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Rationale: In chronic obstructive pulmonary disease (COPD), impaired left ventricular (LV) filling might be associated with coexisting heart failure with preserved ejection fraction (HFpEF) or due to reduced pulmonary venous return indicated by small LV size. Objectives: We investigated the all-cause mortality associated with small LV or HFpEF and clinical features discriminating between both patterns of impaired LV filling in patients with COPD. Methods: We performed transthoracic echocardiography (TTE) in patients with stable COPD from the COSYCONET (COPD and Systemic Consequences and Comorbidities Network) cohort to define small LV as LV end-diastolic diameter below the normal range and HFpEF features according to recommendations of the European Society of Cardiology. We assessed the ratio of early to late ventricular filling velocity (E/A), ratio of early mitral inflow velocity to annular early diastolic velocity (E/e'), serum N-terminal pro-brain natriuretic peptide, high-sensitivity troponin I, airflow limitation (FEV 1 ), lung hyperinflation (residual volume), and gas transfer capacity (Dl CO ) and discriminated patients with small LV from those with HFpEF features or no relevant cardiac dysfunction as per TTE (normal TTE ). The primary outcome was all-cause mortality after 4.5 years. Measurements and Main Results: In 1,752 patients with COPD, the frequency of small LV, HFpEF features, and normal TTE was 8%, 16%, and 45%, respectively. Patients with small LV or HFpEF features had higher all-cause mortality rates than patients with normal TTE : hazard ratio, 2.75 (95% confidence interval, 1.54-4.89) and 2.16 (95% confidence interval, 1.30-3.61), respectively. Small LV remained an independent predictor of all-cause mortality after adjusting for confounders including exacerbation frequency and measures of residual lung volume, Dl CO , or FEV 1 . Compared with normal TTE , patients with small LV had reduced LV filling, as indicated by lowered E/A. Yet, in contrast to patients with HFpEF features, patients with small LV had normal LV filling pressure (E/e') and lower concentrations of N-terminal pro-brain natriuretic peptide and high-sensitivity troponin I. Conclusions: In COPD, both small LV and HFpEF features are associated with increased all-cause mortality and represent two distinct patterns of impaired LV filling. Clinical trial registered with www.clinicaltrials.gov (NCT01245933).

Introduction: As with other chronic diseases, the course of chronic obstructive pulmonary disease (COPD) can be expected to be positively influenced if patients are well informed about their disease and undertake appropriate self-management. Assessments of the level of knowledge and management that are comparable should benefit from structured, systematically developed questionnaires. These, however, have not been published in Germany., Methods: A total of 310 patients with COPD were recruited from three pneumological practices and one hospital to develop the questionnaires. Based on statistical criteria and content assessments by medical specialists, two questionnaires on knowledge (17 questions) and self-management (25 questions) were developed by selecting and modifying questions from published studies and training programs. In addition, two short versions with 5 and 3 questions were created to enable a quick assessment of the patients' knowledge and self-management. All questionnaires also included a visual analogue scale for self-assessment of knowledge and self-management. The statistical procedures for systematically guided selection comprised correlation and regression analyses., Results: The questionnaires revealed considerable knowledge deficits in many patients and remarkably unsystematic, incoherent knowledge. The extent of this knowledge was negatively correlated with higher age and positively correlated with participation in training programs; this also applied to self-management. Correlations between the answers to the knowledge questions were higher in patients who had participated in training programs. The visual analogue scales for self-assessment of knowledge and management always correlated with the total number of correct answers., Discussion: The questionnaires on knowledge and self-management in patients with COPD could be used in outpatient settings, including by non-medical staff, in order to quickly identify and correct deficits or as a reason to recommend training programs. The short versions and the analogue scales for self-assessment can give at least first hints. Potentially, training programs should focus more on promoting the coherence of knowledge through better understanding, as this presumably favors long-term knowledge. Older patients and those with a low level of education appear to be particularly in need of specially adapted training programs., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory condition. Given patients with COPD continue to experience exacerbations despite the availability of effective therapies, anti-inflammatory treatments targeting novel pathways are needed. Kinases, notably the phosphoinositide 3-kinases (PI3K), are thought to be involved in chronic airway inflammation, with this pathway proposed as a critical regulator of inflammation and oxidative stress response in COPD. CHF6523 is an inhaled PI3Kδ inhibitor that has shown positive preclinical results. This manuscript reports the results of a study of CHF6523 in patients with stable COPD (chronic bronchitis phenotype), and who had evidence of type-2 inflammation., Methods: This randomised, double-blind, placebo-controlled, two-way crossover study comprised two 28-day treatment periods separated by a 28-day washout. Patients (N = 44) inhaled CHF6523 in one period, and placebo in the other, both twice daily. The primary objective was to assess the safety and tolerability of CHF6523; the secondary objective was to assess CHF6523 pharmacokinetics. Exploratory endpoints included target engagement (the relative reduction in phosphatidylinositol (3,4,5)-trisphosphate [PIP 3 ]), pharmacodynamic evaluations such as airflow obstruction, and hyperinflation, and to identify biomarker(s) of drug response using proteomics and transcriptomics., Results: CHF6523 plasma pharmacokinetics were characterised by an early maximum concentration (C max ), reached 15 and 10 min after dosing on Days 1 and 28, respectively, followed by a rapid decline. Systemic exposure on Day 28 showed limited accumulation, with ratios < 1.6 for C max and area under the curve from 0 to 12 h post-dose, and with steady state achieved on Day 20. Target engagement was confirmed by a significant 29.7% reduction from baseline in induced sputum PIP 3 (29.5% reduction vs. placebo; adjusted ratio 0.705 [0.580, 0.856]; p = 0.001), but this did not translate into an anti-inflammatory pharmacodynamic effect, as assessed through measures including biomarkers and multi-omics. Additionally, although CHF6523 was generally well-tolerated, 95.2% of patients reported cough as an adverse event, most mild to moderate and resolving within one-hour post-dose., Conclusions: These data, together with those from other PI3K inhibitors, suggest that PI3Kδ is not a suitable pathway for the management of COPD, as the achieved target engagement did not translate into any pharmacodynamic anti-inflammatory effect., Trial Registration: ClinicalTrials.gov (NCT04032535); posted 23rd July 2019., (© 2024. The Author(s).)

Background: The single-inhaler triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G) is available for maintenance therapy of chronic obstructive pulmonary disease (COPD). Cardinal features of COPD are lung hyperinflation and reduced exercise capacity. TRIFORCE aimed to evaluate the effect of BDP/FF/G on lung hyperinflation and exercise capacity in patients with COPD., Methods: This double-blind, randomised, active- and placebo-controlled, crossover study recruited adults with COPD aged ≥ 40 years, who were hyperinflated and symptomatic, and were receiving mono- or dual inhaled maintenance COPD therapy. In the three treatment periods, patients were randomised to receive BDP/FF/G, BDP/FF, or placebo, each for 3 weeks, with a 7-10-day washout between treatment periods. Assessments included slow inspiratory spirometry (for resting inspiratory capacity [IC]) and constant work-rate cycle ergometry (for dynamic IC and exercise endurance time). The primary objective was to compare BDP/FF/G and BDP/FF vs. placebo for resting IC at Week 3. Key secondary objectives were to compare BDP/FF/G and BDP/FF vs. placebo for dynamic IC and exercise endurance time during constant work rate cycle ergometry at Week 3., Results: Of 106 patients randomised, 95 completed the study. Resting IC adjusted mean differences vs. placebo were 315 and 223 mL for BDP/FF/G and BDP/FF, respectively (p < 0.001 for both). Adjusted mean differences vs. placebo for the key secondary endpoints were: 245 mL for dynamic IC (p < 0.001) and 69.2 s for exercise endurance time (nominal p < 0.001) with BDP/FF/G, and 96 mL (p = 0.053) and 70.1 s (nominal p < 0.001) with BDP/FF. Differences between BDP/FF/G and BDP/FF for resting and dynamic IC were 92 and 149 mL (p < 0.01 for both). All three treatments were generally well tolerated, with 27.3%, 25.3% and 19.0% of patients reporting adverse events with BDP/FF/G, BDP/FF and placebo, respectively, all mild or moderate., Conclusions: In patients with COPD, BDP/FF/G provided significant and clinically relevant improvements vs. placebo and BDP/FF in static and dynamic hyperinflation, with an improvement vs. placebo in exercise endurance., Trial Registration: ClinicalTrials.gov (NCT05097014), registered 27th October 2021., (© 2024. The Author(s).)

Background: Impulse oscillometry (IOS) allows an effort-independent evaluation of small airway function in asthma. Unfortunately, well-determined minimal clinically important differences (MCIDs) for IOS measures are lacking. Here, we provide MCIDs for frequently used IOS measures, namely frequency dependence of resistance (FDR) and area of reactance (AX), in patients with asthma., Methods: We performed IOS at baseline and 1 year later in adult patients with mild-to-severe asthma (n=235). In a two-step approach, we first applied a distribution-based method to statistically determine the MCID. Next, we validated the proposed MCID according to patient-reported outcome measures (PROMs): Asthma Quality of Life Questionnaire (AQLQ), Asthma Control Questionnaire-7 (ACQ-7) and Asthma Control Test (ACT). We used multivariable analyses to investigate the proposed MCIDs as predictors for improvements in PROMs compared with the established MCID of forced expiratory volume in 1 s (FEV 1 )., Results: The proposed MCID was a decline of ≥0.06 kPa·L -1 ·s -1 and ≥0.65 kPa·L -1 for FDR and AX, respectively. Patients who had changes beyond the MCIDs for both FDR and AX showed greater improvements in all PROMs than those who had not. The mean improvements in PROMs were beyond the established MCIDs for ACQ-7 and AQLQ, and approximated the MCID for ACT. Multivariable analyses demonstrated the MCIDs for both FDR and AX as independent predictors for the MCIDs of all PROMs. The MCID for FDR was a stronger predictor of all PROMs than the MCID for FEV 1 ., Conclusions: This study provides MCIDs for IOS-derived measures in adult patients with asthma and emphasises that small airway function is a distinguished end-point beyond the conventional measure of FEV 1 ., Competing Interests: Conflicts of interest: M. Abdo received travel support from Chiesi and consulting fees from AstraZeneca, all outside the submitted work. E. von Mutius reports personal fees from Pharmaventures, OM Pharma SA, Springer-Verlag GmbH, Elsevier GmbH, Elsevier Ltd, Peptinnovate Ltd, Turun Yliopisto, Tampereen Yliopisto, Helsingin Yliopisto, European Respiratory Society, Deutsche Pharmazeutische Gesellschaft eV, Massachusetts Medical Society, Chinese University of Hongkong, Boehringer Ingelheim, ProtectImmun GmbH, Faculteit Diergeneeskunde, Universität Salzburg, Georg Thieme Verlag, Japanese Society of Pediatric Allergy and Clinical Immunology, and Universiteit Utrecht, all outside the submitted work. K.F. Rabe reports grants from Boehringer Ingelheim and AstraZeneca, as well as personal fees from Boehringer Ingelheim, AstraZeneca, Novartis, Roche, Chiesi Pharmaceuticals, Regeneron, Sanofi and Berlin-Chemie. F. Trinkmann received travel support from Actelion, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Novartis, Mundipharma, TEVA, AstraZeneca, Berlin-Chemie, Bristol-Myers Squibb, Chiesi, GlaxoSmithKline, Novartis, Roche and Sanofi-Aventis, all outside the submitted work. T. Bahmer reports grants from Bundesministerium für Bildung und Forschung (BMBF) (an unrestricted research grant for the German Center for Lung Research (DZL)), during the conduct of the study, and personal fees from AstraZeneca, GlaxoSmithKline, Novartis and Roche, outside the submitted work. The remaining authors report no relevant conflicts of interest., (Copyright ©The authors 2023.)

Background: Comprehensive studies investigated the role of T-cells in asthma which led to personalised treatment options targeting severe eosinophilic asthma. However, little is known about the contribution of B-cells to this chronic inflammatory disease. In this study we investigated the contribution of various B-cell populations to specific clinical features in asthma., Methods: In the All Age Asthma Cohort (ALLIANCE), a subgroup of 154 adult asthma patients and 28 healthy controls were included for B-cell characterisation by flow cytometry. Questionnaires, lung function measurements, blood differential counts and allergy testing of participants were analysed together with comprehensive data on B-cells using association studies and multivariate linear models., Results: Patients with severe asthma showed decreased immature B-cell populations while memory B-cells were significantly increased compared with both mild-moderate asthma patients and healthy controls. Furthermore, increased frequencies of IgA + memory B-cells were associated with impaired lung function and specifically with parameters indicative for augmented resistance in the peripheral airways. Accordingly, asthma patients with small airway dysfunction (SAD) defined by impulse oscillometry showed increased frequencies of IgA + memory B-cells, particularly in patients with mild-moderate asthma. Additionally, IgA + memory B-cells significantly correlated with clinical features of SAD such as exacerbations., Conclusions: With this study we demonstrate for the first time a significant association of increased IgA + memory B-cells with asthma and SAD, pointing towards future options for B-cell-directed strategies in preventing and treating asthma., Competing Interests: Conflict of interest: C. Happle reports grants from Novartis and Pari, outside the submitted work. M.V. Kopp reports grants from Allergopharma GmbH and Vertex GmbH; honoraria for lectures from Allergopharma GmbH, Sanofi GmbH, Infectopharm GmbH, Vertex GmbH and Leti GmbH; advisory board membership at Allergopharma GmbH and Sanofi GmbH; outside the submitted work. E. von Mutius reports royalties from Elsevier GmbH, Georg Thieme Verlag, Springer-Verlag GmbH and Elsevier Ltd; consulting fees from the Chinese University of Hong Kong, European Commission, HiPP GmbH & Co KG and AstraZeneca; lecture honoraria from Massachusetts Medical Society, Springer-Verlag GmbH, Elsevier Ltd, Boehringer Ingelheim International GmbH, European Respiratory Society, Universiteit Utrecht – Faculteit Diergeneeskunde, Universität Salzburg, Springer Medizin Verlag GmbH, Japanese Society of Pediatric Allergy and Clinical Immunology (JSPACI), Klinikum Rechts der Isar, University of Colorado, Paul-Martini-Stiftung and Imperial College London; travel support from Verein zur Förderung der Pneumologie am Krankenhaus Großhansdorf eV, Pneumologie Développement, Mondial Congress & Events GmbH & Co. KG, American Academy of Allergy, Asthma & Immunology, Imperial College London, Margaux Orange, Volkswagen Stiftung, Boehringer Ingelheim International GmbH, European Respiratory Society, Universiteit Utrecht – Faculteit Diergeneeskunde, Österreichische Gesellschaft für Allergologie und Immunologie, Massachusetts Medical Society, OM Pharma SA, Hanson Wade Ltd, iKOMM GmbH, DSI Dansk Borneastma Center, American Thoracic Society, HiPP GmbH & Co. KG and Universiteit Utrecht – Faculteit Bètawetenschappen; outside the submitted work. In addition, E. von Mutius has patent LU101064 (Barn dust extract for the prevention and treatment of diseases) pending, royalties paid to ProtectImmun for patent EP2361632 (Specific environmental bacteria for the protection from and/or the treatment of allergic, chronic inflammatory and/or autoimmune disorders, granted on 19 March 2014), and patents EP1411977 (Composition containing bacterial antigens used for the prophylaxis and the treatment of allergic diseases, granted on 18 April 2007), EP1637147 (Stable dust extract for allergy protection, granted on 10 December 2008) and EP1964570 (Pharmaceutical compound to protect against allergies and inflammatory diseases, granted on 21 November 2012) licensed to ProtectImmun. In addition, E. von Mutius is a member of the EXPANSE (funded by European Commission) Scientific Advisory Board, member of the BEAMS External Scientific Advisory Board (ESAB), member of the Editorial Board of the Journal of Allergy and Clinical Immunology: In Practice, member of the Scientific Advisory Board of the Children's Respiratory and Environmental Workgroup (CREW), member of the International Scientific and Societal Advisory Board (ISSAB) of Utrecht Life Sciences (ULS), University of Utrecht, member of the External Review Panel of the Faculty of Veterinary Science, University of Utrecht, member of the Selection Committee for the Gottfried Wilhelm Leibniz Programme (DFG), member of the International Advisory Board of the Asthma UK Centre for Applied Research (AUKCAR), member of the International Advisory Board of The Lancet Respiratory Medicine, and member of the Scientific Advisory Board of the CHILD (Canadian Healthy Infant Longitudinal Development) study, McMaster University, Hamilton, Canada. T. Bahmer reports grants from Network University Medicine (NUM): National Pandemic Cohort Network (NAPKON); consulting fees and lecture honoraria from AstraZeneca, Novartis, GlaxoSmithKline, Roche and Chiesi; travel support from Chiesi and AstraZeneca; outside the submitted work. K.F. Rabe reports lecture honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi Pharmaceuticals, Novartis, Sanofi Regeneron, GlaxoSmithKline, Berlin-Chemie and Roche; advisory board membership at AstraZeneca and Sanofi Regeneron; leadership roles with the German Center for Lung Research (DZL), German Chest Society (DGP) and American Thoracic Society; outside the submitted work. A. Meyer-Bahlburg reports lecture honoraria from Pfizer; travel support from CSL Behring; advisory board membership with Pfizer; outside the submitted work. G. Hansen reports consulting fees from Sanofi GmbH; lecture honoraria from MedUpdate and AbbVie; outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2022.)

Background: The development of optimal strategies to treat impaired mobility related to ageing and chronic disease requires better ways to detect and measure it. Digital health technology, including body worn sensors, has the potential to directly and accurately capture real-world mobility. Mobilise-D consists of 34 partners from 13 countries who are working together to jointly develop and implement a digital mobility assessment solution to demonstrate that real-world digital mobility outcomes have the potential to provide a better, safer, and quicker way to assess, monitor, and predict the efficacy of new interventions on impaired mobility. The overarching objective of the study is to establish the clinical validity of digital outcomes in patient populations impacted by mobility challenges, and to support engagement with regulatory and health technology agencies towards acceptance of digital mobility assessment in regulatory and health technology assessment decisions., Methods/design: The Mobilise-D clinical validation study is a longitudinal observational cohort study that will recruit 2400 participants from four clinical cohorts. The populations of the Innovative Medicine Initiative-Joint Undertaking represent neurodegenerative conditions (Parkinson's Disease), respiratory disease (Chronic Obstructive Pulmonary Disease), neuro-inflammatory disorder (Multiple Sclerosis), fall-related injuries, osteoporosis, sarcopenia, and frailty (Proximal Femoral Fracture). In total, 17 clinical sites in ten countries will recruit participants who will be evaluated every six months over a period of two years. A wide range of core and cohort specific outcome measures will be collected, spanning patient-reported, observer-reported, and clinician-reported outcomes as well as performance-based outcomes (physical measures and cognitive/mental measures). Daily-living mobility and physical capacity will be assessed directly using a wearable device. These four clinical cohorts were chosen to obtain generalizable clinical findings, including diverse clinical, cultural, geographical, and age representation. The disease cohorts include a broad and heterogeneous range of subject characteristics with varying chronic care needs, and represent different trajectories of mobility disability., Discussion: The results of Mobilise-D will provide longitudinal data on the use of digital mobility outcomes to identify, stratify, and monitor disability. This will support the development of widespread, cost-effective access to optimal clinical mobility management through personalised healthcare. Further, Mobilise-D will provide evidence-based, direct measures which can be endorsed by regulatory agencies and health technology assessment bodies to quantify the impact of disease-modifying interventions on mobility., Trial Registration: ISRCTN12051706., Competing Interests: McRoberts is the manufacturer of the DynaPort. JE is employee of McRoberts. CB has done consultation work for Philipps Healthcare, Bosch Healthcare, Eli Lilly and Gait-up; he has received speaker honoraria from Amgen, Pfizer and Nutricia. LS is working as the Chief Technical Officer for Rölke Pharma. JMH reports having submitted a patent for assessment of mobility using wearable sensors in 400 Parkinson’s disease; the intellectual property rights 401 are held by the Tel Aviv Medical Center. GC has received consulting and speaking fees from Novartis, Sanofi Genzyme, Genzyme Corporation, Merck KGgA, Merck Serono SpA, Celgene Group, F. Hoffman-La Roche, Almirall SpA, Janssen. MFG is a full-time employee of Teva Pharmaceuticals. RRM is a full-time employee of The Novartis Institutes for BioMedical Research. All other authors declare that they have no competing interests.

Rationale: In adults, personalised asthma treatment targets patients with type 2 (T2)-high and eosinophilic asthma phenotypes. It is unclear whether such classification is achievable in children., Objectives: To define T2-high asthma with easily accessible biomarkers and compare resulting phenotypes across all ages., Methods: In the multicentre clinical All Age Asthma Cohort (ALLIANCE), 1125 participants (n=776 asthmatics, n=349 controls) were recruited and followed for 2 years (1 year in adults). Extensive clinical characterisation (questionnaires, blood differential count, allergy testing, lung function and sputum induction (in adults)) was performed at baseline and follow-ups. Interleukin (IL)-4, IL-5 and IL-13 were measured after stimulation of whole blood with lipopolysaccharide (LPS) or anti-CD3/CD28., Measurements and Main Results: Based on blood eosinophil counts and allergen-specific serum IgE antibodies, patients were categorised into four mutually exclusive phenotypes: "atopy-only", "eosinophils-only", "T2-high" (eosinophilia + atopy) and "T2-low" (neither eosinophilia nor atopy). The T2-high phenotype was found across all ages, even in very young children in whom it persisted to a large degree even after 2 years of follow-up. T2-high asthma in adults was associated with childhood onset, suggesting early origins of this asthma phenotype. In both children and adults, the T2-high phenotype was characterised by excessive production of specific IgE to allergens (p<0.0001) and, from school age onwards, by increased production of IL-5 after anti-CD3/CD28 stimulation of whole blood., Conclusions: Using easily accessible biomarkers, patients with T2-high asthma can be identified across all ages delineating a distinct phenotype. These patients may benefit from therapy with biologicals even at a younger age., Competing Interests: Conflict of interest: N. Maison, J. Omony, S. Illi, D. Thiele, A.M. Dittrich, C. Happle, M. Meyer, S. Foth and R. Grychtol have nothing to disclose. C. Skevaki reports grants and personal fees from Hycor Biomedical, Bencard Allergie, Thermo Fisher Scientific as well as grants from Mead Johnson Nutrition (MJN), Universities Giessen and Marburg Lung Centre, the German Centre for Lung Research (DZL), University Hospital Giessen and Marburg, Deutsche Forschungsgemeinschaft (DFG). T. Bahmer reports grants from the Federal Ministry for Education and Research (BMBF) for the German Center for Lung Research (DZL) and personal fees from AstraZeneca, GlaxoSmithKline, Novartis, Roche and Chiesi. M. Weckmann reports grants from Federal Ministry for Education and Research (BMBF), University of Luebeck and German Academic Exchange Service. B. Schaub reports grants from DFG, BMBF, the EU as well from GlaxoSmithKline, Sanofi and Novartis. H. Renz reports grants from German Center for Lung Disease (DZL) and Universities Giessen Marburg Lung Center. M.V. Kopp reports grants and personal fees from Allergopharma GmbH and Vertex GmbH; additional, personal fees from Sanofi GmbH, Infectopharm GmbH and Leti GmbH. E. Rietschel reports personal lecture payments for Nutricia Milupa GmbH and Novartis Pharma, and honoraria for participation in advisory boards for MICE-Mylan, Novartis Pharma GmbH and Boehringer Ingelheim GmbH. K.F. Rabe recieved personal payments or honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi Pharmaceuticals, Novartis, Sanofi & Regeneron, GlaxoSmithKline, Berlin Chemie and Roche; K.F. Rabe also discloses participation on data safety monitoring boards/advisory boards for AstraZeneca and Sanofi Regeneron, and leadership or fiduciary role in the German Center for Lung Research (DZL), German Chest Society (DGP) and American Thoracic Society (ATS). G. Hansen reports grants from German Federal Ministry of Education and Research (BMBF) and German Research Foundation (DFG) as well as personal fees from Sanofi GmbH, MedUpdate, and Abbvie. E. von Mutius reports grants from the German Center for Lung Research (DZL) as well as royalties/licenses held by Elsevier GmbH, Gerog Thieme Verlag, Springer Verlag GmbH, Elsevier Ltd; furthermore, consultation fees were received from the Chinese University of Hong Kong, European Commission, HiPP GmbH and AstraZeneca; E. von Mutius also received payments and/or support for meetings/travel from the Massachusetts Medical Society, Springer-Verlag GmbH, Elsevier Ltd, Böhringer Ingelheim International GmbH, European Respiratory Society (ERS), University Utrecht, Salzburg, Colorado and Imperial College London, Springer Medizin Verlag GmbH, Japanese Society of Pediatric Allergy and Clinical Immunology, Klinkum Rechts der Isar, Paul-Martini-Stiftung; further support for meetings/travel was granted by Verein zur Förderung der Pneumologie am Krankenhaus Groshansdorf, Pneumologie Development Mondial Congress & Events GmbH, American Academy of Allergy, Asthma & Immunology, Margaux Orange, Volkswagen Stiftung, Österreichische Gesellschaft für Allergologie & Immunologie, OM Pharma SA, Hanson Wade Ltd, iKOMM GmbH, DSI Dansk Bornestma Center, American Thoracic Society, HiPP GmbH; E. von Mutius has patent EP2361632, EP1411977, EP1637147 and EP 1964570 (licensed to Protectimmun), furthermore patent LU101064 is pending; E. von Mutius participates in the following data monitoring or advisory boards: EXPANSE, BEAMS External Scientific Advisory Board, Journal of Allergy and Clinical Immunology: in Practice, Children's Respiratory and Environmental Workgroup (CREW), International Scientific & Societal Advisory Board of Utrecht Life Sciences, External Review Panel of the Faculty of Veterinary Science (University of Utrecht), Gottfried Wilhelm Leibniz Programme, Asthma UK for Applied Research, Advisory Board of The Lancet Respiratory Medicine, CHILD (Canadian Healthy Infant Longitudinal Development Study)., (Copyright ©The authors 2022.)

Competing Interests: Mustafa Abdo and Frauke Pedersen report no relevant conflicts of interest. Frederik Trinkmann reports grants from Chiesi for the conduct of the study. He also received travel support from Actelion, Berlin Chemie, Boehringer Ingelheim, Chiesi, Novartis, Mundipharma and TEVA as well as speaker or consultation fees from AstraZeneca, Berlin Chemie, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, GlaxoSmithKline, Novartis and Roche, Sanofi Aventis, all outside the submitted work. Felix Herth and Klaus F. Rabe report no relevant conflict of interest. Anne-Marie Kirsten reports grants from Chiesi for the conduct of the study. Henrik Watz reports grants from Chiesi for the conduct of the study. Grants, personal fees and non-financial support from AZ, grants, personal fees and non-financial support from GSK, grants, personal fees and non-financial support from Chiesi, grants, personal fees and non-financial support from Novartis, grants, personal fees and non-financial support from Bayer, grants, personal fees and non-financial support from BI, outside the submitted work. The authors report no other conflicts of interest in this work.

Background: Little is known about the relationship between airway inflammatory phenotypes and some important asthma features such as small airway dysfunction (SAD)., Objective: To describe the longitudinal impact of airway inflammatory phenotypes on SAD and asthma outcomes., Methods: We measured eosinophil and neutrophil counts in induced sputum at baseline and 1 year later to stratify 197 adult patients with asthma into 4 inflammatory phenotypes. We conducted a comprehensive assessment of lung function using spirometry, body plethysmography, impulse oscillometry, and inert gas single and multiple breath washouts. We compared lung function, asthma severity, exacerbation frequency, and symptom control between the phenotypes. We studied the longitudinal impact of persistent sputum inflammatory phenotypes and the change of sputum cell counts on lung function., Results: Patients were stratified into eosinophilic (23%, n = 45), neutrophilic (33%, n = 62), mixed granulocytic (22%, n = 43), and paucigranulocytic (24%, n = 47) phenotypes. Patients with eosinophilic and mixed granulocytic asthma had higher rates of airflow obstruction and severe exacerbation as well as poorer symptom control than patients with paucigranulocytic asthma. All SAD measures were worse in patients with eosinophilic and mixed asthma than in those with paucigranulocytic asthma (all P values <.05). Eosinophilic asthma also indicated worse distal airflow obstruction, increased ventilation inhomogeneity (all P values <.05), and higher tendency for severe exacerbation (P = .07) than neutrophilic asthma. Longitudinally, persistent mixed granulocytic asthma was associated with the worst follow-up measures of SAD compared with persistent neutrophilic, persistent paucigranulocytic, or nonpersistent asthma phenotypes. In patients with stable forced expiratory volume in 1 second (FEV1), the mean increase in small airway resistance (R5-20) was greater in patients with persistent mixed granulocytic asthma (+103%) than in patients with persistent neutrophilic (+26%), P = .040, or persistent paucigranulocytic asthma (-41%), P = .028. Multivariate models adjusted for confounders and treatment with inhaled or oral corticosteroids or antieosinophilic biologics indicated that the change of sputum eosinophil rather than neutrophil counts is an independent predictor for the longitudinal change in FEV1, forced expiratory flow at 25% to 75% of forced vital capacity, specific effective airway resistance, residual lung volume, and lung clearance index., Conclusions: In asthma, airway eosinophilic inflammation is the main driver of lung function impairment and poor disease outcomes, which might also be aggravated by the coexistence of airway neutrophilia to confer a severe mixed granulocytic asthma phenotype. Persistent airway eosinophilia might be associated with dynamic SAD even in patients with stable FEV1., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale: 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., Competing Interests: Mustafa Abdo reports no conflict of interest. Frederik Trinkmann received travel support from Actelion, Berlin Chemie, Boehringer Ingelheim, Chiesi, Novartis, Mundipharma and TEVA as well as speaker or consultation fees from AstraZeneca, Berlin Chemie, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, GlaxoSmithKline, Novartis and Roche, Sanofi aventis, all outside the submitted work. Anne-Marie Kirsten, Heike biller and Frauke Pedersen report no conflict of interest. Erika von Mutius reports personal fees from Pharmaventures, personal fees from OM Pharma S. A., personal fees from Springer-Verlag GmbH, personal fees from Elsevier GmbH and Elsevier Ltd., personal fees from Peptinnovate Ltd., personal fees from Turun Yliopisto, personal fees from Tampereen Yliopisto, personal fees from Helsingin Yliopisto, personal fees from European Respiratory Society, personal fees from Deutsche Pharmazeutische Gesellschaft e. V., personal fees from Massachusetts Medical Society, personal fees from Chinese University of Hongkong, personal fees from European Commission, personal fees from Böhringer Ingelheim International GmbH, personal fees from Universiteit Utrecht, Faculteit Diergeneeskunde, personal fees from Universität Salzburg, personal fees from Georg Thieme Verlag, personal fees from Japanese Society of Pediatric Allergy and Clinical Immunology (JSPACI), outside the submitted work; In addition, Dr. von Mutius has a patent LU101064 - Barn dust extract for the prevention and treatment of diseases pending, a patent EP2361632: Specific environmental bacteria for the protection from and/or the treatment of allergic, chronic inflammatory and/or autoimmune disorders with royalties paid to ProtectImmun GmbH, a patent EP 1411977: Composition containing bacterial antigens used for the prophylaxis and the treatment of allergic diseases licensed to ProtectImmun GmbH, a patent number EP1637147: Stable dust extract for allergy protection licensed to ProtectImmun GmbH, and a patent EP 1964570: Pharmaceutical compound to protect against allergies and inflammatory diseases licensed to ProtectImmun GmbH. Matthias V. Kopp, Gesine Hansen, Benjamin Waschki, Klaus F. Rabe and Henrik Watz reports no relevant conflict of interest. Thomas Bahmer reports grants from BMBF: Unrestricted research grant for the German Center for Lung Research (DZL), during the conduct of the study; personal fees from AstraZeneca, personal fees from GlaxoSmithKline, personal fees from Novartis, and personal fees from Roche, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2021 Abdo et al.)

Background: Extracellular DNA (e-DNA) and neutrophil extracellular traps (NETs) are linked to asthmatics airway inflammation. However, data demonstrating the characterization of airway inflammation associated with excessive e-DNA production and its impact on asthma outcomes are limited., Objective: To characterize the airway inflammation associated with excessive e-DNA production and its association with asthma control, severe exacerbations and pulmonary function, particularly, air trapping and small airway dysfunction., Methods: We measured e-DNA concentrations in induced sputum from 134 asthma patients and 28 healthy controls. We studied the correlation of e-DNA concentrations with sputum neutrophils, eosinophils and macrophages and the fractional exhaled nitric oxide (FeNO). Lung function was evaluated using spirometry, body plethysmography, impulse oscillometry and inert gas multiple breath washout. We stratified patients with asthma into low-DNA and high-DNA to compare lung function impairments and asthma outcomes., Results: Patients with severe asthma had higher e-DNA concentration (54.2 ± 42.4 ng/µl) than patients with mild-moderate asthma (41.0 ± 44.1 ng/µl) or healthy controls (26.1 ± 16.5 ng/µl), (all p values < 0.05). E-DNA concentrations correlated directly with sputum neutrophils (R = 0.49, p < 0.0001) and negatively with sputum macrophages (R = - 0.36, p < 0.0001), but neither with sputum eosinophils (R = 0.10, p = 0.26), nor with FeNO (R = - 0.10, p = 0.22). We found that 29% of asthma patients (n = 39) had high e-DNA concentrations above the upper 95th percentile value in healthy controls (55.6 ng /μl). High-DNA was associated with broad lung function impairments including: airflow obstruction of the large (FEV 1 ) and small airways (FEF50%, FEF25-75), increased air trapping (RV, RV/TLC), increased small airway resistance (R5-20, sReff), decreased lung elasticity (X5Hz) and increased ventilation heterogeneity (LCI), (all P values < 0.05). We also found that high e-DNA was associated with nearly three-fold greater risk of severe exacerbations (OR 2·93 [95% CI 1.2-7.5]; p = 0·012), worse asthma control test (p = 0.03), worse asthma control questionnaire scores (p = 0.01) and higher doses of inhaled corticosteroids (p = 0.026)., Conclusion: Increased production of extracellular DNA in the airway characterizes a subset of neutrophilic asthma patients who have broad lung function impairments, poor symptom control and increased risk of severe exacerbations.

Rationale: 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 (R 2 = 0.61, p < 0.001). Persistent uncontrolled asthma patients (n=64) had lower physical activity at both baseline (6614 steps/118 min) and follow-up (6195/115). Despite having stable BMI, they also had significant muscle loss (-1.2%, -0.88 kg, p<0.01) and fat accumulation (+1%, +1.1 kg, p<0.01). By contrast, temporarily uncontrolled or controlled asthma patients had higher physical activity at baseline (8670/156) and follow -up (9058/153) with almost unchanged body composition., Conclusion: Persistent uncontrolled asthma is associated with sustained physical inactivity and adverse changes in body composition that might be overlooked by relying solely on BMI. Physical activity is an independent predictor of body composition and reliable long-term marker of symptom control., Competing Interests: Mustafa Abdo reports no conflict of interest. Frederik Trinkmann received travel support from Actelion, Berlin Chemie, Boehringer Ingelheim, Chiesi, Novartis, Mundipharma and TEVA as well as speaker or consultation fees from AstraZeneca, Berlin Chemie, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, GlaxoSmithKline, Novartis and Roche, Sanofi aventis, all outside the submitted work. Anne-Marie Kirsten, Heike biller, Frauke Pedersen and Christian Herzmann report no conflict of interest. Erika von Mutius reports personal fees from Pharmaventures, personal fees from OM Pharma S. A., personal fees from Springer-Verlag GmbH, personal fees from Elsevier GmbH and Elsevier Ltd., personal fees from Peptinnovate Ltd., personal fees from Turun Yliopisto, personal fees from Tampereen Yliopisto, personal fees from Helsingin Yliopisto, personal fees from European Respiratory Society, personal fees from Deutsche Pharmazeutische Gesellschaft e. V., personal fees from Massachusetts Medical Society, personal fees from Chinese University of Hongkong, personal fees from European Commission, personal fees from Böhringer Ingelheim International GmbH, personal fees from Universiteit Utrecht, Faculteit Diergeneeskunde, personal fees from Universität Salzburg, personal fees from Georg Thieme Verlag, personal fees from Japanese Society of Pediatric Allergy and Clinical Immunology (JSPACI), outside the submitted work; In addition, Dr. von Mutius has a patent LU101064 - Barn dust extract for the prevention and treatment of diseases pending, a patent EP2361632: Specific environmental bacteria for the protection from and/or the treatment of allergic, chronic inflammatory and/or autoimmune disorders with royalties paid to ProtectImmun GmbH, a patent EP 1411977: Composition containing bacterial antigens used for the prophylaxis and the treatment of allergic diseases licensed to ProtectImmun GmbH, a patent number EP1637147: Stable dust extract for allergy protection licensed to ProtectImmun GmbH, and a patent EP 1964570: Pharmaceutical compound to protect against allergies and inflammatory diseases licensed to ProtectImmun GmbH. Matthias V. Kopp, Gesine Hansen, Benjamin Waschki, Klaus F. Rabe and Henrik Watz reports no relevant conflict of interest. Thomas Bahmer reports grants from BMBF: Unrestricted research grant for the German Center for Lung Research (DZL), during the conduct of the study; personal fees from AstraZeneca, personal fees from GlaxoSmithKline, personal fees from Novartis, and personal fees from Roche, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2021 Abdo et al.)

Purpose: We recently introduced a sputum cell quality score to rate how cell morphology, cellular debris and squamous cell contamination influence inflammatory cell identification during microscopic evaluation. However, sputum cell quality is generally not considered for the interpretation of sputum fluid phase biomarkers. Therefore, we compared the soluble protein concentrations between sputum samples with different cell quality. The impact of cell quality was compared to other factors potentially affecting soluble biomarker concentrations., Methods: A comprehensive sputum dataset from 154 clinically stable COPD patients was used to analyse the differences and the variability of sputum supernatant concentrations for 23 proteins between low, medium, and high sputum cell quality samples. A model was developed and tested to compare the impact of different factors on sputum supernatant protein levels., Results: Mean percentages of sputum macrophages, neutrophils, eosinophils, monocytes and lymphocytes showed no significant differences between low, medium and high cell quality levels. The mean percentage of squamous cells were lower, while total cell count/mL sputum and cell viability were significantly higher in sputum samples with higher cell quality. The concentrations of Interleukin-6, Interleukin-8 and Tumor Necrosis Factor Receptor 2 were significantly increased in sputum samples of higher cell quality. The variability of most protein concentrations declined with increasing cell quality levels. Sixteen proteins showed significantly negative correlations with the percentage of squamous cells. For 14 proteins we observed a positive correlation with cell number/mL sputum. Multiple regression analysis shows that generally less than 30% of the protein variability can be explained by the included factors., Conclusion: Sputum cell quality has a significant impact on some soluble biomarker concentrations in sputum supernatant. Sputum samples with low sputum cell quality show a higher variability of fluid phase proteins in comparison to medium and high sputum cell quality levels., Competing Interests: Dr Frederik Trinkmann reports personal fees from Actelion, Berlin Chemie, Boehringer Ingelheim, Chiesi, Novartis, Mundipharma, TEVA, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Roche, and Sanofi Aventis, outside the submitted work. Prof. Dr. Klaus F Rabe reports personal fees from Boehringer Ingelheim, AstraZeneca, Novartis, Chiesi, Teva, Sanofi & Regeneron, Berlin Chemie, GSK, and Orion Menarini, outside the submitted work. Prof. Dr. Marina Saetta reports grants from Chiesi Farmaceutici, outside the submitted work. Prof. Dr. Jens M Hohlfeld reports personal fees from Boehringer Ingelheim for consultancy and HAL for lecture fee, grants to my institution from AstraZeneca AB, Novartis, Janssen Pharmaceutica NV, ALK, Boehringer Ingelheim, LETI, GlaxoSmithKline, GSK, Astellas Pharma, Allergopharma, and Sanofi-Aventis, personal fees for consultancy from Merck & Co, Inc., lecture fee from Novartis, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2021 Pedersen et al.)

The 3-min constant speed shuttle test (CSST) was used to examine the effect of tiotropium/olodaterol compared with tiotropium at reducing activity-related breathlessness in patients with chronic obstructive pulmonary disease (COPD).This was a randomised, double-blind, two-period crossover study including COPD patients with moderate to severe pulmonary impairment, lung hyperinflation at rest and a Mahler Baseline Dyspnoea Index <8. Patients received 6 weeks of tiotropium/olodaterol 5/5 µg and tiotropium 5 µg in a randomised order with a 3-week washout period. The speed for the 3-min CSST was determined for each patient such that an intensity of breathing discomfort ≥4 ("somewhat severe") on the modified Borg scale was reached at the end of a completed 3-min CSST.After 6 weeks, there was a decrease in the intensity of breathlessness (Borg dyspnoea score) at the end of the 3-min CSST from baseline with both tiotropium (mean -0.968, 95% CI -1.238- -0.698; n=100) and tiotropium/olodaterol (mean -1.325, 95% CI -1.594- -1.056; n=101). The decrease in breathlessness was statistically significantly greater with tiotropium/olodaterol versus tiotropium (treatment difference -0.357, 95% CI -0.661- -0.053; p=0.0217).Tiotropium/olodaterol reduced activity-related breathlessness more than tiotropium in dyspnoeic patients with moderate to severe COPD exhibiting lung hyperinflation., Competing Interests: Conflict of interest: F. Maltais reports research support from Boehringer Ingelheim, GSK, AstraZeneca, Grifols and Novartis, advisory board participation for Boehringer Ingelheim and GSK, and speaking engagements for Boehringer Ingelheim, Grifols and Novartis. Conflict of interest: J-L. Aumann has nothing to disclose. Conflict of interest: A-M. Kirsten reports institutional compensation for clinical trials from Boehringer Ingelheim, during the conduct of the study; has lectured for Boehringer Ingelheim, AstraZeneca and Berlin-Chemie, and reports institutional compensation for clinical trials from AstraZeneca, Boehringer Ingelheim, Roche, GSK, Novartis, Chiesi, Bayer Healthcare and Sanofi, outside the submitted work. Conflict of interest: É. Nadreau has nothing to disclose. Conflict of interest: H. Macesic is an employee of Boehringer Ingelheim. Conflict of interest: X. Jin is an employee of Boehringer Ingelheim. Conflict of interest: A. Hamilton is an employee of Boehringer Ingelheim. Conflict of interest: D.E. O'Donnell reports grants from AstraZeneca, Boehringer Ingelheim and GSK, during the conduct of the study; and personal fees for serving on speaker bureaus, consultation panels and advisory boards from Almirall, AstraZeneca, Boehringer Ingelheim, GSK, Novartis and Pfizer, outside the submitted work., (Copyright ©ERS 2019.)

Background and Purpose: Fixed-dose combinations of a long-acting beta agonist and an inhaled corticosteroid are more effective than the individual components in COPD. The primary study objective was to demonstrate that the combination indacaterol acetate/mometasone furoate (IND/MF [QMF149]) was non-inferior to the twice-daily combination salmeterol xinafoate/fluticasone propionate (Sal/Flu) in terms of trough FEV 1 at week 12 (day 85). Secondary objectives were to compare the efficacy of IND/MF (QMF149) vs Sal/Flu with respect to other lung function parameters, COPD exacerbations, symptoms and dyspnea, health status/health-related quality of life, and rescue medication use., Materials and Methods: This was a 12-week multicenter, randomized, double-blind, double-dummy, parallel-group, Phase II study in patients with moderate-to-very-severe COPD, who were randomized (1:1) to IND/MF (QMF149) (150/160 µg once daily; n=316) or Sal/Flu (50/500 µg twice daily; n=313)., Results: Over 90% of patients completed the study: 94.6% in the IND/MF (QMF149) group and 92.0% in the Sal/Flu group. The primary objective of non-inferiority of IND/MF (QMF149) to Sal/Flu for trough FEV 1 at week 12 (day 85) was met: the lower limit of the CI (95% CI: 27.7, 83.3 mL) was greater than -60 mL. The analysis for superiority of IND/MF (QMF149) to Sal/Flu demonstrated superiority of IND/MF (QMF149), with a difference of 56 mL ( P <0.001). In addition, IND/MF (QMF149) treatment significantly improved COPD exacerbation-related parameters during the 12-week period. Other significant improvements with IND/MF (QMF 149) vs Sal/Flu were noted for dyspnea at week 12 and other COPD symptoms and COPD rescue medication use over the 12 weeks. The safety and tolerability profiles of both the treatments were similar., Conclusion: IND/MF (QMF149) (150/160 µg once daily) offered superior lung function and symptom efficacy and a favorable safety profile compared with Sal/Flu (50/500 µg twice daily) in patients with moderate-to-very severe COPD., Competing Interests: Disclosure AMT, BH and AR are employees of Novartis Pharma AG. WC is an employee of Novartis Pharmaceuticals Corporation. KMB declares that no personal payments were received from any pharmaceutical entity in the past 5 years. KMB and JB are full-time employees of Insaf Respiratory Research Institute. AMK is an employee of the Pulmonary Research Institute at LungClinic Grosshansdorf. AMK received speaking honoraria, honoraria for participation in advisory board meetings, and travel support for attending congresses in respiratory medicine from Boehringer Ingelheim, AstraZeneca, and Novartis. RNVZS has received honoraria for academic work from Novartis, AZ, CIPLA, ASPEN, Pfizer, GSK, and MSD. The authors report no other conflicts of interest in this work.

Background: Change in the prevalence of asthma-like symptoms in populations of ageing adults is likely to be influenced by smoking, asthma treatment and atopy., Methods: The European Community Respiratory Health Survey collected information on prevalent asthma-like symptoms from representative samples of adults aged 20-44 years (29 centres in 13 European countries and Australia) at baseline and 10 and 20 years later (n=7844). Net changes in symptom prevalence were determined using generalised estimating equations (accounting for non-response through inverse probability weighting), followed by meta-analysis of centre level estimates., Findings: Over 20 years the prevalence of 'wheeze' and 'wheeze in the absence of a cold' decreased (-2.4%, 95% CI -3.5 to -1.3%; -1.5%, 95% CI -2.4 to -0.6%, respectively) but the prevalence of asthma attacks, use of asthma medication and hay fever/nasal allergies increased (0.6%, 95% CI 0.1 to 1.11; 3.6%, 95% CI 3.0 to 4.2; 2.7%, 95% CI 1.7 to 3.7). Changes were similar in the first 10 years compared with the second 10 years, except for hay fever/nasal allergies (increase seen in the first 10 years only). Decreases in these wheeze-related symptoms were largely seen in the group who gave up smoking, and were seen in those who reported hay fever/nasal allergies at baseline., Interpretation: European adults born between 1946 and 1970 have, over the last 20 years, experienced less wheeze, although they were more likely to report asthma attacks, use of asthma medication and hay fever. Decrease in wheeze is largely attributable to smoking cessation, rather than improved treatment of asthma. It may also be influenced by reductions in atopy with ageing., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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 <5,000; AUROC 0.90, 0.81, and 0.80, respectively; 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., (The Author(s). Published by S. Karger AG, Basel.)

Background: The TORRACTO ® study evaluated the effects of tiotropium/olodaterol versus placebo on endurance time during constant work-rate cycling and constant speed shuttle walking in patients with chronic obstructive pulmonary disease (COPD) after 12 weeks of treatment., Methods: The effects of once-daily tiotropium/olodaterol (2.5/5 and 5/5 μg) on endurance time during constant work-rate cycle ergometry (CWRCE) after 6 and 12 weeks of treatment were compared with placebo in patients with COPD in a randomized, double-blind, placebo-controlled, parallel-group clinical trial. Endurance time during the endurance shuttle walk test (ESWT) after 6 and 12 weeks of treatment was also evaluated in a subset of patients., Results: A total of 404 patients received treatment, with 165 participating in the ESWT substudy. A statistically significant improvement in endurance time during CWRCE was observed after 12 weeks (primary endpoint) with tiotropium/olodaterol 5/5 µg [14% ( p = 0.02)] but not with tiotropium/olodaterol 2.5/5 µg [9% ( p = 0.14)] versus placebo. In the ESWT substudy, a trend to improvement in endurance time during ESWT after 12 weeks (key secondary endpoint) was observed with tiotropium/olodaterol 5/5 µg [21% ( p = 0.055)] and tiotropium/olodaterol 2.5/5 µg [21% ( p = 0.056)] versus placebo., Conclusion: Tiotropium/olodaterol 5/5 µg improved endurance time during cycle ergometry versus placebo, with a strong tendency to also improve walking endurance time. [ ClinicalTrials.gov identifier: NCT01525615.].

Background: While current therapies reduce symptoms in chronic obstructive pulmonary disease (COPD) patients, substantial unmet need remains and novel treatments are highly desired. Phosphoinositide 3-kinase δ (PI3Kδ) is a lipid kinase specifically expressed in leucocytes and involved in their recruitment and activation. This study evaluated the safety, pharmacokinetics (PK) and dose-response characteristics of inhaled GSK2269557, a PI3Kδ inhibitor, in moderate-to-severe COPD patients with stable disease., Methods: In this randomised, double-blind, placebo controlled, parallel group study, patients received once daily inhaled treatment with GSK2269557 1000 μg or placebo for 14 days (Part A, primary aim safety, N = 28 patients). In part B of the study (primary aim pharmacodynamic dose-response, N = 36 patients), GSK2269557 100, 200, 500, 700, 1000, 2000 μg or placebo was given for 14 days. In both Part A and B, GSK2269557 was added to the usual maintenance therapy. Safety, PK assessments and induced sputum collection for cytokine analysis were conducted at baseline and after 7 and 14 days of treatment. Adverse events (AEs) were monitored throughout., Results: In Part A, mean age was 61.7 years (SD 6.7), 29% were females, and mean FEV 1 % predicted was 59.7% (SD 11.4) 2 . In Part B, mean age was 63.3 years (SD 6.3), 44% were females, and mean FEV 1 % predicted was 56.5% (SD 11.5) 2 . GSK2269557 was well tolerated in both parts of the study; the most commonly reported AEs were cough and headache, with cough being reported with a greater incidence in the GSK2269557 groups vs. placebo (Part A: 19% vs. 14% and Part B: range of 0-80% for different doses vs. 0% on placebo). No drug-related serious AEs or clinically significant changes in any other safety parameters were reported. GSK2269557 was rapidly absorbed into plasma following all doses with a maximum peak at approximately 2 h. Following repeat administration, accumulation in plasma was approximately 2-3 fold from Day 1 to Day 7. At Day 14, relative to placebo, sputum interleukin (IL)-8 and IL-6 levels were reduced on average by 32% and 29% respectively after inhalation of GSK2269557 1000 μg in Part A. In Part B, although inhibition of both IL-8 and IL-6 levels was observed, the levels were variable and there was insufficient evidence to support a monotonic dose-response., Conclusions: In this study, inhaled GSK2269557 had an acceptable safety profile for progression into larger studies in COPD patients. Moreover, inhalation of GSK2269557 resulted in suppression of sputum IL-8 and IL-6 levels, consistent with the known anti-inflammatory activity of a PI3Kδ inhibitor. Inhibition of inflammatory cytokines in the airway compartment may contribute to the potential therapeutic benefit of a PI3Kδ inhibitor in chronically inflamed COPD patients., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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, FEV 1 % 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 <57 min) spent significantly more time in light (p<0.01) and moderate-to-vigorous physical activity (p<0.01)., 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., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

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 < 0.01). After adjustment for confounders (sex, age, therapy), a standardized increase (i.e. one SD) in SPD, FVC%pred. or DLCO%pred. was associated with a more than halved risk of death (HR < 0.50; p < 0.01). Compared to baseline, SPD, FVC, and 6MWD annually declined in survivors by 973 SPD, 130 ml and 9 m, resulting in relative declines of 48.3% (p < 0.001), 13.3% (p < 0.001) and 7.8% (p = 0.055), respectively., Conclusion: While PA predicts mortality of IPF patients similar to established functional measures, longitudinal decline of PA seems to be disproportionally large. Our data suggest that the clinical impact of disease progression could be underestimated by established functional measures.

Background: A previous Phase IIIb study (NCT01462929) in patients with moderate to severe COPD demonstrated that 6 weeks of treatment with aclidinium led to improvements in 24-hour bronchodilation comparable to those with tiotropium, and improvement of symptoms versus placebo. This post hoc analysis was performed to assess the effect of treatment in the symptomatic patient group participating in the study., Methods: Symptomatic patients (defined as those with Evaluating Respiratory Symptoms [E-RS™] in COPD baseline score ≥10 units) received aclidinium bromide 400 μg twice daily (BID), tiotropium 18 μg once daily (QD), or placebo, for 6 weeks. Lung function, COPD respiratory symptoms, and incidence of adverse events (AEs) were assessed., Results: In all, 277 symptomatic patients were included in this post hoc analysis. Aclidinium and tiotropium treatment improved forced expiratory volume in 1 second (FEV 1 ) from baseline to week 6 at all time points over 24 hours versus placebo. In addition, improvements in FEV 1 from baseline during the nighttime period were observed for aclidinium versus tiotropium on day 1 (aclidinium 157 mL, tiotropium 67 mL; P <0.001) and week 6 (aclidinium 153 mL, tiotropium 90 mL; P <0.05). Aclidinium improved trough FEV 1 from baseline versus placebo and tiotropium at day 1 (aclidinium 136 mL, tiotropium 68 mL; P <0.05) and week 6 (aclidinium 137 mL, tiotropium 71 mL; P <0.05). Aclidinium also improved early-morning and nighttime symptom severity, limitation of early-morning activities, and E-RS Total and domain scores versus tiotropium (except E-RS Chest Symptoms) and placebo over 6 weeks. Tolerability showed similar incidence of AEs in each arm., Conclusion: In this post hoc analysis of symptomatic patients with moderate to severe COPD, aclidinium 400 μg BID provided additional improvements compared with tiotropium 18 μg QD in: 1) bronchodilation, particularly during the nighttime, 2) daily COPD symptoms (E-RS), 3) early-morning and nighttime symptoms, and 4) early-morning limitation of activity., Competing Interests: Disclosure JB has received consulting fees, speaker’s fees, and travel expenses from AstraZeneca and has also received compensation for organizing or participating in advisory boards for Cytos, Boehringer Ingelheim, Almirall, AstraZeneca, Novartis, and Revotar Biopharmaceuticals. The institution where JB is currently employed has received compensation for the design, performance, or participation in single or multicenter clinical trials in the past 5 years from several companies including Almirall, Altana, AstraZeneca, Boehringer Ingelheim, Cytos, GSK, Meda Pharmaceuticals, Merck Sharp & Dohme, Mundipharma, Novartis, Pfizer, and Revotar Biopharmaceuticals. RM has received consulting fees, speaker’s fees, and travel expenses from Boehringer Ingelheim and has also received compensation for participating in advisory boards for Boehringer Ingelheim, Almirall, AstraZeneca, and Novartis. Furthermore, RM has received compensation for participation in multicenter clinical trials in the past 5 years from several companies including Almirall, AstraZeneca, Boehringer Ingelheim, GSK, Merck Sharp & Dohme, Mundipharma, Novartis, Pearl, Roche, and Takeda. A-MK is a current employee of Pulmonary Research Institute at LungenClinic Grosshansdorf; the institution received compensation for the design of and/or participation in clinical trials from Almirall, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Pfizer, Infinity Pharmaceuticals, TEVA, Sterna Biologicals, Chiesi, Bayer, and Takeda. Furthermore, A-MK has received consulting fees, and speaker’s fees from AstraZeneca, Boehringer Ingelheim, and Roche. FC and EGG are employees of AstraZeneca PLC, Barcelona, Spain, and former employees of Almirall S.A., Barcelona, Spain.

Background: Long-acting bronchodilators, including anticholinergics glycopyrronium and tiotropium, are central to symptomatic management of chronic obstructive pulmonary disease (COPD). In patients with moderate to severe COPD, glycopyrronium has demonstrated comparable efficacy to open-label and single-blinded tiotropium, but with faster onset of bronchodilation. The FAST study assessed the efficacy of glycopyrronium compared with tiotropium in serial spirometry and body plethysmography assessments to further characterize the earlier onset of action associated with glycopyrronium., Methods: In this German multicentre, randomised, double-blinded, double-dummy, cross-over study, patients with moderate-to-severe COPD received single-dose of glycopyrronium 44 μg and tiotropium 18 μg via the Breezhaler ® and Handihaler ® devices, respectively. Primary objective was to demonstrate superiority of glycopyrronium over tiotropium in terms of improvement in forced expiratory volume in 1 s as assessed by the area under the curve from 0 to 2 h (FEV 1 AUC 0-2h ). Secondary endpoints were functional residual capacity (FRC), residual volume (RV), inspiratory capacity (IC), and specific airway resistance (sR aw ), all measured by body plethysmography., Results: Of the 152 patients randomised, 99.3% completed the study. After inhalation of the single dose, glycopyrronium demonstrated superiority over tiotropium in early bronchodilation as assessed by improvement in FEV 1 AUC 0-2h (least squares mean treatment difference = 37 mL; 95% CI: 16, 59 mL; p < 0.01) and FEV 1 at 15 min post-dose (least square mean treatment difference = 36 mL; 95% CI: 14, 58 mL; p < 0.01). Both treatments showed similar improvements in FRC pleth , RV, and IC. Glycopyrronium showed statistically significant improvement in sR aw compared with tiotropium over the first 90 min after dosing, with the difference of 0.184 kPa × s at 90 min post-dose (95% CI: 0.315,0.054 kPa × s; p < 0.01)., Conclusions: Glycopyrronium was superior to tiotropium in terms of early bronchodilation. Although both glycopyrronium and tiotropium showed similar improvements in static lung volume parameters, glycopyrronium reduced specific airway resistance faster than tiotropium, which could in part explain the earlier FEV 1 response seen with glycopyrronium., Trial Registration: ClinicalTrials.govNCT01922271., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: The coexistence of chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) is frequent and might be inter-related through inflammation-related processes reflected by specific markers. Here, we studied angiopoietin-like protein 4 (ANGPTL4), an upcoming cardiovascular marker, in stable COPD, and its relationship to cardiovascular function with respect to well-known CVD risk factors., Methods: In a prospective COPD cohort study, we investigated serum ANGPTL4 levels, vascular status (ankle-brachial index (ABI)) and cardiac function (N-terminal pro-B-type natriuretic peptide (NT-proBNP)) as well as airflow limitation, objectively measured physical activity, the metabolic syndrome, high-sensitive C reactive protein (hs-CRP) and other CVD risk factors at 2 time points. We initially studied 74 stable COPD patients and 18 controls. For internal validation, we additionally studied 160 COPD patients of a former visit., Results: ANGPTL4 was significantly elevated in COPD patients compared with controls (p=0.026). After correction for traditional CVD risk factors, including hs-CRP, higher levels of ANGPTL4 were independently associated with lower ABI (p=0.023) and higher NT-proBNP (p<0.001). These findings were confirmed in the internal validation analysis, which included echocardiographic assessments., Conclusions: Serum ANGPTL4 is independently associated with cardiovascular function in COPD and might qualify as a biomarker reflecting a pathogenic link between COPD and CVD., Competing Interests: Conflicts of Interest: None declared.

Background: This study was conducted to confirm the 24-hour bronchodilator efficacy and pharmacokinetic profile of once-daily tiotropium Respimat ® 5 μg add-on to inhaled corticosteroids (ICS) in adults with symptomatic asthma. It used a trial protocol designed to minimize the risk of pharmacokinetic sample contamination resulting from improper sampling procedure, sample handling, or device handling during priming and subsequent inhalation procedure., Methods: A Phase II, randomized, double-blind, two-way crossover study (NCT01696071) comparing two daily dosing regimens of tiotropium for 4 weeks, once-daily 5 μg (evening dosing) or twice-daily 2.5 μg (morning and evening dosing), as add-on to maintenance therapy with ICS (400-800 μg budesonide or equivalent) as controller medication. There was no washout between treatment periods., Results: An increase in the area under the curve of the 24-hour forced expiratory volume in 1 second profile from study baseline was observed following once-daily tiotropium 5 μg (217 mL) and twice-daily 2.5 μg (219 mL), with no difference between the two regimens (-2 mL [95% confidence interval: -38, 34]). In a subset of the study population, total tiotropium exposure, expressed as area under the plasma concentration versus time curve over 24 hours, was comparable between dosing regimens. Unexpected tiotropium plasma levels were observed in two patients, possibly because of contamination., Conclusions: The observed bronchodilator efficacy over 24 hours was similar with once-daily tiotropium 5 μg and twice-daily 2.5 μg as add-on to ICS therapy, supporting the suitability of once-daily dosing to provide sustained improvements in lung function in adults with symptomatic asthma., Competing Interests: Author Disclosure Statement K-MB is employed by insaf Respiratory Research Institute GmbH and has received compensation from various pharmaceutical companies for organizing or participating in advisory board and scientific meetings, and for the design, performance, or participation in single- or multicenter clinical trials. RD has received personal fees from Boehringer Ingelheim, Novartis, GlaxoSmithKline, and Almirall, outside the submitted work. DD has received consulting fees, lecturing fees, and payment from Boehringer Ingelheim for the development of educational activities. A-MK is employed by Pulmonary Research Institute at LungClinic Grosshansdorf, which has been compensated for the conduct of the study, and received compensation for scientific meetings or lectures from various pharmaceutical companies, including Boehringer Ingelheim. AS, RS, and PMZ are employees of, and PC is a former employee of, Boehringer Ingelheim.

The efficacy and safety of twice-daily aclidinium bromide/formoterol fumarate was compared with that of salmeterol/fluticasone propionate in patients with stable, moderate-to-severe chronic obstructive pulmonary disease (COPD).AFFIRM COPD (Aclidinium and Formoterol Findings in Respiratory Medicine COPD) was a 24-week, double-blind, double-dummy, active-controlled study. Patients were randomised (1:1) to aclidinium/formoterol 400/12 µg twice-daily via Genuair/Pressair or salmeterol/fluticasone 50/500 µg twice-daily via Accuhaler. The primary end-point was peak forced expiratory volume in 1 s (FEV 1 ) at week 24. Other end-points included Transition Dyspnoea Index (TDI) focal score at week 24, TDI and St George's Respiratory Questionnaire (SGRQ) responders, COPD Assessment Test and SGRQ scores, assessment of COPD symptoms and exacerbations, use of reliever medication, and device preference. Adverse events were monitored throughout.In total, 933 patients were eligible (mean age 63.4 years, 65.1% male). Aclidinium/formoterol was superior to salmeterol/fluticasone in peak FEV 1 and noninferior in TDI. Health status and reduction in exacerbation risk were similar in both groups. While both treatments were well tolerated, pneumonia occurred less frequently with aclidinium/formoterol than salmeterol/fluticasone.In stable COPD, aclidinium/formoterol significantly improved bronchodilation versus salmeterol/fluticasone, with equivalent benefits in symptom control and reduction in exacerbation risk. Both treatments were well tolerated and treatment-related adverse events were less common with aclidinium/formoterol., (Copyright ©ERS 2016.)

Background: Two replicate, double-blind, placebo-controlled, 6-week crossover studies assessed the effect of the once-daily long-acting β2-agonist olodaterol 5 μg and 10 μg on constant work-rate cycle endurance in patients with moderate to very severe chronic obstructive pulmonary disease., Methods: Patients received placebo, olodaterol 5 μg once daily (QD) and olodaterol 10 μg QD in a randomised order for 6 weeks each, with a 2-week washout period in between. The primary end point was change in endurance time during constant work-rate cycle ergometry to symptom limitation at 75 % maximal work capacity after 6 weeks of treatment (2 h post-dose), based on log10-transformed data. Key secondary end points were inspiratory capacity at isotime and intensity of breathing discomfort at isotime., Results: 151 and 157 patients were randomised and treated in Studies 1222.37 and 1222.38, respectively, with 147 and 154 being included in the full analysis sets. Mean endurance time at week 6 was increased compared to placebo by 14.0 % (Study 1222.37; p < 0.001) and 11.8 % (Study 1222.38; p < 0.01) with olodaterol 5 μg, and by 13.8 % (Study 1222.37; p < 0.001) and 10.5 % (Study 1222.38; p < 0.01) with olodaterol 10 μg. Inspiratory capacity at isotime increased with olodaterol 5 μg (Study 1222.37, 0.182 L, p < 0.0001; Study 1222.38, 0.084 L, p < 0.05) and 10 μg (Study 1222.37, 0.174 L; Study 1222.38, 0.166 L; both studies, p < 0.0001), and breathing discomfort was significantly reduced in Study 1222.37 (olodaterol 5 μg, 0.77 Borg units, p < 0.001; olodaterol 10 μg, 0.63 Borg units, p < 0.01) but not Study 1222.38., Conclusions: These studies provide further characterisation of the efficacy of olodaterol, showing that improvements in airflow (forced expiratory volume in 1 s) are associated with increases in inspiratory capacity and improvements in exercise endurance time., Trial Registrations: NCT01040130 (1222.37) and NCT01040793 (1222.38).

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., (© 2016 S. Karger AG, Basel.)

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: This study investigated the effects on 24-h lung function and lung volume of a once-daily fixed-dose combination (FDC) of the long-acting muscarinic antagonist tiotropium and the long-acting β2-agonist olodaterol in patients with chronic obstructive pulmonary disease., Methods: This was a randomised, double-blind, placebo-controlled, Phase III trial with an incomplete crossover design. Patients received four of the following six treatment options for 6 weeks each: placebo, olodaterol 5 μg, tiotropium 2.5 μg, tiotropium 5 μg, tiotropium + olodaterol FDC 2.5/5 μg and tiotropium + olodaterol FDC 5/5 μg, all delivered via the Respimat(®) inhaler. The primary end point was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 24 h (AUC0-24) response after 6 weeks of treatment; key secondary end points were FEV1 AUC from 0 to 12 h and AUC from 12 to 24 h, and further end points included lung-volume parameters measured using body plethysmography (subset of patients), measures of peak and trough FEV1, and incidence of adverse events., Results: A significant improvement in FEV1 AUC0-24 response was observed with tiotropium + olodaterol 5/5 μg and 2.5/5 μg versus placebo and monotherapies after 6 weeks of treatment; mean response with tiotropium + olodaterol 5/5 μg versus placebo was 0.280 L (p < 0.0001). Differences to monotherapies with tiotropium + olodaterol 5/5 μg were 0.115 L versus olodaterol 5 μg, 0.127 L versus tiotropium 2.5 μg and 0.110 L versus tiotropium 5 μg (p < 0.0001 for all comparisons). Secondary end points supported these data. No safety concerns were identified., Conclusions: Overall, this study demonstrated improvements in lung function over 24 h with an FDC of tiotropium + olodaterol over tiotropium or olodaterol alone, with no observed difference in tolerability. ClinicalTrials.gov number: NCT01559116., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The most prevalent phenotype of asthma is characterized by eosinophil-dominated inflammation that is driven by a type 2 helper T cell (Th2). Therapeutic targeting of GATA3, an important transcription factor of the Th2 pathway, may be beneficial. We evaluated the safety and efficacy of SB010, a novel DNA enzyme (DNAzyme) that is able to cleave and inactivate GATA3 messenger RNA (mRNA)., Methods: We conducted a randomized, double-blind, placebo-controlled, multicenter clinical trial of SB010 involving patients who had allergic asthma with sputum eosinophilia and who also had biphasic early and late asthmatic responses after laboratory-based allergen provocation. A total of 40 patients could be evaluated; 21 were assigned to receive 10 mg of SB010, and 19 were assigned to receive placebo, with each study drug administered by means of inhalation once daily for 28 days. An allergen challenge was performed before and after the 28-day period. The primary end point was the late asthmatic response as quantified by the change in the area under the curve (AUC) for forced expiratory volume in 1 second (FEV1)., Results: After 28 days, SB010 attenuated the mean late asthmatic response by 34%, as compared with the baseline response, according to the AUC for FEV1, whereas placebo was associated with a 1% increase in the AUC for FEV1 (P=0.02). The early asthmatic response with SB010 was attenuated by 11% as measured by the AUC for FEV1, whereas the early response with placebo was increased by 10% (P=0.03). Inhibition of the late asthmatic response by SB010 was associated with attenuation of allergen-induced sputum eosinophilia and with lower levels of tryptase in sputum and lower plasma levels of interleukin-5. Allergen-induced levels of fractional exhaled nitric oxide and airway hyperresponsiveness to methacholine were not affected by either SB010 or placebo., Conclusions: Treatment with SB010 significantly attenuated both late and early asthmatic responses after allergen provocation in patients with allergic asthma. Biomarker analysis showed an attenuation of Th2-regulated inflammatory responses. (Funded by Sterna Biologicals and the German Federal Ministry of Education and Research; ClinicalTrials.gov number, NCT01743768.).

Background: Chronic obstructive pulmonary disease (COPD) is characterized by neutrophil-dominated airway mucosal inflammation and elevated neutrophil counts in sputum and lung tissue. CXC chemokine receptor 2 (CXCR2) is predominantly expressed on neutrophils and mediates the migration of neutrophils to inflammatory sites. AZD5069 is a small molecule CXCR2 antagonist with the potential to inhibit neutrophil migration into the airways in patients with COPD., Methods: This 4-week, randomized, double-blind, placebo-controlled, parallel-group, multi-center, Phase IIa study evaluated the safety and tolerability of AZD5069 in patients with moderate-to-severe COPD (ClinicalTrials.gov identifier: NCT01233232). The pharmacokinetics and effect of AZD5069 on blood neutrophil counts were also assessed. Patients completed daily diary cards and attended weekly clinic visits for safety assessments., Results: 87 patients (mean FEV1 56% pred; mean age 64 years; 69% male) were randomized to receive placebo (n = 29), AZD5069 50 mg bid (n = 30) or AZD5069 80 mg bid (n = 28) for 4 weeks. AZD5069 was well tolerated with adverse events (AEs) reported in 9 (31%), 10 (33%) and 6 (21%) patients in the placebo, AZD5069 50 mg and AZD5069 80 mg groups, respectively. AEs were generally mild or moderate in severity. The incidence of infections, the most commonly reported AE, was similar across the three groups (17%, 17% and 11% of patients in the placebo, AZD5069 50 and 80 mg groups, respectively). Blood neutrophil counts decreased on average from baseline by 14-40% and 13-36% in the AZD5069 50 mg and 80 mg groups, respectively, and 4 patients discontinued from the study due to decreased neutrophil count, 3 in the AZD5069 50 mg group and 1 in the 80 mg group. The systemic exposure (AUC and Cmax) of AZD5069 increased less than in proportion to the dose and there was a large overlap in the individual exposures between the two dose levels., Conclusions: AZD5069 was well tolerated overall in those patients who completed study treatment, with no increase in infection rates in either dosage group compared with placebo. Further studies with AZD5069 appear to be warranted., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Rationale: Asthma is a chronic inflammatory airway disease of the whole bronchial tree. In this exploratory study we investigated the effects of beclomethasone/formoterol (becl/form) and budesonide/formoterol (bud/form) fixed combinations on lung function and airway inflammation in patients with mild to moderate asthma., Methods: 22 adult patients with asthma (mean FEV1 91.6% pred.) were recruited to this prospective phase IV, double-blind, double-dummy, two-way cross-over, single-centre, randomised study. After a 7 days run-in period with bud 200 μg bid patients were randomised to receive 4 weeks of becl/form (100/6 μg) bid in a pressurised metered dose inhaler or bud/form (160/4.5 μg) bid administered via dry powder inhaler. We measured spirometry, bodyplethysmography, impulse oscillometry, nitric oxide (NO) and its alveolar fraction (CAlv), and assessed sputum cellularity., Results: CAlv significantly decreased after 4 weeks of treatment in each treatment period. The adjusted geometric mean (log transformed data, end of treatment vs. baseline) was 0.942 ppb (95% CI: 0.778-1.141 ppb) for becl/form and 0.903 ppb (95% CI: 0.741-1.099 ppb) for bud/form. Impulse oscillometry revealed a significant decrease in mean Delta R5-R20 of -0.033 kPa * L(-1) * sec(-1) for becl/form (95% CI: -0.064 to -0.002) and of -0.048 033 kPa * L(-1) * sec(-1) for bud/form (95% CI: -0.079 to -0.017). Other parameters of lung function and NO showed numerically small and in most cases statistically non-significant changes., Conclusions: In patients with mild to moderate asthma pre-treated with inhaled corticosteroids, the use of ICS/LABA formulations led to improvements of CAlv and Delta R5-R20 indicating that these parameters might be helpful to further assess the effects of inhaled ICS/LABA combinations on lung function and airway inflammation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Prior to using a new multi-analyte platform for the detection of markers in sputum it is advisable to assess whether sputum processing, especially mucus homogenization by dithiothreitol (DTT), affects the analysis. In this study we tested a novel Human Inflammation Multi Analyte Profiling® Kit (v1.0 Luminex platform; xMAP®). Induced sputum samples of 20 patients with stable COPD (mean FEV1, 59.2% pred.) were processed in parallel using standard processing (with DTT) and a more time consuming sputum dispersion method with phosphate buffered saline (PBS) only. A panel of 47 markers was analyzed in these sputum supernatants by the xMAP®. Twenty-five of 47 analytes have been detected in COPD sputum. Interestingly, 7 markers have been detected in sputum processed with DTT only, or significantly higher levels were observed following DTT treatment (VDBP, α-2-Macroglobulin, haptoglobin, α-1-antitrypsin, VCAM-1, and fibrinogen). However, standard DTT-processing resulted in lower detectable concentrations of ferritin, TIMP-1, MCP-1, MIP-1β, ICAM-1, and complement C3. The correlation between processing methods for the different markers indicates that DTT processing does not introduce a bias by affecting individual sputum samples differently. In conclusion, our data demonstrates that the Luminex-based xMAP® panel can be used for multi-analyte profiling of COPD sputum using the routinely applied method of sputum processing with DTT. However, researchers need to be aware that the absolute concentration of selected inflammatory markers can be affected by DTT., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Extrapulmonary involvement by sarcoidosis is observed in about 30-40% of patients with sarcoidosis. Little is known about the frequency and clinical characteristics of sinonasal sarcoidosis., Methods: We retrospectively analyzed 12 cases of biopsy-proven sinonasal sarcoidosis. Patients were identified from a patient population of 1360 patients with sarcoidosis at the Outpatient Clinic for Sarcoidosis and Rare Lung Diseases at LungClinic Grosshansdorf, a tertiary care hospital for respiratory medicine., Results: The most frequent signs and symptoms were nasal polyps (4 cases), epistaxis (3 cases), nasal crusts (8 cases) and anosmia (5 cases). Pulmonary sarcoidosis of the patients was staged as stage I (n = 1) and stage II (n = 11) on chest radiographs. Spirometry was normal in 11 patients. 7 patients had a diffusion capacity of the lung for carbon monoxide of less than 90% of predicted. Other organs were affected in 8 patients. All patients received systemic corticosteroid treatment and most patients received topical steroids. 5 patients received steroid sparing agents. Repeated sinus surgery had to be performed in 4 patients., Conclusions: Sinonasal involvement is a rare disease manifestation of sarcoidosis with a frequency slightly lower than 1% in our patient population. The clinical course of sinonasal sarcoidosis can be complicated by relapse despite systemic immunosuppressive treatment and repeated sinus surgery.