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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

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

Background:Infection control measures for coronavirus disease 2019 (COVID-19) might have affected management and clinical state of patients with COPD. We analysed to which extent this common notion is fact-based.Methods:Patients of the COSYCONET cohort were contacted with three recurring surveys (COVID1, 2 and 3 at 0, 3 and 6 months, respectively). The questionnaires comprised behaviour, clinical and functional state, and medical treatment. The responses to the questionnaires were compared amongst themselves and with pre-COVID information from the last visit of COSYCONET.Results:Overall, 594 patients were contacted and 375 patients (58% males, forced expiratory volume in 1 s (FEV1) 61±22% predicted) provided valid data in COVID1 and COVID2. Five patients reported infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Most patients – except for patients with higher education – reported compliance with recommended protective measures, whereby compliance to hygiene, contact and access to physicians slightly improved between COVID1 and COVID2. Also, patients obtained more information from physicians than from public media. In the majority of cases, the personal physician could not be substituted by remote consultation. Over time, symptoms slightly increased and self-assessed physical capacity decreased. Results of COVID3 were similar. Women and patients with more exacerbations and dyspnoea avoided medical consultations, whereas Global Initiative for Chronic Obstructive Lung Disease (GOLD) D patients were more amenable to tele-consultation.Conclusion:In well-characterised COPD patients, we observed on average slight deteriorations of clinical state during the period of COVID-19 restrictions, with high and partially increasing adherence to protective measures. The data suggest that in particular, women and GOLD D patients should be actively contacted by physicians to identify deteriorations.

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.

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

Background Air trapping and lung hyperinflation are major determinants of prognosis and response to therapy in chronic obstructive pulmonary disease (COPD). They are often determined by body plethysmography, which has limited availability, and so the question arises as to what extent they can be estimated via spirometry. Methods We used data from visits 1–5 of the COPD cohort COSYCONET. Predictive parameters were derived from visit 1 data, while visit 2–5 data was used to assess reproducibility. Pooled data then yielded prediction models including sex, age, height, and body mass index as covariates. Hyperinflation was defined as ratio of residual volume (RV) to total lung capacity (TLC) above the upper limit of normal. (ClinicalTrials.gov identifier: NCT01245933). Results Visit 1 data from 1988 patients (Global Initiative for Chronic Obstructive Lung Disease grades 1–4, n=187, 847, 766, 188, respectively) were available for analysis (n=1231 males, 757 females; mean±sd age 65.1±8.4 years; forced expiratory volume in 1 s (FEV1) 53.1±18.4 % predicted (% pred); forced vital capacity (FVC) 78.8±18.8 % pred; RV/TLC 0.547±0.107). In total, 7157 datasets were analysed. Among measures of hyperinflation, RV/TLC showed the closest relationship to FEV1 % pred and FVC % pred, which were sufficient for prediction. Their relationship to RV/TLC could be depicted in nomograms. Even when neglecting covariates, hyperinflation was predicted by FEV1 % pred, FVC % pred or their combination with an area under the curve of 0.870, 0.864 and 0.889, respectively. Conclusions The degree of air trapping/hyperinflation in terms of RV/TLC can be estimated in a simple manner from forced spirometry, with an accuracy sufficient for inferring the presence of hyperinflation. This may be useful for clinical settings, where body plethysmography is not available., This proposed method allows estimation of hyperinflation in COPD by spirometry, obviating the need for body plethysmography or further techniques. Results are depicted in easily applicable nomograms that can be used in clinical practice. https://bit.ly/3c0tUNL

Asthma with fixed airflow obstruction (AFO) is an important understudied sub-phenotype encompassing features of both asthma and COPD. We aimed to determine the prevalence and comorbidities of AFO patients in a large multi-cohort sample. Patients at least 50 years of age with lung function data were from nine European cohorts (69,866 participants), including population-based studies, COPD-based studies and asthma-based studies. AFO was defined as a documented doctor diagnosis of asthma and FEV1/FVC ratio The prevalence of AFO (n=2,378) differed between population-based cohorts (2.0%, n=1,299/63,504), COPD-based cohorts (15.9%, n= 857/5,402) and asthma-based cohorts (23.1%, n= 222/960). The LLN-based definition showed lower AFO prevalence in the general and asthmatic populations (1.4% and 15.7%) but higher prevalence (20.6%) in a smoking COPD population. While hypertension was the most prevalent comorbidity in all 3 conditions, AFO patients were significantly more likely to be diagnosed with depression, osteoporosis, coronary artery disease and gastroesophageal reflux compared to asthma-alone or COPD-alone. AFO has a prevalence ranging from 2.0% in the general population to 23.1% in an asthma population. The LLN-based definition seems to detect more patients suffering from AFO in populations with substantial smoking history. AFO patients have frequent comorbidities which may underlie their worse health outcomes.

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.

Chronic airflow limitation is the common denominator of patients with chronic obstructive pulmonary disease (COPD). However, it is not possible to predict morbidity and mortality of individual patients based on the degree of lung function impairment, nor does the degree of airflow limitation allow guidance regarding therapies. Over the last decades, understanding of the factors contributing to the heterogeneity of disease trajectories, clinical presentation, and response to existing therapies has greatly advanced. Indeed, diagnostic assessment and treatment algorithms for COPD have become more personalized. In addition to the pulmonary abnormalities and inhaler therapies, extra-pulmonary features and comorbidities have been studied and are considered essential components of comprehensive disease management, including lifestyle interventions. Despite these advances, predicting and/or modifying the course of the disease remains currently impossible, and selection of patients with a beneficial response to specific interventions is unsatisfactory. Consequently, non-response to pharmacologic and non-pharmacologic treatments is common, and many patients have refractory symptoms. Thus, there is an ongoing urgency for a more targeted and holistic management of the disease, incorporating the basic principles of P4 medicine (predictive, preventive, personalized, and participatory). This review describes the current status and unmet needs regarding personalized medicine for patients with COPD. Also, it proposes a systems medicine approach, integrating genetic, environmental, (micro)biological, and clinical factors in experimental and computational models in order to decipher the multilevel complexity of COPD. Ultimately, the acquired insights will enable the development of clinical decision support systems and advance personalized medicine for patients with COPD.

BACKGROUND: Lung function impairment in COPD is known to be related to reductions of left heart size, while short-term interventional trials with bronchodilators showed positive effects on cardiac parameters. We investigated whether COPD maintenance therapy has analogous long-term effects. METHODS: Pooled data of GOLD grade 1-4 patients from visits 1 and 3 (1.5y apart) of the COSYCONET cohort were used. Medication was categorized as use of ICS, LABA+ICS, LABA+LAMA and triple therapy (LABA+LAMA+ICS), contrasting "always" versus "never". Echocardiographic parameters comprised left ventricular end-diastolic and -systolic diameter (LVEDD, LVESD), ejection fraction (LVEF) and left atrial diameter (LA). Associations were identified by multiple regression analysis, as well as propensity score analysis. RESULTS: Overall, 846 patients (mean age 64.5y; 41% female) were included, 53% using ICS at both visits, 51% LABA+ICS, 56% LABA+LAMA, 40% LABA+LAMA+ICS (triple) therapy. Conversely, 30%, 32%, 28% and 42% had no ICS, LABA+ICS, LABA+LAMA or triple therapy, respectively, at both visits. Among echocardiographic measures, only LA showed statistically significant associations (increases) with medication, whereby significant effects were linked to ICS, LABA+ICS and LABA+LAMA (p&nbsp

Background In chronic obstructive pulmonary disease (COPD), gender-specific differences in the prevalence of symptoms and comorbidity are known. Research question We studied whether the relationship between these characteristics depended on gender and carried diagnostic information regarding cardiac comorbidities. Study design and methods The analysis was based on 2046 patients (GOLD grades 1–4, 795 women; 38.8%) from the COSYCONET COPD cohort. Assessments comprised the determination of clinical history, comorbidities, lung function, COPD Assessment Test (CAT) and modified Medical Research Council dyspnea scale (mMRC). Using multivariate regression analyses, gender-specific differences in the relationship between symptoms, single CAT items, comorbidities and functional alterations were determined. To reveal the relationship to cardiac disease (myocardial infarction, or heart failure, or coronary artery disease) logistic regression analysis was performed separately in men and women. Results Most functional parameters and comorbidities, as well as CAT items 1 (cough), 2 (phlegm) and 5 (activities), differed significantly (p Interpretation Gender-specific differences in COPD not only comprised differences in symptoms, comorbidities and functional alterations, but also differences in their mutual relationships. This was reflected in different determinants linked to cardiac disease, thereby indicating that simple diagnostic information might be used differently in men and women. Clinical trial registration The cohort study is registered on ClinicalTrials.gov with identifier NCT01245933 and on GermanCTR.de with identifier DRKS00000284, date of registration November 23, 2010. Further information can be obtained on the website http://www.asconet.net.

Background: Patients with COPD-specific symptoms and history but FEV1/FVC ratio ≥0.7 are a heterogeneous group (former GOLD grade 0) with uncertainties regarding natural history. Objective: We investigated which lung function measures and cutoff values are predictive for deterioration according to GOLD grades and all-cause mortality. Methods: We used visit 1–4 data of the COSYCONET cohort. Logistic and Cox regression analyses were used to identify relevant parameters. GOLD 0 patients were categorized according to whether they maintained grade 0 over the following 2 visits or deteriorated persistently into grades 1 or 2. Their clinical characteristics were compared with those of GOLD 1 and 2 patients. Results: Among 2,741 patients, 374 GOLD 0, 206 grade 1, and 962 grade 2 patients were identified. GOLD 0 patients were characterized by high symptom burden, comparable to grade 2, and a restrictive lung function pattern; those with FEV1/FVC above 0.75 were unlikely to deteriorate over time into grades 1 and 2, in contrast to those with values between 0.70 and 0.75. Regarding mortality risk in GOLD 0, FEV1%predicted and age were the relevant determinants, whereby a cutoff value of 65% was superior to that of 80% as proposed previously. Conclusions: Regarding patients of the former GOLD grade 0, we identified simple criteria for FEV1/FVC and FEV1% predicted that were relevant for the outcome in terms of deterioration over time and mortality. These criteria might help to identify patients with the typical risk profile of COPD among those not fulfilling spirometric COPD criteria.

Background: Lung hyperinflation is major determinant of prognosis and response to therapy in COPD. It is linked to air trapping and usually determined by body plethysmography or gas dilution. As the availability of these methods is limited, the question arises to which extent hyperinflation can be estimated from spirometry. Methods: We used data from patients of GOLD grades 1–4 obtained in Visits 1–5 of the COPD cohort COSYCONET. Predictive parameters were derived from Visit 1 data, while Visit 2–5 data were used to assess reproducibility. Data from all visits were pooled to determine prediction models for males and females, including age, height and BMI as covariates. Hyperinflation was defined as residual volume to total lung capacity ratio (RV/TLC) above the ULN. Results: Visit 1 data from 1988 patients were available for analysis (FEV1 53.1±18.4 %pred; FVC 78.8±18.8 %pred; RV/TLC 0.547±0.107). In total, 7157 data sets were analyzed. Among measures of hyperinflation, RV/TLC turned out to be most reliable, with FEV1 %pred and FVC %pred being sufficient for prediction. Their relationship to RV/TLC could be depicted in nomograms. Even when neglecting the effects of covariates, RV/TLC above ULN could be predicted by FEV1 %pred, FVC %pred or their combination with an AUC of 0.882, 0.869 and 0.899. Other parameters, i.p. slow inspiratory vital capacity, did not play a role. Conclusions: The degree of hyperinflation in terms of RV/TLC can be estimated from forced spirometry, with an accuracy sufficient for inferring the presence of significant hyperinflation defined by RV/TLC above the upper limit of normal. This may be useful for clinical settings, where body plethysmography is not available.

Background: Bronchiectasis is known to be associated with COPD. We studied which degree of radiological alterations was associated with clinical signs of bronchiectasis in COPD. Methods: Visit 4 data (GOLD grades 1-4) of the COSYCONET cohort was analysed. Chest CT scans were evaluated for bronchiectasis in 6 lobes using a 3-point scale (0-2), resulting in a total score of 0-12. We also included data from disease-specific questionnaires, medication, and lung function. Results: 1176 patients were included (mean age 67.3y, 61.1% males), among them 38 (3.2%) with patient-reported physicians’ diagnosis of bronchiectasis and 76 (6.5%) with alpha1-antitrypsin deficiency (AA1D). 429 patients had CT scans, with any signs of bronchiectasis in 46.6%, less than 50% bronchiectasis in ≤2 lobes in 18.6%, in 3-4 lobes in 10.0%, in 5-6 lobes in 15.9%, and more than 50% bronchiectasis in at least 1 lobe in 2.1%. Scores ≥4 were linked to elevated FRC/RV. Links to sputum production, composition (n=105) or inflammatory indices were borderline or absent. Triple therapy was associated with symptoms, but not radiological signs of bronchiectasis. The clinical diagnosis of bronchiectasis correlated with phlegm and cough and with radiological scores of at least 3, optimally ≥5. AA1D was associated with radiological signs of bronchiectasis and only borderline with the clinical diagnosis. Conclusion: Clinical diagnosis and radiological signs of bronchiectasis showed only weak correlations in COPD patients. For a significant correspondence to symptoms and diagnosis, a threshold CT score implying radiological alterations in several lobes was needed, which was about one third of the maximum score.

Evaluating symptoms is a central part of the chronic obstructive pulmonary disease (COPD) assessment system as suggested by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Considering the pros and cons of all currently available tests, GOLD suggests using primarily the modified Medical Research Council dyspnea scale or the COPD Assessment Test. Based on the test results, patients are categorized as having a low or high level of symptoms. This level then becomes one of the 2 dimensions of the ABCD grading system, which was designed to match the best initial treatment option to the individual patient's needs.

Stefan Andreas,1,2 Lorcan McGarvey,3 Ulrich Bothner,4 Matthias Trampisch,4 Alberto de la Hoz,4 Matjaz Fležar,5 Roland Buhl,6 Peter Alter7 1Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; 2LungClinic Immenhausen, Immenhausen, Germany, Member of the German Center for Lung Research (DZL); 3Queen’s University Belfast, Belfast, UK; 4Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 5Klinika Golnik, Golnik, Slovenia; 6Pulmonary Department, Johannes Gutenberg University Mainz, Mainz, Germany; 7Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR); Member of the German Center for Lung Research (DZL), Marburg, GermanyCorrespondence: Stefan AndreasDepartment of Cardiology and Pneumology, University Medical Center Göttingen, Robert-Koch-Str. 40, Göttingen, GermanyTel +49 05673 501 1112Fax +49 05673-501-1101Email stefan.andreas@med.uni-goettingen.deIntroduction: Long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are established maintenance bronchodilator treatments for chronic obstructive pulmonary disease (COPD) with the potential to increase heart rate (HR) and impact blood pressure (BP). While previous studies indicate that HR and BP are not negatively influenced by tiotropium or olodaterol monotherapy, the effect of tiotropium/olodaterol has not been evaluated. We report a post hoc analysis of the effect of dual bronchodilation with tiotropium/olodaterol versus monocomponents on HR and BP in patients with moderate-to-very-severe COPD included in the large TONADO® study.Methods: The TONADO® trials (1237.5 [NCT01431274] and 1237.6 [NCT01431287]) were two replicate, randomized, double-blind, parallel-group, 52-week, Phase III trials that compared tiotropium/olodaterol (5/5 μg and 2.5/5 μg) with tiotropium (5 μg and 2.5 μg) and olodaterol (5 μg) in patients with moderate-to-very-severe COPD. Patients with cardiovascular comorbidities were included. Changes in HR and systolic/diastolic BP were measured before and after dosing with the study medication at each visit (baseline, Week 12, Week 24 and Week 52).Results: Overall, 3,100 patients were included in this analysis. Over 52 weeks, small changes from baseline in mean HR (< 2 beats per minute [bpm]) and small changes from pre- to post-dose (< 1 bpm) were evident at different time points. There was a non-significant increase from baseline in mean diastolic and systolic BP (< 2 mmHg) observed over 52 weeks of treatment. The short-term (1 hour pre- to 1 hour post-dose) mean changes in systolic and diastolic BP over 52 weeks in the tiotropium/olodaterol 5/5 μg group were comparable with those observed for the monocomponents at all time points.Conclusion: There were no differences in HR or BP among patients on tiotropium/olodaterol when compared with monocomponents. This supports the already demonstrated cardiovascular safety profile of tiotropium/olodaterol as long-acting maintenance bronchodilator treatment for COPD, including patients with cardiovascular comorbidities.Keywords: chronic obstructive pulmonary disease, tiotropium, olodaterol, heart rate, blood pressure

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.

Bronchiectasis (BE) might be frequently present in COPD but masked by COPD symptoms. We studied the relationship of clinical signs of bronchiectasis to the presence and extent of its radiological signs in patients of different COPD severity. Visit 4 data (GOLD grades 1-4) of the COSYCONET cohort was used. Chest CT scans were evaluated for bronchiectasis in 6 lobes using a 3-point scale (0: absence, 1: ≤50%, 2: >50% BE-involvement for each lobe). 1176 patients were included (61%male, age 67.3y), among them 38 (3.2%) with reported physicians' diagnosis of bronchiectasis and 76 (6.5%) with alpha1-antitrypsin deficiency (AA1D). CT scans were obtained in 429 patients. Within this group, any signs of bronchiectasis were found in 46.6% of patients, whereby ≤50% BE occurred in 18.6% in ≤2 lobes, in 10.0% in 3-4 lobes, in 15.9% in 5-6 lobes; >50% bronchiectasis in at least 1 lobe was observed in 2.1%. Scores ≥4 correlated with an elevated ratio FRC/RV. The clinical diagnosis of bronchiectasis correlated with phlegm and cough and with radiological scores of at least 3, optimally ≥5. In COPD patients, clinical diagnosis and radiological signs of BE showed only weak correlations. Correlations became significant with increasing BE-severity implying radiological alterations in several lobes. This indicates the importance of reporting both presence and extent of bronchiectasis on CT. Further research is warranted to refine the criteria for CT scoring of bronchiectasis and to determine the relevance of radiologically but not clinically detectible bronchiectasis and their possible implications for therapy in COPD patients.

Background In COPD, the course of the disease including morbidity and mortality is strongly associated with severe exacerbations. The current GOLD recommendations emphasize blood eosinophil counts as a marker for responsiveness to inhaled corticosteroids (ICS). Retrospective analyses from randomized clinical trials indicate a favorable response to systemic corticosteroids in exacerbated COPD patients with blood eosinophils > 2%, however data outside clinical trials are scarce. Patients and methods We retrospectively evaluated data from 1007 cases of patients who were admitted to the University Medical Center Marburg between 01/2013 and 12/2018. All patients had been diagnosed with an acute exacerbation of COPD (ICD-10 J44.0/J44.1). Our analysis was based on a subgroup of 417 patients in whom a full blood cell count was obtained at the day of admission. Patients were predominantly male (63.3%), had a median age of 74 years (IQR 65 years – 83 years) and a median FEV1 of 1.03 l (42.6% predicted). We compared the hospital length of stay and other outcome parameters using established thresholds for the eosinophil blood cell count (100 and 300 eosinophils/μl and 2%). Results Patients with low eosinophils ( 300/μl: 7 days). The median CRP was higher in patients with low eosinophils as compared to the other groups ( 300: 7.1 mg/dl). Time to re-hospitalization or time to death did not differ between strata of eosinophils. Sensitivity analysis in a subgroup of patients in which pneumonia was excluded by chest x-ray did not significantly alter the results. Conclusion The results support the hypothesis that patients with severe COPD exacerbations and elevated blood eosinophil counts respond better to systemic corticosteroid treatment than patients with a non-eosinophilic exacerbation.

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 Cardiovascular comorbidities are common in chronic obstructive pulmonary disease (COPD), and elevated heart rate reflects increased cardiovascular risk over time, which is associated with unfavourable neurohumoral activation. Long-acting β 2 -agonists (LABAs) are established treatments in COPD, but potentially increase heart rate. We report a post hoc pooled analysis of the effect of olodaterol (5 or 10 μg) or formoterol (12 μg) on heart rate and blood pressure (BP) in Global Initiative for Chronic Obstructive Lung Disease Stage 2–4 COPD patients. Methods Four randomised, double-blind, placebo-controlled, Phase III studies were analysed. Changes in heart rate and systolic/diastolic BP were measured before and after dosing with the study medication at each visit. Results At each study visit, the increase in pre-dose heart rate was numerically lower with both LABAs compared with placebo. Systolic and diastolic BP were decreased with all treatments. Short-term (pre-dose to 40 min post-dose) effects of drug administration on heart rate were small and similar for all treatment arms (between −3 and +1 beats per minute). Conclusion Heart rate and BP were not adversely influenced in this study involving long-term administration of olodaterol or formoterol in patients with moderate-to-severe COPD. This supports the cardiovascular safety of LABAs in COPD maintenance treatment.

Die COPD tritt haufig mit Komorbiditaten auf, insbesondere mit solchen kardiovaskularer Art. Neben den bekannten Einflussen auf den rechten Ventrikel rucken zunehmend prima vista subklinische Veranderungen des linken Ventrikels in den Blick. Die zugrundeliegenden Mechanismen werden derzeit erforscht. In der multizentrischen COSYCONET-Kohorte zeigten sich direkte Einflusse von Obstruktion und Uberblahung auf den linken Ventrikel und die elektrischen Herzachsen im EKG.

Chronic obstructive pulmonary disease (COPD) is commonly associated with multiple comorbidities. Our objective was to assess the prevalence of comorbidities in patients with COPD and to relate their prevalence to the severity of the disease by using a large German health care database. Based on the retrospective analysis of a two-year (2013–2014) database from the German Statutory Health Insurance system, we obtained a representative sample of 4,075,493 german insurants. This sample included 146,141 patients with COPD (age: ≥35 years). To these patients, we matched 1:1 by age and gender randomly selected non-COPD controls. We assessed the comorbidities and the use of cardiovascular drugs, and examined COPD subgroups according to lung function (ICD-10-coded FEV1) and the treatment with long-acting inhaled bronchodilators. Compared to non-COPD, patients with COPD had a higher prevalence of hypertension, congestive heart failure, diabetes, gastroesophageal reflux disease, chronic kidney disease, osteoporosis, psychiatric disease and lung cancer, and used more cardiovascular-related drugs. However, the prevalence of comorbidities did not correlate to the severity of airflow limitation. The results of this sizeable nationwide survey support the concept that individuals with COPD need careful evaluation regarding comorbidities. This can already be of relevance in patients with mild to moderate airflow limitation. Take home message Comorbidities in COPD have a complex relationship with disease severity, requiring a comprehensive therapy approach.

Background: Various exercise training programs are used for patients with chronic obstructive pulmonary disease (COPD) of different severity. Objectives: To investigate the impact of individualized high-intensity training on exercise capacity with COPD. Methods: A total of 49 patients agreed to participate. Of these, 31 were assigned to the training group and 18 served as controls. The training group exercised twice a week for 90 min with consecutively increasing loads. At the time of enrollment (T0), as well as after 3 (T1) and 6 (T2) months, a 6-min walk test (6-MWT) was performed and data on health-related quality of life, femoral muscle thickness, and various serum markers were obtained. Results: The training group improved in their 6-MWT results (T0 = 407 ± 152 m vs. T1 = 459 ± 127 m, p = 0.002, vs. T2 = 483.2 ± 130.1 m, p = 0.004), in their cross-sectional area of the musculus rectus femoris (T0 = 6.2 ± 1.2 cm2 vs. T1 = 6.9 ± 1.2 cm2, p = 0.003, vs. 7.5 ± 1.6 cm2, p = 0.002), and in their St. George's Respiratory Questionnaire (SGRQ) score (T0 = 43.3 ± 18.0 vs. T1 = 36.0 ± 18.4, p = 0.001, vs. T2 = 34.7 ± 18. 0, p = 0.004). Serum levels of myostatin, irisin, resistin, and α-Klotho did not change significantly within the training period. Of note, the exercise group showed an inverse relationship between serum levels of resistin and those of α-Klotho after 6 months (r = -0.608, p = 0.021). Conclusions: COPD patients undergoing an individualized, structured, high-intensity training program improved their exercise capacity, gained muscle mass, and improved their quality of life.

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.