Elizabeth C. Oelsner

High attenuation areas on chest computed tomography in community-dwelling adults: the MESA study

Evidence suggests that lung injury, inflammation and extracellular matrix remodelling precede lung fibrosis in interstitial lung disease (ILD). We examined whether a quantitative measure of increased lung attenuation on computed tomography (CT) detects lung injury, inflammation and extracellular matrix remodelling in community-dwelling adults sampled without regard to respiratory symptoms or smoking. We measured high attenuation areas (HAA; percentage of lung voxels between −600 and −250 Hounsfield Units) on cardiac CT scans of adults enrolled in the Multi-Ethnic Study of Atherosclerosis. HAA was associated with higher serum matrix metalloproteinase-7 (mean adjusted difference 6.3% per HAA doubling, 95% CI 1.3–11.5), higher interleukin-6 (mean adjusted difference 8.8%, 95% CI 4.8–13.0), lower forced vital capacity (FVC) (mean adjusted difference −82 mL, 95% CI −119–−44), lower 6-min walk distance (mean adjusted difference −40 m, 95% CI −1–−80), higher odds of interstitial lung abnormalities at 9.5 years (adjusted OR 1.95, 95% CI 1.43–2.65), and higher all cause-mortality rate over 12.2 years (HR 1.58, 95% CI 1.39–1.79). High attenuation areas are associated with biomarkers of inflammation and extracellular matrix remodelling, reduced lung function, interstitial lung abnormalities, and a higher risk of death among community-dwelling adults. Increased lung attenuation on CT may identify subclinical lung injury and inflammation in community-dwelling adults http://ow.ly/97k3300tvKX

Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort

BACKGROUND Present treatment strategies to stratify exacerbation risk in patients with chronic obstructive pulmonary disease (COPD) rely on a history of two or more events in the previous year. We aimed to understand year to year variability in exacerbations and factors associated with consistent exacerbations over time. METHODS In this longitudinal, prospective analysis of exacerbations in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort, we analysed patients aged 40-80 years with COPD for whom 3 years of prospective data were available, identified through various means including care at academic and non-academic medical centres, word of mouth, and existing patient registries. Participants were enrolled in the study between Nov 12, 2010, and July 31, 2015. We classified patients according to yearly exacerbation frequency: no exacerbations in any year; one exacerbation in every year during 3 years of follow-up; and those with inconsistent exacerbations (individuals who had both years with exacerbations and years without during the 3 years of follow-up). Participants were characterised by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric category (1-4) on the basis of post-bronchodilator FEV1. Stepwise logistic regression was used to compare factors associated with one or more acute exacerbations of COPD every year for 3 years versus no exacerbations in the same timeframe. Additionally, a stepwise zero-inflated negative binomial model was used to assess predictors of exacerbation count during follow-up in all patients with available data. Baseline symptom burden was assessed with the COPD assessment test. This trial is registered with ClinicalTrials.gov, number NCT01969344. FINDINGS 2981 patients were enrolled during the study. 1843 patients had COPD, of which 1105 patients had 3 years of complete, prospective follow-up data. 538 (49%) of 1105 patients had at least one acute exacerbation during the 3 years of follow-up, whereas 567 (51%) had none. 82 (7%) of 1105 patients had at least one acute exacerbation each year, whereas only 23 (2%) had two or more acute exacerbations in each year. An inconsistent pattern (both years with and without acute exacerbations) was common (456 [41%] of the group), particularly among GOLD stages 3 and 4 patients (256 [56%] of 456). In logistic regression, consistent acute exacerbations (≥1 event per year for 3 years) were associated with higher baseline symptom burden, previous exacerbations, greater evidence of small airway abnormality on CT, lower interleukin-15 concentrations, and higher interleukin-8 concentrations, than were no acute exacerbations. INTERPRETATION Although acute exacerbations are common, the exacerbation status of most individuals varies markedly from year to year. Among patients who had any acute exacerbation over 3 years, very few repeatedly had two or more events per year. In addition to symptoms and history of exacerbations in the year before study enrolment, we identified several novel biomarkers associated with consistent exacerbations, including CT-defined small airway abnormality, and interleukin-15 and interleukin-8 concentrations. FUNDING National Institutes of Health, and National Heart, Lung, and Blood Institute.Background Current treatment strategies to stratify exacerbation risk rely on history of ≥2 events in the previous year. To understand year-to-year variability and factors associated with consistent exacerbations over time, we present a prospective analysis of the SPIROMICS cohort. Methods We analyzed SPIROMICS participants with COPD and three years of prospective data (n=1,105). We classified participants according to yearly exacerbation frequency. Stepwise logistic regression compared factors associated with individuals experiencing ≥1 AECOPD in every year for three years versus none. Results During three years follow-up, 48·7% of participants experienced at least one AECOPD, while the majority (51·3%) experienced none. Only 2·1% had ≥2 AECOPD in each year. An inconsistent pattern (both years with and years without AECOPD) was common (41·3% of the group), particularly among GOLD stages 3 and 4 subjects (56·1%). In logistic regression, consistent AECOPD (≥1 event per year for three years) as compared to no AECOPD were associated with higher baseline symptom burden assessed with the COPD Assessment Test, previous exacerbations, greater evidence of small airway abnormality by computed tomography, lower Interleukin-15 (IL-15) and elevated Interleukin-8 (IL-8). Conclusions Although AECOPD are common, the exacerbation status of most individuals varies markedly from year to year. Among participants who experienced any AECOPD over three years, very few repeatedly experienced ≥2 events/year. In addition to symptoms and history of exacerbations in the prior year, we identified several novel biomarkers associated with consistent exacerbations, including CT-defined small airway abnormality, IL-15 and IL-8.

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

APOM and high-density lipoprotein cholesterol are associated with lung function and per cent emphysema

Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD. We assessed the association of lung function with 2100 genes selected for cardiovascular diseases among 20 077 European-Americans and 6900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with per cent emphysema and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio and per cent emphysema. We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10−6) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10−7). Both single-nucleotide polymorphisms (SNPs) flank the gene for apolipoprotein M (APOM), a component of high-density lipoprotein (HDL) cholesterol. Both were replicated in an independent cohort. SNPs in a second gene related to apolipoprotein M and HDL, PCSK9, were associated with FEV1/FVC ratio among African-Americans. rs707974 was associated with per cent emphysema among European-Americans and African-Americans and APOM expression was related to FEV1/FVC ratio and per cent emphysema. Higher HDL levels were associated with lower FEV1/FVC ratio and greater per cent emphysema. These findings suggest a novel role for the apolipoprotein M/HDL pathway in the pathogenesis of COPD and emphysema. Findings from this study suggest a novel effect of the APOM/HDL pathway in the pathogenesis of COPD and emphysema http://ow.ly/t8Ao9

Adhesion molecules, endothelin-1 and lung function in seven population-based cohorts.

Abstract Context: Endothelial function is abnormal in chronic obstructive pulmonary disease (COPD); whether endothelial dysfunction causes COPD is unknown. Objective: Test associations of endothelial biomarkers with FEV1 using instrumental variables. Methods: Among 26 907 participants with spirometry, ICAM-1, P-selectin, E-selectin and endothelin-1 were measured in subsets. Results: ICAM-1 and P-selectin were inversely associated with FEV1 among European-Americans (−29 mL and −34 mL per standard deviation of log-transformed biomarker, p < 0.001), as was endothelin-1 among African-Americans (−22 mL, p = 0.008). Genetically-estimated ICAM-1 and P-selectin were not significantly associated with FEV1. The instrumental variable for endothelin-1 was non-informative. Conclusion: Although ICAM-1, P-selectin and endothelin-1 were inversely associated with FEV1, associations for ICAM-1 and P-selectin do not appear causal.

Noninvasive Tests for the Diagnostic Evaluation of Dyspnea Among Outpatients: The Multi-Ethnic Study of Atherosclerosis Lung Study

BACKGROUND Dyspnea on exertion is a common and debilitating symptom, yet evidence for the relative value of cardiac and pulmonary tests for the evaluation of chronic dyspnea among adults without known cardiac or pulmonary disease is limited. METHODS The Multi-Ethnic Study of Atherosclerosis (MESA) enrolled participants aged 45 to 84 years who were free of clinical cardiovascular disease from 6 communities; participants with clinical pulmonary disease were excluded from this report. Dyspnea on exertion was assessed via structured interview. Tests included electrocardiograms, cardiac computed tomography (CT) for coronary artery calcium, cardiac magnetic resonance imaging, spirometry, percent emphysema (percent of lung regions <-950 HU) on CT, inflammatory biomarkers, and N-terminal pro-brain natriuretic peptide (NT-proBNP). Logistic regression was used to identify independent correlates of dyspnea after adjustment for age, sex, body mass index, physical activity, anxiety, and leg pain. RESULTS Among 1969 participants without known cardiopulmonary disease, 9% had dyspnea. The forced expiratory volume in 1 second (FEV1) (P < .001), NT-proBNP (P = .004), and percent emphysema on CT (P = .004) provided independent information on the probability of self-reported dyspnea. Associations with the FEV1 were stronger among smokers and participants with other recent respiratory symptoms or seasonal allergies; associations with NT-proBNP were present only among participants with coexisting symptoms of lower-extremity edema. Only the FEV1 provided a significant improvement in the receiver operating curve. CONCLUSIONS Among adults without known cardiac or pulmonary disease reporting dyspnea on exertion, spirometry, NT-proBNP, and CT imaging for pulmonary parenchymal disease were the most informative tests.

Serum Matrix Metalloproteinase-7, Respiratory Symptoms, and Mortality in Community-Dwelling Adults. MESA (Multi-Ethnic Study of Atherosclerosis)

Rationale: Matrix metalloproteinase‐7 (MMP‐7) has been implicated in interstitial lung disease pathobiology and proposed as a diagnostic and prognostic biomarker of idiopathic pulmonary fibrosis. Objectives: To test associations between serum MMP‐7 and lung function, respiratory symptoms, interstitial lung abnormalities (ILA), and all‐cause mortality in community‐dwelling adults sampled without regard to respiratory symptoms or disease. Methods: We measured serum MMP‐7 in 1,227 participants in MESA (Multi‐Ethnic Study of Atherosclerosis) at baseline. The 5‐year outcome data were available for spirometry (n = 697), cough (n = 722), and dyspnea (n = 1,050). The 10‐year outcome data were available for ILA (n = 561) and mortality (n = 1,227). We used linear, logistic, and Cox regression to control for potential confounders. Measurements and Main Results: The mean (±SD) serum MMP‐7 level was 4.3 (±2.5) ng/ml (range, 1.2‐24.1 ng/ml). In adjusted models, each natural log unit increment in serum MMP‐7 was associated with a 3.7% absolute decrement in FVC% (95% confidence interval [CI] = 0.9‐6.6%), a 1.6‐fold increased odds of exertional dyspnea (95% CI = 1.3‐1.9), a 1.5‐fold increased odds of ILAs (95% CI = 1.1‐2.1), and a 2.2‐fold increased all‐cause mortality rate (95% CI = 1.9‐2.5). The associations with ILA and mortality tended to be stronger among never‐smokers (P values for interaction 0.06 and 0.01, respectively). Conclusions: Serum MMP‐7 levels may be a quantitative biomarker of subclinical extracellular matrix remodeling in the lungs of community‐dwelling adults, which may facilitate investigation of subclinical interstitial lung disease.

High-Attenuation Areas on Chest Computed Tomography and Clinical Respiratory Outcomes in Community-Dwelling Adults

Rationale: Areas of increased lung attenuation visualized by computed tomography are associated with all‐cause mortality in the general population. It is uncertain whether this association is attributable to interstitial lung disease (ILD). Objectives: To determine whether high‐attenuation areas are associated with the risk of ILD hospitalization and mortality in the general population. Methods: We performed a cohort study of 6,808 adults aged 45‐84 years sampled from six communities in the United States. High‐attenuation areas were defined as the percentage of imaged lung volume with attenuation values between −600 and −250 Hounsfield units. An adjudication panel determined ILD hospitalization and death. Measurements and Main Results: After adjudication, 52 participants had a diagnosis of ILD during 75,232 person‐years (median, 12.2 yr) of follow‐up. There were 48 hospitalizations attributable to ILD (crude rate, 6.4 per 10,000 person‐years). Twenty participants died as a result of ILD (crude rate, 2.7 per 10,000 person‐years). High‐attenuation areas were associated with an increased rate of ILD hospitalization (adjusted hazard ratio, 2.6 per 1‐SD increment in high‐attenuation areas; 95% confidence interval, 1.9‐3.5; P < 0.001), a finding that was stronger among men, African Americans, and Hispanics. High‐attenuation areas were also associated with an increased rate of ILD‐specific death (adjusted hazard ratio, 2.3; 95% confidence interval, 1.7‐3.0; P < 0.001). Our findings were consistent among both smokers and nonsmokers. Conclusions: Areas of increased lung attenuation are a novel risk factor for ILD hospitalization and mortality. Measurement of high‐attenuation areas by screening and diagnostic computed tomography may be warranted in at‐risk adults.

Association of emphysema-like lung on cardiac computed tomography and mortality in persons without airflow obstruction: the Multi-Ethnic Study of Atherosclerosis (MESA) Lung 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

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.