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

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

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.

Plasma inflammatory mediators associated with bone metabolism in COPD.

ABSTRACT The association of osteoporosis with COPD is well established, but the relationship between systemic inflammatory mediators and bone metabolism has not been explored. Plasma samples from 40 COPD patients awaiting lung transplantation were analyzed for 27 inflammatory mediators using a multiplex protein array. C-telopeptide type I collagen (CTx), a marker of bone resorption, was measured with ELISA, and N-terminal procollagen propeptide (P1NP), a marker of bone formation, was ascertained with a radioimmunoassay. Associations between inflammatory mediators versus CTx and P1NP with adjustments for steroid and bisphosphonate use were determined. Mean age was 59 years (+/- 6) and FEV(1) was 23.5% (+/- 8.3%) predicted. Ninety-five percent of the subjects had low bone mineral density measured by dual x-ray absorptiometry (DXA). Tumor necrosis factor alpha and interleukin 4 were positively associated with CTx and P1NP. RANTES and eotaxin were inversely associated with CTx and P1NP. Interleukin 2 and interferon gamma were also directly associated with P1NP. Biologically plausible systemic mediators are associated with bone metabolism in patients with severe COPD, offering potential insight into risk factors and underlying mechanisms of bone disease. Furthermore, they may be useful in monitoring disease activity, and serve as targets for biological therapy.

Mortality and Exacerbations by Global Initiative for Chronic Obstructive Lung Disease Groups ABCD: 2011 Versus 2017 in the COPDGene® Cohort.

Background: The Global initiative for chronic Obstructive Lung Disease (GOLD) ABCD groupings were recently modified. The GOLD 2011 guidelines defined increased risk as forced expiratory volume in 1 second (FEV1) < 50% predicted or ≥ 2 outpatient or ≥ 1 hospitalized exacerbation in the prior year, whereas the GOLD 2017 guidelines use only exacerbation history. We compared mortality and exacerbation rates in the Genetic Epidemiology of COPD Study cohort (COPDGene®) by 2011 (exacerbation history/FEV1 and dyspnea) versus 2017 (exacerbations and dyspnea) classifications. Methods: Using data from COPDGene®, we tested associations of ABCD groups with all-cause mortality (Cox models, adjusted for age, sex, race and comorbidities) and longitudinal exacerbations (zero-inflated Poisson models). Results: In 4469 individuals (mean age 63.1 years, 44% female), individual distributions in 2011 versus 2017 systems were: A, 32.0% versus 37.0%; B, 17.6% versus 36.3%; C, 9.4% versus 4.4%; D, 41.0% versus 22.3%; (observed agreement 76% [expected 27.8%], Kappa 0.67, p<0.001). Individuals in group D-2011 had 1.1 ± 1.6 exacerbations/year (mean ± standard deviation [SD]) versus 1.4 ± 1.8 for D-2017 (median follow-up 3.7 years). Using group A as reference, for both systems, mortality (median follow-up 6.8 years) was highest in group D (D-2011, [hazard ratio] HR 5.2 [95% confidence interval (CI) 4.2, 6.4]; D-2017, HR 5.5 [4.5, 6.8]), lowest for group C (HR 1.9 [1.4, 2.6] versus HR 1.9 [1.3, 2.8]) and intermediate for group B (HR 2.6 [2.0, 3.4] versus HR 3.4 [2.8, 4.1]). GOLD 2011 had better mortality discrimination (area under the curve [AUC] 0.68) than GOLD 2017 (AUC 0.66, p<0.001 for comparison) but similar exacerbation rate prediction. Conclusions: Relative to the GOLD 2011 consensus statement, discriminate predictive power of the 2017 ABCD classification is similar for exacerbations but lower for survival.

Lung, Fat and Bone: Increased Adiponectin Associates with the Combination of Smoking-Related Lung Disease and Osteoporosis.

Background: Adiponectin has been proposed as a biomarker of disease severity and progression in chronic obstructive pulmonary disease (COPD) and associated with spirometry-defined COPD and with computed tomography (CT)-measured emphysema. Increased adiponectin plays a role in other diseases including diabetes/metabolic syndrome, cardiovascular disease and osteoporosis. Previous studies of adiponectin and COPD have not assessed the relationship of adiponectin to airway disease in smokers and have not evaluated the effect of other comorbid diseases on the relationship of adiponectin and lung disease. We postulated that adiponectin levels would associate with both airway disease and emphysema in smokers with and without COPD, and further postulated that body composition and the comorbid diseases of osteoporosis, cardiovascular disease and diabetes might influence adiponectin levels. Methods: Current and former smokers from the COPD Genetic Epidemiology study (COPDGene) (n= 424) were assigned to 4 groups based on CT lung characteristics and volumetric Bone Density (vBMD). Emphysema (% low attenuation area at -950) and airway disease (Wall area %) were used to assess smoking-related lung disease (SRLD). Group 1) Normal Lung with Normal vBMD; Group 2) Normal Lung and Osteoporosis; Group 3) SRLD with Normal vBMD; Group 4) SRLD with Osteoporosis. Cardiovascular disease (CVD), diabetes, C-reactive protein (CRP) and T-cadherin (soluble receptor for adiponectin) levels were defined for each group. Body composition was derived from chest CT. Multivariable regression assessed effects of emphysema, wall area %, bone density, comorbid diseases and other key factors on log adiponectin. Results: Group 4, SRLD with Osteoporosis, had significantly higher adiponectin levels compared to other groups and the effect persisted in adjusted models. Systemic inflammation (by CRP) was associated with SRLD in Groups 3 and 4 but not with osteoporosis alone. In regression models, lower bone density and worse emphysema were associated with higher adiponectin. Airway disease was associated with higher adiponectin levels when T-cadherin was added to the model. Male gender, greater muscle and fat were associated with lower adiponectin. Conclusions: Adiponectin is increased with both airway disease and emphysema in smokers. Bone density, and fat and muscle composition are all significant factors predicting adiponectin that should be considered when it is used as a biomarker of COPD. Increased adiponectin from chronic inflammation may play a role in the progression of bone loss in COPD and other lung diseases.

Reduced Bone Density and Vertebral Fractures in Smokers. Men and COPD Patients at Increased Risk.

RATIONALE: Former smoking history and chronic obstructive pulmonary disease (COPD) are potential risk factors for osteoporosis and fractures. Under existing guidelines for osteoporosis screening, women are included but men are not, and only current smoking is considered. OBJECTIVES: To demonstrate the impact of COPD and smoking history on the risk of osteoporosis and vertebral fracture in men and women. METHODS: Characteristics of participants with low volumetric bone mineral density (vBMD) were identified and related to COPD and other risk factors. We tested associations of sex and COPD with both vBMD and fractures adjusting for age, race, body mass index (BMI), smoking, and glucocorticoid use. MEASUREMENTS AND MAIN RESULTS: vBMD by calibrated quantitative computed tomography (QCT), visually scored vertebral fractures, and severity of lung disease were determined from chest CT scans of 3,321 current and ex-smokers in the COPDGene study. Low vBMD as a surrogate for osteoporosis was calculated from young adult normal values. Male smokers had a small but significantly greater risk of low vBMD (2.5 SD below young adult mean by calibrated QCT) and more fractures than female smokers. Low vBMD was present in 58% of all subjects, was more frequent in those with worse COPD, and rose to 84% among subjects with very severe COPD. Vertebral fractures were present in 37% of all subjects and were associated with lower vBMD at each Global Initiative for Chronic Obstructive Lung Disease stage of severity. Vertebral fractures were most common in the midthoracic region. COPD and especially emphysema were associated with both low vBMD and vertebral fractures after adjustment for steroid use, age, pack-years of smoking, current smoking, and exacerbations. Airway disease was associated with higher bone density after adjustment for other variables. Calibrated QCT identified more subjects with abnormal values than the standard dual-energy X-ray absorptiometry in a subset of subjects and correlated well with prevalent fractures. CONCLUSIONS: Male smokers, with or without COPD, have a significant risk of low vBMD and vertebral fractures. COPD was associated with low vBMD after adjusting for race, sex, BMI, smoking, steroid use, exacerbations, and age. Screening for low vBMD by using QCT in men and women who are smokers will increase opportunities to identify and treat osteoporosis in this at-risk population.

The influence of radiographic phenotype and smoking status on peripheral blood biomarker patterns in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by both airway remodeling and parenchymal destruction. The identification of unique biomarker patterns associated with airway dominant versus parenchymal dominant patterns would support the existence of unique phenotypes representing independent biologic processes. A cross-sectional study was performed to examine the association of serum biomarkers with radiographic airway and parenchymal phenotypes of COPD. METHODOLOGY/PRINCIPAL FINDINGS: Serum from 234 subjects enrolled in a CT screening cohort was analyzed for 33 cytokines and growth factors using a multiplex protein array. The association of serum markers with forced expiratory volume in one second percent predicted (FEV1%) and quantitative CT measurements of airway thickening and emphysema was assessed with and without stratification for current smoking status. Significant associations were found with several serum inflammatory proteins and measurements of FEV1%, airway thickening, and parenchymal emphysema independent of smoking status. The association of select analytes with airway thickening and emphysema was independent of FEV1%. Furthermore, the relationship between other inflammatory markers and measurements of physiologic obstruction or airway thickening was dependent on current smoking status. CONCLUSIONS/SIGNIFICANCE: Airway and parenchymal phenotypes of COPD are associated with unique systemic serum biomarker profiles. Serum biomarker patterns may provide a more precise classification of the COPD syndrome, provide insights into disease pathogenesis and identify targets for novel patient-specific biological therapies.