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The aim of this study was to characterize the practice of telemediated training for patients with very severe Chronic Obstructive Pulmonary Disease (COPD) and to inform the development of clinical/professional practice. Inspired by ethnographic methodology, participating observation, informal and formal interviews were conducted with patients (11), their partners (4), and physiotherapists (6) at sites where the telemediated training was practiced. Postphenomenology was used as theoretical and analytical framework. Telemediated training in the homes of the patients takes place where most daily activities happen, and together with activities in the rehabilitation units they are included in the training in a reduced or amplified version that may compromise the privacy of the patients. The mediated image and sound challenge the training and communication activities and the possibility for the physiotherapists to estimate the condition of the patients. Consequently, the physiotherapists lower how much they push the patients in the exercises. Making training accessible to very severely ill patients with COPD through homebased telemediation comes with several trade-offs. This study can be used to educate clinical practice before and during the practicing of telemediated services, which need to be organized in a way that allows continuous adjustment. The technology itself is not a neutral device in online health care provision. Health professionals should therefore: Play an active role in structuring the content, communication, and inclusion of the patients' context during online health care provision. Receive training in how to spot ways in which online health care provision transforms traditional practice and to how to work around its limitations. Organize online health care practices in ways that allow for continuous adjustment (for which they need back up from management). [ABSTRACT FROM AUTHOR]

Summary: Background: Inhaled longacting β[sub 2] agonists improve lung function and health status in symptomatic chronic obstructive pulmonary disease (COPD), whereas inhaled corticosteroids reduce the frequency of acute episodes of symptom exacerbation and delay deterioration in health status. We postulated that a combination of these treatments would be better than each component used alone. Methods: 1465 patients with COPD were recruited from outpatient departments in 25 countries. They were treated in a randomised, double-blind, parallel-group, placebo-controlled study with either 50 μ g salmeterol twice daily (n=372), 500 μ g fluticasone twice daily (n=374), 50 μ g salmeterol and 500 μ g fluticasone twice daily (n=358), or placebo (n=361) for 12 months. The primary outcome was the pretreatment forced expiratory volume in 1 s (FEV[sub 1]) after 12 months treatment' and after patients had abstained from all bronchodilators for at least 6 h and from study medication for at least 12 h. Secondary outcomes were other lung function measurements, symptoms and rescue treatment use, the number of exacerbations, patient withdrawals, and disease-specific health status. We assessed adverse events, serum cortisol concentrations, skin bruising, and electrocardiograms. Analysis was as predefined in the study protocol. Findings: All active treatments improved lung function, symptoms, and health status and reduced use of rescue medication and frequency of exacerbations. Combination therapy improved pretreatment FEV[sub 1] significantly more than did placebo (treatment difference 133 mL, 95% CI 105-161, p<0.0001), salmeterol (73 mL, 46-101, p<0.0001), or fluticasone alone (95 mL, 67-122, p<0.0001). Combination treatment produced a clinically significant improvement in health status and the greatest reduction in daily symptoms. All treatments were well tolerated with no difference in the frequency of adverse events, bruising, or clinically significant falls... [ABSTRACT FROM AUTHOR]

Background: COPD is a leading cause of mortality.Research Question: We hypothesized that applying machine learning to clinical and quantitative CT imaging features would improve mortality prediction in COPD.Study Design and Methods: We selected 30 clinical, spirometric, and imaging features as inputs for a random survival forest. We used top features in a Cox regression to create a machine learning mortality prediction (MLMP) in COPD model and also assessed the performance of other statistical and machine learning models. We trained the models in subjects with moderate to severe COPD from a subset of subjects in Genetic Epidemiology of COPD (COPDGene) and tested prediction performance in the remainder of individuals with moderate to severe COPD in COPDGene and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). We compared our model with the BMI, airflow obstruction, dyspnea, exercise capacity (BODE) index; BODE modifications; and the age, dyspnea, and airflow obstruction index.Results: We included 2,632 participants from COPDGene and 1,268 participants from ECLIPSE. The top predictors of mortality were 6-min walk distance, FEV1 % predicted, and age. The top imaging predictor was pulmonary artery-to-aorta ratio. The MLMP-COPD model resulted in a C index ≥ 0.7 in both COPDGene and ECLIPSE (6.4- and 7.2-year median follow-ups, respectively), significantly better than all tested mortality indexes (P < .05). The MLMP-COPD model had fewer predictors but similar performance to that of other models. The group with the highest BODE scores (7-10) had 64% mortality, whereas the highest mortality group defined by the MLMP-COPD model had 77% mortality (P = .012).Interpretation: An MLMP-COPD model outperformed four existing models for predicting all-cause mortality across two COPD cohorts. Performance of machine learning was similar to that of traditional statistical methods. The model is available online at: https://cdnm.shinyapps.io/cgmortalityapp/. [ABSTRACT FROM AUTHOR]

Background Anxiety and dyspnea, 2 major symptoms in patients with chronic obstructive pulmonary disease (COPD), are associated with high morbidity and mortality. Thus, critically evaluating and synthesizing the existing literature employing pulmonary rehabilitation (PR) and other behavioral therapies in the treatment of anxiety and dyspnea in patients with COPD may help clinicians determine the most efficacious potential treatments. We aim to examine the efficacy of PR and behavioral therapy [eg, cognitive behavioral therapy (CBT) and counseling] and other adjunct modalities used in patients with COPD. Methods We extracted relevant studies searching the published literature using an electronic database CINAHL, Medline, PubMed, Science Direct, and the Web of Science was conducted (spanning January 1, 2006 to November 15, 2016). Studies were included if they conducted PR and behavioral therapy (CBT, self-management, yoga) to treat anxiety and/or dyspnea in patients with COPD with or without randomized controlled trial. Results The 47 studies selected included 4595 participants (PR = 3756 and behavioral therapy = 839), ranging in age from 58 to 75 years. The total number of participants receiving a treatment was 3928, and 667 participants served in control groups. In the majority of studies, PR and CBT are effective in the treatment of anxiety and dyspnea in the short term, but the long-term benefit is limited. In addition, self-management, yoga therapy, and CBT plus PR were beneficial. Conclusions PR and CBT reduced both anxiety and dyspnea symptoms in patients with COPD in the short term. However, maintenance programs and the long-term benefits of PR and CBT remain inconclusive. Generally, the studies were relatively small and uncontrolled. Thus, prospective and randomized controlled trials with larger sample sizes are needed. [ABSTRACT FROM AUTHOR]

Background Depression increases disability and health care utilization in older patients with chronic obstructive pulmonary disease (COPD). Objectives To determine contribution of depressive symptoms to the incidence of moderate-severe and severe acute exacerbations of COPD (AECOPD) over 3 years. Design We analyzed data collected from a prospective cohort of patients with COPD (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; ECLIPSE). Setting Multicentered outpatient. Participants A total of 2059 patients with COPD with complete data (63.7% men, mean age 63.4 + 7.1 years). Measurements Depression was assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). Moderate-severe AECOPDs were collected; a subset of very severe AECOPD was defined as requiring hospital admission. Results A total of 540 (26%) patients with COPD reported high depressive symptoms (CES-D ≥16). High depressive symptoms at baseline related to an increased risk of moderate-severe and severe AECOPD during the follow-up (odds ratio [OR] 1.18; 95% confidence interval [CI] 1.07–1.30; for moderate-severe and OR 1.36; 95% CI 1.09–1.69 for severe events risk of hospitalizations) independent of key covariates of an AECOPD history before recruitment in the study, history of gastroesophageal reflux, baseline severity of airflow limitation, and white blood cell count that were also associated with an increased risk of moderate to severe exacerbations (all P < .001). Conclusion Presence of high depressive symptoms at baseline were associated with subsequent moderate-severe exacerbations and hospital admissions in patients with COPD over 3 years, independent of a history of exacerbations and other demographic and clinical factors. Targeted personalized medicine that focuses both on AECOPD risk and depression may be a step forward to improving prognosis of patients with COPD. [ABSTRACT FROM AUTHOR]

Introduction: COPD is underdiagnosed, and measurement of spirometry alongside low-dose computed tomography (LDCT) screening for lung cancer is one strategy to increase earlier diagnosis of this disease., Methods: Ever-smokers at high risk of lung cancer were invited to the Yorkshire Lung Screening Trial for a lung health check (LHC) comprising LDCT screening, pre-bronchodilator spirometry and a smoking cessation service. In this cross-sectional study we present data on participant demographics, respiratory symptoms, lung function, emphysema on imaging and both self-reported and primary care diagnoses of COPD. Multivariable logistic regression analysis identified factors associated with possible underdiagnosis and misdiagnosis of COPD in this population, with airflow obstruction defined as forced expiratory volume in 1 s/forced vital capacity ratio <0.70., Results: Out of 3920 LHC attendees undergoing spirometry, 17% had undiagnosed airflow obstruction with respiratory symptoms, representing potentially undiagnosed COPD. Compared to those with a primary care COPD code, this population had milder symptoms, better lung function and were more likely to be current smokers (p≤0.001 for all comparisons). Out of 836 attendees with a primary care COPD code who underwent spirometry, 19% did not have airflow obstruction, potentially representing misdiagnosed COPD, although symptom burden was high., Discussion: Spirometry offered alongside LDCT screening can potentially identify cases of undiagnosed and misdiagnosed COPD. Future research should assess the downstream impact of these findings to determine whether any meaningful changes to treatment and outcomes occur, and to assess the impact on co-delivering spirometry on other parameters of LDCT screening performance such as participation and adherence. Additionally, work is needed to better understand the aetiology of respiratory symptoms in those with misdiagnosed COPD, to ensure that this highly symptomatic group receive evidence-based interventions., Competing Interests: Conflicts of interest: C. Bradley reports that the European Respiratory Society funded their attendance at the ERS International Congress in 2021 as they won a Best Abstract prize. Conflicts of interest: P. Alexandris has nothing to disclose. Conflicts of interest: D.R. Baldwin reports honoraria for presenting from MSD, Roche, BMS and AstraZeneca. Conflicts of interest: R. Booton has nothing to disclose. Conflicts of interest: M. Darby has nothing to disclose. Conflicts of interest: C.J. Eckert has nothing to disclose. Conflicts of interest: R. Gabe has nothing to disclose. Conflicts of interest: N. Hancock has nothing to disclose. Conflicts of interest: S. Janes reports consulting fees from AstraZeneca, Johnson and Johnson, Bard1 (consultancy) and Optellum (advisory board), honoraria from Chiesi for a lecture, and Takeda funded their attendance at conference. Conflicts of interest: M. Kennedy has nothing to disclose. Conflicts of interest: J. Lindop has nothing to disclose. Conflicts of interest: R.D. Neal has nothing to disclose. Conflicts of interest: S. Rogerson has nothing to disclose. Conflicts of interest: B. Shinkins is a member of the the UK National Screening Committee (unpaid). Conflicts of interest: I. Simmonds has nothing to disclose. Conflicts of interest: S. Upperton has nothing to disclose. Conflicts of interest: J. Vestbo reports payment from Boehringer Ingelheim to their hospital for an investigator-initiated clinical trial; consulting fees from AstraZeneca, ALK Abello, Boehringer Ingelheim, GSK, Novartis and TEVA; honoraria for presenting from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK and Novartis; and participant on data safety monitoring board or advisory board for Astra Zeneca and GSK. Conflicts of interest: P.A.J. Crosbie reports consulting fees and stock options from Everest Detection, and honoraria from AstraZeneca, Novartis and North West eHealth. Conflicts of interest: M.E.J. Callister has nothing to disclose., (Copyright ©The authors 2023.)

Purpose: The modified-Medical Research Council (mMRC) breathlessness scale consists of five grades that contain of a description of different activities. It has wide utility in the assessment of disability due to breathlessness but was originally developed before the advent of modern psychometric methodology and, for example contains more than one activity per grade. We conducted an evaluation of the mMRC structure., Patients and Methods: Cognitive debriefing was conducted with COPD patients to elicit their understanding of each mMRC activity. In a cross-sectional study, patients completed the mMRC scale (grades 0-4) and an MRC-Expanded (MRC-Ex) version consisting of 10-items, each containing one mMRC activity. Each activity was then given a 4-point response scale (0 "not at all" to 4 "all of the time") and all 10 items were given to 203 patients to complete Rasch analysis and assess the pattern of MRC item severity and its hierarchical structure., Results: Cognitive debriefing with 36 patients suggested ambiguity with the term "strenuous exercise" and perceived severity differences between mMRC activities. 203 patients completed the mMRC-Ex. Strenuous exercise was located third on the ascending severity scale. Rasch identified the mildest term was "walking up a slight hill" (logit -2.76) and "too breathless to leave the house" was the most severe (logit 3.42)., Conclusion: This analysis showed that items that were combined into a single mMRC grade may be widely separated in terms of perceived severity when assessed individually. This suggests that mMRC grades as a measure of individual disability related to breathlessness contain significant ambiguity due to the combination of activities of different degrees of perceived severity into a single grade., Competing Interests: Professor Dave Singh reports personal fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, Epiendo, personal fees from Genentech, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Novartis, Pulmatrix, Sanofi, Synairgen, Teva, Theravance, Verona, outside the submitted work. Dr Jorgen Vestbo reports personal fees from AstraZeneca, grants from Boehringer-Ingelheim, personal fees from Chiesi, GSK, Novartis, ALK-Abello, Teva, Boehringer-Ingelheim, outside the submitted work. Professor Paul W Jones reports he is an employee of GlaxoSmithKline, outside the submitted work. The authors have no other conflicts of interest in relation to this work., (© 2022 Yorke et al.)

Background: Chronic obstructive pulmonary disease (COPD) is associated with significant morbidity, mortality and healthcare costs. Beta blockers are well-established drugs widely used to treat cardiovascular conditions. Observational studies consistently report that beta blocker use in people with COPD is associated with a reduced risk of COPD exacerbations. The bisoprolol in COPD study (BICS) investigates whether adding bisoprolol to routine COPD treatment has clinical and cost-effective benefits. A sub-study will risk stratify participants for heart failure to investigate whether any beneficial effect of bisoprolol is restricted to those with unrecognised heart disease., Methods: BICS is a pragmatic randomised parallel group double-blind placebo-controlled trial conducted in UK primary and secondary care sites. The major inclusion criteria are an established predominant respiratory diagnosis of COPD (post-bronchodilator FEV 1 < 80% predicted, FEV 1 /FVC < 0.7), a self-reported history of ≥ 2 exacerbations requiring treatment with antibiotics and/or oral corticosteroids in a 12-month period since March 2019, age ≥ 40 years and a smoking history ≥ 10 pack years. A computerised randomisation system will allocate 1574 participants with equal probability to intervention or control groups, stratified by centre and recruitment in primary/secondary care. The intervention is bisoprolol (1.25 mg tablets) or identical placebo. The dose of bisoprolol/placebo is titrated up to a maximum of 4 tablets a day (5 mg bisoprolol) over 4-7 weeks depending on tolerance to up-dosing of bisoprolol/placebo-these titration assessments are completed by telephone or video call. Participants complete the remainder of the 52-week treatment period on the final titrated dose (1, 2, 3, 4 tablets) and during that time are followed up at 26 and 52 weeks by telephone or video call. The primary outcome is the total number of participant reported COPD exacerbations requiring oral corticosteroids and/or antibiotics during the 52-week treatment period. A sub-study will risk stratify participants for heart failure by echocardiography and measurement of blood biomarkers., Discussion: The demonstration that bisoprolol reduces the incidence of exacerbations would be relevant not only to patients and clinicians but also to healthcare providers, in the UK and globally., Trial Registration: Current controlled trials ISRCTN10497306 . Registered on 16 August 2018., (© 2022. The Author(s).)

Impact of the UK lockdown on early COPD https://bit.ly/3laMsmi., Competing Interests: Conflict of interest: G.C. Donaldson reports grants from AstraZeneca, and personal fees from AstraZeneca, the American Thoracic Society, FWO Flanders and Novartis, outside the submitted work. Conflict of interest: A.I. Ritchie has nothing to disclose. Conflict of interest: P.M.A. Calverley reports grants and personal fees from GlaxoSmithKline, personal fees from AstraZeneca, Boehringer Ingelheim, Phillips Respironics, Novartis, Recipharm and Zambon, and personal fees and nonfinancial support from Boehringer Ingelheim outside the submitted work. Conflict of interest: J. Vestbo reports personal fees from AstraZeneca and Boehringer Ingelheim, grants from Boehringer Ingelheim, and personal fees from Chiesi, GSK, Novartis and TEVA, outside the submitted work. Conflict of interest: M. Fageras has nothing to disclose. Conflict of interest: A. de la Hoz reports a salary from Boehringer Ingelheim International. Conflict of interest: E. Bucchioni is an employee of Chiesi. Conflict of interest: C.H. Compton is an employee of and holds shares in GSK. Conflict of interest: K. Mezzi is a Novartis Pharma AG employee. Conflict of interest: J.A. Wedzicha reports grants from GSK, meeting expenses only (no personal fees since January 2015) from Novartis, Boehringer Ingelheim and AstraZeneca, and a grant from Chiesi outside the submitted work., (Copyright ©The authors 2021.)

Populations with COPD demonstrate higher survival in overweight and obese compared with normal weight; the "obesity paradox". Relationships in less-severe COPD are unclear, as is the impact of cardiovascular risk, and few studies include individuals at extremes of obesity.  We examined the relationship between body mass index (BMI; defined as underweight: <20 kg·m -2 , normal: 20-25 kg·m -2 , overweight: 25- <30 kg·m -2 , obese class I: 30- <35 kg·m -2 , class II: 35- <40 kg·m -2 and class III: ≥40 kg·m -2 ), morbidity, and mortality in the SUMMIT trial population (n=16 485), characterised by moderate COPD and heightened cardiovascular risk with a substantial proportion with class III obesity. The association between BMI category and time to event was modelled via proportional hazards (reference normal weight) adjusted for demographics and cardiorespiratory disease.  Consistent with the paradox, underweight individuals demonstrated higher mortality (hazard ratio (HR) 1.31 (95% CI 1.04-1.64)), with lower mortality among overweight (HR 0.62 (95% CI 0.52-0.73)) and obese class I (HR 0.75 (95% CI 0.62-0.90)). However, mortality increased in obese class III (HR 1.36 (95% CI 1.00-1.86)). Death was primarily attributable to cardiovascular causes.  Within a large, multinational cohort with moderate COPD and increased cardiovascular risk, the phenomenon of reduced mortality with obesity did not persist at BMI >40 kg·m -2 , suggesting that obesity may not remain protective at the extremes in this population., Competing Interests: Conflict of interest: E.P. Brigham has nothing to disclose. Conflict of interest: J.A. Anderson is an employee of and owns shares in GSK. Conflict of interest: R.D. Brook reports personal fees from GSK for a steering committee during the conduct of the study. Conflict of interest: P.M.A. Calverley reports that he was a member of the SUMMIT Science Committee supported by GSK; and he was paid for the conduct of the SUMMIT study by GSK, was paid for speaking at a company meeting and for advice on study design by AstraZeneca, he advised on development of new trials and has spoken for Boehringer Ingelheim at sponsored meetings, and he has received personal fees for speaking at sponsored meeting from Novartis, outside the submitted work. Conflict of interest: B.R. Celli reports personal fees from GlaxoSmithKline during the conduct of the study; and personal fees from AstraZeneca, Sanofi Aventis, Chiesi, Novartis, Menarini and Pulmonx outside the submitted work. Conflict of interest: N.J. Cowans reports this study was funded by GlaxoSmithKline plc.; and he is an employee of Veramed Ltd, a contract research organisation undertaking contracted statistical analyses of respiratory studies funded by GlaxoSmithKline plc. Conflict of interest: C. Crim is an employee of GSK and holds GSK stocks/shares; this study was funded by GSK (NCT01313676, GSK study number 113782; Study to Understand Mortality and Morbidity In COPD Trial (SUMMIT)). Conflict of interest: J.E. Diserens reports this study was funded by GlaxoSmithKline plc.; and he is an employee of Veramed Ltd, a contract research organisation undertaking contracted statistical analyses of respiratory studies funded by GlaxoSmithKline plc. Conflict of interest: F.J. Martinez reports grants from the NHLBI during the conduct of the study; and grants from the National Institutes of Health, personal fees from Continuing Education and Forest Laboratories, other support from Janssen, and personal fees from GlaxoSmithKline, Nycomed/Takeda, AstraZeneca, Boehringer Ingelheim, Bellerophon (formerly Ikaria), Genentech, Novartis, Pearl, Roche, Sunovion, Theravance, CME Incite, Annenberg Center for Health Sciences at Eisenhower, Integritas, InThought, the National Association for Continuing Education, Paradigm Medical Communications, LLC, PeerVoice, UpToDate, Haymarket Communications, the Western Society of Allergy and Immunology, Proterixbio (formerly Bioscale), Unity Biotechnology, ConCert Pharmaceuticals, Lucid, Methodist Hospital, Columbia University, Prime Healthcare Ltd, WebMD, PeerView Network, the California Society of Allergy and Immunology, Chiesi and the Puerto Rico Thoracic Society, outside the submitted work. Conflict of interest: M.C. McCormack reports support from UpToDate outside the submitted work. Conflict of interest: D.E. Newby reports grants and personal fees from GSK during the conduct of the study. Conflict of interest: J.C. Yates is an employee of and owns shares in GSK. Conflict of interest: J. Vestbo was partly reimbursed for his work as Chair of the SUMMIT Steering Committee buy GlaxoSmithKline during the conduct of the study; and reports consultancy for COPD phase 2 and 3 programmes and payment for lectures including service in speaker bureaus from GlaxoSmithKline, Chiesi Pharmaceuticals, Boehringer Ingelheim, Novartis and AstraZeneca, outside the submitted work. Conflict of interest: T.D. Wu has nothing to disclose. Conflict of interest: R.A Wise reports grants and personal fees from GlaxoSmithKline during the conduct of the study; grants and personal fees from AstraZeneca/Medimmune and Boehringer Ingelheim, personal fees from Contrafect, Pulmonx, Roche/Genentech, Spiration, Sunovion, Pearl Therapeutics, Merck, Circassia, Pneuma, Verona, Bonti, Denali, Aradigm, Mylan, Theravance, Propeller Health, Kiniksa and Syneos, outside the submitted work., (Copyright ©The authors 2021.)

U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of "omic" datasets that are at the core of this systems medicine approach., (Copyright ©ERS 2015.)

Background: Recently, several proteins of the extracellular matrix have been characterised as active contributors to allergic airway disease. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein abundant in the lung, whose biological functions remain poorly understood. In the current study we investigated the role of MFAP4 in experimental allergic asthma., Methods: MFAP4-deficient mice were subjected to alum/ovalbumin and house dust mite induced models of allergic airway disease. In addition, human healthy and asthmatic primary bronchial smooth muscle cell cultures were used to evaluate MFAP4-dependent airway smooth muscle responses., Results: MFAP4 deficiency attenuated classical hallmarks of asthma, such as eosinophilic inflammation, eotaxin production, airway remodelling and hyperresponsiveness. In wild-type mice, serum MFAP4 was increased after disease development and correlated with local eotaxin levels. MFAP4 was expressed in human bronchial smooth muscle cells and its expression was upregulated in asthmatic cells. Regarding the underlying mechanism, we showed that MFAP4 interacted with integrin αvβ5 and promoted asthmatic bronchial smooth muscle cell proliferation and CCL11 release dependent on phosphatidyloinositol-3-kinase but not extracellular signal-regulated kinase pathway., Conclusions: MFAP4 promoted the development of asthmatic airway disease in vivo and pro-asthmatic functions of bronchial smooth muscle cells in vitro. Collectively, our results identify MFAP4 as a novel contributor to experimental asthma, acting through modulation of airway smooth muscle cells., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this Official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management., Methods: Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarized, and then salient knowledge gaps were identified., Results: Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus., Conclusions: Great strides have been made in the diagnosis, assessment, and management of COPD as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS Research Statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centered outcomes.

Background: In 2010 the COPD Foundation established the COPD Biomarkers Qualification Consortium (CBQC) as a partnership between the Foundation, the Food and Drug Administration (FDA), and the pharmaceutical industry to pool publicly-funded and industry data to develop innovative tools to facilitate the development and approval of new therapies for COPD. We present data from the initial project seeking regulatory qualification of fibrinogen as a biomarker for the stratification of COPD patients into clinical trials., Methods: This analysis pooled data from 4 publicly-funded studies and 1 industry study into a common database resulting in 6376 individuals with spirometric evidence of COPD. We used a threshold of 350 mg/dL to determine high vs. low fibrinogen, and determined the subsequent risk of hospitalizations from exacerbations and death using Cox proportional hazards models., Results: High fibrinogen levels at baseline were present in 2853 (44.7%) of individuals with COPD. High fibrinogen was associated with an increased risk of hospitalized COPD exacerbations within 12 months (hazard ratio [HR]: 1.64; 95% confidence interval [CI]: 1.39-1.93) among participants in the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. High fibrinogen was associated with an increased risk of death within 36 months (HR: 1.94; 95% CI: 1.62-2.31) among all participants., Conclusions: Fibrinogen levels ≥ 350 mg/dL identify COPD individuals at an increased risk of exacerbations and death and could be a useful biomarker for enriching clinical trials in the COPD population.

Accelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1&#95;A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.