Tsuneo Yamashiro

Lung volumes and emphysema in smokers with interstitial lung abnormalities.

BACKGROUND Cigarette smoking is associated with emphysema and radiographic interstitial lung abnormalities. The degree to which interstitial lung abnormalities are associated with reduced total lung capacity and the extent of emphysema is not known. METHODS We looked for interstitial lung abnormalities in 2416 (96%) of 2508 high-resolution computed tomographic (HRCT) scans of the lung obtained from a cohort of smokers. We used linear and logistic regression to evaluate the associations between interstitial lung abnormalities and HRCT measurements of total lung capacity and emphysema. RESULTS Interstitial lung abnormalities were present in 194 (8%) of the 2416 HRCT scans evaluated. In statistical models adjusting for relevant covariates, interstitial lung abnormalities were associated with reduced total lung capacity (-0.444 liters; 95% confidence interval [CI], -0.596 to -0.292; P<0.001) and a lower percentage of emphysema defined by lung-attenuation thresholds of -950 Hounsfield units (-3%; 95% CI, -4 to -2; P<0.001) and -910 Hounsfield units (-10%; 95% CI, -12 to -8; P<0.001). As compared with participants without interstitial lung abnormalities, those with abnormalities were more likely to have a restrictive lung deficit (total lung capacity <80% of the predicted value; odds ratio, 2.3; 95% CI, 1.4 to 3.7; P<0.001) and were less likely to meet the diagnostic criteria for chronic obstructive pulmonary disease (COPD) (odds ratio, 0.53; 95% CI, 0.37 to 0.76; P<0.001). The effect of interstitial lung abnormalities on total lung capacity and emphysema was dependent on COPD status (P<0.02 for the interactions). Interstitial lung abnormalities were positively associated with both greater exposure to tobacco smoke and current smoking. CONCLUSIONS In smokers, interstitial lung abnormalities--which were present on about 1 of every 12 HRCT scans--were associated with reduced total lung capacity and a lesser amount of emphysema. (Funded by the National Institutes of Health and the Parker B. Francis Foundation; ClinicalTrials.gov number, NCT00608764.).

Pulmonary Hypertension and Computed Tomography Measurement of Small Pulmonary Vessels in Severe Emphysema

RATIONALE Vascular alteration of small pulmonary vessels is one of the characteristic features of pulmonary hypertension in chronic obstructive pulmonary disease. The in vivo relationship between pulmonary hypertension and morphological alteration of the small pulmonary vessels has not been assessed in patients with severe emphysema. OBJECTIVES We evaluated the correlation of total cross-sectional area of small pulmonary vessels (CSA) assessed on computed tomography (CT) scans with the degree of pulmonary hypertension estimated by right heart catheterization. METHODS In 79 patients with severe emphysema enrolled in the National Emphysema Treatment Trial (NETT), we measured CSA less than 5 mm(2) (CSA(<5)) and 5 to 10 mm(2) (CSA(5-10)), and calculated the percentage of total CSA for the lung area (%CSA(<5) and %CSA(5-10), respectively). The correlations of %CSA(<5) and %CSA(5-10) with pulmonary arterial mean pressure (Ppa) obtained by right heart catheterization were evaluated. Multiple linear regression analysis using Ppa as the dependent outcome was also performed. MEASUREMENTS AND MAIN RESULTS The %CSA(<5) had a significant negative correlation with Ppa (r = -0.512, P < 0.0001), whereas the correlation between %CSA(5-10) and Ppa did not reach statistical significance (r = -0.196, P = 0.083). Multiple linear regression analysis showed that %CSA(<5) and diffusing capacity of carbon monoxide (DL(CO)) % predicted were independent predictors of Ppa (r(2) = 0.541): %CSA (<5) (P < 0.0001), and DL(CO) % predicted (P = 0.022). CONCLUSIONS The %CSA(<5) measured on CT images is significantly correlated to Ppa in severe emphysema and can estimate the degree of pulmonary hypertension.

Quantitative CT Assessment of Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is characterized by the presence of airflow limitation that is caused by a combination of small airway remodeling and emphysema-induced loss of elastic recoil. The management of COPD depends on the relative distribution and severity of these two pathologic processes, factors that may vary widely even among patients with a similar degree of airflow limitation. Standard lung function testing with spirometry is unhelpful for distinguishing the specific contribution of each process. Pathologic changes such as emphysema and modification of the small and large airways are better evaluated with quantitative analyses of image data from multidetector computed tomography (CT). CT-based quantitative analyses can help differentiate the COPD phenotype (emphysema-predominant, airway-predominant, or mixed), which is crucial information for determining the appropriate management strategy.

Statins and Pulmonary Fibrosis: The Potential Role of NLRP3 Inflammasome Activation

RATIONALE The role of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) in the development or progression of interstitial lung disease (ILD) is controversial. OBJECTIVES To evaluate the association between statin use and ILD. METHODS We used regression analyses to evaluate the association between statin use and interstitial lung abnormalities (ILA) in a large cohort of smokers from COPDGene. Next, we evaluated the effect of statin pretreatment on bleomycin-induced fibrosis in mice and explored the mechanism behind these observations in vitro. MEASUREMENTS AND MAIN RESULTS In COPDGene, 38% of subjects with ILA were taking statins compared with 27% of subjects without ILA. Statin use was positively associated in ILA (odds ratio, 1.60; 95% confidence interval, 1.03-2.50; P = 0.04) after adjustment for covariates including a history of high cholesterol or coronary artery disease. This association was modified by the hydrophilicity of statin and the age of the subject. Next, we demonstrate that statin administration aggravates lung injury and fibrosis in bleomycin-treated mice. Statin pretreatment enhances caspase-1-mediated immune responses in vivo and in vitro; the latter responses were abolished in bone marrow-derived macrophages isolated from Nlrp3(-/-) and Casp1(-/-) mice. Finally, we provide further insights by demonstrating that statins enhance NLRP3-inflammasome activation by increasing mitochondrial reactive oxygen species generation in macrophages. CONCLUSIONS Statin use is associated with ILA among smokers in the COPDGene study and enhances bleomycin-induced lung inflammation and fibrosis in the mouse through a mechanism involving enhanced NLRP3-inflammasome activation. Our findings suggest that statins may influence the susceptibility to, or progression of, ILD. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

Quantitative CT Measurement of Cross-sectional Area of Small Pulmonary Vessel in COPD: Correlations with Emphysema and Airflow Limitation

RATIONALE AND OBJECTIVES Pulmonary vascular alteration is one of the characteristic features of chronic obstructive pulmonary disease (COPD). Recent studies suggest that vascular alteration is closely related to endothelial dysfunction and may be further influenced by emphysema. However, the relationship between morphological alteration of small pulmonary vessels and the extent of emphysema has not been assessed in vivo. The objectives of this study are: to evaluate the correlation of total cross-sectional area (CSA) of small pulmonary vessels with the extent of emphysema and airflow obstruction using CT scans and to assess the difference of total CSA between COPD phenotypes. MATERIALS AND METHODS We measured CSA less than 5 mm(2) and 5-10 mm(2), and calculated the percentage of the total CSA for the lung area (%CSA < 5, and %CSA5-10, respectively) using CT scans in 191 subjects. The extent of emphysema (%LAA-950) was calculated, and the correlations of %CSA < 5 and %CSA5-10 with %LAA-950 and results of pulmonary function tests (PFTs) were evaluated. The differences in %CSA between COPD phenotypes were also assessed. RESULTS The %CSA < 5 had significant negative correlations with %LAA-950 (r = -0.83, P < .0001). There was a weak but statistically significant correlation of %CSA < 5 with forced expiratory volume in 1 second (FEV1)% predicted (r = 0.29, P < .0001) and FEV1/forced vital capacity (r = 0.45, P < .0001). A %CSA 5-10 had weak correlations with %LAA-950 and results of PFTs. %CSA < 5 was significantly higher in bronchitis phenotype than in the emphysema phenotype (P < .0001). CONCLUSIONS Total CSA of small pulmonary vessels at sub-subsegmental levels strongly correlates with the extent of emphysema (%LAA-950) and reflects differences between COPD phenotypes.

Collapsibility of lung volume by paired inspiratory and expiratory CT scans: Correlations with lung function and mean lung density

RATIONALE AND OBJECTIVES To evaluate the relationship between measurements of lung volume (LV) on inspiratory/expiratory computed tomography (CT) scans, pulmonary function tests (PFT), and CT measurements of emphysema in individuals with chronic obstructive pulmonary disease. MATERIALS AND METHODS Forty-six smokers (20 females and 26 males; age range 46-81 years), enrolled in the Lung Tissue Research Consortium, underwent PFT and chest CT at full inspiration and expiration. Inspiratory and expiratory LV values were automatically measured by open-source software, and the expiratory/inspiratory (E/I) ratio of LV was calculated. Mean lung density (MLD) and low attenuation area percent (<-950 HU) were also measured. Correlations of LV measurements with lung function and other CT indices were evaluated by the Spearman rank correlation test. RESULTS LV E/I ratio significantly correlated with the following: the percentage of predicted value of forced expiratory volume in the first second (FEV(1)), the ratio of FEV(1) to forced vital capacity (FVC), and the ratio of residual volume (RV) to total lung capacity (TLC) (FEV(1)%P, R = -0.56, P < .0001; FEV(1)/FVC, r = -0.59, P < .0001; RV/TLC, r = 0.57, P < .0001, respectively). A higher correlation coefficient was observed between expiratory LV and expiratory MLD (r = -0.73, P < .0001) than between inspiratory LV and inspiratory MLD (r = -0.46, P < .01). LV E/I ratio showed a very strong correlation to MLD E/I ratio (r = 0.95, P < .0001). CONCLUSIONS LV E/I ratio can be considered to be equivalent to MLD E/I ratio and to reflect airflow limitation and air-trapping. Higher collapsibility of lung volume, observed by inspiratory/expiratory CT, indicates less severe conditions in chronic obstructive pulmonary disease.

Airway wall attenuation: a biomarker of airway disease in subjects with COPD.

The computed tomographic (CT) densities of imaged structures are a function of the CT scanning protocol, the structure size, and the structure density. For objects that are of a dimension similar to the scanner point spread function, CT will underestimate true structure density. Prior investigation suggests that this process, termed contrast reduction, could be used to estimate the strength of thin structures, such as cortical bone. In this investigation, we endeavored to exploit this process to provide a CT-based measure of airway disease that can assess changes in airway wall thickening and density that may be associated with the mural remodeling process in subjects with chronic obstructive pulmonary disease (COPD). An initial computer-based study using a range of simulated airway wall sizes and densities suggested that CT measures of airway wall attenuation could detect changes in both wall thickness and structure density. A second phantom-based study was performed using a series of polycarbonate tubes of known density. The results of this again demonstrated the process of contrast reduction and further validated the computer-based simulation. Finally, measures of airway wall attenuation, wall thickness, and wall area (WA) divided by total cross-sectional area, WA percent (WA%), were performed in a cohort of 224 subjects with COPD and correlated with spirometric measures of lung function. The results of this analysis demonstrated that wall attenuation is comparable to WA% in predicting lung function on univariate correlation and remain as a statistically significant correlate to the percent forced expiratory volume in 1 s predicted when adjusted for measures of both emphysema and WA%. These latter findings suggest that the quantitative assessment of airway wall attenuation may offer complementary information to WA% in characterizing airway disease in subjects with COPD.

Airway Count and Emphysema Assessed by Chest CT Imaging Predicts Clinical Outcome in Smokers

BACKGROUND Recently, it has been shown that emphysematous destruction of the lung is associated with a decrease in the total number of terminal bronchioles. It is unknown whether a similar decrease is visible in the more proximal airways. We aimed to assess the relationships between proximal airway count, CT imaging measures of emphysema, and clinical prognostic factors in smokers, and to determine whether airway count predicts the BMI, airflow obstruction, dyspnea, and exercise capacity (BODE) index. METHODS In 50 smokers, emphysema was measured on CT scans and airway branches from the third to eighth generations of the right upper lobe apical bronchus were counted manually. The sum of airway branches from the sixth to eighth generations represented the total airway count (TAC). For each subject, the BODE index was determined. We used logistic regression to assess the ability of TAC to predict a high BODE index (≥ 7 points). RESULTS TAC was inversely associated with emphysema (r = -0.54, P < .0001). TAC correlated with the modified Medical Research Council dyspnea score (r = -0.42, P = .004), FEV(1)% predicted (r = 0.52, P = .0003), 6-min walk distance (r = 0.36, P = .012), and BODE index (r = -0.55, P < .0001). The C-statistics, which correspond to the area under the receiver operating characteristic curve, for the ability of TAC alone and TAC, emphysema, and age to predict a high BODE index were 0.84 and 0.92, respectively. CONCLUSIONS TAC is lower in subjects with greater emphysematous destruction and is a predictor of a high BODE index. These results suggest that CT imaging-based TAC may be a unique COPD-related phenotype in smokers.

Relationship of Emphysema and Airway Disease Assessed by CT to Exercise Capacity in COPD

OBJECTIVE To assess the association of emphysema and airway disease assessed by volumetric computed tomography (CT) with exercise capacity in subjects with chronic obstructive pulmonary disease (COPD). METHODS We studied 93 subjects with COPD (Forced Expiratory Volume in 1 s [FEV(1)] %predicted mean +/- SD 57.1 +/- 24.3%, female gender = 40) enrolled in the Lung Tissue Research Consortium. Emphysema was defined as percentage of low attenuation areas less than a threshold of -950 Hounsfield units (%LAA-950) on CT scan. The wall area percentage (WA%) of the 3rd to 6th generations of the apical bronchus of right upper lobe (RB1) were analyzed. The 6-min walk distance (6MWD) test was used as a measure of exercise capacity. RESULTS The 6MWD was inversely associated with %LAA-950 (r = -0.53, p < 0.0001) and with the WA% of 6th generation of RB1 only (r = -0.28, p = 0.009). In a multivariate regression model including CT indices of emphysema and airway disease that were adjusted for demographic and physiologic variables as well as brand of CT scanner, only the %LAA-950 remained significantly associated with exercise performance. Holding other covariates fixed, this model showed that a 10% increase of CT emphysema reduced the distance walked in 6 min 28.6 m (95% Confidence Interval = -51.2, -6.0, p = 0.01). CONCLUSION These results suggest that the extent of emphysema but not airway disease measured by volumetric CT contributes independently to exercise limitation in subjects with COPD.

Interstitial Lung Abnormalities and Reduced Exercise Capacity

RATIONALE The relationship between interstitial lung abnormalities (ILA) and exercise capacity has not been comprehensively evaluated. OBJECTIVES To assess the validity of the 6-minute walk test in subjects with ILA, and to examine the association between ILA and 6-minute walk distance (6MWD). METHODS Spearman correlation coefficients were used to assess the strength of the relationships between 6MWD and relevant measures of dyspnea, health-related quality of life, and pulmonary function in a cohort of 2,416 people who smoke from the COPDGene study. Unadjusted and adjusted linear and logistic regression models were used to assess the strength of the association between ILA and 6MWD. MEASUREMENTS AND MAIN RESULTS In all subjects, and in those with ILA, 6MWD in COPDGene was associated with relevant clinical and physiologic measures. The mean 6MWD in COPDGene subjects with ILA was 386 m (SD, 128 m), and 82% and 19% of subjects with ILA had 6MWDs less than or equal to 500 and 250 m, respectively. ILA was associated with a reduced 6MWD in univariate (-30 m; 95% confidence interval, -50 to -10; P = 0.004) and multivariate models (-19 m; 95% confidence interval, -33 to -5; P = 0.008). Compared with subjects without ILA, subjects with ILA had an 80% and 77% increase in their odds to have a walk distance limited to less than or equal to 500 and 250 m, respectively. Although these findings were dependent on ILA subtype, they were not limited to those with COPD. CONCLUSIONS Our study demonstrates that ILA is associated with measurable decrements in the 6MWD of people who smoke. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).