Search

BACKGROUND: Improved understanding of the pathways associated with airway pathophysiologic features in COPD will identify new predictive biomarkers and novel therapeutic targets. RESEARCH QUESTION: Which physiologic pathways are altered in the airways of patients with COPD and will predict exacerbations? STUDY DESIGN AND METHODS: We applied a mass spectrometric panel of metabolomic biomarkers related to mucus hydration and inflammation to sputa from the multicenter Subpopulations and Intermediate Outcome Measures in COPD Study. Biomarkers elevated in sputa from patients with COPD were evaluated for relationships to measures of COPD disease severity and their ability to predict future exacerbations. RESULTS: Sputum supernatants from 980 patients were analyzed: 77 healthy nonsmokers, 341 smokers with preserved spirometry, and 562 patients with COPD (178 with Global Initiative on Chronic Obstructive Lung Disease [GOLD] stage 1 disease, 303 with GOLD stage 2 disease, and 81 with GOLD stage 3 disease) were analyzed. Biomarkers from multiple pathways were elevated in COPD and correlated with sputum neutrophil counts. Among the most significant analytes (false discovery rate, 0.1) were sialic acid, hypoxanthine, xanthine, methylthioadenosine, adenine, and glutathione. Sialic acid and hypoxanthine were associated strongly with measures of disease severity, and elevation of these biomarkers was associated with shorter time to exacerbation and improved prediction models of future exacerbations. INTERPRETATION: Biomarker evaluation implicated pathways involved in mucus hydration, adenosine metabolism, methionine salvage, and oxidative stress in COPD airway pathophysiologic characteristics. Therapies that target these pathways may be of benefit in COPD, and a simple model adding sputum-soluble phase biomarkers improves prediction of pulmonary exacerbations. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.gov

Rationale: Individuals with Chronic Obstructive Pulmonary Disease (COPD) have a high prevalence of depression, which is associated with increased COPD hospitalizations and readmissions. Objectives:...

Rationale: Diagnosis of chronic obstructive pulmonary disease (COPD) relies on abnormal spirometry. However, spirometry may underestimate the effects of smoking, missing smokers with respiratory di...

Summary Background We previously described the contributions of increased total airway mucin concentrations to the pathogenesis and diagnosis of the chronic bronchitic component of chronic obstructive pulmonary disease (COPD). Here, we investigated the relative contribution of each of the major airway gel-forming mucins, MUC5AC and MUC5B, to the initiation, progression, and early diagnosis of airways disease in COPD. Methods SPIROMICS was a multicentre, observational study in patients aged 40–80 years recruited from six clinical sites and additional subsites in the USA. In this analysis, MUC5AC and MUC5B were quantitated by stable isotope-labelled mass spectrometry in induced sputum samples from healthy never-smokers, ever-smokers at risk for COPD, and ever-smokers with COPD. Participants were extensively characterised using results from questionnaires, such as the COPD assessment test (CAT) and St George's Respiratory Questionnaire; quantitative CT, such as residual volume/total lung capacity ratio (RV/TLC) and parametric response mapping-functional small airway disease (PRM-fSAD); and pulmonary function tests, such as FEV1, forced vital capacity (FVC), and forced expiratory flow, midexpiratory phase (FEF25–75%). Absolute concentrations of both MUC5AC and MUC5B were related to cross-sectional (baseline, initial visit) and 3-year follow-up longitudinal data, including lung function, small airways obstruction, prospective acute exacerbations, and smoking status as primary outcomes. This study is registered with ClinicalTrials.gov (NCT01969344). Findings This analysis included 331 participants (mean age 63 years [SEM 9·40]), of whom 40 were healthy never-smokers, 90 were at-risk ever-smokers, and 201 were ever-smokers with COPD. Increased MUC5AC concentrations were more reliably associated with manifestations of COPD than were MUC5B concentrations, including decreased FEV1 and FEF25–75%, and increased prospective exacerbation frequency, RV/TLC, PRM-fSAD, and COPD assessment scores. MUC5AC concentrations were more reactive to cigarette smoke exposure than were MUC5B concentrations. Longitudinal data from 3-year follow-up visits generated a multivariate-adjusted odds ratio for two or more exacerbations of 1·24 (95% CI 1·04–1·47, p=0·015) for individuals with high baseline MUC5AC concentration. Increased MUC5AC, but not MUC5B, concentration at baseline was a significant predictor of FEV1, FEV1/FVC, FEF25–75%, and CAT score decline during the 3-year follow-up. Moreover, current smokers in the at-risk group showed raised MUC5AC concentrations at initial visits and decreased lung function over 3 years. By contrast, former smokers in the at-risk group showed normal MUC5AC concentrations at the initial visit and preserved lung function over 3 years. Interpretation These data indicate that increased MUC5AC concentration in the airways might contribute to COPD initiation, progression, exacerbation risk, and overall pathogenesis. Compared with MUC5B, greater relative changes in MUC5AC concentrations were observed as a function of COPD severity, and MUC5AC concentration seems to be an objective biomarker to detect disease in at-risk and pre-COPD individuals. These data suggest that MUC5AC-producing pathways could be potential targets for future therapeutic strategies. Thus, MUC5AC could be a novel biomarker for COPD prognosis and for testing the efficacy of therapeutic agents. Funding National Institutes of Health; National Heart, Lung, and Blood Institute.

Rationale: Racial residential segregation has been associated with worse health outcomes, but the link with chronic obstructive pulmonary disease (COPD) morbidity has not been established.Objective...

Increased outdoor concentrations of fine particulate matter (PM2.5 ) and oxides of nitrogen (NO2 , NOx ) are associated with respiratory and cardiovascular morbidity in adults and children. However, people spend most of their time indoors and this is particularly true for individuals with chronic obstructive pulmonary disease (COPD). Both outdoor and indoor air pollution may accelerate lung function loss in individuals with COPD, but it is not feasible to measure indoor pollutant concentrations in all participants in large cohort studies. We aimed to understand indoor exposures in a cohort of adults (SPIROMICS Air, the SubPopulations and Intermediate Outcome Measures in COPD Study of Air pollution). We developed models for the entire cohort based on monitoring in a subset of homes, to predict mean 2-week-measured concentrations of PM2.5 , NO2 , NOx , and nicotine, using home and behavioral questionnaire responses available in the full cohort. Models incorporating socioeconomic, meteorological, behavioral, and residential information together explained about 60% of the variation in indoor concentration of each pollutant. Cross-validated R2 for best indoor prediction models ranged from 0.43 (NOx ) to 0.51 (NO2 ). Models based on questionnaire responses and estimated outdoor concentrations successfully explained most variation in indoor PM2.5 , NO2 , NOx , and nicotine concentrations.

Background Little is known about the concordance of atopy with asthma COPD overlap. Among individuals with COPD, a better understanding of the phenotypes characterized by asthma overlap and atopy is needed to better target therapies. Research Question What is the overlap between atopy and asthma status among individuals with COPD, and how are categories defined by the presence of atopy and asthma status associated with clinical and radiologic phenotypes and outcomes in the Genetic Epidemiology of COPD Study (COPDGene) and Subpopulation and Intermediate Outcome Measures in COPD Study (SPIROMICS)? Study Design and Methods Four hundred three individuals with COPD from SPIROMICS and 696 individuals from COPDGene with data about specific IgEs to 10 common allergens and mixes (simultaneous assessment of combination of allergens in similar category) were included. Comparison groups were defined by atopic and asthma status (neither, atopy alone, atopic asthma, nonatopic asthma, with atopy defined as any positive specific IgE (≥0.35 KU/L) to any of the 10 allergens or mixes and asthma defined as self-report of doctor-diagnosed current asthma). Multivariable regression analyses (linear, logistic, and zero inflated negative binomial where appropriate) adjusted for age, sex, race, lung function, smoking status, pack-years smoked, and use of inhaled corticosteroids were used to determine characteristics of groups and relationship with outcomes (exacerbations, clinical outcomes, CT metrics) separately in COPDGene and SPIROMICS, and then adjusted results were combined using meta-analysis. Results The prevalence of atopy was 35% and 36% in COPD subjects from SPIROMICS and COPDGene, respectively, and less than 50% overlap was seen between atopic status with asthma in both cohorts. In meta-analysis, individuals with nonatopic asthma had the most impaired symptom scores (effect size for St. George's Respiratory Questionnaire total score, 4.2; 95% CI, 0.4-7.9; effect size for COPD Assessment Test score, 2.8; 95% CI, 0.089-5.4), highest risk for exacerbations (incidence rate ratio, 1.41; 95% CI, 1.05-1.88) compared with the group without atopy or asthma. Those with atopy and atopic asthma were not at increased risk for adverse outcomes. Interpretation Asthma and atopy had incomplete overlap among former and current smokers with COPD in COPDGene and SPIROMICS. Nonatopic asthma was associated with adverse outcomes and exacerbation risk in COPD, whereas groups having atopy alone and atopic asthma had less risk.

Background Hypogammaglobulinemia (serum IgG levels Research Question To determine the relationship between hypogammaglobulinemia and the risk of hospitalization in patients with COPD. Study Design and Methods Serum IgG levels were measured on baseline samples from four COPD cohorts (n = 2,259): Azithromycin for Prevention of AECOPD (MACRO, n = 976); Simvastatin in the Prevention of AECOPD (STATCOPE, n = 653), Long-Term Oxygen Treatment Trial (LOTT, n = 354), and COPD Activity: Serotonin Transporter, Cytokines and Depression (CASCADE, n = 276). IgG levels were determined by immunonephelometry (MACRO; STATCOPE) or mass spectrometry (LOTT; CASCADE). The effect of hypogammaglobulinemia on COPD hospitalization risk was evaluated using cumulative incidence functions for this outcome and deaths (competing risk). Fine-Gray models were performed to obtain adjusted subdistribution hazard ratios (SHR) related to IgG levels for each study and then combined using a meta-analysis. Rates of COPD hospitalizations per person-year were compared according to IgG status. Results The overall frequency of hypogammaglobulinemia was 28.4%. Higher incidence estimates of COPD hospitalizations were observed among participants with low IgG levels compared with those with normal levels (Gray's test, P Interpretation Hypogammaglobulinemia is associated with a higher risk of COPD hospital admissions.

Author(s): Stott-Miller, Marni; Mullerova, Hana; Miller, Bruce; Tabberer, Maggie; El Baou, Celine; Keeley, Tom; Martinez, Fernando J; Han, Meilan; Dransfield, Mark; Hansel, Nadia N; Cooper, Christopher B; Woodruff, Prescott; Ortega, Victor E; Comellas, Alejandro P; Paine Iii, Robert; Kanner, Richard E; Anderson, Wayne; Drummond, M Bradley; Kim, Victor; Tal-Singer, Ruth; Lazaar, Aili L | Abstract: BackgroundChronic cough and phlegm are frequently reported chronic obstructive pulmonary disease (COPD) symptoms. Prior research classified chronic mucus hypersecretion (CMH) based on the presence of these symptoms for ≥3 months, called chronic bronchitis (CB) if respiratory infection symptoms were present for 1-2 years (Medical Research Council [MRC] definition). We explored whether the COPD Assessment Test (CAT), a simple measure developed for routine clinical use, captures CMH populations and outcomes similarly to MRC and St. George's Respiratory Questionnaire (SGRQ) definitions.MethodsWe identified CMH in the SPIROMICS COPD cohort using (a) MRC definitions, (b) SGRQ questions for cough and phlegm (both as most/several days a week), and (c) CAT cough and phlegm questions. We determined optimal cut-points for CAT items and described exacerbation frequencies for different CMH definitions. Moderate exacerbations required a new prescription for antibiotics/oral corticosteroids or emergency department visit; severe exacerbations required hospitalization. Results were stratified by smoking status.ResultsIn a population of 1431 participants (57% male; mean FEV1% predicted 61%), 47% and 49% of evaluable participants had SGRQ- or CAT-defined CMH, respectively. A cut-point of ≥2 for cough and phlegm items defined CMH in CAT. Among SGRQ-CMH+ participants, 80% were also defined as CMH+ by the CAT. CMH+ participants were more likely to be current smokers. A higher exacerbation frequency was observed for presence of CMH+ versus CMH- in the year prior to baseline for all CMH definitions; this trend continued across 3 years of follow-up, regardless of smoking status.ConclusionItems from the CAT identified SGRQ-defined CMH, a frequent COPD trait that correlated with exacerbation frequency. The CAT is a short, simple questionnaire and a potentially valuable tool for telemedicine or real-world trials. CAT-based CMH is a novel approach for identifying clinically important characteristics in COPD that can be ascertained in these settings.

Background Although inhaled therapy reduces exacerbations among patients with COPD, the effectiveness of providing inhaled treatment per risk stratification models remains unclear. Research Question Are inhaled regimens that align with the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy associated with clinically important outcomes? Study Design and Methods We conducted secondary analyses of Long-term Oxygen Treatment Trial (LOTT) data. The trial enrolled patients with COPD with moderate resting or exertional hypoxemia between 2009 and 2015. Our exposure was the patient-reported inhaled regimen at enrollment, categorized as either aligning with, undertreating, or potentially overtreating per the 2017 GOLD strategy. Our primary composite outcome was time to death or first hospitalization for COPD. Additional outcomes included individual components of the composite outcome and time to first exacerbation. We generated multivariable Cox proportional hazard models across strata of GOLD-predicted exacerbation risk (high vs low) to estimate between-group hazard ratios for time to event outcomes. We adjusted models a priori for potential confounders, clustered by site. Results The trial enrolled 738 patients (73.4% men; mean age, 68.8 years). Of the patients, 571 (77.4%) were low risk for future exacerbations. Of the patients, 233 (31.6%) reported regimens aligning with GOLD recommendations; most regimens (54.1%) potentially overtreated. During a 2.3-year median follow-up, 332 patients (44.9%) experienced the composite outcome. We found no difference in time to composite outcome or death among patients reporting regimens aligning with recommendations compared with undertreated patients. Among patients at low risk, potential overtreatment was associated with higher exacerbation risk (hazard ratio, 1.42; 95% CI, 1.09-1.87), whereas inhaled corticosteroid treatment was associated with 64% higher risk of pneumonia (incidence rate ratio, 1.64; 95% CI, 1.01-2.66). Interpretation Among patients with COPD with moderate hypoxemia, we found no difference in clinical outcomes between inhaled regimens aligning with the 2017 GOLD strategy compared with those that were undertreated. These findings suggest the need to reevaluate the effectiveness of risk stratification model-based inhaled treatment strategies.

Author(s): Cooper, Christopher B; Paine, Robert; Curtis, Jeffrey L; Kanner, Richard E; Martinez, Carlos H; Meldrum, Catherine A; Bowler, Russell; O'Neal, Wanda; Hoffman, Eric A; Couper, David; Quibrera, Miguel; Criner, Gerald; Dransfield, Mark T; Han, MeiLan K; Hansel, Nadia N; Krishnan, Jerry A; Lazarus, Stephen C; Peters, Stephen P; Barr, R Graham; Martinez, Fernando J; Woodruff, Prescott G; SPIROMICS investigators | Abstract: RationaleSome COPD patients develop extreme breathlessness, decreased exercise capacity and poor health status yet respiratory disability is poorly characterized as a distinct phenotype.ObjectiveTo define respiratory disability in COPD based on available functional measures and to determine associations with risk for exacerbations and death.MethodsWe analyzed baseline data from a multi-center observational study (SPIROMICS). This analysis includes 2332 participants (472 with severe COPD, 991 with mild/moderate COPD, 726 smokers without airflow obstruction and 143 non-smoking controls).MeasurementsWe defined respiratory disability by ≥4 of 7 criteria: mMRC dyspnea scale ≥3; Veterans Specific Activity Questionnaire l5; 6-minute walking distance l250 m; St George's Respiratory Questionnaire activity domain g60; COPD Assessment Test g20; fatigue (FACIT-F Trial Outcome Index) l50; SF-12 l20.ResultsUsing these criteria, respiratory disability was identified in 315 (13.5%) participants (52.1% female). Frequencies were severe COPD 34.5%; mild-moderate COPD 11.2%; smokers without obstruction 5.2% and never-smokers 2.1%. Compared with others, participants with disability had more emphysema (13.2 vs. 6.6%) and air-trapping (37.0 vs. 21.6%) on HRCT (Pl0.0001). Using principal components analysis to derive a disability score, two factors explained 71% of variance, and a cut point -1.0 reliably identified disability. This disability score independently predicted future exacerbations (s=0.34; CI 0.12, 0.64; P=0.003) and death (HR 2.97; CI 1.54, 5.75; P=0.001). Thus, participants with disability by this criterion had almost three times greater mortality compared to those without disability.ConclusionOur novel SPIROMICS respiratory disability score in COPD was associated with worse airflow obstruction as well as airway wall thickening, lung parenchymal destruction and certain inflammatory biomarkers. The disability score also proved to be an independent predictor of future exacerbations and death. These findings validate disability as an important phenotype in the spectrum of COPD.

Background The relationship between 25-hydroxyvitamin D (25-OH-vitamin D) and COPD outcomes remains unclear. Using the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), we determined associations among baseline 25-OH-vitamin D and cross-sectional and longitudinal lung function and COPD exacerbations. Methods Serum 25-OH-vitamin D level was measured in stored samples from 1,609 SPIROMICS participants with COPD. 25-OH-vitamin D levels were modeled continuously and dichotomized as deficient ( Results Vitamin D deficiency was present in 21% of the cohort and was more prevalent in the younger, active smokers, and blacks. Vitamin D deficiency was independently associated with lower % predicted FEV1 (by 4.11%) at enrollment (95% CI, –6.90% to –1.34% predicted FEV1; P = .004), 1.27% predicted greater rate of FEV1 decline after 1 year (95% CI, –2.32% to –0.22% predicted/y; P = .02), and higher odds of any COPD exacerbation in the prior year (OR, 1.32; 95% CI, 1.00-1.74; P = .049). Each 10-ng/mL decrease in 25-OH-vitamin D was associated with lower baseline lung function (–1.04% predicted; 95% CI, –1.96% to –0.12% predicted; P = .03) and increased odds of any exacerbation in the year before enrollment (OR, 1.11; 95% CI, 1.01-1.22; P = .04). Conclusions Vitamin D deficiency is associated with worse cross-sectional and longitudinal lung function and increased odds of prior COPD exacerbations. These findings identify 25-OH-vitamin D levels as a potentially useful marker of adverse COPD-related outcomes.

Rationale: The role of PI (protease inhibitor) type Z heterozygotes and additional rare variant genotypes in the gene encoding alpha-1 antitrypsin, SERPINA1 (serpin peptidase inhibitor, clade A, me...

Rationale: Lung function peaks in early adulthood and declines thereafter. We hypothesized that increasing age would be associated with smaller airway tree caliber across the adult lifespan. Methods: A sample of non-smoking adults age 20 to 97 years old free of clinical lung disease was created by harmonization of four studies: MESA Lung, CanCOLD, SPIROMICS, and the Iowa Computed Tomography (CT) Study which performed computed tomography to quantify airway lumen diameters and total lung volume. Airway tree caliber was quantified as the mean of 19 airway lumen diameters at standard locations (trachea-to-subsegments) in standardized units. Sex-specific airway tree caliber regression models were fit with restricted cubic spline terms for age, body height and total lung volume. Age and airway tree caliber relationship was assessed while keeping body height and total lung volume fixed. Sensitivity analyses stratified by sex, study, scanner, and race-ethnicity. Results: Among 1,056 participants (median [range] age: 67 [20-97] years, 57% female), increasing age from 20 to 50 years was associated with larger airway caliber followed by a plateau (Figure). Compared with aged 51-60 years, participants aged 20-30, 31-40, and 41-50 years exhibited mean standardized differences in caliber of -0.53, -0.33 and -0.13 SD respectively with p Conclusion: Increasing age from early to mid-adulthood was associated with larger airway tree caliber

Author(s): Barjaktarevic, Igor Z; Buhr, Russell G; Wang, Xiaoyan; Hu, Scott; Couper, David; Anderson, Wayne; Kanner, Richard E; Paine Iii, Robert; Bhatt, Surya P; Bhakta, Nirav R; Arjomandi, Mehrdad; Kaner, Robert J; Pirozzi, Cheryl S; Curtis, Jeffrey L; O'Neal, Wanda K; Woodruff, Prescott G; Han, MeiLan K; Martinez, Fernando J; Hansel, Nadia; Wells, James Michael; Ortega, Victor E; Hoffman, Eric A; Doerschuk, Claire M; Kim, Victor; Dransfield, Mark T; Drummond, M Bradley; Bowler, Russell; Criner, Gerard; Christenson, Stephanie A; Ronish, Bonnie; Peters, Stephen P; Krishnan, Jerry A; Tashkin, Donald P; Cooper, Christopher B; NHLBI SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) | Abstract: ObjectiveBronchodilator responsiveness (BDR) is prevalent in COPD, but its clinical implications remain unclear. We explored the significance of BDR, defined by post-bronchodilator change in FEV1 (BDRFEV1) as a measure reflecting the change in flow and in FVC (BDRFVC) reflecting the change in volume.MethodsWe analyzed 2974 participants from a multicenter observational study designed to identify varying COPD phenotypes (SPIROMICS). We evaluated the association of BDR with baseline clinical characteristics, rate of prospective exacerbations and mortality using negative binomial regression and Cox proportional hazards models.ResultsA majority of COPD participants exhibited BDR (52.7%). BDRFEV1 occurred more often in earlier stages of COPD, while BDRFVC occurred more frequently in more advanced disease. When defined by increases in either FEV1 or FVC, BDR was associated with a self-reported history of asthma, but not with blood eosinophil counts. BDRFVC was more prevalent in subjects with greater emphysema and small airway disease on CT. In a univariate analysis, BDRFVC was associated with increased exacerbations and mortality, although no significance was found in a model adjusted for post-bronchodilator FEV1.ConclusionWith advanced airflow obstruction in COPD, BDRFVC is more prevalent in comparison to BDRFEV1 and correlates with the extent of emphysema and degree of small airway disease. Since these associations appear to be related to the impairment of FEV1, BDRFVC itself does not define a distinct phenotype nor can it be more predictive of outcomes, but it can offer additional insights into the pathophysiologic mechanism in advanced COPD.Clinical trials registrationClinicalTrials.gov: NCT01969344T4.

Background Aspirin use in COPD has been associated with reduced all-cause mortality in meta-regression analysis with few equivocal studies. However, the effect of aspirin on COPD morbidity is unknown. Methods Self-reported daily aspirin use was obtained at baseline from SPIROMICS participants with COPD (FEV1/FVC Results Among 1,698 participants, 45% reported daily aspirin use at baseline. Propensity score matching resulted in 503 participant pairs. Aspirin users had a lower incidence rate of total AECOPD (adjusted incidence rate ratio [IRR], 0.78; 95% CI, 0.65-0.94), with similar effect for moderate but not severe AECOPD (IRR, 0.86; 95% CI, 0.63-1.18). Aspirin use was associated with lower total St. George's Respiratory Questionnaire score (β, –2.2; 95% CI, –4.1 to –0.4), reduced odds of moderate-severe dyspnea (modified Medical Research Council questionnaire score ≥ 2; adjusted odds ratio, 0.69; 95% CI, 0.51-0.93), and COPD Assessment Test score (β, –1.1; 95% CI, –1.9 to –0.2) but not 6-min walk distance (β, 0.7 m; 95% CI, –14.3 to 15.6). Conclusions Daily aspirin use is associated with reduced rate of COPD exacerbations, less dyspnea, and better quality of life. Randomized clinical trials of aspirin use in COPD are warranted to account for unmeasured and residual confounding. Trial Registry ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.gov

Secondary polycythemia has long been recognized as a consequence of chronic pulmonary disease and hypoxemia and is associated with lower mortality and fewer hospitalizations among individuals with chronic obstructive pulmonary disease (COPD)-prescribed long-term oxygen therapy. This study investigates the association of polycythemia with COPD severity, phenotypic features, and respiratory exacerbations in a contemporary and representative sample of individuals with COPD. Current and former smokers with COPD (forced expiratory volume in 1 second [FEV(1)] to forced vital capacity [FVC] ratio

Rationale: Black adults have worse health outcomes compared with white adults in certain chronic diseases, including chronic obstructive pulmonary disease (COPD).Objectives: To determine to what degree disadvantage by individual and neighborhood socioeconomic status (SES) may contribute to racial disparities in COPD outcomes.Methods: Individual and neighborhood-scale sociodemographic characteristics were determined in 2,649 current or former adult smokers with and without COPD at recruitment into SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study). We assessed whether racial differences in symptom, functional, and imaging outcomes (St. George's Respiratory Questionnaire, COPD Assessment Test score, modified Medical Research Council dyspnea scale, 6-minute-walk test distance, and computed tomography [CT] scan metrics) and severe exacerbation risk were explained by individual or neighborhood SES. Using generalized linear mixed model regression, we compared respiratory outcomes by race, adjusting for confounders and individual-level and neighborhood-level descriptors of SES both separately and sequentially.Measurements and Main Results: After adjusting for COPD risk factors, Black participants had significantly worse respiratory symptoms and quality of life (modified Medical Research Council scale, COPD Assessment Test, and St. George's Respiratory Questionnaire), higher risk of severe exacerbations and higher percentage of emphysema, thicker airways (internal perimeter of 10 mm), and more air trapping on CT metrics compared with white participants. In addition, the association between Black race and respiratory outcomes was attenuated but remained statistically significant after adjusting for individual-level SES, which explained up to 12-35% of racial disparities. Further adjustment showed that neighborhood-level SES explained another 26-54% of the racial disparities in respiratory outcomes. Even after accounting for both individual and neighborhood SES factors, Black individuals continued to have increased severe exacerbation risk and persistently worse CT outcomes (emphysema, air trapping, and airway wall thickness).Conclusions: Disadvantages by individual- and neighborhood-level SES each partly explain disparities in respiratory outcomes between Black individuals and white individuals. Strategies to narrow the gap in SES disadvantages may help to reduce race-related health disparities in COPD; however, further work is needed to identify additional risk factors contributing to persistent disparities.

BackgroundThe purpose of this study was to explore the association between perceived social support and COPD outcomes and to determine whether the associations are mediated by depressive symptoms.MethodsSubjects with COPD who were enrolled as part of SPIROMICS were included in this analysis. Questionnaires relating to quality of life, symptom burden, and functional status were administered at annual clinic visits for over a 3 year period. In both cross-sectional and longitudinal analyses, we examined the association of social support as measured by the FACIT-F with COPD outcomes. Cross sectional analyses used multivariable linear or logistic regression, adjusting for covariates. For longitudinal analyses, generalized linear mixed models with random intercepts were used. Models were adjusted with and without depressive symptoms and mediation analyses performed.ResultsOf the 1831 subjects with COPD, 1779 completed the FACIT- F questionnaire. In adjusted cross-sectional analysis without depressive symptoms, higher perceived social support was associated with better quality of life, well-being, 6 minute walk distance, and less dyspnea. When also adjusting for depressive symptoms, all associations between social support and COPD outcomes were attenuated and no longer statistically significant. Mediation analysis suggested that depressive symptoms explained the majority (> = 85%) of the association between social support and measured COPD outcomes. Results of the longitudinal analysis were consistent with the cross-sectional analyses. There was no association between social support and odds of exacerbations.ConclusionHigher social support was associated with better COPD outcomes across several measures of morbidity including quality of life, respiratory symptoms, and functional status. In addition, these associations were largely attenuated when accounting for depressive symptoms suggesting that the beneficial association of social support with COPD outcomes may be largely mediated by the association between social support and depression.Trial registrationSPIROMICS was approved by Institutional Review Boards at each center and all participants provided written informed consent (clinicaltrials.gov:NCT01969344).

Background: Risk factor identification is a proven strategy in advancing treatments and preventive therapy for many chronic conditions. Quantifying the impact of those risk factors on health outcomes can consolidate and focus efforts on individuals with specific high-risk profiles. Using multiple risk factors and longitudinal outcomes in 2 independent cohorts, we developed and validated a risk score model to predict mortality in current and former cigarette smokers. Methods: We obtained extensive data on current and former smokers from the COPD Genetic Epidemiology (COPDGene(®)) study at enrollment. Based on physician input and model goodness-of-fit measures, a subset of variables was selected to fit final Weibull survival models separately for men and women. Coefficients and predictors were translated into a point system, allowing for easy computation of mortality risk scores and probabilities. We then used the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) cohort for external validation of our model. Results: Of 9867 COPDGene participants with standard baseline data, 17.6% died over 10 years of follow-up, and 9074 of these participants had the full set of baseline predictors (standard plus 6-minute walk distance and computed tomography variables) available for full model fits. The average age of participants in the cohort was 60 for both men and women, and the average predicted 10-year mortality risk was 18% for women and 25% for men. Model time-integrated area under the receiver operating characteristic curve statistics demonstrated good predictive model accuracy (0.797 average), validated in the external cohort (0.756 average). Risk of mortality was impacted most by 6-minute walk distance, forced expiratory volume in 1 second and age, for both men and women. Conclusions: Current and former smokers exhibited a wide range of mortality risk over a 10- year period. Our models can identify higher risk individuals who can be targeted for interventions to reduce risk of mortality, for participants with or without chronic obstructive pulmonary disease (COPD) using current Global initiative for chronic Obstructive Lung Disease (GOLD) criteria.

BACKGROUND: Mild expiratory flow limitation may not be recognized using traditional spirometric criteria based on the ratio of FEV(1)/FVC. RESEARCH QUESTION: Does slow vital capacity (SVC) instead of FVC increase the sensitivity of spirometry to identify patients with early or mild obstructive lung disease? STUDY DESIGN AND METHODS: We included 854 current and former smokers from the Subpopulations and Intermediate Outcome Measures in COPD Study cohort with a postbronchodilator FEV(1)/FVC ≥ 0.7 and FEV(1) % predicted of ≥ 80% at enrollment. We compared baseline characteristics, chest CT scan features, exacerbations, and progression to COPD (postbronchodilator FEV(1)/FVC, < 0.7) during the follow-up period between 734 participants with postbronchodilator FEV(1)/SVC of ≥ 0.7 and 120 with postbronchodilator FEV(1)/SVC < 0.7 at the enrollment. We performed multivariate linear and logistic regression models and negative binomial and interval-censored proportion hazards regression models adjusted for demographics and smoking exposure to examine the association of FEV(1)/SVC < 0.7 with those characteristics and outcomes. RESULTS: Participants with FEV(1)/SVC < 0.7 were older and had lower FEV(1) and more emphysema than those with FEV(1)/SVC ≥ 0.7. In adjusted analysis, individuals with postbronchodilator FEV(1)/SVC < 0.7 showed a greater percentage of emphysema by 0.45% (95% CI, 0.09%-0.82%), percentage of gas trapping by 2.52% (95% CI, 0.59%-4.44%), and percentage of functional small airways disease based on parametric response mapping by 2.78% (95% CI, 0.72%-4.83%) at baseline than those with FEV(1)/SVC ≥ 0.7. During a median follow-up time of 1,500 days, an FEV(1)/SVC < 0.7 was not associated with total exacerbations (incident rate ratio [IRR], 1.61; 95% CI, 0.97-2.64), but was associated with severe exacerbations (IRR, 2.60; 95% CI, 1.04-4.89). An FEV(1)/SVC < 0.7 was associated with progression to COPD during a 3-year follow-up even after adjustment for demographics and smoking exposure (hazard ratio, 3.93; 95% CI, 2.71-5.72). We found similar results when we examined the association of prebronchodilator FEV(1)/SVC < 0.7 or FEV(1)/SVC less than the lower limit of normal with chest CT scan features and progression to COPD. INTERPRETATION: Low FEV(1) to SVC in current and former smokers with normal spirometry results can identify individuals with CT scan features of COPD who are at risk for severe exacerbations and is associated with progression to COPD in the future. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01969344T4; URL: www.clinicaltrials.gov

Background The identification of smoking-related lung disease in current and former smokers with normal FEV1 is complex, leading to debate regarding using a ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) of less than 0.70 versus the predicted lower limit of normal (LLN) for diagnosis of airflow obstruction. We hypothesized that the discordant group of ever-smokers with FEV1/FVC between the LLN and 0.70 is heterogeneous, and aimed to characterize the burden of smoking-related lung disease in this group. Methods We compared spirometry, chest CT characteristics, and symptoms between 161 ever-smokers in the discordant group and 940 ever-smokers and 190 never-smokers with normal FEV1 and FEV1/FVC > 0.70 in the SPIROMICS cohort. We also estimated sensitivity and specificity for diagnosing objective radiographic evidence of chronic obstructive pulmonary disease (COPD) using different FEV1/FVC criteria thresholds. Results The discordant group had more CT defined emphysema and non-emphysematous gas trapping, lower post-bronchodilator FEV1 and FEF25–75, and higher respiratory medication use compared with the other two groups. Within the discordant group, 44% had radiographic CT evidence of either emphysema or non-emphysematous gas trapping; an FEV1/FVC threshold of 0.70 has greater sensitivity but lower specificity compared with LLN for identifying individuals with CT abnormality. Conclusions Ever-smokers with normal FEV1 and FEV1/FVC LLN are a heterogeneous group that includes significant numbers of individuals with and without radiographic evidence of smoking-related lung disease. These findings emphasize the limitations of diagnosing COPD based on spirometric criteria alone. Electronic supplementary material The online version of this article (10.1186/s12931-018-0911-z) contains supplementary material, which is available to authorized users.

Background Classification of COPD is usually based on the severity of airflow, which may not sensitively differentiate subpopulations. Using a multiscale imaging-based cluster analysis (MICA), we aim to identify subpopulations for current smokers with COPD. Methods Among the SPIROMICS subjects, we analyzed computed tomography images at total lung capacity (TLC) and residual volume (RV) of 284 current smokers. Functional variables were derived from registration of TLC and RV images, e.g. functional small airways disease (fSAD%). Structural variables were assessed at TLC images, e.g. emphysema and airway wall thickness and diameter. We employed an unsupervised method for clustering. Results Four clusters were identified. Cluster 1 had relatively normal airway structures; Cluster 2 had an increase of fSAD% and wall thickness; Cluster 3 exhibited a further increase of fSAD% but a decrease of wall thickness and airway diameter; Cluster 4 had a significant increase of fSAD% and emphysema. Clinically, Cluster 1 showed normal FEV1/FVC and low exacerbations. Cluster 4 showed relatively low FEV1/FVC and high exacerbations. While Cluster 2 and Cluster 3 showed similar exacerbations, Cluster 2 had the highest BMI among all clusters. Conclusions Association of imaging-based clusters with existing clinical metrics suggests the sensitivity of MICA in differentiating subpopulations.

BACKGROUND: High N-terminal pro-brain natriuretic peptide (NT-proBNP) during COPD exacerbations is associated with worse clinical outcomes. The prognostic value of NT-proBNP measured during clinical stability has not been well characterized. METHODS: We studied SPIROMICS participants 40–80 years of age with COPD GOLD spirometric stages 1–4. The association between baseline NT-proBNP and incident COPD exacerbations within one year of follow-up was tested using zero-inflated Poisson regression models adjusted for age, gender, race, body mass index, current smoking status, smoking history, FEV(1) percent predicted, COPD Assessment Test score, exacerbation history, total lung capacity on chest CT and cardiovascular disease (any of coronary artery disease, myocardial infarction or congestive heart failure). RESULTS: Among 1,051 participants (mean age 66.1 years, 41.4% women), mean NT-proBNP was 608.9 pg/ml. Subjects in GOLD stage D had the highest mean NT-proBNP. After one year of follow-up, 268 participants experienced one or more COPD exacerbations. One standard deviation increase in baseline NT-proBNP was associated with a 13% increase in the risk of incident exacerbations (incident risk ratio 1.13; 95% CI 1.06–1.19; p

Rationale: Rural residence is associated with poor outcomes in several chronic diseases. The association between rural residence and chronic obstructive pulmonary disease (COPD) exacerbations remains unclear.Objectives: In this work, we sought to determine the independent association between rural residence and COPD-related outcomes, including COPD exacerbations, airflow obstruction, and symptom burden.Methods: A total of 1,684 SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) participants with forced expiratory volume in 1 second/forced vital capacity < 0.70 had geocoding-defined rural-urban residence status determined (N = 204 rural and N = 1,480 urban). Univariate and multivariate logistic and negative binomial regressions were performed to assess the independent association between rurality and COPD outcomes, including exacerbations, lung function, and symptom burden. The primary exposure of interest was rural residence, determined by geocoding of the home address to the block level at the time of study enrollment. Additional covariates of interest included demographic and clinical characteristics, occupation, and occupational exposures. The primary outcome measures were exacerbations determined over a 1-year course after enrollment by quarterly telephone calls and at an annual research clinic visit. The odds ratio (OR) and incidence rate ratio (IRR) of exacerbations that required treatment with medications, including steroids or antibiotics (total exacerbations), and exacerbations leading to hospitalization (severe exacerbations) were determined after adjusting for relevant covariates.Results: Rural residence was independently associated with a 70% increase in the odds of total exacerbations (OR, 1.70 [95% confidence interval (CI), 1.13-2.56]; P = 0.012) and a 46% higher incidence rate of total exacerbations (IRR 1.46 [95% CI, 1.02-2.10]; P = 0.039). There was no association between rural residence and severe exacerbations. Agricultural occupation was independently associated with increased odds and incidence of total and severe exacerbations. Inclusion of agricultural occupation in the analysis attenuated the association between rural residence and the odds and incidence rate of total exacerbations (OR, 1.52 [95% CI, 1.00-2.32]; P = 0.05 and IRR 1.39 [95% CI, 0.97-1.99]; P = 0.07). There was no difference in symptoms or airflow obstruction between rural and urban participants.Conclusions: Rural residence is independently associated with increased odds and incidence of total, but not severe, COPD exacerbations. These associations are not fully explained by agriculture-related exposures, highlighting the need for future research into potential mechanisms of the increased risk of COPD exacerbations in the rural population.

Thrombocytosis has been associated with COPD prevalence and increased all-cause mortality in patients with acute exacerbation of COPD (AECOPD); but whether it is associated with morbidity in stable COPD is unknown. This study aims to determine the association of thrombocytosis with COPD morbidity including reported AECOPD, respiratory symptoms and exercise capacity. Participants with COPD were included from two multi-center observational studies (SPIROMICS and COPDGene). Cross-sectional associations of thrombocytosis (platelet count ≥350 × 109/L) with AECOPD during prior year (none vs. any), exertional dyspnea (modified Medical Research Council (mMRC) score ≥ 2), COPD Assessment Test (CAT) score ≥ 10, six-minute-walk distance (6MWD), and St. George Respiratory questionnaire (SGRQ) were modeled using multivariable logistic or linear regression. A pooled effect estimate for thrombocytosis was produced using meta-analysis of data from both studies. Thrombocytosis was present in 124/1820 (6.8%) SPIROMICS participants and 111/2185 (5.1%) COPDGene participants. In meta-analysis thrombocytosis was associated with any AECOPD (adjusted odds ratio [aOR] 1.5; 95% confidence interval [95% CI]: 1.1–2.0), severe AECOPD (aOR 1.5; 95% CI: 1.1–2.2), dyspnea (mMRC ≥ 2 aOR 1.4; 95% CI: 1.0–1.9), respiratory symptoms (CAT ≥ 10 aOR 1.6; 95% CI: 1.1–2.4), and higher SGRQ score (β 2.7; 95% CI: 0.5, 5). Thrombocytosis was also associated with classification into Global Initiative for Chronic Obstructive Lung Disease (GOLD) group D (aOR 1.7 95% CI: 1.2–2.4). Thrombocytosis was associated with higher likelihood of prior exacerbation and worse symptoms. Platelet count, a commonly measured clinical assay, may be a biomarker for moderate-severe COPD symptoms, guide disease classification and intensity of treatment. Future longitudinal studies investigating the role of platelets in COPD progression may be warranted. ClinicalTrials.gov: NCT01969344 (SPIROMICS) and NCT00608764 (COPDGene).

Summary Background Increased concentrations of eosinophils in blood and sputum in chronic obstructive pulmonary disease (COPD) have been associated with increased frequency of exacerbations, reduced lung function, and corticosteroid responsiveness. We aimed to assess whether high eosinophil concentrations in either sputum or blood are associated with a severe COPD phenotype, including greater exacerbation frequency, and whether blood eosinophils are predictive of sputum eosinophils. Methods We did a multicentre observational study analysing comprehensive baseline data from SPIROMICS in patients with COPD aged 40–80 years who had a smoking history of at least 20 pack-years, recruited from six clinical sites and additional subsites in the USA between Nov 12, 2010, and April 21, 2015. Inclusion criteria for this analysis were SPIROMICS baseline visit data with complete blood cell counts and, in a subset, acceptable sputum counts. We stratified patients on the basis of blood and sputum eosinophil concentrations and compared their demographic characteristics, as well as results from questionnaires, clinical assessments, and quantitative CT (QCT). We also analysed whether blood eosinophil concentrations reliably predicted sputum eosinophil concentrations. This study is registered with ClinicalTrials.gov (NCT01969344). Findings Of the 2737 patients recruited to SPIROMICS, 2499 patients were smokers and had available blood counts, and so were stratified by mean blood eosinophil count: 1262 patients with low ( 1 percentage predicted than the low sputum eosinophil group both before (65·7% [IQR 51·8–81·3] vs 75·7% [59·3–90·2], p vs 82·9% [67·8–95·9], p=0·001) bronchodilation. QCT density measures for emphysema and air trapping were significantly higher in the high sputum eosinophil group than the low sputum eosinophil group. Exacerbations requiring corticosteroids treatment were more common in the high versus low sputum eosinophil group (p=0·002). FEV 1 percentage predicted was significantly different between low and high blood eosinophil groups, but differences were less than those observed between the sputum groups. The high blood eosinophil group had slightly increased airway wall thickness (0·02 mm difference, p=0·032), higher St George Respiratory Questionnaire symptom scores (p=0·037), and increased wheezing (p=0·018), but no evidence of an association with COPD exacerbations (p=0·35) or the other indices of COPD severity, such as emphysema measured by CT density, COPD assessment test scores, Body-mass index, airflow Obstruction, Dyspnea, and Exercise index, or Global Initiative for Chronic Obstructive Lung Disease stage. Blood eosinophil counts showed a weak but significant association with sputum eosinophil counts (receiver operating characteristic area under the curve of 0·64, p Interpretation In a large, well characterised cohort of former and current smoking patients with a broad range of COPD severity, high concentrations of sputum eosinophils were a better biomarker than high concentrations of blood eosinophils to identify a patient subgroup with more severe disease, more frequent exacerbations, and increased emphysema by QCT. Blood eosinophils alone were not a reliable biomarker for COPD severity or exacerbations, or for sputum eosinophils. Clinical trials targeting eosinophilic inflammation in COPD should consider assessing sputum eosinophils. Funding National Institutes of Health, and National Heart, Lung, and Blood Institute.

BackgroundChronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitic and emphysematous components. In one biophysical model, the concentration of mucin on the airway surfaces is hypothesized to be a key variable that controls mucus transport in healthy persons versus cessation of transport in persons with muco-obstructive lung diseases. Under this model, it is postulated that a high mucin concentration produces the sputum and disease progression that are characteristic of chronic bronchitis.MethodsWe characterized the COPD status of 917 participants from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) using questionnaires administered to participants, chest tomography, spirometry, and examination of induced sputum. Total mucin concentrations in sputum were measured with the use of size-exclusion chromatography and refractometry. In 148 of these participants, the respiratory secreted mucins MUC5AC and MUC5B were quantitated by means of mass spectrometry. Data from chronic-bronchitis questionnaires and data on total mucin concentrations in sputum were also analyzed in an independent 94-participant cohort.ResultsMean (±SE) total mucin concentrations were higher in current or former smokers with severe COPD than in controls who had never smoked (3166±402 vs. 1515±152 μg per milliliter) and were higher in participants with two or more respiratory exacerbations per year than in those with zero exacerbations (4194±878 vs. 2458±113 μg per milliliter). The absolute concentrations of MUC5B and MUC5AC in current or former smokers with severe COPD were approximately 3 times as high and 10 times as high, respectively, as in controls who had never smoked. Receiver-operating-characteristic curve analysis of the association between total mucin concentration and a diagnosis of chronic bronchitis yielded areas under the curve of 0.72 (95% confidence interval [CI], 0.65 to 0.79) for the SPIROMICS cohort and 0.82 (95% CI, 0.73 to 0.92) for the independent cohort.ConclusionsAirway mucin concentrations may quantitate a key component of the chronic bronchitis pathophysiologic cascade that produces sputum and mediates disease severity. Studies designed to explore total mucin concentrations in sputum as a diagnostic biomarker and therapeutic target for chronic bronchitis appear to be warranted. (Funded by the National Heart, Lung, and Blood Institute and others.).

Importance Few studies have investigated the association of long-term ambient ozone exposures with respiratory morbidity among individuals with a heavy smoking history. Objective To investigate the association of historical ozone exposure with risk of chronic obstructive pulmonary disease (COPD), computed tomography (CT) scan measures of respiratory disease, patient-reported outcomes, disease severity, and exacerbations in smokers with or at risk for COPD. Design, Setting, and Participants This multicenter cross-sectional study, conducted from November 1, 2010, to July 31, 2018, obtained data from the Air Pollution Study, an ancillary study of SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study). Data analyzed were from participants enrolled at 7 (New York City, New York; Baltimore, Maryland; Los Angeles, California; Ann Arbor, Michigan; San Francisco, California; Salt Lake City, Utah; and Winston-Salem, North Carolina) of the 12 SPIROMICS clinical sites. Included participants had historical ozone exposure data (n = 1874), were either current or former smokers (≥20 pack-years), were with or without COPD, and were aged 40 to 80 years at baseline. Healthy persons with a smoking history of 1 or more pack-years were excluded from the present analysis. Exposures The 10-year mean historical ambient ozone concentration at participants’ residences estimated by cohort-specific spatiotemporal modeling. Main Outcomes and Measures Spirometry-confirmed COPD, chronic bronchitis diagnosis, CT scan measures (emphysema, air trapping, and airway wall thickness), 6-minute walk test, modified Medical Research Council (mMRC) Dyspnea Scale, COPD Assessment Test (CAT), St. George’s Respiratory Questionnaire (SGRQ), postbronchodilator forced expiratory volume in the first second of expiration (FEV1) % predicted, and self-report of exacerbations in the 12 months before SPIROMICS enrollment, adjusted for demographics, smoking, and job exposure. Results A total of 1874 SPIROMICS participants were analyzed (mean [SD] age, 64.5 [8.8] years; 1479 [78.9%] white; and 1013 [54.1%] male). In adjusted analysis, a 5-ppb (parts per billion) increase in ozone concentration was associated with a greater percentage of emphysema (β = 0.94; 95% CI, 0.25-1.64;P = .007) and percentage of air trapping (β = 1.60; 95% CI, 0.16-3.04;P = .03); worse scores for the mMRC Dyspnea Scale (β = 0.10; 95% CI, 0.03-0.17;P = .008), CAT (β = 0.65; 95% CI, 0.05-1.26;P = .04), and SGRQ (β = 1.47; 95% CI, 0.01-2.93;P = .048); lower FEV1% predicted value (β = −2.50; 95% CI, −4.42 to −0.59;P = .01); and higher odds of any exacerbation (odds ratio [OR], 1.37; 95% CI, 1.12-1.66;P = .002) and severe exacerbation (OR, 1.37; 95% CI, 1.07-1.76;P = .01). No association was found between historical ozone exposure and chronic bronchitis, COPD, airway wall thickness, or 6-minute walk test result. Conclusions and Relevance This study found that long-term historical ozone exposure was associated with reduced lung function, greater emphysema and air trapping on CT scan, worse patient-reported outcomes, and increased respiratory exacerbations for individuals with a history of heavy smoking. The association between ozone exposure and adverse respiratory outcomes suggests the need for continued reevaluation of ambient pollution standards that are designed to protect the most vulnerable members of the US population.