Guideline Alignment and Medication Concordance in COPD.

BACKGROUND: Provider adherence to clinical treatment guidelines in COPD is low. However, for patients to receive guideline-aligned care, providers not only must prescribe guideline-aligned care, but also must communicate that regimen successfully to patients to ensure medication concordance. The rate of medication concordance between patients and providers and its impact on clinical management is unknown in COPD. RESEARCH QUESTION: To examine rates of guideline alignment and medication concordance and to identify patient-level factors that place patients at risk for these types of poor disease management outcomes. STUDY DESIGN AND METHODS: This study was a secondary data analysis of the Medication Adherence Research in COPD study (2017-2023). Participants were categorized into 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage. Medication regimens were classified as aligned or nonaligned with 2017 GOLD guidelines. Nonaligned regimens were stratified further into overuse and underuse categories. Medication concordance between provider-reported and participant-reported regimens was determined. Factors associated with guideline alignment and medication concordance were evaluated using logistic regression. RESULTS: Of 191 participants, 51% of provider-reported regimens were guideline aligned, with 86% of nonaligned regimens reflecting overuse with an inhaled corticosteroid (ICS). Thirty-eight percent of participants reported different regimens than their providers, of which > 80% reflected participants not reporting medications their providers reported prescribing. Participants did not report long-acting muscarinic antagonists and long-acting beta-agonists at similar rates as ICSs. Greater symptom burden and absence of a pulmonologist on the care team were associated with both guideline misalignment and medication discordance. Cognitive impairment and Black race additionally were associated with medication discordance. INTERPRETATION: Guideline misalignment and medication discordance were common and were driven by overuse of ICSs and unreported medications, respectively. The patient-level factors associated with medication discordance highlight the importance of improving patient-provider communication to improve clinical management in COPD.

Higher Plasma Omega-3 Levels are Associated With Improved Exacerbation Risk and Respiratory-Specific Quality of Life in COPD.

Background: Omega-3 polyunsaturated fatty acids (PUFAs) have been associated with systemic anti-inflammatory responses. Dietary intake of omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has also been associated with lower COPD morbidity using self-report food frequency questionnaires. Objective: To investigate the relationship between measured PUFA intake using plasma EPA+DHA levels and COPD morbidity. Methods: Former smokers with moderate-severe COPD living in low-income communities were enrolled in a 6-month prospective cohort study. Participants completed standardized questionnaires, spirometry, and plasma samples at 3-month intervals. Total plasma PUFAs were analyzed using gas chromatography/ mass spectrometry for DHA and EPA concentrations. Linear or logistic mixed model regression was used to evaluate EPA+DHA's and COPD morbidity's association, accounting for demographics, lung function, pack years, comorbidities, and neighborhood poverty. Results: 133 plasma EPA+DHA samples from 57 participants were available. Participants exhibited average plasma EPA and DHA levels of 14.7±7.3 µg/mL and 40.2±17.2 µg/mL, respectively, across the three clinic visits. Each standard deviation increase in EPA+DHA levels was associated with 2.7 points lower SGRQ score (95% CI -5.2, -0.2) and lower odds of moderate exacerbation (OR 0.4; 95% CI 0.2, 0.9) but lacked significant association with CAT score (95% CI -2.4, 0.8), mMRC (95% CI -02, 0.2), or severe exacerbations (95% CI 0.3, 1.4). Conclusion: Plasma EPA+DHA levels are associated with better respiratory-specific quality of life and lower odds of moderate exacerbations in patients with moderate-to-severe COPD. Further research is warranted to investigate the efficacy of an omega-3 dietary intervention in the management of COPD morbidities.

Changes in Spirometry Interpretative Strategies: Implications for Classifying COPD and Predicting Exacerbations.

BACKGROUND: Recent guidelines for spirometry interpretation recommend both race-neutral reference equations and use of z score thresholds to define severity of airflow obstruction. RESEARCH QUESTION: How does the transition from race-specific to race-neutral equations impact severity classifications for patients with COPD when using % predicted vs z score thresholds, and do changes in severity correspond to clinical risk? STUDY DESIGN AND METHODS: This retrospective cohort study included Black and White patients with COPD and available spirometry from the Johns Hopkins Health System. Global Lung Function Initiative (GLI) 2012 (race-specific) equations and GLI Global (race-neutral) equations were used to determine FEV1 % predicted and z score values. Patients were classified as having mild, moderate, or severe disease according to % predicted or z score thresholds. Associations between a change in severity classification from race-specific to race-neutral with COPD exacerbations and all-cause hospitalizations were evaluated using logistic regression. RESULTS: This cohort included 13,324 patients, of whom 9,232 patients (69.3%) were White (mean age, 65.7 years) and 4,092 patients (30.7%) were Black (mean age, 61.1 years). More Black than White patients showed a change in severity classification between approaches when using % predicted thresholds (20.2% vs 6.1%; P < .001), but not with z score thresholds (12.6% vs 12.3%; P = .68). An increased severity classification with a race-neutral approach was associated with increased risk of exacerbation when using z score thresholds (OR, 2.34; 95% CI, 1.51-3.63), but not when using % predicted thresholds (OR, 1.08; 95% CI, 0.61-1.93). A decreased severity classification with a race-neutral approach was associated with lower risk of exacerbation with both % predicted (OR, 0.49; 95% CI, 0.28-0.87) and z score (OR 0.67; 95% CI, 0.50-0.90) thresholds. INTERPRETATION: The proportions of Black and White individuals reclassified were similar with z score thresholds, and changes in severity corresponded to clinical risk with z scores. These results support recent recommendations for use of race-neutral equations and z score thresholds for spirometry interpretation.

Loss of Airway Phylogenetic Diversity Is Associated with Clinical and Pathobiological Markers of Disease Development in COPD.

RATIONALE: The airway microbiome has the potential to shape COPD pathogenesis, but its relationship to outcomes in milder disease is unestablished. OBJECTIVES: Identify sputum microbiome characteristics associated with markers of COPD in participants of the SubPopulations and InteRmediate Outcome Measures of COPD Study (SPIROMICS). METHODS: Sputum DNA from 877 participants were analyzed using 16S rRNA gene sequencing. Relationships between baseline airway microbiota composition and clinical, radiographic and muco-inflammatory markers, including longitudinal lung function trajectory, were examined. MEASUREMENTS AND MAIN RESULTS: Participant data represented predominantly milder disease (GOLD 0-2: N=732/877). Phylogenetic diversity (range of different species within a sample) correlated positively with baseline lung function, declined with higher GOLD stage, and correlated negatively with symptom burden, radiographic markers of airway disease, and total mucin concentrations (p<0.001). In co-variate adjusted regression models, organisms robustly associated with better lung function included members of Alloprevotella, Oribacterium, and Veillonella. Conversely, lower lung function, greater symptoms and radiographic measures of small airway disease associated with enrichment in members of Streptococcus, Actinobacillus, Actinomyces, and other genera. Baseline sputum microbiota features also associated with lung function trajectory during SPIROMICS follow up (stable/improved, decliner, or rapid decliner). The 'stable/improved' group (slope of FEV1 regression ≥ 66th percentile) had higher bacterial diversity at baseline, associated with enrichment in Prevotella, Leptotrichia, and Neisseria. In contrast, the 'rapid decliner' group (FEV1 slope ≤ 33rd percentile) had significantly lower baseline diversity, associated with enrichment in Streptococcus. CONCLUSIONS: In SPIROMICS baseline airway microbiota features demonstrate divergent associations with better or worse COPD-related outcomes.

Indoor particulate matter concentrations and air cleaner intervention association with biomarkers in former smokers with COPD.

BACKGROUND: Indoor pollutants have been associated with worse clinical outcomes in chronic obstructive pulmonary disease (COPD). Elevated biomarkers are associated with ambient pollution exposure, however the association with indoor pollution remains unclear. METHODS: Former smokers with spirometry-confirmed COPD were randomized to portable air cleaner or placebo. Indoor particulate matter (PM2.5, PM10, and ultrafine particles [UFP; PM<0.1]) and biomarkers were measured longitudinally at pre-specified intervals and course PM fraction (PM10-2.5) was calculated. Biomarkers were categorized based on associations with biologic mechanisms: inflammation (white blood cell count, interleukin [IL]-6, IL-8, IL-1ß, tumor necrosis factor-α, interferon-γ, serum amyloid A), platelet activation (P-selectin, CD40 ligand [CD40L], 11-dehdydro-thromboxane-B2 [11dTxB2]), endothelial dysfunction (Vascular Cell Adhesion Molecule [VCAM]-1, Intercellular Adhesion Molecule [ICAM]-1), and oxidative stress (thiobarbituric acid reactive substances [TBARS], 8-hydroxydeoxyguanosine, 8-isoprostane). Associations between PM concentrations and each biomarker were analyzed using multivariable linear mixed models. An intention-to-treat analysis was performed to evaluate the air cleaner intervention on the biomarker levels longitudinally. RESULTS: Fifty-eight participants were randomized to each group. Finer PM was more strongly associated with higher IL-8 (mean difference per doubling: UFP 13.9% [p = 0.02], PM2.5 6.8% [p = 0.002], PM10-2.5 5.0% [p = 0.02]) while interferon-γ was associated with UFP and IL-1ß with PM10-2.5. UFP and PM2.5 were associated with elevated levels of the oxidative stress biomarkers TBARS and 8-isoprostane respectively. For platelet activation markers, UFP was associated with higher 11dTxB2 while PM2.5 was associated with higher P-selectin and CD40L. Pollutants were not associated with biomarkers of endothelial dysfunction. In intention-to-treat analysis there was no association of the air cleaner intervention with any of the biomarkers. DISCUSSION: Among former smokers with COPD, elevated levels of indoor air pollutants, particularly ultrafine particles (PM<0.1), were associated with elevated biomarkers of inflammation, platelet activation, and oxidative stress. However, an air cleaner intervention that reduced PM did not significantly reduce biomarker levels.

Lung Structure and Risk of Sleep Apnea in SPIROMICS.

Rationale: The SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS) is a prospective cohort study that enrolled 2981 participants with the goal of identifying new chronic obstructive pulmonary disease (COPD) subgroups and intermediate markers of disease progression. Individuals with COPD and obstructive sleep apnea (OSA) experience impaired quality of life and more frequent exacerbations. COPD severity also associates with computed tomography scan-based emphysema and alterations in airway dimensions. Objectives: The objective was to determine whether the combination of lung function and structure influences the risk of OSA among current and former smokers. Methods: Using 2 OSA risk scores, the Berlin Sleep Questionnaire (BSQ), and the DOISNORE50 (Diseases, Observed apnea, Insomnia, Snoring, Neck circumference > 18 inches, Obesity with body mass index [BMI] > 32, R = are you male, Excessive daytime sleepiness, 50 = age ≥ 50) (DIS), 1767 current and former smokers were evaluated for an association of lung structure and function with OSA risk. Measurements and Main Results: The study cohort's mean age was 63 years, BMI was 28 kg/m2, and forced expiratory volume in 1 second (FEV1) was 74.8% predicted. The majority were male (55%), White (77%), former smokers (59%), and had COPD (63%). A high-risk OSA score was reported in 36% and 61% using DIS and BSQ respectively. There was a 9% increased odds of a high-risk DIS score (odds ratio [OR]=1.09, 95% confidence interval [CI]:1.03-1.14) and nominally increased odds of a high-risk BSQ score for every 10% decrease in FEV1 %predicted (OR=1.04, 95%CI: 0.998-1.09). Lung function-OSA risk associations persisted after additionally adjusting for lung structure measurements (%emphysema, %air trapping, parametric response mapping for functional small airways disease, , mean segmental wall area, tracheal %wall area, dysanapsis) for DIS (OR=1.12, 95%CI:1.03-1.22) and BSQ (OR=1.09, 95%CI:1.01-1.18). Conclusions: Lower lung function independently associates with having high risk for OSA in current and former smokers. Lung structural elements, especially dysanapsis, functional small airways disease, and tracheal %wall area strengthened the effects on OSA risk.

Food Insecurity is Associated With COPD Morbidity and Perceived Stress.

Background: Low socioeconomic status (SES) has been associated with worse clinical outcomes in chronic obstructive pulmonary disease (COPD). Food insecurity is more common among individuals with low SES and has been associated with poor outcomes in other chronic illnesses, but its impact on COPD has not been studied. Methods: Former smokers with spirometry-confirmed COPD were recruited from low-income areas of Baltimore, Maryland, and followed for 9 months as part of a cohort study of diet and indoor air pollution. Food insecurity and respiratory outcomes, including COPD exacerbations and patient-reported outcomes, were assessed at regular intervals. The association between food insecurity and COPD outcomes was analyzed using generalized linear mixed models. Additional analyses examined the association of COPD morbidity with subdomains of food insecurity and the association of food insecurity with psychological well-being measures. Results: Ninety-nine participants had available data on food insecurity and COPD outcomes. A total of 26.3% of participants were food insecure at 1 or more times during the study. After adjusting for individual SES, neighborhood poverty, and low healthy food access, food insecurity was associated with a higher incidence rate of moderate and severe exacerbations and worse dyspnea, COPD health status, and respiratory-specific quality of life. Subdomains of food insecurity were independently associated with worse patient-reported outcomes. Food insecurity was additionally associated with higher perceived stress. Discussion: Among former smokers with COPD, food insecurity was associated with a higher incidence of exacerbations, worse patient-reported outcomes, and higher perceived stress. Subdomains of food insecurity were independently associated with worse patient-reported outcomes.

Diffusing Capacity as a Predictor of Hospitalizations in a Clinical Cohort of Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) hospitalizations are a major burden on patients. Diffusing capacity of the lung for carbon monoxide (DlCO) is a potential predictor that has not been studied in large cohorts. Objectives: This study used electronic health record data to evaluate whether clinically obtained DlCO predicts COPD hospitalizations. Methods: We performed time-to-event analyses of individuals with COPD and DlCO measurements from the Johns Hopkins COPD Precision Medicine Center of Excellence. Cox proportional hazard methods were used to model time from DlCO measurement to first COPD hospitalization and composite first hospitalization or death, adjusting for age, sex, race, body mass index, smoking status, forced expiratory volume in 1 second (FEV1), history of prior COPD hospitalization, and comorbidities. To identify the utility of including DlCO in risk models, area under the receiver operating curve (AUC) values were calculated for models with and without DlCO. Results were externally validated in a separate analogous cohort. Results: Of 2,793 participants, 368 (13%) had a COPD hospitalization within 3 years. In adjusted analyses, for every 10% decrease in DlCO% predicted, risk of COPD hospitalization increased by 10% (hazard ratio, 1.1; 95% confidence interval, 1.1-1.2; P < 0.001). Similar associations were observed for COPD hospitalizations or death. The model including demographics, comorbidities, FEV1, DlCO, and prior COPD hospitalizations performed well, with an AUC of 0.85 and an AUC of 0.84 in an external validation cohort. Conclusions: Diffusing capacity is a strong predictor of COPD hospitalizations in a clinical cohort of individuals with COPD, independent of airflow obstruction and prior hospitalizations. These findings support incorporation of DlCO in risk assessment of patients with COPD.

Decreased fucosylation impacts epithelial integrity and increases risk for COPD.

COPD causes significant morbidity and mortality worldwide. Epithelial damage is fundamental to disease pathogenesis, although the mechanisms driving disease remain undefined. Published evidence from a COPD cohort (SPIROMICS) and confirmed in a second cohort (COPDgene) demonstrate a polymorphism in Fucosyltransferese-2 (FUT2) is a trans-pQTL for E-cadherin, which is critical in COPD pathogenesis. We found by MALDI-TOF analysis that FUT2 increased terminal fucosylation of E-cadherin. Using atomic force microscopy, we found that FUT2-dependent fucosylation enhanced E-cadherin-E-cadherin bond strength, mediating the improvement in monolayer integrity. Tracheal epithelial cells from Fut2-/- mice have reduced epithelial integrity, which is recovered with reconstitution of Fut2. Overexpression of FUT2 in COPD derived epithelia rescues barrier function. Fut2-/- mice show increased susceptibility in an elastase model of disease developing both emphysema and fibrosis. We propose this is due to the role of FUT2 in proliferation and cell differentiation. Overexpression of FUT2 significantly increased proliferation. Loss of Fut2 results in accumulation of Spc+ cells suggesting a failure of alveolar type 2 cells to undergo transdifferentiation to alveolar type 1. Using a combination of population data, genetically manipulated mouse models, and patient-derived cells, we present a novel mechanism by which post-translational modifications modulate tissue pathology and serve as a proof of concept for the development of a disease-modifying target in COPD.

Evaluation of Calibration Approaches for Indoor Deployments of PurpleAir Monitors.

Low-cost air quality monitors are growing in popularity among both researchers and community members to understand variability in pollutant concentrations. Several studies have produced calibration approaches for these sensors for ambient air. These calibrations have been shown to depend primarily on relative humidity, particle size distribution, and particle composition, which may be different in indoor environments. However, despite the fact that most people spend the majority of their time indoors, little is known about the accuracy of commonly used devices indoors. This stems from the fact that calibration data for sensors operating in indoor environments are rare. In this study, we sought to evaluate the accuracy of the raw data from PurpleAir fine particulate matter monitors and for published calibration approaches that vary in complexity, ranging from simply applying linear corrections to those requiring co-locating a filter sample for correction with a gravimetric concentration during a baseline visit. Our data includes PurpleAir devices that were co-located in each home with a gravimetric sample for 1-week periods (265 samples from 151 homes). Weekly-averaged gravimetric concentrations ranged between the limit of detection (3 µg/m3) and 330 µg/m3. We found a strong correlation between the PurpleAir monitor and the gravimetric concentration (R>0.91) using internal calibrations provided by the manufacturer. However, the PurpleAir data substantially overestimated indoor concentrations compared to the gravimetric concentration (mean bias error ≥ 23.6 µg/m3 using internal calibrations provided by the manufacturer). Calibrations based on ambient air data maintained high correlations (R ≥ 0.92) and substantially reduced bias (e.g. mean bias error = 10.1 µg/m3 using a US-wide calibration approach). Using a gravimetric sample from a baseline visit to calibrate data for later visits led to an improvement over the internal calibrations, but performed worse than the simpler calibration approaches based on ambient air pollution data. Furthermore, calibrations based on ambient air pollution data performed best when weekly-averaged concentrations did not exceed 30 µg/m3, likely because the majority of the data used to train these models were below this concentration.

Indoor Pollution and Lung Function Decline in Current and Former Smokers: SPIROMICS AIR.

Rationale: Indoor pollutants have been associated with chronic obstructive pulmonary disease morbidity, but it is unclear whether they contribute to disease progression. Objectives: We aimed to determine whether indoor particulate matter (PM) and nitrogen dioxide (NO2) are associated with lung function decline among current and former smokers. Methods: Of the 2,382 subjects with a history of smoking in SPIROMICS AIR, 1,208 participants had complete information to estimate indoor PM and NO2, using individual-based prediction models, in relation to measured spirometry at two or more clinic visits. We used a three-way interaction model between time, pollutant, and smoking status and assessed the indoor pollutant-associated difference in FEV1 decline separately using a generalized linear mixed model. Measurements and Main Results: Participants had an average rate of FEV1 decline of 60.3 ml/yr for those currently smoking compared with 35.2 ml/yr for those who quit. The association of indoor PM with FEV1 decline differed by smoking status. Among former smokers, every 10 µg/m3 increase in estimated indoor PM was associated with an additional 10 ml/yr decline in FEV1 (P = 0.044). Among current smokers, FEV1 decline did not differ by indoor PM. The results of indoor NO2 suggest trends similar to those for PM ⩽2.5 µm in aerodynamic diameter. Conclusions: Former smokers with chronic obstructive pulmonary disease who live in homes with high estimated PM have accelerated lung function loss, and those in homes with low PM have lung function loss similar to normal aging. In-home PM exposure may contribute to variability in lung function decline in people who quit smoking and may be a modifiable exposure.

Decreased Cardiac Autonomic Function is Associated with Higher Exacerbation Risk and Symptom Burden in Chronic Obstructive Pulmonary Disease.

Current measures of chronic obstructive pulmonary disease (COPD) severity, including lung function, do not fully explain symptom burden, and there is a need to identify predictors of exacerbation risk and morbidity. Autonomic dysfunction may be implicated in both cardiovascular and respiratory morbidity in COPD and convey risk for exacerbations. Heart rate variability (HRV) is a marker of cardiac autonomic function that is predictive of cardiovascular health and has promise as a non-invasive COPD biomarker. The CLEAN AIR Heart study provided an opportunity to investigate the association between HRV and COPD morbidity among former smokers with moderate-severe COPD. Eighty-five participants, contributing 305 HRV measurements, underwent repeated clinical assessments over 4 study periods that included a 24-Holter monitoring assessment of HRV. HRV measures of interest were standard deviation of normal-to-normal intervals, (SDNN) (overall HRV) and root-mean-square of successive differences (RMSSD) (parasympathetic function). Exacerbation risk was assessed using negative binomial models, and mixed-effects models analyzed associations between HRV and symptoms. Decreases in SDNN (incidence rate ratio [IRR]1.40; 95% confidence interval [CI] 1.13 to1.74) and RMSSD (IRR 1.60; 95% CI 1.07 to 2.37) were associated with severe exacerbation risk. Decreases in SDNN were associated with higher St George's Respiratory Questionnaire scores, COPD Assessment Test scores, and chronic bronchitis symptoms. Findings demonstrate that HRV is associated with COPD symptom burden and exacerbation risk. HRV may represent an important biomarker with the potential to identify high-risk COPD populations.

Reduced quantity and function of pneumococcal antibodies are associated with exacerbations of COPD in SPIROMICS.

While hypogammaglobulinemia is associated with COPD exacerbations, it is unknown whether frequent exacerbators have specific defects in antibody production/function. We hypothesized that reduced quantity/function of serum pneumococcal antibodies correlate with exacerbation risk in the SPIROMICS cohort. We measured total pneumococcal IgG in n = 764 previously vaccinated participants with COPD. In a propensity-matched subset of n = 200 with vaccination within five years (n = 50 without exacerbations in the previous year; n = 75 with one, n = 75 with ≥2), we measured pneumococcal IgG for 23 individual serotypes, and pneumococcal antibody function for 4 serotypes. Higher total pneumococcal IgG, serotype-specific IgG (17/23 serotypes), and antibody function (3/4 serotypes) were independently associated with fewer prior exacerbations. Higher pneumococcal IgG (5/23 serotypes) predicted lower exacerbation risk in the following year. Pneumococcal antibodies are inversely associated with exacerbations, supporting the presence of immune defects in frequent exacerbators. With further study, pneumococcal antibodies may be useful biomarkers for immune dysfunction in COPD.

A cross sectional pilot study to assess the role of phthalates on respiratory morbidity among patients with chronic obstructive pulmonary disease.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) affects ∼16 million U.S. adults. Phthalates, synthetic chemicals in consumer products, may adversely impact pulmonary function and airway inflammation; however, their role on COPD morbidity remains unknown. OBJECTIVE: We examined associations between phthalate exposures and respiratory morbidity among 40 COPD patients who were former smokers. METHODS: We quantified 11 phthalate biomarkers in urine samples collected at baseline in a 9-month prospective cohort study in Baltimore, Maryland. COPD baseline morbidity measures included: health status and quality of life measures (CAT: COPD Assessment Test, CCQ: Clinical COPD Questionnaire, SGRQ: St. George's Respiratory Questionnaire; mMRC: Modified Medical Research Council Dyspnea Scale), and lung function. Information on prospective exacerbation data was monitored monthly during the 9-month longitudinal follow-up period. To examine associations between morbidity measures and phthalate exposures, we used multivariable linear and Poisson regression models for continuous and count outcomes, respectively, adjusting for age, sex, race/ethnicity, education, and smoking pack-years. RESULTS: Higher mono-n-butyl phthalate (MBP) concentrations were associated with increased CAT(ß, 2.41; 95%CI, 0.31-4.51), mMRC (ß, 0.33; 95%CI 0.11-0.55), and SGRQ (ß, 7.43; 95%CI 2.70-12.2) scores at baseline. Monobenzyl phthalate (MBzP) was also positively associated with CCQ and SGRQ scores at baseline. Higher concentrations of the molar sum of Di (2-ethylhexyl) phthalate (DEHP) were associated with increased incidence of exacerbations during the follow-up period (incidence rate ratio, IRR = 1.73; 95%CI 1.11, 2.70 and IRR = 1.94; 95%CI 1.22, 3.07, for moderate and severe exacerbations, respectively). MEP concentrations were inversely associated with incidence of exacerbations during the follow-up period. CONCLUSIONS: We found that exposure to select phthalates was associated with respiratory morbidity among COPD patients. Findings warrant further examination in larger studies given widespread phthalate exposures and potential implications for COPD patients should relationships observed be causal.

Tumor MK2 transcript levels are associated with improved response to chemotherapy and patient survival in non-small cell lung cancer.

Non-small cell lung cancers (NSCLCs) demonstrate intrinsic resistance to cell death, even after chemotherapy. Previous work suggested defective nuclear translocation of active caspase-3 in observed resistance to cell death. We have identified mitogen-activated protein kinase-activated protein kinase 2 (MK2; encoded by the gene MAPKAPK2) is required for caspase-3 nuclear translocation in the execution of apoptosis in endothelial cells. The objective was to determine MK2 expression in NSCLCs and the association between MK2 and clinical outcomes in patients with NSCLC. Clinical and MK2 mRNA data were extracted from two demographically distinct NSCLC clinical cohorts, North American (The Cancer Genome Atlas, TCGA) and East Asian (EA). Tumor responses following first round of chemotherapy were dichotomized as clinical response (complete response, partial response, and stable disease) or progression of disease. Multivariable survival analyses were performed using Cox proportional hazard ratios and Kaplan-Meier curves. NSCLC exhibited lower MK2 expression than SCLC cell lines. In patients, lower tumor MK2 transcript levels were observed in those presenting with late-stage NSCLC. Higher MK2 expression was associated with clinical response following initial chemotherapy and independently associated with improved 2-yr survival in two distinct cohorts, 0.52 (0.28-0.98) and 0.1 (0.01-0.81), TCGA and EA, respectively, even after adjusting for common oncogenic driver mutations. Survival benefit of higher MK2 expression was unique to lung adenocarcinoma when comparing across various cancers. This study implicates MK2 in apoptosis resistance in NSCLC and suggests prognostic value of MK2 transcript levels in patients with lung adenocarcinoma.

Airway and Systemic Prostaglandin E2 Association with COPD Symptoms and Macrophage Phenotype.

Background: Polymorphisms and products of the cyclooxygenase (COX) pathway have been associated with the development of chronic obstructive pulmonary disease (COPD) and adverse outcomes. COX-produced prostaglandin E2 (PGE-2) may play a role in the inflammation observed in COPD, potentially through deleterious airway macrophage polarization. A better understanding of the role of PGE-2 in COPD morbidity may inform trials for therapeutics targeting the COX pathway or PGE-2. Methods: Urine and induced sputum were collected from former smokers with moderate-severe COPD. The major urinary metabolite of PGE-2 (PGE-M) was measured, and ELISA was performed on sputum supernatant for PGE-2 airway measurement. Airway macrophages underwent flow cytometry phenotyping (surface CD64, CD80, CD163, CD206, and intracellular IL-1ß, TGF-ß1). Health information was obtained the same day as the biologic sample collection. Exacerbations were collected at baseline and then monthly telephone calls. Results: Among 30 former smokers with COPD (mean±SD age 66.4±8.88 years and forced expiratory volume in 1 second [FEV1] 62.4±8.37 percent predicted), a 1 pg/mL increase in sputum PGE-2 was associated with higher odds of experiencing at least one exacerbation in the prior 12 months (odds ratio 3.3; 95% confidence interval: 1.3 to15.0), worse respiratory symptoms and health status. PGE-M was not associated with exacerbations or symptoms. Neither airway PGE-2 nor urinary PGE-M was uniformly associated with an M1 or M2 polarization. Conclusions: Elevated levels of sputum PGE-2, rather than systemic PGE-2, is associated with increased respiratory symptoms and history of exacerbation among individuals with COPD. Additional studies focused on mechanism of action are warranted.

MK2 nonenzymatically promotes nuclear translocation of caspase-3 and resultant apoptosis.

We have previously identified mitogen-activated protein kinase-activated protein kinase 2 (MK2) is required for caspase-3 nuclear translocation in the execution of apoptosis; however, little is known of the underlying mechanisms. Therefore, we sought to determine the role of kinase and nonkinase functions of MK2 in promoting nuclear translocation of caspase-3. We identified two non-small cell lung cancer cell lines for use in these experiments based on low MK2 expression. Wild-type, enzymatic and cellular localization mutant MK2 constructs were expressed using adenoviral infection. Cell death was evaluated by flow cytometry. In addition, cell lysates were harvested for protein analyses. Phosphorylation of caspase-3 was determined using two-dimensional gel electrophoresis followed by immunoblotting and in vitro kinase assay. Association between MK2 and caspase-3 was evaluated using proximity-based biotin ligation assays and co-immunoprecipitation. Overexpression of MK2 resulted in nuclear translocation of caspase-3 and caspase-3-mediated apoptosis. MK2 directly phosphorylates caspase-3; however, phosphorylation status of caspase-3 or MK2-dependent phosphorylation of caspase-3 did not alter caspase-3 activity. The enzymatic function of MK2 was dispensable in nuclear translocation of caspase-3. MK2 and caspase-3 associated together and a nonenzymatic function of MK2, chaperoned nuclear trafficking, is required for caspase-3-mediated apoptosis. Taken together, our results demonstrate a nonenzymatic role for MK2 in the nuclear translocation of caspase-3. Furthermore, MK2 may function as a molecular switch in regulating the transition between the cytosolic and nuclear functions of caspase-3.

Association of Occupational Exposures and Chronic Obstructive Pulmonary Disease Morbidity.

OBJECTIVE: The aim of the study is to determine whether aggregate measures of occupational exposures are associated with chronic obstructive pulmonary disease (COPD) outcomes in the Subpopulations and Intermediate Outcome Measures in COPD study cohort. METHODS: Individuals were assigned to six predetermined exposure hazard categories based on self-reported employment history. Multivariable regression, adjusted for age, sex, race, current smoking status, and smoking pack-years determined the association of such exposures to odds of COPD and morbidity measures. We compared these with the results of a single summary question regarding occupational exposure. RESULTS: A total of 2772 individuals were included. Some exposure estimates, including "gases and vapors" and "dust and fumes" exposures resulted in associations with effect estimates over two times the estimated effect size when compared with a single summary question. CONCLUSIONS: Use of occupational hazard categories can identify important associations with COPD morbidity while use of single-point measures may underestimate important differences in health risks.

Principal stratification analysis to determine health benefit of indoor air pollution reduction in a randomized environmental intervention in COPD: Results from the CLEAN AIR study.

BACKGROUND: Indoor air quality represents a modifiable exposure to Chronic Obstructive Pulmonary Disease (COPD) health. In a randomized controlled trial (CLEAN AIR study), air cleaner assignment had causal effect in improving COPD outcomes. It is unclear, however, what is the treatment effect among those for whom intervention reduced air pollution and whether it was reduction in fine particulate matter (PM2.5) or nitrogen dioxide (NO2) that contributed to such improvement. Because pollution is a posttreatment variable, treatment effect cannot be assessed while controlling for pollution using intention-to-treat (ITT) analysis. OBJECTIVE: Using principal stratification method, we assess indoor pollutants as the intermediate variable, and determine the causal effect of reducing indoor air pollution on COPD health. METHOD: In randomized controlled trial, former smokers with COPD received either active or placebo HEPA air cleaners and were followed for 6 months. Saint George's Respiratory Questionnaire (SGRQ) was the primary outcome and secondary measures included SGRQ subscales, COPD assessment test (CAT), dyspnea (mMRC), and breathlessness, cough, and sputum scale (BCSS). Indoor PM2.5 and NO2 were measured. Principal stratification analysis was performed to assess the treatment effect while controlling for pollution reduction. RESULTS: Among those showing at least 40 % PM2.5 reduction through air cleaners, the intervention showed improvement in respiratory symptoms for the active (vs. placebo), and the size of treatment effect shown for this subgroup was larger than that for the overall sample. In this subgroup, those with active air cleaners (vs. placebo) showed 7.7 points better SGRQ (95%CI: -14.3, -1.1), better CAT (ß = -5.5; 95%CI: -9.8, -1.2), mMRC (ß = -0.6; 95%CI: -1.1, -0.1), and BCSS (ß = -1.8; 95%CI: -3.0, -0.5). Among those showing at least 40 % NO2 reduction through air cleaners, there was no intervention difference in outcomes. CONCLUSION: Air cleaners caused clinically significant improvement in respiratory health for individuals with COPD through reduction in indoor PM2.5. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02236858.