors contributed equally to this workCorrespondence: Hendrik Suhling Email suhling.hendrik@mh-hannover.deBackground: Anti-IL-5 antibodies represent an established therapy for severe eosinophilic asthma (SEA), but some patients show inadequate response. The objective of this study was to assess the effects of a switch to anti-IL-5Rα therapy in patients with inadequate response to anti-IL-5 therapy.Methods: In this retrospective multi-centre, real-life study, we analysed all SEA patients switched from anti-IL-5 to anti-IL-5Rα therapy due to inadequate response or intolerability. Pulmonary function tests, blood gas analyses, asthma control tests (ACT) and oral corticosteroid (OCS) usage were analysed and compared at three timepoints: baseline (BL, before anti-IL-5 therapy), timepoint 1 (T1, under anti-IL-5 therapy) and timepoint 2 (T2, under anti-IL-5Rα therapy).Results: Of 665 patients treated with anti-IL-5 antibodies, 70 were switched to anti-IL-5Rα and 60 were included in the analysis. Median treatment duration was 8 months [IQR 5; 15] for anti-IL-5 and 5 months [IQR 4; 6] for anti-IL-5Rα therapy. FEV1 was 61% of predicted at BL [IQR 41; 74], 61% [IQR 43; 79] at T1 and 68% [IQR 49; 87] at T2 (pT1-T2=0.011). ACT score was 10 [IQR 8; 13], 16 [IQR 10; 19] and 19 [IQR 14; 22], respectively (both p< 0.001). The number of patients requiring OCS was reduced from 41 (BL) to 32 (T1) and 19 (T2) (both p< 0.001). Ten patients discontinued anti-IL-5Rα therapy due to insufficient efficacy (n=7) and adverse events (n=3).Conclusion: Switching from anti-IL-5 to anti-IL-5Rα therapy in patients with inadequate response was associated with significantly improved FEV1, asthma control and OCS reduction.Keywords: benralizumab, eosinophils, mepolizumab, reslizumab, severe asthma

Benjamin Waschki,1–3 Henrik Watz,2,3 Olaf Holz,4,5 Helgo Magnussen,2,3 Beata Olejnicka,6 Tobias Welte,5,7 Klaus F Rabe,1,3 Sabina Janciauskiene5,7 1Pneumology, LungenClinic Grosshansdorf, Grosshansdorf, Germany; 2Pulmonary Research Institute at LungenClinic Grosshansdorf, Grosshansdorf, Germany; 3Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 4Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany; 5Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany; 6Department of Medicine, Trelleborg Hospital, Trelleborg, Sweden; 7Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany Introduction: Plasminogen activator inhibitor-1 (PAI-1), a major inhibitor of fibrinolysis, is associated with thrombosis, obesity, insulin resistance, dyslipidemia, and premature aging, which all are coexisting conditions of chronic obstructive pulmonary disease (COPD). The role of PAI-1 in COPD with respect to metabolic and cardiovascular functions is unclear. Methods: In this study, which was nested within a prospective cohort study, the serum levels of PAI-1 were cross-sectionally measured in 74 stable COPD patients (Global Initiative for Chronic Obstructive Lung Disease [GOLD] Stages I–IV) and 18 controls without lung disease. In addition, triglycerides, high-density lipoprotein cholesterol, fasting plasma glucose, waist circumference, blood pressure, smoking status, high-sensitive C-reactive protein (hs-CRP), adiponectin, ankle–brachial index, N-terminal pro-B-type natriuretic peptide, and history of comorbidities were also determined. Results: The serum levels of PAI-1 were significantly higher in COPD patients than in controls, independent of a broad spectrum of possible confounders including metabolic and cardiovascular dysfunction. A multivariate regression analysis revealed triglyceride and hs-CRP levels to be the best predictors of PAI-1 within COPD. GOLD Stages II and III remained independently associated with higher PAI-1 levels in a final regression analysis. Conclusion: The data from the present study showed that the serum levels of PAI-1 are higher in patients with COPD and that moderate-to-severe airflow limitation, hypertriglyceridemia, and systemic inflammation are independent predictors of an elevated PAI-1 level. PAI-1 may be a potential biomarker candidate for COPD-specific and extra-pulmonary manifestations. Keywords: plasminogen activator inhibitor-1, chronic obstructive pulmonary disease, cardiovascular disease, inflammation, hypertriglyceridemia, ankle-brachial index, N-terminal pro-B-type natriuretic peptide