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Hartmut Timmermann,1 Katrin Milger,2 Johann Christian Virchow,3 Olaf Schmidt,4 Karl-Christian Bergmann,5 Dirk Koschel,6 Claus Neurohr,7 Florian Scholz,8 Sebastian Heck,9 Dirk Skowasch10 1Schwerpunktpraxis Colonnaden, Hamburg, Germany; 2Medicine V, Ludwig-Maximilians-University (LMU) Munich, Member of the German Center for Lung Research (DZL), Comprehensive Pneumology Center Munich (CPC-M), Munich, Germany; 3Abteilungen für Pneumologie / Intensivmedizin, Universitätmedizin Rostock, Rostock, Germany; 4Studienzentrum KPPK, Pneumologische Gemeinschaftspraxis, Koblenz, Germany; 5Institute of Allergology, Charité–Universitätsmedizin, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Corporate Member of Freie Universität Berlin and Humboldt-Universität Berlin, Berlin, Germany; 6Fachkrankenhaus Coswig, Lung Centre, Coswig, and Division of Pulmonology, Medical Department I, University Hospital Carl Gustav Carus, Dresden, Germany; 7Abteilung für Pneumologie und Beatmungsmedizin, Robert-Bosch-Krankenhaus Lungenzentrum Stuttgart, Stuttgart, Germany; 8IQVIA Commercial GmbH & Co. OHG, Frankfurt am Main, Germany; 9GlaxoSmithKline GmbH & Co. KG, Munich, Germany; 10Department of Internal Medicine II – Pneumology, University Hospital Bonn, Bonn, GermanyCorrespondence: Hartmut Timmermann, Schwerpunktpraxis Colonnaden 72, Hamburg, 20354, Germany, Tel +49 4086648880, Fax +49 40866488824, Email timmermann@allergopraxis.dePurpose: It has been estimated that, in 2019, 54,000 patients in Germany had uncontrolled GINA step 4/5 asthma. In the current study we analyzed which health care providers were involved in the management of these patients and their role in disease phenotyping.Patients and Methods: The year 2019 was retrospectively analyzed using the IQVIATM LRx, a longitudinal anonymized prescription database, and the electronic, anonymized medical records database, the IQVIA Disease Analyzer.Results: Of 54,000 uncontrolled GINA step 4/5 asthma patients in Germany, 52% had consulted both general practitioners (GPs) and pulmonologists, and 48% were seen exclusively by a GP. Of these 54,000 patients, 45% were being prescribed and were thus overusing short-acting β 2-agonists (SABAs) and oral corticosteroids (OCS) for ≥ 2 years, 26% for ≥ 3 years, and 16% for ≥ 4 years. In most regions, pulmonologists saw one of their uncontrolled GINA step 4/5 asthma patients per week. Laboratory tests from consultations with a GP were available for only 10% of patients referred to a pulmonologist. In 50% of uncontrolled asthma patients treated according to GINA step 4/5, these were initiated by the pulmonologist, and 34% received laboratory testing within the first year (in GINA step 4/5 asthma, the numbers are 20% and 18%, respectively).Conclusion: Fifty percent of uncontrolled asthma patients treated according to GINA step 4/5 were regularly seen by pulmonologists, who performed most of the phenotyping confirming their importance in the management of severe, uncontrolled asthma in Germany. To understand treatment pathways for these patients, further studies are needed.Keywords: prescription database, biological treatment, laboratory test, uncontrolled GINA step 4/5 asthma, Germany

Stephanie Korn,1 Katrin Milger,2 Dirk Skowasch,3 Christian Schulz,4 Cordula Mohrlang,5 Martin Wernitz,5 Thomas Paulsson,6 Michael Hennig,5 Roland Buhl7 1IKF Pneumologie Mainz, Mainz and Thoraxklinik Heidelberg, Heidelberg, Germany; 2Department of Medicine V, University Hospital, LMU Munich, Munich and Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany; 3University Hospital Bonn, Pneumology, Bonn, Germany; 4University Hospital Regensburg, Internal Medicine II, Pneumology, Regensburg, Germany; 5GlaxoSmithKline GmbH & Co. KG, Munich, Germany; 6GlaxoSmithKline Plc, Brentford, UK; 7Pulmonary Department, Johannes Gutenberg University Mainz, Mainz, GermanyCorrespondence: Cordula Mohrlang, GlaxoSmithKline GmbH & Co. KG, Prinzregentenplatz 9, München, D-81675, Germany, Tel + 49 163 360 5201, Email cordula.c.mohrlang@gsk.comPurpose: The German Asthma Net (GAN) operates a Severe Asthma Registry that provides an overview of the clinical presentation and management of patients with severe asthma. Based upon data from the GAN registry, the MepoGAN study aimed to describe clinical profiles and treatment outcomes of patients who were treated with the anti-IL-5 monoclonal antibody mepolizumab (NucalaTM) in routine practice in Germany.Patients and Methods: The MepoGAN study is a descriptive retrospective non-interventional cohort study. Mepolizumab patients enrolled in the GAN registry were evaluated with results being described in two different data sets: Cohort 1 (n=131) started on mepolizumab when the patients entered the registry. Results were reported after 4 months of therapy. Patients in Cohort 2 (n=220) were on treatment with mepolizumab at the time of enrollment and follow-up data were collected after a further year of treatment. Outcome measures included asthma control, lung function, disease symptoms, OCS use, and exacerbations.Results: Patients enrolled in the registry who started on mepolizumab in Cohort 1 had a mean age of 55 years, were former smokers in 51% of the cases, had a mean blood eosinophil count of 500 cells/μL, and frequently had maintenance OCS use (55%). In this real-world setting, mepolizumab therapy was associated with a clinically relevant reduction in blood eosinophils (− 445.7 cells/μL), OCS use (− 30%), and improvement in asthma control. Fifty-five percent (vs 10% at baseline) of the patients reported controlled or partially controlled asthma 4 months after starting therapy. In patients who were already treated with mepolizumab at registry enrollment (Cohort 2), asthma control and lung function remained stable after a further year of observation.Conclusion: The GAN registry data confirm the effectiveness of mepolizumab in a real-world setting. Treatment benefits are maintained over time. While the asthma of patients treated in routine practice was more severe, the results observed with mepolizumab are broadly consistent with RCTs.Keywords: severe asthma, registry, real-world, mepolizumab, patient profile, asthma control

Karl-Christian Bergmann,1 Dirk Skowasch,2 Hartmut Timmermann,3 Robert Lindner,4 Johann Christian Virchow,5 Olaf Schmidt,6 Dirk Koschel,7 Claus Neurohr,8 Sebastian Heck,9 Katrin Milger10 1Institute for Allergology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Berlin, Germany; 2Department of Internal Medicine II – Pneumology, University Hospital Bonn, Bonn, Germany; 3Schwerpunktpraxis Colonnaden, Hamburg, Germany; 4IQVIA Commercial GmbH & Co. OHG, Frankfurt Am Main, Germany; 5Universitätsmedizin Rostock - Zentrum für Innere Medizin, Medizinische Klinik I, Abteilung Pneumologie & Interdisziplinäre Internistische Intensivmedizin, Rostock, Germany; 6Pneumologische Gemeinschaftspraxis und Studienzentrum KPPK, Koblenz, Germany; 7Fachkrankenhaus Coswig, Lung Centre, Coswig, and Division of Pulmonology, Medical Department I, University Hospital Carl Gustav Carus, Dresden, Germany; 8Abteilung für Pneumologie und Beatmungsmedizin, Robert-Bosch-Krankenhaus Lungenzentrum, Stuttgart, Germany; 9GlaxoSmithKline GmbH & Co. KG, Munich, Germany; 10Department of Medicine V, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, GermanyCorrespondence: Karl-Christian Bergmann, Institute for Allergology-Charité, Luisenstraße 2, Berlin, 10117, Germany, Tel +491711934508, Fax +49 30 549090609, Email karlchristianbergmann@gmail.comPurpose: Asthma is one of the most prevalent chronic diseases in Germany affecting 4– 5% of all adults and 10% of children. Despite the availability of biologicals in recent years, studies show patients with inadequately controlled severe asthma in real life. The aim of the current study was to characterize and estimate the number of patients with NVL/GINA level 4 or 5 asthma and signs of poor control in Germany.Patients and Methods: In 2021, we retrospectively analyzed data collected during 2019 using the IQVIA™ LRx and IQVIA™ Disease Analyzer databases which contain anonymized longitudinal data covering approximately 80% of statutory health insurance (GKV) prescriptions in Germany with most relevant information about prescriptions, basic patient demographics or location of the prescriber; the IQVIA™ Disease Analyzer anonymized electronic medical records from a representative sample of office-based GPs and specialists. An expert committee of pulmonologists from different hospitals and expert practices supported the study. Asthma patients treated according to NVL/GINA 4/5 who used SABAs frequently (≥ 3 on days with no ICS-containing prescriptions/year) and/or received prescriptions for oral corticosteroids (OCS) (score of ≥ 2/year, a pulmonologist prescription scored 1.0, GP 0.75) were classified as severe, uncontrolled asthma.Results: In 2019, 3.4 million patients received at least two prescriptions of respiratory medications and 2.4 million patients on maintenance respiratory treatment have asthma. A total of 625,000 asthma patients were treated according to NVL/GINA step 4 or 5. Among these, 54,000 were uncontrolled according to the pre-defined OCS and/or SABA use, which corresponds to approximately 15% of patients in certain regions.Conclusion: In 2019, approximately 54,000 patients in Germany treated according to NVL/GINA step 4/5 had evidence suggestive for poor asthma control, up to 15% of patients in certain regions. Yet, only 12,000 patients overall were being treated with biologicals suggesting a possible treatment gap that requires further investigation.Keywords: prescription database, disease analyzer, uncontrolled asthma, oral corticosteroid, OCS, short-acting β 2-agonist, SABA

Arschang Valipour,1 Pallav L Shah,2 Felix J Herth,3 Christophe Pison,4 Christian Schumann,5 Ralf-Harto Hübner,6 Peter I Bonta,7 Romain Kessler,8 Wolfgang Gesierich,9 Kaid Darwiche,10 Bernd Lamprecht,11 Thierry Perez,12 Dirk Skowasch,13 Gaetan Deslee,14 Armelle Marceau,15 Frank C Sciurba,16 Reinoud Gosens,17 Jorine E Hartman,18 Francesca Conway,2 Marina Duller,1 Martin Mayse,19 Holly S Norman,19 Dirk-Jan Slebos18 On behalf of the AIRFLOW-2 Trial Study Group1Department of Respiratory and Critical Care Medicine, Karl-Landsteiner-Institute for Lung Research and Pulmonary Oncology, Krankenhaus Nord-Klinik Floridsdorf, Vienna, Austria; 2Royal Brompton & Harefield NHS Trust, Chelsea & Westminster Hospital and Imperial College, London, UK; 3Thoraxklinik, Department of Pneumology and Critical Care Medicine and Translational Lung Research Center Heidelberg (TLRCH), University of Heidelberg, Heidelberg, Germany; 4CHU Grenoble Alpes, Service Hospitalier Universitaire Pneumologie Physiologie; Université Grenoble Alpes, Grenoble, France; 5Clinic of Pneumology, Thoracic Oncology, Sleep- and Respiratory Critical Care, Klinikverbund Allgaeu, Kempten and Immenstadt, Germany; 6Charité Universitätsmedizin Berlin, Medizinische Klinik m. Schw. Infektiologie und Pneumologie, Campus Virchow, Berlin, Germany; 7Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; 8Service de Pneumologie, Nouvel Hôpital Civil, Université de Strasbourg, Strasbourg, France; 9Asklepios-Fachkliniken Munich-Gauting, Comprehensive Pneumology Center Munich, Gauting, Germany; 10Department of Pulmonary Medicine, Section of Interventional Pneumology, Ruhrlandklinik - University Hospital Essen, University of Duisburg-Essen, Essen, Germany; 11Department of Pulmonary Medicine, Kepler Universitatsklinikum GmbH, Linz, Austria; 12CHU de Lille – Hôpital Calmette, Lille, France; 13Department of Internal Medicine II - Cardiology/Pneumology, University of Bonn, Bonn, Germany; 14CHU de Reims, Hôpital Maison Blanche, Service de Pneumologie, Reims, France; 15Service de Pneumologie, Hôpital Universitaire Bichat, Paris, France; 16University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 17Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands; 18Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 19Nuvaira, Inc., Minneapolis, MN, USACorrespondence: Dirk-Jan SlebosDepartment of Pulmonary Diseases/Interventional Bronchoscopy AA11, University Medical Center Groningen, PO Box 30001, Groningen, the NetherlandsTel +31 503612357Fax +31503619320Email d.j.slebos@umcg.nlPurpose: COPD exacerbations are associated with worsening clinical outcomes and increased healthcare costs, despite use of optimal medical therapy. A novel bronchoscopic therapy, targeted lung denervation (TLD), which disrupts parasympathetic pulmonary innervation of the lung, has been developed to reduce clinical consequences of cholinergic hyperactivity and its impact on COPD exacerbations. The AIRFLOW-2 study assessed the durability of safety and efficacy of TLD additive to optimal drug therapy compared to sham bronchoscopy and optimal drug therapy alone in subjects with moderate-to-severe, symptomatic COPD two years post randomization.Patients and Methods: TLD was performed in COPD patients (FEV1 30– 60% predicted, CAT≥ 10 or mMRC≥ 2) in a 1:1 randomized, sham-controlled, double-blinded multicenter study (AIRFLOW-2) using a novel lung denervation system (Nuvaira, Inc., USA). Subjects remained blinded until their 12.5-month follow-up visit when control subjects were offered the opportunity to undergo TLD. A time-to-first-event analysis on moderate and severe and severe exacerbations of COPD was performed.Results: Eighty-two subjects (FEV1 41.6± 7.4% predicted, 50.0% male, age 63.7± 6.8 yrs, 24% with prior year respiratory hospitalization) were randomized. Time-to-first severe COPD exacerbation was significantly lengthened in the TLD arm (p=0.04, HR=0.38) at 2 years post-TLD therapy and trended towards similar attenuation for moderate and severe COPD exacerbations (p=0.18, HR=0.71). No significant changes in lung function or SGRQ-C were found 2 years post randomization between groups.Conclusion: In a randomized trial, TLD demonstrated a durable effect of significantly lower risk of severe AECOPD over 2 years. Further, lung function and quality of life remained stable following TLD.Clinical Trial Registration: NCT02058459.Keywords: COPD exacerbation, targeted lung denervation, bronchoscopy, COPD

Izabela Tuleta, Tarik Farrag, Laura Busse, Carmen Pizarro, Christian Schaefer, Simon Pingel, Georg Nickenig, Dirk Skowasch, Nadjib Schahab Department of Internal Medicine II – Cardiology, Pulmonology and Angiology, University of Bonn, Bonn, Germany Abstract: Atherosclerosis and COPD are both systemic inflammatory diseases that may influence each other. The aim of the present study was to determine the prevalence of COPD in patients with cerebral and/or peripheral artery disease and to assess factors associated with the presence of COPD. Following the diagnosis of cerebral and/or peripheral artery disease by means of duplex sonography, 166 consecutive patients underwent body plethysmography with capillary blood gas analysis. Thereafter, blood tests with determination of different parameters such as lipid profile, inflammatory and coagulation markers were conducted in remaining 136 patients who fulfilled inclusion criteria of the study. Thirty-six out of 136 patients suffered from COPD, mostly in early stages of the disease. Residual volume indicating emphysema was increased (162.9%±55.9% vs 124.5%±37.0%, p

Carmen Pizarro,1,* Neele Herweg-Steffens,1,* Martin Buchenroth,2 Wolfgang Schulte,3 Christian Schaefer,1 Christoph Hammerstingl,1 Nikos Werner,1 Georg Nickenig,1 Dirk Skowasch1 1Department of Internal Medicine II – Cardiology, Pneumology and Angiology, University Hospital Bonn, Germany; 2Department of Pneumology, Johanniter Hospital Bonn, Germany; 3Department of Pneumology, Malteser Hospital Bonn/Rhein-Sieg, Germany *These authors contributed equally to this work Background: In acute exacerbation of COPD, increased plasma levels of cardiac troponin are frequent and associated with increased mortality. Thus, we aimed at prospectively determining the diagnostic value of coronary angiography in patients with exacerbated COPD and concomitantly elevated cardiac troponin. Patients and methods: A total of 88 patients (mean age 72.9±9.2 years, 56.8% male) hospitalized for acute exacerbation of COPD with elevated plasma troponin were included. All patients underwent coronary angiography within 72 hours after hospitalization. Complementary 12-lead electrocardiogram, transthoracic echocardiography, pulmonary function, and angiological testing were performed.Results: Coronary angiography objectified the presence of ischemic heart disease (IHD) in 59 patients (67.0%), of whom 34 patients (38.6% of total study population) underwent percutaneous coronary intervention. Among these 34 intervened patients, the vast majority (n=26, 76.5%) had no previously known IHD, whereas only eight out of 34 patients (23.5%) presented an IHD history. Patients requiring coronary intervention showed significantly reduced left ventricular ejection fraction (45.8%±13.1% vs 55.1%±13.3%, P=0.01) and a significantly more frequent electrocardiographic ST-segment depression (20.6% vs 7.4%, P=0.01). Neither additional laboratory parameters for inflammation and myocardial injury nor lung functional measurements differed significantly between the groups. Conclusion: Angiographically confirmed IHD that required revascularization occurred in 38.6% of exacerbated COPD patients with elevated cardiac troponin. In this considerable portion of patients, coronary angiography emerged to be of diagnostic and therapeutic value. Keywords: COPD, acute exacerbation, troponin elevation, coronary angiography, ischemic heart disease

Carmen Pizarro,* Fabian van Essen,* Fabian Linnhoff, Robert Schueler, Christoph Hammerstingl, Georg Nickenig, Dirk Skowasch, Marcel Weber Department of Internal Medicine II, Cardiology, Pneumology and Angiology, University Hospital Bonn, Bonn, Germany *These authors contributed equally to this work Background: COPD and congestive heart failure represent two disease entities of growing global burden that share common etiological features. Therefore, we aimed to identify the degree of left ventricular (LV) dysfunction in COPD as a function of COPD severity stages and concurrently placed particular emphasis on the presence of overlapping obstructive sleep apnea (OSA).Methods: A total of 85 COPD outpatients (64.1±10.4 years, 54.1% males) and 20 controls, matched for age, sex, and smoking habits, underwent speckle tracking echocardiography for LV longitudinal strain imaging. Complementary 12-lead electrocardiography, laboratory testing, and overnight screening for sleep-disordered breathing using the SOMNOcheck micro® device were performed.Results: Contrary to conventional echocardiographic parameters, speckle tracking echocardiography revealed significant impairment in global LV strain among COPD patients compared to control smokers (-13.3%±5.4% vs -17.1%±1.8%, P=0.04). On a regional level, the apical septal LV strain was reduced in COPD (P=0.003) and associated with the degree of COPD severity (P=0.02). With regard to electrocardiographic findings, COPD patients exhibited a significantly higher mean heart rate than controls (71.4±13.0 beats per minute vs 60.3±7.7 beats per minute, P=0.001) that additionally increased over Global Initiative for Chronic Obstructive Lung Disease stages (P=0.01). Albeit not statistically significant, COPD led to elevated N-terminal pro-brain natriuretic peptide levels (453.2±909.0 pg/mL vs 96.8±70.0 pg/mL, P=0.08). As to somnological testing, the portion of COPD patients exhibiting overlapping OSA accounted for 5.9% and did not significantly vary either in comparison to controls (P=0.07) or throughout the COPD Global Initiative for Chronic Obstructive Lung Disease stages (P=0.49). COPD-OSA overlap solely correlated with nocturnal hypoxemic events, whereas LV performance status was unrelated to coexisting OSA.Conclusion: To conclude, COPD itself seems to be accompanied with decreased LV deformation properties that worsen over COPD severity stages, but do not vary in case of overlapping OSA. Keywords: chronic obstructive pulmonary disease, speckle tracking echocardiography, left ventricular dysfunction, overlap syndrome

Introduction Intermittent hypoxia as a surrogate of obstructive sleep apnea is associated with different cardiovascular complications. However, the effects of intermittent hypoxia on the lung tissue are less known. Therefore, the aim of our present study was to investigate if intermittent hypoxia may influence oxidative stress, inflammation, and protease/antiprotease system in the lung. Additionally, potential protective properties of anti-inflammatory and anti-oxidative drugs have been evaluated. Methods 32 mice were divided into four groups: (1) intermittent hypoxia, (2) intermittent hypoxia with infliximab, (3) intermittent hypoxia with l-glutathione, and (4) normoxia. After 4 weeks, lungs and blood were collected. Levels of reactive oxygen species in the lung were calculated by L-O12-enhanced chemiluminescence. CD68-positive lung macrophages were detected by immunofluorescence. Concentrations of elastase and desmosine in lung and of alpha-1-antitrypsin in blood were calculated by means of enzyme-linked immunosorbent assay. Results Compared to a control, intermittent hypoxia augmented the release of free oxygen radicals, expression of CD68+ macrophages, and concentration of elastase in the lung tissue. Despite increased blood levels of protective alpha-1-antitrypsin, concentrations of desmosine-degradation product of elastin were higher versus control. The application of anti-inflammatory infliximab und anti-oxidative l-glutathione prevented at least partly the above-observed hypoxia-associated changes. Conclusions Intermittent hypoxia contributes to the lung damage by increased oxidative stress, inflammation, and disbalance in protease/antiprotease system. Infliximab and l-glutathione may prevent adverse hypoxia-induced lung alternations., Author(s): I. Tuleta[sup.1] , F. Stockigt[sup.1] , U. R. Juergens[sup.1] , C. Pizarro[sup.1] , J. W. Schrickel[sup.1] , G. Kristiansen[sup.2] , G. Nickenig[sup.1] , D. Skowasch[sup.1] Author Affiliations: (1) Department [...]