Two CHRN susceptibility variants for COPD are genetic determinants of emphysema and chest computed tomography manifestations in Chinese patients.
ABSTRACT: Quantitative computed tomography (CT) measures of emphysema have been shown to be associated with increased mortality in humans, but genetic variants affecting the quantitative parameters of chest CT that measure degree of emphysema have not yet been examined. In this study, using available chest CT data from a total of 344 emphysema patients, we assessed the correlations between five chronic obstructive pulmonary disease (COPD) susceptibility variants in the cholinergic receptor nicotinic (CHRN) genes and the degree of emphysema and chest CT manifestations. We verified that most of the parameters were significantly correlated with the degree of emphysema. Compared to rs76071148AA and TT genotype carriers, the rs76071148AT genotype carriers exhibited a decreased probability of having severe emphysema (odds ratio [OR] =0.63, 95% confidence interval [CI] =0.40-0.99), whereas the variant rs8040868C allele was negatively correlated with the emphysema index (P=0.002). Interestingly, further stratification analysis grouped by spirometry-diagnosed COPD status revealed that the variant rs8040868C (CT + CC) genotypes exerted a protective effect against severe emphysema with borderline significance (OR =0.41, 95% CI =0.16-1.05) and affected the mean lung density, emphysema index, ratio of airway wall thickness to airway dimensions (AWT/AD), and AWT grade in spirometry-diagnosed non-COPD subjects. The rs76071148 variant was also significantly associated with AWT/AD and AWT grade in those individuals. In summary, we determined that rs8040868 and rs76071148 are promising indicators of the degree of emphysema and chest CT manifestations, especially in spirometry-diagnosed non-COPD subjects.
Project description:The coexistence of COPD and asthma is widely recognized but has not been well described. This study characterizes clinical features, spirometry, and chest CT scans of smoking subjects with both COPD and asthma.We performed a cross-sectional study comparing subjects with COPD and asthma to subjects with COPD alone in the COPDGene Study.119 (13%) of 915 subjects with COPD reported a history of physician-diagnosed asthma. These subjects were younger (61.3 vs 64.7 years old, p=0.0001) with lower lifetime smoking intensity (43.7 vs 55.1 pack years, p=0.0001). More African-Americans reported a history of asthma (33.6% vs 15.6%, p<0.0001). Subjects with COPD and asthma demonstrated worse disease-related quality of life, were more likely to have had a severe COPD exacerbation in the past year, and were more likely to experience frequent exacerbations (OR 3.55 [2.19, 5.75], p<0.0001). Subjects with COPD and asthma demonstrated greater gas-trapping on chest CT. There were no differences in spirometry or CT measurements of emphysema or airway wall thickness.Subjects with COPD and asthma represent a relevant clinical population, with worse health-related quality of life. They experience more frequent and severe respiratory exacerbations despite younger age and reduced lifetime smoking history.ClinicalTrials.gov: NCT00608764.
Project description:Decreased diffusing capacity of the lung for carbon monoxide (DLCO) is associated with emphysema. DLCO is also related to decreased arterial oxygen tension (PaO2), but there are limited data on associations between PaO2 and computed tomography (CT) derived measures of emphysema and airway wall thickness.To examine whether CT measures of emphysema and airway wall thickness are associated with level of arterial oxygen tension beyond that provided by measurements of diffusion capacity and spirometry.The study sample consisted of 271 smoking or ex-smoking COPD patients from the Bergen COPD Cohort Study examined in 2007-2008. Emphysema was assessed as percent of low-attenuation areas<-950 Hounsfield units (%LAA), and airway wall thickness as standardised measure at an internal perimeter of 10 mm (AWT-Pi10). Multiple linear regression models were fitted with PaO2 as the outcome variable, and %LAA, AWT-Pi10, DLCO and carbon monoxide transfer coefficient (KCO) as main explanatory variables. The models were adjusted for sex, age, smoking status, and haemoglobin concentration, as well as forced expiratory volume in one second (FEV1).Sixty two per cent of the subjects were men, mean (SD) age was 64 (7) years, mean (SD) FEV1 in percent predicted was 50 (15)%, and mean PaO2 (SD) was 9.3 (1.1) kPa. The adjusted regression coefficient (CI) for PaO2 was -0.32 (-0.04-(-0.019)) per 10% increase in %LAA (p<0.01). When diffusion capacity and FEV1 were added to the model, respectively, the association lost its statistical significance. No relationship between airway wall thickness and PaO2 was found.CT assessment of airway wall thickness is not associated with arterial oxygen tension in COPD patients. Emphysema score measured by chest CT, is related to decreased PaO2, but cannot replace measurements of diffusion capacity in the clinical evaluation of hypoxaemia.
Project description:BACKGROUND:The mechanisms underlying airflow obstruction in COPD cannot be distinguished by standard spirometry. We ascertain whether mathematical modeling of airway biomechanical properties, as assessed from spirometry, could provide estimates of emphysema presence and severity, as quantified by computed tomography (CT) metrics and CT-based radiomics. METHODS:We quantified presence and severity of emphysema by standard CT metrics (VIDA) and co-registration analysis (ImbioLDA) of inspiratory-expiratory CT in 194 COPD patients who underwent pulmonary function testing. According to percentages of low attenuation area below -?950 Hounsfield Units (%LAA-950insp) patients were classified as having no emphysema (NE) with %LAA-950insp?<?6, moderate emphysema (ME) with %LAA-950insp???6 and?<?14, and severe emphysema (SE) with %LAA-950insp???14. We also obtained stratified clusters of emphysema CT features by an automated unsupervised radiomics approach (CALIPER). An emphysema severity index (ESI), derived from mathematical modeling of the maximum expiratory flow-volume curve descending limb, was compared with pulmonary function data and the three CT classifications of emphysema presence and severity as derived from CT metrics and radiomics. RESULTS:ESI mean values and pulmonary function data differed significantly in the subgroups with different emphysema degree classified by VIDA, ImbioLDA and CALIPER (p?<?0.001 by ANOVA). ESI differentiated NE from ME/SE CT-classified patients (sensitivity 0.80, specificity 0.85, AUC 0.86) and SE from ME CT-classified patients (sensitivity 0.82, specificity 0.87, AUC 0.88). CONCLUSIONS:Presence and severity of emphysema in patients with COPD, as quantified by CT metrics and radiomics can be estimated by mathematical modeling of airway function as derived from standard spirometry.
Project description:Gas trapping quantified on chest CT scans has been proposed as a surrogate for small airway disease in COPD. We sought to determine if measurements using paired inspiratory and expiratory CT scans may be better able to separate gas trapping due to emphysema from gas trapping due to small airway disease.Smokers with and without COPD from the COPDGene Study underwent inspiratory and expiratory chest CT scans. Emphysema was quantified by the percent of lung with attenuation?<?-950HU on inspiratory CT. Four gas trapping measures were defined: (1) Exp(-856), the percent of lung?<?-856HU on expiratory imaging; (2) E/I MLA, the ratio of expiratory to inspiratory mean lung attenuation; (3) RVC(856-950), the difference between expiratory and inspiratory lung volumes with attenuation between -856 and -950 HU; and (4) Residuals from the regression of Exp(-856) on percent emphysema.In 8517 subjects with complete data, Exp(-856) was highly correlated with emphysema. The measures based on paired inspiratory and expiratory CT scans were less strongly correlated with emphysema. Exp(-856), E/I MLA and RVC(856-950) were predictive of spirometry, exercise capacity and quality of life in all subjects and in subjects without emphysema. In subjects with severe emphysema, E/I MLA and RVC(856-950) showed the highest correlations with clinical variables.Quantitative measures based on paired inspiratory and expiratory chest CT scans can be used as markers of small airway disease in smokers with and without COPD, but this will require that future studies acquire both inspiratory and expiratory CT scans.
Project description:BACKGROUND: Increased airway wall thickness (AWT) and parenchymal lung destruction both contribute to airflow limitation. Advances in computed tomography (CT) post-processing imaging allow to quantify these features. The aim of this Dutch population study is to assess the relationships between AWT, lung function, emphysema and respiratory symptoms. METHODS: AWT and emphysema were assessed by low-dose CT in 500 male heavy smokers, randomly selected from a lung cancer screening population. AWT was measured in each lung lobe in cross-sectionally reformatted images with an automated imaging program at locations with an internal diameter of 3.5 mm, and validated in smaller cohorts of patients. The 15th percentile method (Perc15) was used to assess the severity of emphysema. Information about respiratory symptoms and smoking behavior was collected by questionnaires and lung function by spirometry. RESULTS: Median AWT in airways with an internal diameter of 3.5 mm (AWT3.5) was 0.57 (0.44 - 0.74) mm. Median AWT in subjects without symptoms was 0.52 (0.41-0.66) and in those with dyspnea and/or wheezing 0.65 (0.52-0.81) mm (p<0.001). In the multivariate analysis only AWT3.5 and emphysema independently explained 31.1%and 9.5%of the variance in FEV1%predicted, respectively, after adjustment for smoking behavior. CONCLUSIONS: Post processing standardization of airway wall measurements provides a reliable and useful method to assess airway wall thickness. Increased airway wall thickness contributes more to airflow limitation than emphysema in a smoking male population even after adjustment for smoking behavior.
Project description:Emphysematous smokers with normal spirometry form a considerable proportion of the clinical population. However, despite presenting with respiratory symptoms and activity limitation, they cannot be diagnosed with chronic obstructive lung disease (COPD) according to current criteria. Thus, we aimed to determine whether emphysema in smokers has a different pathogenesis from that in patients with COPD. We compared 12 pairs of lung tissue samples from emphysematous patients with normal spirometry and COPD, and determined the degree of emphysema using computed tomography. With a focus on COPD-related pathogenesis, we independently assessed inflammatory response, protease-antiprotease balance, oxidative stress, and apoptosis in both groups. Both groups showed similar pathological changes at a comparable degree of emphysema; the expression of inflammatory factors was comparable, with overexpression of proteases and decreased levels of antiproteases. Moreover, there was no significant difference in the activities of glutathione and superoxide dismutase, and expression of apoptosis-related factors. In conclusion, emphysema in smokers with normal spirometry and in patients with COPD had similar pathogenesis. Forced expiratory volume in 1?second cannot be used as the sole diagnostic criterion in patients with COPD; early intervention is of great importance to such patients.
Project description:Phenotyping of chronic obstructive pulmonary disease (COPD) with computed tomography (CT) is used to distinguish between emphysema- and airway-dominated type. The phenotype is reflected in correlations with lung function measures. Among these, the relative value of body plethysmography has not been quantified. We addressed this question using CT scans retrospectively collected from clinical routine in a large COPD cohort. Three hundred and thirty five patients with baseline data of the German COPD cohort COPD and Systemic Consequences-Comorbidities Network were included. CT scans were primarily evaluated using a qualitative binary emphysema score. The binary score was positive for emphysema in 52.5% of patients, and there were significant differences between the positive/negative groups regarding forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity (FVC), intrathoracic gas volume (ITGV), residual volume (RV), specific airway resistance (sRaw), transfer coefficient (KCO), transfer factor for carbon monoxide (TLCO), age, pack-years, and body mass index (BMI). Stepwise discriminant analyses revealed the combination of FEV1/FVC, RV, sRaw, and KCO to be significantly related to the binary emphysema score. The additional positive predictive value of body plethysmography, however, was only slightly higher than that of the conventional combination of spirometry and diffusing capacity, which if taken alone also achieved high predictive values, in contrast to body plethysmography. The additional information on the presence of CT-diagnosed emphysema as conferred by body plethysmography appeared to be minor compared to the well-known combination of spirometry and CO diffusing capacity.
Project description:RATIONALE AND OBJECTIVES:Many patients with chronic obstructive pulmonary disease (COPD) have marked discordance between forced expiratory volume in 1 second (FEV1) and degree of emphysema on computed tomography (CT). Biomechanical differences between these patients have not been studied. We aimed to identify reasons for the discordance between CT and spirometry in some patients with COPD. MATERIALS AND METHODS:Subjects with Global initiative for chronic Obstructive Lung Disease stages I-IV from a large multicenter study (The Genetic Epidemiology of COPD) were arranged by percentiles of %predicted FEV1 and emphysema on CT. Three categories were created using differences in percentiles: Catspir with predominant airflow obstruction/minimal emphysema, CatCT with predominant emphysema/minimal airflow obstruction, and Catmatched with matched FEV1 and emphysema. Image registration was used to derive Jacobian determinants, a measure of lung elasticity, anisotropy, and strain tensors, to assess biomechanical differences between groups. Regression models were created with the previously mentioned categories as outcome variable, adjusting for demographics, scanner type, quantitative CT-derived emphysema, gas trapping, and airway thickness (model 1), and after adding biomechanical CT metrics (model 2). RESULTS:Jacobian determinants, anisotropy, and strain tensors were strongly associated with FEV1. With Catmatched as control, model 2 predicted Catspir and CatCT better than model 1 (Akaike information criterion 255.8 vs. 320.8). In addition to demographics, the strongest independent predictors of FEV1 were Jacobian mean (??=?1.60,95%confidence intervals [CI]?=?1.16 to 1.98; P?<?0.001), coefficient of variation (CV) of Jacobian (??=?1.45,95%CI?=?0.86 to 2.03; P?<?0.001), and CV of strain (??=?1.82,95%CI?=?0.68 to 2.95; P?=?0.001). CVs of Jacobian and strain are both potential markers of biomechanical lung heterogeneity. CONCLUSIONS:CT-derived measures of lung mechanics improve the link between quantitative CT and spirometry, offering the potential for new insights into the linkage between regional parenchymal destruction and global decrement in lung function in patients with COPD.
Project description:The demographic, physiological, and computed tomography (CT) features associated with pneumothorax in smokers with and without chronic obstructive pulmonary disease (COPD) are not clearly defined.We evaluated the hypothesis that pneumothorax in smokers is associated with male sex, tall and thin stature, airflow obstruction, and increased total and subpleural emphysema.The study included smokers with and without COPD from the COPDGene Study, with quantitative chest CT analysis. Pleural-based emphysema was assessed on the basis of local histogram measures of emphysema. Pneumothorax history was defined by subject self-report.Pneumothorax was reported in 286 (3.2%) of 9,062 participants. In all participants, risk of prior pneumothorax was significantly higher in men (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.08-2.22) and non-Hispanic white subjects (OR, 1.90; 95% CI, 1.34-2.69). Risk of prior pneumothorax was associated with increased percent CT emphysema in all participants and participants with COPD (OR, 1.04 for each 1% increase in emphysema; 95% CI, 1.03-1.06). Increased pleural-based emphysema was independently associated with risk of past pneumothorax in all participants (OR, 1.05 for each 1% increase; 95% CI, 1.01-1.10). In smokers with normal spirometry, risk of past pneumothorax was associated with non-Hispanic white race and lifetime smoking intensity (OR, 1.20 for every 10 pack-years; 95% CI, 1.09-1.33).Among smokers, pneumothorax is associated with male sex, non-Hispanic white race, and increased percentage of total and subpleural CT emphysema. Pneumothorax was not independently associated with height or lung function, even in participants with COPD. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).
Project description:Heart Failure (HF) and chronic obstructive pulmonary disease (COPD) are morbid diseases that often coexist. In patients with coexisting disease, COPD is an independent risk factor for readmission and mortality. However, spirometry is often inaccurate in those with active heart failure. Therefore, we investigated the association between the presence of emphysema on computed tomography (CT) and readmission rates in smokers admitted with heart failure (HF). The cohort included a consecutive group of smokers discharged with HF from a tertiary center between January 1, 2014 and April 1, 2014 who also had a CT of the chest for dyspnea. The primary endpoint was any readmission for HF before April 1, 2016; secondary endpoints were 30-day readmission for HF, length of stay and all-cause mortality. Over the study period, there were 225 inpatient smokers with HF who had a concurrent chest CT (155 [69%] males, age 69±11 years, ejection fraction [EF] 46±18%, 107 [48%] LVEF of < 50%). Emphysema on CT was present in 103 (46%) and these were older, had a lower BMI, more pack-years, less diabetes and an increased afterload. During a follow-up of 2.1 years, there were 110 (49%) HF readmissions and 55 (24%) deaths. When separated by emphysema on CT, any readmission, 30-day readmission, length of stay and mortality were higher among HF patients with emphysema. In multivariable regression, emphysema by CT was associated with a two-fold higher (adjusted HR 2.11, 95% CI 1.41-3.15, p < 0.001) risk of readmission and a trend toward increased mortality (adjusted HR 1.70 95% CI 0.86-3.34, p = 0.12). In conclusion, emphysema by CT is a frequent finding in smokers hospitalized with HF and is associated with adverse outcomes in HF. This under recognized group of patients with both emphysema and heart failure may benefit from improved recognition and characterization of their co-morbid disease processes and optimization of therapies for their lung disease.