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Was ist neu? Diagnostik und Einschätzung des Schweregrads: Eine Diagnosestellung erfordert den spirometrischen Nachweis einer nachweisbaren obstruktiven Ventilationsstörung. GOLD empfiehlt weiterhin das FEV1/FVC-Verhältnis von Pharmakologische Therapie: Die Initialtherapie erfolgt nach dem ABE-Scheme. GOLD legt besonderen Wert auf die Auswahl des richtigen Inhalationssystems. Für die Follow-up-Situation ist entscheidend, ob die Patienten nur unter Symptomen leiden oder zwischenzeitlich unter Therapie auch Exazerbationen aufgetreten sind. Therapie und Auswirkung auf die Mortalität: Eine Reihe von nicht medikamentösen Therapiemaßnahmen hat signifikante Auswirkungen auf die Mortalität: diese reichen von Rauchentwöhnung über Rehabilitation, Langzeitsauerstofftherapie und nicht invasive Beatmung bis zur Lungenvolumenreduktion. Die Behandlung mit Triple-Therapien kann bei Patienten, die unter Therapie Exazerbationen entwickeln, einen signifikanten Überlebensvorteil im Vergleich zu LABA und LAMA bedingen. Exazerbationen GOLD schlägt eine neue Definition von COPD vor, die Symptome, Zeitverlauf, klinische Zeichen und Ursachen beinhaltet. Noch bedeutsamer ist aber die empfohlene Einteilung des Schweregrades, der jetzt auch darauf abhebt, dass wichtige Differenzialdiagnosen (insbesondere Herzinsuffizienz, Pneumonie, Lungenembolie) ausgeschlossen werden.

Zusammenfassung Einleitung Die nächtliche kontinuierliche positive Überdruckatmung (CPAP) gilt als therapeutischer Goldstandard einer obstruktiven Schlafapnoe (OSA). Die CPAP-Therapie stellt zumeist eine Dauertherapie mit geringen Nebenwirkungen dar. Trotzdem ist die Therapietreue unbefriedigend. In dieser Arbeit wurden die Therapietreue betrachtet und typische Probleme katalogisiert. Methode 1078 OSA-Patienten wurden nach diagnostischer Polygrafie (PG) oder Polysomnografie (PSG) auf eine CPAP-Therapie eingestellt. Die Therapietreue wurde nach 3 Monaten nachverfolgt. Folgende Therapieadhärenz-Gruppen wurden festgelegt: 1. gute CPAP-Einstellung und Nutzung, 2. CPAP-Abbruch nach anfänglicher Nutzung, 3. mangelnde CPAP-Nutzung wegen Nebenwirkungen, 4. Abbruch aufgrund fehlender Motivation/geringem Leidensdruck, 5. Masken-Unverträglichkeit, 6. CPAP-Versagen aufgrund fehlenden Therapieeffekts, 7. Umstellung auf anderes Beatmungsverfahren, 8. keine Kontrolle erfolgt. Ergebnisse Von 1078 CPAP-Patienten erschienen 830 Patienten (77 %) zur Therapiekontrolle. Hiervon waren 450 Patienten (54,2%) in Gruppe 1, 216 Patienten (26%) in Gruppe 2, 71 Patienten (8,5%) in Gruppe 3, 35 Patienten (4,2%) in Gruppe 4, 14 Patienten (1,7%) in Gruppe 5, 3 Patienten (0,4 %) in Gruppe 6 und 41 Patienten (4,9%) in Gruppe 7. Ein geringer obstruktiver Ereignisindex, niedriger CPAP-Druck und tendenziell auch ein geringer Epworth-Sleepiness-Score waren Prädiktoren für CPAP-Versagen. Für die Therapietreue konnten keine signifikanten Prädiktoren dargestellt werden. Diskussion Eine effektive Therapienutzung von 54% nach 3 Monaten ist ein suboptimales Ergebnis. Prädiktoren für CPAP-Versagen waren Parameter, die vor Therapie auf geringen Leidensdruck der Patienten deuteten. Trotz großer Patientenkohorte konnten keine signifikanten CPAP-Adhärenz-Prädiktoren durch anthropometrische oder PSG-Daten dargestellt werden. Vielmehr könnten Erfahrungen in den ersten Therapietagen ausschlaggebend sein. CPAP-Geräte bieten Komforteinstellungen, die kenntnisgerecht auf den Patienten individualisiert werden müssen. Eine große Auswahl an unterschiedlichen Maskenformen erfordert Erfahrung und Training bei der patientenorientierten Maskenanpassung. Eine 3-monatige Wiedervorstellung erscheint zu lang, um Therapieprobleme zeitnah mit dem Patienten zu besprechen. Telemedizinische Möglichkeiten oder kurzfristige telefonische Beratungsoptionen sollten in Betracht gezogen werden.

ZusammenfassungCOSYCONET 1 ist die derzeit einzige international konkurrenzfähige deutsche COPD-Kohorte. Die Rekrutierung begann Ende 2010 und endete im Dezember 2013. Sie resultierte in 2741 Patienten mit der Diagnose einer COPD, die in der Folge in regelmäßigen Visiten nachuntersucht wurden. Diese Visiten umfassten eine umfangreiche funktionelle und klinische Charakterisierung. Auf der Basis dieses hochwertigen Datensatzes war es möglich, eine Vielzahl klinischer Fragen zu beantworten. Diese reichten vom Verschreibungsverhalten über die genaue Analyse verschiedener Komorbiditäten, v.a. kardiovaskulärer Art, bis zu Biomarkern, radiologischen und gesundheitsökonomischen Analysen. Inzwischen wurden mehr als 60 Publikationen zu COSYCONET international veröffentlicht. Die nachstehende Arbeit liefert eine Übersicht über alle bislang erhaltenen Ergebnisse, mit einem besonderen Fokus darauf, deren wechselseitigen Zusammenhang sowie die möglichen praktischen Konsequenzen herauszuarbeiten. Ferner werden einige Informationen über die Folgestudie COSYCONET 2 gegeben.

Peter Alter,1 Jan Orszag,2,3 Emiel FM Wouters,4,5 Claus F Vogelmeier,1 Rudolf A Jörres2 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; 2Institute 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, Germany; 3Department of Anaesthesiology, University Hospital, LMU Munich, Munich, Germany; 4Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht, Netherlands; 5Ludwig Boltzmann Institute for Lung Health, Vienna, AustriaCorrespondence: Peter Alter, Department of Medicine, Pulmonary and Critical Care Medicine, Philipps-University of Marburg (UMR), Baldingerstrasse, Marburg, 35033, Germany, Email Alter@uni-marburg.deAbstract: Body plethysmography is a fundamental method for the assessment of static lung volumes. Although equipment is provided by several manufacturers, there are no established cross-vendor tools for quality control. In the process of quality control and analysis of data on hyperinflation from the large COPD cohort COSYCONET, hints appeared that plethysmographs of different vendors might yield different values for static lung volumes. Functional residual capacity (FRC) differed about 0.67 litres between plethysmographs of the manufacturer Vyaire and Ganshorn. Absolute differences of residual lung volume (RV) and total lung capacity (TLC) were similar. It appears undeniable that differences of this magnitude have an impact on clinical interpretation. Thus, device harmonization seems to be required.Keywords: lung function, body plethysmography, static lung volumes, functional residual capacity

BackgroundEffectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) Working Group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies.MethodsCOMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult and paediatric clinicians, pharmaceutical representatives, and health regulators from across Europe. Evidence included a systematic review of development, validity and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients’ and carers’ views about outcome measures. It was discussed using a modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria.ResultsBoth adult and paediatric COM sets include forced expiratory volume in 1 s (FEV1) as z-scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire and Asthma Control Test or Childhood Asthma Control Test, while the adult COM set includes the Severe Asthma Questionnaire and Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately).ConclusionsThis patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.

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

Zusammenfassung Einleitung Die nächtliche kontinuierliche positive Überdruckatmung (CPAP) gilt als therapeutischer Goldstandard einer obstruktiven Schlafapnoe (OSA). Die CPAP-Therapie stellt zumeist eine Dauertherapie mit geringen Nebenwirkungen dar. Trotzdem ist die Therapietreue unbefriedigend. In dieser Arbeit wurden die Therapietreue betrachtet und typische Probleme katalogisiert. Methode 1078 OSA-Patienten wurden nach diagnostischer Polygrafie (PG) oder Polysomnografie (PSG) auf eine CPAP-Therapie eingestellt. Die Therapietreue wurde nach 3 Monaten nachverfolgt. Folgende Therapieadhärenz-Gruppen wurden festgelegt: 1. gute CPAP-Einstellung und Nutzung, 2. CPAP-Abbruch nach anfänglicher Nutzung, 3. mangelnde CPAP-Nutzung wegen Nebenwirkungen, 4. Abbruch aufgrund fehlender Motivation/geringem Leidensdruck, 5. Masken-Unverträglichkeit, 6. CPAP-Versagen aufgrund fehlenden Therapieeffekts, 7. Umstellung auf anderes Beatmungsverfahren, 8. keine Kontrolle erfolgt. Ergebnisse Von 1078 CPAP-Patienten erschienen 830 Patienten (77 %) zur Therapiekontrolle. Hiervon waren 450 Patienten (54,2 %) in Gruppe 1, 216 Patienten (26 %) in Gruppe 2, 71 Patienten (8,5 %) in Gruppe 3, 35 Patienten (4,2 %) in Gruppe 4, 14 Patienten (1,7 %) in Gruppe 5, 3 Patienten (0,4 %) in Gruppe 6 und 41 Patienten (4,9 %) in Gruppe 7. Ein geringer obstruktiver Ereignisindex, niedriger CPAP-Druck und tendenziell auch ein geringer Epworth-Sleepiness-Score waren Prädiktoren für CPAP-Versagen. Für die Therapietreue konnten keine signifikanten Prädiktoren dargestellt werden. Diskussion Eine effektive Therapienutzung von 54 % nach 3 Monaten ist ein suboptimales Ergebnis. Prädiktoren für CPAP-Versagen waren Parameter, die vor Therapie auf geringen Leidensdruck der Patienten deuteten. Trotz großer Patientenkohorte konnten keine signifikanten CPAP-Adhärenz-Prädiktoren durch anthropometrische oder PSG-Daten dargestellt werden. Vielmehr könnten Erfahrungen in den ersten Therapietagen ausschlaggebend sein. CPAP-Geräte bieten Komforteinstellungen, die kenntnisgerecht auf den Patienten individualisiert werden müssen. Eine große Auswahl an unterschiedlichen Maskenformen erfordert Erfahrung und Training bei der patientenorientierten Maskenanpassung. Eine 3-monatige Wiedervorstellung erscheint zu lang, um Therapieprobleme zeitnah mit dem Patienten zu besprechen. Telemedizinische Möglichkeiten oder kurzfristige telefonische Beratungsoptionen sollten in Betracht gezogen werden.

Kathrin Kahnert,1 Rudolf A Jörres,2 Tanja Lucke,2 Franziska C Trudzinski,3 Pontus Mertsch,1 Christiane Bickert,1 Joachim H Ficker,4 Jürgen Behr,1 Robert Bals,5 Henrik Watz,6 Tobias Welte,7 Claus F Vogelmeier,8 Peter Alter8 On behalf of COSYCONET Study Group1Department of Medicine V, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany; 2Institute 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, 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 Respiratory Medicine, Nürnberg General Hospital, Paracelsus Medical University, Nürnberg, Germany; 5Department of Internal Medicine V - Pulmonology, Allergology, Intensive Care Medicine, Saarland University Hospital, Homburg, Germany; 6Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 7Clinic for Pneumology, Hannover Medical School, Member of the German Center for Lung Research (DZL), Hannover, Germany; 8Department of Medicine, Pulmonary and Critical Care Medicine, University of Marburg (UMR), Germany, Member of the German Center for Lung Research (DZL), Marburg, GermanyCorrespondence: Kathrin KahnertDepartment of Medicine V, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, GermanyTel +49 89 4400 52590Fax +49 89 4400 54905Email kathrin.kahnert@med.uni-muenchen.deBackground: Patients with chronic obstructive pulmonary disease (COPD) often have osteoporosis and diabetes as comorbid conditions. Anti-diabetic medication, including metformin, has protective effects on osteoporosis in experimental studies. We therefore studied whether patients with COPD receiving anti-diabetic medication had a lower osteoporosis prevalence in a large COPD cohort, COSYCONET.Methods: Assessment of osteoporosis was based on patients’ reports of physician-based diagnoses and the presence of disease-specific medication. The predictive value of physical characteristics, lung function, comorbidities, cardiovascular medication, and the use of anti-inflammatory diabetes medication, including metformin, sulfonylureas, glinides or DPP4I, was evaluated using logistic regression analysis. ClinicalTrials.gov: NCT01245933.Results: In total, 2222 patients were eligible for analysis (863 [39%] female, mean age 65 y), 515 of whom had higher symptoms and exacerbations (Global Initiative for Chronic Obstructive Lung Disease group D). Osteoporosis was present in 15.8% of the overall cohort, and in 24.1% of GOLD D patients. Regression analyses identified the following as associated with osteoporosis (p < 0.05): female sex, higher age, lower body-mass index, asthma, higher air trapping, oral steroids, and cardiovascular medication. Although oral anti-diabetic medication was overall not associated with a lower prevalence of osteoporosis (p = 0.131), anti-inflammatory anti-diabetic medication (p = 0.009) and metformin-containing therapy (p = 0.039) were. This was driven by GOLD D patients.Conclusion: In a large COPD cohort, anti-inflammatory diabetes therapy, including metformin, was associated with a lower prevalence of osteoporosis, especially in patients with higher symptoms and exacerbations. These findings suggest a protective effect of common anti-diabetic medication on osteoporosis, possibly as a result of attenuated systemic inflammation.Keywords: chronic obstructive pulmonary disease, oral corticosteroids, inhaled corticosteroids, anti-inflammatory, metformin, diabetes

COSYCONET 1 is the only German COPD cohort which is large enough to be internationally comparable. The recruitment, which started in 2010 and ended in December 2013, comprised 2741 patients with the diagnosis of COPD who were subsequently investigated in regular follow-up visits. All visits included a comprehensive functional and clinical characterisation. On the basis of this detailed data set, it was possible to address a large number of clinical questions. These questions ranged from the prescription of medication, the detailed analysis of comorbidities, in particular cardiovascular disease, and biomarker assessment to radiological and health-economic aspects. Currently, more than 60 publications of COSYCONET data are internationally available. The present overview provides a description of all the results that were obtained, focussing on the relationship between different clinical and functional aspects as well as their potential practical consequences. In addition, information on the follow-up study COSYCONET 2 is given.COSYCONET 1 ist die derzeit einzige international konkurrenzfähige deutsche COPD-Kohorte. Die Rekrutierung begann Ende 2010 und endete im Dezember 2013. Sie resultierte in 2741 Patienten mit der Diagnose einer COPD, die in der Folge in regelmäßigen Visiten nachuntersucht wurden. Diese Visiten umfassten eine umfangreiche funktionelle und klinische Charakterisierung. Auf der Basis dieses hochwertigen Datensatzes war es möglich, eine Vielzahl klinischer Fragen zu beantworten. Diese reichten vom Verschreibungsverhalten über die genaue Analyse verschiedener Komorbiditäten, v.a. kardiovaskulärer Art, bis zu Biomarkern, radiologischen und gesundheitsökonomischen Analysen. Inzwischen wurden mehr als 60 Publikationen zu COSYCONET international veröffentlicht. Die nachstehende Arbeit liefert eine Übersicht über alle bislang erhaltenen Ergebnisse, mit einem besonderen Fokus darauf, deren wechselseitigen Zusammenhang sowie die möglichen praktischen Konsequenzen herauszuarbeiten. Ferner werden einige Informationen über die Folgestudie COSYCONET 2 gegeben.

Alterations in body composition, including a low fat-free mass index (FFMI), are common in patients with chronic obstructive pulmonary disease (COPD) and occur regardless of body weight.Is the impact of low FFMI on exercise capacity, health-related quality of life (HRQL) and systemic inflammation different among COPD patients stratified in different body mass index classifications?We analysed baseline data of COPD patients from the COSYCONET (COPD and Systemic Consequences - Comorbidities Network) cohort. Assessments included lung function, bioelectrical impedance analysis, six-minute walk distance (6MWD), HRQL and inflammatory markers. Patients were stratified in underweight (UW), normal weight (NW), pre-obese (PO) and obese (OB) according to BMI and as presenting low, normal or high FFMI using 252137 COPD patients (GOLD 1-4, 61% males, age: 65±8years, FEVIn patients with COPD with lower weight, such as UW patients, higher FFMI is independently associated with better exercise capacity. In contrast, in PO and OB COPD patients, a higher FFMI were not consistently associated with better outcomes.

Background Lung emphysema is an important phenotype of chronic obstructive pulmonary disease (COPD), and CT scanning is strongly recommended to establish the diagnosis. This study aimed to identify criteria by which physicians with limited technical resources can improve the diagnosis of emphysema. Methods We studied 436 COPD patients with prospective CT scans from the COSYCONET cohort. All items of the COPD Assessment Test (CAT) and the St George’s Respiratory Questionnaire (SGRQ), the modified Medical Research Council (mMRC) scale, as well as data from spirometry and CO diffusing capacity, were used to construct binary decision trees. The importance of parameters was checked by the Random Forest and AdaBoost machine learning algorithms. Results When relying on questionnaires only, items CAT 1 & 7 and SGRQ 8 & 12 sub-item 3 were most important for the emphysema- versus airway-dominated phenotype, and among the spirometric measures FEV1/FVC. The combination of CAT item 1 (≤ 2) with mMRC (> 1) and FEV1/FVC, could raise the odds for emphysema by factor 7.7. About 50% of patients showed combinations of values that did not markedly alter the likelihood for the phenotypes, and these could be easily identified in the trees. Inclusion of CO diffusing capacity revealed the transfer coefficient as dominant measure. The results of machine learning were consistent with those of the single trees. Conclusions Selected items (cough, sleep, breathlessness, chest condition, slow walking) from comprehensive COPD questionnaires in combination with FEV1/FVC could raise or lower the likelihood for lung emphysema in patients with COPD. The simple, parsimonious approach proposed by us might help if diagnostic resources regarding respiratory diseases are limited. Trial registration ClinicalTrials.gov, Identifier: NCT01245933, registered 18 November 2010, https://clinicaltrials.gov/ct2/show/record/NCT01245933. Supplementary Information The online version contains supplementary material available at 10.1186/s12931-021-01837-2.

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

Chronic obstructive pulmonary disease (COPD) is frequently associated with coronary artery disease (CAD). When considering computed tomography (CT) for COPD phenotyping, coronary vessel wall calcification would be a potential marker of cardiac disease. However, non-ECG gated scans as used in COPD monitoring do not comply with established quantitative approaches using ECG-triggered CT and the Agatston score. We studied the diagnostic potential of Agatston scores from non-triggered scans for cardiac disease. The study population was a sub-group of the COPD cohort COSYCONET that underwent CT scanning in addition to comprehensive clinical assessments, echocardiographic data and physician-based diagnoses of comorbidities. Agatston scores from non-contrast enhanced, non-triggered CT were used to identify a cut-off value for CAD via ROC analysis. 399 patients were included (152 female, mean age 66.0 ± 8.2 y). In terms of CAD, an Agatston score ≥1500 AU performed best (AUC 0.765; 95% CI: 0.700, 0.831) and was superior to the conventional cut-off value (400 AU). Using this value for defining groups, there were differences (p lt; 0.05) in lung function, left atrial diameter and left ventricular end-systolic diameter as well as CT-determined central airway wall thickness pointing towards a bronchitis phenotype. In multivariate analysis, BMI, hyperlipidemia, arterial hypertension, GOLD D (p lt; 0.05) but particularly Agatston score ≥1500 AU (Odds ratio 10.5; 95% CI: 4.8; 22.6)) were predictors of CAD. We conclude that in COPD patients, Agatston scores derived from non-ECG gated CT showed a much higher cut-off value (1500 AU) for actionable coronary artery disease than the score derived from ECG-triggered CT in cardiology patients.

Evidence suggests that intranasal application of oxytocin facilitates empathy and modulates its underlying neural processes, which are often impaired in individuals with autism spectrum disorders (ASD). Oxytocin has therefore been considered a promising candidate for the treatment of social difficulties in ASD. However, evidence linking oxytocin treatment to social behavior and brain function in ASD is limited and heterogeneous effects might depend on variations in the oxytocin-receptor gene (OXTR). We examined 25 male ASD patients without intellectual disability in a double-blind, cross-over, placebo-controlled fMRI-protocol, in which a single dose of oxytocin or placebo was applied intranasally. Patients performed three experiments in the MRI examining empathy for other’s physical pain, basic emotions, and social pain. All participants were genotyped for the rs53576 single-nucleotide polymorphism of the OXTR. Oxytocin increased bilateral amygdala responsiveness during the physical pain task for both painful and neutral stimuli. Other than that, there were no effects of oxytocin treatment. OXTR genotype did not significantly interact with oxytocin treatment. Our results contribute to the growing body of empirical literature suggesting heterogenous effects of oxytocin administration in ASD. To draw clinically relevant conclusions regarding the usefulness of oxytocin treatment, however, empirical studies need to consider methods of delivery, dose, and moderating individual factors more carefully in larger samples.

High resting heart rate (RHR) is associated with higher mortality in the general population and in cardiovascular disease. Less is known about the association of RHR with outcome in chronic obstructive pulmonary disease (COPD). In particular, the time-updated RHR (most recent value before the event) appears informative. This is the first study to investigate the association of time-updated RHR with mortality in COPD. We compared the baseline and time-updated RHR related to survival in 2218 COPD patients of the German COSYCONET cohort (COPD and Systemic Consequences—Comorbidities Network). Patients with a baseline RHR > 72 beats per minute (bmp) had a significantly (p = 0.049) higher all-cause mortality risk (adjusted hazard ratio (HR) of 1.37 (1.00–1.87) compared to baseline RHR ≤ 72 bpm. The time-updated RHR > 72 bpm was markedly superior (HR 1.79, 1.30–2.46, p = 0.001). Both, increased baseline and time-updated RHR, were independently associated with low FEV1, low TLCO, a history of diabetes, and medication with short-acting beta agonists (SABAs). In conclusion, increased time-updated RHR is associated with higher mortality in COPD independent of other predictors and superior to baseline RHR. Increased RHR is linked to lung function, comorbidities and medication. Whether RHR is an effective treatment target in COPD, needs to be proven in controlled trials.

Background: Oxygenated hemoglobin(OxyHem) is a simple-to-measure marker of oxygen content capable of predicting all-cause mortality in stable chronic obstructive pulmonary disease (COPD). Objectives: We aimed to analyze its predictive value during acute exacerbations of COPD (AECOPD). Methods: In this retrospective study, data from 227 patients discharged after severe AECOPD at RoMed Clinical Center Rosenheim, Germany, between January 2012 and March 2018, was analyzed. OxyHem (hemoglobin concentration [Hb] × fractional SpO2, g/dL) was calculated from oxygen saturation measured by pulse oximetry and hemoglobin assessed within 24 h after admission. The follow-up (1.7 ± 1.5 years) covered all-cause mortality, including readmissions for severe AECOPD. Results: During the follow-up period, 127 patients died, 56 due to AECOPD and 71 due to other reasons. Survivors and non-survivors showed differences in age, FVC % predicted, C-reactive protein, hemoglobin, Cr, Charlson Comorbidity Index (CCI), and OxyHem (p < 0.05 each). Significant independent predictors of survival were BMI, Cr or CCI, FEV1 % predicted or FVC % predicted, Hb, or OxyHem. The predictive value of OxyHem (p = 0.006) was superior to that of Hb or SpO2 and independent of oxygen supply during blood gas analysis. OxyHem was also predictive when using a cutoff value of 12.1 g/dL identified via receiver operating characteristic curves in analyses including either the CCI (hazard ratio 1.85; 95% CI 1.20, 2.84; p = 0.005) or Cr (2.04; 95% CI 1.35, 3.10; p = 0.001) as covariates. Conclusion: The concentration of OxyHem provides independent, easy-to-assess information on long-term mortality risk in COPD, even if measured during acute exacerbations. It therefore seems worth to be considered for broader clinical use.

Aims: Chronic obstructive pulmonary disease (COPD) and cardiovascular diseases are thought to be linked through various factors. We aimed to assess the relationship between airway obstruction, lung hyperinflation and diastolic filling in COPD. Methods: The study population was a subset of the COPD cohort COSYCONET. Echocardiographic parameters included the left atrial diameter (LA), early (E) and late (A) transmitral flow, mitral annulus velocity (e'), E wave deceleration time (E[dt]), and isovolumic relaxation time (IVRT). We quantified the effect of various predictors including forced expiratory volume in 1 s (FEV1) and intrathoracic gas volume (ITGV) on the echocardiographic parameters by multiple linear regression and integrated the relationships into a path analysis model. Results: A total of 615 COPD patients were included (mean FEV1 52.6% predicted). In addition to influences of age, BMI and blood pressure, ITGV was positively related to e'-septal and negatively to LA, FEV1 positively to E(dt) (p < 0.05 each). The effect of predictors was most pronounced for LA, e'-septal and E(dt), and less for E/A, IVRT and E/e'. Path analysis was used to take into account the additional relationships between the echocardiographic parameters themselves, demonstrating that their associations with the predictors were maintained and robust. Conclusions: Airway obstruction and lung hyperinflation were significantly associated with cardiac diastolic filling in patients with COPD, suggesting a decreased preload rather than an inherently impaired myocardial relaxation itself. This suggests that a reduction in obstruction and hyperinflation could help to improve cardiac filling.

Chronic obstructive pulmonary disease (COPD) is a leading cause of death with a considerable part of the population dying from cardiovascular diseases. High-sensitivity troponin I (hs-TnI) might help to better identify COPD patients at high risk of mortality. We aimed to study the predictive value of hs-TnI for all-cause mortality beyond established COPD assessments, and after consideration of relevant cardiovascular risk factors and prevalent cardiovascular diseases, in a broad population with stable COPD.Circulating hs-TnI concentrations together with a wide range of respiratory and cardiovascular markers were evaluated in 2085 patients with stable COPD across all severity stages enrolled in the multicentre COSYCONET cohort study. The primary outcome was all-cause mortality over 3 years of follow-up.Hs-TnI was detectable in 2020 (96.9%) patients. The median hs-TnI concentration was 3.8 ng·L−1 (interquartile range 2.5–6.6 ng·L−1), with levels above the 99th percentile reference limit of 27 ng·L−1 observed in 1.8% of patients. In Cox regression analyses including adjustments for airflow limitation, dyspnoea grade, exercise capacity and history of severe exacerbations, as well as traditional cardiovascular risk factors, estimated glomerular filtration rate, ankle–brachial index, N-terminal pro-brain natriuretic peptides and prevalent cardiovascular diseases, hs-TnI was a significant predictor for all-cause mortality, both as a continuous variable (hazard ratio (HR) for log hs-TnI 1.28, 95% CI 1.01–1.62) and categorised according to the cut-off of 6 ng·L−1 (HR 1.63, 95% CI 1.10–2.42).In patients with stable COPD, hs-TnI is a strong predictor of all-cause mortality beyond established COPD mortality predictors, and independent of a broad range of cardiovascular risk factors and prevalent cardiovascular diseases. Hs-TnI concentrations well below the upper reference limit provide further prognostic value for all patients with COPD when added to established risk assessments.

Introduction The COPD classification proposed by the Global Initiative for Obstructive Lung Disease was recently revised, and the A to D grouping is now based on symptoms and exacerbations only. Potential associations with comorbidities have not been assessed so far. Thus the aim of the present study was to determine the relationship between the revised (2017) GOLD groups A-D and major comorbidities. Methods We used baseline data from the COPD cohort COSYCONET. Comorbidities were identified from patient self-reports and disease-specific medication: gastrointestinal disorders, asthma, sleep apnea, hyperuricemia, hyperlipidemia, diabetes, osteoporosis, mental disorders, heart failure, hypertension, coronary artery disease. The A-D groups were based on either the COPD Assessment Test or the modified Medical Research Council scale. Exacerbations were also categorized as per GOLD recommendations. Results Data from 2228 patients were analyzed. Using GOLD group A as a reference, group D was associated with nearly all comorbidities, followed by group B and C. When groups A-D were dichotomized as AC vs. BD (symptoms) and AB vs. CD (exacerbations), all comorbidities correlated with symptoms and/or exacerbations. This was true for both mMRC- and CAT-based categorizations. Conclusions These findings suggest that the recently modified GOLD categorization is clinically relevant beyond being purely an assessment of symptoms and exacerbations. As the A-D groups correlated with the risk of important comorbidities, with some differences in terms of the correlation with symptoms and exacerbations, the findings underline the importance of identifying comorbidities in COPD, particularly in non-responders to therapy who have high symptoms and/or exacerbation rates.

Background Beyond smoking, several risk factors for the development of chronic obstructive pulmonary disease (COPD) have been described, among which socioeconomic status including education is of particular interest. We studied the contribution of education to lung function and symptoms relative to smoking in a group of never-smokers with COPD compared to a group of long-time ex-smokers with COPD. Methods We used baseline data of the COSYCONET cohort, including patients of GOLD grades 1-4 who were either never-smokers (n=150, age 68.5y, 53.3% female) or ex-smokers (≥10 packyears) for at least 10 years (n=616, 68.3y, 29.9% female). Socioeconomic status was analyzed using education level and mortality was assessed over a follow-up period of 4.5 years. Analyses were performed using ANOVA and regression models. Results Spirometric lung function did not differ between groups, whereas CO diffusing capacity and indicators of lung hyperinflation/air-trapping showed better values in the never-smoker group. In both groups, spirometric lung function depended on the education level, with better values for higher education. Quality of life and 6-MWD were significantly different in never-smokers as well as patients with higher education. Asthma, alpha-1-antitrypsin deficiency, and bronchiectasis were more often reported in never-smokers, and asthma was more often reported in patients with higher education. Higher education was also associated with reduced mortality (hazard ratio 0.46; 95% CI 0.22-0.98). Conclusion Overall, in the COSYCONET COPD cohort, differences in functional status between never-smokers and long-time ex-smokers were not large. Compared to that, the dependence on education level was more prominent, with higher education associated with better outcomes, including mortality. These data indicate that non-smoking COPD patients' socioeconomic factors are relevant and should be taken into account by clinicians.

Carolina Fischer,1 Rudolf A Jörres,1 Peter Alter,2 Franziska C Trudzinski,3 Önder Yildirim,4 Robert Bals,5 Claus F Vogelmeier,2 Diego Kauffmann-Guerrero,6 Jürgen Behr,6 Henrik Watz,7 Rolf Holle,8 Kathrin Kahnert6 And members of the COSYCONET study group1Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Munich, Germany; 2Department of Medicine, Pulmonary and Critical Care Medicine, University of Marburg (UMR), Germany, Marburg, Germany; 3Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany; 4Institute of Lung Biology and Disease (ILBD), Comprehensive Pneumology Center Munich (CPC-M), Munich, Germany; 5Department of Internal Medicine V - Pulmonology, Allergology, Intensive Care Medicine, Saarland University Hospital, Homburg, Germany; 6Department of Medicine V, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Munich, Germany; 7Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Grosshansdorf, Germany; 8Institute for Medical Informatics, Biometry and Epidemiology, University Hospital, LMU Munich, Munich, GermanyCorrespondence: Kathrin Kahnert, Department of Medicine V, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Ziemssenstraße 1, Munich, 80336, Germany, Email Kathrin.Kahnert@med.uni-muenchen.deIntroduction: In many chronic diseases, including COPD, the patients’ basic knowledge of the disorder has been shown to be relevant for the course of the disease. We studied which clinical and functional characteristics were related to this knowledge as well as the patients’ satisfaction with their knowledge about COPD.Methods: The study population comprised 645 patients of GOLD grades 1– 4 who participated in Visit 6 of the COSYCONET cohort (COPD and Systemic Consequences - Comorbidities Network). The assessments covered a broad panel of clinical and functional characteristics, including generic and disease-specific quality of life and the COPD Assessment Test (CAT). The study aim was addressed by two questions, referring to patients’ knowledge of the meaning of FEV1 and the overall satisfaction with their knowledge of COPD.Results: Knowledge of FEV1 was higher in patients of higher spirometric GOLD grades or exacerbation risk, in males, with higher educational level, and after participation in a prior educational training on COPD. Patients with more detailed knowledge showed a higher satisfaction with their knowledge. Satisfaction was associated with higher generic quality of life and a lower CAT score. Furthermore, satisfaction was higher in patients with a treatment plan but lower in patients with cardiac comorbidities. It appeared that females with basic education, high burden from COPD and low quality of life had the greatest knowledge deficits.Discussion: The results suggest room for education programs adapted to the educational level of the participants. They also emphasize the major role of a disease management plan for the patients.Keywords: chronic obstructive pulmonary disease, knowledge, education, satisfaction

Background Patients with chronic obstructive pulmonary disease (COPD) are at risk of developing cardiac arrhythmias and elevated heart rate. A theoretical mechanistic association based on the interaction of long-acting β2-agonists (LABAs) with adrenoreceptors in the heart and vasculature is assumed as a potential class-related risk. Therefore, we performed a pooled analysis of Holter electrocardiogram (ECG) data from four 48-week, randomized, double-blind, placebo-controlled, parallel-group, Phase III clinical trials evaluating olodaterol (5 μg or 10 μg) or formoterol (12 µg) versus placebo. Methods We analyzed Holter ECG data from a representative subset of 775 patients with Global Initiative for Chronic Obstructive Lung Disease stage 2-4 COPD from four studies (1222.11-14) assessing olodaterol (5 μg and 10 μg) and formoterol (12 µg) versus placebo. Results No statistically significant (P>0.3) or clinically relevant differences in the shift from baseline of premature supraventricular or ventricular beats were observed among the active treatment and the placebo groups. Minor and transient differences were observed in the adjusted mean heart rate from baseline during treatment in all groups. There was a numerically small but statistically significant increase for formoterol at Week 24, olodaterol 5 μg at Weeks 12 and 40, and olodaterol 10 μg at Week 40 (all less than 3.0 beats per minute). Mean heart rates returned to a statistically non-significant change at Week 48 for all treatment groups. No increase in major adverse cardiovascular events was observed. Conclusion Treatment with olodaterol or formoterol is not associated with arrhythmias or a persistent increase in heart rate as assessed by Holter ECG in patients with COPD. Trial registration ClinicalTrials.gov identifiers: NCT00782210 (1222.11); NCT00782509 (1222.12); NCT00793624 (1222.13); NCT00796653 (1222.14).

Stefan Andreas,1,2 Ulrich Bothner,3 Alberto de la Hoz,3 Isabel Kloer,3 Matthias Trampisch,3 Peter Alter4 1Department of Cardiology and Pneumology, University Medical Centre Göttingen, Göttingen, Germany; 2LungClinic Immenhausen, Immenhausen, Germany, Member of the German Center for Lung Research (DZL); 3Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 4Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Marburg, Germany, Member of the German Center for Lung Research (DZL)Correspondence: Stefan AndreasDepartment of Cardiology and Pneumology, Robert-Koch-Str. 40., Göttingen, GermanyTel +49 05673 501 1112Fax +49 05673 501 1101Email stefan.andreas@med.uni-goettingen.deBackground: Patients with chronic obstructive pulmonary disease (COPD) and cardiovascular comorbidities may have an increased risk of medication-related cardiac arrhythmias. We therefore performed an analysis of Holter electrocardiogram (ECG) data from two large, long-term, controlled clinical COPD trials to investigate whether tiotropium/olodaterol increased the risk of cardiac arrhythmia and mean heart rate.Methods: We analyzed Holter ECG data from a representative subset of patients (N=506) from the two pooled replicate studies (TONADO 1 and 2) assessing tiotropium/olodaterol 5/5 μg therapy versus tiotropium 5 μg or olodaterol 5 μg monotherapy, inhaled once daily (two single inhalations) using the Respimat® Soft Mist™ inhaler device. Additionally, major adverse cardiac events (MACE) with tiotropium/olodaterol were assessed versus the respective monotherapies.Results: After 12 weeks of treatment, there was no difference in the number of patients who had an increase or decrease from baseline in 24-hour supraventricular premature beats or ventricular premature beats between tiotropium/olodaterol 5/5 μg combination therapy and its monocomponents. Compared with baseline, a small but statistically significant increase in adjusted mean heart rate was observed for tiotropium 5 μg (+1.6 beats per minute [bpm]; P=0.0010), but no difference was observed for olodaterol 5 μg (+0.3 bpm; P=0.2778) or tiotropium/olodaterol 5/5 μg (– 0.1 bpm; P=0.4607). MACE and fatal MACE were limited to 1 to 3 patients across treatment groups.Conclusion: Compared with the compounds given as monotherapy, treatment with tiotropium/olodaterol fixed-dose combination therapy is not associated with medically relevant or statistically significant effects on arrhythmia as assessed by Holter ECG. Based on these findings, there is no evidence to assume a clinically relevant impact on cardiac function from dual tiotropium/olodaterol treatment.Trial Registration: TONADO 1 (ClinicalTrials.gov: NCT01431274); TONADO 2 (ClinicalTrials.gov: NCT01431287).Keywords: tiotropium, olodaterol, Holter ECG, heart rate, arrhythmia, safety