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In this trial evaluating mepolizumab, an anti–interleukin-5 antibody, the rate of COPD exacerbations among patients whose COPD was characterized by an increased number of eosinophils in the circulating blood was lower with mepolizumab than with placebo.

Background: A recent systematic review showed Japan’s mortality from chronic obstructive pulmonary disease (COPD) is the lowest among 204 countries, despite notably higher smoking rates in men in Japan than in the United States. This study aims to compare (1) trends in smoking rates, (2) trends in COPD mortality, and (3) the spirometry-based COPD prevalence in the general adult population between Japan and the United States.Methods: Age- and sex-specific smoking rates from the 1980s through 2010s and COPD mortality from 1999 through 2019 were obtained from national surveys and official statistics (International Classification of Diseases-10th codes J40–44), respectively. A systematic review and meta-analysis was performed to estimate COPD prevalence in Japan, while the National Health and Nutrition Examination Survey 2007–2012 was used for the United States. A fixed ratio of 0.7 of forced expiratory volume in the first second of forced vital capacity was used to define COPD.Results: Over the past 4 decades, men in Japan consistently had 20–30% higher smoking rates than their United States counterparts. From 1999–2019, age-adjusted COPD mortality in men in Japan was only a third of the United States, whereas that in women was less than a tenth in 2019. Synthesizing data from 11 studies, involving 89,955 participants, Japan’s COPD prevalence was more than 10% lower than in the United States in almost all age groups for both sexes.Conclusion: This study showed markedly lower rates of COPD in Japan than in the United States. Investigating factors contributing to the paradoxical observations could lead to advancing COPD risk reduction strategies.

Prevalence and risk factors for respiratory symptoms and airway obstruction in HIV-infected subjects in the era of highly active antiretroviral therapy (HAART) are unknown. We evaluated respiratory symptoms and measured airway obstruction to identify the impact of HAART and other risk factors on respiratory symptoms and pulmonary function. Two hundred thirty-four HIV-infected adults without acute respiratory symptoms were recruited from an HIV clinic. All subjects were interviewed and performed spirometry. Multivariate linear and logistic regressions were performed to determine predictors of respiratory symptoms, forced expiratory volume in one second (FEV(1)) percent predicted, and FEV(1)/forced vital capacity (FEV(1)/FVC). Thirty-one percent of subjects reported at least one respiratory symptom. Smoking status (current or former versus never) (odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.41-5.22, p = 0.003), higher log plasma HIV viral levels (OR = 1.12, 95%CI = 1.02-1.24, p = 0.02), and lower FEV(1)/FVC (OR = 1.06 for every 0.01 decrease in FEV(1)/FVC, 95%CI = 1.02-1.14, p = 0.001) were independent predictors of respiratory symptoms. Age (p = 0.04), pack-year smoking history (p<0.001), previous bacterial pneumonia (p = 0.007), and HAART use (p = 0.04) were independent predictors of decreased FEV(1)/FVC. Respiratory symptoms remain common in HIV-infected subjects, especially in those with a smoking history. Subjects who were older, had a greater pack-year history of smoking, or previous bacterial pneumonia had lower FEV(1)/FVC ratios. Interestingly, use of HAART was independently associated with a decreased FEV(1)/FVC, possibly secondary to an immune response to subclinical infections, increased autoimmunity, or other factors associated with HAART use.

One of the characteristics of severe emphysema is hyperinflation of regions of the lungs. In this trial, valves that prevented air entry but allowed air to escape were placed in lobar airways. Patients receiving endobronchial valves had modest improvements in lung function and exercise performance. Emphysema is a leading cause of disability and death. Lung-volume–reduction surgery, in which selected areas of hyperinflated lungs are resected, improves exercise tolerance and prolongs life in selected patients. However, concern regarding the risk of perioperative death and complications contributes to underutilization. 1 – 4 Less invasive bronchoscopic techniques that are based on the presumed physiological effects of lung-volume–reduction surgery have been developed. 5 – 10 Early uncontrolled trials using unidirectional valves placed in selected lung airways to block regional inflation while allowing exhalation have reported improvements in lung function and symptoms with modest risk, including distal pneumonia or pneumothorax. 5 , 6 , 9 , 11 – . . .

Introduction COPD is associated with an increased AFib-related morbidity and mortality. There are several AFib risk prediction models available, but none have been validated in the COPD population. Our study aims to identify spirometric and radiographic variables that are associated with an increased risk of AFib. Secondarily, we hope to determine if these associated variables improve the risk discrimination of established AFib risk prediction models in individuals with COPD. Methods We evaluated 755 participants from a single center tobacco-exposed cohort at baseline. At this study visit, the following were performed: demographic, medical history, and symptom questionnaires, PFT, and CT imaging. We performed logistic regression analysis to determine cardiopulmonary variables associated with prevalent AFib. The multivariable analysis was adjusted for sex, age, number of pack years, BMI, self-reported heart failure, and anti-hypertensive medication use. Exposure variables that were statistically significant in the logistic regression analysis were added in succession to current AFib risk prediction models, CHA 2 DS 2 -VASc and CHARGE-AF, to create updated models. C-statistics were calculated for both risk scores alone as well as with each updated model. Results DLco (OR 0.40, CI 0.18–0.86), heart volume (OR 13.12, CI 2.32–74.17), percentage of emphysema (OR 2.77, CI 1.04–7.40), and mMRC (OR 1.17, CI 1.02–1.35) were associated with prevalent AFib in the multivariable logistic regression analysis. When conducting the discrimination analysis of the AFib risk prediction scores, the addition of these cardiopulmonary variables improved CHARGE-AF, from C-statistic 0.53 to 0.63 ( p  < 0.03). Conclusions We identified cardiopulmonary factors associated with an increased risk of AFib in a tobacco-exposed cohort. The incorporation of lung function, CT parameters, and symptom scores in validated AFib prediction models may improve AFib risk discrimination in our chronic lung disease populations. Clinical trial number not applicable. Trial registration This study was supported by the National Institute of Health (NIH) National Heart, Lung and Blood Institute (NHLBI) grants 1R01HL128289 (J.B.) and P50HL084948 (F.C.S.).

Beyond exposure to cigarette smoking and aging, the factors that influence lung function decline to incident chronic obstructive pulmonary disease (COPD) remain unclear. Advancements have been made in categorizing COPD into emphysema and airway predominant disease subtypes; however, predicting which healthy individuals will progress to COPD is difficult because they can exhibit profoundly different disease trajectories despite similar initial risk factors. This study aimed to identify clinical, genetic, and radiological features that are directly linked-and subsequently predict-abnormal lung function. We employed graph modeling on 2,643 COPDGene participants (aged 45 to 80 years, 51.25% female, 35.1% African Americans; enrollment 11/2007-4/2011) with smoking history but normal spirometry at study enrollment to identify variables that are directly linked to future lung function abnormalities. We developed logistic regression and random forest predictive models for distinguishing individuals who maintain lung function from those who decline. Of the 131 variables analyzed, 6 were identified as informative to future lung function abnormalities, namely forced expiratory flow in the middle range (FEF25-75%), average lung wall thickness in a 10 mm radius (Pi10), severe emphysema, age, sex, and height. We investigated whether these features predict individuals leaving GOLD 0 status (normal spirometry according to Global Initiative for Obstructive Lung Disease (GOLD) criteria). Linear models, trained with these features, were quite predictive (area under receiver operator characteristic curve or AUROC = 0.75). Random forest predictors performed similarly to logistic regression (AUROC = 0.7), indicating that no significant nonlinear effects were present. The results were externally validated on 150 participants from Specialized Center for Clinically Oriented Research (SCCOR) cohort (aged 45 to 80 years, 52.7% female, 4.7% African Americans; enrollment: 7/2007-12/2012) (AUROC = 0.89). The main limitation of longitudinal studies with 5- and 10-year follow-up is the introduction of mortality bias that disproportionately affects the more severe cases. However, our study focused on spirometrically normal individuals, who have a lower mortality rate. Another limitation is the use of strict criteria to define spirometrically normal individuals, which was unavoidable when studying factors associated with changes in normalized forced expiratory volume in 1 s (FEV1%predicted) or the ratio of FEV1/FVC (forced vital capacity). This study took an agnostic approach to identify which baseline measurements differentiate and predict the early stages of lung function decline in individuals with previous smoking history. Our analysis suggests that emphysema affects obstruction onset, while airway predominant pathology may play a more important role in future FEV1 (%predicted) decline without obstruction, and FEF25-75% may affect both.

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by abnormal cellular responses to cigarette smoke, resulting in tissue destruction and airflow limitation. Autophagy is a degradative process involving lysosomal turnover of cellular components, though its role in human diseases remains unclear. Increased autophagy was observed in lung tissue from COPD patients, as indicated by electron microscopic analysis, as well as by increased activation of autophagic proteins (microtubule-associated protein-1 light chain-3B, LC3B, Atg4, Atg5/12, Atg7). Cigarette smoke extract (CSE) is an established model for studying the effects of cigarette smoke exposure in vitro. In human pulmonary epithelial cells, exposure to CSE or histone deacetylase (HDAC) inhibitor rapidly induced autophagy. CSE decreased HDAC activity, resulting in increased binding of early growth response-1 (Egr-1) and E2F factors to the autophagy gene LC3B promoter, and increased LC3B expression. Knockdown of E2F-4 or Egr-1 inhibited CSE-induced LC3B expression. Knockdown of Egr-1 also inhibited the expression of Atg4B, a critical factor for LC3B conversion. Inhibition of autophagy by LC3B-knockdown protected epithelial cells from CSE-induced apoptosis. Egr-1(-/-) mice, which displayed basal airspace enlargement, resisted cigarette-smoke induced autophagy, apoptosis, and emphysema. We demonstrate a critical role for Egr-1 in promoting autophagy and apoptosis in response to cigarette smoke exposure in vitro and in vivo. The induction of autophagy at early stages of COPD progression suggests novel therapeutic targets for the treatment of cigarette smoke induced lung injury.

Idiopathic pulmonary fibrosis (IPF) is an untreatable and often fatal lung disease that is increasing in prevalence and is caused by complex interactions between genetic and environmental factors. Epigenetic mechanisms control gene expression and are likely to regulate the IPF transcriptome. To identify methylation marks that modify gene expression in IPF lung. We assessed DNA methylation (comprehensive high-throughput arrays for relative methylation arrays [CHARM]) and gene expression (Agilent gene expression arrays) in 94 patients with IPF and 67 control subjects, and performed integrative genomic analyses to define methylation-gene expression relationships in IPF lung. We validated methylation changes by a targeted analysis (Epityper), and performed functional validation of one of the genes identified by our analysis. We identified 2,130 differentially methylated regions (DMRs; <5% false discovery rate), of which 738 are associated with significant changes in gene expression and enriched for expected inverse relationship between methylation and expression (P < 2.2 × 10(-16)). We validated 13/15 DMRs by targeted analysis of methylation. Methylation-expression quantitative trait loci (methyl-eQTL) identified methylation marks that control cis and trans gene expression, with an enrichment for cis relationships (P < 2.2 × 10(-16)). We found five trans methyl-eQTLs where a methylation change at a single DMR is associated with transcriptional changes in a substantial number of genes; four of these DMRs are near transcription factors (castor zinc finger 1 [CASZ1], FOXC1, MXD4, and ZDHHC4). We studied the in vitro effects of change in CASZ1 expression and validated its role in regulation of target genes in the methyl-eQTL. These results suggest that DNA methylation may be involved in the pathogenesis of IPF.

The question addressed by the study Good biological indicators capable of predicting chronic obstructive pulmonary disease (COPD) phenotypes and clinical trajectories are lacking. Because nuclear and mitochondrial genomes are damaged and released by cigarette smoke exposure, plasma cell-free mitochondrial and nuclear DNA (cf-mtDNA and cf-nDNA) levels could potentially integrate disease physiology and clinical phenotypes in COPD. This study aimed to determine whether plasma cf-mtDNA and cf-nDNA levels are associated with COPD disease severity, exacerbations, and mortality risk. Materials and methods We quantified mtDNA and nDNA copy numbers in plasma from participants enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE, n  = 2,702) study and determined associations with relevant clinical parameters. Results Of the 2,128 participants with COPD, 65% were male and the median age was 64 (interquartile range, 59–69) years. During the baseline visit, cf-mtDNA levels positively correlated with future exacerbation rates in subjects with mild/moderate and severe disease (Global Initiative for Obstructive Lung Disease [GOLD] I/II and III, respectively) or with high eosinophil count (≥ 300). cf-nDNA positively associated with an increased mortality risk (hazard ratio, 1.33 [95% confidence interval, 1.01–1.74] per each natural log of cf-nDNA copy number). Additional analysis revealed that individuals with low cf-mtDNA and high cf-nDNA abundance further increased the mortality risk (hazard ratio, 1.62 [95% confidence interval, 1.16–2.25] per each natural log of cf-nDNA copy number). Answer to the question Plasma cf-mtDNA and cf-nDNA, when integrated into quantitative clinical measurements, may aid in improving COPD severity and progression assessment. Take-home message In this COPD cohort, we found that elevated cf-nDNA predicts mortality while elevated cf-mtDNA predicts future exacerbations, with a hazard ratio of 1.3. Integration of both cf-mtDNA and cf-nDNA measures improved mortality predictions to 1.66 in our study.

Objectives To determine the optimal threshold by quantitatively assessing the extent of emphysema at the level of the entire lung and at the level of individual lobes using a large, diverse dataset of computed tomography (CT) examinations. Methods This study comprises 573 chest CT examinations acquired from subjects with different levels of airway obstruction (222 none, 83 mild, 141 moderate, 63 severe and 64 very severe). The extent of emphysema was quantified using the percentage of the low attenuation area (LAA%) divided by the total lung or lobe volume(s). The correlations between the extent of emphysema, and pulmonary functions and the five-category classification were assessed using Pearson and Spearman’s correlation coefficients, respectively. When quantifying emphysema using a density mask, a wide range of thresholds from −850 to −1,000 HU were used. Results The highest correlations of LAA% with the five-category classification and PFT measures ranged from −925 to −965 HU for each individual lobe and the entire lung. However, the differences between the highest correlations and those obtained at −950 HU are relatively small. Conclusion Although there are variations in the optimal cut-off thresholds for individual lobes, the single threshold of −950 HU is still an acceptable threshold for density-based emphysema quantification. Key Points • CT is widely used to assess the severity of emphysema • Density mask technique helps clinicians assess the extent of emphysema with CT • A standardised cut - off for density mask analysis at lobe level is desirable • −950 HU is acceptable for density-based emphysema quantification at the lobar level