Implications of Mean Pulmonary Arterial Wedge Pressure Trajectories in Pulmonary Arterial Hypertension.

Rationale: The mean pulmonary arterial wedge pressure (mPAWP) is the critical hemodynamic factor differentiating group 1 pulmonary arterial hypertension (PAH) from group 2 pulmonary hypertension associated with left heart disease. Despite the discrepancy between the mPAWP upper physiologic normal and current PAH definitions, the implications of the initial mPAWP for PAH clinical trajectory are poorly understood. Objectives: To model longitudinal mPAWP trajectories in PAH over 10 years and examine the clinical and hemodynamic factors associated with trajectory membership. Methods: Adult patients with PAH with two or more right heart catheterizations were identified from a multiinstitution healthcare system in eastern Massachusetts. mPAWP trajectories were constructed via group-based trajectory modeling. Feature selection was performed in least absolute shrinkage and selection operator regression. Logistic regression was used to assess associations between trajectory membership, baseline characteristics, and transplant-free survival. Measurements and Main Results: Among 301 patients with PAH, there were two distinct mPAWP trajectories, termed "mPAWP-high" (n = 71; 23.6%) and "mPAWP-low" (n = 230; 76.4%), based on the ultimate mPAWP value. Initial mPAWP clustered around median 12 mm Hg (interquartile range [IQR], 8-14 mm Hg) in the mPAWP-high and 9 mm Hg (IQR, 6-11 mm Hg) in the mPAWP-low trajectories (P < 0.001). After feature selection, initial mPAWP ⩾12 mm Hg predicted an mPAWP-high trajectory (odds ratio, 3.2; 95% confidence interval, 1.4-6.1; P = 0.0006). An mPAWP-high trajectory was associated with shorter transplant-free survival (vs. mPAWP-low, median, 7.8 vs. 11.3 yr; log-rank P = 0.017; age-adjusted P = 0.217). Conclusions: Over 10 years, the mPAWP followed two distinct trajectories, with 25% evolving into group 2 pulmonary hypertension physiology. Using routine baseline data, longitudinal mPAWP trajectory could be predicted accurately, with initial mPAWP ⩾12 mm Hg as one of the strongest predictors.

Genetically Predicted Body Mass Index and Mortality in COPD.

RATIONALE: BMI is associated with COPD mortality, but the underlying mechanisms are unclear. The effect of genetic variants aggregated into a polygenic score may elucidate causal mechanisms and predict risk. OBJECTIVES: To examine the associations of genetically predicted BMI with all-cause and cause-specific mortality in COPD. METHODS: We developed a polygenic score for BMI (PGSBMI) and tested for associations of the PGSBMI with all-cause, respiratory, and cardiovascular mortality in participants with COPD from the COPDGene, ECLIPSE, and Framingham Heart studies. We calculated the difference between measured BMI and PGS-predicted BMI (BMIdiff) and categorized participants into groups of discordantly low (BMIdiff < 20th percentile), concordant (BMIdiff between 20th - 80th percentile), and discordantly high (BMIdiff > 80th percentile) BMI. We applied Cox models, examined potential non-linear associations of the PGSBMI and BMIdiff with mortality, and summarized results with meta-analysis. MEASUREMENTS AND MAIN RESULTS: We observed significant non-linear associations of measured BMI and BMIdiff, but not PGSBMI, with all-cause mortality. In meta-analyses, a one standard deviation increase in the PGSBMI was associated with an increased hazard for cardiovascular mortality (HR=1.29, 95% CI=1.12-1.49), but not with respiratory or all-cause mortality. Compared to participants with concordant measured and genetically predicted BMI, those with discordantly low BMI had higher mortality risk for all-cause (HR=1.57, CI=1.41-1.74) and respiratory death (HR=2.01, CI=1.61-2.51). CONCLUSIONS: In people with COPD, higher genetically predicted BMI is associated with higher cardiovascular mortality but not respiratory mortality. Individuals with discordantly low BMI have higher all-cause and respiratory mortality compared to those with concordant BMI.

From pre-COPD to COPD: a Simple, Low cost and easy to IMplement (SLIM) risk calculator.

BACKGROUND: The lifetime risk of developing clinical COPD among smokers ranges from 13% to 22%. Identifying at-risk individuals who will develop overt disease in a reasonable timeframe may allow for early intervention. We hypothesised that readily available clinical and physiological variables could help identify ever-smokers at higher risk of developing chronic airflow limitation (CAL). METHODS: Among 2273 Lovelace Smokers' Cohort (LSC) participants, we included 677 (mean age 54 years) with normal spirometry at baseline and a minimum of three spirometries, each 1 year apart. Repeated spirometric measurements were used to determine incident CAL. Using logistic regression, demographics, anthropometrics, smoking history, modified Medical Research Council dyspnoea scale, St George's Respiratory Questionnaire, comorbidities and spirometry, we related variables obtained at baseline to incident CAL as defined by the Global Initiative for Chronic Obstructive Lung Disease and lower limit of normal criteria. The predictive model derived from the LSC was validated in subjects from the COPDGene study. RESULTS: Over 6.3 years, the incidence of CAL was 26 cases per 1000 person-years. The strongest independent predictors were forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.75, having smoked ≥30 pack-years, body mass index (BMI) ≤25 kg·m2 and symptoms of chronic bronchitis. Having all four predictors increased the risk of developing CAL over 6 years to 85% (area under the receiver operating characteristic curve (AUC ROC) 0.84, 95% CI 0.81-0.89). The prediction model showed similar results when applied to subjects in the COPDGene study with a follow-up period of 10 years (AUC ROC 0.77, 95% CI 0.72-0.81). CONCLUSION: In middle-aged ever-smokers, a simple predictive model with FEV1/FVC, smoking history, BMI and chronic bronchitis helps identify subjects at high risk of developing CAL.

Comorbidities and mortality risk in adults younger than 50 years of age with chronic obstructive pulmonary disease.

RATIONALE AND OBJECTIVE: Patients with chronic obstructive pulmonary disease (COPD), usually diagnosed after the 6th decade, frequently suffer from comorbidities. Whether COPD patients 50 years or younger (Young COPD) have similar comorbidities with the same frequency and mortality impact as aged-matched controls or older COPD patients is unknown. METHODS: We compared comorbidity number, prevalence and type in 3 groups of individuals with ≥ 10 pack-years of smoking: A Young (≤ 50 years) COPD group (n = 160), an age-balanced control group without airflow obstruction (n = 125), and Old (> 50 years) COPD group (n = 1860). We also compared survival between the young COPD and control subjects. Using Cox proportional model, we determined the comorbidities associated with mortality risk and generated Comorbidomes for the "Young" and "Old" COPD groups. RESULTS: The severity distribution by GOLD spirometric stages and BODE quartiles were similar between Young and Old COPD groups. After adjusting for age, sex, and pack-years, the prevalence of subjects with at least one comorbidity was 31% for controls, 77% for the Young, and 86% for older COPD patients. Compared to controls, "Young" COPDs' had a nine-fold increased mortality risk (p < 0.0001). "Comorbidomes" differed between Young and Old COPD groups, with tuberculosis, substance use, and bipolar disorders being distinct comorbidities associated with increased mortality risk in the Young COPD group. CONCLUSIONS: Young COPD patients carry a higher comorbidity prevalence and mortality risk compared to non-obstructed control subjects. Young COPD differed from older COPD patients by the behavioral-related comorbidities that increase their risk of premature death.

Chest CT-assessed comorbidities and all-cause mortality risk in COPD patients in the BODE cohort.

BACKGROUND AND OBJECTIVE: The availability of chest computed tomography (CT) imaging can help diagnose comorbidities associated with chronic obstructive pulmonary disease (COPD). Their systematic identification and relationship with all-cause mortality have not been explored. Furthermore, whether their CT-detected prevalence differs from clinical diagnosis is unknown. METHODS: The prevalence of 10 CT-assessed comorbidities was retrospectively determined at baseline in 379 patients (71% men) with mild to severe COPD attending pulmonary clinics. Anthropometrics, smoking history, dyspnoea, lung function, exercise capacity, BODE (BMI, Obstruction, Dyspnoea and Exercise capacity) index and exacerbations rate were recorded. The prevalence of CT-determined comorbidities was compared with that recorded clinically. Over a median of 78 months of observation, the independent association with all-cause mortality was analysed. A 'CT-comorbidome' graphically expressed the strength of their association with mortality risk. RESULTS: Coronary artery calcification, emphysema and bronchiectasis were the most prevalent comorbidities (79.8%, 62.7% and 33.9%, respectively). All were underdiagnosed before CT. Coronary artery calcium (hazard ratio [HR] 2.09; 95% CI 1.03-4.26, p = 0.042), bronchiectasis (HR 2.12; 95% CI 1.05-4.26, p = 0.036) and low psoas muscle density (HR 2.61; 95% CI 1.23-5.57, p = 0.010) were independently associated with all-cause mortality and helped define the 'CT-comorbidome'. CONCLUSION: This study of COPD patients shows that systematic detection of 10 CT-diagnosed comorbidities, most of which were not detected clinically, provides information of potential use to patients and clinicians caring for them.

Metabolic and cardiorespiratory effects of decreasing lung hyperinflation with budesonide/formoterol in COPD: a randomized, double-crossover, placebo-controlled, multicenter trial.

BACKGROUND: Studies suggest that acute decreases in lung hyperinflation at rest improves cardiac function and increases lung vascular perfusion from decompression of a compromised heart. In those studies, changes in resting oxygen uptake induced by medications, an alternative explanation for compensatory increased cardiac function, were not explored. METHODS: This double-blind, multicenter, double-crossover study enrolled adults with chronic obstructive pulmonary disease, resting hyperinflation, and > 10% improvement in inspiratory capacity after 2 inhalations of budesonide/formoterol 160/4.5 µg. Metabolic, cardiac, and ventilatory function were measured 60 min pre-/post-dose at each visit. Primary endpoint was change in resting oxygen uptake for budesonide/formoterol versus placebo. RESULTS: Fifty-one patients (median age: 63 years) received treatment. Compared with placebo, budesonide/formoterol significantly increased resting oxygen uptake (mean change from baseline: 1.25 vs 11.37 mL/min; P = 0.007) as well as tidal volume and minute ventilation. This occurred despite improvements in the inspiratory capacity, forced vital capacity, and expiratory volume in 1 s. No significant treatment differences were seen for oxygen saturation, respiratory rate, and resting dyspnea. There was a numerical increase in oxygen pulse (oxygen uptake/heart rate). Correlations between inspiratory capacity and oxygen pulse were weak. CONCLUSIONS: Budesonide/formoterol treatment in resting hyperinflated patients with COPD results in significant deflation. The increase in oxygen uptake and minute ventilation at lower lung volumes, without changes in heart rate and with minimal improvement in oxygen pulse, suggests increased oxygen demand as a contributor to increased cardiac function. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02533505.

ADAM15 expression is increased in lung CD8+ T cells, macrophages, and bronchial epithelial cells in patients with COPD and is inversely related to airflow obstruction.

BACKGROUND: A disintegrin and metalloproteinase domain-15 (ADAM15) is expressed by activated leukocytes, and fibroblasts in vitro. Whether ADAM15 expression is increased in the lungs of COPD patients is not known. METHODS: ADAM15 gene expression and/or protein levels were measured in whole lung and bronchoalveolar lavage (BAL) macrophage samples obtained from COPD patients, smokers, and non-smokers. Soluble ADAM15 protein levels were measured in BAL fluid (BALF) and plasma samples from COPD patients and controls. Cells expressing ADAM15 in the lungs were identified using immunostaining. Staining for ADAM15 in different cells in the lungs was related to forced expiratory volume in 1 s (FEV1), ratio of FEV1 to forced vital capacity (FEV1/FVC), and pack-years of smoking history. RESULTS: ADAM15 gene expression and/or protein levels were increased in alveolar macrophages and whole lung samples from COPD patients versus smokers and non-smokers. Soluble ADAM15 protein levels were similar in BALF and plasma samples from COPD patients and controls. ADAM15 immunostaining was increased in macrophages, CD8+ T cells, epithelial cells, and airway α-smooth muscle (α-SMA)-positive cells in the lungs of COPD patients. ADAM15 immunostaining in macrophages, CD8+ T cells and bronchial (but not alveolar) epithelial cells was related inversely to FEV1 and FEV1/FVC, but not to pack-years of smoking history. ADAM15 staining levels in airway α-SMA-positive cells was directly related to FEV1/FVC. Over-expressing ADAM15 in THP-1 cells reduced their release of matrix metalloproteinases and CCL2. CONCLUSIONS: These results link increased ADAM15 expression especially in lung leukocytes and bronchial epithelial cells to the pathogenesis of COPD.

RNA-sequencing across three matched tissues reveals shared and tissue-specific gene expression and pathway signatures of COPD.

BACKGROUND: Multiple gene expression studies have been performed separately in peripheral blood, lung, and airway tissues to study COPD. We performed RNA-sequencing gene expression profiling of large-airway epithelium, alveolar macrophage and peripheral blood samples from the same subset of COPD cases and controls from the COPDGene study who underwent bronchoscopy at a single center. Using statistical and gene set enrichment approaches, we sought to improve the understanding of COPD by studying gene sets and pathways across these tissues, beyond the individual genomic determinants. METHODS: We performed differential expression analysis using RNA-seq data obtained from 63 samples from 21 COPD cases and controls (includes four non-smokers) via the R package DESeq2. We tested associations between gene expression and variables related to lung function, smoking history, and CT scan measures of emphysema and airway disease. We examined the correlation of differential gene expression across the tissues and phenotypes, hypothesizing that this would reveal preserved and private gene expression signatures. We performed gene set enrichment analyses using curated databases and findings from prior COPD studies to provide biological and disease relevance. RESULTS: The known smoking-related genes CYP1B1 and AHRR were among the top differential expression results for smoking status in the large-airway epithelium data. We observed a significant overlap of genes primarily across large-airway and macrophage results for smoking and airway disease phenotypes. We did not observe specific genes differentially expressed in all three tissues for any of the phenotypes. However, we did observe hemostasis and immune signaling pathways in the overlaps across all three tissues for emphysema, and amyloid and telomere-related pathways for smoking. In peripheral blood, the emphysema results were enriched for B cell related genes previously identified in lung tissue studies. CONCLUSIONS: Our integrative analyses across COPD-relevant tissues and prior studies revealed shared and tissue-specific disease biology. These replicated and novel findings in the airway and peripheral blood have highlighted candidate genes and pathways for COPD pathogenesis.

Plasma metabolomics and clinical predictors of survival differences in COPD patients.

BACKGROUND: Plasma metabolomics profile (PMP) in COPD has been associated with clinical characteristics, but PMP's relationship to survival has not been reported. We determined PMP differences between patients with COPD who died an average of 2 years after enrollment (Non-survivors, NS) compared to those who survived (S) and also with age matched controls (C). METHODS: We studied prospectively 90 patients with severe COPD and 30 controls. NS were divided in discovery and validation cohorts (30 patients each) and the results compared to the PMP of 30 S and C. All participants completed lung function tests, dyspnea scores, quality of life, exercise capacity, BODE index, and plasma metabolomics by liquid and gas chromatography / mass spectometry (LC/MS, LC/MS2, GC/MS). Statistically, we used Random Forest Analysis (RFA) and Support Vector Machine (SVM) to determine metabolites that differentiated the 3 groups and compared the ability of metabolites vs. clinical characteristics to classify patients into survivors and non-survivors. RESULTS: There were 79 metabolites statistically different between S and NS [p < 0.05 and false discovery rate (q value) < 0.1]. RFA and SVM classification of COPD survivors and non-survivors had a predicted accuracy of 74 and 85% respectively. Elevation of tricyclic acid cycle intermediates branched amino acids depletion and increase in lactate, fructose and xylonate showed the most relevant differences between S vs. NS suggesting alteration in mitochondrial oxidative energy generation. PMP had similar predictive power for risk of death as information provided by clinical characteristics. CONCLUSIONS: A plasma metabolomic profile characterized by an oxidative energy production difference between survivors and non-survivors was observed in COPD patients 2 years before death.

Comparison of the 2017 and 2015 Global Initiative for Chronic Obstructive Lung Disease Reports. Impact on Grouping and Outcomes.

RATIONALE: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) document has modified the grading system directing pharmacotherapy, but how this relates to the previous one from 2015 and to comorbidities, hospitalizations, and mortality risk is unknown. OBJECTIVES: The aim of this study was to evaluate the changes in the GOLD groups from 2015 to 2017 and to assess the impact on severity, comorbidities, and mortality within each group. METHODS: We prospectively enrolled and followed, for a mean of 5 years, 819 patients with chronic obstructive pulmonary disease (84% male) in clinics in Spain and the United States. We determined anthropometrics, lung function (FEV1%), dyspnea score (modified Medical Research Council scale), ambulatory and hospital exacerbations, and the body mass index, obstruction, dyspnea, and exercise capacity (BODE) and Charlson indexes. We classified patients by the 2015 and 2017 GOLD ABCD system, and compared the differential realignment of the same patients. We related the effect of the reclassification in BODE and Charlson distribution as well as chronic obstructive pulmonary disease and all-cause mortality between the two classifications. MEASUREMENTS AND MAIN RESULTS: Compared with 2015, the 2017 grading decreased by half the proportion of patients in groups C and D (20.5% vs. 11.2% and 24.6% vs. 12.9%; P < 0.001). The distribution of Charlson also changed, whereas group D was higher than B in 2015, they become similar in the 2017 system. In 2017, the BODE index and risk of death were higher in B and D than in A and C. The mortality risk was better predicted by the 2015 than the 2017 system. CONCLUSIONS: Compared with 2015, the GOLD ABCD 2017 classification significantly shifts patients from grades C and D to categories A and B. The new grading system equalizes the Charlson comorbidity score in all groups and minimizes the differences in BODE between groups B and D, making the risk of death similar between them.

Lung-Function Trajectories Leading to Chronic Obstructive Pulmonary Disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is thought to result from an accelerated decline in forced expiratory volume in 1 second (FEV1) over time. Yet it is possible that a normal decline in FEV1 could also lead to COPD in persons whose maximally attained FEV1 is less than population norms. METHODS: We stratified participants in three independent cohorts (the Framingham Offspring Cohort, the Copenhagen City Heart Study, and the Lovelace Smokers Cohort) according to lung function (FEV1 ≥80% or <80% of the predicted value) at cohort inception (mean age of patients, approximately 40 years) and the presence or absence of COPD at the last study visit. We then determined the rate of decline in FEV1 over time among the participants according to their FEV1 at cohort inception and COPD status at study end. RESULTS: Among 657 persons who had an FEV1 of less than 80% of the predicted value before 40 years of age, 174 (26%) had COPD after 22 years of observation, whereas among 2207 persons who had a baseline FEV1 of at least 80% of the predicted value before 40 years of age, 158 (7%) had COPD after 22 years of observation (P<0.001). Approximately half the 332 persons with COPD at the end of the observation period had had a normal FEV1 before 40 years of age and had a rapid decline in FEV1 thereafter, with a mean (±SD) decline of 53±21 ml per year. The remaining half had had a low FEV1 in early adulthood and a subsequent mean decline in FEV1 of 27±18 ml per year (P<0.001), despite similar smoking exposure. CONCLUSIONS: Our study suggests that low FEV1 in early adulthood is important in the genesis of COPD and that accelerated decline in FEV1 is not an obligate feature of COPD. (Funded by an unrestricted grant from GlaxoSmithKline and others.).

Emphysema and extrapulmonary tissue loss in COPD: a multi-organ loss of tissue phenotype.

We tested whether emphysema progression accompanies enhanced tissue loss in other body compartments in 1817 patients from the ECLIPSE chronic obstructive pulmonary disease (COPD) cohort.Clinical and selected systemic biomarker measurements were compared in subjects grouped by quantitative tomography scan emphysema quartiles using the percentage of low attenuation area (LAA%). Lowest and highest quartile patients had amino-acid metabolomic profiles. We related LAA% to 3 years decline in lung function (forced expiratory volume in 1 s (FEV1)), body mass index (BMI), fat-free mass index (FFMI) and exacerbations, hospitalisations and mortality rates.Participants with more baseline emphysema had lower FEV1, BMI and FFMI, worse functional capacity, and less cardiovascular disease but more osteoporosis. Systemic C-reactive protein and interleukin-6 levels were similar among groups, but club cell protein 16 was higher and interleukin-8, surfactant protein D and soluble receptor for advanced glycation end product were lower with more emphysema. Metabolomics differed between extreme emphysema quartiles. Patients with more emphysema had accelerated FEV1, BMI and FFMI decline and more exacerbations, hospitalisations and mortality.COPD patients with more emphysema undergo excessive loss of pulmonary and extrapulmonary tissue, which is probably related to abnormal tissue maintenance. Because of worse clinical outcomes, we propose this subgroup be named the multi-organ loss of tissue (MOLT) COPD phenotype.

A Pilot Study Linking Endothelial Injury in Lungs and Kidneys in Chronic Obstructive Pulmonary Disease.

RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) frequently have albuminuria (indicative of renal endothelial cell injury) associated with hypoxemia. OBJECTIVES: To determine whether (1) cigarette smoke (CS)-induced pulmonary and renal endothelial cell injury explains the association between albuminuria and COPD, (2) CS-induced albuminuria is linked to increases in the oxidative stress-advanced glycation end products (AGEs) receptor for AGEs (RAGE) pathway, and (3) enalapril (which has antioxidant properties) limits the progression of pulmonary and renal injury by reducing activation of the AGEs-RAGE pathway in endothelial cells in both organs. METHODS: In 26 patients with COPD, 24 ever-smokers without COPD, 32 nonsmokers who underwent a renal biopsy or nephrectomy, and in CS-exposed mice, we assessed pathologic and ultrastructural renal lesions, and measured urinary albumin/creatinine ratios, tissue oxidative stress levels, and AGEs and RAGE levels in pulmonary and renal endothelial cells. The efficacy of enalapril on pulmonary and renal lesions was assessed in CS-exposed mice. MEASUREMENTS AND MAIN RESULTS: Patients with COPD and/or CS-exposed mice had chronic renal injury, increased urinary albumin/creatinine ratios, and increased tissue oxidative stress and AGEs-RAGE levels in pulmonary and renal endothelial cells. Treating mice with enalapril attenuated CS-induced increases in urinary albumin/creatinine ratios, tissue oxidative stress levels, endothelial cell AGEs and RAGE levels, pulmonary and renal cell apoptosis, and the progression of chronic renal and pulmonary lesions. CONCLUSIONS: Patients with COPD and/or CS-exposed mice have pulmonary and renal endothelial cell injury linked to increased endothelial cell AGEs and RAGE levels. Albuminuria could identify patients with COPD in whom angiotensin-converting enzyme inhibitor therapy improves renal and lung function by reducing endothelial injury.

Prevalence of persistent blood eosinophilia: relation to outcomes in patients with COPD.

The impact of blood eosinophilia in chronic obstructive pulmonary disease (COPD) remains controversial.To evaluate the prevalence and stability of a high level of blood eosinophils (≥300 cells·µL-1) and its relationship to outcomes, we determined blood eosinophils at baseline and over 2 years in 424 COPD patients (forced expiratory volume in 1 s (FEV1) 60% predicted) and 67 smokers without COPD from the CHAIN cohort, and in 308 COPD patients (FEV1 60% predicted) in the BODE cohort. We related eosinophil levels to exacerbations and survival using Cox hazard analysis.In COPD patients, 15.8% in the CHAIN cohort and 12.3% in the BODE cohort had persistently elevated blood eosinophils at all three visits. A significant proportion (43.8%) of patients had counts that oscillated above and below the cut-off points, while the rest had persistent eosinophil levels <300 cells·µL-1 A similar eosinophil blood pattern was observed in controls. Exacerbation rates did not differ in patients with and without eosinophilia. All-cause mortality was lower in patients with high eosinophils compared with those with values <300 cells·µL-1 (15.8% versus 33.7%; p=0.026).In patients with COPD, blood eosinophils ≥300 cells·µL-1 persisting over 2 years was not a risk factor for COPD exacerbations. High eosinophil count was associated with better survival.

Prospective comparison of non-invasive risk markers of major cardiovascular events in COPD patients.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is an independent risk factor for cardiovascular (CV) disease, one of the most frequent causes of death in COPD patients. The goal of the present study was to evaluate the prognostic value of non-invasive CV risk markers in COPD patients. METHODS: CV risk was prospectively evaluated in 287 COPD patients using non-invasive markers including the Framingham score, the Systematic Coronary Risk Evaluation (SCORE) charts, coronary arterial calcium (CAC), epicardial adipose tissue (EAT), as well as clinical, biochemical and physiological variables. The predictive power of each parameter was explored using CV events as the main outcome. RESULTS: During a median follow up of 65 months (ICR: 36-100), 44 CV events were recorded, 12 acute myocardial infarctions (27.3%), 10 ischemic heart disease/angina (22.7%), 12 peripheral artery disease events requiring surgery (27.3%) and 10 strokes (22.7%). A total of 35 CV deaths occurred during that period. Univariable analysis determined that age, hypertension, CRP, total Cholesterol, LDL-Cholesterol, Framingham score and CAC were independently associated with CV events. Multivariable analysis identified CAC as the best predictor of CV events (HR; 95%CI: 1.32; 1.19-1.46, p < 001). CONCLUSIONS: In COPD patients attending pulmonary clinics, CAC was the best independent non-invasive predictor of CV events. This tool may help evaluate the risk for a CV event in patients with COPD. Larger studies should reproduce and validate these findings.

Quantitative computed tomography assessment of bronchiolitis obliterans syndrome after lung transplantation.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is a clinical manifestation of chronic allograft rejection following lung transplantation. We examined the quantitative measurements of the proximal airway and vessels and pathologic correlations in subjects with BOS. METHODS: Patients who received a lung transplant at the Brigham and Women's Hospital between December 1, 2002 and December 31, 2010 were included in this study. We characterized the quantitative CT measures of proximal airways and vessels and pathological changes. RESULTS: Ninety-four (46.1%) of the 204 subjects were included in the study. There was a significant increase in the airway vessel ratio in subjects who developed progressive BOS compared to controls and non-progressors. There was a significant increase in airway lumen area and decrease in vessel cross-sectional area in patients with BOS compared to controls. Patients with BOS had a significant increase in proximal airway fibrosis compared to controls. CONCLUSIONS: BOS is characterized by central airway dilation and vascular remodeling, the degree of which is correlated to decrements in lung function. Our data suggest that progressive BOS is a pathologic process that affects both the central and distal airways.

A novel nonhuman primate model of cigarette smoke-induced airway disease.

Small animal models of chronic obstructive pulmonary disease (COPD) have several limitations for identifying new therapeutic targets and biomarkers for human COPD. These include a pulmonary anatomy that differs from humans, the limited airway pathologies and lymphoid aggregates that develop in smoke-exposed mice, and the challenges associated with serial biological sampling. Thus, we assessed the utility of cigarette smoke (CS)-exposed cynomolgus macaque as a nonhuman primate (NHP) large animal model of COPD. Twenty-eight NHPs were exposed to air or CS 5 days per week for up to 12 weeks. Bronchoalveolar lavage and pulmonary function tests were performed at intervals. After 12 weeks, we measured airway pathologies, pulmonary inflammation, and airspace enlargement. CS-exposed NHPs developed robust mucus metaplasia, submucosal gland hypertrophy and hyperplasia, airway inflammation, peribronchial fibrosis, and increases in bronchial lymphoid aggregates. Although CS-exposed NHPs did not develop emphysema over the study time, they exhibited pathologies that precede emphysema development, including increases in the following: i) matrix metalloproteinase-9 and proinflammatory mediator levels in bronchoalveolar lavage fluid, ii) lung parenchymal leukocyte counts and lymphoid aggregates, iii) lung oxidative stress levels, and iv) alveolar septal cell apoptosis. CS-exposed NHPs can be used as a model of airway disease occurring in COPD patients. Unlike rodents, NHPs can safely undergo longitudinal sampling, which could be useful for assessing novel biomarkers or therapeutics for COPD.

Predictors and outcomes of unplanned early rehospitalization in the first year following lung transplantation.

Unplanned early rehospitalization (UER), defined as an unscheduled admission within 30 days of a hospital discharge, is associated with graft loss and recipient mortality in some solid organ transplants but has not been investigated in lung transplant. In this retrospective study, we collected socio-demographic and clinical factors to determine predictors and outcomes of UER in the first year following lung transplantation. There were 193 patients who underwent lung transplantation and survived to discharge during the 7.9-year study period. There were 116 (60.1%) patients with at least one UER. Infections (32.8%) and post-surgical complications (11.8%) were the most common reasons for UER. On multivariate analysis, the strongest predictor of having an UER was discharge to a long-term acute care facility (odds ratio: 3.01, 95% confidence interval [CI] 1.46-6.20; P=.003). Patients with any UER in the first year following transplantation had worse adjusted survival (hazard ratio: 1.89, 95% CI 1.02-3.50; P=.04). It is unclear, however, to what extent UERs reflect preventable outcomes. Further large-scale, prospective research is needed to identify the extent to which certain types of UER are modifiable and to define patients at high-risk for preventable UER.

B Cell-Activating Factor. An Orchestrator of Lymphoid Follicles in Severe Chronic Obstructive Pulmonary Disease.

RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) have increased pulmonary lymphoid follicle (LF) counts. B cell-activating factor of tumor necrosis factor family (BAFF) regulates B cells in health, but its role in COPD pathogenesis is unclear. OBJECTIVES: To determine whether BAFF expression in pulmonary LFs correlates with COPD severity, LF size or number, and/or readouts of B-cell function in LFs. METHODS: We correlated BAFF immunostaining in LFs in lung explants or biopsies from nonsmoking control subjects (NSC), smokers without COPD (SC), and patients with COPD with the number and size of LFs, and LF B-cell apoptosis, activation, and proliferation. We analyzed serum BAFF levels and BAFF expression in B cells in blood and bronchoalveolar lavage samples from the same subject groups. We assessed whether: (1) cigarette smoke extract (CSE) increases B-cell BAFF expression and (2) recombinant BAFF (rBAFF) rescues B cells from CSE-induced apoptosis by inhibiting activation of nuclear factor-κB (NF-κB). MEASUREMENTS AND MAIN RESULTS: Patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage IV COPD had increased numbers and larger pulmonary LFs than patients with GOLD stages I-II COPD and SC. We identified two main types of pulmonary LFs: (1) type A, the predominant type in GOLD stages I-II COPD and SC, characterized by abundant apoptotic but few BAFF-positive cells (mostly B cells); and (2) type B, the main type in GOLD stage IV COPD, characterized by abundant BAFF-positive cells but few apoptotic cells (mostly B cells). BAFF levels were also higher in blood and bronchoalveolar lavage B cells in patients with COPD versus NSC and SC. Surprisingly, rBAFF blocked CSE-induced B-cell apoptosis by inhibiting CSE-induced NF-κB activation. CONCLUSIONS: Our data support the hypothesis that B-cell BAFF expression creates a self-perpetuating loop contributing to COPD progression by promoting pulmonary B-cell survival and LF expansion.