R. G. Barr

Racial and ethnic disparities in idiopathic pulmonary fibrosis: A UNOS/OPTN database analysis.

We previously reported poorer survival among non‐Hispanic blacks and Hispanics with idiopathic pulmonary fibrosis (IPF) compared to non‐Hispanic whites at our center. In the current study, we hypothesized that these disparities would exist in a nationwide cohort of wait‐listed patients with IPF. We performed a retrospective cohort study of 2635 patients with IPF listed for lung transplantation between 1995 and 2003 at 94 transplant centers in the United States. The age‐adjusted mortality rate was higher among non‐Hispanic blacks [hazard ratio (HR) = 1.24, 95% confidence interval (CI) 1.06–1.45, p = 0.009] and Hispanics (HR = 1.29, 95% CI 1.06–1.56, p = 0.01) compared to non‐Hispanic whites. These findings persisted after adjustment for transplantation, medical comorbidities and socioeconomic status. Worse lung function at the time of listing appeared to explain some of these differences (HR for non‐Hispanic blacks after adjustment for forced vital capacity percent predicted = 1.16, 95% CI 0.98–1.36, p = 0.09; HR for Hispanics = 1.21, 95% CI 0.99–1.48, p = 0.056). In summary, black and Hispanic patients with IPF have worse survival than whites after listing for lung transplant.

Tiotropium for stable chronic obstructive pulmonary disease: a meta-analysis

Background: A systematic review was undertaken to evaluate the efficacy of tiotropium, a long acting anticholinergic drug, on clinical events, symptom scales, pulmonary function, and adverse events in stable chronic obstructive pulmonary disease (COPD). Methods: A systematic search was made of the Cochrane trials database, MEDLINE, EMBASE, CINAHL, and a hand search of 20 respiratory journals. Missing data were obtained from authors and the manufacturer. Randomised controlled trials of ⩾12 weeks’ duration comparing tiotropium with placebo, ipratropium bromide, or long acting β2 agonists (LABA) were reviewed. Studies were pooled to yield odds ratios (OR) or weighted mean differences with 95% confidence intervals (CI). Results: Nine trials (8002 patients) met the inclusion criteria. Tiotropium reduced the odds of a COPD exacerbation (OR 0.73; 95% CI 0.66 to 0.81) and related hospitalisation (OR 0.68; 95% CI 0.54 to 0.84) but not pulmonary (OR 0.50; 95% CI 0.19 to 1.29) or all-cause (OR 0.96; 95% CI 0.63 to 1.47) mortality compared with placebo and ipratropium. Reductions in exacerbations and hospitalisations compared with LABA were not statistically significant. Similar patterns were evident for quality of life and symptom scales. Tiotropium yielded greater increases in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) from baseline to 6–12 months than did placebo, ipratropium, and LABA. Decline in FEV1 over 1 year was 30 ml (95% CI 7 to 53) slower with tiotropium than with placebo and ipratropium (data were not available for LABA). Reports of dry mouth and urinary tract infections were increased with tiotropium. Conclusions: Tiotropium reduced COPD exacerbations and related hospitalisations, improved quality of life and symptoms, and may have slowed the decline in FEV1. Long term trials are warranted to evaluate the effects of tiotropium on decline in FEV1 and to clarify its role compared with LABA.

Plasma hemostatic factors and endothelial markers in four racial/ethnic groups: the MESA study

Summary.  Background: Hemostatic factors and endothelial markers may play some role in racial/ethnic differences in cardiovascular disease (CVD) rates. However, little information exists on hemostatic factors and endothelial markers across racial/ethnic groups. Objectives: To describe, in four American racial/ethnic groups (Caucasian, Black, Hispanic, and Chinese), mean levels of selected hemostatic factors and endothelial markers. Patients and methods: Multi‐ethnic Study of Atherosclerosis baseline data were used (participant age: 45–84 years). Sex‐specific analysis of covariance models, and t‐tests for pairwise comparisons, were used to compare means of factors and markers. Adjustments were made for demographics and traditional CVD risk factors. Differences were significant at P < 0.05. Results: Blacks had the highest levels of factor VIII, D‐Dimer, plasmin–antiplasmin (PAP), and von Willebrand factor, among the highest levels of fibrinogen and E‐selectin (women only), but among the lowest levels of intercellular adhesion molecule 1 (ICAM‐1), and, in men, the lowest levels of plasminogen activator inhibitor‐1 (PAI‐1). Whites and Hispanics tended to have intermediate levels of factors and markers, although they had the highest levels of ICAM‐1, and Hispanics had the highest mean levels of fibrinogen and E‐selectin (women only). Chinese participants had among the highest levels of PAI‐1, but the lowest, or among the lowest, of all other factors and markers. No soluble thrombomodulin differences were observed. Conclusions: In this large cohort, hemostatic factor and endothelial marker mean levels varied by race/ethnicity, even after adjustment for traditional CVD risk factors.

Subclinical Atherosclerosis, Airflow Obstruction and Emphysema: the MESA Lung Study

Airflow obstruction is an independent risk factor for cardiovascular events in the general population. The affected vascular bed and contribution of emphysema to cardiovascular risk are unclear. We examined whether an obstructive pattern of spirometry and quantitatively defined emphysema were associated with subclinical atherosclerosis in the carotid, peripheral and coronary circulations. The Multi-Ethnic Study of Atherosclerosis recruited participants aged 45–84 yrs without clinical cardiovascular disease. Spirometry, carotid intima-media thickness (IMT), ankle-brachial index (ABI) and coronary artery calcium (CAC) were measured using standard protocols. Percentage of emphysema-like lung was measured in the lung windows of cardiac computed tomography scans among 3,642 participants. Multiple linear regression was used to adjust for cardiac risk factors, including C-reactive protein. Decrements in forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity ratio were associated with greater internal carotid IMT, particularly among smokers (p=0.03 and p<0.001, respectively) whereas percentage emphysema was associated with reduced ABI regardless of smoking history (p=0.004). CAC was associated with neither lung function (prevalence ratio for the presence of CAC in severe airflow obstruction 0.99, 95% CI 0.91–1.07) nor percentage emphysema. An obstructive pattern of spirometry and emphysema were associated distinctly and independently with subclinical atherosclerosis in the carotid arteries and peripheral circulation, respectively, and were not independently related to CAC.

Association between emphysema-like lung on cardiac computed tomography and mortality in persons without airflow obstruction: a cohort study.

Background Whereas low lung function is known to predict mortality in the general population, the prognostic significance of emphysema on computed tomography (CT) in persons without chronic obstructive pulmonary disease (COPD) remains uncertain.Context The clinical significance of emphysematous changes in the lung sometimes seen on computed tomography (CT) in patients who do not have chronic obstructive pulmonary disease is uncertain. Contribution This study examined mortality among participants without airflow obstruction on spirometry who did and did not have emphysematous changes in the lungs on cardiac CT. Emphysematous lung changes on CT were associated with increased mortality, particularly among smokers. Implication Understanding the significance of an incidental finding of emphysematous lung will be increasingly important as the use of CT expands in such areas as lung cancer screening and cardiac calcium scoring. The Editors Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States and globally (1, 2). It is defined physiologically as airflow obstruction on spirometry that does not completely reverse (3). Most medical therapies and almost all randomized clinical trials in COPD target the airways. Such therapies alleviate symptoms and reduce hospitalizations but have not been proved to affect disease progression or reduce mortality (47). Pulmonary emphysema is defined anatomically as destruction of lung parenchyma and loss of intra-alveolar walls (8, 9). It was originally diagnosed on autopsy but can also be assessed via chest computed tomography (CT), which is now recommended as a screening tool for lung cancer among high risk groups (1012). Emphysema is common in the general population; autopsy studies show that most smokers and up to 10% of never-smokers have some degree of the disease (13). Emphysema on CT is a common incidental finding that occurs in 29% of smokers undergoing lung cancer screening (14) and 4% of healthy adults having cardiac scanning (15). Furthermore, emphysema and COPD overlap less than previously believed: Emphysema is frequently observed in the absence of COPD (1618), and approximately half of patients with COPD do not have substantial emphysema (19). Although reduced lung function is known to be associated with increased all-cause mortality in the general population (2022), and although emphysema on CT may portend a worse prognosis in patients with COPD (16, 23) and in selected smokers (14, 24), the prognostic importance of emphysema on CT among patients without COPD and in the broader population of smokers and nonsmokers is unknown. We therefore examined the associations between the extent of emphysema-like lung on CT and mortality among persons who had no airflow obstruction on spirometry (and were therefore free of COPD) in a large, multiethnic, population-based cohort followed for 6 years after spirometry. We studied both smokers and never-smokers because panlobular emphysema is prevalent in both populations (13, 17). Methods Participants MESA (Multi-Ethnic Study of Atherosclerosis) enrolled 6814 participants aged 45 to 84 years who self-reported white, African American, Hispanic, and/or Asian race/ethnicity in 2000 to 2002 (25). Exclusion criteria were history of clinical cardiovascular disease, weight greater than 136 kg (>300 lb) (the maximum for CT scanners at the time), and impediments to long-term participation. Participants were recruited from Forsyth County, North Carolina; northern Manhattan and the Bronx, New York; Baltimore City and Baltimore County, Maryland; St. Paul, Minnesota; Chicago, Illinois; and Los Angeles, California. Five participants were excluded from follow-up after discovery of prebaseline cardiovascular events, and 12 were missing valid CT measurements (Appendix Figure 1). Appendix Figure 1. Study flow diagram. CT = computed tomography; MESA = Multi-Ethnic Study of Atherosclerosis. Follow-up and Mortality Interviewers contacted each MESA participant or a family member to inquire about vital status every 9 to 12 months. The National Death Index (NDI) was also regularly reviewed to ensure complete follow-up for mortality through the most recent NDI update (31 December 2010). Death from any cause was the primary end point. Emphysema-like Lung All MESA participants had cardiac CT at baseline according to standardized protocols on either electron-beam or multidetector CT scanners (26) in 2000 to 2002. For each participant, 2 scans were done at suspended full inspiration from the carina to the lung bases with transverse fields of view that captured the whole lung field. These scans captured an average of 65% of the total lung volume on full-lung scans acquired in a validation study (27) in MESA (Figure 1 and Appendix Table 1). Figure 1. Lung windows from cardiac and full-lung CT scans in a MESA participant. CT = computed tomography; MESA = Multi-Ethnic Study of Atherosclerosis. Left. Cardiac CT scan. The dashed lines indicate the cephalad one eighth and caudal one third, which demarcate the upper-lobe and basilar regions, respectively. Right. Full-lung CT scan. Appendix Table 1. Predictors of Cardiac CT Scan Coverage Among the MESA Validation Study Sample (n= 42), 2000 to 2002 Image attenuation was assessed by using a modified version of the Pulmonary Analysis Software Suite (28, 29) at a single reading center by trained readers without knowledge of other participant information. Emphysema-like lung was defined as the number of lung voxels with outside aircorrected attenuation less than 950 Hounsfield units (HU) based on pathologic comparisons (30) on the scan with higher air volume or, in the case of discordant quality scores, the higher-quality scan (27) (Appendix Figure 2 and Appendix Table 2). To correct for variations in scanner calibration and in the way different scanners handle scatter and beam hardening, we measured the attenuation of air outside the body, which should have a mean attenuation of 1000 HU, for each scan in a region distant from the body and scanner table. The outside aircorrected attenuation of each lung pixel was defined as (measured pixel attenuation)(1000/mean outside-air attenuation). Appendix Figure 2. BlandAltman plot of imaged lung volume on paired cardiac CT scans at the MESA baseline examination, 2000 to 2002, for all MESA Lung Study participants. The average imaged lung volume among the paired scans is shown on the x-axis, and the difference in imaged lung volume between the paired scans is shown on the y-axis. The red lines correspond to the limits of agreement. There was a high level of agreement with respect to imaged lung volume between the paired scans (intraclass correlation coefficient, 0.93) and no evidence for systematic bias across the range of imaged lung volume values. CT = computed tomography; MESA = Multi-Ethnic Study of Atherosclerosis. Appendix Table 2. Predictors of Variability of Imaged Lung Volumes on Paired Cardiac CT Scans Among All MESA Lung Study Participants, 2000 to 2002 Regions of the lung with features suggestive of interstitial lung abnormalities (high-attenuation areas) were defined as the number of lung voxels with attenuation between 600 and 250 HU (31). All of these measures were previously validated against those obtained from full-lung scans in MESA (r= 0.93 for emphysema-like lung) (27, 31). Spirometry Spirometry was attempted between 2004 and 2006 for 3965 participants who had baseline measurements of endothelial function (99% of MESA sample), consented to genetic analyses (99% of MESA sample), and had an examination during the MESA Lung Study recruitment period (Appendix Figure 1). A total of 3847 participants performed maneuvers in accordance with the joint guidelines from the American Thoracic Society and European Respiratory Society (32) on a dry rolling-seal spirometer (Occupational Marketing); results were reviewed by a single investigator (33). Airflow obstruction was defined as an FEV1FVC ratio less than 0.70, in accordance with current guidelines (3). Absence of airflow obstruction on prebronchodilator spirometry when this definition is used effectively excludes COPD, which is defined as a postbronchodilator FEV1FVC ratio less than 0.70 (3). An FEV1FVC ratio less than the lower limit of normal (34) was used to define airflow obstruction for a secondary analysis. Covariates Age, sex, race/ethnicity, educational attainment, cancer history, physician diagnoses of emphysema and asthma, intentional exercise per week, alcohol use, and tobacco use were self-reported at baseline. Never smoking was defined as a lifetime smoking history of fewer than 100 cigarettes, and current smoking was defined as cigarette use within the past 30 days. Urine cotinine was measured for a subset of 3929 participants; 78 (2%) who denied current smoking but had urine cotinine levels greater than 100 ng/mL were reclassified as current smokers. Pack-years were calculated as (cigarettes per day/20)(years smoked). Height; weight; systolic and diastolic blood pressures; and levels of total and high-density lipoprotein cholesterol, creatinine, d-dimer, C-reactive protein, and fasting plasma glucose were measured by using standard techniques (25, 35). Medication use was assessed by validated medication inventory (36). A phantom-adjusted coronary artery calcium Agatston score (37) was calculated from each cardiac CT scan, and the mean of the 2 values was used as previously described (38). Statistical Analysis Statistical tests were based on multivariable-adjusted Cox proportional hazards models and additive Cox models with penalized splines. We used the latter approach to test and account for any potential nonlinearity in associations and to generate plots. The study sample comprised participants with valid spirometry measures who did not have airflow obstruction. We calculated survival time as age at death or, for nondeceased participants, age at last follow-up or the most recent NDI update, whichever occurred later, with left truncation at age at spirometry. We confirmed the proportional hazards assumption via interaction terms with time (P> 0.100). The number of emphysema-like voxels was first adjusted f

Comparison of serum, EDTA plasma and P100 plasma for luminex-based biomarker multiplex assays in patients with chronic obstructive pulmonary disease in the SPIROMICS study.

BackgroundAs a part of the longitudinal Chronic Obstructive Pulmonary Disease (COPD) study, Subpopulations and Intermediate Outcome Measures in COPD study (SPIROMICS), blood samples are being collected from 3200 subjects with the goal of identifying blood biomarkers for sub-phenotyping patients and predicting disease progression. To determine the most reliable sample type for measuring specific blood analytes in the cohort, a pilot study was performed from a subset of 24 subjects comparing serum, Ethylenediaminetetraacetic acid (EDTA) plasma, and EDTA plasma with proteinase inhibitors (P100™).Methods105 analytes, chosen for potential relevance to COPD, arranged in 12 multiplex and one simplex platform (Myriad-RBM) were evaluated in duplicate from the three sample types from 24 subjects. The reliability coefficient and the coefficient of variation (CV) were calculated. The performance of each analyte and mean analyte levels were evaluated across sample types.Results20% of analytes were not consistently detectable in any sample type. Higher reliability and/or smaller CV were determined for 12 analytes in EDTA plasma compared to serum, and for 11 analytes in serum compared to EDTA plasma. While reliability measures were similar for EDTA plasma and P100 plasma for a majority of analytes, CV was modestly increased in P100 plasma for eight analytes. Each analyte within a multiplex produced independent measurement characteristics, complicating selection of sample type for individual multiplexes.ConclusionsThere were notable detectability and measurability differences between serum and plasma. Multiplexing may not be ideal if large reliability differences exist across analytes measured within the multiplex, especially if values differ based on sample type. For some analytes, the large CV should be considered during experimental design, and the use of duplicate and/or triplicate samples may be necessary. These results should prove useful for studies evaluating selection of samples for evaluation of potential blood biomarkers.

Establishing normal reference values in quantitative computed tomography of emphysema.

Quantitative computed tomography (QCT) can provide reliable and valid measures of lung structure and volumes. Similar to lung function measured by spirometry, lung measures obtained by QCT vary by demographic and anthropomorphic factors including sex, race/ethnicity, and height in asymptomatic nonsmokers. Hence, accounting for these factors is necessary to define abnormal from normal QCT values. Prediction equations for QCT may be derived from a sample of asymptomatic individuals to estimate reference values. This review article describes the methodology of reference equation development using, as an example, quantitative densitometry to detect pulmonary emphysema. The process described is generalizable to other QCT measures, including lung volumes, airway dimensions, and gas-trapping. Pulmonary emphysema is defined morphologically by airspace enlargement with alveolar wall destruction and has been shown to correlate with low lung attenuation estimated by QCT. Deriving reference values for a normal quantity of low lung attenuation requires 3 steps. First, criteria that define normal must be established. Second, variables for inclusion must be selected on the basis of an understanding of subject-specific, scanner-specific, and protocol-specific factors that influence lung attenuation. Finally, a reference sample of normal individuals must be selected that is representative of the population in which QCT will be used to detect pulmonary emphysema. Sources of bias and confounding inherent to reference values are also discussed. Reference equation development is a multistep process that can define normal values for QCT measures such as lung attenuation. Normative reference values will increase the utility of QCT in both research and clinical practice.

Location, location, location: studying anatomically comparable airways is highly relevant to understanding COPD

We have read with interest Nakano and colleagues thoughtful comments1 on Smith et al 2 and are pleased to offer the following observations. We believe that a key strength of our paper is that it defines a rigorous sampling strategy to compare airways from matched hierarchical positions within the tracheobronchial tree with control for the known hierarchical gradient in airway dimensions.3 Nakano et al are correct to point out that hierarchical sampling by generation number results in grouping of airways from multiple anatomic locations (eg, segmental and lobar airways); conversely, hierarchical sampling by anatomic location results in grouping of airways from multiple generations.4 It is for this reason that we reported both sampling approaches (tables 2 …

Associations between emphysema-like lung on CT and incident airflow limitation: a general population-based cohort study

Emphysema on CT is associated with accelerated lung function decline in heavy smokers and patients with COPD; however, in the general population, it is not known whether greater emphysema-like lung on CT is associated with incident COPD. We used data from 2045 adult participants without initial prebronchodilator airflow limitation, classified by FEV1/FVC<0.70, in the Multi-Ethnic Study of Atherosclerosis. Emphysema-like lung on baseline cardiac CT, defined as per cent low attenuation areas<—950HU>upper limit of normal, was associated with increased odds of incident airflow limitation at 5-year follow-up on both prebronchodilator (adjusted OR 2.62, 95% CI 1.47 to 4.67) and postbronchodilator (adjusted OR 4.38, 95% CI 1.63 to 11.74) spirometry, independent of smoking history. These results support investigation into whether emphysema-like lung could be informative for COPD risk stratification.