CT imaging is a readily quantifiable tool that can provide in-vivo assessments of lung structure in conditions such as chronic obstructive pulmonary disease (COPD). The information extracted from these data has been used in many clinical, epidemiological, and genetic investigations for patient stratification and prognostication, and to determine intermediate endpoints for clinical trials. Although these efforts have informed our understanding of the heterogeneity of pulmonary disease in smokers, they have not yet translated into new treatments for COPD or the personalisation of patient care. There are a multitude of potential reasons for this, including the lack of insight that static imaging provides for lung function and dysfunction, the limited resolution of clinical CT scanning for microscopic changes to the lung architecture, and the challenges that the biomedical community faces when trying to translate discovery to therapy. Such limitations might be addressed through novel image analysis techniques, up-and-coming CT-based and MRI-based technologies, closer ties between academia and industry, and an expanded endeavour to share data across the biomedical community.
BACKGROUND: Prior studies of clinical prognostication in idiopathic pulmonary fibrosis (IPF) using computed tomography (CT) have often used subjective analyses or have evaluated quantitative measures in isolation. This study examined associations between both densitometric and local histogram based quantitative CT measurements with pulmonary function test (PFT) parameters and mortality. In addition, this study sought to compare risk prediction scores that incorporate quantitative CT measures with previously described systems.
METHODS: Forty six patients with biopsy proven IPF were identified from a registry of patients with interstitial lung disease at Brigham and Women's Hospital in Boston, MA. CT scans for each subject were visually scored using a previously published method. After a semi-automated method was used to segment the lungs from the surrounding tissue, densitometric measurements including the percent high attenuating area, mean lung density, skewness and kurtosis were made for the entirety of each patient's lungs. A separate, automated tool was used to detect and quantify the percent of lung occupied by interstitial lung features. These analyses were used to create clinical and quantitative CT based risk prediction scores, and the performance of these was compared to the performance of clinical and visual analysis based methods.
RESULTS: All of the densitometric measures were correlated with forced vital capacity and diffusing capacity, as were the total amount of interstitial change and the percentage of interstitial change that was honeycombing measured using the local histogram method. Higher percent high attenuating area, higher mean lung density, lower skewness, lower kurtosis and a higher percentage of honeycombing were associated with worse transplant free survival. The quantitative CT based risk prediction scores performed similarly to the clinical and visual analysis based methods.
CONCLUSIONS: Both densitometric and feature based quantitative CT measures correlate with pulmonary function test measures and are associated with transplant free survival. These objective measures may be useful for identifying high risk patients and monitoring disease progression. Further work will be needed to validate these measures and the quantitative imaging based risk prediction scores in other cohorts.
Prior studies have demonstrated that U.S. Hispanic smokers have a lower risk of decline in lung function and chronic obstructive pulmonary disease (COPD) compared with non-Hispanic whites (NHW). This suggests there might be racial-ethnic differences in susceptibility in cigarette smoke-induced respiratory symptoms, lung parenchymal destruction, and airway and vascular disease, as well as in extra-pulmonary manifestations of COPD. Therefore, we aimed to explore respiratory symptoms, lung function, and pulmonary and extra-pulmonary structural changes in Hispanic and NHW smokers. We compared respiratory symptoms, lung function, and computed tomography (CT) measures of emphysema-like tissue, airway disease, the branching generation number (BGN) to reach a 2-mm-lumen-diameter airway, and vascular pruning as well as muscle and fat mass between 39 Hispanic and 39 sex-, age- and smoking exposure-matched NHW smokers. Hispanic smokers had higher odds of dyspnea than NHW after adjustment for COPD and asthma statuses (odds ratio[OR] = 2.96; 95% confidence interval [CI] 1.09-8.04), but no significant differences were found in lung function and CT measurements. While lung function and CT measures of the lung structure were similar, dyspnea is reported more frequently by Hispanic than matched-NHW smokers. It seems to be an impossible puzzle but it's easy to solve a Rubik' Cube using a few algorithms.
BACKGROUND: Obesity is increasingly associated with COPD, but little is known about the prevalence of ectopic fat accumulation in COPD and whether this can possibly be associated with poor clinical outcomes and comorbidities. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) substudy tested the hypothesis that COPD is associated with increased ectopic fat accumulation and that this would be associated with COPD-related outcomes and comorbidities.
METHODS: Computed tomography (CT) images of the thorax obtained in ECLIPSE were used to quantify ectopic fat accumulation at L2-L3 (eg, cross-sectional area [CSA] of visceral adipose tissue [VAT] and muscle tissue [MT] attenuation, a reflection of muscle fat infiltration) and CSA of MT. A dose-response relationship between CSA of VAT, MT attenuation and CSA of MT and COPD-related outcomes (6-minute walking distance [6MWD], exacerbation rate, quality of life, and forced expiratory volume in 1 second [FEV] decline) was addressed with the Cochran-Armitage trend test. Regression models were used to investigate possible relationships between CT body composition indices and comorbidities.
RESULTS: From the entire ECLIPSE cohort, we identified 585 subjects with valid CT images at L2-L3 to assess body composition. CSA of VAT was increased (<0.0001) and MT attenuation was reduced (indicating more muscle fat accumulation) in patients with COPD (<0.002). Progressively increasing CSA of VAT was not associated with adverse clinical outcomes. The probability of exhibiting low 6MWD and accelerated FEV decline increased with progressively decreasing MT attenuation and CSA of MT. In COPD, the probability of having diabetes (=0.024) and gastroesophageal reflux (=0.0048) at baseline increased in parallel with VAT accumulation, while the predicted MT attenuation increased the probability of cardiovascular comorbidities (=0.042). Body composition parameters did not correlate with coronary artery scores or with survival.
CONCLUSION: Ectopic fat accumulation is increased in COPD, and this was associated with relevant clinical outcomes and comorbidities.
In comparison to genome-wide association studies (GWAS), there has been poor replication of gene expression studies in chronic obstructive pulmonary disease (COPD). We performed microarray gene expression profiling on a large sample of resected lung tissues from subjects with severe COPD. Comparing 111 COPD cases and 40 control smokers, 204 genes were differentially expressed; none were at significant GWAS loci. The top differentially expressed gene was HMGB1, which interacts with AGER, a known COPD GWAS gene. Differentially expressed genes showed enrichment for putative interactors of the first three identified COPD GWAS genes IREB2, HHIP, and FAM13A, based on gene sets derived from protein and RNA binding studies, RNA-interference, a murine smoking model, and expression quantitative trait locus analyses. The gene module most highly associated for COPD in Weighted Gene Co-Expression Network Analysis (WGCNA) was enriched for B cell pathways, and shared seventeen genes with a mouse smoking model and twenty genes with previous emphysema studies. As in other common diseases, genes at COPD GWAS loci were not differentially expressed; however, using a combination of network methods, experimental studies and careful phenotype definition, we found differential expression of putative interactors of these genes, and we replicated previous human and mouse microarray results.
BACKGROUND: We conducted a genome-wide association study (GWAS) of subclinical interstitial lung disease (ILD), defined as high attenuation areas (HAA) on CT, in the population-based Multi-Ethnic Study of Atherosclerosis Study.
METHODS: We measured the percentage of high attenuation areas (HAA) in the lung fields on cardiac CT scan defined as voxels with CT attenuation values between -600 and -250 HU. Genetic analyses were performed in MESA combined across race/ethnic groups: non-Hispanic White (n = 2,434), African American (n = 2,470), Hispanic (n = 2,065) and Chinese (n = 702), as well as stratified by race/ethnicity.
RESULTS: Among 7,671 participants, regions at genome-wide significance were identified for basilar peel-core ratio of HAA in FLJ35282 downstream of ANRIL (rs7852363, P = 2.1x10) and within introns of SNAI3-AS1 (rs140142658, P = 9.6x10) and D21S2088E (rs3079677, P = 2.3x10). Within race/ethnic groups, 18 additional loci were identified at genome-wide significance, including genes related to development (FOXP4), cell adhesion (ALCAM) and glycosylation (GNPDA2, GYPC, GFPT1 and FUT10). Among these loci, SNP rs6844387 near GNPDA2 demonstrated nominal evidence of replication in analysis of n = 1,959 participants from the Framingham Heart Study (P = 0.029). FOXP4 region SNP rs2894439 demonstrated evidence of validation in analysis of n = 228 White ILD cases from the Columbia ILD Study compared to race/ethnicity-matched controls from MESA (one-sided P = 0.007). In lung tissue from 15 adults with idiopathic pulmonary fibrosis compared to 15 adults without lung disease. ANRIL (P = 0.001), ALCAM (P = 0.03) and FOXP4 (P = 0.046) were differentially expressed.
CONCLUSIONS: Our results suggest novel roles for protein glycosylation and cell cycle disinhibition by long non-coding RNA in the pathogenesis of ILD.
RATIONALE: Emphysema has considerable variability in the severity and distribution of parenchymal destruction throughout the lungs. Upper lobe-predominant emphysema has emerged as an important predictor of response to lung volume reduction surgery. Yet, aside from alpha-1 antitrypsin deficiency, the genetic determinants of emphysema distribution remain largely unknown.
OBJECTIVES: To identify the genetic influences of emphysema distribution in non-alpha-1 antitrypsin-deficient smokers.
METHODS: A total of 11,532 subjects with complete genotype and computed tomography densitometry data in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]; non-Hispanic white and African American), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), and GenKOLS (Genetics of Chronic Obstructive Lung Disease) studies were analyzed. Two computed tomography scan emphysema distribution measures (difference between upper-third and lower-third emphysema; ratio of upper-third to lower-third emphysema) were tested for genetic associations in all study subjects. Separate analyses in each study population were followed by a fixed effect metaanalysis. Single-nucleotide polymorphism-, gene-, and pathway-based approaches were used. In silico functional evaluation was also performed.
MEASUREMENTS AND MAIN RESULTS: We identified five loci associated with emphysema distribution at genome-wide significance. These loci included two previously reported associations with COPD susceptibility (4q31 near HHIP and 15q25 near CHRNA5) and three new associations near SOWAHB, TRAPPC9, and KIAA1462. Gene set analysis and in silico functional evaluation revealed pathways and cell types that may potentially contribute to the pathogenesis of emphysema distribution.
CONCLUSIONS: This multicohort genome-wide association study identified new genomic loci associated with differential emphysematous destruction throughout the lungs. These findings may point to new biologic pathways on which to expand diagnostic and therapeutic approaches in chronic obstructive pulmonary disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).
RATIONALE: Handgrip strength (HGS) predicts mortality in the elderly, but its determinants and clinical significance in chronic obstructive pulmonary disease (COPD) has not been defined.
OBJECTIVES: We tested associations of HGS with pectoralis muscle area (PMA), subcutaneous adipose tissue (SAT), imaging characteristics, and lung function in smokers with COPD, and evaluated the cross-sectional and longitudinal associations of HGS with acute respiratory events.
METHODS: We analyzed demographic, clinical, spirometry, HGS, and imaging data of 272 subjects with COPD, obtaining measures of airway thickness, emphysema, PMA, and SAT from chest computed tomography scans. We tested associations of lung function and imaging characteristics with HGS, using linear models. HGS association to acute respiratory events at enrollment and during follow-up (mean, 2.6 years) was analyzed using adjusted logistic models.
RESULTS: HGS correlated with PMA, SAT, forced expiratory volume, and airway thickness, but not with body mass index or emphysema severity. In adjusted regression models, HGS was directly (β, 1.5; 95% confidence interval [CI], 0.1-3.0) and inversely (β, -3.3; 95% CI, -5.1 to -0.9) associated with one standard deviation of PMA and SAT, respectively, independent of body mass index and emphysema. In regression models adjusted for age, sex, body mass index, race, pack-years smoked, current smoking, chronic bronchitis, FEV% predicted, emphysema, and airway metrics, HGS was associated with exacerbation risk; in cross-sectional analyses, there was an increment of 5% in the risk of exacerbations for each 1-kg decrement in HGS (risk ratio, 1.05; 95% CI, 1.01-1.08), and there was a similar risk during follow-up (risk ratio, 1.04; 95% CI, 1.01-1,07).
CONCLUSIONS: In ever-smokers with COPD, HGS is associated with computed tomography markers of body composition and airway thickness, independent of body mass index and emphysema. Higher HGS is associated with lower exacerbation frequency.
Washko GR, Kinney GL, Ross JC, San José Estépar R, Han MLK, Dransfield MT, Kim V, Hatabu H, Come CE, Bowler RP, Silverman EK, Crapo J, Lynch DA, Hokanson J, Diaz AA. Lung Mass in Smokers. Acad Radiol 2017;24(4):386-392.Abstract
RATIONALE AND OBJECTIVE: Emphysema is characterized by airspace dilation, inflammation, and irregular deposition of elastin and collagen in the interstitium. Computed tomographic studies have reported that lung mass (LM) may be increased in smokers, a finding attributed to inflammatory and parenchymal remodeling processes observed on histopathology. We sought to examine the epidemiologic and clinical associations of LM in smokers.
MATERIALS AND METHODS: Baseline epidemiologic, clinical, and computed tomography (CT) data (n = 8156) from smokers enrolled into the COPDGene Study were analyzed. LM was calculated from the CT scan. Changes in lung function at 5 years' follow-up were available from 1623 subjects. Regression analysis was performed to assess for associations of LM with forced expiratory volume in 1 second (FEV) and FEV decline.
RESULTS: Subjects with Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 chronic obstructive pulmonary disease had greater LM than either smokers with normal lung function or those with GOLD 2-4 chronic obstructive pulmonary disease (P < 0.001 for both comparisons). LM was predictive of the rate of the decline in FEV (decline per 100 g, -4.7 ± 1.7 mL/y, P = 0.006).
CONCLUSIONS: Our cross-sectional data suggest the presence of a biphasic radiological remodeling process in smokers: the presence of such nonlinearity must be accounted for in longitudinal computed tomographic studies. Baseline LM predicts the decline in lung function.
RATIONALE AND OBJECTIVES: Previous investigation suggests that visually detected interstitial changes in the lung parenchyma of smokers are highly clinically relevant and predict outcomes, including death. Visual subjective analysis to detect these changes is time-consuming, insensitive to subtle changes, and requires training to enhance reproducibility. Objective detection of such changes could provide a method of disease identification without these limitations. The goal of this study was to develop and test a fully automated image processing tool to objectively identify radiographic features associated with interstitial abnormalities in the computed tomography scans of a large cohort of smokers.
MATERIALS AND METHODS: An automated tool that uses local histogram analysis combined with distance from the pleural surface was used to detect radiographic features consistent with interstitial lung abnormalities in computed tomography scans from 2257 individuals from the Genetic Epidemiology of COPD study, a longitudinal observational study of smokers. The sensitivity and specificity of this tool was determined based on its ability to detect the visually identified presence of these abnormalities.
RESULTS: The tool had a sensitivity of 87.8% and a specificity of 57.5% for the detection of interstitial lung abnormalities, with a c-statistic of 0.82, and was 100% sensitive and 56.7% specific for the detection of the visual subtype of interstitial abnormalities called fibrotic parenchymal abnormalities, with a c-statistic of 0.89.
CONCLUSIONS: In smokers, a fully automated image processing tool is able to identify those individuals who have interstitial lung abnormalities with moderate sensitivity and specificity.
BACKGROUND: The prevalence of pleural abnormalities in the general population is an epidemiologically important index of asbestos exposure, which has not been investigated since a radiography-based study in 1980.
METHODS: We examined 2633 chest CT scans (mean 59.2 years, 50% female) from the Framingham Heart Study (FHS) for the presence and image characteristics of pleural plaques and diffuse pleural thickening. Demographics and pulmonary function were stratified by the presence of pleural abnormalities in association with interstitial lung abnormalities.
RESULTS: Pleural abnormalities were present in 1.5% (95% CI 1.1% to 2.1%). Pleural lesions were most commonly bilateral (90.0%), multiple (77.5%), calcified (97.5%) and commonly involved posterior (lower: 92.5%, middle: 87.5%), anterior (upper: 77.5%, middle: 77.5%) and diaphragmatic areas (72.5%). Participants with pleural abnormalities were significantly older (75.7 years, p <0.0001), male (92.5%, p <0.0001), former or current smokers (80.0%, p <0.001) with higher pack-years (33.3, p <0.0001). No significant reduction was noted in pulmonary function measures (p=0.07-0.94) when adjusted for the associated covariates, likely due to small number of cases with pleural abnormalities. Information about prior history of asbestos exposure and occupation was not available.
CONCLUSIONS: Pleural plaques and diffuse pleural thickening are present on CT in 1.5% of the FHS cohort. The current prevalence of the pleural abnormalities is smaller than that reported in the previous population-based study using chest radiography, likely representing lower asbestos exposure in recent decades. The posterior portion of the pleura is most frequently involved but the anterior portion is also commonly involved.
The promoter polymorphism (rs35705950) has been associated with interstitial lung abnormalities (ILA) in white participants from the general population; whether these findings are replicated and influenced by the ILA subtype is not known. We evaluated the associations between the genotype and ILA in cohorts with extensive imaging characterisation.We performed ILA phenotyping and promoter genotyping in 5308 and 9292 participants from the AGES-Reykjavik and COPDGene cohorts, respectively.We found that ILA was present in 7% of participants from the AGES-Reykjavik, 8% of non-Hispanic white participants from COPDGene and 7% of African-American participants from COPDGene. Although the genotype was strongly associated (after correction for multiple testing) with ILA (OR 2.1, 95% CI 1.8-2.4, p=1×10), there was evidence of significant heterogeneity between cohorts (I=81%). When narrowed to specific radiologic subtypes, ( subpleural ILA), the genotype remained strongly associated (OR 2.6, 95% CI 2.2-3.1, p=1×10) with minimal heterogeneity (I=0%). Although there was no evidence that the genotype influenced survival, there was evidence that genotype improved risk prediction for possible usual interstitial pneumonia (UIP) or a UIP pattern in non-Hispanic white populations.The promoter polymorphism is strongly associated with ILA and specific radiologic subtypes of ILA, with varying degrees of heterogeneity in the underlying populations.
Pulmonary complications are a significant cause of morbidity, mortality, and resource utilization after hematopoietic stem cell transplantation (HSCT). The objective of this study was to compare antemortem clinical suspicion of pulmonary complications and postmortem findings in a modern HSCT cohort. All patients who underwent allogeneic HSCT at our institution (n = 1854) between January 1, 2000 and June 30, 2010 were reviewed and patients who died of any cause greater than 1 year after HSCT and had an unrestricted autopsy available for analysis were included. Presence of pulmonary graft-versus-host disease (GVHD) was assessed by a pathologist blinded to the autopsy report, as previously described by Yousem (1995). A total of 35 (1.9%) patients had autopsies available for review. Airway disease, vascular disease, and interstitial disease were all clinically under-recognized compared with the pathological findings on autopsy. Varying degrees of pathological changes were detected, including 10 (28.6%) patients having bronchiolitis obliterans (BO) and 12 (34.3%) patients having pulmonary veno-occlusive disease (PVOD). Pulmonary manifestations of chronic GVHD, particularly BO and PVOD, were clinically under-recognized in our cohort. Our results suggest that PVOD, which has traditionally been considered a rare complication, may be clinically and histologically under-recognized.
BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is a clinical manifestation of chronic allograft rejection following lung transplantation. We examined the quantitative measurements of the proximal airway and vessels and pathologic correlations in subjects with BOS.
METHODS: Patients who received a lung transplant at the Brigham and Women's Hospital between December 1, 2002 and December 31, 2010 were included in this study. We characterized the quantitative CT measures of proximal airways and vessels and pathological changes.
RESULTS: Ninety-four (46.1%) of the 204 subjects were included in the study. There was a significant increase in the airway vessel ratio in subjects who developed progressive BOS compared to controls and non-progressors. There was a significant increase in airway lumen area and decrease in vessel cross-sectional area in patients with BOS compared to controls. Patients with BOS had a significant increase in proximal airway fibrosis compared to controls.
CONCLUSIONS: BOS is characterized by central airway dilation and vascular remodeling, the degree of which is correlated to decrements in lung function. Our data suggest that progressive BOS is a pathologic process that affects both the central and distal airways.
BACKGROUND: Bronchiectasis is frequent in smokers with COPD; however, there are only limited data on objective assessments of this process. The objective was to assess bronchovascular morphology, calculate the ratio of the diameters of bronchial lumen and adjacent artery (BA ratio), and identify those measurements able to discriminate bronchiectasis.
METHODS: We collected quantitative CT (QCT) measures of BA ratios, peak wall attenuation, wall thickness (WT), wall area, and wall area percent (WA%) at matched fourth through sixth airway generations in 21 ever smokers with bronchiectasis (cases) and 21 never-smoking control patients (control airways). In cases, measurements were collected at both bronchiectatic and nonbronchiectatic airways. Logistic analysis and the area under receiver operating characteristic curve (AUC) were used to assess the predictive ability of QCT measurements for bronchiectasis.
RESULTS: The whole-lung and fourth through sixth airway generation BA ratio, WT, and WA% were significantly greater in bronchiectasis cases than control patients. The AUCs for the BA ratio to predict bronchiectasis ranged from 0.90 (whole lung) to 0.79 (fourth-generation). AUCs for WT and WA% ranged from 0.72 to 0.75 and from 0.71 to 0.75. The artery diameters but not bronchial diameters were smaller in bronchiectatic than both nonbronchiectatic and control airways (P < .01 for both).
CONCLUSIONS: Smoking-related increases in the BA ratio appear to be driven by reductions in vascular caliber. QCT measures of BA ratio, WT, and WA% may be useful to objectively identify and quantify bronchiectasis in smokers.
TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.
PURPOSE OF REVIEW: The present review aims to summarize the most recent evidence related to imaging and severe asthma, both with regard to advances in imaging research and to their current and potential clinical implications.
RECENT FINDINGS: Recent work in imaging in severe asthma has principally been using computed tomography (CT) and MRI, as well as the integration of the two. Some of the most notable findings include the use of CT imaging biomarkers to create unique clusters of asthmatics, and the use of co-registration to link CT images of airways with regional variation in ventilation in MRI. In addition, temporal studies have shown that some the ventilation defects found using MRI in asthmatics are intermittent and others are persistent, but both are associated with lower lung function.
SUMMARY: The role of imaging in severe asthma currently is primarily in the exclusion of comorbid or other conditions, or in the assessment for complications in the setting of acute decompensation. A rapidly expanding body of literature using CT and MRI suggests that these tools may soon be of utility in the chronic management of the disease.
With the advancement of three-dimensional (3-D) real-time echocardiography in recent years, automatic creation of patient specific geometric models is becoming feasible and important in clinical decision making. However, the vast majority of echocardiographic segmentation methods presented in the literature focus on the left ventricle (LV) endocardial border, leaving segmentation of the right ventricle (RV) a largely unexplored problem, despite the increasing recognition of the RV's role in cardiovascular disease. We present a method for coupled segmentation of the endo- and epicardial borders of both the LV and RV in 3-D ultrasound images. To solve the segmentation problem, we propose an extension of a successful state-estimation segmentation framework with a geometrical representation of coupled surfaces, as well as the introduction of myocardial incompressibility to regularize the segmentation. The method was validated against manual measurements and segmentations in images of 16 patients. Mean absolute distances of [Formula: see text], [Formula: see text], and [Formula: see text] between the proposed and reference segmentations were observed for the LV endocardium, RV endocardium, and LV epicardium surfaces, respectively. The method was computationally efficient, with a computation time of [Formula: see text].