Alejandro A. Diaz

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.).

Etiology of Community-Acquired Pneumonia in Hospitalized Patients in Chile* The Increasing Prevalence of Respiratory Viruses Among Classic Pathogens

BACKGROUND AND STUDY OBJECTIVES The range and relative impact of microbial pathogens, particularly viral pathogens, as a cause of community-acquired pneumonia (CAP) in hospitalized adults has not received much attention. The aim of this study was to determine the microbial etiology of CAP in adults and to identify the risk factors for various specific pathogens. METHODS We prospectively studied 176 patients (mean [+/- SD] age, 65.8 +/- 18.5 years) who had hospitalized for CAP to identify the microbial etiology. For each patient, sputum and blood cultures were obtained as well as serology testing for Mycoplasma pneumoniae and Chlamydophila pneumoniae, urinary antigen testing for Legionella pneumophila and Streptococcus pneumoniae, and a nasopharyngeal swab for seven respiratory viruses. RESULTS Microbial etiology was determined in 98 patients (55%). S pneumoniae (49 of 98 patients; 50%) and respiratory viruses (32%) were the most frequently isolated pathogen groups. Pneumococcal pneumonia was associated with tobacco smoking of > 10 pack-years (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.2 to 5.4; p = 0.01). Respiratory viruses were isolated more often in fall or winter (28%; p = 0.011), and as an exclusive etiology tended to be isolated in patients >/= 65 years of age (20%; p = 0.07). Viral CAP was associated with antimicrobial therapy prior to hospital admission (OR, 4.5; 95% CI, 1.4 to 14.6). CONCLUSIONS S pneumoniae remains the most frequent pathogen in adults with CAP and should be covered with empirical antimicrobial treatment. Viruses were the second most common etiologic agent and should be tested for, especially in fall or winter, both in young and elderly patients who are hospitalized with CAP.

Association between Functional Small Airway Disease and FEV1 Decline in Chronic Obstructive Pulmonary Disease.

RATIONALE The small conducting airways are the major site of airflow obstruction in chronic obstructive pulmonary disease and may precede emphysema development. OBJECTIVES We hypothesized a novel computed tomography (CT) biomarker of small airway disease predicts FEV1 decline. METHODS We analyzed 1,508 current and former smokers from COPDGene with linear regression to assess predictors of change in FEV1 (ml/yr) over 5 years. Separate models for subjects without and with airflow obstruction were generated using baseline clinical and physiologic predictors in addition to two novel CT metrics created by parametric response mapping (PRM), a technique pairing inspiratory and expiratory CT images to define emphysema (PRM(emph)) and functional small airways disease (PRM(fSAD)), a measure of nonemphysematous air trapping. MEASUREMENTS AND MAIN RESULTS Mean (SD) rate of FEV1 decline in ml/yr for GOLD (Global Initiative for Chronic Obstructive Lung Disease) 0-4 was as follows: 41.8 (47.7), 53.8 (57.1), 45.6 (61.1), 31.6 (43.6), and 5.1 (35.8), respectively (trend test for grades 1-4; P < 0.001). In multivariable linear regression, for participants without airflow obstruction, PRM(fSAD) but not PRM(emph) was associated with FEV1 decline (P < 0.001). In GOLD 1-4 participants, both PRM(fSAD) and PRM(emph) were associated with FEV1 decline (P < 0.001 and P = 0.001, respectively). Based on the model, the proportional contribution of the two CT metrics to FEV1 decline, relative to each other, was 87% versus 13% and 68% versus 32% for PRM(fSAD) and PRM(emph) in GOLD 1/2 and 3/4, respectively. CONCLUSIONS CT-assessed functional small airway disease and emphysema are associated with FEV1 decline, but the association with functional small airway disease has greatest importance in mild-to-moderate stage chronic obstructive pulmonary disease where the rate of FEV1 decline is the greatest. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

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.

Identification of early interstitial lung disease in smokers from the COPDGene Study.

RATIONALE AND OBJECTIVES The aim of this study is to compare two subjective methods for the identification of changes suggestive of early interstitial lung disease (ILD) on chest computed tomographic (CT) scans. MATERIALS AND METHODS The CT scans of the first 100 subjects enrolled in the COPDGene Study from a single institution were examined using a sequential reader and a group consensus interpretation scheme. CT scans were evaluated for the presence of parenchymal changes consistent with ILD using the following scoring system: 0 = normal, 1 = equivocal for the presence of ILD, 2 = highly suspicious for ILD, and 3 = classic ILD changes. A statistical comparison of patients with early ILD to normal subjects was performed. RESULTS There was a high degree of agreement between methods (kappa = 0.84; 95% confidence interval, 0.73-0.94; P < .0001 for the sequential and consensus methods). The sequential reading method had both high positive (1.0) and negative (0.97) predictive values for a consensus read despite a 58% reduction in the number of chest CT evaluations. Regardless of interpretation method, the prevalence of chest CT changes consistent with early ILD in this subset of smokers from COPDGene varied between 5% and 10%. Subjects with early ILD tended to have greater tobacco smoke exposure than subjects without early ILD (P = .053). CONCLUSIONS A sequential CT interpretation scheme is an efficient method for the visual interpretation of CT data. Further investigation is required to independently confirm our findings and further characterize early ILD in smokers.

Computed Tomographic Measures of Pulmonary Vascular Morphology in Smokers and Their Clinical Implications

RATIONALE Angiographic investigation suggests that pulmonary vascular remodeling in smokers is characterized by distal pruning of the blood vessels. OBJECTIVES Using volumetric computed tomography scans of the chest we sought to quantitatively evaluate this process and assess its clinical associations. METHODS Pulmonary vessels were automatically identified, segmented, and measured. Total blood vessel volume (TBV) and the aggregate vessel volume for vessels less than 5 mm(2) (BV5) were calculated for all lobes. The lobe-specific BV5 measures were normalized to the TBV of that lobe and the nonvascular tissue volume (BV5/T(issue)V) to calculate lobe-specific BV5/TBV and BV5/T(issue)V ratios. Densitometric measures of emphysema were obtained using a Hounsfield unit threshold of -950 (%LAA-950). Measures of chronic obstructive pulmonary disease severity included single breath measures of diffusing capacity of carbon monoxide, oxygen saturation, the 6-minute-walk distance, St Georges Respiratory Questionnaire total score (SGRQ), and the body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index. MEASUREMENTS AND MAIN RESULTS The %LAA-950 was inversely related to all calculated vascular ratios. In multivariate models including age, sex, and %LAA-950, lobe-specific measurements of BV5/TBV were directly related to resting oxygen saturation and inversely associated with both the SGRQ and BODE scores. In similar multivariate adjustment lobe-specific BV5/T(issue)V ratios were inversely related to resting oxygen saturation, diffusing capacity of carbon monoxide, 6-minute-walk distance, and directly related to the SGRQ and BODE. CONCLUSIONS Smoking-related chronic obstructive pulmonary disease is characterized by distal pruning of the small blood vessels (<5 mm(2)) and loss of tissue in excess of the vasculature. The magnitude of these changes predicts the clinical severity of disease.

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.

Association Between Interstitial Lung Abnormalities and All-Cause Mortality

IMPORTANCE Interstitial lung abnormalities have been associated with lower 6-minute walk distance, diffusion capacity for carbon monoxide, and total lung capacity. However, to our knowledge, an association with mortality has not been previously investigated. OBJECTIVE To investigate whether interstitial lung abnormalities are associated with increased mortality. DESIGN, SETTING, AND POPULATION Prospective cohort studies of 2633 participants from the FHS (Framingham Heart Study; computed tomographic [CT] scans obtained September 2008-March 2011), 5320 from the AGES-Reykjavik Study (Age Gene/Environment Susceptibility; recruited January 2002-February 2006), 2068 from the COPDGene Study (Chronic Obstructive Pulmonary Disease; recruited November 2007-April 2010), and 1670 from ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; between December 2005-December 2006). EXPOSURES Interstitial lung abnormality status as determined by chest CT evaluation. MAIN OUTCOMES AND MEASURES All-cause mortality over an approximate 3- to 9-year median follow-up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort. RESULTS Interstitial lung abnormalities were present in 177 (7%) of the 2633 participants from FHS, 378 (7%) of 5320 from AGES-Reykjavik, 156 (8%) of 2068 from COPDGene, and in 157 (9%) of 1670 from ECLIPSE. Over median follow-up times of approximately 3 to 9 years, there were more deaths (and a greater absolute rate of mortality) among participants with interstitial lung abnormalities when compared with those who did not have interstitial lung abnormalities in the following cohorts: 7% vs 1% in FHS (6% difference [95% CI, 2% to 10%]), 56% vs 33% in AGES-Reykjavik (23% difference [95% CI, 18% to 28%]), and 11% vs 5% in ECLIPSE (6% difference [95% CI, 1% to 11%]). After adjustment for covariates, interstitial lung abnormalities were associated with a higher risk of death in the FHS (hazard ratio [HR], 2.7 [95% CI, 1.1 to 6.5]; P = .03), AGES-Reykjavik (HR, 1.3 [95% CI, 1.2 to 1.4]; P < .001), COPDGene (HR, 1.8 [95% CI, 1.1 to 2.8]; P = .01), and ECLIPSE (HR, 1.4 [95% CI, 1.1 to 2.0]; P = .02) cohorts. In the AGES-Reykjavik cohort, the higher rate of mortality could be explained by a higher rate of death due to respiratory disease, specifically pulmonary fibrosis. CONCLUSIONS AND RELEVANCE In 4 separate research cohorts, interstitial lung abnormalities were associated with a greater risk of all-cause mortality. The clinical implications of this association require further investigation.

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.