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Mustafa Abdo,1 Frederik Trinkmann,2,3 Anne-Marie Kirsten,4 Heike Biller,1 Frauke Pedersen,1,4 Benjamin Waschki,1 Erika Von Mutius,5 Matthias Kopp,6,7 Gesine Hansen,8 Klaus F Rabe,1 Thomas Bahmer,1,9,&ast; Henrik Watz4,&ast; On behalf of the ALLIANCE study group1LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 2Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany; 3Department of Biomedical Informatics, Heinrich-Lanz-Center, University Medical Center Mannheim, Heidelberg University, Heidelberg, Germany; 4Pulmonary Research Institute at the LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 5Dr von Hauner Children’s Hospital, Ludwig Maximilians University of Munich, Comprehensive Pneumology Center Munich, German Center for Lung Research (DZL), and Institute of Asthma and Allergy Prevention, Helmholtz Centre, Both Munich, Germany; 6Department of Pediatric Respiratory Medicine, Inselspital, University Children’s Hospital of Bern, University of Bern, Bern, Switzerland; 7Division of Pediatric Pneumology & Allergology, University Hospital Schleswig-Holstein-Campus Luebeck, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Luebeck, Germany; 8Department of Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), Hannover, Germany; 9University Hospital Schleswig-Holstein-Campus Kiel, department for Internal Medicine I, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Kiel, Germany&ast;These authors contributed equally to this workCorrespondence: Mustafa AbdoLungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Wöhrendamm 80, Grosshansdorf, 22927, GermanyTel +49 4102 601 2412Email m.abdo@lungenclinic.deRationale: Small airway dysfunction (SAD) is a frequent feature of asthma that has been linked to disease severity and poor symptom control. However, little is known about the role of SAD in nocturnal asthma.Objective: To study the association between the severity of SAD and frequency of nocturnal symptoms compared to conventional lung function testing.Methods: We assessed the frequency of self-reported nocturnal symptoms through the asthma control test. We studied the impact of nocturnal asthma using the Asthma Quality of Life Questionnaire (AQLQ) and the Multidimensional Fatigue Inventory (MFI-20). We assessed the lung function using spirometry, body plethysmography, impulse oscillometry, single and multiple inert gas washout and measured markers of T2-inflammation (blood and sputum eosinophils; fractional exhaled nitric oxide (FeNo)). We stratified the patients according to the presence and frequency of nocturnal asthma.Results: A total of 166 asthma patients were enrolled in the analysis. Eighty-seven patients (52%) reported to have nocturnal symptoms at least once in the last four weeks. The odds ratio of nocturnal asthma correlated with the severity of all non-spirometric measures of SAD, yet neither with airflow obstruction (FEV1 and FEV/FVC) nor with large airway resistance (R20). Patients with frequent nocturnal asthma (n = 29) had a numerical increase of T2 markers and more severe SAD, as indicated by all non-spirometric measures of SAD (all p-values < 0.05), worse overall asthma control, increased fatigue and reduced quality of life (all p-values < 0.01) compared to patients with infrequent nocturnal asthma (n = 58) or patients without nocturnal asthma (n = 79). We identified 63 patients without airflow obstruction, nearly 43% of them (n = 27) had nocturnal asthma. In this subgroup, only markers of air trapping and ventilation heterogeneity were significantly elevated and correlated with the frequency of nocturnal symptoms: LCI (Spearman’s coefficient = − 0.42, p < 0.001), RV% (− 0.32, p = 0.02).Conclusion: SAD is closely associated to asthma with nocturnal symptoms. Spirometry might underestimate the broad spectrum of distal lung function impairments in this population of patients.Keywords: small airway dysfunction, nocturnal asthma, ventilation heterogeneity, air trapping

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.

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.

Mustafa Abdo,1 Benjamin Waschki,2 Anne-Marie Kirsten,3 Frederik Trinkmann,4,5 Heike Biller,1 Christian Herzmann,6 Erika von Mutius,7 Matthias Kopp,8,9 Gesine Hansen,10 Klaus F Rabe,1 Thomas Bahmer,1,11,* Henrik Watz3,* On behalf of the ALLIANCE study group1LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 2Department of Cardiology and Pneumology at Hospital Itzehoe, Itzehoe, Germany; 3Pulmonary Research Institute at the LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 4Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany; 5Department of Biomedical Informatics, Heinrich-Lanz-Center, University Medical Center Mannheim, Heidelberg University, Heidelberg, Germany; 6Research Center Borstel, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Borstel, Germany; 7Dr von Hauner Children’s Hospital, Ludwig Maximilians University of Munich, Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research (DZL), Munich, Germany; 8Department of Pediatric Respiratory Medicine, Inselspital, University Children’s Hospital of Bern, University of Bern, Bern, Switzerland; 9Division of Pediatric Pneumology & Allergology, University Hospital Schleswig-Holstein-Campus Luebeck, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Luebeck, Germany; 10Department of Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), Hannover, Germany; 11University Hospital Schleswig-Holstein-Campus Kiel, Department for Internal Medicine I, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Kiel, Germany*These authors contributed equally to this workCorrespondence: Mustafa AbdoLungenClinic Grosshansdorf GmbH, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Wöhrendamm 80, Großhansdorf, 22927, GermanyTel +49 4102 601 2412Email m.abdo@lungenclinic.deRationale: Asthma, obesity and physical activity (PA) are interrelated. However, longitudinal data with objective PA measures and direct assessment of body composition are still lacking.Objective: To study the impact of symptom control on PA and body composition.Methods: In a longitudinal cohort study of the German Center for Lung Research, we assessed the body composition of 233 asthma patients and 84 healthy controls using bioelectrical impedance analysis. PA (ie average daily steps and time of at least moderate activity, steps/min) was measured by accelerometry for one week. Asthma control was assessed by ACT score, ACQ-5 score and history of severe exacerbations. After two years of follow-up, we studied changes in physical activity and body composition in relation to asthma control.Results: Patients with uncontrolled asthma had increased fat mass and decreased muscle mass compared to patients with controlled asthma or healthy controls. Both fat mass and muscle mass correlated better with asthma control than the body mass index (BMI). In multivariate regressions adjusted for age and sex, asthma control and physical activity were independent predictors of body composition (R2 = 0.61, p&thinsp

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.

Methods We did a multicentre, double-blind, randomised, placebo-controlled, parallel phase 2b trial (RELIEF) in 17 centres with expertise in ILD in Germany. Eligible participants were patients aged 18?80 years with progressive fibrotic ILD due to four diagnoses: collagen or vascular diseases (ie, connective tissue disease-associated ILDs), fibrotic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, or asbestos-induced lung fibrosis. Other eligibility criteria included a forced vital capacity (FVC) of 40?90% predicted, a diffusing capacity of the lung for carbon monoxide of 10?90% predicted, and an annual decline of FVC of at least 5% predicted despite conventional therapy, based on at least three measurements within 6?24 months before enrolment. Patients who had received any previous antifibrotic therapy were excluded. We randomly assigned patients (1:1) to either oral pirfenidone (267 mg three times per day in week 1, 534 mg three times per day in week 2, and 801 mg three times per day thereafter) or matched placebo, added to their ongoing medication. Randomisation was done centrally using permuted block randomisation with varying block sizes stratified by the four diagnostic groups. Patients, investigators, statisticians, monitors, and the study coordinator were masked to treatment assignment until database closure. The placebocontrolled study period was 48 weeks (including up-titration). The primary endpoint was absolute change in percentage of predicted FVC (FVC % predicted) from baseline to week 48 in the intention-to-treat population, with imputation of missing data by the smallest sum of squared differences and attribution of deceased patients to the lowest rank in a rank ANCOVA model. Additionally, we did linear mixed-model repeated measures slope analyses of FVC % predicted longitudinal data over the course of the study as a prespecified sensitivity analysis and post-hoc sensitivity analyses of the primary endpoint in the intention-to-treat population using imputation methods of last observation carried forward [LOCF] and a regression-based multiple imputation procedure. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with EudraCT 2014-000861-32;Background Pirfenidone has been shown to slow disease progression in patients with idiopathic pulmonary fibrosis (IPF). However, there are few treatment options for progressive fibrotic interstitial lung diseases (ILDs)) other than IPF. In view of the pathomechanistic and clinical similarities between IPF and other progressive fibrotic ILDs, we aimed to assess the efficacy and safety of pirfenidone in patients with four non-IPF progressive fibrotic ILDs. Methods We did a multicentre, double-blind, randomised, placebo-controlled, parallel phase 2b trial (RELIEF) in 17 centres with expertise in ILD in Germany. Eligible participants were patients aged 18-80 years with progressive fibrotic ILD due to four diagnoses: collagen or vascular diseases (ie, connective tissue disease-associated ILDs), fibrotic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, or asbestos-induced lung fibrosis. Other eligibility criteria included a forced vital capacity (FVC) of 40-90% predicted, a diffusing capacity of the lung for carbon monoxide of 10-90% predicted, and an annual decline of FVC of at least 5% predicted despite conventional therapy, based on at least three measurements within 6-24 months before enrolment. Patients who had received any previous antifibrotic therapy were excluded. We randomly assigned patients (1:1) to either oral pirfenidone (267 mg three times per day in week 1, 534 mg three times per day in week 2, and 801 mg three times per day thereafter) or matched placebo, added to their ongoing medication. Randomisation was done centrally using permuted block randomisation with varying block sizes stratified by the four diagnostic groups. Patients, investigators, statisticians, monitors, and the study coordinator were masked to treatment assignment until database closure. The placebo controlled study period was 48 weeks (including up-titration). The primary endpoint was absolute change in percentage of predicted FVC (FVC % predicted) from baseline to week 48 in the intention-to-treat population, with imputation of missing data by the smallest sum of squared differences and attribution of deceased patients to the lowest rank in a rank ANCOVA model. Additionally, we did linear mixed-model repeated measures slope analyses of FVC % predicted longitudinal data over the course of the study as a prespecified sensitivity analysis and post-hoc sensitivity analyses of the primary endpoint in the intention-to-treat population using imputation methods of last observation carried forward [LOCF] and a regression-based multiple imputation procedure. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with EudraCT 2014-000861-32; DRKS00009822 and is no longer recruiting. Findings Between April 5, 2016, and Oct 4, 2018, we randomly assigned 127 patients to treatment: 64 to pirfenidone, 63 to placebo. After 127 patients had been randomised, the study was prematurely terminated on the basis of an interim analysis for futility triggered by slow recruitment. After 48 weeks and in the overall population of 127 patients, rank ANCOVA with diagnostic group included as a factor showed a significantly lower decline in FVC % predicted in the pirfenidone group compared with placebo (p=0.043); the result was similar when the model was stratified by diagnostic group (p=0.042). A significant treatment effect was also observed when applying the LOCF and multiple imputation methods to analyses of the primary endpoint.The median difference (Hodges-Lehmann estimate) between pirfenidone and placebo groups for the primary endpoint was 1.69 FVC % predicted (95% CI -0.65 to 4.03). In the linear mixed-model repeated measures slope analysis of FVC % predicted, the estimated difference between treatment and placebo groups from baseline to week 48 was 3.53 FVC % predicted (95% CI 0.21 to 6.86) with imputation of deaths as prespecified, or 2.79 FVC % predicted (95% CI 0.03 to 5.54) without imputation. One death (non-respiratory) occurred in the pirfenidone group (2%) and five deaths (three of which were respiratory) occurred in the placebo group (8%). The most frequent serious adverse events in both groups were infections and infestations (five [8%] in the pirfenidone group, ten [16%] in the placebo group); general disorders including disease worsening (two [3%] in the pirfenidone group, seven [11%] in the placebo group); and cardiac disorders (one ([2%] in the pirfenidone group, 5 [8%] in the placebo group). Adverse events (grade 3-4) of nausea (two patients on pirfenidone, two on placebo), dyspnoea (one patient on pirfenidone, one on placebo), and diarrhoea (one patient on pirfenidone) were also observed. Interpretation In view of the premature study termination, results should be interpreted with care. Nevertheless, our data suggest that in patients with fibrotic ILDs other than IPF who deteriorate despite conventional therapy, adding pirfenidone to existing treatment might attenuate disease progression as measured by decline in FVC. Funding German Center for Lung Research, Roche Pharma.

BACKGROUND Little is known about the role of small airway dysfunction (SAD) and its complex relation with asthma control and physical activity (PA). OBJECTIVE To investigate the interrelations among SAD, risk factors for asthma severity, symptom control, and PA. METHODS We assessed SAD by impulse oscillometry and other sophisticated lung function measures including inert gas washout in adults with asthma (mild to moderate, n = 140; severe, n = 128) and 69 healthy controls from the All Age Asthma Cohort. We evaluated SAD prevalence and its interrelation with risk factors for asthma severity (older age, obesity, and smoking), type 2 inflammation (sputum and blood eosinophils, fractional exhaled nitric oxide), systemic inflammation (high-sensitivity C-reactive protein), asthma control (AC), and PA (accelerometer for 1 week). We applied a clinical model based on structural equation modeling that integrated causal pathways among these clinical variables. RESULTS The prevalence of SAD ranged from 75% to 90% in patients with severe asthma and from 53% to 64% in mild to moderate asthma. Severe SAD was associated with poor AC and low PA. Structural equation modeling indicated that age, obesity, obesity-related systemic inflammation, T2 inflammation, and smoking are independent predictors of SAD. Small airway dysfunction was the main determinant factor of AC, which in turn affected PA. Obesity affected AC directly and through its contribution to SAD and low PA. In addition, PA had bidirectional associations with obesity, SAD, and AC. Structural equation modeling also indicated interrelations among distal airflow limitation, air trapping, and ventilation heterogeneity. CONCLUSIONS Small airway dysfunction is a highly prevalent key feature of asthma that interrelates a spectrum of distal lung function abnormalities with risk factors for asthma severity, asthma control, and physical activity.

Background Anti-T2 biological therapies have proven to effectively reduce acute exacerbations and daily doses of oral steroids in severe eosinophilic asthma. Despite the remarkable clinical efficacy, there are usually only moderate improvements in airflow limitation, suggesting that other measures of lung function like small airway dysfunction (SAD) might better reflect the clinical response. We aimed to investigate if measures of small airway function would predict and correlate with the clinical response to anti-T2 therapy. Methods We studied data of patients who were previously included in the German prospective longitudinal All Age Asthma Cohort (ALLIANCE) that recruits asthma patients of all severity grades and inflammatory phenotypes. The selection criteria for this analysis were adult patients with severe eosinophilic asthma under treatment with anti-T2 biological agents. Asthma control was assessed by asthma control test (ACT) and number of severe exacerbations. Small airway function was assessed by the frequency dependence of resistance (FDR, R5-20)) derived from impulse oscillometry (IOS) and the mean forced expiratory flow between 25 and 75% of the forced vital capacity (FEF25-75). We also studied air trapping (RV and RV/TLC), blood eosinophils and FeNO. Patients were classified into responders and partial or non-responders. Clinical response was defined as at least 50% reduction in annualized severe exacerbations and daily oral steroid doses accompanied with a minimum increase of 3 points in the ACT score. We used a Receiver Operator Characteristic (ROC) to study the capacity of FDR in predicting clinical response compared to other clinical variable like blood eosinophils. We studied the correlation between FDR measures and clinical response, represented by the ACT score and number of exacerbations, using linear regressions. Results 20 patients were included (mean age, 59 ± 9 years; 60% female; mean body mass index (BMI), 27.6 ± 5.4 kg/m2; mean absolute blood eosinophils, 570 ± 389/µl; mean number of severe exacerbations 12 months prior to initiating the biological therapy, 5.0 ± 3; mean predicted FEV1, 76 ± 21%; mean predicted FDR, 224 ± 140%; mean daily prednisolone dose, 6.4 ± 4.9 mg; mean ACT score, 15 ± 5). Responders had significantly higher baseline FDR compared to partial or non-responders but similar FEV1, FEF25–75, RV and RV/TLC. ROC analysis showed that the combination of FDR and blood eosinophils had the best predictive capacity of the clinical response among all tested clinical markers (FeNO, FEV1, FDR, blood eosinophils) with an AUC of 85% [67–100%], (CI = 0.95, p = 0.01). Linear regressions indicated better associations between improvements in FDR and ACT score (R2 = 0.42, p = 0.001) than with FEV1 and ACT score (R2 = 0.25, p = 0.013). Likewise, we observed better associations between improvements in FDR and reduction of exacerbations (R2 = 0.41, p = 0.001) than with FEV1 (R2 = 0.20, p = 0.025). Conclusion Our data suggest that severe SAD may represent a distinct phenotype of eosinophilic asthma that substantially improves under anti-T2 biological therapy. Measures of small airway function might be useful in selecting appropriate patients qualifying for anti-T2 biological therapy in addition to blood eosinophil count.

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.

Rationale: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by multiple subtypes and variable disease progression. While FEV1 is an insufficient candidate for the prediction of disease progression, we investigated, whether copeptin correlates with clinical endpoints and mortality. Methods: We measured copeptin in plasma samples of 1 patients with stable COPD (GOLD 0-4, GOLD A-D) from the German COPD cohort study COSYCONET. Results: In the cross sectional analysis of a linear regression model that considers age, BMI, Gender, cardiovascular index, and packyears of smoking as confounders, copeptin correlated with the impairment of: airway obstruction (FEV1, sRawTot) (p Discussion/Conclusion: While previous groups studied copeptin in patients with COPD exacerbations, we provide evidence that copeptin is a suitable biomarker for all-cause mortality in stable COPD taking into account many covariates.

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: Little is known about physical activity in daily life among patients with sarcoidosis. Fatigue is a frequent and disabling symptom that might negatively affect physical activity levels. Methods: In patients with sarcoidosis, we measured physical activity (steps per day) by accelerometry (SenseWear Armband) for 1 week. We assessed lung function (DLCO, FVC), exercise capacity (6-min walking distance [6MWD]), health-related quality of life (St George’s Respiratory Questionnaire [SGRQ]), generic quality of life (12-Item Short-Form Health Survey [SF-12]), and fatigue (Multidimensional Fatigue Inventory [MFI-20]). Results: We investigated 57 patients with sarcoidosis (mean age 50 years, 56% male, mean DLCO 73% predicted, mean FVC 91% predicted, mean 6MWD 525 m, mean steps per day 7,490), of whom n = 14 (25%) had severe fatigue. The MFI-20 subscales “reduced activity” and “physical fatigue” were weakly associated with steps per day on a bivariate level (Spearman ρ = –0.274 and ρ = –0.277, respectively; p < 0.05), while the other subscales and the total score were not. 6MWD, SGRQ score, and SF-12 (physical health) score showed stronger associations with steps per day in bivariate analyses (Pearson r = 0.499, r = –0.386, and r = 0.467, respectively; p < 0.01), and were independent predictors of steps per day in multivariate linear regression analyses adjusting for confounders (p < 0.05). In ROC curve analyses, 6MWD, SGRQ score, and SF-12 (physical health) score properly identified sedentary patients (steps per day p < 0.01). Fatigue was less predictive (MFI-20 subscale “general fatigue,” AUROC 0.70; p = 0.03). Conclusion: While exercise capacity and quality of life measurements were robust predictors of physical activity in patients with sarcoidosis, associations of objectively measured physical activity with fatigue were surprisingly weak. In sarcoidosis, fatigue might not preclude affected patients from being physically active, although this symptom is subjectively perceived as highly disabling.

Background: Physical activity (PA) is associated with disease severity in idiopathic pulmonary fibrosis (IPF), but longitudinal studies evaluating its prognostic value and changes over time are lacking. Methods: We measured PA (steps per day, SPD) in a cohort of 46 IPF-patients (mean age, 67 years; mean FVC, 76.1%pred.) by accelerometry at baseline, recorded survival status during 3 years follow-up and repeated measurements in survivors. We compared the prognostic value of PA to established mortality predictors including lung function (FVC, DLCO) and 6-min walking-distance (6MWD). Results: During follow-up (median 34 months) 20 patients (43%) died. SPD and FVC best identified non-survivors (AUROC-curve 0.79, p

Background: miRNAs are critically involved in asthma and are actively secreted in extracellular vesicles (EV) for inter-cell communication. We have previously shown that total extracellular miRNAs in plasma can distinguish between asthma and healthy controls (Milger, Allergy, 2017). Thus, we now aimed to investigate if miRNA profiles from plasma EVs are altered in patients with asthma. Methods: We isolated EVs from 1 mL plasma of adult subjects from the ALLIANCE cohort with mild-to-moderate (AM) or severe asthma (AS), and healthy controls (HC) (n=15/group) by size exclusion chromatography (Izon). EVs were characterized by nanoparticle-tracking analysis and flow cytometry. EV RNA was isolated and subjected to small RNA-seq (Illumina). We correlated sequencing data with clinical characteristics and confirmed candidate miRNAs in a new set of EV isolates by RT-qPCR. Results: Isolated EVs had a median size of 131.5 nm and a median concentration of 8.6x10^9 particles/mL in HC, with no significant differences among the groups. RNA-seq detected 139 EV-miRNAs, 35 of which were expressed at moderate to high levels. miR-122-5p was significantly higher in EVs from AS patients compared to HC (log2FC=1.77, padj=0.019) and we observed a trend for miR-191-5p (log2FC=0.39, padj=0.11). Both findings were confirmed by RT-qPCR. Further, miR-191-5p significantly correlated with FEV1%pred (R=-0.38 p=0.013), eosinophil (R=0.45, p=0.0056) and neutrophil (R=-0.37, p=0.027) counts in blood. Conclusion: miR-122-5p and miR-191-5p are increased in EVs from subjects with asthma, and miR-191-5p correlates with lung function impairment and inflammation. Therefore, EV miRNAs might qualify for disease subphenotyping in asthma.

Introduction: A breath test that provides information about the inflammatory phenotype of asthma patients could be a valuable tool in daily clinical practice. We analyzed breath in the adult arm of the ALLIANCE cohort to evaluate if breath VOC patterns differ between asthma phenotypes. Methods: We included 111 patients of three phenotypes: active smokers with asthma (n=29), non-smokers with severe asthma (n=36; ERS/ATS guidelines), and non-smokers with mild-to-moderate asthma (n=46). Patients inhaled pre-cleaned room air and exhaled into an aluminum reservoir tube. The breath was loaded onto two adsorption tubes for the analysis by GC-MS. 134 different VOCs were assessed. Results: The high comparability between simultaneously loaded adsorption tubes and the differences between actively smoking and non-smoking patients (44/134 VOCs with p Conclusion: Breath VOCs appear to be closer related to the clinical than the inflammatory asthma phenotype. One breath VOC might have a clinical relevance as it could support other readily accessible markers like blood eosinophils and exhaled NO to predict the level of eosinophilic airway inflammation.

High resting heart rate (RHR) is associated with higher mortality in general population and in cardiovascular disease. Less is known about the association of RHR with outcome in chronic obstructive pulmonary disease (COPD). This study investigated the influence of RHR on survival of 2741 COPD patients in the multicentre cohort study COSYCONET (German COPD and Systemic Consequences – Comorbidities Network). Patients with a baseline RHR >72 beats per minute (bbp) 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 separates risk more precisely (HR 1.82, 1.22-2.50, p=0.0001) than baseline RHR. In conclusion, an increased RHR is independently associated with a higher mortality in patients with COPD. These results show that RHR, especially time-updated RHR, represents an independent predictor for mortality in COPD. Whether RHR is a treatment target needs to be proven in controlled trials.

The Hamburg City Health Study (HCHS) is a large, prospective, long-term, population-based cohort study and a unique research platform and network to obtain substantial knowledge about several important risk and prognostic factors in major chronic diseases. A random sample of 45,000 participants between 45 and 74 years of age from the general population of Hamburg, Germany, are taking part in an extensive baseline assessment at one dedicated study center. Participants undergo 13 validated and 5 novel examinations primarily targeting major organ system function and structures including extensive imaging examinations. The protocol includes validate self-reports via questionnaires regarding lifestyle and environmental conditions, dietary habits, physical condition and activity, sexual dysfunction, professional life, psychosocial context and burden, quality of life, digital media use, occupational, medical and family history as well as healthcare utilization. The assessment is completed by genomic and proteomic characterization. Beyond the identification of classical risk factors for major chronic diseases and survivorship, the core intention is to gather valid prevalence and incidence, and to develop complex models predicting health outcomes based on a multitude of examination data, imaging, biomarker, psychosocial and behavioral assessments. Participants at risk for coronary artery disease, atrial fibrillation, heart failure, stroke and dementia are invited for a visit to conduct an additional MRI examination of either heart or brain. Endpoint assessment of the overall sample will be completed through repeated follow-up examinations and surveys as well as related individual routine data from involved health and pension insurances. The study is targeting the complex relationship between biologic and psychosocial risk and resilience factors, chronic disease, health care use, survivorship and health as well as favorable and bad prognosis within a unique, large-scale long-term assessment with the perspective of further examinations after 6 years in a representative European metropolitan population. Electronic supplementary material The online version of this article (10.1007/s10654-019-00577-4) contains supplementary material, which is available to authorized users.

Background The combination of chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD) is associated with a higher prevalence of comorbidities and increased mortality. The impact of kidney function on patient-centered outcomes in COPD has not been evaluated. Methods Patients from the German COPD and Systemic Consequences - Comorbidities Network (COSYCONET) cohort COPD were analysed. CKD was diagnosed if the estimated glomerular filtration rate (eGFR) measurements were

BackgroundConventional measures to evaluate COPD may fail to capture systemic problems, particularly musculoskeletal weakness and cardiovascular disease. Identifying these manifestations and assessing their association with clinical outcomes (ie, mortality, exacerbation and COPD hospital admission) is of increasing clinical importance.ObjectiveTo assess associations between 6 min walk distance (6MWD), heart rate, fibrinogen, C reactive protein (CRP), white cell count (WCC), interleukins 6 and 8 (IL-6 and IL-8), tumour necrosis factor-alpha, quadriceps maximum voluntary contraction, sniff nasal inspiratory pressure, short physical performance battery, pulse wave velocity, carotid intima-media thickness and augmentation index and clinical outcomes in patients with stable COPD.MethodsWe systematically searched electronic databases (August 2018) and identified 61 studies, which were synthesised, including meta-analyses to estimate pooled HRs, following Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.ResultsShorter 6MWD and elevated heart rate, fibrinogen, CRP and WCC were associated with higher risk of mortality. Pooled HRs were 0.80 (95% CI 0.73 to 0.89) per 50 m longer 6MWD, 1.10 (95% CI 1.02 to 1.18) per 10 bpm higher heart rate, 3.13 (95% CI 2.14 to 4.57) per twofold increase in fibrinogen, 1.17 (95% CI 1.06 to 1.28) per twofold increase in CRP and 2.07 (95% CI 1.29 to 3.31) per twofold increase in WCC. Shorter 6MWD and elevated fibrinogen and CRP were associated with exacerbation, and shorter 6MWD, higher heart rate, CRP and IL-6 were associated with hospitalisation. Few studies examined associations with musculoskeletal measures.ConclusionFindings suggest 6MWD, heart rate, CRP, fibrinogen and WCC are associated with clinical outcomes in patients with stable COPD. Use of musculoskeletal measures to assess outcomes in patients with COPD requires further investigation.Trial registration numberCRD42016052075.

Background: Cardiovascular (CV) disease is a frequent comorbidity and a major cause of death in COPD. Very low circulating levels of high-sensitivity troponin I (hs-TnI) predict CV events and all-cause mortality in the general population beyond established risk factors. The aim of this study was to evaluate hs-TnI levels and its predictive value for all-cause mortality in stable COPD. Methods: In the multicenter COSYCONET cohort study enrolling stable COPD patients (GOLD stage I-IV), hs-TnI was measured in serum samples collected at the baseline visit using a hs-TnI Assay (Abbott Diagnostics) with a lower limit of detection (LoD) of 1.9 ng/L. Cox regression analyses were used to evaluate the incremental predictive value of hs-TnI for all-cause mortality compared to established risk factors. Results: Among 2045 COPD patients, hs-TnI concentrations were above the LoD in 87.2% (n=1783). The median hs-TnI level was 3.8 ng/L (IQR, 2.5‒6.6 ng/L). 595 patients (28.5%) had elevated hs-TnI levels according to the previously described cut-off value to identify individuals at high risk for CV events and death (i.e. 6 ng/L). No significant association was observed between hs-TnI and airflow limitation. During a median follow-up time of 3.1 years, 185 patients (9.0%) died. An elevated hs-TnI level independently predicted all-cause mortality even after adjustment for CV risk factors (HR 1.39, 95% CI 1.03‒1.89, p=0.034) and for the components of the BODE score, i.e. BMI, FEV1, mMRC dyspnoe scale, and 6MWD, (HR 1.67, 95% CI 1.21‒2.29, p=0.002). Conclusions: High-sensitivity troponin I levels independently predict all-cause mortality in stable patients with COPD beyond well-established prognostic indicators.

Background: Right ventricular (RV) dysfunction is a major prognostic predictor in pulmonary arterial hypertension (PAH). Objectives: The objective of this study was to assess the prognostic impact of a newly developed index merging haemodynamic parameters into 1 variable. Methods: We retrospectively assessed 2 cohorts of 248 patients (164 from Hamburg and 84 from Heidelberg) with invasively diagnosed PAH. During a median follow-up time of 3.6 years (3.1 and 4.0 years for Hamburg and Heidelberg, respectively), the composite endpoint of all-cause mortality and lung transplantation occurred in 57 patients (53 and 4 patients for Hamburg and Heidelberg, respectively). The RV index was developed in the Hamburg cohort and validated in the Heidelberg cohort: (right atrial pressure × pulmonary vascular resistance)/mixed venous oxygen saturation. Results: Patients with a high RV index had a higher incidence of the combined endpoint in Kaplan-Meier analyses in the Hamburg and Heidelberg cohort (p = 0.017 and p = 0.034, respectively). The calculated RV index cut-off value was 91 and identified patients with a worse outcome in the Hamburg cohort and showed a trend in the Heidelberg cohort (p < 0.001 and p = 0.089, respectively). The RV index in Cox regression hazard models was an independent predictor of outcomes after adjustment for sex and age in both cohorts (Hamburg: hazard ratio [HR] 1.26 [95% CI 1.08, 1.47], p = 0.0027; Heidelberg: HR 2.27 [95% CI 1.46, 3.51], p < 0.001). A nomogram based on these results allowed risk stratification. Conclusion: Merging 3 haemodynamic variables into 1 variable, the RV index increased the prognostic power up to an independent risk factor. The RV index is easy to calculate and allows the construction of a nomogram for an individualized risk assessment.

Rationale: Physical activity (PA) has been associated with mortality in patients with COPD. We aimed to investigate 1) this association across the disease severity and 2) whether the previously reported protective effect of PA is due to its quantity and/or intensity. Methods: We pooled data about PA (Sensewear armband), clincial characteristics and mortality from patients with COPD tested in Belgium (n=179), Spain (n= 173), Germany (n=168), United Kingdom (n=101) and Brazil (n=137) for these analyses. The quantity (daily step count) and intensity (mean METs during periods of at least 1.5 METs) of PA were included as exposures. Analyses (Cox proportional hazard regression) were adjusted for age, gender, severity of airflow limitation and BMI. Results: 758 patients (74% male, 67±8 years, FEV 1 56±22 % pred , BMI 27±5 kg.m −2 , 5881±4007 steps/day, mean PA intensity 3.18±0.52 METs) were included and 149 (20%) died during the 4-year follow up. Being more active was related to lower mortality risk (Hazard ratio, 95%CI 0.85 [0.79 to 0.91] per 1000 steps more, p

Background: Little is known about physical activity in daily life in patients with sarcoidosis. Fatigue is a frequent and disabling symptom that might negatively affect physical activity levels. Methods: In patients with sarcoidosis we measured physical activity (steps per day, SPD) by accelerometry (SenseWear Armband) for one week. We assessed lung function (DLCO, FVC), exercise capacity (6-min walk-distance, 6MWD), health-related quality of life (SGRQ), generic quality of life (SF-12), and fatigue (MFI-20). Results: We investigated 57 patients with sarcoidosis (mean age 50 years, 56% male, mean DLCO 73%pred., mean FVC 91%pred., mean 6MWD 525m, mean SPD 7,490) of whom n=14 (25%) had severe fatigue. MFI-20 subscales ‘reduced activity’ and ‘physical fatigue’ were weakly associated with SPD on a bivariate level (Spearman-rho=-0.27, and -0.28; p Conclusion: While exercise capacity and quality of life measurements were robust predictors of physical activity in patients with sarcoidosis, associations of objectively measured physical activity with fatigue were surprisingly weak. In sarcoidosis, fatigue might not preclude affected patients from being physically active, although this symptom is subjectively perceived as highly disabling.

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

Background Sleep disturbances are common in patients with chronic obstructive pulmonary disease (COPD) with a considerable negative impact on their quality of life. However, factors associated with measures of sleep in daily life have not been investigated before nor has the association between sleep and the ability to engage in physical activity on a day-to-day basis been studied.Aims To provide insight into the relationship between actigraphic sleep measures and disease severity, exertional dyspnoea, gender and parts of the week; and to investigate the association between sleep measures and next day physical activity.Methods Data were analysed from 932 patients with COPD (66% male, 66.4 +/- 8.3 years, FEV1% predicted= 50.8 +/- 20.5). Participants had sleep and physical activity continuously monitored using a multisensor activity monitor for a median of 6 days. Linear mixed effects models were applied to investigate the factors associated with sleep impairment and the association between nocturnal sleep and patients' subsequent daytime physical activity.Results Actigraphic estimates of sleep impairment were greater in patients with worse airflow limitation and worse exertional dyspnoea. Patients with better sleep measures (ie, non-fragmented sleep, sleeping bouts >= 225 min, sleep efficiency >= 91% and time spent awake after sleep onset Conclusions There is a relationship between measures of sleep in patients with COPD and the amount of activity they undertake during the waking day. Identifying groups with specific sleep characteristics may be useful information when designing physical activity-enhancing interventions.

BACKGROUND: Physical activity (PA) has been extensively investigated in COPD, curiously there is very limited data for asthma. AIMS: We aimed to investigate levels of PA in adult asthmatics, and to identify associations between PA and lung function. METHODS: We measured PA (steps per day, SPD) in 146 stable asthma patients (severe asthma/SA, n=63; mild-to-moderate asthma/MA, n=83) and 29 healthy controls (HC) by accelerometry (SenseWear Armband) for one week. We measured lung function: airflow limitation (FEV 1 ; PEF), airway resistance (sR eff by bodyplethysmography; R5Hz by impulse oscillometry/IOS) and small airway dysfunction (frequency dependence of resistance/ FDR abs by IOS). In addition, we assessed symptom control (ACQ-5) and dosage of inhaled corticosteroids (ICS). RESULTS: In unadjusted analyses, SA showed significantly lower SPD [median 6174 (4822–9277)] compared to MA and HC (reduction by 21% and 31%, respectively; p In multivariate linear regression analyses adjusting for common confounders, R5Hz and FDR abs were the best lung function predictors for SPD in asthma (p abs remained independent predictors after further adjustment for poor symptom control and high dose ICS treatment (p CONCLUSIONS: Physical activity is substantially reduced in patients with severe asthma. Impulse oscillometric assessments of airway resistance and small airway dysfunction in a tidal breathing maneuver are the best indicators for physical activity limitation in asthma.

BACKGROUND: The observed coexistence of COPD and cardiovascular disease (CVD) may be interrelated through inflammatory processes. Here we investigated the relationship between angiopoietin-like protein 4 (ANGPTL4), an acute phase protein, and cardiovascular function in patients with COPD. METHODS: In a cohort study we assessed serum levels of ANGPTL4, lung function (FEV 1 ), vascular status (ankle-brachial index [ABI]), cardiac function (N-terminal pro-B-Type natriuretic peptide [NT-proBNP], and traditional CVD risk factors like the components of the metabolic syndrome plus hs-CRP, physical activity, and history of coronary artery disease. Our study groups included 74 patients with COPD (GOLD stage I to IV), 12 smoking controls with chronic bronchitis and normal lung function, and 18 non-smoking controls without any lung disease. RESULTS: Levels of ANGPTL4 were increased in COPD patients compared to non-smoking controls (p=0.026). ANGPTL4 did not differ between active smokers and ex- or never-smokers (p=0.75). Using clinically established cut-off values for ABI (i.e. 0.90) and NT-pro-BNP (i.e. 125 pg/mL), we found the level of ANGPTL4 to be clearly different (p=0.010 and p CONCLUSIONS: Serum ANGPTL4 is an independent predictor of vascular and cardiac function in patients with COPD. The increased circulating levels of ANGPTL4 may reflect a pathophysiologic link between COPD and CVD.

Physical activity is reduced in severe asthma; impulse oscillometry was a better predictor than spirometry http://ow.ly/6WdN305D9aV

Background: Little is known about the consequences of idiopathic pulmonary fibrosis (IPF) for physical activity (PA). Objectives: We aimed to investigate levels of PA in IPF and to study associations of PA with lung function, exercise capacity, symptoms, and quality of life. Methods: In stable patients with IPF we measured PA (steps per day, SPD; physical activity level, PAL; minutes of moderate activity, MMA) by accelerometry (SenseWear Armband) for 1 week. We also assessed lung function (forced vital capacity, FVC; diffusing capacity for carbon monoxide, DLCO); exercise capacity (6-minute walking distance, 6MWD); dyspnea (modified Medical Research Council, mMRC); fatigue (Multidimensional Fatigue Inventory, MFI-20), and generic (12-Item Short Form Survey, SF-12) and health-related quality of life (St. George's Respiratory Questionnaire) as further clinical variables. Results: We investigated 48 patients with IPF in two centers (mean age, 67 years; 75% male; 23% on long-term oxygen therapy; mean FVC 75%pred.; mean DLCO 43%pred.; mean 6MWD 355 ± 140 m; mean SPD 5,017 ± 3,360). On a bivariate level, all clinical variables were significantly associated with SPD (p < 0.05). The associations of mMRC, MFI-20, SF-12 (physical health), and 6MWD with SPD were independent of impaired lung function (p < 0.05). At multivariate analyses, either 6MWD (total explained variance of the model, total R2: 42%) or MFI-20 (total R2: 39%) were the strongest independent predictors of SPD. Conclusion: Fatigue and exercise capacity are strong and independent predictors of PA in patients with IPF, which suggests that both measures should be assessed when the consequences of IPF for PA in daily life are studied.

Handgrip strength is a simple measure of upper limb muscle function that is associated with mortality in the general population and in patients with COPD.1 ,2 Recently, normative values for handgrip strength have been proposed based on centile scores in >224 000 healthy adults between 39 and 73 years of age, adjusted for age, sex, height and measurement side.3 As an illustration, in a typical 65-year-old male patient 5th and 10th centile of right handgrip strength range 18–28 kg and 20–30 kg, respectively, depending on the patient's height. It is unclear whether the identification of handgrip weakness based on these centiles has prognostic value in addition to known prognostic parameters like FEV1, age, dyspnoea symptoms (combined in the validated ADO index4) and body mass index (BMI). Therefore, we performed an a posteriori analysis of prospectively collected multicentre data in patients with stable COPD, followed for a median of 3.9 years.2 ,5–7 Handgrip strength was assessed using …

Summary Background Little is known about COPD patients' compliance with physical activity monitoring and how activity relates to disease characteristics in a multi-center setting. Methods In a prospective study at three Northern European sites physical activity and clinical disease characteristics were measured in 134 COPD patients (GOLD-stage II–IV; BODE index 0–9) and 46 controls. Wearing time, steps per day, and the physical activity level (PAL) were measured by a multisensory armband over a period of 6 consecutive days (in total, 144h). A valid measurement period was defined as ≥22 h wearing time a day on at least 5 days. Results The median wearing time was 142 h:17 min (99%), 141 h:1min (98%), and 142 h:24 min (99%), respectively in the three centres. A valid measurement period was reached in 94%, 97%, and 94% of the patients and did not differ across sites ( P = 0.53). The amount of physical activity did not differ across sites (mean steps per day, 4725 ± 3212, P = 0.58; mean PAL, 1.45 ± 0.20, P = 0.48). Multivariate linear regression analyses revealed significant associations of FEV 1 , 6-min walk distance, quadriceps strength, fibrinogen, health status, and dyspnoea with both steps per day and PAL. Previously unrecognized correlates of activity were grade of fatigue, degree of emphysema, and exacerbation rate. Conclusions The excellent compliance with wearing a physical activity monitor irrespective of study site and consistent associations with relevant disease characteristics support the use of activity monitoring as a valid outcome in multi-center studies.

Background Systemic effects of COPD are incompletely reflected by established prognostic assessments. We determined the prognostic value of objectively measured physical activity in comparison with established predictors of mortality and evaluated the prognostic value of noninvasive assessments of cardiovascular status, biomarkers of systemic inflammation, and adipokines. Methods In a prospective cohort study of 170 outpatients with stable COPD (mean FEV1, 56% predicted), we assessed lung function by spirometry and body plethysmography; physical activity level (PAL) by a multisensory armband; exercise capacity by 6-min walk distance test; cardiovascular status by echocardiography, vascular Doppler sonography (ankle-brachial index [ABI]), and N-terminal pro-B-type natriuretic peptide level; nutritional and muscular status by BMI and fat-free mass index; biomarkers by levels of high-sensitivity C-reactive protein, IL-6, fibrinogen, adiponectin, and leptin; and health status, dyspnea, and depressive symptoms by questionnaire. Established prognostic indices were calculated. The median follow-up was 48 months (range, 10-53 months). Results All-cause mortality was 15.4%. After adjustments, each 0.14 increase in PAL was associated with a lower risk of death (hazard ratio [HR], 0.46; 95% CI, 0.33-0.64; P Conclusions We found that objectively measured physical activity is the strongest predictor of all-cause mortality in patients with COPD. In addition, adiponectin level and vascular status provide independent prognostic information in our cohort.

Purpose The aim of this retrospective study was to compare patient characteristics, treatment patterns and treatment results in two groups of patients with limited disease (LD) and extensive disease (ED) small-cell lung cancer (SCLC) in 2004 - 2005 vs. 2007 - 2008. Patients and methods We included all patients with LD or ED SCLC in this retrospective analysis who were diagnosed in our department in the periods 2004 - 2005 and 2007 - 2008. We collected data on patient characteristics, chemotherapy, radiotherapy, treatment response and median survival. Statistical analyses were separately performed for patients in LD and ED SCLC. Results 109 patients had LD SCLC. The response rate on first-line therapy was 74 %. More than half of the cases had recurrent disease. Second-line treatment was given to about two thirds of these patients. Third-line therapy was administered in around 15 % of all cases. Prophylactic cranial irradiation was performed more frequently from 2007 - 2008. The median survival was 17 months. There were no statistically significant differences regarding patient characteristics and treatment results. ED SCLC was present in 188 patients. The response rate was around 68 %. All patients relapsed, second-line therapy was administered in half of these cases; third-line therapy in 10 % of all cases. No statistically significant differences were detected between the two time frames. Median survival was 10 months. Conclusion Overall, no statistically significant differences were present for patients with LD and ED SCLC in 2004 - 2005 vs. 2007 - 2008. Prophylactic cranial irradiation was employed more frequently in LD SCLC from 2007.

Background Little is known about the role of abnormal lung function in heart size and heart dysfunction in patients with COPD. We studied the relationship of lung function with heart size and heart dysfunction and associated consequences for 6-min walk distance (6MWD) in patients with COPD of different severitites. Methods In 138 patients with COPD (Global Initiative for Obstructive Lung Disease [GOLD] I-IV), we measured the size of all cardiac chambers, left ventricular diastolic dysfunction (relaxation and filling), and global right ventricular dysfunction (Tei-index) by echocardiography. We also measured lung function (spirometry, body plethysmography, and diffusion capacity) and 6MWD. Results The size of all cardiac chambers decreased with increasing GOLD stage. Overall, moderate relationships existed between variables of lung function and cardiac chamber sizes. Static hyperinflation (inspiratory-to-total lung capacity ratio [IC/TLC], functional residual capacity, and residual volume) showed stronger associations with cardiac chamber sizes than airway obstruction or diffusion capacity. IC/TLC correlated best with cardiac chamber sizes and was an independent predictor of cardiac chamber sizes after adjustment for body surface area. Patients with an IC/TLC ≤ 0.25 had a significantly impaired left ventricular diastolic filling pattern and a significantly impaired Tei-index compared with patients with an IC/TLC > 0.25. An impaired left ventricular diastolic filling pattern was independently associated with a reduced 6MWD. Conclusions An increasing rate of COPD severity is associated with a decreasing heart size. Hyperinflation could play an important role regarding heart size and heart dysfunction in patients with COPD.

Background The metabolic syndrome is a condition frequently found among individuals > 60 years of age. It predisposes affected individuals to systemic inflammation and physical inactivity. Systemic inflammation and physical inactivity are relevant extrapulmonary markers of morbidity and mortality in patients with COPD. Here, we studied the following: (1) the frequency of the coexisting metabolic syndrome in patients with chronic bronchitis (CB) and COPD of different severities; and (2) its association with systemic inflammation and physical inactivity. Methods In 30 patients with CB (normal spirometry finding) and in 170 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages I to IV), we measured the characteristics of the metabolic syndrome, systemic inflammation (high-sensitivity C-reactive protein [hs-CRP], interleukin-6, fibrinogen), and the physical activity level. Results The frequencies of the metabolic syndrome in patients with CB, GOLD stages I, II, III, and IV, were 53%, 50%, 53%, 37%, and 44%, respectively (average, 47.5%). The levels of hs-CRP and interleukin-6 were significantly increased in patients with the metabolic syndrome, while the physical activity level was significantly decreased. Multivariate linear regression analyses revealed metabolic syndrome, physical activity level, and CB/GOLD stages to be independent predictors of hs-CRP and interleukin-6 levels, and physical activity level to be a predictor of fibrinogen levels. Conclusions In our study, almost one-half of the patients with CB/COPD had coexisting metabolic syndrome, with a slightly lower frequency in patients with severe COPD. The coexisting metabolic syndrome is associated with an increase in the levels of some systemic inflammatory markers and physical inactivity, independent of lung function impairment.

Physical activity is an important parameter related to morbidity and mortality in cardiovascular disease, metabolic syndrome/diabetes, mental disorders, cancer, and chronic obstructive pulmonary disease (COPD). In COPD, lower levels of physical activity as reported by the patients are associated with a faster annual lung function decline, increased number of hospitalizations, and higher risk of mortality. Self-reported physical activity, however, correlates only poorly with objectively quantified physical activity in patients with COPD. Recent data show that physical activity can reliably be measured in a substantial number of patients with COPD. Extrapulmonary effects of COPD are associated with reduced physical activity. Clinical characteristics commonly used to assess disease severity like the forced expiratory volume in 1 s or the 6-min walk distance only incompletely reflect the physical activity of patients with COPD.

The present study aimed to measure physical activity in patients with chronic obstructive pulmonary disease (COPD) to: 1) identify the disease stage at which physical activity becomes limited; 2) investigate the relationship of clinical characteristics with physical activity; 3) evaluate the predictive power of clinical characteristics identifying very inactive patients; and 4) analyse the reliability of physical activity measurements. In total, 163 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I-IV; BODE (body mass index, airway obstruction, dyspnoea, exercise capacity) index score 0-10) and 29 patients with chronic bronchitis (normal spirometry; former GOLD stage 0) wore activity monitors that recorded steps per day, minutes of at least moderate activity, and physical activity levels for 5 days (3 weekdays plus Saturday and Sunday). Compared with patients with chronic bronchitis, steps per day, minutes of at least moderate activity and physical activity levels were reduced from GOLD stage II/BODE score 1, GOLD stage III/BODE score 3/4 and from GOLD stage III/BODE score 1, respectively. Reliability of physical activity measurements improved with the number of measured days and with higher GOLD stages. Moderate relationships were observed between clinical characteristics and physical activity. GOLD stages III and IV best predicted very inactive patients. Physical activity is reduced in patients with chronic obstructive pulmonary disease from Global Initiative for Chronic Obstructive Lung Disease stage II/ body mass index, airway obstruction, dyspnoea, exercise capacity score 1. Clinical characteristics of patients with chronic obstructive pulmonary disease only incompletely reflect their physical activity.

Physical activity is reduced in patients with chronic obstructive pulmonary disease (COPD). COPD has a systemic component that includes significant extrapulmonary effects that may contribute to its severity in individual patients.To investigate the association of extrapulmonary effects of the disease and its comorbidities with reduced physical activity in patients with COPD.In a cross-sectional study, 170 outpatients with COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages I-IV; BODE [body mass index, airway obstruction, dyspnea, and exercise capacity] score 0-10) underwent a series of tests. Physical activity was assessed over 5 to 6 consecutive days by using a multisensor accelerometer armband that records steps per day and the physical activity level (total daily energy expenditure divided by whole-night sleeping energy expenditure). Cardiovascular status was assessed by echocardiography, vascular Doppler sonography, and levels of N-terminal pro-B-type natriuretic peptide. Mental status, metabolic/muscular status, systemic inflammation, and anemia were assessed by Beck Depression Inventory, bioelectrical impedance analysis, handgrip strength, high-sensitivity C-reactive protein/fibrinogen, and hemoglobin, respectively.In a multivariate linear regression analysis using either steps per day or physical activity level as a dependent variable, the extrapulmonary parameters that were associated with reduced physical activity in patients with COPD independently of GOLD stages or BODE score were N-terminal pro-B-type natriuretic peptide levels, echocardiographically measured left ventricular diastolic function, and systemic inflammation.Higher values of systemic inflammation and left cardiac dysfunction are associated with reduced physical activity in patients with COPD.

Rationale: Little is known about the role of physical activity in the course of chronic obstructive pulmonary disease (COPD). Objectives: To assess changes in physical activity in COPD in relation to severity stages and changes in other disease components, and to evaluate the longitudinal association between sustained physical inactivity and disease progression. Methods: In this prospective cohort study, we measured physical activity (multisensory armband), airflow obstruction (FEV1), health status (St. George's Respiratory Questionnaire), exercise capacity (6-min-walk distance [6MWD]), muscle mass (fat-free mass [FFM]), and systemic inflammation (fibrinogen and high-sensitivity C-reactive protein) over a 3-year period in 137 patients with COPD and 26 with chronic bronchitis (normal spirometry). Measurements and Main Results: Independent of baseline disease severity, steps per day, total daily energy expenditure, and (daily) physical activity level (PAL) decreased by 393, 76 kcal, and 0.04 per year, respectively. The decline in PAL was significantly associated with a decline in FEV1 and an increase in St. George's Respiratory Questionnaire total score. Changes in 6MWD, FFM, and inflammatory markers were not associated with changes in PAL. Independent of FEV1, sustained physical inactivity (i.e. PAL(T0andT1) < 1.40) was related to a greater decline in 6MWD and FFM compared with that in patients with some level of activity (i.e., PAL(T0and/orT1) >= 1.40; difference, 17 m/yr and 0.87 kg/yr, respectively). Conclusions: Over time, physical activity substantially decreases across all severity stages of COPD, and this decline is paralleled by a worsening of lung function and health status. Sustained physical inactivity is associated with a progression of exercise intolerance and muscle depletion.

Background: COPD is characterized by exercise intolerance, muscle depletion, and physical inactivity. The aim of this study was to analyze the role of sustained physical inactivity for changes in exercise capacity and skeletal muscle mass in the course of COPD. Methods: In this cohort study, we measured physical activity level (PAL; total daily energy expenditure / resting metabolic rate) via multisensory armband, FEV 1 , 6-minute walk distance (6MWD), and fat-free mass (FFM; bioelectrical impedance) at baseline and after 3 years in 170 patients with COPD (GOLD stage I–IV) and 30 with chronic bronchitis. Patients were longitudinally classified into ”sustained physical inactivity” (i.e. PAL T0+T1 T0orT1 >1.40). Results: During follow-up, we found a significant decrease in PAL, FEV 1 , 6MWD, and FFM (p 1 , sustained physical inactivity was related to a greater decline in 6MWD and FFM compared to that in patients with some level of activity (difference, 21 m/yr and 0.81 kg/yr). Sustained physical inactivity was not related to an accelerated decline in FEV 1 . Conclusions: Sustained physical inactivity over time promotes a progression of exercise intolerance and muscle depletion in patients with COPD.

Rationale Sporadic lymphangioleiomyomatosis (LAM) is an orphan lung disease for which daily physical activity has not been studied so far and it is unclear whether a disease-specific impact beyond airflow limitation exists. Clinical correlates indicating reduced physical activity in addition to established parameters like airflow limitation and hypoxaemia are largely undetermined. Method We measured physical activity (steps per day, SPD; physical activity level, PAL; minutes of moderate activity, MMA) in 34 women with LAM, 32 FEV 1 -matched female patients with COPD and 15 age-matched healthy women for 1 week using an accelerometer. In addition, we assessed lung function measurements, questionnaires for generic and respiratory health status (12-Item Short Form Survey, SF-12; St. George9s Respiratory Questionnaire, SGRQ), dyspnoea (modified Medical Research Council dyspnoea scale, mMRC) and fatigue (Multidimensional Fatigue Inventory, MFI-20). Results Patients with LAM (mean age 52.7 years, mean FEV 1 62.7% predicted) showed reduced SPD, PAL and MMA (p 1 62.6% predicted). In multivariate regression analyses, adjusting for FEV 1 and long-term oxygen therapy, either generic health status (SF-12 physical health) or fatigue (MFI-20) were the strongest independent predictors for SPD in patients with LAM (p=0.006 and p=0.004, respectively). Conclusions Physical activity in daily life is substatially reduced in LAM, when compared with healthy controls and COPD - indicating a disease specific impact. The regular assessment of fatigue and generic health status may improve disease management in LAM by taking daily physical activity of patients with LAM more adequately into account.

This European Respiratory Society (ERS) statement provides a comprehensive overview on physical activity in patients with chronic obstructive pulmonary disease (COPD). A multidisciplinary Task Force of experts representing the ERS Scientific Group 01.02 “Rehabilitation and Chronic Care” determined the overall scope of this statement through consensus. Focused literature reviews were conducted in key topic areas and the final content of this Statement was agreed upon by all members. The current knowledge regarding physical activity in COPD is presented, including the definition of physical activity, the consequences of physical inactivity on lung function decline and COPD incidence, physical activity assessment, prevalence of physical inactivity in COPD, clinical correlates of physical activity, effects of physical inactivity on hospitalisations and mortality, and treatment strategies to improve physical activity in patients with COPD. This Task Force identified multiple major areas of research that need to be addressed further in the coming years. These include, but are not limited to, the disease-modifying potential of increased physical activity, and to further understand how improvements in exercise capacity, dyspnoea and self-efficacy following interventions may translate into increased physical activity. The Task Force recommends that this ERS statement should be reviewed periodically (e.g. every 5–8 years). Michael Polkey's contribution to this work was part funded by the NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, UK, who part fund his salary. Thierry Trooster's contribution was partly funded by the Flemish Research Foundation (#G.0871.13). Anouk Vaes' contribution to this work was partially funded by "Stichting de Weijerhorst" and Point-One funding from AgentschapNL, Dutch Ministry of Economic affairs, the Netherlands. Martijn A. Spruit's contribution to this work was partially funded by Point-One funding from AgentschapNL, Dutch Ministry of Economic affairs, the Netherlands. Benjamin Waschki's contribution to this work was partially funded by the German Center for Lung Research, Germany. The Task Force co-chairs are grateful to the ERS for funding this ERS statement.

Chronic obstructive pulmonary disease (COPD) has significant extrapulmonary effects, among others, on cardiovascular disease. Heart failure can frequently be found in patients with COPD. Etiology of heart failure in COPD is only poorly understood but may be related to the high frequency of ischemic heart disease in this population. Furthermore, recent data suggest that diastolic left ventricular dysfunction may have a role for heart failure in COPD.