Lung Epithelium Releases Growth Differentiation Factor 15 in Response to Pathogen-mediated Injury.

GDF15 (growth differentiation factor 15) is a stress cytokine with several proposed roles, including support of stress erythropoiesis. Higher circulating GDF15 levels are prognostic of mortality during acute respiratory distress syndrome, but the cellular sources and downstream effects of GDF15 during pathogen-mediated lung injury are unclear. We quantified GDF15 in lower respiratory tract biospecimens and plasma from patients with acute respiratory failure. Publicly available data from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were reanalyzed. We used mouse models of hemorrhagic acute lung injury mediated by Pseudomonas aeruginosa exoproducts in wild-type mice and mice genetically deficient for Gdf15 or its putative receptor, Gfral. In critically ill humans, plasma levels of GDF15 correlated with lower respiratory tract levels and were higher in nonsurvivors. SARS-CoV-2 infection induced GDF15 expression in human lung epithelium, and lower respiratory tract GDF15 levels were higher in coronavirus disease (COVID-19) nonsurvivors. In mice, intratracheal P. aeruginosa type II secretion system exoproducts were sufficient to induce airspace and plasma release of GDF15, which was attenuated with epithelial-specific deletion of Gdf15. Mice with global Gdf15 deficiency had decreased airspace hemorrhage, an attenuated cytokine profile, and an altered lung transcriptional profile during injury induced by P. aeruginosa type II secretion system exoproducts, which was not recapitulated in mice deficient for Gfral. Airspace GDF15 reconstitution did not significantly modulate key lung cytokine levels but increased circulating erythrocyte counts. Lung epithelium releases GDF15 during pathogen injury, which is associated with plasma levels in humans and mice and can increase erythrocyte counts in mice, suggesting a novel lung-blood communication pathway.

Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis.

BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D. METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test. RESULTS: Using a Bonferroni-corrected significance threshold of P<1.6×10-4, we identified 3 genes (ATP1B1, ARVCF, and LIPG) associated with CAC and 2 genes (ABCG8 and EIF2B2) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both ATP1B1 and ARVCF also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis. CONCLUSIONS: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC.

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.

Phenotypes, Etiotypes, and Endotypes of Exacerbations of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease is a major health problem with a high prevalence, a rising incidence, and substantial morbidity and mortality. Its course is punctuated by acute episodes of increased respiratory symptoms, termed exacerbations of chronic obstructive pulmonary disease (ECOPD). ECOPD are important events in the natural history of the disease, as they are associated with lung function decline and prolonged negative effects on quality of life. The present-day therapy for ECOPD with short courses of antibiotics and steroids and escalation of bronchodilators has resulted in only modest improvements in outcomes. Recent data indicate that ECOPD are heterogeneous, raising the need to identify distinct etioendophenotypes, incorporating traits of the acute event and of patients who experience recurrent events, to develop novel and targeted therapies. These characterizations can provide a complete clinical picture, the severity of which will dictate acute pharmacological treatment, and may also indicate whether a change in maintenance therapy is needed to reduce the risk of future exacerbations. In this review we discuss the latest knowledge of ECOPD types on the basis of clinical presentation, etiology, natural history, frequency, severity, and biomarkers in an attempt to characterize these events.

Causes of and Clinical Features Associated with Death in Tobacco Cigarette Users by Lung Function Impairment.

Rationale: Cigarette smoking contributes to the risk of death through different mechanisms. Objectives: To determine how causes of and clinical features associated with death vary in tobacco cigarette users by lung function impairment. Methods: We stratified current and former tobacco cigarette users enrolled in Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) into normal spirometry, PRISm (Preserved Ratio Impaired Spirometry), Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1-2 COPD, and GOLD 3-4 COPD. Deaths were identified via longitudinal follow-up and Social Security Death Index search. Causes of death were adjudicated after a review of death certificates, medical records, and next-of-kin interviews. We tested associations between baseline clinical variables and all-cause mortality using multivariable Cox proportional hazards models. Measurements and Main Results: Over a 10.1-year median follow-up, 2,200 deaths occurred among 10,132 participants (age 59.5 ± 9.0 yr; 46.6% women). Death from cardiovascular disease was most frequent in PRISm (31% of deaths). Lung cancer deaths were most frequent in GOLD 1-2 (18% of deaths vs. 9-11% in other groups). Respiratory deaths outpaced competing causes of death in GOLD 3-4, particularly when BODE index ⩾7. St. George's Respiratory Questionnaire score ⩾25 was associated with higher mortality in all groups: Hazard ratio (HR), 1.48 (1.20-1.84) normal spirometry; HR, 1.40 (1.05-1.87) PRISm; HR, 1.80 (1.49-2.17) GOLD 1-2; HR, 1.65 (1.26-2.17) GOLD 3-4. History of respiratory exacerbations was associated with higher mortality in GOLD 1-2 and GOLD 3-4, quantitative emphysema in GOLD 1-2, and airway wall thickness in PRISm and GOLD 3-4. Conclusions: Leading causes of death vary by lung function impairment in tobacco cigarette users. Worse respiratory-related quality of life is associated with all-cause mortality regardless of lung function.

Insomnia in chronic obstructive pulmonary disease and associations with healthcare utilization and costs.

Insomnia has been linked to adverse chronic obstructive pulmonary disease (COPD) outcomes including exacerbations, yet its impact on COPD-related healthcare utilization and costs is unknown. In this study, we investigated the associations between insomnia and healthcare utilization and costs in patients with COPD. A retrospective cohort of veterans with COPD were identified from national Veterans Affairs administration data for fiscal years 2012-2017. Insomnia was operationalized as having an insomnia diagnosis based on International Classification of Disease codes or having a prescription of > 30 doses of a sedative-hypnotic medication in a given fiscal year. The index date for insomnia was the first date when dual criteria for COPD and insomnia was met. The index date for those without insomnia was set as the COPD index date. Our primary outcomes were 1-year healthcare utilization and costs related to outpatient visits and hospitalizations after index date. COPD-related healthcare utilization variables included number of prescription fills of corticosteroids and/or antibiotics and outpatient visits and hospitalizations with a primary diagnosis of COPD. Out of 1,011,646 patients (96% men, mean age 68.4 years) diagnosed with COPD, 407,363 (38.8%) had insomnia. After adjustment for confounders, insomnia was associated with higher rates of outpatient visits, hospitalizations, and fills for corticosteroids and/or antibiotics, longer hospital length of stay, and $10,344 higher hospitalization costs in the 12 months after index date. These findings highlight the importance of insomnia as a potentially modifiable target for reducing the burden of COPD on patients and healthcare systems.

Associations Between Muscle Weakness and Clinical Outcomes in Current and Former Smokers.

Introduction: Smokers with chronic obstructive pulmonary disease (COPD) are at increased risk of muscle weakness. There are limited data describing weakness in smokers with normal spirometry and preserved ratio-impaired spirometry (PRISm), 2 subgroups at risk of respiratory symptom burden and activity limitations. In this study, we evaluated the associations of 2 weakness measures, sit-to-stand (STS) and handgrip strength (HGS), with clinical outcomes in smokers with COPD, normal spirometry, and PRISm. Methods: We evaluated 1972 current and former smokers from the COPD Genetic Epidemiology (COPDGene®) cohort with STS and HGS measurements at their 10-year study visit. Multivariable regression modeling was used to assess associations between weakness measures and the 6-minute walk distance (6MWD) test, the St George's Respiratory Questionnaire (SGRQ), the Short-Form-36 (SF-36), severe exacerbations, and prospective mortality, reported as standardized coefficients (ß), odds ratios (ORs), or hazard ratios (HRs). Results: Compared with HGS, STS was more strongly associated with the 6MWD (ß=0.45, p<0.001 versus. ß=0.25, p<0.001), SGRQ (ß=-0.24, p<0.001 versus ß=-0.18, p<0.001), SF-36 Physical Functioning (ß=0.36, p<0.001 versus ß=0.25, p<0.001), severe exacerbations (OR 0.95, p=0.04 versus OR 0.97, p=0.01), and prospective mortality (HR 0.83, p=0.001 versus HR 0.94, p=0.03). Correlations remained after stratification by spirometric subgroups. Compared with males, females had larger magnitude effect sizes between STS and clinical outcomes. Conclusions: STS and HGS are easy to perform weakness measures that provide important information about functional performance, health-related quality of life, severe exacerbations, and survival in smokers, regardless of spirometric subgroup. This iterates the importance of screening current and former smokers for weakness in the outpatient setting.

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.

Clinical Markers Associated With Risk of Suicide or Drug Overdose Among Individuals With Smoking Exposure: A Longitudinal Follow-up Study of the COPDGene Cohort.

BACKGROUND: Studies have shown that COPD and smoking are associated with increased suicide risk. To date, there are no prospective studies examining suicide risk among individuals with smoking exposure along a spectrum of pulmonary diseases ranging from normal spirometry to severe COPD. RESEARCH QUESTION: Which clinical variables predict death by suicide or overdose of indeterminate intent in a large cohort of individuals with smoking exposure within the Genetic Epidemiology of COPD (COPDGene) study? STUDY DESIGN AND METHODS: We studied data from 9,930 participants involved in COPDGene, a multisite, prospective cohort study of individuals with smoking exposure. Primary cause of adjudicated deaths was identified by using death certificates, family reports, and medical records. Time to death by suicide/overdose was examined as the primary outcome in Cox regression models including age, sex, race, BMI, pack-years, current smoking status, airflow limitation (FEV1 % predicted), dyspnea (modified Medical Research Council scale score ≥ 2), 6-min walk distance, supplemental oxygen use, and severe exacerbations in the prior year with time-varying covariates and other causes of death as a competing risk. RESULTS: The cohort was 47% female and 33% Black (67% White); they had a mean ± SD age of 59.6 ± 9.0 years and a mean FEV1 % predicted of 76.1 ± 25.5. Sixty-three individuals died by suicide/overdose. Factors associated with risk of suicide/overdose were current smoking (hazard ratio [HR], 6.44; 95% CI, 2.64-15.67), use of sedative/hypnotics (HR, 2.33; 95% CI, 1.24-4.38), and dyspnea (HR, 2.23; 95% CI, 1.34-3.70). Lower risk was associated with older age (per-decade HR, 0.45; 95% CI, 0.31-0.67), higher BMI (HR, 0.95; 95% CI, 0.91-0.99), and African-American race (HR, 0.41; 95% CI, 0.23-0.74). Severity of airflow limitation (FEV % predicted) was not associated with suicide risk. INTERPRETATION: In this well-characterized cohort of individuals with smoking exposure with and without COPD, risk factors for suicide/overdose were identified that emphasize the subjective experience of illness over objective assessments of lung function.

Increased chest CT derived bone and muscle measures capture markers of improved morbidity and mortality in COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a disease of accelerated aging and is associated with comorbid conditions including osteoporosis and sarcopenia. These extrapulmonary conditions are highly prevalent yet frequently underdiagnosed and overlooked by pulmonologists in COPD treatment and management. There is evidence supporting a role for bone-muscle crosstalk which may compound osteoporosis and sarcopenia risk in COPD. Chest CT is commonly utilized in COPD management, and we evaluated its utility to identify low bone mineral density (BMD) and reduced pectoralis muscle area (PMA) as surrogates for osteoporosis and sarcopenia. We then tested whether BMD and PMA were associated with morbidity and mortality in COPD. METHODS: BMD and PMA were analyzed from chest CT scans of 8468 COPDGene participants with COPD and controls (smoking and non-smoking). Multivariable regression models tested the relationship of BMD and PMA with measures of function (6-min walk distance (6MWD), handgrip strength) and disease severity (percent emphysema and lung function). Multivariable Cox proportional hazards models were used to evaluate the relationship between sex-specific quartiles of BMD and/or PMA derived from non-smoking controls with all-cause mortality. RESULTS: COPD subjects had significantly lower BMD and PMA compared with controls. Higher BMD and PMA were associated with increased physical function and less disease severity. Participants with the highest BMD and PMA quartiles had a significantly reduced mortality risk (36% and 46%) compared to the lowest quartiles. CONCLUSIONS: These findings highlight the potential for CT-derived BMD and PMA to characterize osteoporosis and sarcopenia using equipment available in the pulmonary setting.

Circulating 1,3-Beta-D-Glucan is Associated with Lung Function, Respiratory Symptoms, and Mediators of Matrix Degradation in Chronic Obstructive Pulmonary Disease.

Introduction: Factors beyond cigarette smoke likely contribute to chronic obstructive pulmonary disease (COPD) pathogenesis. Prior studies demonstrate fungal colonization of the respiratory tract and increased epithelial barrier permeability in COPD. We sought to determine whether 1,3-beta-d-glucan (BDG), a polysaccharide component of the fungal cell wall, is detectable in the plasma of individuals with COPD and associates with clinical outcomes and matrix degradation proteins. Methods: BDG was measured in the plasma of current and former smokers with COPD. High BDG was defined as a value greater than the 95th percentile of BDG in smokers without airflow obstruction. Pulmonary function, emphysema, and symptoms were compared between COPD participants with high versus low BDG. The relationship between plasma BDG, matrix metalloproteinases (MMP) 1, 7, and 9, and tissue inhibitor of matrix metalloproteinases (TIMP) 1, 2, and 4 was assessed adjusting for age, sex, and smoking status. Results: COPD participants with high BDG plasma levels (19.8%) had lower forced expiratory volume in 1 second to forced vital capacity ratios (median 31.9 versus 39.3, p=0.025), higher St George's Respiratory Questionnaire symptom scores (median 63.6 versus 57.4, p=0.016), and greater prevalence of sputum production (69.4% versus 52.0%) and exacerbations (69.4% versus 48%) compared to COPD participants with low BDG. BDG levels directly correlated with MMP1 (r=0.27, p<0.001) and TIMP1 (r=0.16, p=0.022) in unadjusted and adjusted analyses. Conclusions: Elevated plasma BDG levels correlate with worse lung function, greater respiratory morbidity, and circulating markers of matrix degradation in COPD. These findings suggest that targeting dysbiosis or enhancing epithelial barrier integrity may have disease-modifying effects in COPD.

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

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults comprising 14 established US prospective cohort studies. Starting as early as 1971, investigators in the C4R cohort studies have collected data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R links this pre-coronavirus disease 2019 (COVID-19) phenotyping to information on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute and postacute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and reflects the racial, ethnic, socioeconomic, and geographic diversity of the United States. C4R ascertains SARS-CoV-2 infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey conducted via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations and high-quality event surveillance. Extensive prepandemic data minimize referral, survival, and recall bias. Data are harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these data will be pooled and shared widely to expedite collaboration and scientific findings. This resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including postacute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term health trajectories.

Longitudinal Association Between Muscle Loss and Mortality in Ever Smokers.

BACKGROUND: Body composition measures, specifically low weight or reduced muscle mass, are associated with mortality in COPD, but the effect of longitudinal body composition changes is undefined. RESEARCH QUESTION: Is the longitudinal loss of fat-free mass (FFM) associated with increased mortality, including in those with initially normal or elevated body composition metrics? STUDY DESIGN AND METHODS: Participants with complete data for at least one visit in the COPDGene study (n = 9,268) and the ECLIPSE study (n = 1,760) were included and monitored for 12 and 8 years, respectively. Pectoralis muscle area (PMA) was derived from thoracic CT scans and used as a proxy for FFM. A longitudinal mixed submodel for PMA and a Cox proportional hazards submodel for survival were fitted on a joint distribution, using a shared random intercept parameter and Markov chain Monte Carlo parameter estimation. RESULTS: Both cohorts demonstrated a left-shifted distribution of baseline FFM, not reflected in BMI, and an increase in all-cause mortality risk associated with longitudinal loss of PMA. For each 1-cm2 PMA loss, mortality increased 3.1% (95% CI, 2.4%-3.7%; P < .001) in COPDGene, and 2.4% (95% CI, 0.9%-4.0%; P < .001) in ECLIPSE. Increased mortality risk was independent of enrollment values for BMI and disease severity [BODE (body mass, airflow obstruction, dyspnea, and exercise capacity) index quartiles] and was significant even in participants with initially greater than average PMA. INTERPRETATION: Longitudinal loss of PMA is associated with increased all-cause mortality, regardless of BMI or initial muscle mass. Consideration of novel screening tests and further research into mechanisms contributing to muscle decline may improve risk stratification and identify novel therapeutic targets in ever smokers.

Association of Systemic Inflammation with Depressive Symptoms in Individuals with COPD.

RATIONALE: Depression is a prevalent comorbidity of chronic obstructive pulmonary disease (COPD) that, along with COPD, has been associated with inflammation. An association between inflammation and depression in COPD has not been validated in a large COPD cohort. METHODS: Individuals from the University of Pittsburgh SCCOR cohort and the COPDGene cohort with tobacco use history and airway obstruction (FEV1/FVC <0.7) were evaluated using the Beck Depression Inventory II (BDI-II) and the Hospital Anxiety and Depression Scale (HADS), respectively. Participants completed symptom-related questionnaires and plasma IL-6 measurements. T-test, Fisher's Exact tests and logistic regression were used for statistical analysis. RESULTS: The SCCOR cohort included 220 obstructed participants: 44% female and 21.4% with elevated depressive symptoms. GOLD staging distribution was predominantly stage I and II. The COPDGene cohort included 745 obstructed participants: 44% female and 13.0% with elevated depressive symptoms. GOLD distribution was predominantly stage II and III. In the SCCOR cohort, correlation between IL-6 and depressive symptoms trended toward significance (p= 0.08). Multivariable modeling adjusted for FEV1, age, gender and medical comorbidities showed a significant association (OR = 1.70, 95% CI = 1.08-2.69). IL-6 was significantly associated with elevated depressive symptoms in COPDGene in both univariate (p=0.001) and multivariable modeling (OR = 1.52, 95% CI =1.13-2.04). CONCLUSION: Elevated plasma IL-6 levels are associated with depressive symptoms in individuals with COPD independent of airflow limitation and comorbid risk factors for depression. Our results suggest that systemic inflammation may play a significant and possibly bidirectional role in depression associated with COPD.

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

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 (FEV1 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). FEV1 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, FEV1 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.

Brief Report: Association Between Pain, Pulmonary Function, and Respiratory Symptoms in People With HIV.

BACKGROUND: People with HIV (PWH) experience chronic pain and respiratory symptoms, which are closely related in the general population. Pain may affect the impaired pulmonary function seen in PWH beyond its association with HIV alone. Our objective was to investigate the relationship of pain severity to pulmonary function, respiratory symptoms, and sleep disturbance in PWH. SETTING: Study sites included the University of Pittsburgh, University of California San Francisco, and University of Washington. METHODS: Pain, dyspnea, and sleep were assessed using the Brief Chronic Pain Questionnaire, St. George's Respiratory Questionnaire, and Pittsburgh Sleep Quality Index. Participants performed prebronchodilator and postbronchodilator spirometry and 6-minute walk test. Associations between pain severity, lung function, dyspnea, and sleep were assessed with bivariate and multiple quantile regression analysis adjusted for age, sex, race, body mass index, and smoking status. RESULTS: Of 159 PWH, the median age was 56 years with 30.8% women. Two-thirds experienced pain in the past week, with 40.3% reporting chronic pain. Pain severity was higher with female sex (P = 0.038), non-White race (P = 0.005), current smoking (P = 0.003), and lower CD4+ count (P = 0.035). In adjusted analysis, higher pain severity was correlated with reduced postbronchodilator forced expiratory volume in 1 second %predicted (P = 0.008), reduced postbronchodilator forced vital capacity %predicted (P = 0.019), and chronic obstructive pulmonary disease (P = 0.032). Greater pain severity was strongly associated with a higher St. George's Respiratory Questionnaire score (P < 0.001) and sleep disturbance (P < 0.001). CONCLUSIONS: In PWH, pain is common and associated with airflow obstruction, dyspnea, and sleep disturbance. Future studies assessing pain severity and pulmonary function over time could clarify the direction of this association and the impact on quality of life.

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

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.

Metformin use and respiratory outcomes in asthma-COPD overlap.

BACKGROUND: Metformin is associated with improved respiratory outcomes in asthma; however, metformin in COPD and asthma-COPD overlap (ACO) remains unexplored. OBJECTIVE: To determine the association between metformin use and respiratory outcomes in COPD and ACO. STUDY DESIGN AND METHODS: Participants with COPD (FEV1/FVC < 0.70) in the Genetic Epidemiology of COPD study (COPDGene®) were categorized as ACO (n = 510), defined as concurrent physician-diagnosed asthma before age 40 years, or COPD alone (n = 3459). We estimated the association of baseline metformin use with (1) rate of total and severe respiratory exacerbations during follow-up, (2) cross-sectional St. George's Respiratory Questionnaire (SGRQ) score, six-minute walk distance (6MWD), and post-bronchodilator FEV1 percent predicted (FEV1pp), and (3) 5-year change in SGRQ, 6MWD, and FEV1pp. We also examined change in SGRQ, 6MWD and FEV1pp among participants who initiated metformin during follow-up (n = 108) compared to persistent metformin non-users (n = 2080). Analyses were adjusted for sociodemographic factors, medications, and comorbidities. RESULTS: Among participants with ACO, metformin use was associated with lower rate of total (adjusted incidence rate ratio [aIRR] 0.3; 95% confidence interval [95%CI] 0.11, 0.77) and severe exacerbations (aIRR 0.29; 95%CI 0.10, 0.89). Among participants with COPD alone, there was no association between metformin use with total (aIRR 0.98; 95%CI 0.62, 1.5) or severe exacerbations (aIRR 1.3; 95% CI 0.68, 2.4) (p-interaction < 0.05). Metformin use was associated with lower baseline SGRQ score (adjusted mean difference [aMD] - 2.7; 95%CI - 5.3, - 0.2) overall. Metformin initiation was associated with improved SGRQ score (aMD -10.0; 95% CI - 18.7, - 1.2) among participants with ACO but not COPD alone (p-interaction < 0.05). There was no association between metformin use and 6MWD or FEV1pp in any comparison. CONCLUSIONS: Metformin use was associated with fewer respiratory exacerbations and improved quality of life among individuals with ACO but not COPD alone. Results suggest a potential role for metformin in ACO which requires further prospective study. TRIAL REGISTRY: NCT00608764.