Early Evidence of Chronic Obstructive Pulmonary Disease Obscured by Race-Specific Prediction Equations.

Rationale: The identification of early chronic obstructive pulmonary disease (COPD) is essential to appropriately counsel patients regarding smoking cessation, provide symptomatic treatment, and eventually develop disease-modifying treatments. Disease severity in COPD is defined using race-specific spirometry equations. These may disadvantage non-White individuals in diagnosis and care. Objectives: Determine the impact of race-specific equations on African American (AA) versus non-Hispanic White individuals. Methods: Cross-sectional analyses of the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort were conducted, comparing non-Hispanic White (n = 6,766) and AA (n = 3,366) participants for COPD manifestations. Measurements and Main Results: Spirometric classifications using race-specific, multiethnic, and "race-reversed" prediction equations (NHANES [National Health and Nutrition Examination Survey] and Global Lung Function Initiative "Other" and "Global") were compared, as were respiratory symptoms, 6-minute-walk distance, computed tomography imaging, respiratory exacerbations, and St. George's Respiratory Questionnaire. Application of different prediction equations to the cohort resulted in different classifications by stage, with NHANES and Global Lung Function Initiative race-specific equations being minimally different, but race-reversed equations moving AA participants to more severe stages and especially between the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0 and preserved ratio impaired spirometry groups. Classification using the established NHANES race-specific equations demonstrated that for each of GOLD stages 1-4, AA participants were younger, had fewer pack-years and more current smoking, but had more exacerbations, shorter 6-minute-walk distance, greater dyspnea, and worse BODE (body mass index, airway obstruction, dyspnea, and exercise capacity) scores and St. George's Respiratory Questionnaire scores. Differences were greatest in GOLD stages 1 and 2. Race-reversed equations reclassified 774 AA participants (43%) from GOLD stage 0 to preserved ratio impaired spirometry. Conclusions: Race-specific equations underestimated disease severity among AA participants. These effects were particularly evident in early disease and may result in late detection of COPD.

Myeloid Heterogeneity Mediates Acute Exacerbations of Pulmonary Fibrosis.

Epidemiological evidence indicates that exposure to particulate matter is linked to the development of idiopathic pulmonary fibrosis (IPF) and increases the incidence of acute exacerbations of IPF. In addition to accelerating the rate of lung function decline, exposure to fine particulate matter (particulate matter smaller than 2.5 µm [PM2.5]) is a risk factor for increased mortality in subjects with IPF. In this article, we show that exposure to PM2.5 mediates monocyte recruitment and fibrotic progression in mice with established fibrosis. In mice with established fibrosis, bronchoalveolar lavage cells showed monocyte/macrophage heterogeneity after exposure to PM2.5. These cells had a significant inflammatory and anti-inflammatory signature. The mixed heterogeneity of cells contributed to the proinflammatory and anti-inflammatory response. Although monocyte-derived macrophages were recruited to the lung in bleomycin-injured mice treated with PM2.5, recruitment of monocytes expressing Ly6Chi to the lung promoted progression of fibrosis, reduced lung aeration on computed tomography, and impacted lung compliance. Ly6Chi monocytes isolated from PM2.5-exposed fibrotic mice showed enhanced expression of proinflammatory markers compared with fibrotic mice exposed to vehicle. Moreover, IPF bronchoalveolar lavage cells treated ex vivo with PM2.5 showed an exaggerated inflammatory response. Targeting Ly6Chi monocyte recruitment inhibited fibrotic progression in mice. Moreover, the adoptive transfer of Ly6Chi monocytes exacerbated established fibrosis. These observations suggest that enhanced recruitment of Ly6Chi monocytes with a proinflammatory phenotype mediates acute exacerbations of pulmonary fibrosis, and targeting these cells may provide a potential novel therapeutic target to protect against acute exacerbations of IPF.

Race-Specific Spirometry Equations Do Not Improve Models of Dyspnea and Quantitative Chest CT Phenotypes.

BACKGROUND: Race-specific spirometry reference equations are used globally to interpret lung function for clinical, research, and occupational purposes, but inclusion of race is under scrutiny. RESEARCH QUESTION: Does including self-identified race in spirometry reference equation formation improve the ability of predicted FEV1 values to explain quantitative chest CT abnormalities, dyspnea, or Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification? STUDY DESIGN AND METHODS: Using data from healthy adults who have never smoked in both the National Health and Nutrition Survey (2007-2012) and COPDGene study cohorts, race-neutral, race-free, and race-specific prediction equations were generated for FEV1. Using sensitivity/specificity, multivariable logistic regression, and random forest models, these equations were applied in a cross-sectional analysis to populations of individuals who currently smoke and individuals who formerly smoked to determine how they affected GOLD classification and the fit of models predicting quantitative chest CT phenotypes or dyspnea. RESULTS: Race-specific equations showed no advantage relative to race-neutral or race-free equations in models of quantitative chest CT phenotypes or dyspnea. Race-neutral reference equations reclassified up to 19% of Black participants into more severe GOLD classes, while race-neutral/race-free equations may improve model fit for dyspnea symptoms relative to race-specific equations. INTERPRETATION: Race-specific equations offered no advantage over race-neutral/race-free equations in three distinct explanatory models of dyspnea and chest CT scan abnormalities. Race-neutral/race-free reference equations may improve pulmonary disease diagnoses and treatment in populations highly vulnerable to lung disease.

Rehabilitation for People with Respiratory Disease and Frailty: An Official American Thoracic Society Workshop Report.

People with respiratory disease have increased risk of developing frailty, which is associated with worse health outcomes. There is growing evidence of the role of rehabilitation in managing frailty in people with respiratory disease. However, several challenges remain regarding optimal methods of identifying frailty and delivering rehabilitation for this population. The aims of this American Thoracic Society workshop were to outline key definitions and concepts around rehabilitation for people with respiratory disease and frailty, synthesize available evidence, and explore how programs may be adapted to align to the needs and experiences of this population. Across two half-day virtual workshops, 20 professionals from diverse disciplines, professions, and countries discussed key developments and identified opportunities for future research, with additional input via online correspondence. Participants highlighted a "frailty rehabilitation paradox" whereby pulmonary rehabilitation can effectively reduce frailty, but programs are challenging for some individuals with frailty to complete. Frailty should not limit access to rehabilitation; instead, the identification of frailty should prompt comprehensive assessment and tailored support, including onward referral for additional specialist input. Exercise prescriptions that explicitly consider symptom burden and comorbidities, integration of additional geriatric or palliative care expertise, and/or preemptive planning for disruptions to participation may support engagement and outcomes. To identify and measure frailty in people with respiratory disease, tools should be selected on the basis of sensitivity, specificity, responsiveness, and feasibility for their intended purpose. Research is required to expand understanding beyond the physical dimensions of frailty and to explore the merits and limitations of telerehabilitation or home-based pulmonary rehabilitation for people with chronic respiratory disease and frailty.

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.

Use of the Spirometric "Fixed-Ratio" Underdiagnoses COPD in African-Americans in a Longitudinal Cohort Study.

BACKGROUND: COPD diagnosis is tightly linked to the fixed-ratio spirometry criteria of FEV1/FVC < 0.7. African-Americans are less often diagnosed with COPD. OBJECTIVE: Compare COPD diagnosis by fixed-ratio with findings and outcomes by race. DESIGN: Genetic Epidemiology of COPD (COPDGene) (2007-present), cross-sectional comparing non-Hispanic white (NHW) and African-American (AA) participants for COPD diagnosis, manifestations, and outcomes. SETTING: Multicenter, longitudinal US cohort study. PARTICIPANTS: Current or former smokers with ≥ 10-pack-year smoking history enrolled at 21 clinical centers including over-sampling of participants with known COPD and AA. Exclusions were pre-existing non-COPD lung disease, except for a history of asthma. MEASUREMENTS: Subject diagnosis by conventional criteria. Mortality, imaging, respiratory symptoms, function, and socioeconomic characteristics, including area deprivation index (ADI). Matched analysis (age, sex, and smoking status) of AA vs. NHW within participants without diagnosed COPD (GOLD 0; FEV1 ≥ 80% predicted and FEV1/FVC ≥ 0.7). RESULTS: Using the fixed ratio, 70% of AA (n = 3366) were classified as non-COPD, versus 49% of NHW (n = 6766). AA smokers were younger (55 vs. 62 years), more often current smoking (80% vs. 39%), with fewer pack-years but similar 12-year mortality. Density distribution plots for FEV1 and FVC raw spirometry values showed disproportionate reductions in FVC relative to FEV1 in AA that systematically led to higher ratios. The matched analysis demonstrated GOLD 0 AA had greater symptoms, worse DLCO, spirometry, BODE scores (1.03 vs 0.54, p < 0.0001), and greater deprivation than NHW. LIMITATIONS: Lack of an alternative diagnostic metric for comparison. CONCLUSIONS: The fixed-ratio spirometric criteria for COPD underdiagnosed potential COPD in AA participants when compared to broader diagnostic criteria. Disproportionate reductions in FVC relative to FEV1 leading to higher FEV1/FVC were identified in these participants and associated with deprivation. Broader diagnostic criteria for COPD are needed to identify the disease across all populations.

Idiopathic pulmonary fibrosis is more strongly associated with coronary artery disease than chronic obstructive pulmonary disease.

INTRODUCTION: Previous studies have shown that the population attributable risk of low forced expiratory volume in one second (FEV1) for coronary artery disease (CAD) is substantial. FEV1 can be low either because of airflow obstruction or ventilatory restriction. It is not known if low FEV1 arising from spirometric obstruction or restriction are differently associated with CAD. METHODS: We analyzed high resolution computed tomography (CT) scans acquired at full inspiration in lifetime non-smoker adults with no lung disease (controls) and those with chronic obstructive pulmonary disease enrolled in the Genetic Epidemiology of COPD (COPDGene) study. We also analyzed CT scans of adults with idiopathic pulmonary fibrosis (IPF) from a cohort of patients attending a quaternary referral clinic. Participants with IPF were matched 1:1 by FEV1 %predicted to adults with COPD and 1:1 by age to lifetime non-smokers. Coronary artery calcium (CAC), a surrogate for CAD, was measured by visual quantification on CT using the Weston score. Significant CAC was defined as Weston score ≥7. Multivariable regression models were used to test the association of the presence of COPD or IPF with CAC, with adjustment for age, sex, body-mass-index, smoking status, hypertension, diabetes mellitus, and hyperlipidemia. RESULTS: We included 732 subjects in the study; 244 with IPF, 244 with COPD, and 244 lifetime non-smokers. The mean (SD) age was 72.6 (8.1), 62.6 (7.4), and 67.3 (6.6) years, and median (IQR) CAC was 6 (6), 2 (6), and 1 (4), in IPF, COPD, and non-smokers, respectively. On multivariable analyses, the presence of COPD was associated with higher CAC compared to non-smokers (adjusted regression coefficient, ß = 1.10 ± SE0.51; P = 0.031). The presence of IPF was also associated with higher CAC compared to non-smokers (ß = 03.43 ± SE0.41; P < 0.001). The adjusted odds ratio for having significant CAC was 1.3, 95% CI 0.6 to 2.8; P = 0.53 in COPD and 5.6, 95% CI 2.9 to 10.9; P < 0.001 in IPF, compared to non-smokers. In sex stratified analyses, these associations were mainly noted in women. CONCLUSION: Adults with IPF displayed higher coronary artery calcium than those with COPD after accounting for age and lung function impairment.

Parameter D: New Measure of Airflow Obstruction.

Rationale: Currently used spirometry measures of airflow obstruction are influenced by demographics, predominantly by age, complicating selection of diagnostic thresholds for the presence of airflow obstruction. Objectives: To develop diagnostic thresholds for Parameter D, a new metric for detection of airflow obstruction, which quantifies the rate of rise of expiratory volume over time. Methods: We analyzed spirometry data of normal subjects enrolled in the 2007-2008, 2009-2010, and 2011-2012 NHANES (National Health and Nutrition Examination Survey) cohorts and calculated Parameter D using the expiratory volume-time curve. Relationships between demographics and lung function (forced expiratory volume in 1 second [FEV1], FEV1/forced vital capacity [FVC], and Parameter D) were tested using generalized linear models in NHANES and UK Biobank. The variation in lung function explained by demographics was estimated using R2. A diagnostic threshold was developed for Parameter D using population-based percentiles. Based on concordance between the lower limit of normal (LLN) for FEV1/FVC and the Parameter D threshold, four groups were identified: normal (no airflow obstruction by either criterion), D+chronic obstructive pulmonary disease (D+COPD; positive by Parameter D only), D-COPD (positive by LLN only), and COPD (positive by both criteria), and associations with structural lung disease, exacerbations, and mortality were tested using multivariable analyses. Results: In contrast to FEV1 and FEV1/FVC, demographics cumulatively explained only 9% of the variance in Parameter D in NHANES (n = 4,945) and 3% in UK BioBank (n = 109,623). In COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) (n = 9,542), a diagnostic threshold of -3.15 resulted in the identification of an additional 10.8% of participants with airflow obstruction. A total of 3.7% had FEV1/FVC < LLN but were missed by the Parameter D threshold. Compared with subjects in the normal group, after adjustment for age, sex, race, body mass index, pack-years of smoking, and current smoking status, D+COPD was associated with worse structural lung disease (odds ratio [OR] for ⩾5% emphysema, 1.71; 95% confidence interval [CI], 1.37-2.12; OR for functional small airway disease ⩾ 15%, 2.1; 95% CI, 1.79-2.67) and significant symptoms (OR for modified Medical Research Council dyspnea score ⩾ 2, 1.25; 95% CI, 1.07-1.47; OR for St. George's respiratory questionnaire ⩾ 25, 1.31; 95% CI, 1.13-1.53), a greater frequency of exacerbations (incidence rate ratio, 1.26; 95% CI, 1.10-1.46), and higher mortality (hazard ratio, 1.32; 95% CI, 1.10-1.57). Over 5 years, 28% of the D+COPD group versus 8% of normal group progressed to COPD by traditional criteria. Conclusions: Parameter D is not affected by age, and a normal population-based diagnostic threshold results in the early identification of additional individuals with airflow obstruction with a substantial amount of structural lung disease and respiratory symptoms.

Prevalence of abnormal spirometry in individuals with a smoking history and no known obstructive lung disease.

INTRODUCTION: Recent evidence suggests a high prevalence of undiagnosed chronic obstructive pulmonary disease (COPD). These individuals are at risk of exacerbations and delayed treatment. We analyzed an at-risk population for the prevalence of abnormal spirometry to provide clarity into who should undergo early spirometry. METHODS: We analyzed data from the COPDGene study. Participants with ≥10 pack-years of smoking were included. Individuals with self-reported or physician-diagnosed COPD, asthma, chronic bronchitis, emphysema and/or were on inhalers were excluded. Parsimonious multivariable logistic regression models identified factors associated with abnormal spirometry, defined as either airflow obstruction (AFO) or preserved ratio impaired spirometry. Variables were selected for the final model using a stepwise backward variable elimination process which minimized Akaike information criterion (AIC). Similarly, during the 5-year follow-up period, we assessed factors associated with incident diagnosis of COPD. RESULTS: Of 5055 individuals, 1064 (21%) had undiagnosed AFO. Age, pack-years, current smoking and a history of acute bronchitis were associated with AFO while body mass index, female sex, and Black race were inversely associated. Among 2800 participants with 5-year follow-up, 532 (19%) had an incident diagnosis of COPD. Associated risk factors included mMRC ≥2, chronic productive cough, respiratory exacerbations during the follow-up period, and abnormal spirometry. Age was inversely associated. CONCLUSIONS: The prevalence of undiagnosed COPD is high in at-risk populations. We found multiple factors associated with undiagnosed COPD and incident diagnosis of COPD at follow up. These results can be used to identify those at risk for undiagnosed COPD to facilitate earlier diagnosis and treatment.

Predicting severe chronic obstructive pulmonary disease exacerbations using quantitative CT: a retrospective model development and external validation study.

BACKGROUND: Quantitative CT is becoming increasingly common for the characterisation of lung disease; however, its added potential as a clinical tool for predicting severe exacerbations remains understudied. We aimed to develop and validate quantitative CT-based models for predicting severe chronic obstructive pulmonary disease (COPD) exacerbations. METHODS: We analysed the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS) cohort, a multicentre study done at 12 clinical sites across the USA, of individuals aged 40-80 years from four strata: individuals who never smoked, individuals who smoked but had normal spirometry, individuals who smoked and had mild to moderate COPD, and individuals who smoked and had severe COPD. We used 3-year follow-up data to develop logistic regression classifiers for predicting severe exacerbations. Predictors included age, sex, race, BMI, pulmonary function, exacerbation history, smoking status, respiratory quality of life, and CT-based measures of density gradient texture and airway structure. We externally validated our models in a subset from the Genetic Epidemiology of COPD (COPDGene) cohort. Discriminative model performance was assessed using the area under the receiver operating characteristic curve (AUC), which was also compared with other predictors, including exacerbation history and the BMI, airflow obstruction, dyspnoea, and exercise capacity (BODE) index. We evaluated model calibration using calibration plots and Brier scores. FINDINGS: Participants in SPIROMICS were enrolled between Nov 12, 2010, and July 31, 2015. Participants in COPDGene were enrolled between Jan 10, 2008, and April 15, 2011. We included 1956 participants from the SPIROMICS cohort who had complete 3-year follow-up data: the mean age of the cohort was 63·1 years (SD 9·2) and 1017 (52%) were men and 939 (48%) were women. Among the 1956 participants, 434 (22%) had a history of at least one severe exacerbation. For the CT-based models, the AUC was 0·854 (95% CI 0·852-0·855) for at least one severe exacerbation within 3 years and 0·931 (0·930-0·933) for consistent exacerbations (defined as ≥1 acute episode in each of the 3 years). Models were well calibrated with low Brier scores (0·121 for at least one severe exacerbation; 0·039 for consistent exacerbations). For the prediction of at least one severe event during 3-year follow-up, AUCs were significantly higher with CT biomarkers (0·854 [0·852-0·855]) than exacerbation history (0·823 [0·822-0·825]) and BODE index 0·812 [0·811-0·814]). 6965 participants were included in the external validation cohort, with a mean age of 60·5 years (SD 8·9). In this cohort, AUC for at least one severe exacerbation was 0·768 (0·767-0·769; Brier score 0·088). INTERPRETATION: CT-based prediction models can be used for identification of patients with COPD who are at high risk of severe exacerbations. The newly identified CT biomarkers could potentially enable investigation into underlying disease mechanisms responsible for exacerbations. FUNDING: National Institutes of Health and the National Heart, Lung, and Blood Institute.

Bronchodilator Responsiveness in Tobacco-Exposed People With or Without COPD.

BACKGROUND: Bronchodilator responsiveness (BDR) in obstructive lung disease varies over time and may be associated with distinct clinical features. RESEARCH QUESTION: Is consistent BDR over time (always present) differentially associated with obstructive lung disease features relative to inconsistent (sometimes present) or never (never present) BDR in tobacco-exposed people with or without COPD? STUDY DESIGN AND METHODS: We retrospectively analyzed data from 2,269 tobacco-exposed participants in the Subpopulations and Intermediate Outcome Measures in COPD Study with or without COPD. We used various BDR definitions: change of ≥ 200 mL and ≥ 12% in FEV1 (FEV1-BDR), change in FVC (FVC-BDR), and change in in FEV1, FVC or both (ATS-BDR). Using generalized linear models adjusted for demographics, smoking history, FEV1 % predicted after bronchodilator administration, and number of visits that the participant completed, we assessed the association of BDR group: (1) consistent BDR, (2) inconsistent BDR, and (3) never BDR with asthma, CT scan features, blood eosinophil levels, and FEV1 decline in participants without COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 0) and the entire cohort (participants with or without COPD). RESULTS: Both consistent and inconsistent ATS-BDR were associated with asthma history and greater small airways disease (%parametric response mapping functional small airways disease) relative to never ATS-BDR in participants with GOLD stage 0 disease and the entire cohort. We observed similar findings using FEV1-BDR and FVC-BDR definitions. Eosinophils did not vary consistently among BDR groups. Consistent BDR was associated with FEV1 decline over time relative to never BDR in the entire cohort. In participants with GOLD stage 0 disease, both the inconsistent ATS-BDR group (OR, 3.20; 95% CI, 2.21-4.66; P < .001) and consistent ATS-BDR group (OR, 9.48; 95% CI, 3.77-29.12; P < .001) were associated with progression to COPD relative to the never ATS-BDR group. INTERPRETATION: Demonstration of BDR, even once, describes an obstructive lung disease phenotype with a history of asthma and greater small airways disease. Consistent demonstration of BDR indicated a high risk of lung function decline over time in the entire cohort and was associated with higher risk of progression to COPD in patients with GOLD stage 0 disease.

Lung Function in Women With and Without Human Immunodeficiency Virus.

BACKGROUND: Prior studies have found that human immunodeficiency virus (HIV) infection is associated with impaired lung function and increased risk of chronic lung disease, but few have included large numbers of women. In this study, we investigate whether HIV infection is associated with differences in lung function in women. METHODS: This was a cross-sectional analysis of participants in the Women's Interagency HIV Study, a racially and ethnically diverse multicenter cohort of women with and without HIV. In 2018-2019, participants at 9 clinical sites were invited to perform spirometry. Single-breath diffusing capacity for carbon monoxide (DLCO) was also measured at selected sites. The primary outcomes were the post-bronchodilator forced expiratory volume in 1 second (FEV1) and DLCO. Multivariable regression modeling was used to analyze the association of HIV infection and lung function outcomes after adjustment for confounding exposures. RESULTS: FEV1 measurements from 1489 women (1062 with HIV, 427 without HIV) and DLCO measurements from 671 women (463 with HIV, 208 without HIV) met standards for quality and reproducibility. There was no significant difference in FEV1 between women with and without HIV. Women with HIV had lower DLCO measurements (adjusted difference, -0.73 mL/min/mm Hg; 95% confidence interval, -1.33 to -.14). Among women with HIV, lower nadir CD4 + cell counts and hepatitis C virus infection were associated with lower DLCO measurements. CONCLUSIONS: HIV was associated with impaired respiratory gas exchange in women. Among women with HIV, lower nadir CD4 + cell counts and hepatitis C infection were associated with decreased respiratory gas exchange.

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.

Sex Differences in Airways at Chest CT: Results from the COPDGene Cohort.

Background The prevalence of chronic obstructive pulmonary disease (COPD) in women is fast approaching that in men, and women experience greater symptom burden. Although sex differences in emphysema have been reported, differences in airways have not been systematically characterized. Purpose To evaluate whether structural differences in airways may underlie some of the sex differences in COPD prevalence and clinical outcomes. Materials and Methods In a secondary analyses of a multicenter study of never-, current-, and former-smokers enrolled from January 2008 to June 2011 and followed up longitudinally until November 2020, airway disease on CT images was quantified using seven metrics: airway wall thickness, wall area percent, and square root of the wall thickness of a hypothetical airway with internal perimeter of 10 mm (referred to as Pi10) for airway wall; and lumen diameter, airway volume, total airway count, and airway fractal dimension for airway lumen. Least-squares mean values for each airway metric were calculated and adjusted for age, height, ethnicity, body mass index, pack-years of smoking, current smoking status, total lung capacity, display field of view, and scanner type. In ever-smokers, associations were tested between each airway metric and postbronchodilator forced expiratory volume in 1 second (FEV1)-to-forced vital capacity (FVC) ratio, modified Medical Research Council dyspnea scale, St George's Respiratory Questionnaire score, and 6-minute walk distance. Multivariable Cox proportional hazards models were created to evaluate the sex-specific association between each airway metric and mortality. Results In never-smokers (n = 420), men had thicker airway walls than women as quantified on CT images for segmental airway wall area percentage (least-squares mean, 47.68 ± 0.61 [standard error] vs 45.78 ± 0.55; difference, -1.90; P = .02), whereas airway lumen dimensions were lower in women than men after accounting for height and total lung capacity (segmental lumen diameter, 8.05 mm ± 0.14 vs 9.05 mm ± 0.16; difference, -1.00 mm; P < .001). In ever-smokers (n = 9363), men had greater segmental airway wall area percentage (least-squares mean, 52.19 ± 0.16 vs 48.89 ± 0.18; difference, -3.30; P < .001), whereas women had narrower segmental lumen diameter (7.80 mm ± 0.05 vs 8.69 mm ± 0.04; difference, -0.89; P < .001). A unit change in each of the airway metrics (higher wall or lower lumen measure) resulted in lower FEV1-to-FVC ratio, more dyspnea, poorer respiratory quality of life, lower 6-minute walk distance, and worse survival in women compared with men (all P < .01). Conclusion Airway lumen sizes quantified at chest CT were smaller in women than in men after accounting for height and lung size, and these lower baseline values in women conferred lower reserves against respiratory morbidity and mortality for equivalent changes compared with men. © RSNA, 2022 Online supplemental material is available for this article.

Lung function impairment and risk of incident heart failure: the NHLBI Pooled Cohorts Study.

AIMS: The aim is to evaluate associations of lung function impairment with risk of incident heart failure (HF). METHODS AND RESULTS: Data were pooled across eight US population-based cohorts that enrolled participants from 1987 to 2004. Participants with self-reported baseline cardiovascular disease were excluded. Spirometry was used to define obstructive [forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.70] or restrictive (FEV1/FVC ≥0.70, FVC <80%) lung physiology. The incident HF was defined as hospitalization or death caused by HF. In a sub-set, HF events were sub-classified as HF with reduced ejection fraction (HFrEF; EF <50%) or preserved EF (HFpEF; EF ≥50%). The Fine-Gray proportional sub-distribution hazards models were adjusted for sociodemographic factors, smoking, and cardiovascular risk factors. In models of incident HF sub-types, HFrEF, HFpEF, and non-HF mortality were treated as competing risks. Among 31 677 adults, there were 3344 incident HF events over a median follow-up of 21.0 years. Of 2066 classifiable HF events, 1030 were classified as HFrEF and 1036 as HFpEF. Obstructive [adjusted hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.07-1.27] and restrictive physiology (adjusted HR 1.43, 95% CI 1.27-1.62) were associated with incident HF. Obstructive and restrictive ventilatory defects were associated with HFpEF but not HFrEF. The magnitude of the association between restrictive physiology and HFpEF was similar to associations with hypertension, diabetes, and smoking. CONCLUSION: Lung function impairment was associated with increased risk of incident HF, and particularly incident HFpEF, independent of and to a similar extent as major known cardiovascular risk factors.

Pooled Cohort Probability Score for Subclinical Airflow Obstruction.

Rationale: Early detection of chronic obstructive pulmonary disease (COPD) is a public health priority. Airflow obstruction is the single most important risk factor for adverse COPD outcomes, but spirometry is not routinely recommended for screening. Objectives: To describe the burden of subclinical airflow obstruction (SAO) and to develop a probability score for SAO to inform potential detection and prevention programs. Methods: Lung function and clinical data were harmonized and pooled across nine U.S. general population cohorts. Adults with respiratory symptoms, inhaler use, or prior diagnosis of COPD or asthma were excluded. A probability score for prevalent SAO (forced expiratory volume in 1 second/forced vital capacity < 0.70) was developed via hierarchical group-lasso regularization from clinical variables in strata of sex and smoking status, and its discriminative accuracy for SAO was assessed in the pooled cohort as well as in an external validation cohort (NHANES [National Health and Nutrition Examination Survey] 2011-2012). Incident hospitalizations and deaths due to COPD (respiratory events) were defined by adjudication or administrative criteria in four of nine cohorts. Results: Of 33,546 participants (mean age 52 yr, 54% female, 44% non-Hispanic White), 4,424 (13.2%) had prevalent SAO. The incidence of respiratory events (Nat-risk = 14,024) was threefold higher in participants with SAO versus those without (152 vs. 39 events/10,000 person-years). The probability score, which was based on six commonly available variables (age, sex, race and/or ethnicity, body mass index, smoking status, and smoking pack-years) was well calibrated and showed excellent discrimination in both the testing sample (C-statistic, 0.81; 95% confidence interval [CI], 0.80-0.82) and in NHANES (C-statistic, 0.83; 95% CI, 0.80-0.86). Among participants with predicted probabilities ⩾ 15%, 3.2 would need to undergo spirometry to detect one case of SAO. Conclusions: Adults with SAO demonstrate excess respiratory hospitalization and mortality. A probability score for SAO using commonly available clinical risk factors may be suitable for targeting screening and primary prevention strategies.