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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 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

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.

Background Adherence to COPD medication is often considered to be lower than in other chronic diseases. In view of the frequent comorbidities of COPD, the economic impact of nonadherence and the potential for adverse effects, a direct comparison between the adherence to respiratory and nonrespiratory medication in the same patients seems of particular interest. Objectives We aimed to investigate the intake of respiratory and nonrespiratory medication in the same patients with COPD and frequent comorbidities. Method Within the COPD cohort COSYCONET, we contacted 1042 patients, mailing them a list with all medication regarding all their diseases, asking for regular, irregular and non-intake. Results Valid responses were obtained in 707 patients covering a wide spectrum of drugs. Intake of LABA, LAMA or ICS was regular in 91.9% of patients, even higher for cardiovascular and antidiabetes medication but lower for hyperlipidemia and depression/anxiety medication. Regular intake of respiratory medication did not depend on GOLD groups A-D or grades 1-4, was highest in patients with concomitant cardiovascular disorders and was lowest for concomitant asthma. It was slightly larger for LAMA and LABA administered via combined compared to single inhalers, and lower when similar compounds were prescribed twice. Most differences did not reach statistical significance owing to the overall high adherence. Conclusion Our results indicate a high adherence to respiratory medication in participants of a COPD cohort, especially in those with cardiovascular comorbidities. Compared to the lower adherence reported in the literature for COPD patients, our observations still suggest some room for improvement, possibly through disease management programs.

The COPD Assessment Test (CAT) is in widespread use for the evaluation of patients with chronic obstructive pulmonary disease (COPD). We assessed whether the CAT items carry additional information beyond the sum score regarding COPD characteristics including emphysema. Patients of GOLD grades 1 to 4 from the COPD cohort COSYCONET (German COPD and Systemic Consequences - Comorbidities Network) with complete CAT data were included (n = 2270), of whom 493 had chest CT evaluated for the presence of emphysema. Comorbidities and lung function were assessed following standardised procedures. Cross-sectional data analysis was based on multiple regression analysis of the single CAT items against a panel of comorbidities, lung function, or CT characteristics (qualitative score, 15th percentile of mean lung density), with age, BMI and gender as covariates. This was supported by exploratory factor analysis. Regarding the relationship to comorbidities and emphysema, there were marked differences between CAT items, especially items 1 and 2 versus 3 to 8. This grouping was basically confirmed by factor analysis. Items 4 and 5, and to a lower degree 1, 2 and 6, appeared to be informative regarding the presence of emphysema, whereas the total score was not or less informative. Regarding comorbidities, similar findings as for the total CAT score were obtained for the modified Medical Research Council scale (mMRC) which was also informative regarding emphysema. Our findings suggest that the usefulness of the CAT can be increased if evaluated on the basis of single items which may be indicating the presence of comorbidities and emphysema.

Background Peripheral neuropathy is a common comorbidity in COPD. We aimed to investigate associations between alterations commonly found in COPD and peripheral neuropathy, with particular emphasize on the distinction between direct and indirect effects. Methods We used visit 4 data of the COPD cohort COSYCONET, which included indicators of polyneuropathy (repeated tuning fork and monofilament testing), excluding patients with diabetes a/o increased HbA1c. These indicators were analysed for the association with COPD characteristics, including lung function, blood gases, 6-min walk distance (6-MWD), timed-up-and-go-test (TUG), exacerbation risk according to GOLD, C-reactive protein (CRP), and ankle-brachial index (ABI). Based on the results of conventional regression analyses adjusted for age, BMI, packyears and gender, we utilized structural equation modelling (SEM) to quantify the network of direct and indirect relationships between parameters. Results 606 patients were eligible for analysis. The indices of polyneuropathy were highly correlated with each other and related to base excess (BE), ABI and TUG. ABI was linked to neuropathy and 6-MWD, exacerbations depended on FEV1, 6-MWD and CRP. The associations could be summarized into a SEM comprising polyneuropathy as a latent variable (PNP) with three measured indicator variables. Importantly, PNP was directly dependent on ABI and particularly on BE. When also including patients with diabetes and/or elevated values of HbA1c (n = 742) the SEM remained virtually the same. Conclusion We identified BE and ABI as major determinants of peripheral neuropathy in patients with COPD. All other associations, particularly those with lung function and physical capacity, were indirect. These findings underline the importance of alterations of the micromilieu in COPD, in particular the degree of metabolic compensation and vascular status.

Background Adherence to COPD medication is often considered to be lower than in other chronic diseases. In view of the frequent comorbidities of COPD, the economic impact of nonadherence and the potential for adverse effects, a direct comparison between the adherence to respiratory and nonrespiratory medication in the same patients seems of particular interest. Objectives We aimed to investigate the intake of respiratory and nonrespiratory medication in the same patients with COPD and frequent comorbidities. Method Within the COPD cohort COSYCONET, we contacted 1042 patients, mailing them a list with all medication regarding all their diseases, asking for regular, irregular and non-intake. Results Valid responses were obtained in 707 patients covering a wide spectrum of drugs. Intake of LABA, LAMA or ICS was regular in 91.9% of patients, even higher for cardiovascular and antidiabetes medication but lower for hyperlipidemia and depression/anxiety medication. Regular intake of respiratory medication did not depend on GOLD groups A-D or grades 1–4, was highest in patients with concomitant cardiovascular disorders and was lowest for concomitant asthma. It was slightly larger for LAMA and LABA administered via combined compared to single inhalers, and lower when similar compounds were prescribed twice. Most differences did not reach statistical significance owing to the overall high adherence. Conclusion Our results indicate a high adherence to respiratory medication in participants of a COPD cohort, especially in those with cardiovascular comorbidities. Compared to the lower adherence reported in the literature for COPD patients, our observations still suggest some room for improvement, possibly through disease management programs.

Background The German COPD cohort study COSYCONET (" CO PD and SY stemic consequences- CO morbidities NET work") investigates the interaction of lung disease, comorbidities and systemic inflammation. Recruitment took place from 2010 to 2013 in 31 study centers. In addition to the baseline visit, follow-up visits are scheduled at 6, 18, 36 and 54 months after baseline. The study also comprises a biobank, image bank, and includes health economic data. Here we describe the study design of COSYCONET and present baseline data of our COPD cohort. Methods Inclusion criteria were broad in order to cover a wide range of patterns of the disease. In each visit, patients undergo a large panel of assessments including e.g. clinical history, spirometry, body plethysmography, diffusing capacity, blood samples, 6-min walk-distance, electrocardiogram and echocardiography. Chest CTs are collected if available and CTs and MRIs are performed in a subcohort. Data are entered into eCRFs and subjected to several stages of quality control. Results Overall, 2741 subjects with a clinical diagnosis of COPD were included (59% male; mean age 65 ± 8.6 years (range 40–90)). Of these, 8/35/32/9% presented with GOLD stages I–IV; 16% were uncategorized, including the former GOLD-0 category. 24% were active smokers, 68% ex-smokers and 8% never-smokers. Data completeness was 96% for the baseline items. Conclusion The German COPD cohort comprises patients with advanced and less advanced COPD. This is particularly useful for studying the time course of COPD in relation to comorbidities. Baseline data indicate that COSYCONET offers the opportunity to investigate our research questions in a large-scale, high-quality dataset.

Introduction Influences of airway obstruction and pulmonary hyperinflation on cardiac function and morphology have been suspected in COPD. We comprehensively analyzed pulmonary-cardiac interrelations with focus on left ventricular wall stress using structural equation modeling (SEM). Methods In the present analysis, data from 1,435 COSYCONET patients neither exhibiting prior left ventricular (LV) dilatation nor heart valve disease more than moderate were analyzed. Multivariate regression analyses and SEM were used to describe the relationship between lung function and echocardiographic parameters. Results The study population comprised 209/111/548/449/118 patients of GOLD categories 0 to IV. The most consistent and best fitting SEM comprised two latent variables (constructs): “LUFU” with indicators FEV1%pred, FEV1/FVC, ITGV%pred and Reff, and “ECHO” with indicators LV endsystolic wall stress and volume as well as enddiastolic wall stress. Both constructs LUFU and ECHO were related to each other (p=0.011). Additionally, the indicator ITGV%pred was directly linked to ECHO (p=0.048). Conclusions Even in patients with apparently normal LV diameters, significant effects of lung function on LV wall stress were found. The associations are consistent with the view that airway obstruction and lung hyperinflation exert increased distending forces on the LV leading to increased wall stress and dilatation. This might favour the development of relevant LV disease especially regarding wall stress, with unfavourable prognostic consequences. Funded by Bundesministerium fur Bildung und Forschung (BMBF), Kompetenznetz Asthma/COPD.

Background: In large cohort studies comorbidities are commonly self-reported by the patients. Although this is a feasible way to collect information, it only represents conditions memorized. In order to improve the use of all available information, we developed a detailed procedure to compare self-reported comorbidities with medication and applied this to the data of the German COPD cohort COSYCONET. Methods: Approach I was based solely on ICD-10-codes for the diseases and the indications of medications. To deal with the non-specificity of medications, Approach II focused on disease-specific medication and ATC-codes. The relationship between comorbidities and medication was expressed by a four-level concordance score. Results: Approach I and II demonstrated that the patterns of concordance scores markedly differed between diseases. On average, Approach I resulted in more than 50% concordance of all reported diseases to at least one medication. Approach II showed particularly large differences in its ability of matching with medications, due to large differences in the disease-specificity of drugs, e.g. for diabetes versus specific cardiovascular disorders. Conclusion: Both approaches provide defined strategies to confirm self-reported diagnoses via medication. Approach I covers a broad spectrum of diseases and medications but is limited regarding disease-specific information. Approach II is based on medications specific for a disease and can reach higher concordance. The strategies described are generally applicable in large studies to extract as much information as possible from the available data. Funded by BMBF COSYCONET and Mundipharma GmbH .

COSYCONET investigates the interrelationship of COPD and comorbidities with regard to course and prognosis of the disease. The present analysis examined the prevalence of selected common diseases in the COPD cohort compared to apparently lung-healthy subjects from the population-based reference cohorts KORA and SHIP. Spirometry was performed in all subjects and COPD patients were graded according to GOLD criteria. Subjects from KORA/SHIP without known COPD, asthma or chronic bronchitis and with FEV1/FVC≥0.7 were regarded as apparently lung-healthy. Prevalences of myocardial infarction, stroke, diabetes, hypertension, obesity and cancer were compared between COPD patients and lung-healthy subjects using logistic regression analysis accounting for sex, age and smoking status. 2741 COPD patients and 4729 lung-healthy subjects were included in the analysis (age range 40-90y). The percentage of males was higher in the COPD cohort compared to the lung-healthy subjects (59% vs. 49%).The disease prevalences in COPD patients vs. controls were 8% vs. 4% for myocardial infarction, 4% vs. 3% for stroke, 14% vs. 10% for diabetes, 56% vs. 41% for hypertension, 11% vs. 7% for cancer and 25% vs. 31% for obesity. In the logistic regression analysis the associations between COPD and disease prevalence were significant for myocardial infarction, hypertension and obesity (p The COPD patients showed a higher prevalence of myocardial infarction and hypertension and a lower prevalence of obesity compared to lung-healthy subjects. The possible impact of COPD severity will be examined in further analyses. Funded by BMBF FKZ 01GI0881, 01GI0882, 01GI0883, 01ET0713, 01ET1003A.

Objective In large cohort studies comorbidities are usually self- reported by the patients. This way to collect health information only represents conditions known, memorized and openly reported by the patients. Several studies addressed the relationship between self- reported comorbidities and medical records or pharmacy data, but none of them provided a structured, documented method of evaluation. We thus developed a detailed procedure to compare self- reported comorbidities with information on comorbidities derived from medication inspection. This was applied to the data of the German COPD cohort COSYCONET. Methods Approach I was based solely on ICD10-Codes for the diseases and the indications of medications. To overcome the limitations due to potential non-specificity of medications, Approach II was developed using more detailed information, such as ATC-Codes specific for one disease. The relationship between reported comorbidities and medication was expressed by a four-level concordance score. Results Approaches I and II demonstrated that the patterns of concordance scores markedly differed between comorbidities in the COSYCONET data. On average, Approach I resulted in more than 50% concordance of all reported diseases to at least one medication. The more specific Approach II showed larger differences in the matching with medications, due to large differences in the disease-specificity of drugs. The highest concordance was achieved for diabetes and three combined cardiovascular disorders, while it was substantial for dyslipidemia and hyperuricemia, and low for asthma. Conclusion Both approaches represent feasible strategies to confirm self-reported diagnoses via medication. Approach I covers a broad spectrum of diseases and medications but is limited regarding disease-specificity. Approach II uses the information from medications specific for a single disease and therefore can reach higher concordance scores. The strategies described in a detailed and reproducible manner are generally applicable in large studies and might be useful to extract as much information as possible from the available data.

The myosuppressins (X1DVX2HX3FLRFamide), which reduce the frequency of insect muscle contractions, constitute a subgroup of the FMRFamide-related peptides. In the cockroach Leucophaea maderae, we have examined whether leucomyosuppressin (pQDVDHVFLRFamide) is present in the accessory medulla, viz., the circadian clock, which governs circadian locomotor activity rhythms. Antisera that specifically recognize leucomyosuppressin stain one to three neurons near the accessory medulla. MALDI-TOF mass spectrometry has confirmed the presence of leucomyosuppressin in the isolated accessory medulla. Injections of 1.15 pmol leucomyosuppressin into the vicinity of the accessory medulla at various circadian times have revealed no statistically significant effects on the phase of circadian locomotor activity rhythms. This is consistent with the morphology of the myosuppressin-immunoreactive neurons, which restrict their arborizations to the circadian clock and other optic lobe neuropils. Thus, leucomyosuppressin might play a role in the circadian system other than in the control of locomotor activity rhythms.

Adipokinetic hormone (AKH) peptides in insects serve the endocrine control of energy supply. They also produce, however, neuronal, vegetative, and motor effects, suggesting that AKHs orchestrate adaptive behavior by multiple actions. We have cloned, for Periplaneta americana, the AKH receptor to determine its localization and, based on current measurements in neurons and heterologous expression systems, the mechanisms of AKH actions. Apart from fat body, various neurons express the AKH receptor, among them abdominal dorsal unpaired median (DUM) neurons, which release the biogenic amine octopamine. They are part of the arousal system and are involved in the control of circulation and respiration. Both the two Periplaneta AKHs activate the Gspathway, and AKH I also potently activates Gq. AKH I and—with much less efficacy—AKH II accelerate spiking of DUM neurons through an increase of the pacemaking Ca2+current. Because the AKHs are released from the corpora cardiaca into the hemolymph, they must penetrate the blood-brain barrier for acting on neurons. That this happens was shown electrophysiologically by applying AKH I to an intact ganglion. Systemically injected AKH I stimulates locomotion potently in striking contrast to AKH II. This behavioral difference can be traced back conclusively to the different effectiveness of the AKHs on the level of G proteins. Our findings also show that AKHs act through the same basic mechanisms on neuronal and nonneuronal cells, and they support an integration of metabolic and neuronal effects in homoeostatic mechanisms.