Bronchodilators in Tobacco-Exposed Persons with Symptoms and Preserved Lung Function.

BACKGROUND: Many persons with a history of smoking tobacco have clinically significant respiratory symptoms despite an absence of airflow obstruction as assessed by spirometry. They are often treated with medications for chronic obstructive pulmonary disease (COPD), but supporting evidence for this treatment is lacking. METHODS: We randomly assigned persons who had a tobacco-smoking history of at least 10 pack-years, respiratory symptoms as defined by a COPD Assessment Test score of at least 10 (scores range from 0 to 40, with higher scores indicating worse symptoms), and preserved lung function on spirometry (ratio of forced expiratory volume in 1 second [FEV1] to forced vital capacity [FVC] ≥0.70 and FVC ≥70% of the predicted value after bronchodilator use) to receive either indacaterol (27.5 µg) plus glycopyrrolate (15.6 µg) or placebo twice daily for 12 weeks. The primary outcome was at least a 4-point decrease (i.e., improvement) in the St. George's Respiratory Questionnaire (SGRQ) score (scores range from 0 to 100, with higher scores indicating worse health status) after 12 weeks without treatment failure (defined as an increase in lower respiratory symptoms treated with a long-acting inhaled bronchodilator, glucocorticoid, or antibiotic agent). RESULTS: A total of 535 participants underwent randomization. In the modified intention-to-treat population (471 participants), 128 of 227 participants (56.4%) in the treatment group and 144 of 244 (59.0%) in the placebo group had at least a 4-point decrease in the SGRQ score (difference, -2.6 percentage points; 95% confidence interval [CI], -11.6 to 6.3; adjusted odds ratio, 0.91; 95% CI, 0.60 to 1.37; P = 0.65). The mean change in the percent of predicted FEV1 was 2.48 percentage points (95% CI, 1.49 to 3.47) in the treatment group and -0.09 percentage points (95% CI, -1.06 to 0.89) in the placebo group, and the mean change in the inspiratory capacity was 0.12 liters (95% CI, 0.07 to 0.18) in the treatment group and 0.02 liters (95% CI, -0.03 to 0.08) in the placebo group. Four serious adverse events occurred in the treatment group, and 11 occurred in the placebo group; none were deemed potentially related to the treatment or placebo. CONCLUSIONS: Inhaled dual bronchodilator therapy did not decrease respiratory symptoms in symptomatic, tobacco-exposed persons with preserved lung function as assessed by spirometry. (Funded by the National Heart, Lung, and Blood Institute and others; RETHINC ClinicalTrials.gov number, NCT02867761.).

A combinatorial F box protein directed pathway controls TRAF adaptor stability to regulate inflammation.

Uncontrolled activation of tumor necrosis factor receptor-associated factor (TRAF) proteins may result in profound tissue injury by linking surface signals to cytokine release. Here we show that a ubiquitin E3 ligase component, Fbxo3, potently stimulates cytokine secretion from human inflammatory cells by destabilizing a sentinel TRAF inhibitor, Fbxl2. Fbxo3 and TRAF protein in circulation positively correlated with cytokine responses in subjects with sepsis, and we identified a polymorphism in human Fbxo3, with one variant being hypofunctional. A small-molecule inhibitor targeting Fbxo3 was sufficient to lessen severity of cytokine-driven inflammation in several mouse disease models. These studies identified a pathway of innate immunity that may be useful to detect subjects with altered immune responses during critical illness or provide a basis for therapeutic intervention targeting TRAF protein abundance.

Cell-free DNA levels associate with COPD exacerbations and mortality.

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.

FEV1/FVC Severity Stages for Chronic Obstructive Pulmonary Disease.

Rationale: The diagnosis of chronic obstructive pulmonary disease (COPD) is based on a low FEV1/FVC ratio, but the severity of COPD is classified using FEV1% predicted (ppFEV1). Objectives: To test a new severity classification scheme for COPD using FEV1/FVC ratio, a more robust measure of airflow obstruction than ppFEV1. Methods: In COPDGene (Genetic Epidemiology of COPD) (N = 10,132), the severity of airflow obstruction was categorized by Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1-4 (ppFEV1 of ⩾80%, ⩾50-80%, ⩾30-50%, and <30%). A new severity classification (STaging of Airflow obstruction by Ratio; STAR) was tested in COPDGene-FEV1/FVC ⩾0.60 to <0.70, ⩾0.50 to <0.60, ⩾0.40 to <0.50, and <0.40, respectively, for stages 1-4-and applied to the combined Pittsburgh SCCOR and Emphysema COPD Research Registry for replication (N = 2,017). Measurements and Main Results: The agreements (weighted Bangdiwala B values) between GOLD and the new FEV1/FVC ratio severity stages were 0.89 in COPDGene and 0.88 in the Pittsburgh cohort. In COPDGene and the Pittsburgh cohort, compared with GOLD staging, STAR provided significant discrimination between the absence of airflow obstruction and stage 1 for all-cause mortality, respiratory quality of life, dyspnea, airway wall thickness, exacerbations, and lung function decline. No major differences were noted for emphysema, small airway disease, and 6-minute-walk distance. The STAR classification system identified a greater number of adults with stage 3/4 disease who would be eligible for lung transplantation and lung volume reduction procedure evaluations. Conclusions: The new STAR severity classification scheme provides discrimination for mortality that is similar to the GOLD classification but with a more uniform gradation of disease severity. STAR differentiates patients' symptoms, disease burden, and prognosis better than the existing scheme based on ppFEV1, and is less sensitive to race/ethnicity and other demographic characteristics.

Adenine nucleotide translocase regulates airway epithelial metabolism, surface hydration and ciliary function.

Airway hydration and ciliary function are critical to airway homeostasis and dysregulated in chronic obstructive pulmonary disease (COPD), which is impacted by cigarette smoking and has no therapeutic options. We utilized a high-copy cDNA library genetic selection approach in the amoeba Dictyostelium discoideum to identify genetic protectors to cigarette smoke. Members of the mitochondrial ADP/ATP transporter family adenine nucleotide translocase (ANT) are protective against cigarette smoke in Dictyostelium and human bronchial epithelial cells. Gene expression of ANT2 is reduced in lung tissue from COPD patients and in a mouse smoking model, and overexpression of ANT1 and ANT2 resulted in enhanced oxidative respiration and ATP flux. In addition to the presence of ANT proteins in the mitochondria, they reside at the plasma membrane in airway epithelial cells and regulate airway homeostasis. ANT2 overexpression stimulates airway surface hydration by ATP and maintains ciliary beating after exposure to cigarette smoke, both of which are key functions of the airway. Our study highlights a potential for upregulation of ANT proteins and/or of their agonists in the protection from dysfunctional mitochondrial metabolism, airway hydration and ciliary motility in COPD.This article has an associated First Person interview with the first author of the paper.

CT pectoralis muscle area is associated with DXA lean mass and correlates with emphysema progression in a tobacco-exposed cohort.

INTRODUCTION: Muscle loss is an important extrapulmonary manifestation of COPD. Dual energy X-ray absorptiometry (DXA) is the method of choice for body composition measurement but is not widely used for muscle mass evaluation. The pectoralis muscle area (PMA) is quantifiable by CT and predicts cross-sectional COPD-related morbidity. There are no studies that compare PMA with DXA measures or that evaluate longitudinal relationships between PMA and lung disease progression. METHODS: Participants from our longitudinal tobacco-exposed cohort had baseline and 6-year chest CT (n=259) and DXA (n=164) data. Emphysema was quantified by CT density histogram parenchymal scoring using the 15th percentile technique. Fat-free mass index (FFMI) and appendicular skeletal mass index (ASMI) were calculated from DXA measurements. Linear regression model relationships were reported using standardised coefficient (ß) with 95% CI. RESULTS: PMA was more strongly associated with DXA measures than with body mass index (BMI) in both cross-sectional (FFMI: ß=0.76 (95% CI 0.65 to 0.86), p<0.001; ASMI: ß=0.76 (95% CI 0.66 to 0.86), p<0.001; BMI: ß=0.36 (95% CI 0.25 to 0.47), p<0.001) and longitudinal (ΔFFMI: ß=0.43 (95% CI 0.28 to 0.57), p<0.001; ΔASMI: ß=0.42 (95% CI 0.27 to 0.57), p<0.001; ΔBMI: ß=0.34 (95% CI 0.22 to 0.46), p<0.001) models. Six-year change in PMA was associated with 6-year change in emphysema (ß=0.39 (95% CI 0.23 to 0.56), p<0.001) but not with 6-year change in airflow obstruction. CONCLUSIONS: PMA is an accessible measure of muscle mass and may serve as a useful clinical surrogate for assessing skeletal muscle loss in smokers. Decreased PMA correlated with emphysema progression but not lung function decline, suggesting a difference in the pathophysiology driving emphysema, airflow obstruction and comorbidity risk.

Incident low muscle mass is associated with greater lung disease and lower circulating leptin in a tobacco-exposed longitudinal cohort.

BACKGROUND: Muscle loss is prevalent in chronic obstructive pulmonary disease (COPD). Prior studies evaluating musculoskeletal dysfunction in COPD have focused on individuals with baseline low muscle mass. Currently, there is limited data evaluating clinical characteristics and outcomes associated with progression to incident low muscle mass in a tobacco-exposed cohort of individuals with baseline normal muscle mass. METHODS: We evaluated 246 participants from a single-center longitudinal tobacco-exposed cohort with serial spirometry, thoracic imaging, dual energy x-ray absorptiometry (DXA) measurements, walk testing, and plasma adipokine measurements. DXA-derived fat free mass index (FFMI) and appendicular skeletal mass index (ASMI) were used as surrogates for muscle mass. Participants with incident low muscle mass (LM) at follow-up were characterized by FFMI < 18.4 kg/m2 in males and < 15.4 kg/m2 in females and/or ASMI < 7.25 kg/m2 in males and < 5.67 kg/m2 in females. RESULTS: Twenty-five (10%) participants progressed to incident low muscle mass at follow-up. At baseline, the LM subgroup had greater active smoking prevalence (60% v. 38%, p = 0.04), lower FFMI (17.8 ± 1.7 kg/m2 v. 19.7 ± 2.9 kg/m2, p = 0.002), lower ASMI (7.3 ± 0.9 kg/m2 v. 8.2 ± 1.2 kg/m2, p = 0.0003), and lower plasma leptin (14.9 ± 10.1 ng/mL v. 24.0 ± 20.9 ng/mL, p = 0.04). At follow-up, the LM subgroup had higher COPD prevalence (68% v. 43%, p = 0.02), lower FEV1/FVC (0.63 ± 0.12 v. 0.69 ± 0.12, p = 0.02), lower %DLco (66.5 ± 15.9% v. 73.9 ± 16.8%, p = 0.03), and higher annual rate of FFMI decline (-0.17 kg/m2/year v. -0.04 kg/m2/year, p = 0.006). There were no differences in age, gender distribution, pack years smoking history, or walk distance. CONCLUSIONS: We identified a subgroup of tobacco-exposed individuals with normal baseline muscle mass who progressed to incident DXA-derived low muscle mass. This subgroup demonstrated synchronous lung disease and persistently low circulating leptin levels. Our study suggests the importance of assessing for muscle loss in conjunction with lung function decline when evaluating individuals with tobacco exposure.

Clinically stable covid-19 patients presenting to acute unscheduled episodic care venues have increased risk of hospitalization: secondary analysis of a randomized control trial.

BACKGROUND: Assessment for risks associated with acute stable COVID-19 is important to optimize clinical trial enrollment and target patients for scarce therapeutics. To assess whether healthcare system engagement location is an independent predictor of outcomes we performed a secondary analysis of the ACTIV-4B Outpatient Thrombosis Prevention trial. METHODS: A secondary analysis of the ACTIV-4B trial that was conducted at 52 US sites between September 2020 and August 2021. Participants were enrolled through acute unscheduled episodic care (AUEC) enrollment location (emergency department, or urgent care clinic visit) compared to minimal contact (MC) enrollment (electronic contact from test center lists of positive patients).We report the primary composite outcome of cardiopulmonary hospitalizations, symptomatic venous thromboembolism, myocardial infarction, stroke, transient ischemic attack, systemic arterial thromboembolism, or death among stable outpatients stratified by enrollment setting, AUEC versus MC. A propensity score for AUEC enrollment was created, and Cox proportional hazards regression with inverse probability weighting (IPW) was used to compare the primary outcome by enrollment location. RESULTS: Among the 657 ACTIV-4B patients randomized, 533 (81.1%) with known enrollment setting data were included in this analysis, 227 from AUEC settings and 306 from MC settings. In a multivariate logistic regression model, time from COVID test, age, Black race, Hispanic ethnicity, and body mass index were associated with AUEC enrollment. Irrespective of trial treatment allocation, patients enrolled at an AUEC setting were 10-times more likely to suffer from the adjudicated primary outcome, 7.9% vs. 0.7%; p < 0.001, compared with patients enrolled at a MC setting. Upon Cox regression analysis adjustment patients enrolled at an AUEC setting remained at significant risk of the primary composite outcome, HR 3.40 (95% CI 1.46, 7.94). CONCLUSIONS: Patients with clinically stable COVID-19 presenting to an AUEC enrollment setting represent a population at increased risk of arterial and venous thrombosis complications, hospitalization for cardiopulmonary events, or death, when adjusted for other risk factors, compared with patients enrolled at a MC setting. Future outpatient therapeutic trials and clinical therapeutic delivery programs of clinically stable COVID-19 patients may focus on inclusion of higher-risk patient populations from AUEC engagement locations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04498273.

Benralizumab for the Prevention of COPD Exacerbations.

BACKGROUND: The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known. METHODS: In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. <220 per cubic millimeter]) who had frequent exacerbations despite receiving guideline-based inhaled treatment. Patients were randomly assigned to receive benralizumab (30 or 100 mg in GALATHEA; 10, 30, or 100 mg in TERRANOVA) every 8 weeks (every 4 weeks for the first three doses) or placebo. The primary end point was the treatment effect of benralizumab, measured as the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56 in patients with baseline blood eosinophil counts of 220 per cubic millimeter or greater. Safety was also assessed. RESULTS: In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo. CONCLUSIONS: Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by AstraZeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA ClinicalTrials.gov numbers, NCT02138916 and NCT02155660.).

Metoprolol for the Prevention of Acute Exacerbations of COPD.

BACKGROUND: Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials. METHODS: In this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol. RESULTS: A total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV1) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group. CONCLUSIONS: Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.).

Unpaired data empowers association tests.

MOTIVATION: There is growing interest in the biomedical research community to incorporate retrospective data, available in healthcare systems, to shed light on associations between different biomarkers. Understanding the association between various types of biomedical data, such as genetic, blood biomarkers, imaging, etc. can provide a holistic understanding of human diseases. To formally test a hypothesized association between two types of data in Electronic Health Records (EHRs), one requires a substantial sample size with both data modalities to achieve a reasonable power. Current association test methods only allow using data from individuals who have both data modalities. Hence, researchers cannot take advantage of much larger EHR samples that includes individuals with at least one of the data types, which limits the power of the association test. RESULTS: We present a new method called the Semi-paired Association Test (SAT) that makes use of both paired and unpaired data. In contrast to classical approaches, incorporating unpaired data allows SAT to produce better control of false discovery and to improve the power of the association test. We study the properties of the new test theoretically and empirically, through a series of simulations and by applying our method on real studies in the context of Chronic Obstructive Pulmonary Disease. We are able to identify an association between the high-dimensional characterization of Computed Tomography chest images and several blood biomarkers as well as the expression of dozens of genes involved in the immune system. AVAILABILITY AND IMPLEMENTATION: Code is available on https://github.com/batmanlab/Semi-paired-Association-Test. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Bronchoscopic Lung Volume Reduction Coil Treatment for Severe Emphysema: A Systematic Review and Meta-Analysis of Individual Participant Data.

BACKGROUND: Lung volume reduction coil (LVR-coil) treatment provides a minimally invasive treatment option for severe emphysema patients which has been studied in multiple clinical trials. OBJECTIVES: The aim of the study was to assess the effect of LVR-coil treatment on pulmonary function, quality of life, and exercise capacity using individual participant data. METHOD: PubMed, Web of Science, and EMBASE were searched until May 17, 2021. Prospective single-arm and randomized controlled trials that evaluated the effect of LVR-coil treatment on forced expiratory volume in 1 s (FEV1), residual volume (RV), St. George Respiratory Questionnaire (SGRQ) total score, and/or 6-min walk distance (6MWD) and were registered in an official clinical trial database were eligible for inclusion. Individual patient data were requested, and a linear mixed effects model was used to calculate overall treatment effects. RESULTS: Eight trials were included in the final analysis, representing 680 individual patients. LVR-coil treatment resulted in a significant improvement in FEV1 at 3- (0.09 L [95% confidence interval (95% CI): 0.06-0.12]) and 6-month follow-up (0.07 L [95% CI: 0.03-0.10]), a significant reduction in RV at 3- (-0.45L [95% CI: -0.62 to -0.28]), 6- (-0.33L [95% CI: -0.52 to -0.14]), and 12-month follow-up (-0.36L [95% CI: -0.64 to -0.08]), a significant reduction in SGRQ total score at 3- (-12.3 points [95% CI: -15.8 to -8.8]), 6- (-10.1 points [95% CI: -12.8 to -7.3]), and 12-month follow-up (-9.8 points [95% CI: -15.0 to -4.7]) and a significant increase in 6MWD at 3-month follow-up (38 m [95% CI: 18-58]). CONCLUSIONS: LVR-coil treatment in emphysema patients results in sustained improvements in pulmonary function and quality of life and shorter lived improvements in exercise capacity. Since the owner of this LVR-coil has decided to stop the production and newer generations LVR-coils are currently being developed, these results can act as a reference for future studies and clinical guidance.

Elevated plasma level of Pentraxin 3 is associated with emphysema and mortality in smokers.

BACKGROUND: Pentraxin 3 (PTX3) influences innate immunity and inflammation, host defence, the complement cascade and angiogenesis. PTX3 expression in lung and blood of subjects with tobacco exposure, and its potential relationship with disease pattern and clinical outcome are poorly understood. METHODS: Using independent platforms and cohorts, we identified associations of PTX3 gene expression in lung tissue and plasma from current and former tobacco smokers (with and without chronic obstructive pulmonary disease, COPD) to disease phenotypes including quantitative CT determined emphysema, lung function, symptoms and survival. Two putative regulatory variants of the PTX3 gene were examined for association with COPD manifestations. The relationship between plasma PTX3 and hyaluronic acid levels was further examined. RESULTS: PTX3 gene expression in lung tissue was directly correlated with emphysema severity (p<0.0001). Circulating levels of PTX3 were inversely correlated with FEV1 (p=0.006), and positively associated with emphysema severity (p=0.004) and mortality (p=0.008). Two PTX3 gene regulatory variants were associated with a lower risk for emphysema and expiratory airflow obstruction, and plasma levels of PTX3 and hyaluronic acid were related. CONCLUSIONS: These data show strong and overlapping associations of lung and blood PTX3 levels, and PTX3 regulatory gene variants, with the severity of airflow obstruction, emphysema and mortality among smokers. These findings have potential implications regarding the pathogenesis of smoking-related lung diseases and warrant further exploration for the use of PTX3 as a predictive biomarker.

Gene coexpression networks reveal novel molecular endotypes in alpha-1 antitrypsin deficiency.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that causes early onset pulmonary emphysema and airways obstruction. The complete mechanisms via which AATD causes lung disease are not fully understood. To improve our understanding of the pathogenesis of AATD, we investigated gene expression profiles of bronchoalveolar lavage (BAL) and peripheral blood mononuclear cells (PBMCs) in AATD individuals. METHODS: We performed RNA-Seq on RNA extracted from matched BAL and PBMC samples isolated from 89 subjects enrolled in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Subjects were stratified by genotype and augmentation therapy. Supervised and unsupervised differential gene expression analyses were performed using Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene profiles associated with subjects' clinical variables. The genes in the most significant WGCNA module were used to cluster AATD individuals. Gene validation was performed by NanoString nCounter Gene Expression Assay. RESULT: We observed modest effects of AATD genotype and augmentation therapy on gene expression. When WGCNA was applied to BAL transcriptome, one gene module, ME31 (2312 genes), correlated with the highest number of clinical variables and was functionally enriched with numerous immune T-lymphocyte related pathways. This gene module identified two distinct clusters of AATD individuals with different disease severity and distinct PBMC gene expression patterns. CONCLUSIONS: We successfully identified novel clusters of AATD individuals where severity correlated with increased immune response independent of individuals' genotype and augmentation therapy. These findings may suggest the presence of previously unrecognised disease endotypes in AATD that associate with T-lymphocyte immunity and disease severity.

Relationship between Emphysema Progression at CT and Mortality in Ever-Smokers: Results from the COPDGene and ECLIPSE Cohorts.

Background The relationship between emphysema progression and long-term outcomes is unclear. Purpose To determine the relationship between emphysema progression at CT and mortality among participants with emphysema. Materials and Methods In a secondary analysis of two prospective observational studies, COPDGene (clinicaltrials.gov, NCT00608764) and Evaluation of Chronic Obstructive Pulmonary Disease Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE; clinicaltrials.gov, NCT00292552), emphysema was measured at CT at two points by using the volume-adjusted lung density at the 15th percentile of the lung density histogram (hereafter, lung density perc15) method. The association between emphysema progression rate and all-cause mortality was analyzed by using Cox regression adjusted for ethnicity, sex, baseline age, pack-years, and lung density, baseline and change in smoking status, forced expiratory volume in 1 second, and 6-minute walk distance. In COPDGene, respiratory mortality was analyzed by using the Fine and Gray method. Results A total of 5143 participants (2613 men [51%]; mean age, 60 years ± 9 [standard deviation]) in COPDGene and 1549 participants (973 men [63%]; mean age, 62 years ± 8) in ECLIPSE were evaluated, of which 2097 (40.8%) and 1179 (76.1%) had emphysema, respectively. Baseline imaging was performed between January 2008 and December 2010 for COPDGene and January 2006 and August 2007 for ECLIPSE. Follow-up imaging was performed after 5.5 years ± 0.6 in COPDGene and 3.0 years ± 0.2 in ECLIPSE, and mortality was assessed over the ensuing 5 years in both. For every 1 g/L per year faster rate of decline in lung density perc15, all-cause mortality increased by 8% in COPDGene (hazard ratio [HR], 1.08; 95% CI: 1.01, 1.16; P = .03) and 6% in ECLIPSE (HR, 1.06; 95% CI: 1.00, 1.13; P = .045). In COPDGene, respiratory mortality increased by 22% (HR, 1.22; 95% CI: 1.13, 1.31; P < .001) for the same increase in the rate of change in lung density perc15. Conclusion In ever-smokers with emphysema, emphysema progression at CT was associated with increased all-cause and respiratory mortality. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Lee and Park in this issue.

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

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 (FEV1) 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 FEV1 (P < 0.001), and emphysema severity (P < 0.001). In an inverse-variance weighted meta-analysis, one SD lower log10-transformed sRAGE was associated with 105 ± 22 mL lower FEV1 and 4.14 ± 0.55 g/L lower adjusted lung density. After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV1 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.

Automated quantification of COVID-19 severity and progression using chest CT images.

OBJECTIVE: To develop and test computer software to detect, quantify, and monitor progression of pneumonia associated with COVID-19 using chest CT scans. METHODS: One hundred twenty chest CT scans from subjects with lung infiltrates were used for training deep learning algorithms to segment lung regions and vessels. Seventy-two serial scans from 24 COVID-19 subjects were used to develop and test algorithms to detect and quantify the presence and progression of infiltrates associated with COVID-19. The algorithm included (1) automated lung boundary and vessel segmentation, (2) registration of the lung boundary between serial scans, (3) computerized identification of the pneumonitis regions, and (4) assessment of disease progression. Agreement between radiologist manually delineated regions and computer-detected regions was assessed using the Dice coefficient. Serial scans were registered and used to generate a heatmap visualizing the change between scans. Two radiologists, using a five-point Likert scale, subjectively rated heatmap accuracy in representing progression. RESULTS: There was strong agreement between computer detection and the manual delineation of pneumonic regions with a Dice coefficient of 81% (CI 76-86%). In detecting large pneumonia regions (> 200 mm3), the algorithm had a sensitivity of 95% (CI 94-97%) and specificity of 84% (CI 81-86%). Radiologists rated 95% (CI 72 to 99) of heatmaps at least "acceptable" for representing disease progression. CONCLUSION: The preliminary results suggested the feasibility of using computer software to detect and quantify pneumonic regions associated with COVID-19 and to generate heatmaps that can be used to visualize and assess progression. KEY POINTS: • Both computer vision and deep learning technology were used to develop computer software to quantify the presence and progression of pneumonia associated with COVID-19 depicted on CT images. • The computer software was tested using both quantitative experiments and subjective assessment. • The computer software has the potential to assist in the detection of the pneumonic regions, monitor disease progression, and assess treatment efficacy related to COVID-19.

Effect of Antimicrobial Therapy on Respiratory Hospitalization or Death in Adults With Idiopathic Pulmonary Fibrosis: The CleanUP-IPF Randomized Clinical Trial.

Importance: Alteration in lung microbes is associated with disease progression in idiopathic pulmonary fibrosis. Objective: To assess the effect of antimicrobial therapy on clinical outcomes. Design, Setting, and Participants: Pragmatic, randomized, unblinded clinical trial conducted across 35 US sites. A total of 513 patients older than 40 years were randomized from August 2017 to June 2019 (final follow-up was January 2020). Interventions: Patients were randomized in a 1:1 allocation ratio to receive antimicrobials (n = 254) or usual care alone (n = 259). Antimicrobials included co-trimoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily plus folic acid 5 mg daily, n = 128) or doxycycline (100 mg once daily if body weight <50 kg or 100 mg twice daily if ≥50 kg, n = 126). No placebo was administered in the usual care alone group. Main Outcomes and Measures: The primary end point was time to first nonelective respiratory hospitalization or all-cause mortality. Results: Among the 513 patients who were randomized (mean age, 71 years; 23.6% women), all (100%) were included in the analysis. The study was terminated for futility on December 18, 2019. After a mean follow-up time of 13.1 months (median, 12.7 months), a total of 108 primary end point events occurred: 52 events (20.4 events per 100 patient-years [95% CI, 14.8-25.9]) in the usual care plus antimicrobial therapy group and 56 events (18.4 events per 100 patient-years [95% CI, 13.2-23.6]) in the usual care group, with no significant difference between groups (adjusted HR, 1.04 [95% CI, 0.71-1.53; P = .83]. There was no statistically significant interaction between the effect of the prespecified antimicrobial agent (co-trimoxazole vs doxycycline) on the primary end point (adjusted HR, 1.15 [95% CI 0.68-1.95] in the co-trimoxazole group vs 0.82 [95% CI, 0.46-1.47] in the doxycycline group; P = .66). Serious adverse events occurring at 5% or greater among those treated with usual care plus antimicrobials vs usual care alone included respiratory events (16.5% vs 10.0%) and infections (2.8% vs 6.6%); adverse events of special interest included diarrhea (10.2% vs 3.1%) and rash (6.7% vs 0%). Conclusions and Relevance: Among adults with idiopathic pulmonary fibrosis, the addition of co-trimoxazole or doxycycline to usual care, compared with usual care alone, did not significantly improve time to nonelective respiratory hospitalization or death. These findings do not support treatment with these antibiotics for the underlying disease. Trial Registration: ClinicalTrials.gov Identifier: NCT02759120.

Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial.

Importance: Acutely ill inpatients with COVID-19 typically receive antithrombotic therapy, although the risks and benefits of this intervention among outpatients with COVID-19 have not been established. Objective: To assess whether anticoagulant or antiplatelet therapy can safely reduce major adverse cardiopulmonary outcomes among symptomatic but clinically stable outpatients with COVID-19. Design, Setting, and Participants: The ACTIV-4B Outpatient Thrombosis Prevention Trial was designed as a minimal-contact, adaptive, randomized, double-blind, placebo-controlled trial to compare anticoagulant and antiplatelet therapy among 7000 symptomatic but clinically stable outpatients with COVID-19. The trial was conducted at 52 US sites between September 2020 and June 2021; final follow-up was August 5, 2021. Prior to initiating treatment, participants were required to have platelet count greater than 100 000/mm3 and estimated glomerular filtration rate greater than 30 mL/min/1.73 m2. Interventions: Random allocation in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days. Main Outcomes and Measures: The primary end point was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause. The primary analyses for efficacy and bleeding events were limited to participants who took at least 1 dose of trial medication. Results: On June 18, 2021, the trial data and safety monitoring board recommended early termination because of lower than anticipated event rates; at that time, 657 symptomatic outpatients with COVID-19 had been randomized (median age, 54 years [IQR, 46-59]; 59% women). The median times from diagnosis to randomization and from randomization to initiation of study treatment were 7 days and 3 days, respectively. Twenty-two randomized participants (3.3%) were hospitalized for COVID-19 prior to initiating treatment. Among the 558 patients who initiated treatment, the adjudicated primary composite end point occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5-mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group. The risk differences compared with placebo for the primary end point were 0.0% (95% CI not calculable) in the aspirin group, 0.7% (95% CI, -2.1% to 4.1%) in the 2.5-mg apixaban group, and 1.4% (95% CI, -1.5% to 5.0%) in the 5-mg apixaban group. Risk differences compared with placebo for bleeding events were 2.0% (95% CI, -2.7% to 6.8%), 4.5% (95% CI, -0.7% to 10.2%), and 6.9% (95% CI, 1.4% to 12.9%) among participants who initiated therapy in the aspirin, prophylactic apixaban, and therapeutic apixaban groups, respectively, although none were major. Findings inclusive of all randomized patients were similar. Conclusions and Relevance: Among symptomatic clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome. However, the study was terminated after enrollment of 9% of participants because of an event rate lower than anticipated. Trial Registration: ClinicalTrials.gov Identifier: NCT04498273.

CD70 Activation Decreases Pulmonary Fibroblast Production of Extracellular Matrix Proteins.

Idiopathic pulmonary fibrosis (IPF) is a lethal, medically refractory syndrome characterized by intrapulmonary accumulations of extracellular matrix (ECM) proteins produced by fibroblasts. Activation, clonal expansion, and differentiation of lymphocytes are also frequently present in IPF. Activated T cells are known to exert several effects that promote ECM production, but opposing homeostatic actions, wherein T cells can inhibit fibrosis, are less well understood. We found that CD27, a TNF receptor ubiquitously expressed on naive T cells, is downregulated on CD4 T cells of patients with IPF and that CD70, the sole ligand for CD27, is present on human pulmonary fibroblasts. We hypothesized that cognate engagements between lymphocyte CD27 and fibroblast CD70 could have functional consequences. Accordingly, a series of subsequent studies were conducted to examine the possible role of CD27-CD70 interactions in the regulation of fibrogenesis. Using IB, flow cytometry, RT-PCR, and kinomic assays, we found that fibroblast CD70 expression was inversely correlated with cell density and upregulated by TGF-ß1 (transforming growth factor-ß1). CD70 agonists, including T-cell-derived soluble CD27, markedly diminished fibroblast collagen and fibronectin synthesis, and these effects were potent enough to also inhibit profibrotic actions of TGF-ß1 on ECM production in vitro and in two distinct ex vivo human skin models. CD70 activation was mediated by AKT (protein kinase B) and complex interconnected signaling pathways, and it was abated by prior CD70 knockdown. These results show that the CD70-CD27 axis modulates T-cell-fibroblast interactions and may be an important regulator of fibrosis and wound healing. Fibroblast CD70 could also be a novel target for specific mechanistically based antifibrosis treatments.