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Background: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality. Here we present a large observational study on the association of COPD and exacerbations with mortality (AvoidEx Mortality)., Methods: A real-world, observational cohort study with longitudinal analyses of German healthcare claims data in patients ≥40 years of age with a COPD diagnosis from 2011 to 2018 (n = 250,723) was conducted. Patients entered the cohort (index date) upon the first COPD diagnosis. To assess the impact of COPD on all-cause death, a propensity score-matched control group of non-COPD patients was constructed. The number and severity of exacerbations during a 12-month pre-index period were used to form subgroups. For each exacerbation subgroup the exacerbations during 12 months prior to death were analysed., Results: COPD increases the all-cause mortality risk by almost 60% (HR 1.57 (95% CI 1.55-1.59)) in comparison to matched non-COPD controls, when controlling for other baseline covariates. The cumulative risk of death after 8 years was highest in patients with a history of more than one moderate or severe exacerbation. Among all deceased COPD patients, 17.2% had experienced a severe, and 34.8% a moderate exacerbation, within 3 months preceding death. Despite increasing exacerbation rates towards death, more than the half of patients were not receiving any recommended pharmacological COPD therapy in the year before death., Conclusion: Our study illustrates the impact of COPD on mortality risk and highlights the need for consequent COPD management comprising exacerbation assessment and treatment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Joanna Diesing reports financial support was provided by WIG2 GmbH Scientific Institute for Health Economics and Health Service Research. Patrick Timpel reports financial support was provided by WIG2 GmbH Scientific Institute for Health Economics and Health Service Research. Nils Kossack reports financial support was provided by WIG2 GmbH Scientific Institute for Health Economics and Health Service Research. Marc Pignot reports financial support was provided by ZEG - Berlin Center for Epidemiology and Health Research GmbH. Felix W Friedrich reports financial support for data analysis and medical writing provided by AstraZeneca. Melanie Abram reports financial support was provided by AstraZeneca. Marija Halbach reports financial support was provided by AstraZeneca. Claus F Vogelmeier reports financial support was provided by AstraZeneca. Claus F Vogelmeier reports a relationship with Boehringer Ingelheim that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with CSL Behring that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with Chiesi Pharmaceuticals GMBH that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with GlaxoSmithKline that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with Grifols Deutschland GmbH Head Office that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with A Menarini Pharma GmbH that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with Novartis that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with Nuvaira Inc that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with MedUpdate that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with Aerogen Ltd that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with Sanofi-Aventis Deutschland GmbH that includes: consulting or advisory and funding grants. Claus F Vogelmeier reports a relationship with Roche that includes: consulting or advisory and funding grants., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation, respiratory symptoms, inflammation of the airways, and systemic manifestations of the disease. Genetic susceptibility and environmental factors are important in the development of the disease, particularly exposure to cigarette smoke which is the most notable risk factor. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are the cause of cystic fibrosis (CF), which shares several pathophysiological pulmonary features with COPD, including airway obstruction, chronic airway inflammation and bacterial colonization; in addition, both diseases also present systemic defects leading to comorbidities such as pancreatic, gastrointestinal, and bone-related diseases. In patients with COPD, systemic CFTR dysfunction can be acquired by cigarette smoking, inflammation, and infection. This dysfunction is, on average, about half of that found in CF. Herein we review the literature focusing on acquired CFTR dysfunction and the potential role in the pathogenesis of comorbidities associated with COPD and chronic bronchitis., Competing Interests: Declaration of competing interest In the past 36 months, M. Miravitlles has received consulting fees from AstraZeneca, Atriva Therapeutics, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, CSL Behring, Inhibrx, Mereo Biopharma, Verona Pharma, Spin Therapeutics, ONO Pharma, Palobiofarma SL, Takeda, Novartis, Novo Nordisk, Sanofi and Grifols, speaker fees from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Chiesi, Cipla, Janssen, Kamada, Menarini, Takeda, Speciality Therapeutics, Zambon, CSL Behring, Grifols and Novartis, support for attending meetings/travel from Novartis, Boehringer Ingelheim and Menarini, research grants from Grifols, and has participated on a data safety monitoring board for Mereo. G.J. Criner has no declarations. M.A. Mall declares editorial support from Novartis Pharma AG since the initial planning of the work, and declares grants from German Ministry for Education and Research and the German Research Foundation, consulting fees from Abbvie, Antabio, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotech, Pieris Pharmaceuticals, Santhera, Sterna Biologicals and Vertex Paharmaceuticals, lecture fees from Arrowhead Pharmaceuticals, Boehringer Ingelheim and Vertex Pharmaceuticals, travel reimbursement from Boehringer Ingelheim and Vertex Pharmaceuticals, and personal fees for participation on advisory boards from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Santhera, Enterprise Therapeutics, Antabio, Kither Biotech, Pari and Abbvie; an elected unpaid member of the ECFS board. S.M. Rowe declares grant support for clinical trials conducted through university grants/contracts from Novartis, TranslateBio, Galapagos/Abbvie, Vertex Pharmaceuticals, research grant through University grants/contracts from Synedgen/Synspira, Eloxx, Ionis and AstraZeneca, consulting fees services on the design and conduct of clinical trials from Arcturus, Cystetic Medicines, Galapagos/Abbvie, Ionis, Novartis, Renovion, Synedgen/Synspira, Vertex Pharmaceuticals, support for travel to attend meetings from Vertex Pharmaceuticals; co-chair of the Next Generation Steering Committee with Vertex Pharmaceuticals, research product for investigator initiated research provided from Synedgen/Synspira and Renovion, consulting services on the design and conduct of clinical trials including stock options for Synedgen/Synspira and Renovion within the past 36 months; MTAs for investigator-initiated and externally funded research efforts from Ionis, Galapagos/Abbvie and Synedgen/Synspira, all in the past 36 months; and declares six patents. C.F. Vogelmeier declares institution grants from German Ministry of Education and Science (BMBF), AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, GlaxoSmithKline, Grifols and Novartis, consulting fees from Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Insmed, Menarini, Novartis and Nuvaira, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Insmed, Menarini and Novartis, in the past 36 months. B. Hederer was an employee of Novartis Pharma AG at the timing of writing this manuscript. M. Schoenberger is a full-time employee of Novartis Pharma AG and retains Novartis stock. P. Altman was an employee of Novartis Pharmaceutical Corporation at time of writing this manuscript., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Most patients with chronic obstructive pulmonary disease (COPD) have at least one additional, clinically relevant chronic disease. Those with the most severe airflow obstruction will die from respiratory failure, but most patients with COPD die from non-respiratory disorders, particularly cardiovascular diseases and cancer. As many chronic diseases have shared risk factors (eg, ageing, smoking, pollution, inactivity, and poverty), we argue that a shift from the current paradigm in which COPD is considered as a single disease with comorbidities, to one in which COPD is considered as part of a multimorbid state-with co-occurring diseases potentially sharing pathobiological mechanisms-is needed to advance disease prevention, diagnosis, and management. The term syndemics is used to describe the co-occurrence of diseases with shared mechanisms and risk factors, a novel concept that we propose helps to explain the clustering of certain morbidities in patients diagnosed with COPD. A syndemics approach to understanding COPD could have important clinical implications, in which the complex disease presentations in these patients are addressed through proactive diagnosis, assessment of severity, and integrated management of the COPD multimorbid state, with a patient-centred rather than a single-disease approach., Competing Interests: Declaration of interests LMF declares consulting fees from Chiesi Farmaceutici; payment or honoraria for lectures, presentations, manuscript writing, or educational events from Novartis, Chiesi Farmaceutici, Chiesi Italia, GSK, AstraZeneca, and Alfasigma; and participation on a data safety monitoring board (DSMB) for Novartis and Chiesi, all outside of the submitted work. LMF was formerly a member of the Global Initiative for Chronic Obstructive Lung Disease (GOLD). BRC declares consultancy fees from GSK, AstraZeneca, Menarini, Sanofi Aventis, and Axios; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from GSK, AstraZeneca, Menarini, Chiesi, and Regeneron; support for attending meetings or travel from GSK and Sanofi Aventis; and participation on a DSMB or advisory board for GSK, AstraZeneca, AZ Therapeutics, Sanofi Aventis, and Vertex, all outside of the submitted work. BRC is a member of GOLD. AA declares grants for research projects from GSK, AstraZeneca, and Menarini; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from GSK, AstraZeneca, Chiesi, Menarini, CIPLA, Zambon, and Sanofi Regeneron, all outside of the submitted work. AA holds the Chair of the Board of Directors of GOLD. GJC is member of GOLD. MTD declares grants paid to his institution from the US Department of Defense, American Lung Association, and National Institutes of Health; royalties from UpToDate; consulting fees from AstraZeneca, GSK, Novartis, Pulmonx, and Teva; and an unpaid role on the Board of Directors of the COPD Foundation, all outside of the submitted work. MD declares consulting fees from Sanofi Regeneron, outside of the submitted work. JKK declares grants paid to her institution from the American Thoracic Society Fellowship in Health Equity, Research Assistance for Primary Parents Award, COMMUNITY Center Investigator Development Core, Weill Cornell Medicine Dean's Diversity and Healthcare Disparity Research Award, and the National Institutes of Health (T32 HL134629); medical writing support from Novartis; medication samples delivered to her institution by Boehringer Ingelheim and GSK; and a donor gift to her institution from the Donna Redel Research Fund, all outside of the submitted work. LL declares fees to her institution from AstraZeneca for expert consultation, Chiesi for a lecture, and IPSA vzw, for lectures, outside of the submitted work. MM declares honoraria for lectures on COPD from AstraZeneca and GSK, outside of the submitted work. MMdO is a member of GOLD. SSS declares payments to his institution from Cipla for lectures, presentations, speakers bureaus, manuscript writing, or educational events. SSS has an unpaid leadership or fiduciary role with the Indian Chest Society, outside of the submitted work, and is a member of GOLD. DS declares grants to her institution from Curetis and AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from CSL Behring, Berlin-Chemie Menarini, Novartis, GSK, AstraZeneca, Vifor, Merck, Chiesi, Grifols, MSD, and Sanofi; and participation on a DSMB or advisory board for CSL Behring, Berlin-Chemie Menarini, Novartis, GSK, AstraZeneca, Vifor, Merck, Chiesi, Grifols, MSD, and Sanofi, all outside of the submitted work. LEGWV declares research grants to his institution from The Family Kamprad Foundation (20190024), the Swedish government and country council (ALF grant ALFGBG-824371), The Swedish Heart and Lung Foundation (20200150), and Svensk Lungmedicinsk Förening; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from GSK, AstraZeneca, Boehringer, Novartis, Chiesi, Resmed, and Pulmonx, all outside of the submitted work. CFV declares grants to his institution from the German Ministry of Education and Science, AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, GSK, Grifols, and Novartis; consulting fees from Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GSK, Insmed, Menarini, Novartis, and Nuvaira; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GSK, Insmed, Menarini, Novartis, Roche, and Sanofi, all outside the submitted work. CFV holds the Chair of the Science Committee of GOLD., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Alterations in body composition, including a low fat-free mass index (FFMI), are common in patients with COPD and occur regardless of body weight., Research Question: Is the impact of low FFMI on exercise capacity, health-related quality of life (HRQL), and systemic inflammation different among patients with COPD stratified in different BMI classifications?, Study Design and Methods: We analyzed baseline data of patients with COPD from the COPD and Systemic Consequences-Comorbidities Network (COSYCONET) cohort. Assessments included lung function, bioelectrical impedance analysis, 6-min walk distance (6MWD), HRQL, and inflammatory markers. Patients were stratified in underweight, normal weight (NW), preobese, and obese according to BMI and as presenting low, normal, or high FFMI using 25th and 75th percentiles of reference values. Linear mixed models were used to investigate the associations between fat-free mass (FFM) and fat mass with secondary outcomes in each BMI group., Results: Two thousand one hundred thirty-seven patients with COPD (Global Initiative for Chronic Obstructive Lung Disease stages 1-4; 61% men; mean ± SD age, 65 ± 8 years; mean ± SD FEV 1 , 52.5 ± 18.8% predicted) were included. The proportions of patients in underweight, NW, preobese, and obese groups were 12.3%, 31.3%, 39.6%, and 16.8%, respectively. The frequency of low FFMI decreased from lower to higher BMI groups (underweight, 81%; NW, 53%; preobese, 42%; and obese, 39%). FFM was associated with the 6MWD in the underweight group, even when adjusting for a broad set of covariates (P < .05). HRQL was not associated with FFM after adjustment for lung function or dyspnea (P > .32). Fat mass was associated with higher systemic inflammation in the NW and preobese groups (P < .05)., Interpretation: In patients with COPD with lower weight, such as underweight patients, higher FFMI is associated independently with better exercise capacity. In contrast, in preobese and obese patients with COPD, a higher FFMI was not consistently associated with better outcomes., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Competing Interests: AA gave presentations at symposia for, served on scientific advisory boards for, received research funds from, or did a combination thereof for AstraZeneca, Chiesi, GlaxoSmithKline, Menarini, MSD, Nuvaira, Orion, Sanofi, and Zambon. CFV gave presentations at symposia, served on scientific advisory boards, or did both for Aerogen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, GlaxoSmithKline, Grifols, Insmed, Menarini, Novartis, Nuvaira, and MedUpdate. DMGH received sponsorship to attend international meetings and honoraria for lecturing, attending advisory boards, and preparing educational materials from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, GlaxoSmithKline, Inogen, Menarini, MedUpdate, Novartis, Pfizer, Sandoz, and Sanofi.

Chronic obstructive pulmonary disease (COPD) is frequently associated with coronary artery disease (CAD). When considering computed tomography (CT) for COPD phenotyping, coronary vessel wall calcification would be a potential marker of cardiac disease. However, non-ECG gated scans as used in COPD monitoring do not comply with established quantitative approaches using ECG-triggered CT and the Agatston score. We studied the diagnostic potential of Agatston scores from non-triggered scans for cardiac disease. The study population was a sub-group of the COPD cohort COSYCONET that underwent CT scanning in addition to comprehensive clinical assessments, echocardiographic data and physician-based diagnoses of comorbidities. Agatston scores from non-contrast enhanced, non-triggered CT were used to identify a cut-off value for CAD via ROC analysis. 399 patients were included (152 female, mean age 66.0 ± 8.2 y). In terms of CAD, an Agatston score ≥1500 AU performed best (AUC 0.765; 95% CI: 0.700, 0.831) and was superior to the conventional cut-off value (400 AU). Using this value for defining groups, there were differences (p &lt; 0.05) in lung function, left atrial diameter and left ventricular end-systolic diameter as well as CT-determined central airway wall thickness pointing towards a bronchitis phenotype. In multivariate analysis, BMI, hyperlipidemia, arterial hypertension, GOLD D (p &lt; 0.05) but particularly Agatston score ≥1500 AU (Odds ratio 10.5; 95% CI: 4.8; 22.6)) were predictors of CAD. We conclude that in COPD patients, Agatston scores derived from non-ECG gated CT showed a much higher cut-off value (1500 AU) for actionable coronary artery disease than the score derived from ECG-triggered CT in cardiology patients., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests. Financial support provided to individuals is disclosed on the conflict of interest declaration provided from each single author., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Early MAXimisation of bronchodilation for improving COPD stability (EMAX) was a large, multicentre, multi-national, randomised, double-blind, 24-week trial. EMAX evaluated the efficacy and safety of dual bronchodilator therapy with umeclidinium bromide (UMEC)/vilanterol (VI) versus monotherapy with either UMEC or salmeterol (SAL) in symptomatic patients with chronic obstructive pulmonary disease (COPD) at low exacerbation risk who were not taking concomitant inhaled corticosteroid (ICS). EMAX generated evidence covering a wide range of patient-centred endpoints in COPD in addition to measures of lung function, clinical deterioration and safety. In addition, prospective and post hoc secondary analyses have generated clinically valuable information regarding the effects of baseline patient characteristics on treatment outcomes. Importantly, as concomitant ICS use was not permitted in this study, EMAX compared dual long-acting muscarinic antagonist (LAMA)/long-acting β 2 -agonist (LABA) therapy with LAMA or LABA monotherapy without potential confounding due to concurrent ICS use or withdrawal. EMAX demonstrated beneficial treatment effects of UMEC/VI over UMEC or SAL monotherapy as maintenance treatment across a range of different patient characteristics, with no forfeit in safety. Thus, the trial provided novel insights into the role of LAMA/LABA versus LABA and LAMA monotherapies as maintenance therapy for patients with symptomatic COPD at low risk of exacerbations. This article will explore the clinical implications of the main findings to date of the EMAX trial and consider the key learnings this trial offers for future trial design in COPD., Competing Interests: Disclosures FM has received research grants for participating in multicentre trials for AstraZeneca, Boehringer Ingelheim, GSK, Sanofi and Novartis, and has received unrestricted research grants and personal fees from Boehringer Ingelheim, Grifols and Novartis. CFV has received grants from AstraZeneca, Boehringer Ingelheim, GSK, Grifols and Novartis, and has received lecturing and personal fees from AstraZeneca, Boehringer Ingelheim, Berlin Chemie/Menarini, Chiesi, CSL Behring, GSK, Grifols, MedUpdate, Novartis, Aerogen and Nuvaira. EMK has served on advisory boards, speaker panels or received travel reimbursement for Amphastar, AstraZeneca, Boehringer Ingelheim, Connect Biopharma, GSK, Mylan, Novartis, Pearl, Sunovion, Teva and Theravance, and has received consulting fees from Cipla and GSK. LHB has received honoraria for giving a lecture or attending an advisory board for Airsonett, ALK-Abelló, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Meda, Novartis and Teva. PWJ, IHB, DAL and CC are GSK employees and hold shares and stocks in GSK. LT is a contingent worker on assignment at GSK. IPN was an employee of GSK at the time of the EMAX trial, holds stocks and shares in GSK, and was a contingent worker on assignment at AstraZeneca., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Chronic kidney disease (CKD) represents a global public health problem with high disease related morbidity and mortality. Since CKD etiology is heterogeneous, early recognition of patients at risk for progressive kidney injury is important. Here, we evaluated the tubular epithelial derived glycoprotein dickkopf-3 (DKK3) as a urinary marker for the identification of progressive kidney injury in a non-CKD cohort of patients with chronic obstructive pulmonary disease (COPD) and in an experimental model. In COSYCONET, a prospective multicenter trial comprising 2,314 patients with stable COPD (follow-up 37.1 months), baseline urinary DKK3, proteinuria and estimated glomerular filtration rate (eGFR) were tested for their association with the risk of declining eGFR and the COPD marker, forced expiratory volume in one second. Baseline urinary DKK3 but not proteinuria or eGFR identified patients with a significantly higher risk for over a 10% (odds ratio: 1.54, 95% confidence interval: 1.13-2.08) and over a 20% (2.59: 1.28-5.25) decline of eGFR during follow-up. In particular, DKK3 was associated with a significantly higher risk for declining eGFR in patients with eGFR over 90 ml/min/1.73m 2 and proteinuria under 30 mg/g. DKK3 was also associated with declining COPD marker (2.90: 1.70-4.68). The impact of DKK3 was further explored in wild-type and Dkk3-/- mice subjected to cigarette smoke-induced lung injury combined with a CKD model. In this model, genetic abrogation of DKK3 resulted in reduced pulmonary inflammation and preserved kidney function. Thus, our data highlight urinary DKK3 as a possible marker for early identification of patients with silent progressive CKD and for adverse outcomes in patients with COPD., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Lung function impairment in COPD is known to be related to reductions of left heart size, while short-term interventional trials with bronchodilators showed positive effects on cardiac parameters. We investigated whether COPD maintenance therapy has analogous long-term effects., Methods: Pooled data of GOLD grade 1-4 patients from visits 1 and 3 (1.5 y apart) of the COSYCONET cohort were used. Medication was categorized as use of ICS, LABA + ICS, LABA + LAMA and triple therapy (LABA + LAMA + ICS), contrasting "always" versus "never". Echocardiographic parameters comprised left ventricular end-diastolic and -systolic diameter (LVEDD, LVESD), ejection fraction (LVEF) and left atrial diameter (LA). Associations were identified by multiple regression analysis, as well as propensity score analysis., Results: Overall, 846 patients (mean age 64.5 y; 41% female) were included, 53% using ICS at both visits, 51% LABA + ICS, 56% LABA + LAMA, 40% LABA + LAMA + ICS (triple) therapy. Conversely, 30%, 32%, 28% and 42% had no ICS, LABA + ICS, LABA + LAMA or triple therapy, respectively, at both visits. Among echocardiographic measures, only LA showed statistically significant associations (increases) with medication, whereby significant effects were linked to ICS, LABA + ICS and LABA + LAMA (p < 0.05 each, "always" versus "never") and propensity score analyses underlined the role of LABA + LAMA., Conclusions: In this observational study, COPD maintenance therapy, especially LABA + LAMA, was linked to left atrial size, consistent with the results of short-term interventional trials. These findings suggest that maintenance medication for COPD does not only improve lung function and patient reported outcomes but may also have an impact on the cardiovascular system., Trial Registration: NCT01245933., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: Malaria is a serious health threat in tropical countries. The causative parasite of Malaria tropica, the severe form, is the protozoan Plasmodium falciparum. In humans, it infects red blood cells, compromising blood flow and tissue perfusion. This study aims to identify potential biomarkers and RNA networks in leukocyte transcriptomes from patients suffering from Malaria tropica., Materials and Methods: We identified differentially regulated mRNAs and microRNAs in peripheral blood leukocytes of healthy donors and Malaria patients. Genes whose expression changes were not attributable to changes in leukocyte composition were used for bioinformatics analysis and network construction. Using a previously published cohort of community-acquired pneumonia (CAP) patients, we established discriminating transcriptomic features versus Malaria. We aimed to establish differences between the patient groups by principal component (PCA) and receiving operator characteristic (ROC) analyses and in silico cell type deconvolution., Key Findings: We found 870 genes that were significantly differentially expressed between healthy donors and Malaria patients. E2F1, BIRC5 and CCNB1 were identified to be primarily responsible for PCA separation of these two groups. We searched for biological function and found that cell cycle processes were strongly activated. By in silico cell type deconvolution, we attribute this to an expansion of γδ T cells. Additional discrimination between CAP and Malaria yielded 445 differentially expressed genes, among which immune proteasome transcripts PSMB8, PSMB9 and PSMB10 were significantly induced in Malaria., Significance: We identified transcripts from patient leukocytes that differentiate between healthy, Malaria and CAP, and indicate a biological context with potential pathophysiological relevance., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Low-income and middle-income countries (LMICs) bear a disproportionately high burden of the global morbidity and mortality caused by chronic respiratory diseases (CRDs), including asthma, chronic obstructive pulmonary disease, bronchiectasis, and post-tuberculosis lung disease. CRDs are strongly associated with poverty, infectious diseases, and other non-communicable diseases (NCDs), and contribute to complex multi-morbidity, with major consequences for the lives and livelihoods of those affected. The relevance of CRDs to health and socioeconomic wellbeing is expected to increase in the decades ahead, as life expectancies rise and the competing risks of early childhood mortality and infectious diseases plateau. As such, the World Health Organization has identified the prevention and control of NCDs as an urgent development issue and essential to the achievement of the Sustainable Development Goals by 2030. In this Review, we focus on CRDs in LMICs. We discuss the early life origins of CRDs; challenges in their prevention, diagnosis, and management in LMICs; and pathways to solutions to achieve true universal health coverage., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Frequency of moderate and severe chronic obstructive pulmonary disease exacerbations is an important endpoint in clinical trials, but makes them large and lengthy when powered to evaluate it. We aimed to develop a composite endpoint (COPDCompEx) that could predict treatment effect on exacerbations, enabling the design of shorter early phase clinical trials requiring fewer patients., Methods: In this post hoc analysis, data from 20 randomized controlled trials were used to develop and test COPDCompEx. Diary events were tested against predefined threshold values for peak expiratory flow, reliever medication use, and symptoms. A COPDCompEx event was defined as first occurrence of a diary event, a moderate or severe exacerbation, or a study dropout. Ratios of event frequency, treatment effect and future trial sample size were compared between COPDCompEx and moderate and severe exacerbations., Findings: At 3 months, the proportion of patients experiencing COPDCompEx events increased over 3-fold versus exacerbations alone. All components contributed to COPDCompEx event rate. Treatment effects at 3 months were closely matched between COPDCompEx and exacerbations, and the large net gain in power substantially reduced the required sample size., Interpretation: COPDCompEx may be used to predict treatment effect on moderate and severe exacerbations of chronic obstructive pulmonary disease. This may enable the design of shorter Phase 2 clinical trials requiring fewer patients when compared with current exacerbation studies, with exacerbations as a key Phase 3 endpoint. This would, therefore, allow more efficient decision-making with reduced burden and risk to study participants., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Bronchiectasis (BE) might be frequently present in COPD but masked by COPD symptoms. We studied the relationship of clinical signs of bronchiectasis to the presence and extent of its radiological signs in patients of different COPD severity. Visit 4 data (GOLD grades 1-4) of the COSYCONET cohort was used. Chest CT scans were evaluated for bronchiectasis in 6 lobes using a 3-point scale (0: absence, 1: ≤50%, 2: >50% BE-involvement for each lobe). 1176 patients were included (61%male, age 67.3y), among them 38 (3.2%) with reported physicians' diagnosis of bronchiectasis and 76 (6.5%) with alpha1-antitrypsin deficiency (AA1D). CT scans were obtained in 429 patients. Within this group, any signs of bronchiectasis were found in 46.6% of patients, whereby ≤50% BE occurred in 18.6% in ≤2 lobes, in 10.0% in 3-4 lobes, in 15.9% in 5-6 lobes; >50% bronchiectasis in at least 1 lobe was observed in 2.1%. Scores ≥4 correlated with an elevated ratio FRC/RV. The clinical diagnosis of bronchiectasis correlated with phlegm and cough and with radiological scores of at least 3, optimally ≥5. In COPD patients, clinical diagnosis and radiological signs of BE showed only weak correlations. Correlations became significant with increasing BE-severity implying radiological alterations in several lobes. This indicates the importance of reporting both presence and extent of bronchiectasis on CT. Further research is warranted to refine the criteria for CT scoring of bronchiectasis and to determine the relevance of radiologically but not clinically detectible bronchiectasis and their possible implications for therapy in COPD patients., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Guidelines for chronic obstructive pulmonary disease (COPD) recommend supplementing pharmacotherapy with non-pharmacological interventions. Little is known about the use of such interventions by patients. We analyzed the utilization of a number of non-pharmacological interventions and identified potential determinants of use., Methods: Based on self-reports, use of interventions (smoking cessation, influenza vaccination, physiotherapy, sports program, patient education, pulmonary rehabilitation) and recommendation to use were assessed in 1410 patients with COPD. The utilization was analyzed according to sex and severity of disease. Potential determinants of utilization included demographic variables and disease characteristics and were analyzed using logistic regression models., Results: Influenza vaccination in the previous autumn/winter was reported by 73% of patients. About 19% were currently participating in a reimbursed sports program, 10% received physiotherapy, 38% were ever enrolled in an educational program, and 34% had ever participated in an outpatient or inpatient pulmonary rehabilitation program. Out of 553 current or former smokers, 24% had participated in a smoking cessation program. While reports of having received a recommendation to use mainly did not differ according to sex, women showed significantly (p < 0.05) higher utilization rates than men for all interventions except influenza vaccination. Smoking was a predictor for not having received a recommendation for utilization and also significantly associated with a reduced odds of utilization. We found a correlation between recommendation to use and utilization., Conclusions: Utilization of non-pharmacological interventions was lower in men and smokers. A recommendation or offer to use by the physician could help to increase uptake., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is currently a leading cause of death worldwide, and its burden is expected to rise in the coming years. Common COPD symptoms include dyspnea, cough and/or sputum production. Some patients may experience acute worsening of symptoms (known as an exacerbation), and therefore require additional therapy. Exacerbations are mainly triggered by respiratory infections and environmental factors. Healthcare professionals face many challenges in COPD management, including the heterogeneity of the disease and under-reporting of symptoms. The authors review these challenges and provide recommendations for the best methods to assess COPD. The goals of COPD treatment include recognising the impact that both symptoms and exacerbations have on patients' lives when considering optimal patient-focused management. The review discusses the need for COPD management strategies to include both pharmacologic and non-pharmacologic approaches and provides recommendations for monitoring treatment outcomes and adjusting management strategies accordingly. Novel treatment strategies including precision medicine and point-of-care testing are also discussed., Competing Interests: Declaration of competing interest CFV reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Mundipharma and Novartis, personal fees from Berlin Chemie/Menarini, CSL Behring, Nuvaira and Teva, and grants from the German Federal Ministry of Education and Research (BMBF) Competence Network Asthma and COPD (ASCONET), outside the submitted work. MR-R reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Menarini, Mundipharma, Novartis, Pfizer, Teva and Bial, and grants and personal fees from GlaxoSmithKline, outside the submitted work. DS reports personal fees from Apellis, Cipla, Genentech, Peptinnovate and Skyepharma, and grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Glenmark, Merck, Mundipharma, Novartis, Pfizer, Pulmatrix, Teva, Theravance and Verona, outside the submitted work. MKH reports personal fees from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim and Mylan, and other from Novartis and Sunovion, outside the submitted work. RR-R has nothing to disclose. GTF reports grants, personal fees and non-financial support from Boehringer Ingelheim, during the conduct of the study; grants, personal fees and non-financial support from Boehringer Ingelheim, Novartis, AstraZeneca, Pearl Therapeutics and Sunovion; personal fees from Verona, Mylan, Innoviva, GlaxoSmithKline and Circassia; and grants and personal fees from Theravance, outside the submitted work., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The COPD Assessment Test (CAT) is in widespread use for the evaluation of patients with chronic obstructive pulmonary disease (COPD). We assessed whether the CAT items carry additional information beyond the sum score regarding COPD characteristics including emphysema. Patients of GOLD grades 1 to 4 from the COPD cohort COSYCONET (German COPD and Systemic Consequences - Comorbidities Network) with complete CAT data were included (n = 2270), of whom 493 had chest CT evaluated for the presence of emphysema. Comorbidities and lung function were assessed following standardised procedures. Cross-sectional data analysis was based on multiple regression analysis of the single CAT items against a panel of comorbidities, lung function, or CT characteristics (qualitative score, 15th percentile of mean lung density), with age, BMI and gender as covariates. This was supported by exploratory factor analysis. Regarding the relationship to comorbidities and emphysema, there were marked differences between CAT items, especially items 1 and 2 versus 3 to 8. This grouping was basically confirmed by factor analysis. Items 4 and 5, and to a lower degree 1, 2 and 6, appeared to be informative regarding the presence of emphysema, whereas the total score was not or less informative. Regarding comorbidities, similar findings as for the total CAT score were obtained for the modified Medical Research Council scale (mMRC) which was also informative regarding emphysema. Our findings suggest that the usefulness of the CAT can be increased if evaluated on the basis of single items which may be indicating the presence of comorbidities and emphysema., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Cardiovascular comorbidities are common in chronic obstructive pulmonary disease (COPD). We examined the association between airflow limitation, hyperinflation and the left ventricle (LV)., Methods: Patients from the COPD cohort COSYCONET underwent evaluations including forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), effective airway resistance (R eff ), intrathoracic gas volume (ITGV), and echocardiographic LV end-diastolic volume (LVEDV), stroke volume (LVSV), end-systolic volume (LVESV), and end-diastolic and end-systolic LV wall stress. Data from Visit 1 (baseline) and Visit 3 (18 months later) were used. In addition to comparisons of both visits, multivariate regression analysis was conducted, followed by structural equation modelling (SEM) with latent variables "Lung" and "Left heart"., Results: A total of 641 participants were included in this analysis. From Visit 1 to Visit 3, there were significant declines in FEV 1 and FEV 1 /FVC, and increases in R eff , ITGV and LV end-diastolic wall stress, and a borderline significant decrease in LV mass. There were significant correlations of: FEV 1 % predicted with LVEDV and LVSV; R eff with LVSV; and ITGV with LV mass and LV end-diastolic wall stress. The SEM fitted the data of both visits well (comparative fit index: 0.978, 0.962), with strong correlation between "Lung" and "Left heart"., Conclusions: We demonstrated a relationship between lung function impairment and LV wall stress in patients with COPD. This supports the hypothesis that LV impairment in COPD could be initiated or promoted, at least partly, by mechanical factors exerted by the lung disorder., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: Chronic obstructive pulmonary disease (COPD) and cardiovascular diseases are thought to be linked through various factors. We aimed to assess the relationship between airway obstruction, lung hyperinflation and diastolic filling in COPD., Methods: The study population was a subset of the COPD cohort COSYCONET. Echocardiographic parameters included the left atrial diameter (LA), early (E) and late (A) transmitral flow, mitral annulus velocity (e'), E wave deceleration time (E[dt]), and isovolumic relaxation time (IVRT). We quantified the effect of various predictors including forced expiratory volume in 1 s (FEV 1 ) and intrathoracic gas volume (ITGV) on the echocardiographic parameters by multiple linear regression and integrated the relationships into a path analysis model., Results: A total of 615 COPD patients were included (mean FEV 1 52.6% predicted). In addition to influences of age, BMI and blood pressure, ITGV was positively related to e'-septal and negatively to LA, FEV 1 positively to E(dt) (p < 0.05 each). The effect of predictors was most pronounced for LA, e'-septal and E(dt), and less for E/A, IVRT and E/e'. Path analysis was used to take into account the additional relationships between the echocardiographic parameters themselves, demonstrating that their associations with the predictors were maintained and robust., Conclusions: Airway obstruction and lung hyperinflation were significantly associated with cardiac diastolic filling in patients with COPD, suggesting a decreased preload rather than an inherently impaired myocardial relaxation itself. This suggests that a reduction in obstruction and hyperinflation could help to improve cardiac filling., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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

Chronic obstructive pulmonary disease (COPD) is commonly associated with multiple comorbidities. Our objective was to assess the prevalence of comorbidities in patients with COPD and to relate their prevalence to the severity of the disease by using a large German health care database. Based on the retrospective analysis of a two-year (2013-2014) database from the German Statutory Health Insurance system, we obtained a representative sample of 4,075,493 german insurants. This sample included 146,141 patients with COPD (age: ≥35 years). To these patients, we matched 1:1 by age and gender randomly selected non-COPD controls. We assessed the comorbidities and the use of cardiovascular drugs, and examined COPD subgroups according to lung function (ICD-10-coded FEV1) and the treatment with long-acting inhaled bronchodilators. Compared to non-COPD, patients with COPD had a higher prevalence of hypertension, congestive heart failure, diabetes, gastroesophageal reflux disease, chronic kidney disease, osteoporosis, psychiatric disease and lung cancer, and used more cardiovascular-related drugs. However, the prevalence of comorbidities did not correlate to the severity of airflow limitation. The results of this sizeable nationwide survey support the concept that individuals with COPD need careful evaluation regarding comorbidities. This can already be of relevance in patients with mild to moderate airflow limitation., Take Home Message: Comorbidities in COPD have a complex relationship with disease severity, requiring a comprehensive therapy approach., (Copyright © 2017. Published by Elsevier Ltd.)

Introduction: The 2017 update to the Global Initiative for Obstructive Lung Disease (GOLD) strategy document includes recommendations for treatment intensification or step-down in chronic obstructive pulmonary disease (COPD), although recognises that limited supporting information is available. DACCORD is an ongoing observational, non-interventional study, recruiting patients following COPD maintenance treatment change or initiation, a subset of whom were receiving a long-acting β 2 -agonist (LABA) plus a long-acting muscarinic antagonist (LAMA) fixed-dose combination (FDC) on entry. Since there were no requirements in terms of prior medication (and no washout before commencing LABA/LAMA FDC), this provides an opportunity to generate 'real world' data to test the GOLD 2017 recommendations., Methods: To reduce heterogeneity, the current analyses include patients receiving indacaterol/glycopyrronium at baseline, and who, prior to the study, were receiving no COPD maintenance medication ('none'), LABA or LAMA monotherapy ('mono'), LABA plus inhaled corticosteroid (ICS; 'LABA/ICS'), or triple therapy ('triple'). At the baseline visit, data collected included: demographic and disease characteristics; COPD Assessment Test (CAT); and exacerbations in the 6 months prior to entry. At 3, 6, 9 and 12 months data on exacerbations were collected, with CAT recorded at 3 and 12 months., Results: A total of 2724 patients were included in the baseline analyses: 795, 954, 598 and 377 in the 'none', 'mono', 'LABA/ICS' and 'triple' subgroups, respectively. There were no clinically relevant differences in baseline demographics between the four groups. In terms of disease characteristics, the 'triple' group had the highest proportion of patients with a disease duration of more than 1 year since diagnosis and with severe/very severe airflow limitation, but a similar percentage of non-exacerbators compared to the 'none' group. Over the 1-year follow-up, the majority of patients in all four subgroups did not exacerbate (exacerbation rates 0.16, 0.19, 0.21, and 0.26 in the 'none', 'mono', 'LABA/ICS' and 'triple' groups, respectively). At 12 months, 61.4%, 65.0%, 71.0% and 52.4% of patients had a clinically relevant improvement in CAT score., Conclusions: Overall, the results support the GOLD recommendations in suggesting that a switch from a mono-bronchodilator or LABA plus ICS to LABA/LAMA FDC is a valid treatment option for patients with COPD. The results also validate the use of a LABA/LAMA FDC as initial maintenance treatment for COPD, and provide first 'real world' evidence to support the newly added 'step down' recommendation (from triple to LABA/LAMA FDC)., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Long-term safety, particularly cardiovascular safety, is of special interest in maintenance treatment of chronic obstructive pulmonary disease (COPD) with long-acting β 2 -agonists and long-acting muscarinic antagonists, given potential cardiovascular effects., Methods: Two 52-week Phase III trials (TONADO ® ) investigated tiotropium/olodaterol (5/5 and 2.5/5 μg) versus tiotropium 2.5, 5 μg and olodaterol 5 μg. In a pre-specified safety analysis, investigator-reported treatment-emergent adverse events (AEs), electrocardiogram and laboratory data were pooled. All serious AE (SAE) reports were reviewed by an independent Adjudication Committee, which assessed whether deaths, hospitalisations or intubations were respiratory, cardiovascular, cerebrovascular or other disease related. Subgroup analyses investigated cardiovascular safety including major cardiac events in patients with cardiovascular co-morbidities., Results: This analysis comprised 3100 patients with moderate to very severe COPD, treated for ≤1 year, including 784 patients with cardiovascular co-morbidities. AEs were balanced across treatments in the total population as well as in patient subgroups with pre-existing cardiovascular co-morbidities. The incidence and nature of events were consistent with the disease under study and a 1-year trial duration. 494/3100 patients contributed to an adjudicated analysis of SAEs: 260 had respiratory-related, 53 had cardiovascular-related and 16 had cerebrovascular-related SAEs. Incidences of these SAEs were comparable between treatments. There was no evidence of any increased risk for the combination compared to the monotherapy groups., Conclusions: These data provide confidence for clinicians that tiotropium/olodaterol 5/5 μg can be safely administered once-daily to patients with moderate to very severe COPD long-term, including those with significant cardiovascular co-morbidity., Trial Registry: ClinicalTrials.gov, Nos.: NCT01431274, NCT01431287., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In several trials, beneficial prognostic effects of highly unsaturated fatty acids (HUFAs) in heart failure were shown. Because other studies showed no incremental benefit in nearly preserved cardiac function, the question arises, whether the degree of cardiac dysfunction is involved. It is hypothesized that increased left ventricular (LV) wall stress affects the endogenous hepatic HUFA metabolism, which in turn exhibits adverse cardiac consequences., Methods: Cardiac magnetic resonance imaging was performed in 30 patients with suspected cardiomyopathy. The serum fatty acid profile was assessed using gas chromatography/mass spectrometry., Results: Docosahexaenoic acid (DHA; P = 0.002) and eicosapentaenoic acid (EPA; by trend) levels were decreased in patients with reduced LV ejection fraction (≤ 50%) or LV dilatation (≥ 90 mL/m(2)). Decreased DHA (P = 0.003) and EPA (P = 0.022) levels were associated with a reduced LV ejection fraction. Decreased DHA level was correlated with increased end-diastolic (P = 0.047) and end-systolic LV wall stress (P = 0.001). Pseudocholinesterase activity was inversely correlated with end-diastolic (P = 0.020) and end-systolic LV wall stress (P = 0.025)., Conclusions: DHA level was significantly reduced in heart failure. Similar, but less pronounced effects were found for EPA and arachidonic acid by trend. Increased LV wall stress was correlated with a reduced DHA level. Increased LV wall stress exhibits various adverse consequences (eg, increased oxygen consumption, favouring of arrhythmias, and an unfavourable remodelling). The increase of wall stress was paralleled by reduced HUFA level. Increased LV wall stress was correlated with reduced pseudocholinesterase, which is suggestive of hepatic congestion (ie, a cardiohepatic syndrome, involved in the altered fatty acid profile in heart failure) and has major consequences regarding the dose-efficacy of HUFA treatment., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Introduction: Heart failure can be caused by systolic or diastolic dysfunction. Diagnosing diastolic dysfunction remains challenging, although several criteria have been identified. Ventricular wall stress is crucially involved. It is hypothesized whether increased end-diastolic and end-systolic ventricular wall stress as assessed by the wall stress index is associated with cardiac dysfunction and thus provide novel diagnostic criteria., Methods: 1050 consecutive patients with suspected non-ischemic heart failure covering a broad spectrum from normal to severely impaired cardiac function were observed. Cardiac magnetic resonance imaging was performed to assess left ventricular (LV) volumes, myocardial mass, peak ejection (PER) and filling rate (PFR)., Results: A reduced PFR was found in 348 patients (33.1%), which resulted from 275 of 422 patients (65.2%) with reduced and from 73 of 628 patients (11.6%) with preserved LVEF (p<0.0001). Increased LV volume and mass was correlated with reduced PER and PFR (p<0.0001). Increased end-diastolic wall stress was the strongest predictor of a reduced PER (OR 4.5 [2.6 to 7.8], p<0.0001) and increased end-systolic wall stress predicted a reduced PFR (OR 1.2 [1.1 to 1.3], p<0.0001). Increased end-systolic wall stress was correlated with increased pulmonary pressure (p<0.0001). Normal end-systolic wall stress<18 kPa had a favorable predictive value for the absence of an impaired filling and increased pulmonary capillary pressure., Conclusion: Increased end-diastolic wall stress precedes a reduced ventricular ejection rate and increased end-systolic wall stress determines an impaired diastolic filling. It is thus suggested to add assessment of ventricular wall stress as diagnostic criterion of heart failure., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: COPD and heart failure occur with a considerable coincidence. Beside well-known mechanisms of increased right heart load in COPD, dedicated changes of the left ventricle (LV) are ill-defined and the question remains, whether specific interactions exist beyond common shared risk factors., Methods: LV wall stress was calculated based on cardiac magnetic resonance imaging in 28 patients with COPD (GOLD I to III) and coexistent heart failure (LVEF 42 ± 19%) due to non-ischaemic and ischaemic cardiomyopathy., Results: LV enddiastolic (p = 0.048) and endsystolic wall stress (p = 0.034) increased from GOLD stage I to III. Reduced FEV1 was correlated with increased enddiastolic (p = 0.0210) and endsystolic LV volume (p = 0.0413) and with increased enddiastolic (p = 0.0161) and endsystolic LV wall stress (p = 0.0315), respectively. Increased wall stress was associated with a decreased FEV1/FVC ratio., Conclusions: The severity of airflow limitation in COPD was correlated with increased LV wall stress. It is suggested that respiration in pulmonary obstruction is associated with an increased negative intrathoracic pressure when compared with normal lung function, which is transmitted to the heart and increases the transmural pressure gradient and thereby distending forces on the heart. Increased ventricular wall stress is known to be associated with a broad variety of unfavourable consequences, which should be taken into account to contribute to a worse prognosis in COPD., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The effect of β2-adrenergic receptor (ADRB2) polymorphisms on the treatment response to longacting bronchodilators in chronic obstructive pulmonary disease (COPD) is unclear. We aimed to establish whether ADRB2 polymorphisms differentially affected COPD exacerbation outcomes in response to tiotropium versus salmeterol., Methods: We did a prespecified analysis of the ADRB2 polymorphisms Arg16Gly and Gln27Glu within the 1 year randomised, double-blind, double-dummy, parallel-group Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, comparing the effects of treatment with tiotropium or salmeterol on exacerbations in 7376 patients with COPD. One blood sample was collected for pharmacogenetic testing from each patient who elected to participate in the substudy. Random assignment of patients to treatment groups was not stratified according to genotypes. Genomic DNA was extracted from whole-blood specimens and samples were genotyped for the two SNPs, rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu). All assays were done in technical duplicates and 10% of samples that were randomly chosen were repeated as technical duplicates in a second independent genotyping process. Our primary endpoint was the risk of a first exacerbation of COPD based on time to first exacerbation data. An exacerbation of COPD was defined as the increase or new onset of more than one symptom of COPD (cough, sputum, wheezing, dyspnoea, or chest tightness), with at least one of the symptoms lasting for 3 days or more and needing treatment with antibiotics or systemic glucocorticoids (moderate exacerbations), or admission to hospital (severe exacerbations). POET-COPD is registered with ClinicalTrials.gov, number NCT00563381., Findings: 5125 patients gave informed consent for genotyping. The distributions of ADRB2 genotypes were well matched among groups. Polymorphisms at aminoacid 27 did not affect exacerbation outcomes. In the salmeterol group, patients with Arg16Arg genotype had a significantly reduced exacerbation risk compared with patients with Arg16Gly (p=0·0130) and Gly16Gly (p=0·0018) genotypes (proportion of patients with at least one exacerbation was 32·3% in Arg16Arg, 39·8% in Arg16Gly, and 42·1% in Gly16Gly). By contrast, exacerbation risk was not modified by polymorphisms at aminoacid 16 in the tiotropium group. The effect of the Arg16Gly polymorphism on treatment response to salmeterol was dependent on the use of inhaled corticosteroids (ICS). In patients untreated with ICS at baseline, Arg16Gly and Arg16Arg genotypes were associated with significantly prolonged time to first exacerbation compared with Gly16Gly (vs Arg16Gly p=0·0164; Arg16Arg p=0·0316; proportion of patients with at least one exacerbation was 28·3% in Arg16Arg, 31·6% in Arg16Gly, and 39·2% in Gly16Gly), whereas in patients on ICS at baseline, only the Arg16Arg genotype was associated with significantly prolonged time to first exacerbation compared with Gly16Gly (p=0·0198; not Arg16Gly p=0·64; proportion of patients with at least one exacerbation was 35·9% in Arg16Arg, 46·7% in Arg16Gly, and 44·8% in Gly16Gly). The respiratory disorders, in particular worsening of COPD, were the most common serious adverse events., Interpretation: Patients with the Arg16Arg genotype had better exacerbation outcomes in response to salmeterol than Gly16Gly and Arg16Gly genotypes, suggesting a potential differential Arg16Gly genotype effect on treatment response to longacting β-agonists (LABAs). However, the use of ADRB2 polymorphisms for predicting LABA treatment response is still limited and further prospective validation will be needed to advance the mechanistic understanding of β-adrenergic polymorphisms and their association with clinical features of COPD., Funding: Boehringer Ingelheim and Pfizer., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: QVA149 is an inhaled fixed-dose combination therapy under development for the treatment of chronic obstructive pulmonary disease (COPD). It combines indacaterol (a longacting β2-agonist) with glycopyrronium (a longacting muscarinic antagonist) as a dual bronchodilator. We aimed to compare the efficacy, safety, and tolerability of QVA149 versus salmeterol-fluticasone (SFC) over 26 weeks in patients with moderate-to-severe COPD., Methods: In this multicentre double-blind, double-dummy, parallel-group study, 523 patients (age 40 years or older, Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages II-III, without exacerbations in the previous year) were randomly assigned (1:1; via automated, interactive response technology and stratified for smoking status) to once-daily QVA149 110/50 μg or twice-daily SFC 50/500 μg for 26 weeks. Efficacy was assessed in the full analysis set (randomised patients who received at least one dose of study drug); safety was assessed in all patients who received at least one dose of study drug. The primary endpoint was to demonstrate the superiority of QVA149 compared with SFC for the standardised area under the curve from 0 to 12 h post dose for forced expiratory volume in 1 second (FEV1 AUC0-12h) after 26 weeks of treatment. This trial was registered at ClinicalTrial.gov, NCT01315249., Findings: Between March 25, 2011, and March 12, 2012, 259 patients were randomly assigned to receive QVA149 and 264 to receive SFC. At week 26, FEV1 AUC0-12h was significantly higher with QVA149 than with SFC (treatment difference 0·138 L; 95% CI 0·100-0·176; p<0·0001). Overall incidence of adverse events (including COPD exacerbations) was 55·4% (143 of 258) for the QVA149 group and 60·2% (159 of 264) for the SFC group. Incidence of serious adverse events was similar between treatment groups (QVA149, 13 of 258 [5·0%]; SFC 14 of 264 [5·3%]); COPD worsening was the most frequent serious adverse event (one of 13 [0·4%] and three of 14 [1·1%], respectively)., Interpretation: Once-daily QVA149 provides significant, sustained, and clinically meaningful improvements in lung function versus twice-daily SFC, with significant symptomatic benefit. These results indicate the potential of dual bronchodilation as a treatment option for non-exacerbating symptomatic COPD patients., Funding: Novartis Pharma AG., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Spirometry is a frequently performed lung function test and an important tool in medical surveillance examinations of pulmonary diseases. The interpretation of lung function relies on the comparison to reference values derived from a healthy population. The study aim was to compare the lung function data of three representative population-based German studies (Study of Health in Pomerania [SHIP-1], Cooperative Health Research in the Region of Augsburg [KORA-S3] and European Community Respiratory Health Survey Erfurt [ECRHS-I Erfurt]) with existing European spirometry reference values and to establish a new set of comprehensive German prediction equations., Methods: Spirometry was performed in 4133 participants of three population-based surveys using almost identical standardised methods. Current and former smokers, subjects with cardiopulmonary disorders or on medication with potential influence on lung function were excluded. Sex specific prediction equations were established by quantile regression analyses. Comparison was performed to existing European reference values., Results: The healthy reference sample consisted of 1302 (516 male) individuals, aged 20-80 years. Sex specific comprehensive prediction equations adjusted for age and height are provided. Significant differences were found in comparison to previous studies with pronounced lower values of the current population if applying historic prediction equations., Conclusion: The results contribute to the interpretation of lung function examination in providing a comprehensive set of spirometry reference values obtained in a large number of healthy volunteers. Whereas the differences in between the investigated studies are negligible, striking divergence was detected in comparison to historic and recent European spirometry prediction values., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: The efficacy and safety profile of ciclesonide (CIC) in the treatment of asthma was evaluated in a large patient population in a real-life setting in Germany., Methods: 24,037 patients with persistent mild/moderate bronchial asthma were enrolled into three observational studies with identical design. Data were pooled and analyzed. Patients received ciclesonide (160 μg/day) and were observed for 3 months. FEV(1), PEF, NO, asthma episodes, use of rescue medication and adverse drug reactions (ADR) were recorded., Results: Mean (95% CI) FEV(1) significantly increased from 80.7 [80.5; 80.9]% of predicted at baseline to 90.1 [89.9; 90.2]% after 3 months (n = 20,297), mean PEF significantly increased from 338 [335; 340] l/min to 392 [390; 395] l/min (n = 8100). NO was significantly reduced from 53.6 [51.8; 55.4] ppb to 26.2 [25.2; 27.1] ppb (n = 971). The percentage of patients with daily symptoms declined from 24.3% to 1.9%, night-time symptoms from 13.3% to 1.3%, and β(2)-agonists use from 26.9% to 8.8%. ADRs were reported by 51 patients (0.2%). Most frequent ADRs were: dysphonia (n = 11), cough (n = 10), dyspnoea, throat irritation, and oral candidiasis (n = 5 each). 46 patients terminated the study prematurely, 41 due to ADR and 5 due to unknown/missing reason. One patient died due to cardiac failure (no causal relation)., Conclusion: These observational studies under real-life conditions support findings from controlled clinical studies regarding efficacy and tolerability of ciclesonide in patients with mild to moderate bronchial asthma. No unexpected ADRs were detected., (Copyright © 2010 Elsevier Ltd. All rights reserved.)