Mortality and Exacerbation Risk by Body Mass Index in Patients with COPD in TIOSPIR and UPLIFT

RATIONALE: There is an association between body mass index (BMI) and mortality in chronic obstructive pulmonary disease (COPD), with underweight individuals having higher mortality risk. Mortality and exacerbation risks among individuals with higher BMI are unclear. OBJECTIVES: To examine the relationship between BMI and adverse outcomes in COPD. METHODS: This post hoc analysis included data from TIOSPIR (Tiotropium Safety and Performance in Respimat) (N = 17,116) and tiotropium-treated patients in UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) (N = 2,986). BMI classes (underweight [BMI < 20 kg/m(2)], normal weight [BMI 20 to <25 kg/m(2)], overweight [BMI 25 to <30 kg/m(2)], obesity class I [BMI 30 to <35 kg/m(2)], obesity class II [BMI 35 to <40 kg/m(2)], and obesity class III [BMI ⩾ 40 kg/m(2)]) were examined for adjusted associations with mortality, exacerbation, and nonfatal cardiovascular event risk using over 50,000 patient-years of cumulative follow-up data. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression models. RESULTS: In TIOSPIR, obesity prevalence was 22%, overweight 32%, and underweight 12%. The proportion of females was highest in obesity classes II and III. Overweight and obese participants had better baseline lung function versus other BMI classes; underweight participants were more likely to be current smokers. Underweight participants had a significantly higher risk of death (HR, 1.88; 95% CI, 1.62–2.20; P < 0.0001) and severe exacerbations (HR, 1.31; 95% CI, 1.16–1.47; P < 0.0001) versus normal-weight participants; however, overweight and obese participants were at lower to no additional risk. Results from UPLIFT were similar to TIOSPIR. CONCLUSIONS: These results suggest that there is a strong association between body weight, COPD events, and risk of death. A holistic management approach taking into account respiratory and cardiovascular risk factors and nutritional status is needed to improve the general well-being of patients with COPD

Diffusing Capacity and Mortality in Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) mortality risk is often estimated using the BODE (body mass index, obstruction, dyspnea, exercise capacity) index, including body mass index, forced expiratory volume in 1 second, dyspnea score, and 6-minute walk distance. Diffusing capacity of the lung for carbon monoxide (DlCO) is a potential predictor of mortality that reflects physiology distinct from that in the BODE index. Objectives: This study evaluated DlCO as a predictor of mortality using participants from the COPDGene study. Methods: We performed time-to-event analyses of individuals with COPD (former or current smokers with forced expiratory volume in 1 second/forced vital capacity &lt; 0.7) and DlCO measurements from the COPDGene phase 2 visit. Cox proportional hazard methods were used to model survival, adjusting for age, sex, pack-years, smoking status, BODE index, computed tomography (CT) percent emphysema (low attenuation areas below -950 Hounsfield units), CT airway wall thickness, and history of cardiovascular or kidney diseases. C statistics for models with DlCO and BODE scores were used to compare discriminative accuracy. Results: Of 2,329 participants, 393 (16.8%) died during the follow-up period (median = 4.9 yr). In adjusted analyses, for every 10% decrease in DlCO percent predicted, mortality increased by 28% (hazard ratio = 1.28; 95% confidence interval, 1.17-1.41, P &lt; 0.001). When compared with other clinical predictors, DlCO percent predicted performed similarly to BODE (C statistic DlCO = 0.68; BODE = 0.70), and the addition of DlCO to BODE improved its discriminative accuracy (C statistic = 0.71). Conclusions: Diffusing capacity, a measure of gas transfer, strongly predicted all-cause mortality in individuals with COPD, independent of BODE index and CT evidence of emphysema and airway wall thickness. These findings support inclusion of DlCO in prognostic models for COPD

A Simplified Score to Quantify Comorbidity in COPD

Importance Comorbidities are common in COPD, but quantifying their burden is difficult. Currently there is a COPD-specific comorbidity index to predict mortality and another to predict general quality of life. We sought to develop and validate a COPD-specific comorbidity score that reflects comorbidity burden on patient-centered outcomes. Materials and Methods Using the COPDGene study (GOLD II-IV COPD), we developed comorbidity scores to describe patient-centered outcomes employing three techniques: 1) simple count, 2) weighted score, and 3) weighted score based upon statistical selection procedure. We tested associations, area under the Curve (AUC) and calibration statistics to validate scores internally with outcomes of respiratory disease-specific quality of life (St. George's Respiratory Questionnaire, SGRQ), six minute walk distance (6MWD), modified Medical Research Council (mMRC) dyspnea score and exacerbation risk, ultimately choosing one score for external validation in SPIROMICS. Results Associations between comorbidities and all outcomes were comparable across the three scores. All scores added predictive ability to models including age, gender, race, current smoking status, pack-years smoked and FEV1 (p<0.001 for all comparisons). Area under the curve (AUC) was similar between all three scores across outcomes: SGRQ (range 0·7624–0·7676), MMRC (0·7590–0·7644), 6MWD (0·7531–0·7560) and exacerbation risk (0·6831–0·6919). Because of similar performance, the comorbidity count was used for external validation. In the SPIROMICS cohort, the comorbidity count performed well to predict SGRQ (AUC 0·7891), MMRC (AUC 0·7611), 6MWD (AUC 0·7086), and exacerbation risk (AUC 0·7341). Conclusions Quantifying comorbidity provides a more thorough understanding of the risk for patient-centered outcomes in COPD. A comorbidity count performs well to quantify comorbidity in a diverse population with COPD

Lower serum IgA is associated with COPD exacerbation risk in SPIROMICS

Background Decreased but measurable serum IgA levels (≤70 mg/dL) have been associated with risk for infections in some populations, but are unstudied in COPD. This study tested the hypothesis that subnormal serum IgA levels would be associated with exacerbation risk in COPD. Methods Data were analyzed from 1,049 COPD participants from the observational cohort study SPIROMICS (535 (51%) women; mean age 66.1 (SD 7.8), 338 (32%) current smokers) who had baseline serum IgA measured using the Myriad RBM biomarker discovery platform. Exacerbation data was collected prospectively (mean 944.3 (SD 281.3) days), and adjusted linear, logistic and zero-inflated negative binomial regressions were performed. Results Mean IgA was 269.1 mg/dL (SD 150.9). One individual had deficient levels of serum IgA (<7 mg/dL) and 25 (2.4%) had IgA level ≤70 mg/dL. Participants with IgA ≤70 mg/dL were younger (62 vs. 66 years, p = 0.01) but otherwise similar to those with higher IgA. In adjusted models, IgA ≤70 mg/dL was associated with higher exacerbation incidence rates (IRR 1.71, 95% CI 1.01–2.87, p = 0.044) and greater risk for any severe exacerbation (OR 2.99, 95% CI 1.30–6.94, p = 0.010). In adjusted models among those in the lowest decile (<120 mg/dL), each 10 mg/dL decrement in IgA (analyzed continuously) was associated with more exacerbations during follow-up (β 0.24, 95% CI 0.017–0.46, p = 0.035). Conclusions Subnormal serum IgA levels were associated with increased risk for acute exacerbations, supporting mildly impaired IgA levels as a contributing factor in COPD morbidity. Additionally, a dose-response relationship between lower serum IgA and number of exacerbations was found among individuals with serum IgA in the lowest decile, further supporting the link between serum IgA and exacerbation risk. Future COPD studies should more comprehensively characterize immune status to define the clinical relevance of these findings and their potential for therapeutic correction

Black carbon content in airway macrophages is associated with increased severe exacerbations and worse COPD morbidity in SPIROMICS

Background Airway macrophages (AM), crucial for the immune response in chronic obstructive pulmonary disease (COPD), are exposed to environmental particulate matter (PM), which they retain in their cytoplasm as black carbon (BC). However, whether AM BC accurately reflects environmental PM2.5 exposure, and can serve as a biomarker of COPD outcomes, is unknown. Methods We analyzed induced sputum from participants at 7 of 12 sites SPIROMICS sites for AM BC content, which we related to exposures and to lung function and respiratory outcomes. Models were adjusted for batch (first vs. second), age, race (white vs. non-white), income (<$35,000,$35,000~$74,999, ≥$75,000, decline to answer), BMI, and use of long-acting beta-agonist/long-acting muscarinic antagonists, with sensitivity analysis performed with inclusion of urinary cotinine and lung function as covariates. Results Of 324 participants, 143 were current smokers and 201 had spirometric-confirmed COPD. Modeled indoor fine (< 2.5 μm in aerodynamic diameter) particulate matter (PM2.5) and urinary cotinine were associated with higher AM BC. Other assessed indoor and ambient pollutant exposures were not associated with higher AM BC. Higher AM BC was associated with worse lung function and odds of severe exacerbation, as well as worse functional status, respiratory symptoms and quality of life. Conclusion Indoor PM2.5 and cigarette smoke exposure may lead to increased AM BC deposition. Black carbon content in AMs is associated with worse COPD morbidity in current and former smokers, which remained after sensitivity analysis adjusting for cigarette smoke burden. Airway macrophage BC, which may alter macrophage function, could serve as a predictor of experiencing worse respiratory symptoms and impaired lung function

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group