Twenty four-month follow-up after bullectomy, unilateral and bilateral lung volume reduction surgery: a single-center retrospective analysis of consecutive cases.

PURPOSE: While pharmacologic therapy remains the cornerstone of lung emphysema treatment, surgery is an additional therapeutic option in selected patient groups with advanced emphysema. The aim of lung volume reduction surgery (LVRS) is to improve lung function, exercise capacity, quality of life and survival. We sought to determine the therapeutic value of surgical resection in specific patients with lung emphysema. PATIENTS AND METHODS: A retrospective study was performed consisting of 58 patients with lung emphysema who underwent surgical intervention over a 10-year period and were followed for 2 years postoperatively. The clinical characteristics recorded were FEV1 (forced expiratory volume in 1 s), the 6-min walk test (6-MWT), the Modified Medical Research Council (mMRC), body mass index (BMI) and quality of life prior to and 6, 12 and 24 months after surgical intervention. Moreover, all peri- and post-operative complications were noted. RESULTS: Out of 58 emphysema patients (72% male, FEV1 (L) 2.21 ± 0.17, RV (L) 3.39 ± 0.55), 19 underwent surgical bullectomy, 31 unilateral LVRS and 8 sequential bilateral LVRS. Six months after surgery, there was a statistically significant improvement in FEV1, RV, TLC, 6-MWT and mMRC. Over a period of 12 to 24 months postoperatively, clinical benefit gradually declines most likely due to COPD progression but patients still experienced a significant improvement in FEV1. The most common postoperative complications were persistent air leakage (> 7 days), arrhythmia and subcutaneous emphysema in 60%, 51.6% and 22.4%, respectively. No deaths were observed after surgical intervention. CONCLUSION: In a selected patient population, surgery led to significant improvement of lung function parameters, exercise capacity and quality of life. Over a period of 12 to 24 months postoperatively, clinical benefit gradually decreased most likely due to COPD progression.

Bronchoscopic Lung Volume Reduction as the Treatment of Choice versus Robotic-Assisted Lung Volume Reduction Surgery in Similar Patients with Emphysema - An Initial Experience of the Benefits and Complications.

Objective: There is an assumption that because EBLVR requires less use of hospital resources, offsetting the higher cost of endobronchial valves, it should therefore be the treatment of choice wherever possible. We have tested this hypothesis in a retrospective analysis of the two in similar groups of patients. Methods: In a 4-year experience, we performed 177 consecutive LVR procedures: 83 patients underwent Robot Assisted Thoracoscopic (RATS) LVRS and 94 EBLVR. EBLVR was intentionally precluded by evidence of incomplete fissure integrity or intra-operative assessment of collateral ventilation. Unilateral RATS LVRS was performed in these cases together with those with unsuitable targets for EBLVR. Results: EBLVR was uncomplicated in 37 (39%) cases; complicated by post-procedure spontaneous pneumothorax (SP) in 28(30%) and required revision in 29 (31%). In the LVRS group, 7 (8%) patients were readmitted with treatment-related complications, but no revisional procedure was needed. When compared with uncomplicated EBLVR, LVRS had a significantly longer operating time: 85 (14-82) vs 40 (15-151) minutes (p<0.001) and hospital stay: 7.5 (2-80) vs 2 (1-14) days (p<0.01). However, LVRS had a similar total operating time to both EBLVR requiring revision: 78 (38-292) minutes and hospital stay to EBLVR complicated by pneumothorax of 11.5 (6.5-24.25) days. Use of critical care was significantly longer in RATS group, and it was also significantly longer in EBV with SP group than in uncomplicated EBV group. Conclusion: Endobronchial LVR does use less hospital resources than RATS LVRS in comparable groups if the recovery is uncomplicated. However, this advantage is lost if one includes the resources needed for the treatment of complications and revisional procedures. Any decision to favour EBLVR over LVRS should not be based on the assumption of a smoother, faster perioperative course.

Artificial Intelligence-Based Emphysema Quantification in Routine Chest Computed Tomography: Correlation With Spirometry and Visual Emphysema Grading.

OBJECTIVE: The aim of the study is to assess the correlation between artificial intelligence (AI)-based low attenuation volume percentage (LAV%) with forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) and visual emphysema grades in routine chest computed tomography (CT). Furthermore, optimal LAV% cutoff values for predicting a FEV1/FVC < 70% or moderate to more extensive visual emphysema grades were calculated. METHODS: In a retrospective study of 298 consecutive patients who underwent routine chest CT and spirometry examinations, LAV% was quantified using an AI-based software with a threshold < -950 HU. The FEV1/FVC was derived from spirometry, with FEV1/FVC < 70% indicating airway obstruction. The mean time interval of CT from spirometry was 3.87 ± 4.78 days. Severity of emphysema was visually graded by an experienced chest radiologist using an established 5-grade ordinal scale (Fleischner Society classification system). Spearman correlation coefficient between LAV% and FEV1/FVC was calculated. Receiver operating characteristic determined the optimal LAV% cutoff values for predicting a FEV1/FVC < 70% or a visual emphysema grade of moderate or higher (Fleischner grade 3-5). RESULTS: Significant correlation between LAV% and FEV1/FVC was found (ϱ = -0.477, P < 0.001). Increasing LAV% corresponded to higher visual emphysema grades. For patients with absent visual emphysema, mean LAV% was 2.98 ± 3.30, for patients with trace emphysema 3.22 ± 2.75, for patients with mild emphysema 3.90 ± 3.33, for patients with moderate emphysema 6.41 ± 3.46, for patients with confluent emphysema 9.02 ± 5.45, and for patients with destructive emphysema 16.90 ± 8.19. Optimal LAV% cutoff value for predicting a FEV1/FVC < 70 was 6.1 (area under the curve = 0.764, sensitivity = 0.773, specificity = 0.665), while for predicting a visual emphysema grade of moderate or higher, it was 4.7 (area under the curve = 0.802, sensitivity = 0.766, specificity = 0.742). Furthermore, correlation between visual emphysema grading and FEV1/FVC was found. In patients with FEV1/FVC < 70% a high proportion of subjects had emphysema grade 3 (moderate) or higher, whereas in patients with FEV1/FVC ≥ 70%, a larger proportion had emphysema grade 3 (moderate) or lower. The sensitivity for visual emphysema grading predicting a FEV1/FVC < 70% was 56.3% with an optimal cutoff point at a visual grade of 4 (confluent), demonstrating a lower sensitivity compared with LAV% (77.3%). CONCLUSIONS: A significant correlation between AI-based LAV% and FEV1/FVC as well as visual CT emphysema grades can be found in routine chest CT suggesting that AI-based LAV% measurement might be integrated as an add-on functional parameter in the evaluation of chest CT in the future.

Quantitative determination of pulmonary emphysema in follow-up LD-CTs of patients with COVID-19 infection.

PURPOSE: To evaluate the association between the coronavirus disease 2019 (COVID-19) and post-inflammatory emphysematous lung alterations on follow-up low-dose CT scans. METHODS: Consecutive patients with proven COVID-19 infection and a follow-up CT were retrospectively reviewed. The severity of pulmonary involvement was classified as mild, moderate and severe. Total lung volume, emphysema volume and the ratio of emphysema/-to-lung volume were quantified semi-automatically and compared inter-individually between initial and follow-up CT and to a control group of healthy, age- and sex-matched patients. Lung density was further assessed by drawing circular regions of interest (ROIs) into non-affected regions of the upper lobes. RESULTS: A total of 32 individuals (mean age: 64 ± 13 years, 12 females) with at least one follow-up CT (mean: 52 ± 66 days, range: 5-259) were included. In the overall cohort, total lung volume, emphysema volume and the ratio of lung-to-emphysema volume did not differ significantly between the initial and follow-up scans. In the subgroup of COVID-19 patients with > 30 days of follow-up, the emphysema volume was significantly larger as compared to the subgroup with a follow-up < 30 days (p = 0.045). Manually measured single ROIs generally yielded lower attenuation values prior to COVID-19 pneumonia, but the difference was not significant between groups (all p > 0.05). CONCLUSION: COVID-19 patients with a follow-up CT >30 days showed significant emphysematous lung alterations. These findings may help to explain the long-term effect of COVID-19 on pulmonary function and warrant validation by further studies.

Plasma sRAGE levels strongly associate with centrilobular emphysema assessed by HRCT scans.

BACKGROUND: There is a strong need for biomarkers to better characterize individuals with COPD and to take into account the heterogeneity of COPD. The blood protein sRAGE has been put forward as promising biomarker for COPD in general and emphysema in particular. Here, we measured plasma sRAGE levels using quantitative LC-MS and assessed whether the plasma sRAGE levels associate with (changes in) lung function, radiological emphysema parameters, and radiological subtypes of emphysema. METHODS: Three hundred and twenty-four COPD patients (mean FEV1: 63%predicted) and 185 healthy controls from the COPDGene study were selected. Plasma sRAGE was measured by immunoprecipitation in 96-well plate methodology to enrich sRAGE, followed by targeted quantitative liquid chromatography-mass spectrometry. Spirometry and HRCT scans (inspiration and expiration) with a 5-year follow-up were used; both subjected to high quality control standards. RESULTS: Lower sRAGE values significantly associated with the presence of COPD, the severity of airflow obstruction, the severity of emphysema on HRCT, the heterogeneous distribution of emphysema, centrilobular emphysema, and 5-year progression of emphysema. However, sRAGE values did not associate with airway wall thickness or paraseptal emphysema. CONCLUSIONS: Rather than being a general COPD biomarker, sRAGE is especially a promising biomarker for centrilobular emphysema. Follow-up studies should elucidate whether sRAGE can be used as a biomarker for other COPD phenotypes as well.

Reduced decline of lung diffusing capacity in COPD patients with diabetes and metformin treatment.

We studied whether in patients with COPD the use of metformin for diabetes treatment was linked to a pattern of lung function decline consistent with the hypothesis of anti-aging effects of metformin. Patients of GOLD grades 1-4 of the COSYCONET cohort with follow-up data of up to 4.5 y were included. The annual decline in lung function (FEV1, FVC) and CO diffusing capacity (KCO, TLCO) in %predicted at baseline was evaluated for associations with age, sex, BMI, pack-years, smoking status, baseline lung function, exacerbation risk, respiratory symptoms, cardiac disease, as well as metformin-containing therapy compared to patients without diabetes and metformin. Among 2741 patients, 1541 (mean age 64.4 y, 601 female) fulfilled the inclusion criteria. In the group with metformin treatment vs. non-diabetes the mean annual decline in KCO and TLCO was significantly lower (0.2 vs 2.3, 0.8 vs. 2.8%predicted, respectively; p < 0.05 each), but not the decline of FEV1 and FVC. These results were confirmed using multiple regression and propensity score analyses. Our findings demonstrate an association between the annual decline of lung diffusing capacity and the intake of metformin in patients with COPD consistent with the hypothesis of anti-aging effects of metformin as reflected in a surrogate marker of emphysema.

Development of a nomogram for predicting the presence of combined pulmonary fibrosis and emphysema.

BACKGROUND: In the clinical management of patients with combined pulmonary fibrosis and emphysema (CPFE), early recognition and appropriate treatment is essential. This study was designed to develop an accurate prognostic nomogram model to predict the presence of CPFE. METHODS: We retrospectively enrolled 85 patients with CPFE and 128 patients with idiopathic pulmonary fibrosis (IPF) between January 2015 and January 2020. Clinical characteristics were compared between groups. A multivariable logistic regression analysis was performed to identify risk factors for CPFE. Then, and a nomogram to predict the presence of CPFE was constructed for clinical use. Concordance index (C-index), area under the receiver operating characteristic curve (AUC), and calibration plot was used to evaluate the efficiency of the nomogram. RESULTS: Compared to the IPF group, the proportion of patients with male, smoking and allergies were significantly higher in the CPFE group. In terms of pulmonary function tests, patients with CPFE had lower FEV1/FVC%, DLCO/VA% pred, and higher RV, RV%pred, VC, VC%pred, TLC%pred, VA, TLC, TLC%pred, FVC, FVC%pred and FEV1 with significant difference than the other group. Positive correlation was found between DLCO and VA%, RV%, TLC% in patients with IPF but not in patients with CPFE. By multivariate analysis, male, smoking, allergies, FEV1/FVC% and DLCO/VA%pred were identified as independent predictors of the presence of CPFE. The nomogram was then developed using these five variables. After 1000 internal validations of bootstrap resampling, the C-index of the nomogram was 0.863 (95% CI 0.795-0.931) and the AUC was 0.839 (95% CI 0.764-0.913). Moreover, the calibration plot showed good concordance of incidence of CPFE between nomogram prediction and actual observation (Hosmer-Lemeshow test: P = 0.307). CONCLUSIONS: Patients of CPFE have a characteristic lung function profile including relatively preserved lung volumes and ventilating function, contrasting with a disproportionate reduction of carbon monoxide transfer. By incorporating clinical risk factors, we created a nomogram to predict the presence of CPFE, which may serve as a potential tool to guide personalized treatment.

Factors associated with mortality in rheumatoid arthritis-associated interstitial lung disease: a systematic review and meta-analysis.

BACKGROUND: Interstitial lung disease (ILD) is a common and potentially life-threatening complication for rheumatoid arthritis (RA) patients. However, there is a lack of clear prognostic factors in rheumatoid arthritis-associated interstitial lung disease (RA-ILD) patients. The purpose of this study was to complete a systematic review and meta-analysis of the factors associated with mortality in RA-ILD patients. METHODS: Medline, EMBASE and the Cochrane Library were searched up to September 1, 2020. The Newcastle-Ottawa Scale (NOS) was applied to assess the methodological quality of the eligible studies. Study characteristics and magnitude of effect sizes were extracted. Then, pooled hazard ratios (HRs) with the corresponding 95% confidence intervals (CIs) and pooled risk ratios (RRs) with 95% CIs were calculated to assess the factors associated with mortality in RA-ILD. RESULTS: Twenty-three of 3463 articles were eligible, and ten factors associated with mortality for RA-ILD were evaluated in the meta-analysis. Older age (HRs = 1.04, 95% CI 1.03-1.05), male sex (HRs = 1.44, 95% CI 1.21-1.73), having a smoking history (HRs = 1.42, 95% CI 1.03-1.96), lower diffusing capacity of the lung for carbon monoxide (DLCO)% predicted (HRs = 0.98, 95% CI 0.97-1.00), forced vital capacity (FVC)% predicted (HRs = 0.99, 95% CI 0.98-1.00), composite physiological index (CPI) (HRs = 1.04, 95% CI 1.02-1.06), usual interstitial pneumonia (UIP) pattern on HRCT (HRs = 1.88, 95% CI 1.14-3.10 and RRs = 1.90, 95% CI 1.50-2.39), emphysema presence (HRs = 2.31, 95% CI 1.58-3.39), and acute exacerbation of ILD (HRs = 2.70, 95% CI 1.67-4.36) were associated with increased mortality in RA-ILD, whereas rheumatoid factor (RF) positive status was not associated. CONCLUSIONS: Through this systematic review and meta-analysis, we found that older age, male sex, smoking history, higher CPI, lower DLCO% predicted, lower FVC% predicted, UIP pattern on HRCT, emphysema presence and acute exacerbation of ILD were associated with an increased risk of mortality in RA-ILD.

Oral Positive Expiratory Pressure Device for Excessive Dynamic Airway Collapse Caused by Emphysema.

Excessive dynamic airway collapse (EDAC) contributes to breathlessness and reduced quality of life in individuals with emphysema. We tested a novel, portable, oral positive expiratory pressure (o-PEP) device in a patient with emphysema and EDAC. MRI revealed expiratory tracheal narrowing to 80 mm2 that increased to 170 mm2 with the o-PEP device. After 2-weeks use of the o-PEP device for 33% to 66% of activities, breathlessness, quality of life, and exertional dyspnea improved compared with minimal clinically important differences (MCID): University of California-San Diego Shortness of Breath questionnaire score declined 69 to 42 (MCID, ≥5), St. George's Respiratory Questionnaire score decreased 71 to 27 (MCID, ≥4), and before and after the 6-minute walk test Borg score difference improved from Δ3 to Δ2 (MCID, ≥1). During the 6-minute walk test on room air without the use of the o-PEP device, oxyhemoglobin saturation declined 91% to 83%; whereas, with the o-PEP device, the nadir was 90%. Use of the o-PEP device reduced expiratory central airway collapse and improved dyspnea, quality of life, and exertional desaturation in a patient with EDAC and emphysema.

CT-defined emphysema in COPD patients and risk for change in desaturation status in 6-min walk test.

BACKGROUND: Emphysema and exercise induced desaturation (EID) are both related to poorer COPD prognosis. More knowledge of associations between emphysema and desaturation is needed for more efficient disease management. RESEARCH QUESTION: Is emphysema a risk factor for both new and repeated desaturation, and is emphysema of more or less importance than other known risk factors? METHODS: 283 COPD patients completed a 6-min walk test (6MWT) at baseline and one year later in the Bergen COPD cohort study 2006-2011. Degree of emphysema was assessed as percent of low attenuation areas (%LAA) under -950 Hounsfield units using high-resolution computed tomography at baseline. We performed multinomial logistic regression analysis, receiver operating curves (ROC) and area under the curve (AUC) estimations. Dominance analysis was used to rank emphysema and risk factors in terms of importance. RESULTS: A one percent increase in %LAA increases the relative risk (RR) of new desaturation by 10 % (RR 1.1 (95%CI 1.1, 1.2)) and for repeated desaturation by 20 % (RR 1.2 (95%CI 1.1, 1.3)). Compared with other important desaturation risk factors, %LAA ranked as number one in the dominance analysis, accounting for 50 % and 37 % of the predicted variance for new and repeated desaturators, respectively. FEV1% predicted accounted for 9 % and 24 %, and resting SpO2 accounted for 22 % and 21 % for new and repeated desaturation. CONCLUSION: Emphysema increases the risk of developing and repeatedly experiencing EID. Emphysema seems to be a more important risk factor for desaturation than FEV1% predicted and resting saturation.

Reversal of emphysema by restoration of pulmonary endothelial cells.

Chronic obstructive pulmonary disease (COPD) is marked by airway inflammation and airspace enlargement (emphysema) leading to airflow obstruction and eventual respiratory failure. Microvasculature dysfunction is associated with COPD/emphysema. However, it is not known if abnormal endothelium drives COPD/emphysema pathology and/or if correcting endothelial dysfunction has therapeutic potential. Here, we show the centrality of endothelial cells to the pathogenesis of COPD/emphysema in human tissue and using an elastase-induced murine model of emphysema. Airspace disease showed significant endothelial cell loss, and transcriptional profiling suggested an apoptotic, angiogenic, and inflammatory state. This alveolar destruction was rescued by intravenous delivery of healthy lung endothelial cells. Leucine-rich α-2-glycoprotein-1 (LRG1) was a driver of emphysema, and deletion of Lrg1 from endothelial cells rescued vascular rarefaction and alveolar regression. Hence, targeting endothelial cell biology through regenerative methods and/or inhibition of the LRG1 pathway may represent strategies of immense potential for the treatment of COPD/emphysema.

Necroptosis Signaling Promotes Inflammation, Airway Remodeling, and Emphysema in Chronic Obstructive Pulmonary Disease.

Rationale: Necroptosis, mediated by RIPK3 (receptor-interacting protein kinase 3) and MLKL (mixed lineage kinase domain-like), is a form of regulated necrosis that can drive tissue inflammation and destruction; however, its contribution to chronic obstructive pulmonary disease (COPD) pathogenesis is poorly understood. Objectives: To determine the role of necroptosis in COPD. Methods: Total and active (phosphorylated) RIPK3 and MLKL were measured in the lung tissue of patients with COPD and control subjects without COPD. Necroptosis-related mRNA and proteins as well as cell death were examined in lungs and pulmonary macrophages of mice with cigarette smoke (CS)-induced experimental COPD. The responses of Ripk3-/- and Mlkl-/- mice to acute and chronic CS exposure were compared with those of wild-type mice. The combined inhibition of apoptosis (with the pan-caspase inhibitor quinoline-Val-Asp-difluorophenoxymethylketone [qVD-OPh]) and necroptosis (with deletion of Mlkl in mice) was assessed. Measurements and Main Results: The total MLKL protein in the epithelium and macrophages and the pRIPK3 and pMLKL in lung tissue were increased in patients with severe COPD compared with never-smokers or smoker control subjects without COPD. Necroptosis-related mRNA and protein levels were increased in the lungs and macrophages in CS-exposed mice and experimental COPD. Ripk3 or Mlkl deletion prevented airway inflammation upon acute CS exposure. Ripk3 deficiency reduced airway inflammation and remodeling as well as the development of emphysematous pathology after chronic CS exposure. Mlkl deletion and qVD-OPh treatment reduced chronic CS-induced airway inflammation, but only Mlkl deletion prevented airway remodeling and emphysema. Ripk3 or Mlkl deletion and qVD-OPh treatment reduced CS-induced lung-cell death. Conclusions: Necroptosis is induced by CS exposure and is increased in the lungs of patients with COPD and in experimental COPD. Inhibiting necroptosis attenuates CS-induced airway inflammation, airway remodeling, and emphysema. Targeted inhibition of necroptosis is a potential therapeutic strategy in COPD.

Pulmonary Manifestations of GATA2 Deficiency.

BACKGROUND: GATA2 deficiency is a genetic disorder of hematopoiesis, lymphatics, and immunity caused by autosomal dominant or sporadic mutations in GATA2. The disease has a broad phenotype encompassing immunodeficiency, myelodysplasia, leukemia, and vascular or lymphatic dysfunction as well as prominent pulmonary manifestations. RESEARCH QUESTION: What are the pulmonary manifestations of GATA2 deficiency? STUDY DESIGN AND METHODS: A retrospective review was conducted of clinical medical records, diagnostic imaging, pulmonary pathologic specimens, and tests of pulmonary function. RESULTS: Of 124 patients (95 probands and 29 ascertained), the lung was affected in 56%. In addition to chronic infections, pulmonary alveolar proteinosis (11 probands) and pulmonary arterial hypertension (nine probands) were present. Thoracic CT imaging found small nodules in 54% (54 probands and 12 relatives), reticular infiltrates in 40% (45 probands and four relatives), paraseptal emphysema in 25% (30 probands and one relative), ground-glass opacities in 35% (41 probands and two relatives), consolidation in 21% (23 probands and two relatives), and a typical crazy-paving pattern in 7% (eight probands and no relatives). Nontuberculous mycobacteria were the most frequent organisms associated with chronic infection. Allogeneic hematopoietic stem cell transplantation successfully reversed myelodysplasia and immune deficiency and also improved pulmonary hypertension and pulmonary alveolar proteinosis in most patients. INTERPRETATION: GATA2 deficiency has prominent pulmonary manifestations. These clinical observations confirm the essential role of hematopoietic cells in many aspects of pulmonary function, including infections, alveolar proteinosis, and pulmonary hypertension, many of which precede the formal diagnosis, and many of which respond to stem cell transplantation.

The Association Between Lung Hyperinflation and Coronary Artery Disease in Smokers.

BACKGROUND: Smokers manifest varied phenotypes of pulmonary impairment. RESEARCH QUESTION: Which pulmonary phenotypes are associated with coronary artery disease (CAD) in smokers? STUDY DESIGN AND METHODS: We analyzed data from the University of Pittsburgh COPD Specialized Center for Clinically Oriented Research (SCCOR) cohort (n = 481) and the Genetic Epidemiology of COPD (COPDGene) cohort (n = 2,580). Participants were current and former smokers with > 10 pack-years of tobacco exposure. Data from the two cohorts were analyzed separately because of methodologic differences. Lung hyperinflation was assessed by plethysmography in the SCCOR cohort and by inspiratory and expiratory CT scan lung volumes in the COPDGene cohort. Subclinical CAD was assessed as the coronary artery calcium score, whereas clinical CAD was defined as a self-reported history of CAD or myocardial infarction (MI). Analyses were performed in all smokers and then repeated in those with airflow obstruction (FEV1 to FVC ratio, < 0.70). RESULTS: Pulmonary phenotypes, including airflow limitation, emphysema, lung hyperinflation, diffusion capacity, and radiographic measures of airway remodeling, showed weak to moderate correlations (r < 0.7) with each other. In multivariate models adjusted for pulmonary phenotypes and CAD risk factors, lung hyperinflation was the only phenotype associated with calcium score, history of clinical CAD, or history of MI (per 0.2 higher expiratory and inspiratory CT scan lung volume; coronary calcium: OR, 1.2; 95% CI, 1.1-1.5; P = .02; clinical CAD: OR, 1.6; 95% CI, 1.1-2.3; P = .01; and MI in COPDGene: OR, 1.7; 95% CI, 1.0-2.8; P = .05). FEV1 and emphysema were associated with increased risk of CAD (P < .05) in models adjusted for CAD risk factors; however, these associations were attenuated on adjusting for lung hyperinflation. Results were the same in those with airflow obstruction and were present in both cohorts. INTERPRETATION: Lung hyperinflation is associated strongly with clinical and subclinical CAD in smokers, including those with airflow obstruction. After lung hyperinflation was accounted for, FEV1 and emphysema no longer were associated with CAD. Subsequent studies should consider measuring lung hyperinflation and examining its mechanistic role in CAD in current and former smokers.

Emphysema Progression and Lung Function Decline Among Angiotensin Converting Enzyme Inhibitors and Angiotensin-Receptor Blockade Users in the COPDGene Cohort.

BACKGROUND: Attenuation of transforming growth factor ß by blocking angiotensin II has been shown to reduce emphysema in a murine model. General population studies have demonstrated that the use of angiotensin converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) is associated with reduction of emphysema progression in former smokers and that the use of ACEis is associated with reduction of FEV1 progression in current smokers. RESEARCH QUESTION: Is use of ACEi and ARB associated with less progression of emphysema and FEV1 decline among individuals with COPD or baseline emphysema? METHODS: Former and current smokers from the Genetic Epidemiology of COPD Study who attended baseline and 5-year follow-up visits, did not change smoking status, and underwent chest CT imaging were included. Adjusted linear mixed models were used to evaluate progression of adjusted lung density (ALD), percent emphysema (%total lung volume <-950 Hounsfield units [HU]), 15th percentile of the attenuation histogram (attenuation [in HU] below which 15% of voxels are situated plus 1,000 HU), and lung function decline over 5 years between ACEi and ARB users and nonusers in those with spirometry-confirmed COPD, as well as all participants and those with baseline emphysema. Effect modification by smoking status also was investigated. RESULTS: Over 5 years of follow-up, compared with nonusers, ACEi and ARB users with COPD showed slower ALD progression (adjusted mean difference [aMD], 1.6; 95% CI, 0.34-2.9). Slowed lung function decline was not observed based on phase 1 medication (aMD of FEV1 % predicted, 0.83; 95% CI, -0.62 to 2.3), but was when analysis was limited to consistent ACEi and ARB users (aMD of FEV1 % predicted, 1.9; 95% CI, 0.14-3.6). No effect modification by smoking status was found for radiographic outcomes, and the lung function effect was more pronounced in former smokers. Results were similar among participants with baseline emphysema. INTERPRETATION: Among participants with spirometry-confirmed COPD or baseline emphysema, ACEi and ARB use was associated with slower progression of emphysema and lung function decline. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.

Lung function and peak oxygen uptake in chronic obstructive pulmonary disease phenotypes with and without emphysema.

Previous studies of associations of forced expiratory lung volume in one second (FEV1) with peak oxygen uptake (VO2peak) in chronic obstructive pulmonary disease (COPD) have not taken sex, age and height related variance of dynamic lung volumes into account. Nor have such demographic spread of spirometric measures been considered in studies comparing VO2peak between COPD phenotypes characterized by degree of emphysema. We aimed to assess the association of FEV1Z-score with VO2peak in COPD (n = 186) and investigate whether this association differs between emphysema (E-COPD) and non-emphysema (NE-COPD) phenotypes. Corresponding assessments using standardized percent predicted FEV1 (ppFEV1) were performed for comparison. Additionally, phenotype related differences in VO2peak were compared using FEV1Z-score and ppFEV1 as alternative expressions of FEV1. E-COPD and NE-COPD were defined by transfer factor of the lung for carbon monoxide below and above lower limits of normal (LLN), respectively. The associations were assessed in linear regression models. One unit reduction in FEV1Z-score was associated with 1.9 (95% CI 1.4, 2.5) ml/kg/min lower VO2peak. In stratified analyses, corresponding estimates were 2.2 (95% CI 1.4, 2.9) and 1.2 (95% CI 0.2, 2.2) ml/kg/min lower VO2peak in E-COPD and NE-COPD, respectively. The association did not differ statistically by COPD phenotype (p-value for interaction = 0.153). Similar estimates were obtained in analyses using standardized ppFEV1. Compared to NE-COPD, VO2peak was 2.2 (95% CI 0.8, 3.6) and 2.1 (95% CI 0.8, 3.5) ml/kg/min lower in E-COPD when adjusted for FEV1Z-score and ppFEV1, respectively. In COPD, FEV1Z-score is positively associated with VO2peak. This association was stronger in E-COPD but did not differ statistically by phenotype. Both the association of FEV1 with VO2peak and the difference in VO2peak comparing COPD phenotypes seems independent of sex, age and height related variance in FEV1. Mechanisms leading to reduction in FEV1 may contribute to lower VO2peak in E-COPD.