Quantitative Assessment of Emphysema, Air Trapping, and Airway Thickening on Computed Tomography

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1 Lung (2008) 186: DOI /s COPD Quantitative Assessment of Emphysema, Air Trapping, and Airway Thickening on Computed Tomography Young Kyung Lee Æ Yeon-Mok Oh Æ Ji-Hyun Lee Æ Eun Kyung Kim Æ Jin Hwa Lee Æ Namkug Kim Æ Joon Beom Seo Æ Sang Do Lee Æ KOLD Study Group Received: 2 July 2007 / Accepted: 8 January 2008 / Published online: 20 March 2008 Ó Springer Science+Business Media, LLC 2008 Abstract The severity of chronic obstructive pulmonary disease (COPD) is evaluated not only by airflow limitation but also by factors such as exercise capacity and body mass index. Recent advances in CT technology suggest that it might be a useful tool for evaluating the severity of the J. B. Seo and S. D. Lee contributed equally to this work. Y. K. Lee N. Kim J. B. Seo (&) Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Research Institute of Radiology, 388-1, Pungnap-dong, Songpa-ku, Seoul , Korea seojb@amc.seoul.kr; joonbeom.seo@gmail.com Y. K. Lee Department of Radiology, Bundang CHA Hospital, University of Pocheon Jungmoon College of Medicine, Yatap-dong, Bundang-Ku, Seongnam-City, Gyeonggi-Do , Korea Y.-M. Oh S. D. Lee (&) Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Research Institute of Radiology, 388-1, Pungnap-dong, Songpa-ku, Seoul , Korea sdlee@amc.seoul.kr J.-H. Lee E. K. Kim Department of Internal Medicine, Bundang CHA Hospital, University of Pocheon Jungmoon College of Medicine, Yatap-dong, Bundang-Ku, Seongnam-City, Gyeonggi-Do , Korea J. H. Lee Department of Internal Medicine, Ewha Womans University Mokdong Hospital, College of Medicine, Ewha Womans University, Seoul, Korea KOLD Study Group Seoul, Korea disease components of COPD. The aim of this study is to evaluate the correlation between the parameters measured on volumetric CT, including the extent of emphysema, air trapping, and airway thickening, and clinical parameters. CT scans were performed in 34 patients with COPD at full inspiration and expiration. We used in-house software to measure CT parameters, including volume fraction of emphysema (V 950 ), mean lung density (MLD), CT air trapping index (CT ATI), segmental bronchial wall area (WA), lumen area (LA), and wall area percent (WA%). We found that the CT parameters were correlated with the pulmonary function test (PFT) results, body mass index (BMI), the modified Medical Research Council Dyspnea scale (MMRC scale), the six-minute-walk distance (6MWD), and the BODE index. V 950 insp correlated to the BMI, FEV 1, 6MWD, and the BODE index. The CT ATI correlated with the physiologic ATI (VC FVC) (R = 0.345, p = 0.045) and the MMRC scale (R = 0.532, p = 0.001). There was a positive correlation between the WA% and the BMI (R = 0.563, p \ 0.001). MLD exp showed the strongest correlation with the BODE index (R =-0.756, p \ 0.001). We conclude that the severity of emphysema and air trapping measured on CT correlated with the PFT parameters 6MWD and BMI. Keywords COPD Diagnostic imaging MDCT imaging techniques in COPD Lung attenuation Air trapping Wall area BMI Walking test BODE index Respiratory function test Introduction Chronic obstructive pulmonary disease (COPD) is characterized by progressive airway obstruction, and airflow

2 158 Lung (2008) 186: limitation results from lung parenchyma destruction (emphysema) and inflammatory changes of the large and small airways [1]. Quantification of lung emphysema is important in evaluating patients with COPD. Accurate detection of lung parenchyma destruction and knowledge of the location and extent of emphysema make it possible to predict the progression of the disease and treatment outcome. Many studies have been performed to detect and quantify by computed tomography (CT) pulmonary emphysema and airway dimensions in COPD [2 11]. Several studies have shown that forced expiratory volume in 1 second (FEV 1 ) correlates with the disease extent on CT [12 15]. However, most of these studies focused on detecting the extent and severity of abnormally low attenuation only on thin-section, high-resolution CT (HRCT). Only a few studies have been performed to evaluate or quantify the severity of other disease components such as small airways disease, air trapping, and largeairway thickening [16, 17]. The purpose of this prospective study is to evaluate the correlation between the parameters measured on volumetric CT, including the extent of emphysema, air trapping, and airway thickening, and the many clinical parameters, including pulmonary function test (PFT), exercise capacity, body mass index, and BODE index. To evaluate the extent of small airways disease, we developed a CT air-trapping index to represent the ratio of mean lung density (MLD) at full expiration and inspiration. Methods and Materials Clinical Subjects The 82 subjects in this study were taken from the Korean Obstructive Lung Disease (KOLD) cohort for which patients with COPD or asthma had been recruited from pulmonary clinics in 11 hospitals in South Korea from June to December A total of 800 patients will be enrolled until The subjects extracted from the KOLD cohort met all of the following criteria: (1) diagnosed with COPD, i.e., postbronchodilator FEV 1 /FVC \ 0.7 and more than 10 pack-years of smoking history as well as no or minimal abnormality on chest radiographs; (2) from three hospitals which use the same type of scanner; (3) enrolled from June 2005 until December Thirty-four outpatients (33 men, 1 woman) with an average age of 64.5 ± 7.1 years (range = years) were included in the present study. Their average smoking history was 47.0 ± 23.1 pack-years (range = pack-years). All subjects had CT scans and a PFT on the same day. The institutional review board approved the analyses of the clinical and imaging data. Individual informed written consent was obtained from all patients. CT Data Acquisition and Analysis Volumetric CT scans were performed in all patients with COPD at full inspiration and expiration using a 16-MDCT scanner (Somatom Sensation; Siemens Medical Systems, Erlangen, Germany). Scan parameters included 0.75-mm collimation, 100 effmas, 140 kvp, and pitch 1.0. The scale of attenuation coefficients in this CT scanner ranges from to 3072 HU. Patients were scanned craniocaudally. Both scans were performed in a supine position. No patient received intravenous contrast medium. The images were reconstructed using soft kernel (B30f; Siemens Medical Systems) from the thoracic inlet to the lung base. Using in-house software, images of the whole lung were extracted automatically and the attenuation coefficient of each pixel was measured and calculated. The cutoff level between normal lung density and a low-attenuation area was defined as -950 HU [4]. From the CT data, the volume fraction of the lung below -950 HU (V 950 ) and the MLD were calculated automatically. To assess air trapping, the ratio of MLD on expiration and inspiration (CT air-trapping index, CT ATI) was used. Measurement of the airway dimensions was performed near the origin of four segmental bronchi (RB1, LB1 + 2, RB10, LB10) selected by a consensus reading of two radiologists using in-house software. For a more accurate airway measurement, a modified sharpening filter with a kernel size was used. There is no significant difference between measurements from standard kernel (B50f) and soft kernel (B30f) with sharpening filter by phantom experiments [18, 19]. The software automatically detects the airway lumen and the inner and outer boundaries of the airway wall using a full-width-half-maximum method [20 23]. The software was validated using a polyacryl tube with variable inner diameters and wall thickness. In each segmental bronchus, the airway dimensions, including the wall area (WA), lumen area (LA), and wall area percent (WA%), were measured. The WA% was defined as WA/(WA + LA) The mean value of each segmental bronchus was used for statistical analysis. All of these analyses were done by one of the authors (YL) who was blinded to the subjects background data. Pulmonary Function Test Spirometry was performed as recommended by the American Thoracic Society using the Vmax 22 (Sensor- Medics, Yorba Linda, CA) and the PFDX (MedGraphics, St. Paul, MN) [24]. The following values were evaluated: forced vital capacity (FVC), forced expiratory volume in

3 Lung (2008) 186: second (FEV 1 ), ratio of FEV 1 to FVC (FEV 1 /FVC), and mean forced expiratory flow between 25% and 75% of FVC (FEF 25 75% ). All spirometric values were expressed as a percentage of the measured to the predicted value. Lung volumes, including residual volume (RV), vital capacity (VC), and total lung capacity (TLC), were measured by body plethysmography (V6200, SensorMedics or PFDX) [25]. The diffusing capacity was measured according to the single-breath carbon monoxide uptake (Vmax 22 or PFDX) [26]. The air-trapping index (ATI) is the difference between vital capacity and FVC (VC FVC) [27]. It is known to reflect how much air becomes trapped in the lungs during a forced expiration. Clinical Prognostic Factors In addition to pulmonary function, clinical parameters known to be related to COPD prognosis were obtained for all patients. They included exercise capacity of a six-minutewalk distance (6MWD) [28], the degree of dyspnea according to the modified Medical Research Council dyspnea scale (MMRC scale) [29], the body mass index (BMI) in kilograms per square meter [30, 31], and the presence of sputum production for three months during one year. In addition, the BODE index (Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity), an integrative prognostic factor of COPD, was calculated [32]. Statistical Analysis All statistical analyses were performed using SPSS v (SPSS; Chicago, IL). The results were expressed as mean ± standard deviation (SD). The CT indices were correlated with both the pulmonary function values and the clinical prognostic factors using Spearman correlation analysis. Stepwise linear regression analysis was used to evaluate the relationship between the CT indices and the pulmonary function values. The Mann-Whitney test was performed to compare the CT indices in patients with/ without the presence of sputum production for more than three months during one year. A value of p less than 0.05 was considered significant. Results Table 1 Summary of multidetector CT volume data, pulmonary function tests, and other clinical parameters in 34 patients with COPD Variables Mean ± SD Range V 950 insp (%) 21 ± MLD insp -880 ± to -770 V 950 exp (%) 13 ± MLD exp -840 ± to -770 CT ATI 0.96 ± Wall area (WA%) 72 ± BMI (kg/m 2 ) 23 ± MWD (m) 450 ± MMRC scale 2.1 ± BODE index 4.7 ± FEV 1 % pred 45 ± FVC% pred 77 ± FEV 1 /FVC% pred 59 ± TLC% pred 110 ± FEF 25-75% pred 17 ± RV% pred 150 ± DLCO % pred 85 ± Air-trapping index (L) 0.14 ± to 1.2 V 950 insp = volume fraction of the lung below -950 HU at full inspiration; V 950 exp = volume fraction of the lung below -950 HU at full expiration; MLD insp = mean lung density at full inspiration; MLD exp = mean lung density at full expiration; CT ATI (CT air = trapping index) = ratio of MLD exp and MLD insp ; WA% = wall area/( wall area + lumen area) 9 100; BMI = body-mass index; 6MWD = six-minute-walk distance; MMRC scale = Modified Medical Research Council dyspnea scale; FEV 1 = forced expiratory volume in 1 second; FVC = forced vital capacity; TLC = total lung capacity; FEF 25 75% = mean forced expiratory flow between 25% and 75% of FVC; RV = residual volume; DLCO = carbon monoxide diffusing capacity; ATI (air-trapping index) = vital capacity - forced vital capacity Table 1 summarizes the results of each test and the clinical parameters for all patients. Table 2 gives the correlations among CT indices, including the extent of emphysema (volume fraction of the lung below -950 HU), air trapping (CT ATI), and largeairway thickening (WA%), with other clinical parameters as well as with PFT. Volume Fraction of the Lung Below -950 HU (V 950 ) and the MLD V 950 (Fig. 1) and MLD at both full inspiration and expiration were correlated to the BMI. V 950 at full inspiration showed no correlation to the MMRC scale (Fig. 2). V 950 at both full inspiration (Fig. 3) and full expiration was correlated to the 6MWD. MLD at full expiration showed the strongest correlation with the BODE index (R =-0.756, p \ 0.001). V 950 and MLD at both full inspiration and full expiration wwere correlated with FEV 1, FEV 1 /FVC, and carbon monoxide diffusing capacity (DLCO). Stepwise linear regression analysis revealed that MLD on full expiration was an independent significant determinant of FEV 1 (p = 0.042).

4 160 Lung (2008) 186: Table 2 Summary of CT indices representing the extent of emphysema, air-trapping, and large-airway thickening correlated with clinical parameters Variables V 950 insp MLD insp V 950 exp MLD exp CT ATI WA% BMI (kg/m 2 ) FEV 1 % pred MMRC scale 6MWD (m) BODE index DLCO % pred \0.001 \0.001 \0.001 \ \ \ \0.001 \ \ \ \0.001 \0.001 \ \0.001 \0.001 \0.001 \ BMI = body mass index; FEV 1 = forced expiratory volume in 1 second; MMRC scale = Modified Medical Research Council dyspnea scale; 6MWD = six-minute-walk distance; DLCO = carbon monoxide diffusing capacity Values given are R values on top and p values beneath CT Air-Trapping Index (CT ATI) The CT ATI correlated with the physiologic ATI (VC FVC) (R = 0.345, p = 0.045), FEV 1, MMRC scale (Fig. 2), 6MWD (Fig. 3), and the BODE index (R = 0.635, p \ 0.001) (Fig. 4). The CT ATI showed no correlation to the BMI (Fig. 1). CT Index of Airway Dimension (mean wall area, WA%) The WA% showed a positive correlation with the BMI (R = 0.563, p \ 0.001) (Fig. 1) but no correlation with the MMRC scale (Fig. 2), 6MWD (Fig. 3), or the BODE index (Fig. 4). It also showed correlation with FEV 1, FEF 25 75,or DLco (R = 0.044, R = 0.063, and R = 0.091, respectively). The wall area (WA) and lumen area (LA) were not correlated with FEV 1, 6MWD, MMRC scale, or BODE index. The mean wall area (WA%) in patients with the presence of sputum production for more than three months in one year was ± 5.06%. The WA% in patients without the presence of sputum production for more than three months in one year was ± 10.27%. There was a significant difference in the WA% in the two groups (p = 0.005, for both comparisons, Mann-Whitney test). Fig. 1 Correlation of V 950 insp to BMI (A), CT ATI to BMI (B), WA% to BMI (C) in 34 patients

5 Lung (2008) 186: Fig. 2 Correlation of V 950 insp to the MMRC scale (A), CT ATI to the MMRC scale (B), WA% to the MMRC scale (C) in 34 patients Discussion The results of this study suggest that combined analysis of each component of COPD is important not only to assess Fig. 3 Correlation of V 950 insp to 6MWD (A), CT ATI to 6MWD (B), WA% to 6MWD (C) in 34 patients disease severity but also to understand the pathogenesis of COPD. Recently, Fujimoto et al. [33] divided COPD patients into three phenotypes based on the subjective and

6 162 Lung (2008) 186: Fig. 4 Correlation of V 950 insp to BODE index (A), CT ATI to BODE index (B), WA% to BODE index (C) in 34 patients qualitative analyses of emphysema and bronchial wall thickening on CT and showed that there was a significant difference in clinical characteristics and treatment response among the phenotypes. The results of their study and ours implied that the correlation of three structural phenotypes with clinical features suggests a new basis for the heterogeneity of COPD and suggests a new avenue for research. V 950 and MLD on both full inspiration and full expiration were correlated with other clinical parameters as well as with PFT. Many studies have reported that the extent of emphysema on CT correlated best with FEV 1 and DLCO [2 10]. Recently, there has been interest in the various CT morphologic features, e.g., airway abnormalities and the distribution of emphysema, in independently predicted airflow obstruction and in gas transfer [34 38]. Despite numerous and extensive investigations, the morphologic evaluation of COPD by high-resolution CT (HRCT) has not yet been fully standardized [39]. Recent advances in multidetector CT (MDCT) technology has enabled the volumetric acquisition of the whole lung using high spatial resolution by which an accurate, reproducible, and quantitative assessment of the whole lung is thus possible [40]. Martinez et al. [41] have shown the value of CT densitometry for predicting mortality in subjects with severe emphysema. Our study showed that the severity of emphysema as measured on CT correlated with the BODE index as well as with three of the four components of the index, i.e., BMI, FEV 1, and exercise capacity. It may be exaggerated systemic inflammatory response or increased workload of breathing in the emphysematous type of COPD rather than the chronic bronchitis. This might be the reason why the significant negative correlation of V 950 with body mass index was shown in our study [42]. Our results are supported by a similar report that proposes that the CT emphysema score correlates to the BMI and to inflammatory biomarkers [43]. The reason for the poor correlation between V 950 and the MMRC scale is, however, not clearly understood and should be further investigated. Previous observations by Gevenois et al. [4, 5] showed that inspiratory HRCT scanning is accurate in depicting the extent of emphysema, while expiratory scanning more closely reflects hyperinflation and air trapping [6]. In our prospective study, all patients underwent CT scans on both full inspiration and full expiration. We developed the CT air-trapping index by comparing the mean lung density seen on the CT scans at inspiration and expiration in order to assess the extent of small-airway disease. We defined this new index as the ratio of mean lung density, which means the value of Hounsfield units of the whole lung, instead of the ratio of absolute lung volume or mass for following reasons: The Hounsfield unit of each voxel in the lung can represent the weight of lung tissue in each voxel or density. Accordingly, by comparing the mean lung density between inspiration and expiration CT, we can assess the relative change in lung weight in each voxel, hence the collapsed lung tissue. In addition, by using the

7 Lung (2008) 186: ratio instead of absolute volume or mass, the effect of the difference in size of the lung in patients can be minimized. This concept is partially validated by the correlation between the CT air-trapping index and the air-trapping index from PFT. Interestingly, the MMRC scale, which was not correlated with V 950, was correlated with CT ATI (p = 0.001). These results suggest the necessity of the combined analysis of inspiration and expiration CT to obtain the correct assessment of the small-airways component of COPD which is known to be the major determinant of airflow limitation. However, we think that further study is needed to further investigate the usefulness of this index. In this study, MLD at full expiration showed the strongest correlation with the BODE index and was an independent significant determinant of FEV 1 at stepwise regression analysis. It is probably because the MDL at full expiration reflects combined information of both the degree of emphysema and air trapping. The extent of the emphysema can only partially predict the severity of the pulmonary functional changes [44, 45]. Nakano et al. [10, 46] showed that pulmonary function abnormalities are more accurately predicted by a combined evaluation of the extent of low-attenuation areas or emphysema and by the airway wall thickening seen on HRCT. However, contradictory to their results, our study failed to show a direct relationship between the severity of the PFT abnormality and the degree of severity of the large-airway wall thickening or luminal narrowing seen on CT. The reason for this discrepancy is not clearly understood. One possible explanation may be the difference in the study populations. Nakano et al. [10] included all smokers regardless of the presence of clinically significant airway obstruction, whereas we included patients with clinically evident moderate or severe COPD. The heterogeneity of the patient population is the other possible explanation according to a previous study [47]; there is better correlation between PFT and airway dimension at CT in patients with chronic bronchitis than in patients with emphysema. In addition, regional heterogeneity in the extent of airway wall thickening may also possibly explain the difference as we measured the airway dimensions of four segmental bronchi (RB1, LB1 + 2, RB10, LB10), whereas Nakano et al. measured only the right upper lobar bronchus. Finally, the measurement of segmental bronchus, which is a relatively proximal airway, may result in the failure to demonstrate the correlation because recent studies [48, 49] showed that the severity of airflow limitation in vivo in patients with COPD correlated better with the wall area measured in more distal (small) airways such as sixth-order bronchial branches than the wall area of proximal airways. Our study showed that the WA% of patients with the presence of sputum production for more than three months in one year was greater than the WA% of patients without the presence of sputum production. These results suggest that WA% might represent the severity of large-airway thickening or the chronic bronchitis component in COPD. Finally, there was a positive correlation between WA% and BMI, whereas there was a negative correlation between V 950 and BMI. The mechanisms of this interesting result are not yet completely understood but likely involve an imbalance in the ongoing processes of protein degradation and replacement, including alterations in the relative levels or activities of endocrine hormones, inflammatory cytokines, and programmed cell death [50]. In other words, with the same degree of airflow obstruction, patients with more severe large-airway thickening or bronchitis tend to have a higher BMI, whereas patients with more severe emphysema tend to have a lower BMI. There are several limitations of our study. The most important limitation was its small number of patients. However, even with the relatively small patient population, we were able to demonstrate the strong correlations between the CT parameters and many clinical parameters. The high proportion of males in our study cohort was due to prevalence of male heavy smokers in our country. The second limitation was the difficulty in dividing the three components (emphysema, air-trapping, and airway wall thickening) clearly with current technique. In fact, the emphysema index may be influenced by the degree of airtrapping and vice versa. CT has particular advantages for assessing the extent of localized morphologic disease in individual patients. In the near future, advancements in CT scanning technology and software may lead to the assessment of the disease on a lobar and segmental basis and to an understanding of the regional heterogeneity and natural history of each disease component of COPD. In conclusion, our study shows that the quantitative assessment of COPD components, including emphysema, air-trapping, and large-airway thickening, is possible using volumetric inspiration and expiration CT. Acknowledgments The authors thank the members of the Korean Obstructive Lung Disease (KOLD) Cohort study group. 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