The relationship of fat and muscle measurements with emphysema and bronchial wall thickening in smokers.

Introduction: Differences in body composition in patients with COPD may have important prognostic value and may provide opportunities for patient-specific management. We investigated the relation of thoracic fat and muscle with computed tomography (CT)-measured emphysema and bronchial wall thickening. Methods: Low-dose baseline chest CT scans from 1031 male lung cancer screening participants from one site were quantified for emphysema, bronchial wall thickening, subcutaneous fat, visceral fat and skeletal muscle. Body composition measurements were performed by segmenting the first slice above the aortic arch using Hounsfield unit thresholds with region growing and manual corrections. COPD presence and severity were evaluated with pre-bronchodilator spirometry testing. Results: Participants had a median age of 61.5 years (58.6-65.6, 25th-75th percentile) and median number of 38.0 pack-years (28.0-49.5); 549 (53.2%) were current smokers. Overall, 396 (38.4%) had COPD (256 Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1, 140 GOLD 2-3). Participants with COPD had less subcutaneous fat, visceral fat and skeletal muscle (p<0.001 for all). With increasing GOLD stages, subcutaneous (p=0.005) and visceral fat values (p=0.004) were higher, and skeletal muscle was lower (p=0.004). With increasing severity of CT-derived emphysema, subcutaneous fat, visceral fat and skeletal muscle values were lower (p<0.001 for all). With increasing CT-derived bronchial wall thickness, subcutaneous and visceral fat values were higher (p<0.001 for both), without difference in skeletal muscle. All statistical relationships remained when adjusted for age, pack-years and smoking status. Conclusion: COPD presence and emphysema severity are associated with smaller amounts of thoracic fat and muscle, whereas bronchial wall thickening is associated with fat accumulation.

Imaging-derived biomarkers in Asthma: Current status and future perspectives.

Asthma is a common disorder affecting around 315 million individuals worldwide. The heterogeneity of asthma is becoming increasingly important in the era of personalized treatment and response assessment. Several radiological imaging modalities are available in asthma including chest x-ray, computed tomography (CT) and magnetic resonance imaging (MRI) scanning. In addition to qualitative imaging, quantitative imaging could play an important role in asthma imaging to identify phenotypes with distinct disease course and response to therapy, including biologics. MRI in asthma is mainly performed in research settings given cost, technical challenges, and there is a need for standardization. Imaging analysis applications of artificial intelligence (AI) to subclassify asthma using image analysis have demonstrated initial feasibility, though additional work is necessary to inform the role of AI in clinical practice.

Progression of Emphysema and Small Airways Disease in Cigarette Smokers.

BACKGROUND: Little is known about factors associated with emphysema progression in cigarette smokers. We evaluated factors associated with change in emphysema and forced expiratory volume in 1 second (FEV1) in participants with and without chronic obstructive pulmonary disease (COPD). METHODS: This retrospective study included individuals participating in the COPD Genetic Epidemiology study who completed the 5-year follow-up, including inspiratory and expiratory computed tomography (CT) and spirometry. All paired CT scans were analyzed using micro-mapping, which classifies individual voxels as emphysema or functional small airway disease (fSAD). Presence and progression of emphysema and FEV1 were determined based on comparison to nonsmoker values. Logistic regression analyses were used to identify clinical parameters associated with disease progression. RESULTS: A total of 3088 participants were included with a mean ± SD age of 60.7±8.9 years, including 72 nonsmokers. In all Global initiative for chronic Obstructive Lung Disease (GOLD) stages, the presence of emphysema at baseline was associated with emphysema progression (odds ratio [OR]: GOLD 0: 4.32; preserved ratio-impaired spirometry [PRISm]; 5.73; GOLD 1: 5.16; GOLD 2: 5.69; GOLD 3/4: 5.55; all p ≤0.01). If there was no emphysema at baseline, the amount of fSAD at baseline was associated with emphysema progression (OR for 1% increase: GOLD 0: 1.06; PRISm: 1.20; GOLD 1: 1.7; GOLD 3/4: 1.08; all p ≤ 0.03).In 1735 participants without spirometric COPD, progression in emphysema occurred in 105 (6.1%) participants and only 21 (1.2%) had progression in both emphysema and FEV1. CONCLUSIONS: The presence of emphysema is an important predictor of emphysema progression. In patients without emphysema, fSAD is associated with the development of emphysema. In participants without spirometric COPD, emphysema progression occurred independently of FEV1 decline.

Five-year Progression of Emphysema and Air Trapping at CT in Smokers with and Those without Chronic Obstructive Pulmonary Disease: Results from the COPDGene Study.

Background CT is used to quantify abnormal changes in the lung parenchyma of smokers that might overlap chronic obstructive pulmonary disease (COPD), but studies on the progression of expiratory air trapping in smokers are scarce. Purpose To evaluate the relationship between longitudinal changes in forced expiratory volume in 1 second (FEV1) and CT-quantified emphysema and air trapping in smokers. Materials and Methods Cigarette smokers with and those without COPD participating in the multicenter observational COPDGene study were evaluated. Subjects underwent inspiratory and expiratory chest CT and spirometry at baseline and 5-year follow-up. Emphysema was quantified by using adjusted lung density (ALD). Air trapping was quantified by using mean lung density at expiratory CT and CT-measured functional residual capacity-to-total lung volume ratio. Linear models were used to regress quantitative CT measurements taken 5 years apart, and models were fit with and without adding FEV1 as a predictor. Analyses were stratified by Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage (GOLD 0, no COPD; GOLD 1, mild COPD; GOLD 2, moderate COPD; GOLD 3, severe COPD; GOLD 4, very severe COPD). Subjects with preserved FEV1-to-forced vital capacity ratio and reduced FEV1 percentage predicted were categorized as having preserved ratio impaired spirometry (PRISm). Results A total of 4211 subjects (503 with PRISm; 2034 with GOLD 0, 388 with GOLD 1, 816 with GOLD 2, 381 with GOLD 3, 89 with GOLD 4) were evaluated. ALD decreased by 1.7 g/L (95% confidence interval [CI]: -2.5, -0.9) in subjects with GOLD 0 at baseline and by 5.3 g/L (95% CI: -6.2, -4.4) in those with GOLD 1-4 (P < .001 for both). When adjusted for changes in FEV1, corresponding numbers were -2.2 (95% CI: -3.0, -1.3) and -4.6 g/L (95% CI: -5.6, -3.4) (P < .001 for both). Progression in air trapping was identified only in GOLD stage 2-4. Approximately 33%-50% of changes in air trapping in GOLD stages 2-4 were accounted for by changes in FEV1. Conclusion CT measures of emphysema and air trapping increased over 5 years in smokers. Forced expiratory volume in one second accounted for less than 10% of emphysema progression and less than 50% of air trapping progression detected at CT. © RSNA, 2020 Online supplemental material is available for this article.

Reprint of: Voxel-Wise Longitudinal Parametric Response Mapping Analysis of Chest Computed Tomography in Smokers.

RATIONALE AND OBJECTIVES: Chronic obstructive pulmonary disease is a heterogeneous disease characterized by small airway abnormality and emphysema. We hypothesized that a voxel-wise computed tomography analytic approach would identify patterns of disease progression in smokers. MATERIALS AND METHODS: We analyzed 725 smokers in spirometric GOLD stages 0-4 with two chest CTs 5 years apart. Baseline inspiration, follow-up inspiration and follow-up expiration images were spatially registered to baseline expiration so that each voxel had correspondences across all time points and respiratory phases. Voxel-wise Parametric Response Mapping (PRM) was then generated for the baseline and follow-up scans. PRM classifies lung as normal, functional small airway disease (PRMfSAD), and emphysema (PRMEMPH). RESULTS: Subjects with low baseline PRMfSAD and PRMEMPH predominantly had an increase in PRMfSAD on follow-up; those with higher baseline PRMfSAD and PRMEMPH mostly had increases in PRMEMPH. For GOLD 0 participants (n = 419), mean 5-year increases in PRMfSAD and PRMEMPH were 0.3% for both; for GOLD 1-4 participants (n = 306), they were 0.6% and 1.6%, respectively. Eighty GOLD 0 subjects (19.1%) had overall radiologic progression (30.0% to PRMfSAD, 52.5% to PRMEMPH, and 17.5% to both); 153 GOLD 1-4 subjects (50.0%) experienced progression (17.6% to PRMfSAD, 48.4% to PRMEMPH, and 34.0% to both). In a multivariable model, both baseline PRMfSAD and PRMEMPH were associated with development of PRMEMPH on follow-up, although this relationship was diminished at higher levels of baseline PRMEMPH. CONCLUSION: A voxel-wise longitudinal PRM analytic approach can identify patterns of disease progression in smokers with and without chronic obstructive pulmonary disease.

Airway wall thickening on CT: Relation to smoking status and severity of COPD.

Airway wall thickening in cigarette smokers is thought to be a result of inflammatory changes and airway remodeling. This study investigates if CT-derived airway wall thickening associates to disease severity in smokers with and without COPD and if airway wall thickening is reversible by smoking cessation. We examined 2000 smokers and 46 never-smokers who returned for a 5-year follow-up visit in the COPDGene-study. Multivariable regression analyses were performed at visit 1 to associate airway wall thickness (expressed as Pi10) with percent predicted forced expiratory volume in 1 s (FEV1%-predicted), 6-min walking distance (6MWD), and St. George Respiratory Questionnaire (SGRQ). Longitudinal analyses were performed to assess the effect of smoking cessation on Pi10 using linear mixed models. A higher Pi10 was significantly associated with worse FEV1%-predicted, 6MWD, and SGRQ in all GOLD-stages. Longitudinal analyses showed that subjects that quit smoking significantly decreased in Pi10 (ΔPi10 = -0.18 mm, p < 0.001). Subjects that started smoking had a significant increase in Pi10 (ΔPi10 = 0.14 mm, p < 0.001). Pi10 is a clinically relevant biomarker of smoking-related airway injury in smokers with and without COPD. The change in Pi10 with change in smoking status suggests that it can quantify a reversible component of smoking-related airway inflammation.

Voxel-Wise Longitudinal Parametric Response Mapping Analysis of Chest Computed Tomography in Smokers.

RATIONALE AND OBJECTIVES: Chronic obstructive pulmonary disease is a heterogeneous disease characterized by small airway abnormality and emphysema. We hypothesized that a voxel-wise computed tomography analytic approach would identify patterns of disease progression in smokers. MATERIALS AND METHODS: We analyzed 725 smokers in spirometric GOLD stages 0-4 with two chest CTs 5 years apart. Baseline inspiration, follow-up inspiration and follow-up expiration images were spatially registered to baseline expiration so that each voxel had correspondences across all time points and respiratory phases. Voxel-wise Parametric Response Mapping (PRM) was then generated for the baseline and follow-up scans. PRM classifies lung as normal, functional small airway disease (PRMfSAD), and emphysema (PRMEMPH). RESULTS: Subjects with low baseline PRMfSAD and PRMEMPH predominantly had an increase in PRMfSAD on follow-up; those with higher baseline PRMfSAD and PRMEMPH mostly had increases in PRMEMPH. For GOLD 0 participants (n = 419), mean 5-year increases in PRMfSAD and PRMEMPH were 0.3% for both; for GOLD 1-4 participants (n = 306), they were 0.6% and 1.6%, respectively. Eighty GOLD 0 subjects (19.1%) had overall radiologic progression (30.0% to PRMfSAD, 52.5% to PRMEMPH, and 17.5% to both); 153 GOLD 1-4 subjects (50.0%) experienced progression (17.6% to PRMfSAD, 48.4% to PRMEMPH, and 34.0% to both). In a multivariable model, both baseline PRMfSAD and PRMEMPH were associated with development of PRMEMPH on follow-up, although this relationship was diminished at higher levels of baseline PRMEMPH. CONCLUSION: A voxel-wise longitudinal PRM analytic approach can identify patterns of disease progression in smokers with and without chronic obstructive pulmonary disease.

Normalized emphysema scores on low dose CT: Validation as an imaging biomarker for mortality.

The purpose of this study is to develop a computed tomography (CT) biomarker of emphysema that is robust across reconstruction settings, and evaluate its ability to predict mortality in patients at high risk for lung cancer. Data included baseline CT scans acquired between August 2002 and April 2004 from 1737 deceased subjects and 5740 surviving controls taken from the National Lung Screening Trial. Emphysema scores were computed in the original scans (origES) and after applying resampling, normalization and bullae analysis (normES). We compared the prognostic value of normES versus origES for lung cancer and all-cause mortality by computing the area under the receiver operator characteristic curve (AUC) and the net reclassification improvement (NRI) for follow-up times of 1-7 years. normES was a better predictor of mortality than origES. The 95% confidence intervals for the differences in AUC values indicated a significant difference for all-cause mortality for 2 through 6 years of follow-up, and for lung cancer mortality for 1 through 7 years of follow-up. 95% confidence intervals in NRI values showed a statistically significant improvement in classification for all-cause mortality for 2 through 7 years of follow-up, and for lung cancer mortality for 3 through 7 years of follow-up. Contrary to conventional emphysema score, our normalized emphysema score is a good predictor of all-cause and lung cancer mortality in settings where multiple CT scanners and protocols are used.

CT-Based Local Distribution Metric Improves Characterization of COPD.

Parametric response mapping (PRM) of paired CT lung images has been shown to improve the phenotyping of COPD by allowing for the visualization and quantification of non-emphysematous air trapping component, referred to as functional small airways disease (fSAD). Although promising, large variability in the standard method for analyzing PRMfSAD has been observed. We postulate that representing the 3D PRMfSAD data as a single scalar quantity (relative volume of PRMfSAD) oversimplifies the original 3D data, limiting its potential to detect the subtle progression of COPD as well as varying subtypes. In this study, we propose a new approach to analyze PRM. Based on topological techniques, we generate 3D maps of local topological features from 3D PRMfSAD classification maps. We found that the surface area of fSAD (SfSAD) was the most robust and significant independent indicator of clinically meaningful measures of COPD. We also confirmed by micro-CT of human lung specimens that structural differences are associated with unique SfSAD patterns, and demonstrated longitudinal feature alterations occurred with worsening pulmonary function independent of an increase in disease extent. These findings suggest that our technique captures additional COPD characteristics, which may provide important opportunities for improved diagnosis of COPD patients.

Computed tomography quantification of tracheal abnormalities in COPD and their influence on airflow limitation.

PURPOSE: To present a method to automatically quantify tracheal morphology changes during breathing and investigate its contribution to airflow impairment when adding CT measures of emphysema, airway wall thickness, air trapping and ventilation. METHODS: Because tracheal abnormalities often occur localized, a method is presented that automatically determines the most abnormal trachea section based on automatically computed sagittal and coronal lengths. In this most abnormal section, trachea morphology is encoded using four equiangular rays from the center of the trachea and the normalized lengths of these rays are used as features in a classification scheme. Consequently, trachea measurements are used as input for classification into GOLD stages in addition to emphysema, air trapping and ventilation. A database of 200 subjects distributed across all GOLD stages is used to evaluate the classification with a k nearest neighbour algorithm. Performance is assessed in two experimental settings: (a) when only inspiratory scans are taken; (b) when both inspiratory and expiratory scans are available. RESULTS: Given only an inspiratory CT scan, measuring tracheal shape provides complementary information only to emphysema measurements. The best performing set in the inspiratory setting was a combination of emphysema and bronchial measurements. The best performing feature set in the inspiratory-expiratory setting includes measurements of emphysema, ventilation, air trapping, and trachea. Inspiratory and inspiratory-expiratory settings showed similar performance. CONCLUSIONS: The fully automated system presented in this study provides information on trachea shape at inspiratory and expiratory CT. Addition of tracheal morphology features improves the ability of emphysema and air trapping CT-derived measurements to classify COPD patients into GOLD stages and may be relevant when investigating different aspects of COPD.

Computed tomographic findings in subjects who died from respiratory disease in the National Lung Screening Trial.

We evaluated the prevalence of significant lung abnormalities on computed tomography (CT) in patients who died from a respiratory illness other than lung cancer in the National Lung Screening Trial (NLST).In this retrospective case-control study, NLST participants in the CT arm who died of respiratory illness other than lung cancer were matched for age, sex, pack-years and smoking status to a surviving control. A chest radiologist and a radiology resident blinded to the outcome independently scored baseline CT scans visually and qualitatively for the presence of emphysema, airway wall thickening and fibrotic lung disease. The prevalence of CT abnormalities was compared between cases and controls by using chi-squared tests.In total, 167 participants died from a respiratory cause other than lung cancer. The prevalence of severe emphysema, airway wall thickening and fibrotic lung disease were 28.7% versus 4.8%, 26.9% versus 13.2% and 18.6% versus 0.5% in cases and controls, respectively. Radiological findings were significantly more prevalent in deaths compared with controls (all p<0.001).CT-diagnosed severe emphysema, airway wall thickening and fibrosis were much more common in NLST participants who died from respiratory disease, and CT may provide an additional means of identifying these diseases.

Parametric response mapping on chest computed tomography associates with clinical and functional parameters in chronic obstructive pulmonary disease.

BACKGROUND: In the search for specific phenotypes of chronic obstructive pulmonary disease (COPD) computed tomography (CT) derived Parametric Response Mapping (PRM) has been introduced. This study evaluates the association between PRM and currently available biomarkers of disease severity in COPD. METHODS: Smokers with and without COPD were characterized based on questionnaires, pulmonary function tests, body plethysmography, and low-dose chest CT scanning. PRM was used to calculate the amount of emphysema (PRMEmph) and non-emphysematous air trapping (i.e. functional small airway disease, PRMfSAD). PRM was first compared with other biomarkers for emphysema (Perc15) and air trapping (E/I-ratioMLD). Consequently, linear regression models were utilized to study associations of PRM measurements with clinical parameters. RESULTS: 166 participants were included with a mean ± SD age of 50.5 ± 17.7 years. Both PRMEmph and PRMfSAD were more strongly correlated with lung function parameters as compared to Perc15 and E/I-ratioMLD. PRMEmph and PRMfSAD were higher in COPD participants than non-COPD participants (14.0% vs. 1.1%, and 31.6% vs. 8.2%, respectively, both p < 0.001) and increased with increasing GOLD stage (all p < 0.001). Multivariate analysis showed that PRMfSAD was mainly associated with total lung capacity (TLC) (ß = -7.90, p < 0.001), alveolar volume (VA) (ß = 7.79, p < 0.001), and residual volume (ß = 6.78, p < 0.001), whilst PRMEmph was primarily associated with Kco (ß = 8.95, p < 0.001), VA (ß = -6.21, p < 0.001), and TLC (ß = 6.20, p < 0.001). CONCLUSIONS: PRM strongly associates with the presence and severity of COPD. PRM therefore appears to be a valuable tool in differentiating COPD phenotypes.

Follow-up of CT-derived airway wall thickness: Correcting for changes in inspiration level improves reliability.

OBJECTIVES: Airway wall thickness (AWT) is affected by changes in lung volume. This study evaluated whether correcting AWT on computed tomography (CT) for differences in inspiration level improves measurement agreement, reliability, and power to detect changes over time. METHODS: Participants of the Dutch-Belgian lung cancer screening trial who underwent 3-month repeat CT for an indeterminate pulmonary nodule were included. AWT on CT was calculated by the square root of the wall area at a theoretical airway with an internal perimeter of 10mm (Pi10). The scan with the highest lung volume was labelled as the reference scan and the scan with the lowest lung volume was labelled as the comparison scan. Pi10 derived from the comparison scan was corrected by multiplying it with the ratio of CT lung volume of the comparison scan to CT lung volume on the reference scan. Agreement of uncorrected and corrected Pi10 was studied with the Bland-Altman method, reliability with intra-class correlation coefficients (ICC), and power to detect changes over time was calculated. RESULTS: 315 male participants were included. Limit of agreement and reliability for Pi10 was -0.61 to 0.57mm (ICC=0.87), which improved to -0.38 to 0.37mm (ICC=0.94) after correction for inspiration level. To detect a 15% change over 3 months, 71 subjects are needed for Pi10 and 26 subjects for Pi10 adjusted for inspiration level. CONCLUSIONS: Correcting Pi10 for differences in inspiration level improves reliability, agreement, and power to detect changes over time.

Accuracy of CT Pulmonary Artery Diameter for Pulmonary Hypertension in End-Stage COPD.

INTRODUCTION: Pulmonary hypertension (PH) in COPD is associated with a higher mortality and an increased risk on exacerbations compared to COPD patients without PH. The aim was to evaluate the diagnostic value of pulmonary artery (PA) measurements on chest computed tomography (CT) for PH in end-stage COPD. METHODS: COPD patients evaluated for eligibility for lung transplantation between 2004 and 2015 were retrospectively analyzed. Clinical characteristics, chest CTs, spirometry, and right-sided heart catheterizations (RHC) were studied. Diameters of PA and ascending aorta (A) were measured on CT. Diagnostic properties of different cut-offs of PA diameter and PA:A ratio in diagnosing PH were calculated. RESULTS: Of 92 included COPD patients, 30 (32.6 %) had PH at RHC (meanPAP > 25 mm Hg). PA:A > 1 had a negative predictive value (NPV) of 77.9 % and a positive predictive value (PPV) of 63.1 % with an odds ratio (OR (CI 95 %)) of 5.60 (2.00-15.63). PA diameter ≥30 mm had a NPV of 78 % and PPV of 64 % with an OR (CI 95 %) of 6.95 (2.51-19.24). CONCLUSION: A small PA diameter and PA:A make the presence of PH unlikely but cannot exclude its presence in end-stage COPD. A large PA diameter and PA:A maybe used to detect PH early.

Smokers with emphysema and small airway disease on computed tomography have lower bone density.

Osteoporosis is more common in patients with COPD and in smokers. The aim of this study was to assess whether measures of emphysema and airway disease on computed tomography (CT) were associated with lower bone density or vertebral fractures in smokers with and without COPD. For this purpose, we included participants from the NELSON lung cancer screening trial. Bone density was measured as Hounsfield Units in the first lumbar vertebra, and vertebral fractures were assessed semiquantitatively. The 15th percentile method (Perc15) was used to assess emphysema, and the airway lumen perimeter (Pi10) was used for airway wall thickness. Expiratory/inspiratory-ratiomean lung density (E/I-ratioMLD) was used as a measure for air trapping and tracheal index to assess tracheal deformity. Linear regression models and logistic regression models were used to assess associations between CT biomarkers, bone density, and presence of fractures. Exactly 1,093 male participants were eligible for analysis. Lower Perc15 and higher E/I-ratioMLD were significantly associated with lower bone density (b=-1.27, P=0.02 and b=-0.37, P=0.02, respectively). Pi10 and tracheal index were not associated with bone density changes. CT-derived biomarkers were not associated with fracture prevalence. Bone density is lower with increasing extent of emphysema and small airway disease but is not associated with large airway disease and tracheal deformity. This may indicate the necessity to measure bone density early in smokers with emphysema and air trapping to prevent vertebral fractures.

Inter-observer and inter-examination variability of manual vertebral bone attenuation measurements on computed tomography.

OBJECTIVE: To determine inter-observer and inter-examination variability of manual attenuation measurements of the vertebrae in low-dose unenhanced chest computed tomography (CT). METHODS: Three hundred and sixty-seven lung cancer screening trial participants who underwent baseline and repeat unenhanced low-dose CT after 3 months because of an indeterminate lung nodule were included. The CT attenuation value of the first lumbar vertebrae (L1) was measured in all CTs by one observer to obtain inter-examination reliability. Six observers performed measurements in 100 randomly selected CTs to determine agreement with limits of agreement and Bland-Altman plots and reliability with intraclass correlation coefficients (ICCs). Reclassification analyses were performed using a threshold of 110 HU to define osteoporosis. RESULTS: Inter-examination reliability was excellent with an ICC of 0.92 (p < 0.001). Inter-examination limits of agreement ranged from -26 to 28 HU with a mean difference of 1 ± 14 HU. Inter-observer reliability ICCs ranged from 0.70 to 0.91. Inter-examination variability led to 11.2 % reclassification of participants and inter-observer variability led to 22.1 % reclassification. CONCLUSIONS: Vertebral attenuation values can be manually quantified with good to excellent inter-examination and inter-observer reliability on unenhanced low-dose chest CT. This information is valuable for early detection of osteoporosis on low-dose chest CT. KEY POINTS: • Vertebral attenuation values can be manually quantified on low-dose unenhanced CT reliably. • Vertebral attenuation measurements may be helpful in detecting subclinical low bone density. • This could become of importance in the detection of osteoporosis.