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Rationale: Predicting increased risk of future healthcare utilization in chronic obstructive pulmonary disease (COPD) patients is an important goal for improving patient management., Objective: Our objective was to determine the importance of computed tomography (CT) lung imaging measurements relative to other demographic and clinical measurements for predicting future health services use with machine learning in COPD., Materials and Methods: In this retrospective study, lung function measurements and chest CT images were acquired from Canadian Cohort of Obstructive Lung Disease study participants from 2010 to 2017 (https://clinicaltrials.gov, NCT00920348). Up to two follow-up visits (1.5- and 3-year follow-up) were performed and participants were asked for details related to healthcare utilization. Healthcare utilization was defined as any COPD hospitalization or emergency room visit due to respiratory problems in the 12 months prior to the follow-up visits. CT analysis was performed (VIDA Diagnostics Inc.); a total of 108 CT quantitative emphysema, airway and vascular measurements were investigated. A hybrid feature selection method with support vector machine classifier was used to predict healthcare utilization. Performance was determined using accuracy, F1-measure and area under the receiver operating characteristic curve (AUC) and Matthews's correlation coefficient (MC)., Results: Of the 527 COPD participants evaluated, 179 (35%) used healthcare services at follow-up. There were no significant differences between the participants with or without healthcare utilization at follow-up for age (p = 0.50), sex (p = 0.44), BMI (p = 0.05) or pack-years (p = 0.76). The accuracy for predicting subsequent healthcare utilization was 80% ± 3% (F1-measure = 74%, AUC = 0.80, MC = 0.6) when all measurements were considered, 76% ± 6% (F1-measure = 72%, AUC = 0.77, MC = 0.55) for CT measurements alone and 65% ± 5% (F1-measure = 60%, AUC = 0.67, MC = 0.34) for demographic and lung function measurements alone., Conclusion: The combination of CT lung imaging and conventional measurements leads to greater prediction accuracy of subsequent health services use than conventional measurements alone, and may provide needed prognostic information for patients suffering from COPD., (Copyright © 2022 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Rationale: Peripheral airway obstruction is a key feature of chronic obstructive pulmonary disease (COPD), but the mechanisms of airway loss are unknown. This study aims to identify the molecular and cellular mechanisms associated with peripheral airway obstruction in COPD., Methods: Ten explanted lung specimens donated by patients with very severe COPD treated by lung transplantation and five unused donor control lungs were sampled using systematic uniform random sampling (SURS), resulting in 240 samples. These samples were further examined by micro-computed tomography (CT), quantitative histology and gene expression profiling., Results: Micro-CT analysis showed that the loss of terminal bronchioles in COPD occurs in regions of microscopic emphysematous destruction with an average airspace size of ≥500 and <1000 µm, which we have termed a "hot spot". Based on microarray gene expression profiling, the hot spot was associated with an 11-gene signature, with upregulation of pro-inflammatory genes and downregulation of inhibitory immune checkpoint genes, indicating immune response activation. Results from both quantitative histology and the bioinformatics computational tool CIBERSORT, which predicts the percentage of immune cells in tissues from transcriptomic data, showed that the hot spot regions were associated with increased infiltration of CD4 and CD8 T-cell and B-cell lymphocytes., Interpretation: The reduction in terminal bronchioles observed in lungs from patients with COPD occurs in a hot spot of microscopic emphysema, where there is upregulation of IFNG signalling, co-stimulatory immune checkpoint genes and genes related to the inflammasome pathway, and increased infiltration of immune cells. These could be potential targets for therapeutic interventions in COPD., Competing Interests: Conflict of interest: F. Xu has nothing to disclose. Conflict of interest: D.M. Vasilescu has nothing to disclose. Conflict of interest: D. Kinose has nothing to disclose. Conflict of interest: N. Tanabe has nothing to disclose. Conflict of interest: K.W. Ng has nothing to disclose. Conflict of interest: H.O. Coxson has nothing to disclose. Conflict of interest: J.D. Cooper has nothing to disclose. Conflict of interest: T-L. Hackett has nothing to disclose. Conflict of interest: S.E. Verleden has nothing to disclose. Conflict of interest: B.M. Vanaudenaerde has nothing to disclose. Conflict of interest: C.S. Stevenson reports other (salary) from Johnson and Johnson, outside the submitted work. Conflict of interest: M.E. Lenburg reports grants from Genentech, during the conduct of the study and other (stock) from Metera Pharmaceuticals, outside the submitted work. Conflict of interest: A. Spira is an employee of Johnson and Johnson. Conflict of interest: W.C. Tan reports personal fees for advisory board work from GlaxoSmithKline, Canada, and AstraZenenca, Canada, outside the submitted work. Conflict of interest: D.D. Sin reports grants and personal fees for lectures from AstraZeneca and personal fees for lectures from Boehringer Ingelheim, outside the submitted work. Conflict of interest: R.T. Ng has nothing to disclose. Conflict of interest: J.C. Hogg reports grants from Genentech, Johnson and Johnson Corporation, Canadian Institute of Health Research, US National Institutes of Health, Katholieke Universiteit Leuven, Parker B Francis Foundation, St Paul's Hospital Foundation, BCLUNG Association and BC Heart and Stroke Foundation, during the conduct of the study., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with abnormal skeletal muscle morphology and function. Objectives: To test the hypothesis that in vivo diaphragm muscle morphology assessed by computed tomography (CT) imaging would be associated with COPD severity, exacerbations, health status, and exercise capacity. Methods: The COPD Morphometry Study is a cross-sectional study that enrolled a clinical sample of smokers with COPD. Spirometry was performed and COPD severity was defined according to guidelines. Three-dimensional left hemidiaphragm morphology was segmented from contiguous axial CT images acquired at maximal inspiration, yielding quantitative measures of diaphragm CT density in Hounsfield units, dome height, and muscle volume. Exacerbations prompting pharmacotherapy or hospitalization in the preceding 12 months and St. George's Respiratory Questionnaire for COPD were assessed. Incremental symptom-limited cycle ergometry quantified peak oxygen uptake ([Formula: see text]o 2Peak ). Associations were adjusted for age, sex, body height, body mass index, and smoking status. Results: Among 65 smokers with COPD (75% male; [mean ± standard deviation (SD)] 56 ± 26 pack-years; forced expiratory volume in 1 second [FEV 1 ] percentage predicted 55 ± 23%), mean diaphragm CT density was 3.1 ± 10 Hounsfield units, dome height was 5.2 ± 1.3 cm, and muscle volume was 57 ± 24 cm 3 . A 1-SD decrement in the diaphragm CT density was associated with 8.3% lower FEV 1 , 3.27-fold higher odds of exacerbation history, 9.7-point higher score on the St. George's Respiratory Questionnaire for COPD, and 2.5 ml/kg/min lower [Formula: see text]o 2Peak . A 1-SD decrement in dome height was associated with 11% lower FEV 1 and 1.3 ml/kg/min lower [Formula: see text]o 2Peak . There were no associations with diaphragm volume observed. Conclusions: CT-assessed diaphragm morphology was associated with COPD severity, exacerbations, impaired health status, and exercise intolerance. The mechanisms and functional impact of lower diaphragm CT density merit investigation.

Rationale: There are no validated measures of disease activity in COPD. Since "active" disease is expected to have worse outcomes ( e.g. mortality), we explored potential markers of disease activity in patients enrolled in the ECLIPSE cohort in relation to 8-year all-cause mortality., Methods: We investigated 1) how changes in relevant clinical variables over time (1 or 3 years) relate to 8-year mortality; 2) whether these variables inter-relate; and 3) if any clinical, imaging and/or biological marker measured cross-sectionally at baseline relates to any activity component., Results: Results showed that 1) after 1 year, hospitalisation for COPD, exacerbation frequency, worsening of body mass index, airflow obstruction, dyspnoea and exercise (BODE) index or health status (St George's Respiratory Questionnaire (SGRQ)) and persistence of systemic inflammation were significantly associated with 8-year mortality; 2) at 3 years, the same markers, plus forced expiratory volume in 1 s (FEV 1 ) decline and to a lesser degree computed tomography (CT) emphysema, showed association, thus qualifying as markers of disease activity; 3) changes in FEV 1 , inflammatory cytokines and CT emphysema were not inter-related, while the multidimensional indices (BODE and SGRQ) showed modest correlations; and 4) changes in these markers could not be predicted by any baseline cross-sectional measure., Conclusions: In COPD, 1- and 3-year changes in exacerbation frequency, systemic inflammation, BODE and SGRQ scores and FEV 1 decline are independent markers of disease activity associated with 8-year all-cause mortality. These disease activity markers are generally independent and not predictable from baseline measurements., Competing Interests: Conflict of interest: B. Celli reports grants and personal fees for scientific committee work from GlaxoSmithKline, during the conduct of the study; grants and provision of research facilities from AstraZeneca, personal fees for consultancy and scientific committee work from GlaxoSmithKline, personal fees for consultancy from Boehringer Ingelheim, Sanofi-Aventis, Menarini, Chiesi and Pulmonx, outside the submitted work. Conflict of interest: N. Locantore is an employee and shareholder of GSK. Conflict of interest: J.C. Yates is an employee of and owns shares in GSK. Conflict of interest: P. Bakke reports personal fees for advisory board work and lectures from GlaxoSmithKline, AstraZeneca and Boehringer Ingelheim, personal fees for advisory board work from Chiesi, outside the submitted work. Conflict of interest: P.M.A. Calverley reports personal fees from GSK, Boehringer Ingelheim, Novartis, Zambon, Respironics and Recipharm, outside the submitted work. Conflict of interest: C. Crim is an employee and shareholder of GlaxoSmithKline. Conflict of interest: H.O. Coxson reports grants and personal fees for scientific committee work from GSK, during the conduct of the study. Conflict of interest: D.A. Lomas reports grants and personal fees from GlaxoSmithKline, during the conduct of the study; grants and personal fees for advisory board work and lectures from GlaxoSmithKline, personal fees for advisory board work from Griffols, outside the submitted work. Conflict of interest: W. MacNee reports personal fees for scientific committee work from GSK, during the conduct of the study; personal fees from GSK and AstraZeneca, grants and personal fees from Pfizer, outside the submitted work. Conflict of interest: B.E. Miller is an employee and shareholder of GSK. Conflict of interest: H. Mullerova is a former employee of GlaxoSmithKline. Conflict of interest: S.I. Rennard is a former employee of AstraZeneca, has provided consultancy to GSK, Verona, Bergenbio and NovoVentures, and currently holds shares in AstraZeneca, outside of the submitted work. Prior to 2007, S.I. Rennard received funding from the tobacco industry for studies relating to harm reduction and to the impact of tobacco smoke on stem cells, and also consulted with RJ Reynolds (without personal fee) on the topic of harm reduction: funding from RJ Reynolds to evaluate the effect of a harm reduction product in normal smokers (1996) and in subjects with chronic bronchitis (1999) and to assess the effect of smoking cessation on lower respiratory tract inflammation (2000); participation in a Philip Morris multicentre study to assess biomarkers of smoke exposure (2002); funding for a clinical trial from the Institute for Science and Health (2005), which receives support from the tobacco industry, to evaluate biomarkers in exhaled breath associated with smoking cessation and reduction (this study was supplemented with funding from Lorillard and RJ Reynolds); grants from the Philip Morris External Research Program (2005) to assess the impact of cigarette smoking on circulating stem cells in the mouse; consultancy for RJ Reynolds on the topic of harm reduction until 2007 (no personal remuneration). There are no active tobacco-industry funded projects. All ties with tobacco industry companies and entities supported by tobacco companies were terminated in 2007. Conflict of interest: E.K. Silverman reports grants, personal fees and travel expenses from GlaxoSmithKline, grants from NIH, during the conduct of the study. Conflict of interest: E. Wouters reports personal fees for advisory board work from Nycomed and Boehringer Ingelheim BV, grants and personal fees for lectures from AstraZeneca and GSK, personal fees for lectures from Novartis and Chiesi, outside the submitted work. Conflict of interest: R. Tal-Singer reports is an employee and shareholder of GlaxoSmithKline. Conflict of interest: A. Agusti reports personal fees for scientific committee work from GSK, during the conduct of the study; personal fees from AstraZeneca, Chiesi and Nuvaira, grants and personal fees from Menarini and GSK, outside the submitted work. Conflict of interest: J. Vestbo reports personal fees for steering committee work from GSK, during the conduct of the study; personal fees for lectures and consultancy from AstraZeneca, Chiesi and Novartis, grants and personal fees for lectures and consultancy from Boehringer Ingelheim, grants and personal fees for consultancy from GSK, outside the submitted work; and has a family member employed by Chiesi (Denmark)., (Copyright ©ERS 2021.)

Rationale: Although centrilobular emphysema (CLE) and paraseptal emphysema (PSE) are commonly identified on multidetector computed tomography (MDCT), little is known about the pathology associated with PSE compared with that of CLE. Objectives: To assess the pathological differences between PSE and CLE in chronic obstructive pulmonary disease (COPD). Methods: Air-inflated frozen lung specimens ( n  = 6) obtained from patients with severe COPD treated by lung transplantation were scanned with MDCT. Frozen tissue cores were taken from central ( n  = 8) and peripheral ( n  = 8) regions of each lung, scanned with micro-computed tomography (microCT), and processed for histology. The core locations were registered to the MDCT, and a percentage of PSE or CLE was assigned by radiologists to each of the regions. MicroCT scans were used to measure number and structural change of terminal bronchioles. Furthermore, microCT-based volume fractions of CLE and PSE allowed classifying cores into mild emphysema, CLE-dominant, and PSE-dominant. Measurements and Main Results: The percentages of PSE measured on MDCT and microCT were positively associated ( P  = 0.015). The number of terminal bronchioles per milliliter of lung and cross-sectional lumen area were significantly lower and wall area percentage was significantly higher in CLE-dominant regions compared with mild emphysema and PSE-dominant regions (all P  < 0.05), whereas no difference was found between PSE-dominant and mild emphysema samples (all P  > 0.5). Immunohistochemistry showed significantly higher infiltration of neutrophils ( P  = 0.002), but not of macrophages, CD4, CD8, or B cells, in PSE compared with CLE regions. Conclusions: The terminal bronchioles are relatively preserved, whereas neutrophilic inflammation is increased in PSE-dominant regions compared with CLE-dominant regions in patients with COPD.

Computed tomography (CT) is commonly used in the evaluation and management of patients with diffuse lung pathologies, including chronic obstructive pulmonary disease (COPD) and fibrotic interstitial lung disease (ILD). In clinical practice, the qualitative (visual) assessment of CT images by a radiologist provides insight into the diagnosis of diffuse lung disease, estimates disease severity, and supports the identification of complications. Quantitative CT (qCT) is an emerging technique that provides some advantages over qualitative assessment. qCT can allow early and accurate detection of emphysema and airway disease, as well as aiding the evaluation of disease burden in both COPD and ILD. This approach is starting to be used as a surrogate biomarker in clinical trials to assess response to therapy. Artificial intelligence techniques have recently been incorporated into qCT, with such rapid evolution that it is currently difficult to determine the exact role it will eventually play in evaluating patients with COPD or pulmonary fibrosis. This article reviews the current state of the art for qualitative and qCT assessment of both COPD and fibrotic ILD. Current areas of controversy and limitations of these techniques are discussed, along with the potential future role of artificial intelligence. Recommendations are provided with regard to the current use of these techniques in the management of patients with diffuse lung disease.

Importance: Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD), yet much of COPD risk remains unexplained., Objective: To determine whether dysanapsis, a mismatch of airway tree caliber to lung size, assessed by computed tomography (CT), is associated with incident COPD among older adults and lung function decline in COPD., Design, Setting, and Participants: A retrospective cohort study of 2 community-based samples: the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study, which involved 2531 participants (6 US sites, 2010-2018) and the Canadian Cohort of Obstructive Lung Disease (CanCOLD), which involved 1272 participants (9 Canadian sites, 2010-2018), and a case-control study of COPD: the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), which involved 2726 participants (12 US sites, 2011-2016)., Exposures: Dysanapsis was quantified on CT as the geometric mean of airway lumen diameters measured at 19 standard anatomic locations divided by the cube root of lung volume (airway to lung ratio)., Main Outcomes and Measures: Primary outcome was COPD defined by postbronchodilator ratio of forced expired volume in the first second to vital capacity (FEV1:FVC) less than 0.70 with respiratory symptoms. Secondary outcome was longitudinal lung function. All analyses were adjusted for demographics and standard COPD risk factors (primary and secondhand tobacco smoke exposures, occupational and environmental pollutants, and asthma)., Results: In the MESA Lung sample (mean [SD] age, 69 years [9 years]; 1334 women [52.7%]), 237 of 2531 participants (9.4%) had prevalent COPD, the mean (SD) airway to lung ratio was 0.033 (0.004), and the mean (SD) FEV1 decline was -33 mL/y (31 mL/y). Of 2294 MESA Lung participants without prevalent COPD, 98 (4.3%) had incident COPD at a median of 6.2 years. Compared with participants in the highest quartile of airway to lung ratio, those in the lowest had a significantly higher COPD incidence (9.8 vs 1.2 cases per 1000 person-years; rate ratio [RR], 8.12; 95% CI, 3.81 to 17.27; rate difference, 8.6 cases per 1000 person-years; 95% CI, 7.1 to 9.2; P < .001) but no significant difference in FEV1 decline (-31 vs -33 mL/y; difference, 2 mL/y; 95% CI, -2 to 5; P = .30). Among CanCOLD participants (mean [SD] age, 67 years [10 years]; 564 women [44.3%]), 113 of 752 (15.0%) had incident COPD at a median of 3.1 years and the mean (SD) FEV1 decline was -36 mL/y (75 mL/y). The COPD incidence in the lowest airway to lung quartile was significantly higher than in the highest quartile (80.6 vs 24.2 cases per 1000 person-years; RR, 3.33; 95% CI, 1.89 to 5.85; rate difference, 56.4 cases per 1000 person-years; 95% CI, 38.0 to 66.8; P<.001), but the FEV1 decline did not differ significantly (-34 vs -36 mL/y; difference, 1 mL/y; 95% CI, -15 to 16; P=.97). Among 1206 SPIROMICS participants (mean [SD] age, 65 years [8 years]; 542 women [44.9%]) with COPD who were followed up for a median 2.1 years, those in the lowest airway to lung ratio quartile had a mean FEV1 decline of -37 mL/y (15 mL/y), which did not differ significantly from the decline in MESA Lung participants (P = .98), whereas those in highest quartile had significantly faster decline than participants in MESA Lung (-55 mL/y [16 mL/y ]; difference, -17 mL/y; 95% CI, -32 to -3; P = .004)., Conclusions and Relevance: Among older adults, dysanapsis was significantly associated with COPD, with lower airway tree caliber relative to lung size associated with greater COPD risk. Dysanapsis appears to be a risk factor associated with COPD.

Background: Chronic obstructive pulmonary disease (COPD) is underdiagnosed in the community. Thoracic CT scans are widely used for diagnostic and screening purposes for lung cancer. In this proof-of-concept study, we aimed to evaluate a software pipeline for the automated detection of COPD, based on deep learning and a dataset of low-dose CTs that were performed for early detection of lung cancer., Methods: We examined the use of deep residual networks, a type of artificial residual network, for the automated detection of COPD. Three versions of the residual networks were independently trained to perform COPD diagnosis using random subsets of CT scans collected from the PanCan study, which enrolled ex-smokers and current smokers at high risk of lung cancer, and evaluated the networks using three-fold cross-validation experiments. External validation was performed using 2153 CT scans acquired from a separate cohort of individuals with COPD in the ECLIPSE study. Spirometric data were used to define COPD, with stages defined according to the GOLD criteria., Findings: The best performing networks achieved an area under the receiver operating characteristic curve (AUC) of 0·889 (SD 0·017) in three-fold cross-validation experiments. When the same set of networks was applied to the ECLIPSE cohort without any modifications to the trained models, they achieved an AUC of 0·886 (0·017), a positive predictive value of 0·847 (0·056), and a negative predictive value of 0·755 (0·097), which is a greater performance than the best quantitative CT measure, the percentage of lung volumes of less than or equal to -950 Hounsfield units (AUC 0·742)., Interpretation: Our proposed approach could identify patients with COPD among ex-smokers and current smokers without a previous diagnosis of COPD, with clinically acceptable performance. The use of deep residual networks on chest CT scans could be an effective case-finding tool for COPD detection and diagnosis, particularly in ex-smokers and current smokers who are being screened for lung cancer., Funding: Data Science Institute, University of British Columbia; Canadian Institutes of Health Research., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Fatty liver disease is associated with cardiometabolic disorders and represents a potential key comorbidity in Chronic Obstructive Pulmonary Disease (COPD). Some intermediary mechanisms of fatty liver disease (including its histological component steatosis) include tissue hypoxia, low-grade inflammation and oxidative stress that are key features of COPD. Despite these shared physiological pathways, the effect of COPD on the prevalence of hepatic steatosis, and the association between hepatic steatosis and comorbidities in this population remain unclear. Liver density measured by computed tomography (CT)-scan is a non-invasive surrogate of fat infiltration, with lower liver densities reflecting more fat infiltration and a liver density of 40 Hounsfield Units (HU) corresponding to a severe 30% fat infiltration., Patients and Methods: We took advantage of the international cohort ECLIPSE in which non-enhanced chest CT-scans were obtained in 1554 patients with COPD and 387 healthy controls to analyse the liver density at T12-L1., Results: The distribution of liver density was similar and the prevalence of severe steatosis (density<40 HU) was not different (4.7% vs 5.2%, p=0.7) between COPD and controls. In patients with COPD, the lowest liver density quartile was associated, after age and sex adjustment, with coronary artery disease (OR a =1.59, 95% CI 1.12 to 2.24) and stroke (OR a =2.20, 95% CI 1.07 to 4.50), in comparison with the highest liver density quartile., Conclusion: The present data indicate that a low liver density emerged as a predictor of cardiovascular comorbidities in the COPD population. However, the distribution of liver density and the prevalence of severe steatosis were similar in patients with COPD and control subjects., Competing Interests: MM, NA and IV have no conflicts of interest to declare. DV reports research grants from Astra Zeneca outside the submitted work. JPD reports personal fees from Abbott Laboratories, AstraZeneca, Sanofi, GSK, Torrent Pharmaceuticals Ltd., Merck and Pfizer Canada Inc., outside the submitted work. HOC reports personal fees and grants from GSK during the conduct of the original ECLIPSE study and no other conflicts during the present study. JLP reports a grant from a consortium of homecare providers (ADIR assistance, Agiradom, IPS, ISIS Medical, LINDE, LVL Medical, SOS Oxygen and Vitalaire) and CPAP companies (Bréas, Philips, Resmed and Sefam), grants from Air Liquide Foundation, Astra-Zeneca, Mutualia, Philips, RESMED, Fisher and Paykel, and personal fees from JAZZ, ITAMAR, Perimetre, Philips, Fisher and Paykel, RESMED, Astra-Zeneca, SEFAM, Agiradom, ELIA and Teva outside the submitted work. FM reports grants and personal fees from Boehringer Ingelheim and GSK, grants from Nycomed and AstraZeneca, and grants and personal fees from Novartis and Grifols outside the submitted work. All fees are pooled with other revenues of the group of pulmonologists to which FM is a member and then shared among members of the group. The authors report no other conflicts of interest in this work., (© 2019 Viglino et al.)

Background: Osteoporosis is prevalent in individuals with COPD. Updated evidence is required to complement the previous systematic review on this topic to provide best practice. The aim of this systematic review and meta-analysis was to quantitatively synthesize data from studies with respect to the prevalence and risk factors for osteoporosis among individuals with COPD., Methods: EMBASE, CINAHL, MEDLINE, and PubMed databases were searched for articles containing the key words "COPD," "osteoporosis," "prevalence," and "risk factor." Eligibility screening, data extraction, and quality assessment of the retrieved articles were conducted independently by two reviewers. Meta-analyses were performed to determine osteoporosis prevalence and risk factors in individuals with COPD. Meta-regression analyses were conducted to explore the sources of heterogeneity., Results: The pooled global prevalence from 58 studies was 38% (95% CI, 34-43). The presence of COPD increased the likelihood of having osteoporosis (OR, 2.83). Other significant risk factors for osteoporosis in COPD patients were BMI < 18.5 kg/m 2 (OR, 4.26) and the presence of sarcopenia (OR, 3.65)., Conclusions: Osteoporosis is prevalent in individuals with COPD, and the prevalence seems to be high and similar in many countries. Patients with COPD should be screened for osteoporosis and contributing risk factors., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Exercise limitation is common in chronic obstructive pulmonary disease (COPD). We determined the impact of pulmonary emphysema on the physiological response to exercise independent of contemporary measures of COPD severity. Smokers 40-79 years old with COPD underwent computed tomography, pulmonary function tesing, and symptom-limited incremental exercise testing. COPD severity was quantified according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) by spirometry (GOLD 1-4); and symptom burden and exacerbation risk (GOLD A-D). Emphysema severity was quantified as the percent lung volume <-950 Hounsfield units. Regression models adjusted for age, gender, body size, smoking status, airflow limitation, symptom burden and exacerbation risk. Among 67 COPD subjects (age 67 ± 8 years; 75% male; GOLD 1-4: 11%, 43%, 30%, 16%), median percent emphysema was 11%, and peak power output (PPO) was 61 ± 32 W. Higher percent emphysema independently predicted lower PPO (-24 W per 10% increment in emphysema; 95%CI -41 to -7 W). Throughout exercise, higher percent emphysema predicted 1) higher minute ventilation, ventilatory equivalent for CO 2 , and heart rate; and 2) lower oxy-hemoglobin saturation, and end-tidal PCO 2 . Independent of contemporary measures of COPD severity, the extent of pulmonary emphysema predicts lower exercise capacity, ventilatory inefficiency, impaired gas-exchange and increased heart rate response to exercise.

Background: The concept that small conducting airways less than 2 mm in diameter become the major site of airflow obstruction in chronic obstructive pulmonary disease (COPD) is well established in the scientific literature, and the last generation of small conducting airways, terminal bronchioles, are known to be destroyed in patients with very severe COPD. We aimed to determine whether destruction of the terminal and transitional bronchioles (the first generation of respiratory airways) occurs before, or in parallel with, emphysematous tissue destruction., Methods: In this cross-sectional analysis, we applied a novel multiresolution CT imaging protocol to tissue samples obtained using a systematic uniform sampling method to obtain representative unbiased samples of the whole lung or lobe of smokers with normal lung function (controls) and patients with mild COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 1), moderate COPD (GOLD 2), or very severe COPD (GOLD 4). Patients with GOLD 1 or GOLD 2 COPD and smokers with normal lung function had undergone lobectomy and pneumonectomy, and patients with GOLD 4 COPD had undergone lung transplantation. Lung tissue samples were used for stereological assessment of the number and morphology of terminal and transitional bronchioles, airspace size (mean linear intercept), and alveolar surface area., Findings: Of the 34 patients included in this study, ten were controls (smokers with normal lung function), ten patients had GOLD 1 COPD, eight had GOLD 2 COPD, and six had GOLD 4 COPD with centrilobular emphysema. The 34 lung specimens provided 262 lung samples. Compared with control smokers, the number of terminal bronchioles decreased by 40% in patients with GOLD 1 COPD (p=0·014) and 43% in patients with GOLD 2 COPD (p=0·036), the number of transitional bronchioles decreased by 56% in patients with GOLD 1 COPD (p=0·0001) and 59% in patients with GOLD 2 COPD (p=0·0001), and alveolar surface area decreased by 33% in patients with GOLD 1 COPD (p=0·019) and 45% in patients with GOLD 2 COPD (p=0·0021). These pathological changes were found to correlate with lung function decline. We also showed significant loss of terminal and transitional bronchioles in lung samples from patients with GOLD 1 or GOLD 2 COPD that had a normal alveolar surface area. Remaining small airways were found to have thickened walls and narrowed lumens, which become more obstructed with increasing COPD GOLD stage., Interpretation: These data show that small airways disease is a pathological feature in mild and moderate COPD. Importantly, this study emphasises that early intervention for disease modification might be required by patients with mild or moderate COPD., Funding: Canadian Institutes of Health Research., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Pain, commonly localized to the trunk in individuals with COPD, may be due to osteoporosis-related vertebral deformity and chest wall hyper-expansion causing misalignment of joints between the ribs and vertebrae. The purpose of this study was to determine if thoracic vertebral deformity and arthropathy were independent contributors to trunk pain in COPD patients compared to people with a significant smoking history., Method: Participants completed the Brief Pain Inventory (BPI) on the same day as chest CT scans and spirometry. Current and ex-smokers were separated into COPD (n = 91) or non-COPD (n = 80) groups based on spirometry. Subsequently, CT images were assessed for thoracic vertebral deformity, bone attenuation values, and arthropathy of thoracic vertebral joints., Results: The trunk area was the most common pain location in both COPD and non-COPD groups. Thoracic vertebral deformity and costotransverse joint arthropathy were independent contributors to trunk pain in COPD patients (adjusted OR = 3.55 and 1.30, respectively) whereas alcohol consumption contributed to trunk pain in the non-COPD group (adjusted OR = 0.35 in occasional alcohol drinkers; 0.08 in non-alcohol drinkers). The spinal deformity index and the number of narrowed disc spaces were significantly positively related to the BPI intensity, interference, and total scores significantly in COPD patients., Conclusion: Trunk pain, at least in part, is caused by thoracic vertebral deformity, and costotransverse and intervertebral arthropathy in patients living with COPD. The results of this study provided the foundation for the management of pain, which requires further exploration., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: In smokers, the lung parenchyma is characterized by inflammation and emphysema, processes that can result in local gain and loss of lung tissue. CT measures of lung density might reflect lung tissue changes; however, longitudinal data regarding the effects of CT lung tissue on FEV 1 in smokers with and without COPD are scarce., Methods: The 15th percentile of CT lung density was obtained from the scans of 3,390 smokers who completed baseline and 5-year follow-up of the Genetic Epidemiology of COPD (COPDGene) study visits. The longitudinal relationship between total lung capacity-adjusted lung density (TLC-PD15) and FEV 1 was assessed by using multivariable mixed models. Separate models were performed in smokers at risk, smokers with preserved ratio and impaired spirometry (PRISm), and smokers with COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging system., Results: The direction of the relationship between lung density and lung function was GOLD stage dependent. In smokers with PRISm, a 1-g/L decrease in TLC-PD15 was associated with an increase of 2.8 mL FEV 1 (P = .02). In contrast, among smokers with GOLD III to IV COPD, a 1-g/L decrease in TLC-PD15 was associated with a decrease of 4.1 mL FEV 1 (P = .002)., Conclusions: A decline in TLC-PD15 was associated with an increase or decrease in FEV 1 depending on disease severity. The associations are GOLD stage specific, and their presence might influence the interpretation of future studies that use CT lung density as an intermediate study end point for a decline in lung function., Trial Registry: ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

The small conducting airways are the major site of obstruction in chronic obstructive pulmonary disease (COPD). This study examined small airway pathology using a novel combination of multidetector row computed tomography (MDCT), micro-computed tomography (microCT) and histology.Airway branches visible on specimen MDCT were counted and the dimensions of the third- to fifth-generation airways were computed, while the terminal bronchioles (designated TB), preterminal bronchioles (TB-1) and pre-preterminal bronchioles (TB-2) were examined with microCT and histology in eight explanted lungs with end-stage COPD and seven unused donor lungs that served as controls.On MDCT, COPD lungs showed a decrease in the number of 2-2.5 mm diameter airways and the lumen area of fifth-generation airways, while on microCT there was a reduction in the number of terminal bronchioles as well as a decrease in the luminal areas, wall volumes and alveolar attachments to the walls of TB, TB-1 and TB-2 bronchioles. The combination of microCT and histology showed increased B-cell infiltration into the walls of TB-1 and TB-2 bronchioles, and this change was correlated with a reduced number of alveolar attachments in COPD.Small airways disease extends from 2 mm diameter airways to the terminal bronchioles in COPD. Destruction of alveolar attachments may be driven by a B-cell-mediated immune response in the preterminal bronchioles., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2018.)

In addition to dyspnea and fatigue, pain is a prevalent symptom in chronic obstructive pulmonary disease (COPD). Understanding the relative prevalence, magnitude, and interference with aspects of daily living of these symptoms can improve COPD management. Therefore, the purposes of this study were to: (1) compare the prevalence and magnitude of dyspnea, fatigue, and pain and how each limits aspects of daily living; (2) determine the association between pain and the other two symptoms; and (3) assess the impact of these symptoms on quality of life in COPD. Participants were recruited from pulmonary rehabilitation programs. Pain, dyspnea, and fatigue were measured using the Brief Pain Inventory (BPI), Brief Fatigue Inventory (BFI), and Dyspnea Inventory (DI), respectively. Quality of life was measured using the Clinical COPD Questionnaire (CCQ). The prevalence of dyspnea, fatigue, and pain were 93%, 77%, and 74%, respectively. Individuals with COPD reported similar severity scores of the three symptoms. Dyspnea interfered with general activity more than pain (F 1.7,79.9 = 3.1, p < 0.05), whilst pain interfered with mood (F 1.8, 82.7 = 3.6, p < 0.05) and sleep (F 1,46 = 7.4, p < 0.01) more than dyspnea and fatigue. These three symptoms were moderately-to-highly correlated with each other (ρ = 0.49-0.78, p < 0.01) and all individually impacted quality of life. In summary, pain is a common symptom in addition to dyspnea and fatigue in COPD; all three interfere similarly among aspects of daily living with some exceptions. Accordingly, management of COPD should include a multifaceted approach that addresses pain as well as dyspnea and fatigue.

Rationale: Studies of excised lungs show that significant airway attrition in the "quiet" zone occurs early in chronic obstructive pulmonary disease (COPD)., Objectives: To determine if the total number of airways quantified in vivo using computed tomography (CT) reflects early airway-related disease changes and is associated with lung function decline independent of emphysema in COPD., Methods: Participants in the multicenter, population-based, longitudinal CanCOLD (Canadian Chronic Obstructive Lung Disease) study underwent inspiratory/expiratory CT at visit 1; spirometry was performed at four visits over 6 years. Emphysema was quantified as the CT inspiratory low-attenuation areas below -950 Hounsfield units. CT total airway count (TAC) was measured as well as airway inner diameter and wall area using anatomically equivalent airways., Measurements and Main Results: Participants included never-smokers (n = 286), smokers with normal spirometry at risk for COPD (n = 298), Global Initiative for Chronic Obstructive Lung Disease (GOLD) I COPD (n = 361), and GOLD II COPD (n = 239). TAC was significantly reduced by 19% in both GOLD I and GOLD II compared with never-smokers (P < 0.0001) and by 17% in both GOLD I and GOLD II compared with at-risk participants (P < 0.0001) after adjusting for low-attenuation areas below -950 Hounsfield units. Further analysis revealed parent airways with missing daughter branches had reduced inner diameters (P < 0.0001) and thinner walls (P < 0.0001) compared with those without missing daughter branches. Among all CT measures, TAC had the greatest influence on FEV 1 (P < 0.0001), FEV 1 /FVC (P < 0.0001), and bronchodilator responsiveness (P < 0.0001). TAC was independently associated with lung function decline (FEV 1 , P = 0.02; FEV 1 /FVC, P = 0.01)., Conclusions: TAC may reflect the airway-related disease changes that accumulate in the "quiet" zone in early/mild COPD, indicating that TAC acquired with commercially available software across various CT platforms may be a biomarker to predict accelerated COPD progression.

CT imaging is a readily quantifiable tool that can provide in-vivo assessments of lung structure in conditions such as chronic obstructive pulmonary disease (COPD). The information extracted from these data has been used in many clinical, epidemiological, and genetic investigations for patient stratification and prognostication, and to determine intermediate endpoints for clinical trials. Although these efforts have informed our understanding of the heterogeneity of pulmonary disease in smokers, they have not yet translated into new treatments for COPD or the personalisation of patient care. There are a multitude of potential reasons for this, including the lack of insight that static imaging provides for lung function and dysfunction, the limited resolution of clinical CT scanning for microscopic changes to the lung architecture, and the challenges that the biomedical community faces when trying to translate discovery to therapy. Such limitations might be addressed through novel image analysis techniques, up-and-coming CT-based and MRI-based technologies, closer ties between academia and industry, and an expanded endeavour to share data across the biomedical community., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To determine comorbidities that cause pain and the potential contributors to pain in individuals with chronic obstructive pulmonary disease (COPD)., Design: Prospective cross-sectional survey study., Setting: Pulmonary rehabilitation programs of 6 centers., Participants: A convenience sample of individuals with COPD (N=137) who attended pulmonary rehabilitation programs. In total, 100 (73%) returned the survey packages. Of those responders, 96 participants (70%) were included in the analyses., Interventions: Not applicable., Main Outcome Measures: Pain was measured using the Brief Pain Inventory. The questionnaire used to obtain information about health conditions that might contribute to pain and a medication record asked, in lay terms, about comorbidities that cause pain. The health conditions that cause pain were then validated by health professionals. Demographics, fatigue, dyspnea, quality of life, and self-efficacy were also measured using questionnaires., Results: Pain was reported in 71% (68/96) of participants. Low back pain was the most common location (41%). Arthritis (75%), back problems (47%), and muscle cramps (46%) were the most common comorbidities that caused pain. Lower self-efficacy, and renting rather than home ownership increased the likelihood of pain (P<.05). Pain severity and Brief Fatigue Inventory scores contributed to pain interference scores (P<.05)., Conclusions: Pain was highly prevalent in pulmonary rehabilitation program participants with COPD. The most common causes of pain were musculoskeletal conditions. Pain severity and higher levels of fatigue contributed to how pain interfered with daily aspects of living. The assessment and management of pain need to be addressed within the overall care of individuals with COPD., (Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Obesity is increasingly associated with COPD, but little is known about the prevalence of ectopic fat accumulation in COPD and whether this can possibly be associated with poor clinical outcomes and comorbidities. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) substudy tested the hypothesis that COPD is associated with increased ectopic fat accumulation and that this would be associated with COPD-related outcomes and comorbidities., Methods: Computed tomography (CT) images of the thorax obtained in ECLIPSE were used to quantify ectopic fat accumulation at L2-L3 (eg, cross-sectional area [CSA] of visceral adipose tissue [VAT] and muscle tissue [MT] attenuation, a reflection of muscle fat infiltration) and CSA of MT. A dose-response relationship between CSA of VAT, MT attenuation and CSA of MT and COPD-related outcomes (6-minute walking distance [6MWD], exacerbation rate, quality of life, and forced expiratory volume in 1 second [FEV 1 ] decline) was addressed with the Cochran-Armitage trend test. Regression models were used to investigate possible relationships between CT body composition indices and comorbidities., Results: From the entire ECLIPSE cohort, we identified 585 subjects with valid CT images at L2-L3 to assess body composition. CSA of VAT was increased ( P <0.0001) and MT attenuation was reduced (indicating more muscle fat accumulation) in patients with COPD ( P <0.002). Progressively increasing CSA of VAT was not associated with adverse clinical outcomes. The probability of exhibiting low 6MWD and accelerated FEV 1 decline increased with progressively decreasing MT attenuation and CSA of MT. In COPD, the probability of having diabetes ( P =0.024) and gastroesophageal reflux ( P =0.0048) at baseline increased in parallel with VAT accumulation, while the predicted MT attenuation increased the probability of cardiovascular comorbidities ( P =0.042). Body composition parameters did not correlate with coronary artery scores or with survival., Conclusion: Ectopic fat accumulation is increased in COPD, and this was associated with relevant clinical outcomes and comorbidities., Competing Interests: Disclosure MM, NA, IV, ER, MCW and JTM have no conflicts of interest to declare. JPD reports personal fees from Abbott Laboratories, AstraZeneca, GSK, Merck and Pfizer Canada Inc. and personal fees from Abbott Laboratories, Sanofi and Torrent Pharmaceuticals Ltd. outside the submitted work. EFMW reports personal fees from Nycomed, AstraZeneca, GSK and Novartis outside the submitted work. GRW reports other fees from GSK and other fees from Genentech outside the submitted work. HOC reports personal fees from GSK, grants from GSK during the conduct of the study, personal fees from Samsung and grants from Spiration Inc. outside the submitted work. WM reports personal fees and other fees from GSK, Pfizer, AstraZeneca and Boehringer Ingelheim, and grants from British Heart Foundation, Chief Scientist Office and Medical Research Council outside the submitted work. DDS reports personal fees from Amgen, grants and personal fees from AstraZeneca, personal fees from Boehringer Ingelheim and grants from Novartis outside the submitted work. FM reports grants and personal fees from Boehringer Ingelheim and GSK, grants from Nycomed and grants and personal fees from Novartis outside the submitted work. All fees are pooled with other revenues of the group of pulmonologists to which FM is a member and then shared among members of the group. The authors report no other conflicts of interest in this work.

While the recent development of quantitative imaging methods have led to their increased use in the diagnosis and management of many chronic diseases, medical imaging still plays a limited role in the management of chronic obstructive pulmonary disease (COPD). In this review we highlight three pulmonary imaging modalities: computed tomography (CT), magnetic resonance imaging (MRI) and optical coherence tomography (OCT) imaging and the COPD biomarkers that may be helpful for managing COPD patients. We discussed the current role imaging plays in COPD management as well as the potential role quantitative imaging will play by identifying imaging phenotypes to enable more effective COPD management and improved outcomes., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Thoracic computed tomography (CT) scans are widely performed in clinical practice, often leading to detection of airway or parenchymal abnormalities in asymptomatic or minimally symptomatic individuals. However, clinical relevance of CT abnormalities is uncertain in the general population., Methods: We evaluated data from 1361 participants aged ≥40 years from a Canadian prospective cohort comprising 408 healthy never-smokers, 502 healthy ever-smokers, and 451 individuals with spirometric evidence of chronic obstructive pulmonary disease (COPD) who had thoracic CT scans. CT images of subjects were visually scored for respiratory bronchiolitis(RB), emphysema(E), bronchial-wall thickening(BWT), expiratory air-trapping(AT), and bronchiectasis(B). Multivariable logistic regression models were used to assess associations of CT features with respiratory symptoms, dyspnea, health status as determined by COPD assessment test, and risk of clinically significant exacerbations during 12 months follow-up., Results: About 11% of life-time never-smokers demonstrated emphysema on CT scans. Prevalence increased to 30% among smokers with normal lung function and 36%, 50%, and 57% among individuals with mild, moderate or severe/very severe COPD, respectively. Presence of emphysema on CT was associated with chronic cough (OR,2.11; 95%CI,1.4-3.18); chronic phlegm production (OR,1.87; 95% CI,1.27-2.76); wheeze (OR,1.61; 95% CI,1.05-2.48); dyspnoea (OR,2.90; 95% CI,1.41-5.98); CAT score≥10(OR,2.17; 95%CI,1.42-3.30) and risk of ≥2 exacerbations over 12 months (OR,2.17; 95% CI, 1.42-3.0)., Conclusions: Burden of thoracic CT abnormalities is high among Canadians ≥40 years of age, including never-smokers and smokers with normal lung function. Detection of emphysema on CT scans is associated with pulmonary symptoms and increased risk of exacerbations, independent of smoking or lung function., Competing Interests: DDM, JCH, JMF, DOD, MK, CJH, RR, RC, SA, PL, and LZ have no conflict to declare. JL reports consultancy for CT scans vendors GE, Samsung, and Philips. DDS reports personal fees from Almirall, AstraZeneca, Amgen, and Novatis, and grants from AstraZeneca, outside the submitted work. FM reports grants and personal fees from GSK, Boehringer Ingelheim, and Novartis, and grants from Nycomed, and AstraZeneca during the conduct of the study. KRC reports grants from Novartis, Almirall, Boehringer Ingelheim, Forest, GSK, AstraZeneca, Amgen, Roche, CSL Behring, Grifols, Genentech, and Kamada, during the conduct of the study; and other from CIHR-GSK Research Chair in Respiratory Health Care Delivery, outside the submitted work. PH has received fees for delivering accredited CME and/or consultancy on advisory board for AstraZeneca, Boehringer Ingelheim, Bayer, CSL Behring, Grifols, GlaxoSmithKline, Merck, Novartis, Roche. Dr.Hernandez's institution has received funding for conducting research from Boehringer Ingelheim, Grifols, and CSL Behring. HOC reports personal fees from GSK, and Samsung, and grants from GSK, and Spiration Inc, outside the submitted work. JB and WCT report grants from the Canadian Institute of Heath Research (CIHR/Rx&D Collaborative Research Program Operating Grants- 93326) with industry partners Astra Zeneca Canada Ltd., Boehringer-Ingelheim Canada Ltd, GlaxoSmithKline Canada Ltd, Merck, Novartis Pharma Canada Inc., Nycomed Canada Inc., and Pfizer Canada Ltd., during the conduct of the study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) result in considerable morbidity and mortality. However, there are no objective biomarkers to diagnose AECOPD., Methods: We used multiple reaction monitoring mass spectrometry to quantify 129 distinct proteins in plasma samples from patients with COPD. This analytical approach was first performed in a biomarker cohort of patients hospitalized with AECOPD (Cohort A, n = 72). Proteins differentially expressed between AECOPD and convalescent states were chosen using a false discovery rate <0.01 and fold change >1.2. Protein selection and classifier building were performed using an elastic net logistic regression model. The performance of the biomarker panel was then tested in two independent AECOPD cohorts (Cohort B, n = 37, and Cohort C, n = 109) using leave-pair-out cross-validation methods., Results: Five proteins were identified distinguishing AECOPD and convalescent states in Cohort A. Biomarker scores derived from this model were significantly higher during AECOPD than in the convalescent state in the discovery cohort (p<0.001). The receiver operating characteristic cross-validation area under the curve (CV-AUC) statistic was 0.73 in Cohort A, while in the replication cohorts the CV-AUC was 0.77 for Cohort B and 0.79 for Cohort C., Conclusions: A panel of five biomarkers shows promise in distinguishing AECOPD from convalescence and may provide the basis for a clinical blood test to diagnose AECOPD. Further validation in larger cohorts is necessary for future clinical translation.

Context: Dyspnea, fatigue, and pain are common in individuals with chronic obstructive pulmonary disease (COPD). However, questionnaires with a similar format are not available to assess their relative severity and interference., Objectives: To determine the reliability and validity of the Brief Fatigue Inventory (BFI) and Dyspnea Inventory (DI) in COPD patients who attend pulmonary rehabilitation programs., Methods: Participants were recruited from four pulmonary rehabilitation programs to complete a survey package containing: the Chronic Respiratory Questionnaire (CRQ), BFI, and DI; and one week later, to complete the BFI and DI. Retrospective data of the CRQ, BFI, and DI were retrieved from one of the programs., Results: For the prospective component, there was an 85% response rate (n = 91) for the first package and 83.5% response rate (n = 76) for the second package. Retrospectively, CRQ, BFI, and DI data were retrieved from 48 charts. The BFI and DI demonstrated excellent internal consistency (Cronbach alpha = 0.96 both), and high test-retest reliability (intraclass correlation3,1 = 0.86 and 0.91, respectively). By comparison to the fatigue and dyspnea domains of the CRQ, the BFI showed high concurrent validity (ρ = -0.83), whereas the DI showed moderate (ρ = -0.57) to high (ρ = -0.78) concurrent validity. Factor analysis provided evidence that the items in the BFI and DI measured the intended constructs., Conclusion: The BFI and DI are valid and reliable measures to evaluate fatigue and dyspnea in COPD patients and could be used concurrently with the Brief Pain Inventory to inform the relative severity and interference of these common symptoms in COPD., (Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Rationale: After adjustment for the amount of smoking, women have a 50% increased risk of chronic obstructive pulmonary disease (COPD) compared with men. The anatomic basis and/or mechanism(s) of these sex-related differences in COPD are unknown., Objectives: To characterize the impact of female sex hormones on chronic cigarette smoke-induced airway remodeling and emphysema in a mouse model of COPD., Methods: Airway remodeling and emphysema were determined morphometrically in male, female, and ovariectomized mice exposed to 6 months of cigarette smoke. Antioxidant- and transforming growth factor (TGF)-β-related genes were profiled in airway tissues. The selective estrogen receptor modulator tamoxifen was also administered during smoke exposure in a short-term model. Airway wall thickness of male and female human smokers at risk of or with mild COPD was measured using optical coherence tomography., Measurements and Main Results: Small airway wall remodeling was increased in female but not male or ovariectomized mice and was associated with increased distal airway resistance, down-regulation of antioxidant genes, increased oxidative stress, and activation of TGF-β1. These effects were prevented by ovariectomy. Use of tamoxifen as a therapeutic intervention mitigated smoke-induced increase in oxidative stress in female mice. Compared with male human smokers, female human smokers had significantly thicker airway walls., Conclusions: The excess risk of small airway disease in female mice after chronic smoke exposure was associated with increased oxidative stress and TGF-β1 signaling and also was related to the effects of female sex hormones. Estrogen receptor antagonism might be of value in reducing oxidative stress in female smokers.

Importance: Interstitial lung abnormalities have been associated with lower 6-minute walk distance, diffusion capacity for carbon monoxide, and total lung capacity. However, to our knowledge, an association with mortality has not been previously investigated., Objective: To investigate whether interstitial lung abnormalities are associated with increased mortality., Design, Setting, and Population: Prospective cohort studies of 2633 participants from the FHS (Framingham Heart Study; computed tomographic [CT] scans obtained September 2008-March 2011), 5320 from the AGES-Reykjavik Study (Age Gene/Environment Susceptibility; recruited January 2002-February 2006), 2068 from the COPDGene Study (Chronic Obstructive Pulmonary Disease; recruited November 2007-April 2010), and 1670 from ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; between December 2005-December 2006)., Exposures: Interstitial lung abnormality status as determined by chest CT evaluation., Main Outcomes and Measures: All-cause mortality over an approximate 3- to 9-year median follow-up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort., Results: Interstitial lung abnormalities were present in 177 (7%) of the 2633 participants from FHS, 378 (7%) of 5320 from AGES-Reykjavik, 156 (8%) of 2068 from COPDGene, and in 157 (9%) of 1670 from ECLIPSE. Over median follow-up times of approximately 3 to 9 years, there were more deaths (and a greater absolute rate of mortality) among participants with interstitial lung abnormalities when compared with those who did not have interstitial lung abnormalities in the following cohorts: 7% vs 1% in FHS (6% difference [95% CI, 2% to 10%]), 56% vs 33% in AGES-Reykjavik (23% difference [95% CI, 18% to 28%]), and 11% vs 5% in ECLIPSE (6% difference [95% CI, 1% to 11%]). After adjustment for covariates, interstitial lung abnormalities were associated with a higher risk of death in the FHS (hazard ratio [HR], 2.7 [95% CI, 1.1 to 6.5]; P = .03), AGES-Reykjavik (HR, 1.3 [95% CI, 1.2 to 1.4]; P < .001), COPDGene (HR, 1.8 [95% CI, 1.1 to 2.8]; P = .01), and ECLIPSE (HR, 1.4 [95% CI, 1.1 to 2.0]; P = .02) cohorts. In the AGES-Reykjavik cohort, the higher rate of mortality could be explained by a higher rate of death due to respiratory disease, specifically pulmonary fibrosis., Conclusions and Relevance: In 4 separate research cohorts, interstitial lung abnormalities were associated with a greater risk of all-cause mortality. The clinical implications of this association require further investigation.

Despite decades of research, and the growing healthcare and societal burden of chronic obstructive pulmonary disease (COPD), therapeutic COPD breakthroughs have not occurred. Sub-optimal COPD patient phenotyping, an incomplete understanding of COPD pathogenesis and a scarcity of sensitive tools that provide patient-relevant intermediate endpoints likely all play a role in the lack of new, efficacious COPD interventions. In other words, COPD patients are still diagnosed based on the presence of persistent airflow limitation measured using spirometry. Spirometry measurements reflect the global sum of all the different possible COPD pathologies and perhaps because of this, we lose sight of the different contributions of airway and parenchymal abnormalities. With recent advances in thoracic X-ray computed tomography (CT) and magnetic resonance imaging (MRI), lung structure and function abnormalities may be regionally identified and measured. These imaging endpoints may serve as biomarkers of COPD that can be used to better phenotype patients. Therefore, here we review novel CT and MRI measurements that help reveal COPD phenotypes and what COPD really 'looks' like, beyond spirometric indices. We discuss MR and CT imaging approaches for generating reproducible and sensitive measurements of COPD phenotypes related to pulmonary ventilation and perfusion as well as airway and parenchyma anatomical and morphological features. These measurements may provide a way to advance the development and testing of new COPD interventions and therapies., (© 2015 Asian Pacific Society of Respirology.)

Purpose: To determine the role of imaging measurements of emphysema and airway disease in determining chronic obstructive pulmonary disease (COPD) symptoms and exercise limitation in patients with COPD, particularly in patients with mild-to-moderate disease., Materials and Methods: Participants (n = 116) with Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade U (unclassified) or grade I-IV COPD provided informed consent to an ethics board-approved HIPAA-compliant protocol and underwent spirometry and plethysmography, completed the St George's Respiratory Questionnaire (SGRQ), completed a 6-minute walk test for the 6-minute walk distance (6MWD), and underwent hyperpolarized helium 3 ((3)He) magnetic resonance (MR) imaging and computed tomography (CT). Emphysema was estimated by using the MR imaging apparent diffusion coefficient (ADC) and the relative area of the CT attenuation histogram with attenuation of -950 HU or less (RA950). Airway disease was measured by using the CT airway wall thickness of airways with an internal perimeter of 10 mm and total airway count. Ventilation defect percentage at (3)He MR imaging was used to measure ventilation. Multivariable regression models for the 6MWD and SGRQ symptom subscore were used to evaluate the relationships between physiologic and imaging measurements., Results: Multivariate modeling for the 6MWD in 80 patients with GOLD grade U-II COPD showed that ADC (β = 0.34, P = .04), diffusing capacity of the lung for carbon monoxide (β = 0.60, P = .0008), and residual volume/total lung capacity (β = -0.26, P = .02) were significant variables, while forced expiratory volume in 1 second (FEV1) and airway disease measurements were not. In 36 patients with GOLD grade III or IV disease, FEV1 (β = 0.48, P = .01) was the only significant contributor in a multivariate model for 6MWD. MR imaging emphysema measurements also made the greatest relative contribution to symptoms in patients with milder (GOLD grade U-II) COPD (ADC: β = 0.60, P = .005; RA950: β = -0.52, P = .02; FEV1: β = -0.45, P = .0002) and in grade III or IV disease (ADC: β = 0.95, P = .01; RA950: β = -0.62, P = .07; airway count: β = -0.49, P = .01)., Conclusion: In patients with mild-to-moderate COPD, MR imaging emphysema measurements played a dominant role in the expression of exercise limitation, while both CT and MR imaging measurements of emphysema explained symptoms.

The purpose of this statement is to describe and define the phenotypic abnormalities that can be identified on visual and quantitative evaluation of computed tomographic (CT) images in subjects with chronic obstructive pulmonary disease (COPD), with the goal of contributing to a personalized approach to the treatment of patients with COPD. Quantitative CT is useful for identifying and sequentially evaluating the extent of emphysematous lung destruction, changes in airway walls, and expiratory air trapping. However, visual assessment of CT scans remains important to describe patterns of altered lung structure in COPD. The classification system proposed and illustrated in this article provides a structured approach to visual and quantitative assessment of COPD. Emphysema is classified as centrilobular (subclassified as trace, mild, moderate, confluent, and advanced destructive emphysema), panlobular, and paraseptal (subclassified as mild or substantial). Additional important visual features include airway wall thickening, inflammatory small airways disease, tracheal abnormalities, interstitial lung abnormalities, pulmonary arterial enlargement, and bronchiectasis., ((©) RSNA, 2015.)

Rationale: Low educational attainment is a risk factor of chronic obstructive pulmonary disease (COPD). There is limited knowledge on the relationship between educational level and computed tomography measures of emphysema and airway wall thickness (AWT)., Objectives: We hypothesized that low educational attainment is associated with increased emphysema and AWT in ever-smokers with and without COPD., Methods: We included 462 and 485 ever-smokers with and without COPD in a cross-sectional study, aged 40-86 years. The sample was divided into groups reflecting educational attainment: primary, secondary, and university. We performed linear regression to examine associations between educational attainment and both emphysema and AWT separately for those with and without COPD. We adjusted for sex, age, smoking status, age of onset of smoking, pack-years, height, and body mass index., Measurements and Main Results: Compared with university education, in subjects with COPD, primary education was associated with a 68.1% (95% confidence interval = 14.2-147.6%; P = 0.01) relative increase in emphysema and secondary education was associated with a 50.6% (95% confidence interval = 5.7-114.6%; P = 0.02) relative increase. There was a nonsignificant trend toward an association between lower educational attainment and increased emphysema among those without COPD (P = 0.18), yet greater age appeared to modify this association (P = 0.01). We did not detect significant linear relationships between educational attainment and AWT in subjects with or without COPD., Conclusions: Lower educational attainment was associated with increased emphysema among adults with COPD. Among those without COPD, this association was more pronounced with increasing age. No significant linear relationship between educational attainment and AWT was found. Clinicians treating adults with emphysema should keep in mind that factors related to low education beyond that of smoking and occupational dust exposure might be of importance to the disease.

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. 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 summarised, and then salient knowledge gaps were identified. Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. 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-centred outcomes., (Copyright ©ATS/ERS 2015.)

Background: To evaluate ultra-short-echo-time (UTE) MRI pulmonary signal-intensity measurements and reproducibility in chronic obstructive pulmonary disease (COPD)., Methods: A two-dimensional sequence (echo-time = 0.05 ms; acquisition-time = 13 s) with interleaved half-pulse excitation and radial ramp-sampling was used with compressed-sensing to reconstruct UTE images from under-sampled data. Five healthy volunteers and 15 subjects with COPD provided written informed consent to imaging and pulmonary-function-tests. Healthy volunteers underwent MRI at four lung volumes: full-expiration, functional-residual-capacity (FRC), FRC+1L, and full-inhalation; COPD patients underwent computed-tomography (CT) and MRI at FRC+1L. Three-week reproducibility was evaluated and the relative area of the density histogram ≤ -950 HU (RA950 ) was compared with mean MRI signal-intensity. The 15th percentile of signal-intensity-histogram (SI15 ) was compared with the 15th percentile of the CT-density-histogram (HU15 )., Results: In healthy subjects, signal-intensity correlated with the inverse of lung volume (r = 0.99; P = 0.007). Contrast-to-noise and signal-to-noise ratios were significantly improved for 32-channel UTE (P < 0.01). The coefficient of variation for 3-week repeated measurements was 4%. There were significant correlations for signal-intensity with RA950 (r = -0.71; P = 0.005), FEV1 /FVC (r = 0.59; P = 0.02), and for SI15 with HU15 (r = 0.62; P = 0.01)., Conclusion: Pulmonary signal-intensity is reproducible and related to tissue density. In COPD subjects with and without bronchiectasis, signal-intensity was also related to pulmonary function and CT measurements., (© 2014 Wiley Periodicals, Inc.)

Background: Poor health status has been associated with morbidity and mortality in patients with COPD. To date, the impact of changes in health status on these outcomes remains unknown., Aims: To explore the relationship of clinically relevant changes in health status with exacerbation, hospitalisation or death in patients with COPD., Methods: Characteristics and health status (St George's Respiratory Questionnaire, SGRQ) were assessed over a period of 3 years in 2138 patients with COPD enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study: a longitudinal, prospective, observational study. Associations between change in health status (=4 units in SGRQ score) during year 1 and time to first exacerbation, hospitalisation and death during 2-year follow-up were assessed using Kaplan-Meier plots and log-rank test., Results: 1832 (85.7%) patients (age 63.4±7.0 years, 65.4% male, FEV1 48.7±15.6% predicted) underwent assessment at baseline and 1 year. Compared with those who deteriorated, patients with improved or stable health status in year 1 have a lower likelihood of exacerbation (HR 0.78 (95% CI 0.67 to 0.89), p<0.001 and 0.84 (0.73 to 0.97), p=0.016, respectively), hospitalisation (0.72 (0.58 to 0.90), p=0.004 and 0.77 (0.62 to 0.96), p=0.023, respectively) or dying (0.61 (0.39 to 0.95), p=0.027 and 0.58 (0.37 to 0.92), p=0.019, respectively) during 2-year follow-up. This effect persisted after stratification for age and the number of exacerbations and hospitalisations during the first year of the study., Conclusions: Patients with stable or improved health status during year 1 of ECLIPSE had a lower likelihood of exacerbation, hospitalisation or dying during 2-year follow-up. Interventions that stabilise and improve health status may also improve outcomes in patients with COPD., Trial Registration Number: NCT00292552, registered at ClinicalTrials.gov., (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.

Rationale and Objectives: In this proof-of-concept demonstration, we aimed to quantitatively and qualitatively compare pulmonary ventilation abnormalities derived from Fourier decomposition of free-breathing (1)H magnetic resonance imaging (FDMRI) to hyperpolarized (3)He MRI in subjects with chronic obstructive pulmonary disease (COPD) and bronchiectasis., Materials and Methods: All subjects provided written informed consent to a protocol approved by a local research ethics board and Health, Canada, and they underwent MRI, computed tomography (CT), spirometry, and plethysmography during a single 2-hour visit. Semiautomated segmentation was used to generate ventilation defect measurements derived from FDMRI and (3)He MRI, and these were compared using analysis of variance and Pearson correlations., Results: Twenty-six subjects were evaluated including 12 COPD subjects (67 ± 9 years) and 14 bronchiectasis subjects (70 ± 11 years). For COPD subjects, FDMRI and (3)He MRI ventilation defect percent (VDP) was 7 ± 6% and 24 ± 14%, respectively (P < .001; bias = -16 ± 9%). In COPD subjects, FDMRI was significantly correlated with (3)He MRI VDP (r = .88; P = .0001), (3)He MRI apparent diffusion coefficient (r = .71; P < .05), airways resistance (r = .60; P < .05), and RA950 (r = .80; P < .01). In subjects with bronchiectasis, FDMRI VDP (5 ± 3%) and (3)He MRI VDP (18 ± 9%) were significantly different (P < .001) and not correlated (P > .05). The Dice similarity coefficient (DSC) for FDMRI and (3)He MRI ventilation was 86 ± 7% for COPD and 86 ± 4% for bronchiectasis subjects (P > .05); the DSC for FDMRI ventilation defects and CT RA950 was 19 ± 20% in COPD and 2 ± 3% in bronchiectasis subjects (P < .01)., Conclusions: FDMRI and (3)He MRI VDP were strongly related in COPD but not in bronchiectasis subjects. In COPD only, FDMRI ventilation defects were spatially related with (3)He ventilation defects and emphysema., (Copyright © 2015 AUR. Published by Elsevier Inc. All rights reserved.)

It is well-established that COPD patients have a burden of vascular disease that cannot be fully-explained by smoking history but the mechanistic links between atherosclerosis and pulmonary disease in COPD patients are not well-understood. Moreover, in ex-smokers without symptoms or other evidence of COPD, subclinical pulmonary and vascular disease, although potentially present, has not been described or evaluated. Hence our aim was to use sensitive three-dimensional (3D) pulmonary and carotid imaging to quantify pulmonary airway/parenchyma abnormalities and atherosclerosis in ex-smokers without airflow limitation or symptoms consistent with COPD. We evaluated 61 subjects without airflow limitation including 34 never- (72 ± 6 years) and 27 ex-smokers (73 ± 9 years), who provided written informed consent to spirometry, plethysmography, (3)He magnetic resonance imaging (MRI) and carotid ultrasound (US) and, for ex-smokers alone, thoracic X-ray computed tomography (CT). Ex-smokers had significantly greater (3)He ventilation defect percent (VDP = 7%, p = 0.001) and carotid total plaque volume (TPV = 250 mm(3), p = 0.002) than never-smokers, although there were no significant differences for spirometry or plethysmography, and CT airway and emphysema measurements were normal. There were univariate relationships for (3)He VDP with carotid intima media thickness (IMT, r = 0.42, p = 0.004), TPV (r = 0.41, p = 0.006) and vessel wall volume (VWV, r = 0.40, p = 0.007). Multivariate models that included age, BMI, FEV1, DLCO and VDP showed that only VDP significantly predicted IMT (β = 0.41, p = 0.001), VWV (β = 0.45, p = 0.003) and TPV (β = 0.38, p = 0.005). In summary, there was imaging evidence of mild airways disease and carotid plaque burden that were related and significantly greater in ex-smokers without airflow limitation than in never-smokers.

Purpose: To evaluate the predictive value of imaging and clinical and physiological measurements of chronic obstructive pulmonary disease ( COPD chronic obstructive pulmonary disease ) in patients monitored for more than 5 years for pulmonary exacerbations that required hospitalization., Materials and Methods: Exacerbations requiring hospitalization were monitored over 5 years in 91 subjects who provided written informed consent. Study was local research ethics board and Health Canada approved and HIPAA compliant. Subjects with COPD chronic obstructive pulmonary disease underwent spirometry, plethysmography, diffusing capacity of carbon monoxide, St George's Respiratory Questionnaire, 6-minute walk test, and imaging. Computed tomographic (CT) wall area and relative area with attenuation values less than -950 HU ( RA950 relative area with attenuation values less than -950 HU ), helium 3 ((3)He) magnetic resonance (MR) imaging ventilation defect percentage ( VDP ventilation defect percentage ), and apparent diffusion coefficient were generated. Zero-inflated Poisson model was used to compare number of hospitalizations with lung function and imaging measurements., Results: Twenty-four subjects were hospitalized 58 times and had significantly worse forced expiratory volume in 1 second ( FEV1 forced expiratory volume in 1 second ) (P < .0001), CT RA950 relative area with attenuation values less than -950 HU (P = .02), and (3)He VDP ventilation defect percentage (P < .0001) than values in 67 subjects who were not hospitalized. In mild to moderate COPD chronic obstructive pulmonary disease , nine hospitalized subjects had significantly worse FEV1 forced expiratory volume in 1 second (P = .02) and (3)He VDP ventilation defect percentage (P = .02) than values in 52 subjects who were not hospitalized. (3)He VDP ventilation defect percentage was quantitatively related to CT airway morphology (r = 0.26, P = .01) and quantitatively (r = 0.61, P < .0001) and spatially related to emphysema; this spatial relationship was significantly greater for hospitalized patients with COPD chronic obstructive pulmonary disease than unhospitalized patients (P = .0006). For all subjects, number of prior hospitalizations (P < .0001), 6-minute walk test distance (P < .0001), CT RA950 relative area with attenuation values less than -950 HU (P = .03), and (3)He VDP ventilation defect percentage (P = .002) were significantly related to number of hospitalizations. For 61 subjects with mild to moderate COPD chronic obstructive pulmonary disease , only (3)He VDP ventilation defect percentage was significantly associated with COPD chronic obstructive pulmonary disease exacerbations (P = .01)., Conclusion: (3)He MR imaging VDP ventilation defect percentage represents a mixed airways-emphysema phenotype and helps identify subjects with mild to moderate COPD chronic obstructive pulmonary disease who are at risk for exacerbation that requires hospitalization., (© RSNA, 2014.)

Hypoxemia is a major complication of chronic obstructive pulmonary disease (COPD) that correlates with disease prognosis. Identifying genetic variants associated with oxygenation may provide clues for deciphering the heterogeneity in prognosis among patients with COPD. However, previous genetic studies have been restricted to investigating COPD candidate genes for association with hypoxemia. To report results from the first genome-wide association study (GWAS) of resting oxygen saturation (as measured by pulse oximetry [Spo2]) in subjects with COPD, we performed a GWAS of Spo2 in two large, well characterized COPD populations: COPDGene, including both the non-Hispanic white (NHW) and African American (AA) groups, and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). We identified several suggestive loci (P < 1 × 10(-5)) associated with Spo2 in COPDGene in the NHW (n = 2810) and ECLIPSE (n = 1758) groups, and two loci on chromosomes 14 and 15 in the AA group (n = 820) from COPDGene achieving a level of genome-wide significance (P < 5 × 10(-8)). The chromosome 14 single-nucleotide polymorphism, rs6576132, located in an intergenic region, was nominally replicated (P < 0.05) in the NHW group from COPDGene. The chromosome 15 single-nucleotide polymorphisms were rare in subjects of European ancestry, so the results could not be replicated. The chromosome 15 region contains several genes, including TICRR and KIF7, and is proximal to RHCG (Rh family C glyocoprotein gene). We have identified two loci associated with resting oxygen saturation in AA subjects with COPD, and several suggestive regions in subjects of European descent with COPD. Our study highlights the importance of investigating the genetics of complex traits in different racial groups.

Background: Chronic obstructive pulmonary disease (COPD) has been classically divided into blue bloaters and pink puffers. The utility of these clinical subtypes is unclear. However, the broader distinction between airway-predominant and emphysema-predominant COPD may be clinically relevant. The objective was to define clinical features of emphysema-predominant and non-emphysematous COPD patients., Methods: Current and former smokers from the Genetic Epidemiology of COPD Study (COPDGene) had chest computed tomography (CT) scans with quantitative image analysis. Emphysema-predominant COPD was defined by low attenuation area at -950 Hounsfield Units (LAA-950) ≥10%. Non-emphysematous COPD was defined by airflow obstruction with minimal to no emphysema (LAA-950 < 5%)., Results: Out of 4197 COPD subjects, 1687 were classified as emphysema-predominant and 1817 as non-emphysematous; 693 had LAA-950 between 5-10% and were not categorized. Subjects with emphysema-predominant COPD were older (65.6 vs 60.6 years, p < 0.0001) with more severe COPD based on airflow obstruction (FEV1 44.5 vs 68.4%, p < 0.0001), greater exercise limitation (6-minute walk distance 1138 vs 1331 ft, p < 0.0001) and reduced quality of life (St. George's Respiratory Questionnaire score 43 vs 31, p < 0.0001). Self-reported diabetes was more frequent in non-emphysematous COPD (OR 2.13, p < 0.001), which was also confirmed using a strict definition of diabetes based on medication use. The association between diabetes and non-emphysematous COPD was replicated in the ECLIPSE study., Conclusions: Non-emphysematous COPD, defined by airflow obstruction with a paucity of emphysema on chest CT scan, is associated with an increased risk of diabetes. COPD patients without emphysema may warrant closer monitoring for diabetes, hypertension, and hyperlipidemia and vice versa., Trial Registration: Clinicaltrials.gov identifiers: COPDGene NCT00608764, ECLIPSE NCT00292552.

Rationale and Objectives: Computed tomography (CT) of the chest can be used to assess pectoralis muscle area (PMA) and subcutaneous adipose tissue (SAT) area. Adipose tissue content is associated with inflammatory mediators in chronic obstructive pulmonary disease (COPD) subjects. Based on gender differences in body composition, we aimed to assess the hypothesis that in subjects with COPD, the relationships between PMA, SAT, and blood biomarkers of inflammation differ by gender., Materials and Methods: We compared chest CT measures of PMA and SAT on a single slice at aortic arch and supraesternal notch levels from 73 subjects (28 women) with COPD between genders. The relationships of PMA and SAT area to biomarkers were assessed using within-gender regression models., Results: Women had a lesser PMA and a greater SAT area than men (difference range for PMA, 13.3-22.8 cm²; for SAT, 11.8-12.4 cm²; P < .05 for all comparisons) at both anatomic levels. These differences in PMA and SAT remained significant after adjustment for age and body mass index. Within-gender regression models adjusted for age showed that SAT was directly associated with C-reactive protein (for aortic arch level, P = .04) and fibrinogen (for both anatomic locations, P = .003) only in women, whereas PMA was not associated with any biomarkers in either gender., Conclusions: It appears that in subjects with COPD, there are gender-based differences in the relationships between subcutaneous adipose tissue and inflammatory biomarkers., (Copyright © 2014 AUR. Published by Elsevier Inc. All rights reserved.)

Background: Chronic Obstructive Pulmonary Disease (COPD) is a progressive airway disease characterised by neutrophilic airway inflammation or bronchitis. Neutrophilic bronchitis is associated with both bacterial colonisation and lung function decline and is common in exacerbations of COPD. Despite current available therapies to control inflammation, neutrophilic bronchitis remains common. This study tested the hypothesis that azithromycin treatment, as an add-on to standard medication, would significantly reduce airway neutrophil and neutrophils chemokine (CXCL8) levels, as well as bacterial load. We conducted a randomised, double-blind, placebo-controlled study in COPD participants with stable neutrophilic bronchitis., Methods: Eligible participants (n = 30) were randomised to azithromycin 250 mg daily or placebo for 12 weeks in addition to their standard respiratory medications. Sputum was induced at screening, randomisation and monthly for a 12 week treatment period and processed for differential cell counts, CXCL8 and neutrophil elastase assessment. Quantitative bacteriology was assessed in sputum samples at randomisation and the end of treatment visit. Severe exacerbations where symptoms increased requiring unscheduled treatment were recorded during the 12 week treatment period and for 14 weeks following treatment. A sub-group of participants underwent chest computed tomography scans (n = 15)., Results: Nine participants with neutrophilic bronchitis had a potentially pathogenic bacteria isolated and the median total bacterial load of all participants was 5.22×107 cfu/mL. Azithromycin treatment resulted in a non-significant reduction in sputum neutrophil proportion, CXCL8 levels and bacterial load. The mean severe exacerbation rate was 0.33 per person per 26 weeks in the azithromycin group compared to 0.93 exacerbations per person in the placebo group (incidence rate ratio (95%CI): 0.37 (0.11,1.21), p = 0.062). For participants who underwent chest CT scans, no alterations were observed., Conclusions: In stable COPD with neutrophilic bronchitis, add-on azithromycin therapy showed a trend to reduced severe exacerbations sputum neutrophils, CXCL8 levels and bacterial load. Future studies with a larger sample size are warranted., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12609000259246.

Background: Chronic obstructive pulmonary disease (COPD) is characterized by expiratory flow limitation, causing air trapping and lung hyperinflation. Hyperinflation leads to reduced exercise tolerance and poor quality of life in COPD patients. Total lung capacity (TLC) is an indicator of hyperinflation particularly in subjects with moderate-to-severe airflow obstruction. The aim of our study was to identify genetic variants associated with TLC in COPD., Methods: We performed genome-wide association studies (GWASs) in white subjects from three cohorts: the COPDGene Study; the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); and GenKOLS (Bergen, Norway). All subjects were current or ex-smokers with at least moderate airflow obstruction, defined by a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) <0.7 and FEV1 < 80% predicted on post-bronchodilator spirometry. TLC was calculated by using volumetric computed tomography scans at full inspiration (TLCCT). Genotyping in each cohort was completed, with statistical imputation of additional markers. To find genetic variants associated with TLCCT, linear regression models were used, with adjustment for age, sex, pack-years of smoking, height, and principal components for genetic ancestry. Results were summarized using fixed-effect meta-analysis., Results: Analysis of a total of 4,543 COPD subjects identified one genome-wide significant locus on chromosome 5p15.2 (rs114929486, β = 0.42L, P = 4.66 × 10-8)., Conclusions: In COPD, TLCCT was associated with a SNP in dynein, axonemal, heavy chain 5 (DNAH5), a gene in which genetic variants can cause primary ciliary dyskinesia. DNAH5 could have an effect on hyperinflation in COPD.

Background: Coronary artery calcification is pathognomonic of coronary artery disease (CAD). Whether CAD in patients with COPD is linked to lung function, functional capacity and/or clinically relevant outcomes is unknown. The objective was to assess the association between CAD and disease severity, functional capacity and outcomes in patients with COPD., Methods: Coronary artery calcium score (CACS; Agatston score) was measured using chest CT in patients with COPD, smokers with normal spirometry and non-smokers from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study., Results: CACS was measured in 942 subjects: 672 with COPD (mean age±SD, 63±7 years; FEV1 49±16% predicted), 199 smokers with normal spirometry (54±9 years; FEV1 110±12% predicted) and 71 non-smokers (55±9 years; FEV1 114±14% predicted). CACS was higher in patients with COPD than smokers or non-smokers (median (IQR), 128 (492) vs 0 (75) vs 0 (3) Agatston units (AU), p<0.001). In patients with COPD, CACS correlated with age, pack-years, 6 min walking distance, modified Medical Research Council Dyspnoea score and circulating levels of interleukin (IL)-6, IL-8, Clara Cell protein 16, surfactant protein D and peripheral blood neutrophil count, but not with emphysema, exacerbation frequency, % predicted FEV1 or decline in FEV1. CACS was higher in patients with COPD who died than in those who survived until 3-year follow-up (CACS 406 vs 103 AU, p<0.001), and was associated with mortality in a Cox proportional hazards model (p=0.036)., Conclusions: Patients with COPD have more CAD than controls and this is associated with increased dyspnoea, reduced exercise capacity and increased mortality. These data indicate that the presence of CAD in patients with COPD is associated with poor clinical outcomes., (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.)

FEV1, measured using spirometry, provides a straightforward, widely available, and inexpensive global measurement of airflow limitation and lung function. For decades, FEV1 has remained the main intermediate endpoint used in research studies and for the development of new chronic obstructive pulmonary disease (COPD) therapies. Not surprisingly, treatments that acutely improve FEV1 dominate as COPD therapies. However, in patients with COPD, the relationship of FEV1 with symptoms and outcomes such as exacerbations and mortality is weak, and, importantly, FEV1 does not take into account the heterogeneity of COPD or its different phenotypes. Thoracic imaging provides a way to quantify airway remodeling, emphysematous destruction, regional ventilation abnormalities (ventilation defects), and gas trapping in ex-smokers in whom FEV1 may be normal and in patients with COPD with very modest lung function deterioration. In individual patients and in COPD cohort studies, thoracic imaging using X-ray computed tomography, and magnetic resonance imaging (conventional (1)H as well as hyperpolarized noble gases such as (129)Xe, (3)He, and inhaled O2 and (19)F) can be used to directly visualize the structural and functional consequences of COPD and thus provide a clearer picture of COPD mechanisms, disease progression, and response to therapy. We briefly describe pulmonary imaging methods that provide a way to visualize and quantify, with high spatial and temporal resolution, regional ventilation abnormalities, gas trapping, emphysema, and airway remodeling in COPD. Finally, we discuss the implications of recent imaging findings and their impact on future biomarker and therapy research aimed at improving COPD outcomes.