Publications by authors named "Graham Barr"

360 Publications

Adipose tissue biomarkers and type 2 diabetes incidence in normoglycemic participants in the MESArthritis Ancillary Study: A cohort study.

PLoS Med 2021 Jul 9;18(7):e1003700. Epub 2021 Jul 9.

Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

Background: Given the central role of skeletal muscles in glucose homeostasis, deposition of adipose depots beneath the fascia of muscles (versus subcutaneous adipose tissue [SAT]) may precede insulin resistance and type 2 diabetes (T2D) incidence. This study was aimed to investigate the associations between computed tomography (CT)-derived biomarkers for adipose tissue and T2D incidence in normoglycemic adults.

Methods And Findings: This study was a population-based multiethnic retrospective cohort of 1,744 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) with normoglycemia (baseline fasting plasma glucose [FPG] less than 100 mg/dL) from 6 United States of America communities. Participants were followed from April 2010 and January 2012 to December 2017, for a median of 7 years. The intermuscular adipose tissue (IMAT) and SAT areas were measured in baseline chest CT exams and were corrected by height squared (SAT and IMAT indices) using a predefined measurement protocol. T2D incidence, as the main outcome, was based on follow-up FPG, review of hospital records, or self-reported physician diagnoses. Participants' mean age was 69 ± 9 years at baseline, and 977 (56.0%) were women. Over a median of 7 years, 103 (5.9%) participants were diagnosed with T2D, and 147 (8.4%) participants died. The IMAT index (hazard ratio [HR]: 1.27 [95% confidence interval [CI]: 1.15-1.41] per 1-standard deviation [SD] increment) and the SAT index (HR: 1.43 [95% CI: 1.16-1.77] per 1-SD increment) at baseline were associated with T2D incidence over the follow-up. The associations of the IMAT and SAT indices with T2D incidence were attenuated after adjustment for body mass index (BMI) and waist circumference, with HRs of 1.23 (95% CI: 1.09-1.38) and 1.29 (95% CI: 0.96-1.74) per 1-SD increment, respectively. The limitations of this study include unmeasured residual confounders and one-time measurement of adipose tissue biomarkers.

Conclusions: In this study, we observed an association between IMAT at baseline and T2D incidence over the follow-up. This study suggests the potential role of intermuscular adipose depots in the pathophysiology of T2D.

Trial Registration: ClinicalTrials.gov NCT00005487.
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http://dx.doi.org/10.1371/journal.pmed.1003700DOI Listing
July 2021

Polycythemia is Associated with Lower Incidence of Severe COPD Exacerbations in the SPIROMICS Study.

Chronic Obstr Pulm Dis 2021 Jul;8(3):326-335

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, United States.

Secondary polycythemia has long been recognized as a consequence of chronic pulmonary disease and hypoxemia and is associated with lower mortality and fewer hospitalizations among individuals with chronic obstructive pulmonary disease (COPD)-prescribed long-term oxygen therapy. This study investigates the association of polycythemia with COPD severity, phenotypic features, and respiratory exacerbations in a contemporary and representative sample of individuals with COPD. Current and former smokers with COPD (forced expiratory volume in 1 second [FEV] to forced vital capacity [FVC] ratio <70%) without a history of hematologic/oncologic disorders were selected from the SubPopulations and InteRmediate Outcomes Measures In COPD Study (SPIROMICS), a multi-center observational cohort. Participants with polycythemia (hemoglobin ≥15g/dL [females] or ≥17g/dL [males]), were compared to individuals without anemia (hemoglobin ≥12g/dL [females] or ≥13g/dL [males]). Cross-sectional outcomes including percent predicted FEV, respiratory symptoms, quality of life, exercise tolerance, and percentage and distribution of emphysema (voxels<-950 Hounsfield units [HU] at total lung capacity) were evaluated using linear or logistic regression. Longitudinal acute exacerbation of COPD (AECOPD) and severe AECOPD (requiring an emergency department visit or hospitalization) were assessed using zero-inflated negative binomial models. Among 1261 participants, 148 (11.7%) had polycythemia. Average follow-up was 4.2±1.7 years and did not differ by presence of polycythemia. In multivariate analysis, compared to participants with normal hemoglobin, polycythemia was associated with a reduced rate of severe AECOPD (adjusted incidence rate ratio 0.57, 95% CI: 0.33-0.98), lower percent predicted FEV, lower resting oxygen saturation, increased upper to lower lobe ratio of emphysema, and a greater degree of emphysema, though the latter was attenuated after adjusting for lung function. There were no significant differences in total AECOPD, patient-reported outcomes, or exercise tolerance. These findings suggest that polycythemia, while associated with less favorable physiologic parameters, is not independently associated with symptoms, and is associated with fewer severe exacerbations. Future studies should explore the potentially protective role of increased hemoglobin beyond the correction of anemia.
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http://dx.doi.org/10.15326/jcopdf.2021.0216DOI Listing
July 2021

Longitudinal Imaging-Based Clusters in Former Smokers of the COPD Cohort Associate with Clinical Characteristics: The SubPopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS).

Int J Chron Obstruct Pulmon Dis 2021;16:1477-1496. Epub 2021 May 31.

Department of Mechanical Engineering, University of Iowa, Iowa City, IA, USA.

Purpose: Quantitative computed tomography (qCT) imaging-based cluster analysis identified clinically meaningful COPD former-smoker subgroups (clusters) based on cross-sectional data. We aimed to identify progression clusters for former smokers using longitudinal data.

Patients And Methods: We selected 472 former smokers from SPIROMICS with a baseline visit and a one-year follow-up visit. A total of 150 qCT imaging-based variables, comprising 75 variables at baseline and their corresponding progression rates, were derived from the respective inspiration and expiration scans of the two visits. The COPD progression clusters identified were then associated with subject demography, clinical variables and biomarkers.

Results: COPD severities at baseline increased with increasing cluster number. Cluster 1 patients were an obese subgroup with rapid progression of functional small airway disease percentage (fSAD%) and emphysema percentage (Emph%). Cluster 2 exhibited a decrease of fSAD% and Emph%, an increase of tissue fraction at total lung capacity and airway narrowing over one year. Cluster 3 showed rapid expansion of Emph% and an attenuation of fSAD%. Cluster 4 demonstrated severe emphysema and fSAD and significant structural alterations at baseline with rapid progression of fSAD% over one year. Subjects with different progression patterns in the same cross-sectional cluster were identified by longitudinal clustering.

Conclusion: qCT imaging-based metrics at two visits for former smokers allow for the derivation of four statistically stable clusters associated with unique progression patterns and clinical characteristics. Use of baseline variables and their progression rates enables identification of longitudinal clusters, resulting in a refinement of cross-sectional clusters.
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http://dx.doi.org/10.2147/COPD.S301466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178702PMC
July 2021

Airway mucin MUC5AC and MUC5B concentrations and the initiation and progression of chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort.

Lancet Respir Med 2021 May 28. Epub 2021 May 28.

Marsico Lung Institute/Cystic Fibrosis and Pulmonary Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address:

Background: We previously described the contributions of increased total airway mucin concentrations to the pathogenesis and diagnosis of the chronic bronchitic component of chronic obstructive pulmonary disease (COPD). Here, we investigated the relative contribution of each of the major airway gel-forming mucins, MUC5AC and MUC5B, to the initiation, progression, and early diagnosis of airways disease in COPD.

Methods: SPIROMICS was a multicentre, observational study in patients aged 40-80 years recruited from six clinical sites and additional subsites in the USA. In this analysis, MUC5AC and MUC5B were quantitated by stable isotope-labelled mass spectrometry in induced sputum samples from healthy never-smokers, ever-smokers at risk for COPD, and ever-smokers with COPD. Participants were extensively characterised using results from questionnaires, such as the COPD assessment test (CAT) and St George's Respiratory Questionnaire; quantitative CT, such as residual volume/total lung capacity ratio (RV/TLC) and parametric response mapping-functional small airway disease (PRM-fSAD); and pulmonary function tests, such as FEV, forced vital capacity (FVC), and forced expiratory flow, midexpiratory phase (FEF). Absolute concentrations of both MUC5AC and MUC5B were related to cross-sectional (baseline, initial visit) and 3-year follow-up longitudinal data, including lung function, small airways obstruction, prospective acute exacerbations, and smoking status as primary outcomes. This study is registered with ClinicalTrials.gov (NCT01969344).

Findings: This analysis included 331 participants (mean age 63 years [SEM 9·40]), of whom 40 were healthy never-smokers, 90 were at-risk ever-smokers, and 201 were ever-smokers with COPD. Increased MUC5AC concentrations were more reliably associated with manifestations of COPD than were MUC5B concentrations, including decreased FEV and FEF, and increased prospective exacerbation frequency, RV/TLC, PRM-fSAD, and COPD assessment scores. MUC5AC concentrations were more reactive to cigarette smoke exposure than were MUC5B concentrations. Longitudinal data from 3-year follow-up visits generated a multivariate-adjusted odds ratio for two or more exacerbations of 1·24 (95% CI 1·04-1·47, p=0·015) for individuals with high baseline MUC5AC concentration. Increased MUC5AC, but not MUC5B, concentration at baseline was a significant predictor of FEV, FEV/FVC, FEF, and CAT score decline during the 3-year follow-up. Moreover, current smokers in the at-risk group showed raised MUC5AC concentrations at initial visits and decreased lung function over 3 years. By contrast, former smokers in the at-risk group showed normal MUC5AC concentrations at the initial visit and preserved lung function over 3 years.

Interpretation: These data indicate that increased MUC5AC concentration in the airways might contribute to COPD initiation, progression, exacerbation risk, and overall pathogenesis. Compared with MUC5B, greater relative changes in MUC5AC concentrations were observed as a function of COPD severity, and MUC5AC concentration seems to be an objective biomarker to detect disease in at-risk and pre-COPD individuals. These data suggest that MUC5AC-producing pathways could be potential targets for future therapeutic strategies. Thus, MUC5AC could be a novel biomarker for COPD prognosis and for testing the efficacy of therapeutic agents.

Funding: National Institutes of Health; National Heart, Lung, and Blood Institute.
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http://dx.doi.org/10.1016/S2213-2600(21)00079-5DOI Listing
May 2021

Quantitative CT-Based Methods for Bone Microstructural Measures and Their Relationships With Vertebral Fractures in a Pilot Study on Smokers.

JBMR Plus 2021 May 19;5(5):e10484. Epub 2021 Mar 19.

Department of Electrical and Computer Engineering, College of Engineering University of Iowa Iowa City IA USA.

Osteoporosis causes fragile bone, and bone microstructural quality is a critical determinant of bone strength and fracture risk. This study pursues technical validation of novel CT-based methods for assessment of peripheral bone microstructure together with a human pilot study examining relationships between bone microstructure and vertebral fractures in smokers. To examine the accuracy and reproducibility of the methods, repeat ultra-high-resolution (UHR) CT and micro-CT scans of cadaveric ankle specimens were acquired. Thirty smokers from the University of Iowa COPDGene cohort were recruited at their 5-year follow-up visits. Chest CT scans, collected under the parent study, were used to assess vertebral fractures. UHR CT scans of distal tibia were acquired for this pilot study to obtain peripheral cortical and trabecular bone (Cb and Tb) measures. UHR CT-derived Tb measures, including volumetric bone mineral density (BMD), network area, transverse trabecular density, and mean plate width, showed high correlation ( > 0.901) with their micro-CT-derived values over small regions of interest (ROIs). Both Cb and Tb measures showed high reproducibility-intra-class correlation (ICC) was greater than 0.99 for all Tb measures except erosion index and greater than 0.97 for all Cb measures. Female sex was associated with lower transverse Tb density ( < 0.1), higher Tb spacing ( < 0.05), and lower cortical thickness ( < 0.001). Participants with vertebral fractures had significantly degenerated values ( < 0.05) for all Tb measures except thickness. There were no statistically significant differences for Cb measures between non-fracture and fracture groups. Vertebral fracture-group differences of Tb measures remained significant after adjustment with chronic obstructive pulmonary disease (COPD) status. Although current smokers at baseline had more fractures-81.8% versus 63.2% for former smokers-the difference was not statistically significant. This pilot cross-sectional human study demonstrates CT-based peripheral bone microstructural differences among smokers with and without vertebral fractures. © 2021 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. © 2021 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101620PMC
May 2021

The Association Between Lung Hyperinflation and Coronary Artery Disease in Smokers.

Chest 2021 May 8. Epub 2021 May 8.

Department of Medicine, University of Pittsburgh, Pittsburgh, PA. Electronic address:

Background: Smokers manifest varied phenotypes of pulmonary impairment.

Research Question: Which pulmonary phenotypes are associated with coronary artery disease (CAD) in smokers?

Study Design And Methods: We analyzed data from the University of Pittsburgh COPD Specialized Center for Clinically Oriented Research (SCCOR) cohort (n = 481) and the Genetic Epidemiology of COPD (COPDGene) cohort (n = 2,580). Participants were current and former smokers with > 10 pack-years of tobacco exposure. Data from the two cohorts were analyzed separately because of methodologic differences. Lung hyperinflation was assessed by plethysmography in the SCCOR cohort and by inspiratory and expiratory CT scan lung volumes in the COPDGene cohort. Subclinical CAD was assessed as the coronary artery calcium score, whereas clinical CAD was defined as a self-reported history of CAD or myocardial infarction (MI). Analyses were performed in all smokers and then repeated in those with airflow obstruction (FEV to FVC ratio, < 0.70).

Results: Pulmonary phenotypes, including airflow limitation, emphysema, lung hyperinflation, diffusion capacity, and radiographic measures of airway remodeling, showed weak to moderate correlations (r < 0.7) with each other. In multivariate models adjusted for pulmonary phenotypes and CAD risk factors, lung hyperinflation was the only phenotype associated with calcium score, history of clinical CAD, or history of MI (per 0.2 higher expiratory and inspiratory CT scan lung volume; coronary calcium: OR, 1.2; 95% CI, 1.1-1.5; P = .02; clinical CAD: OR, 1.6; 95% CI, 1.1-2.3; P = .01; and MI in COPDGene: OR, 1.7; 95% CI, 1.0-2.8; P = .05). FEV and emphysema were associated with increased risk of CAD (P < .05) in models adjusted for CAD risk factors; however, these associations were attenuated on adjusting for lung hyperinflation. Results were the same in those with airflow obstruction and were present in both cohorts.

Interpretation: Lung hyperinflation is associated strongly with clinical and subclinical CAD in smokers, including those with airflow obstruction. After lung hyperinflation was accounted for, FEV and emphysema no longer were associated with CAD. Subsequent studies should consider measuring lung hyperinflation and examining its mechanistic role in CAD in current and former smokers.
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http://dx.doi.org/10.1016/j.chest.2021.04.066DOI Listing
May 2021

Racial Segregation and Respiratory Outcomes among Urban Black Residents with and at Risk of COPD.

Am J Respir Crit Care Med 2021 May 10. Epub 2021 May 10.

Johns Hopkins University, Medicine, Baltimore, Maryland, United States;

Rationale: Racial residential segregation has been associated with worse health outcomes, but the link with COPD morbidity has not been established.

Objectives: To investigate whether racial residential segregation is associated with COPD morbidity among urban Black adults with or at risk of COPD.

Methods: Racial residential segregation was assessed using isolation index, based on 2010 decennial census and baseline address, for Black former and current smokers in the multi-center SPIROMICS study of adults with or at risk for COPD. We tested the association between isolation index and respiratory symptoms, physiologic outcomes, imaging parameters, and exacerbation risk among urban Black residents, adjusting for established COPD risk factors, including smoking. Additional mediation analysis were conducted for factors that could lie on the pathway between segregation and COPD outcomes, including individual and neighborhood socioeconomic status, comorbidity burden, depression/anxiety, and ambient pollution.

Measurements And Results: Among 515 Black participants, those residing in segregated neighborhoods (i.e., isolation index ≥ 0.6) had worse COPD Assessment Test score (β=2.4, 95%CI, 0.7-4.0), dyspnea (mMRC; β=0.29, 95%CI, 0.10-0.47), quality of life (SGRQ; β=6.1, 95%CI, 2.3-9.9), cough and sputum (MCQ; β=0.8, 95%CI, 0.1-1.5), lower FEV1 % predicted (β=-7.3, 95%CI, -10.9 to -3.6), higher rate of any and severe exacerbations and higher percentage emphysema (β=2.3, 95%CI, 0.7-3.9) and air trapping (β=3.8, 95%CI, 0.6-7.1). Adverse associations attenuated with adjustment for potential mediators but remained robust for several outcomes, including dyspnea, FEV1 % predicted, percent emphysema and air trapping.

Conclusions: Racial residential segregation was adversely associated with COPD morbidity among urban Black participants and supports the hypothesis that racial segregation plays a role in explaining health inequities affecting Black communities.
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http://dx.doi.org/10.1164/rccm.202009-3721OCDOI Listing
May 2021

Reply to "the impact of mechanical properties on aortic dilation in patients with COPD and emphysema".

Int J Cardiol 2021 07 30;334:125. Epub 2021 Apr 30.

Department of Radiology, Weill Cornell Medicine, New York, NY, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2021.04.045DOI Listing
July 2021

Letter to the Editor: Response by Authors.

Chronic Obstr Pulm Dis 2021 Apr;8(2):188-189

Department of Medicine, Columbia University Irving Medical Center, New York, New York, United States.

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http://dx.doi.org/10.15326/jcopdf.2021.0225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237973PMC
April 2021

A systematic analysis of protein-altering exonic variants in chronic obstructive pulmonary disease.

Am J Physiol Lung Cell Mol Physiol 2021 Jul 28;321(1):L130-L143. Epub 2021 Apr 28.

Department of Health Sciences, University of Leicester, Leicester, United Kingdom.

Genome-wide association studies (GWASs) have identified regions associated with chronic obstructive pulmonary disease (COPD). GWASs of other diseases have shown an approximately 10-fold overrepresentation of nonsynonymous variants, despite limited exonic coverage on genotyping arrays. We hypothesized that a large-scale analysis of coding variants could discover novel genetic associations with COPD, including rare variants with large effect sizes. We performed a meta-analysis of exome arrays from 218,399 controls and 33,851 moderate-to-severe COPD cases. All exome-wide significant associations were present in regions previously identified by GWAS. We did not identify any novel rare coding variants with large effect sizes. Within GWAS regions on chromosomes 5q, 6p, and 15q, four coding variants were conditionally significant ( < 0.00015) when adjusting for lead GWAS single-nucleotide polymorphisms A common gasdermin B () splice variant (rs11078928) previously associated with a decreased risk for asthma was nominally associated with a decreased risk for COPD [minor allele frequency (MAF) = 0.46, = 1.8e-4]. Two stop variants in coiled-coil α-helical rod protein 1 (), a gene involved in regulating cell proliferation, were associated with COPD (both < 0.0001). The Z allele was associated with a random-effects odds ratio of 1.43 for COPD (95% confidence interval = 1.17-1.74), though with marked heterogeneity across studies. Overall, COPD-associated exonic variants were identified in genes involved in DNA methylation, cell-matrix interactions, cell proliferation, and cell death. In conclusion, we performed the largest exome array meta-analysis of COPD to date and identified potential functional coding variants. Future studies are needed to identify rarer variants and further define the role of coding variants in COPD pathogenesis.
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http://dx.doi.org/10.1152/ajplung.00009.2021DOI Listing
July 2021

Soluble receptor for advanced glycation end products (sRAGE) as a biomarker of COPD.

Respir Res 2021 Apr 27;22(1):127. Epub 2021 Apr 27.

Research and Development, GlaxoSmithKline, Collegeville, PA, USA.

Background: Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publications have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. No cohorts have examined the association between sRAGE and progressive decline of lung function. There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population. This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. A meta-analysis is used to quantify sRAGE associations with clinical phenotypes.

Methods: sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n = 1443); SPIROMICS (n = 1623); ECLIPSE (n = 2349); Pittsburgh COPD SCCOR (n = 399). We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity).

Results: Lower plasma or serum sRAGE values were associated with a COPD diagnosis (P < 0.001), reduced FEV (P < 0.001), and emphysema severity (P < 0.001). In an inverse-variance weighted meta-analysis, one SD lower log-transformed sRAGE was associated with 105 ± 22 mL lower FEV and 4.14 ± 0.55 g/L lower adjusted lung density. After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV decline and emphysema progression only in the ECLIPSE cohort. Non-Hispanic white subjects carrying the rs2070600 minor allele (A) and non-Hispanic African Americans carrying the rs2071288 minor allele (A) had lower sRAGE measurements compare to those with the major allele, but their emphysema-sRAGE regression slopes were similar.

Conclusions: Lower blood sRAGE is associated with more severe airflow obstruction and emphysema, but associations with progression are inconsistent in the cohorts analyzed. In these cohorts, genotype influenced sRAGE measurements and strengthened variance modelling. Thus, genotype should be included in sRAGE evaluations.
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http://dx.doi.org/10.1186/s12931-021-01686-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076883PMC
April 2021

Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium.

Genome Med 2021 04 21;13(1):66. Epub 2021 Apr 21.

Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.

Background: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression.

Methods: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants.

Results: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections.

Conclusions: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.
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http://dx.doi.org/10.1186/s13073-021-00866-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059115PMC
April 2021

Associations of D-dimer with CT Lung Abnormalities, Serum Biomarkers of Lung Injury, and Forced Vital Capacity: MESA Lung Study.

Ann Am Thorac Soc 2021 Apr 16. Epub 2021 Apr 16.

Weill Cornell Medical College, 12295, Department of Medicine, New York, New York, United States.

Rationale: The coagulation cascade may play a role in the pathogenesis of interstitial lung disease through increased production of thrombin and fibrin deposition. Whether circulating coagulation cascade factors are linked to lung inflammation and scarring among community-dwelling adults is unknown.

Objective: To test the hypothesis that higher baseline D-dimer levels are associated with markers of early lung injury and scarring.

Methods: Using the Multi-Ethnic Study of Atherosclerosis cohort (n=6,814), we examined associations of baseline D-dimer levels with high attenuation areas (HAA) from Exam 1 (2000-2002, n=6,184) and interstitial lung abnormalities (ILA) from Exam 5 computed tomography (CT) scans (2010-2012, n=2,227), and serum matrix metalloproteinase-7 (MMP-7) and surfactant protein-A (SP-A) from Exam 1 (n=1,098). We examined longitudinal change in forced vital capacity (FVC) from Exams 3-6 (2004-2018, n=3,562). We used linear, logistic regression, and linear mixed models to examine associations and adjust for potential confounders.

Results: The mean (SD) age of the cohort was 62 (10) years and D-dimer level was 0.35 (0.69) ug/mL. For every 10% increase in D-dimer level, there was an increase in HAA percent of 0.27 (95% CI 0.08 to 0.47) after adjustment for covariates. Associations were stronger among those older than 65 years (p-values for interaction<0.001). A 10% increase in D-dimer level was associated with an odds ratio of 1.05 for ILA (95% CI 0.99 to 1.11). Higher D-dimer levels were associated with higher serum MMP-7 and a faster decline in FVC. D-dimer was not associated with SP-A.

Conclusions: Higher D-dimer levels were associated with a greater burden of lung parenchymal abnormalities detected on CT scan, MMP-7, and FVC decline among community-dwelling adults.
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http://dx.doi.org/10.1513/AnnalsATS.202012-1557OCDOI Listing
April 2021

Adiposity and Interstitial Lung Abnormalities in Community-Dwelling Adults: The MESA Cohort Study.

Chest 2021 Apr 15. Epub 2021 Apr 15.

Department of Medicine, Weill Cornell Medical College, New York, NY.

Background: Obesity is associated with restrictive ventilatory defects and a faster rate of decline in FVC. This association is not exclusively mediated by mechanical factors and may reflect direct pulmonary injury by adipose-derived mediators.

Research Question: Is adipose tissue involved in the pathogenesis of interstitial lung disease (ILD)?

Study Design And Methods: We evaluated the association of CT measures of pericardial, abdominal visceral, and abdominal subcutaneous adipose tissue with high-attenuation areas (HAAs) and interstitial lung abnormalities (ILAs) in a large multicenter cohort study of community-dwelling adults, using multivariable-adjusted models. We secondarily evaluated the association of adipose depot size with FVC and biomarkers of obesity and inflammation.

Results: In fully adjusted models, every doubling in pericardial adipose tissue volume was associated with a 63.4-unit increase in HAA (95% CI, 55.5-71.3), 20% increased odds of ILA (95% CI, -2% to 50%), and a 5.5% decrease in percent predicted FVC (95% CI, -6.8% to -4.3%). IL-6 levels accounted for 8% of the association between pericardial adipose tissue and HAA. Every doubling in visceral adipose tissue area was associated with a 41.5-unit increase in HAA (95% CI, 28.3-54.7), 30% increased odds of ILA (95% CI, -10% to 80%), and a 5.4% decrease in percent predicted FVC (95% CI, -6.6% to -4.3%). IL-6 and leptin accounted for 17% and 18%, respectively, of the association between visceral adipose tissue and HAA.

Interpretation: Greater pericardial and abdominal visceral adipose tissue were associated with CT measures of early lung injury and lower FVC in a cohort of community-dwelling adults. Adipose tissue may represent a modifiable risk factor for ILD.
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http://dx.doi.org/10.1016/j.chest.2021.03.058DOI Listing
April 2021

Quantitative Analysis of Adipose Depots by Using Chest CT and Associations with All-Cause Mortality in Chronic Obstructive Pulmonary Disease: Longitudinal Analysis from MESArthritis Ancillary Study.

Radiology 2021 06 6;299(3):703-711. Epub 2021 Apr 6.

From the Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 601 N Caroline St, JHOC 3171c, Baltimore, MD 21287 (F.P., S.D.); Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (M.S., T.Q.A.C.S., W.S.P., J.A.C.L.); Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wis (D.A.B.); Lundquist Institute at Harbor-University of California Los Angeles School of Medicine, Torrance, Calif (M.B.); Departments of Medicine and Epidemiology, Columbia University Medical Center, New York, NY (R.G.B.); and Division of Preventive Medicine, Department of Family Medicine and Public Health, University of Calif San Diego, La Jolla, Calif (M.A.A.).

Background Obesity and sarcopenia are associated with mortality in chronic obstructive pulmonary disease (COPD). Routine chest CT examinations may allow assessment of obesity and sarcopenia by soft-tissue markers for predicting risks of mortality. Purpose To investigate associations between soft-tissue markers subcutaneous adipose tissue (SAT), intermuscular adipose tissue (IMAT), and pectoralis muscle (PM) index from chest CT with mortality in participants with COPD. Materials and Methods In this secondary analysis of a prospectively enrolled cohort from the Multi-Ethnic Study of Atherosclerosis, participants with available chest CT in 2010-2012 were included. CT examinations were analyzed to determine SAT, IMAT (within PM), and PM areas. The spirometry evaluations were used to establish COPD diagnosis. Mortality data were extracted from the National Death Index (April 2010 to December 2017). The correlations of the soft-tissue markers with fat mass index were studied. The associations of these markers and risks of mortality in participants with COPD were assessed by using Cox proportional-hazard models adjusted for confounders. Results Among 2994 participants who were included (mean age, 69 years ± 9 [standard deviation]; 1551 women), 265 had COPD (9%; mean age, 72 years ± 9; 162 men) and 49 participants with COPD (18%) died during follow-up. The SAT, IMAT, and PM areas had moderate-to-excellent reliabilities (intraclass correlation coefficient, 0.88-0.99). In the 2994 participants, the SAT (ρ = 0.80; 95% CI: 0.78, 0.81; < .001) and IMAT indexes (ρ = 0.37; 95% CI: 0.34, 0.41; < .001) were correlated with fat mass index. Those with COPD and higher SAT index had lower risks of mortality (hazard ratio, 0.2; 95% CI: 0.1, 0.4; < .001, per doubling), whereas a higher IMAT index was associated with a higher risk of mortality (hazard ratio, 1.4; 95% CI: 1.0, 1.9; = .04, per doubling). Conclusion Soft-tissue markers were reliably obtained by using chest CT performed for lung assessment. In participants with chronic obstructive pulmonary disease, a high intermuscular adipose tissue index was associated with a higher risk of mortality than was a high subcutaneous adipose tissue index. © RSNA, 2021 See also the editorial by Sverzellati and Cademartiri in this issue.
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http://dx.doi.org/10.1148/radiol.2021203959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165946PMC
June 2021

Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study: Study Design.

medRxiv 2021 Mar 20. Epub 2021 Mar 20.

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults at risk for coronavirus disease 2019 (COVID-19) comprising 14 established United States (US) prospective cohort studies. For decades, C4R cohorts have collected extensive data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R will link this pre-COVID phenotyping to information on SARS-CoV-2 infection and acute and post-acute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and broadly reflects the racial, ethnic, socioeconomic, and geographic diversity of the US. C4R is ascertaining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations, and high-quality events surveillance. Extensive pre-pandemic data minimize referral, survival, and recall bias. Data are being harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these will be pooled and shared widely to expedite collaboration and scientific findings. This unique resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including post-acute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term trajectories of health and aging.
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http://dx.doi.org/10.1101/2021.03.19.21253986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987050PMC
March 2021

E-Cigarettes and Cardiopulmonary Health.

Function (Oxf) 2021 8;2(2):zqab004. Epub 2021 Feb 8.

Dorothy M. Davis Heart and Lung Research Institute, Colleges of Medicine and Nursing, The Ohio State University, Columbus, OH, USA.

E-cigarettes have surged in popularity over the last few years, particularly among youth and young adults. These battery-powered devices aerosolize e-liquids, comprised of propylene glycol and vegetable glycerin, typically with nicotine, flavors, and stabilizers/humectants. Although the use of combustible cigarettes is associated with several adverse health effects including multiple pulmonary and cardiovascular diseases, the effects of e-cigarettes on both short- and long-term health have only begun to be investigated. Given the recent increase in the popularity of e-cigarettes, there is an urgent need for studies to address their potential adverse health effects, particularly as many researchers have suggested that e-cigarettes may pose less of a health risk than traditional combustible cigarettes and should be used as nicotine replacements. This report is prepared for clinicians, researchers, and other health care providers to provide the current state of knowledge on how e-cigarette use might affect cardiopulmonary health, along with research gaps to be addressed in future studies.
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http://dx.doi.org/10.1093/function/zqab004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948134PMC
February 2021

Hiatal hernia prevalence and natural history on non-contrast CT in the Multi-Ethnic Study of Atherosclerosis (MESA).

BMJ Open Gastroenterol 2021 03;8(1)

Department of Radiology, Weill Cornell Medicine, New York, NY, USA

Objective: To determine the prevalence, risk factors and natural history of hiatal hernia (HH) on CT in the general population.

Materials And Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) acquired full-lung CT on 3200 subjects, aged 53-94 years. Three blinded observers independently determined presence/absence and type (I-IV) of HH. Associations between HH and participant characteristics were assessed via unadjusted and multivariable-adjusted relative risk regression. HH natural history was assessed compared with prior MESA CT.

Results: Excellent interobserver agreement was found for presence (κ=0.86) and type of HH (κ=0.97). Among 316 HH identified (prevalence=9.9%), 223 (71%) were type I and 93 (29%) were type III. HH prevalence increased with age, from 2.4% in 6th decade to 16.6% in 9th decade (unadjusted prevalence ratio (PR)=1.1 (95% CI 1.04 to 1.1)). HH prevalence was greater in women (12.7%) than men (7.0%) (unadjusted PR=1.8 (95% CI 1.5 to 2.3)) and associated with proton pump inhibitor use (p<0.001). In 75 participants with HH with 10-year follow-up, median HH area increased from 9.9 cm to 17.9 cm (p=0.02) with a higher mean body mass index (BMI) in subjects with increasing HH size compared with HH decreasing in size: mean BMI=30.2±6.2 vs 26.8±7.2 (p=0.02).

Conclusion: HH on non-contrast CT is prevalent in the general population, increasing with age, female gender and BMI. Its association with proton pump inhibitor use confirms a role in gastro-oesophageal reflux disease and HH progression is associated with increased BMI.

Trial Registration Number: NCT00005487.
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http://dx.doi.org/10.1136/bmjgast-2020-000565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978087PMC
March 2021

The influence of social support on COPD outcomes mediated by depression.

PLoS One 2021 17;16(3):e0245478. Epub 2021 Mar 17.

Johns Hopkins Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

Background: The purpose of this study was to explore the association between perceived social support and COPD outcomes and to determine whether the associations are mediated by depressive symptoms.

Methods: Subjects with COPD who were enrolled as part of SPIROMICS were included in this analysis. Questionnaires relating to quality of life, symptom burden, and functional status were administered at annual clinic visits for over a 3 year period. In both cross-sectional and longitudinal analyses, we examined the association of social support as measured by the FACIT-F with COPD outcomes. Cross sectional analyses used multivariable linear or logistic regression, adjusting for covariates. For longitudinal analyses, generalized linear mixed models with random intercepts were used. Models were adjusted with and without depressive symptoms and mediation analyses performed.

Results: Of the 1831 subjects with COPD, 1779 completed the FACIT- F questionnaire. In adjusted cross-sectional analysis without depressive symptoms, higher perceived social support was associated with better quality of life, well-being, 6 minute walk distance, and less dyspnea. When also adjusting for depressive symptoms, all associations between social support and COPD outcomes were attenuated and no longer statistically significant. Mediation analysis suggested that depressive symptoms explained the majority (> = 85%) of the association between social support and measured COPD outcomes. Results of the longitudinal analysis were consistent with the cross-sectional analyses. There was no association between social support and odds of exacerbations.

Conclusion: Higher social support was associated with better COPD outcomes across several measures of morbidity including quality of life, respiratory symptoms, and functional status. In addition, these associations were largely attenuated when accounting for depressive symptoms suggesting that the beneficial association of social support with COPD outcomes may be largely mediated by the association between social support and depression.

Trial Registration: SPIROMICS was approved by Institutional Review Boards at each center and all participants provided written informed consent (clinicaltrials.gov: NCT01969344).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245478PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968645PMC
March 2021

Latent traits of lung tissue patterns in former smokers derived by dual channel deep learning in computed tomography images.

Sci Rep 2021 Mar 1;11(1):4916. Epub 2021 Mar 1.

Department of Biomedical Engineering, University of Iowa, Iowa City, IA, USA.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and the traditional variables extracted from computed tomography (CT) images may not be sufficient to describe all the topological features of lung tissues in COPD patients. We employed an unsupervised three-dimensional (3D) convolutional autoencoder (CAE)-feature constructor (FC) deep learning network to learn from CT data and derive tissue pattern-clusters jointly. We then applied exploratory factor analysis (EFA) to discover the unobserved latent traits (factors) among pattern-clusters. CT images at total lung capacity (TLC) and residual volume (RV) of 541 former smokers and 59 healthy non-smokers from the cohort of the SubPopulations and Intermediate Outcome Measures in the COPD Study (SPIROMICS) were analyzed. TLC and RV images were registered to calculate the Jacobian (determinant) values for all the voxels in TLC images. 3D Regions of interest (ROIs) with two data channels of CT intensity and Jacobian value were randomly extracted from training images and were fed to the 3D CAE-FC model. 80 pattern-clusters and 7 factors were identified. Factor scores computed for individual subjects were able to predict spirometry-measured pulmonary functions. Two factors which correlated with various emphysema subtypes, parametric response mapping (PRM) metrics, airway variants, and airway tree to lung volume ratio were discriminants of patients across all severity stages. Our findings suggest the potential of developing factor-based surrogate markers for new COPD phenotypes.
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http://dx.doi.org/10.1038/s41598-021-84547-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921389PMC
March 2021

Defining Resilience to Smoking Related Lung Disease: A Modified Delphi Approach from SPIROMICS.

Ann Am Thorac Soc 2021 Feb 25. Epub 2021 Feb 25.

UCSF, Division of Pulmonary and Critical Care Medicine, Department of Medicine and CVRI, San Francisco, California, United States.

Rationale: Diagnosis of chronic obstructive pulmonary disease (COPD) relies on abnormal spirometry. However, spirometry may underestimate the effects of smoking, missing smokers with respiratory disease that have minimal or no airflow obstruction.

Objectives: Develop a multi-dimensional definition of a lung-related "resilient smoker" that is useful in research studies; then identify a resilient smoker subgroup in the SPIROMICS cohort using this definition.

Methods: We performed a three-round modified Delphi survey among a panel of COPD experts to identify and reach a consensus on clinical and radiographic domains to be included in a lung-related resilient smoker definition. Consensus on domains of resilience was defined as ≥80% of experts voting "agree" or "strongly agree" on a 5-point Likert scale. The Delphi-derived definition of resilience was applied to SPIROMICS to identify resilient smokers, whom we then characterized using known biomarkers of COPD.

Results: Consensus was achieved on 6 of 12 diagnostic items which include: cough and sputum production, dyspnea, radiographic measures of emphysema and small airways disease, exacerbations, and decline in FEV1. Although 892 SPIROMICS participants were classified as smokers with preserved lung function by spirometry, only 149 participants (16.7%) qualified as resilient smokers by our definition. Blood biomarker expression of C-reactive protein (CRP) and soluble tumor necrosis receptor factor1A (sTNFRSF1A) was lower in resilient than non-resilient smokers (P=0.02 and P=0.03).

Conclusions: A Delphi-derived consensus definition of resilient smoker identified 83.3% of smokers with preserved spirometry as "non-resilient" based on the presence of adverse effects of smoking on the lung. Resilient smokers were biologically distinct from non-resilient smokers based on CRP measurements. Clinical trial registered with ClinicalTrials.gov (NCT01969344).
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http://dx.doi.org/10.1513/AnnalsATS.202006-757OCDOI Listing
February 2021

Aortic enlargement in chronic obstructive pulmonary disease (COPD) and emphysema: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD study.

Int J Cardiol 2021 05 13;331:214-220. Epub 2021 Feb 13.

Department of Radiology, Weill Cornell Medicine, NY, New York, USA. Electronic address:

Background: The prevalence of abdominal aortic aneurysm is high in chronic obstructive pulmonary disease (COPD) population. Emphysema involves proteolytic destruction of elastic fibers. Therefore, emphysema may also contribute to thoracic aorta dilatation. This study assessed aorta dilation in smokers stratified by presence of COPD, emphysema and airway thickening.

Methods: Aorta diameters were measured on 3D magnetic resonance angiography in smokers recruited from the Multi-Ethnic Study of Atherosclerosis (MESA), the Emphysema and Cancer Action Project (EMCAP), and the local community. COPD was defined by standard spirometric criteria; emphysema was measured quantitatively on computed tomography and bronchitis was determined from medical history.

Results: Participants (n = 315, age 58-79) included 150 with COPD and 165 without COPD, of whom 56% and 19%, respectively, had emphysema. Subjects in the most severe quartile of emphysematous change showed the largest diameter at all four aorta locations compared to those in the least severe quartiles (all p < 0.001). Comparing subjects with and without COPD, aorta diameters were larger in participants with severe COPD in ascending and arch (both p < 0.001), and abdominal aorta (p = 0.001). Chronic bronchitis and bronchial wall thickness did not correlate with aorta diameter. In subjects with emphysema, subjects with coexistence of COPD showed larger aorta than those without COPD in ascending (p = 0.003), arch (p = 0.002), and abdominal aorta (p = 0.04).

Conclusions: This study showed larger aorta diameter in subjects with COPD and severe emphysema compared to COPD related to chronic bronchitis or bronchial wall thickening.
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http://dx.doi.org/10.1016/j.ijcard.2021.02.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026709PMC
May 2021

Respiratory exacerbations are associated with muscle loss in current and former smokers.

Thorax 2021 06 11;76(6):554-560. Epub 2021 Feb 11.

Division of Pulmonary and Critical Care, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Objectives: Muscle wasting is a recognised extra-pulmonary complication in chronic obstructive pulmonary disease and has been associated with increased risk of death. Acute respiratory exacerbations are associated with reduction of muscle function, but there is a paucity of data on their long-term effect. This study explores the relationship between acute respiratory exacerbations and long-term muscle loss using serial measurements of CT derived pectoralis muscle area (PMA).

Design And Setting: Participants were included from two prospective, longitudinal, observational, multicentre cohorts of ever-smokers with at least 10 pack-year history.

Participants: The primary analysis included 1332 (of 2501) participants from Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) and 4384 (of 10 198) participants from Genetic Epidemiology of COPD (COPDGene) who had complete data from their baseline and follow-up visits.

Interventions: PMA was measured on chest CT scans at two timepoints. Self-reported exacerbation data were collected from participants in both studies through the use of periodic longitudinal surveys.

Main Outcome Measures: Age-related and excess muscle loss over time.

Results: Age, sex, race and body mass index were associated with baseline PMA. Participants experienced age-related decline at the upper end of reported normal ranges. In ECLIPSE, the exacerbation rate over time was associated with an excess muscle area loss of 1.3% (95% CI 0.6 to 1.9, p<0.001) over 3 years and in COPDGene with an excess muscle area loss of 2.1% (95% CI 1.2 to 2.8, p<0.001) over 5 years. Excess muscle area decline was absent in 273 individuals who participated in pulmonary rehabilitation.

Conclusions: Exacerbations are associated with accelerated skeletal muscle loss. Each annual exacerbation was associated with the equivalent of 6 months of age-expected decline in muscle mass. Ameliorating exacerbation-associated muscle loss represents an important therapeutic target.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222105PMC
June 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

Lung microbiota associations with clinical features of COPD in the SPIROMICS cohort.

NPJ Biofilms Microbiomes 2021 02 5;7(1):14. Epub 2021 Feb 5.

Division of Pulmonary/Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA.

Chronic obstructive pulmonary disease (COPD) is heterogeneous in development, progression, and phenotypes. Little is known about the lung microbiome, sampled by bronchoscopy, in milder COPD and its relationships to clinical features that reflect disease heterogeneity (lung function, symptom burden, and functional impairment). Using bronchoalveolar lavage fluid collected from 181 never-smokers and ever-smokers with or without COPD (GOLD 0-2) enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), we find that lung bacterial composition associates with several clinical features, in particular bronchodilator responsiveness, peak expiratory flow rate, and forced expiratory flow rate between 25 and 75% of FVC (FEF). Measures of symptom burden (COPD Assessment Test) and functional impairment (six-minute walk distance) also associate with disparate lung microbiota composition. Drivers of these relationships include members of the Streptococcus, Prevotella, Veillonella, Staphylococcus, and Pseudomonas genera. Thus, lung microbiota differences may contribute to airway dysfunction and airway disease in milder COPD.
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http://dx.doi.org/10.1038/s41522-021-00185-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865064PMC
February 2021

Ratio of FEV/Slow Vital Capacity of < 0.7 Is Associated With Clinical, Functional, and Radiologic Features of Obstructive Lung Disease in Smokers With Preserved Lung Function.

Chest 2021 Jul 1;160(1):94-103. Epub 2021 Feb 1.

Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC.

Background: Mild expiratory flow limitation may not be recognized using traditional spirometric criteria based on the ratio of FEV/FVC.

Research Question: Does slow vital capacity (SVC) instead of FVC increase the sensitivity of spirometry to identify patients with early or mild obstructive lung disease?

Study Design And Methods: We included 854 current and former smokers from the Subpopulations and Intermediate Outcome Measures in COPD Study cohort with a postbronchodilator FEV/FVC ≥ 0.7 and FEV % predicted of ≥ 80% at enrollment. We compared baseline characteristics, chest CT scan features, exacerbations, and progression to COPD (postbronchodilator FEV/FVC, < 0.7) during the follow-up period between 734 participants with postbronchodilator FEV/SVC of ≥ 0.7 and 120 with postbronchodilator FEV/SVC < 0.7 at the enrollment. We performed multivariate linear and logistic regression models and negative binomial and interval-censored proportion hazards regression models adjusted for demographics and smoking exposure to examine the association of FEV/SVC < 0.7 with those characteristics and outcomes.

Results: Participants with FEV/SVC < 0.7 were older and had lower FEV and more emphysema than those with FEV/SVC ≥ 0.7. In adjusted analysis, individuals with postbronchodilator FEV/SVC < 0.7 showed a greater percentage of emphysema by 0.45% (95% CI, 0.09%-0.82%), percentage of gas trapping by 2.52% (95% CI, 0.59%-4.44%), and percentage of functional small airways disease based on parametric response mapping by 2.78% (95% CI, 0.72%-4.83%) at baseline than those with FEV/SVC ≥ 0.7. During a median follow-up time of 1,500 days, an FEV/SVC < 0.7 was not associated with total exacerbations (incident rate ratio [IRR], 1.61; 95% CI, 0.97-2.64), but was associated with severe exacerbations (IRR, 2.60; 95% CI, 1.04-4.89). An FEV/SVC < 0.7 was associated with progression to COPD during a 3-year follow-up even after adjustment for demographics and smoking exposure (hazard ratio, 3.93; 95% CI, 2.71-5.72). We found similar results when we examined the association of prebronchodilator FEV/SVC < 0.7 or FEV/SVC less than the lower limit of normal with chest CT scan features and progression to COPD.

Interpretation: Low FEV to SVC in current and former smokers with normal spirometry results can identify individuals with CT scan features of COPD who are at risk for severe exacerbations and is associated with progression to COPD in the future.

Trial Registry: ClinicalTrials.gov; No.: NCT01969344T4; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2021.01.067DOI Listing
July 2021

Spatially Weighted Coronary Artery Calcium Score and Coronary Heart Disease Events in the Multi-Ethnic Study of Atherosclerosis.

Circ Cardiovasc Imaging 2021 01 19;14(1):e011981. Epub 2021 Jan 19.

Department of Medicine, Vagelos College of Physicians and Surgeons (S.S., D.S., G.B.), Mailman School of Public Health, Columbia University, New York, NY.

Background: A limitation of the Agatston coronary artery calcium (CAC) score is that it does not use all of the calcium density information in the computed tomography scan such that many individuals have a score of zero. We examined the predictive validity for incident coronary heart disease (CHD) events of the spatially weighted coronary calcium score (SWCS), an alternative scoring method for CAC that assigns scores to individuals with Agatston CAC=0.

Methods: The MESA (Multi-Ethnic Study of Atherosclerosis) is a longitudinal study that conducted a baseline exam from 2000 to 2002 in 6814 participants including computed tomography scanning for CAC. Subsequent exams and systematic follow-up of the cohort for outcomes were performed. Statistical models were adjusted using the MESA risk score based on age, sex, race/ethnicity, systolic blood pressure, use of hypertension medications, diabetes, total and HDL (high-density lipoprotein) cholesterol, use of lipid-lowering medications, smoking status, and family history of heart attack.

Results: In the 3286 participants with Agatston CAC=0 at baseline and for whom SWCS was computed, 98 incident CHD events defined as definite or probably myocardial infarction or definite CHD death occurred during a median follow-up of 15.1 years. In this group, SWCS predicted incident CHD events after multivariable adjustment (hazard ratio=1.30 per SD of natural logarithm [SWCS] [95% CI, 1.04-1.60]; =0.005); and progression from Agatston CAC=0 at baseline to CAC>0 at subsequent exams (multivariable-adjusted incidence rate difference per SD of natural logarithm [SWCS] per 100 person-years 1.68 [95% CI, 1.03-2.33]; <0.0001).

Conclusions: SWCS predicts incident CHD events in individuals with Agatston CAC score=0 as well as conversion to Agatston CAC>0 at repeat computed tomography scanning at later exams. SWCS has predictive validity as a subclinical phenotype and marker of CHD risk in individuals with Agatston CAC=0.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.011981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987729PMC
January 2021

Mucus Plugs and Emphysema in the Pathophysiology of Airflow Obstruction and Hypoxemia in Smokers.

Am J Respir Crit Care Med 2021 04;203(8):957-968

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Utah Hospitals and Clinics, Salt Lake City, Utah.

The relative roles of mucus plugs and emphysema in mechanisms of airflow limitation and hypoxemia in smokers with chronic obstructive pulmonary disease (COPD) are uncertain. To relate image-based measures of mucus plugs and emphysema to measures of airflow obstruction and oxygenation in patients with COPD. We analyzed computed tomographic (CT) lung images and lung function in participants in the Subpopulations and Intermediate Outcome Measures in COPD Study. Radiologists scored mucus plugs on CT lung images, and imaging software automatically quantified emphysema percentage. Unadjusted and adjusted relationships between mucus plug score, emphysema percentage, and lung function were determined using regression. Among 400 smokers, 229 (57%) had mucus plugs and 207 (52%) had emphysema, and subgroups could be identified with mucus-dominant and emphysema-dominant disease. Only 33% of smokers with high mucus plug scores had mucus symptoms. Mucus plug score and emphysema percentage were independently associated with lower values for FEV and peripheral oxygen saturation ( < 0.001). The relationships between mucus plug score and lung function outcomes were strongest in smokers with limited emphysema ( < 0.001). Compared with smokers with low mucus plug scores, those with high scores had worse COPD Assessment Test scores (17.4 ± 7.7 vs. 14.4 ± 13.3), more frequent annual exacerbations (0.75 ± 1.1 vs. 0.43 ± 0.85), and shorter 6-minute-walk distance (329 ± 115 vs. 392 ± 117 m) ( < 0.001). Symptomatically silent mucus plugs are highly prevalent in smokers and independently associate with lung function outcomes. These data provide rationale for targeting patients with mucus-high/emphysema-low COPD in clinical trials of mucoactive treatments.Clinical trial registered with www.clinicaltrials.gov (NCT01969344).
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http://dx.doi.org/10.1164/rccm.202006-2248OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048745PMC
April 2021

Randomization to Omega-3 Fatty Acid Supplementation and Endothelial Function in COPD: The COD-Fish Randomized Controlled Trial.

Chronic Obstr Pulm Dis 2021 Jan;8(1)

Department of Medicine, Columbia University Irving Medical Center, New York, New York, United States.

Rationale: Studies suggest a pathogenic role of endothelial dysfunction in chronic obstructive lung disease (COPD). Omega-3 (n-3) polyunsaturated fatty acid (PUFA) supplementation improves endothelial function in other diseases but has not been examined in COPD.

Objective: We hypothesized that n-3 PUFA supplementation would improve systemic endothelial function in COPD. We performed a pilot randomized, placebo-controlled, double-blind, phase 2 superiority trial (NCT00835289).

Methods: Adults with moderate and severe stable COPD (79% with emphysema on computed tomography [CT]) were randomized to high-dose fish oil capsules or placebo daily for 6 months. The primary endpoint was percentage change in brachial artery flow-mediated dilation (FMD) from baseline to 6 months. Secondary endpoints included peripheral arterial tonometry, endothelial microparticles (EMPs), 6-minute walk distance, respiratory symptoms, and pulmonary function.

Results: Thirty-three of 40 randomized participants completed all measurements. Change in FMD after 6 months did not differ between the fish oil and placebo arms (-1.1%, 95% CI -5.0-2.9, =0.59). CD31 EMPs increased in the fish oil arm (0.9%, 95% CI 0.1-1.7, =0.04). More participants in the fish oil arm reported at least a 4-point improvement in the St George's Respiratory Questionnaire (SGRQ) compared to placebo (8 versus 1; =0.01). There were no significant changes in other secondary endpoints. There were 4 serious adverse events determined to be unrelated to the study (3 in the fish oil arm and 1 in the placebo arm).

Conclusion: Randomization to n-3 PUFAs for 6 months did not change systemic endothelial function in COPD. Changes in EMPs and SGRQ suggest n-3 PUFAs might have biologic and clinical effects that warrant further investigation.
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http://dx.doi.org/10.15326/jcopdf.8.1.2020.0132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047614PMC
January 2021

Dysanapsis and COPD-Reply.

JAMA 2020 10;324(15):1572

Department of Medicine, Columbia University Medical Center, New York, New York.

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http://dx.doi.org/10.1001/jama.2020.15654DOI Listing
October 2020
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