ORIGINAL ARTICLE
Quantitative Emphysema Assessment of Pulmonary Function Impairment by Computed Tomography in Chronic Obstructive Pulmonary Disease Guangli Wang, MM, Lin Wang, MM, Zhenshen Ma, MM, Chengqi Zhang, MD, PhD, and Kai Deng, PhD Objective: The objective of this study was to determine the capability of quantitative emphysema by computed tomography (CT) to assess pulmonary function impairment in a population of current smokers with and without airflow limitation. Methods: Seventy-six subjects (30 normal smokers; 8 with mild obstruction; 17 with moderate obstruction; 13 with severe obstruction; 8 with very severe obstruction) underwent CT examinations and pulmonary function tests. For the quantitative assessment, percentages of low attenuation volume (%LAVs) of whole lung, right lung, left lung, and each lobe were obtained. Computed tomography measurements were related to lung function (forced expiratory volume in 1 second [FEV1], ratio of FEV1 to forced vital capacity, diffusing capacity for carbon monoxide [DLCO], ratio of residual volume to total lung capacity [RV/TLC]) by multivariate linear regression analysis. Results: Quantitative CT measurements of emphysema were moderately, negatively correlated to airflow limitation (FEV1 and ratio of FEV1 to forced vital capacity) (r = −0.68 to −0.52, P < 0.001). Except for right middle and lower lobes, all the quantitative CT measurements showed moderate, negative correlations with diffusing capacity (DLCO) (r = −0.63 to −0.54, P ≤ 0.001) and weak to moderate correlations with RV (RV/TLC) (r = 0.36–0.41, P < 0.01). As compared with control samples, the % LAV of whole lung, right lung, left lung, and each lobe was increased in patients with GOLD stages 2, 3, and 4 disease (P < 0.05), and the % LAV of whole lung, right lung and right upper lobe was increased in patients with GOLD stage 1 (P < 0.05). Conclusions: Pulmonary function results, particularly DLCO and RV/ TLC, were primarily affected by the % LAV of the upper lobes. Quantitative CT measurements of emphysema provides a morphological method to investigate lung function impairment in patients with chronic obstructive pulmonary disease. Key Words: pulmonary emphysema, quantitative computed tomography, pulmonary function test, chronic obstructive pulmonary disease (J Comput Assist Tomogr 2015;39: 171–175)
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hronic obstructive pulmonary disease (COPD), a common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive.1 Currently, COPD is a major public health problem and is associated with significant economic and social burden.2 It is important to qualitatively and quantitatively describe the functional status of the patient with COPD. A functional assessment provides pertinent information related to disease severity, management effectiveness, and the patient’s ability to cope with COPD. In addition, the distribution of emphysema also influences disease severity.3–6
From the Department of Radiology, Qianfoshan Hospital Affiliated to Shandong University, Jinan, People’s Republic of China. Received for publication August 15, 2014; accepted October 17, 2014. Reprints: Chengqi Zhang, MD, PhD, Department of Radiology, Qianfoshan Hospital Affiliated to Shandong University, Jinan, People’s Republic of China 250014 (e‐mail: [email protected]). Funding was provided by the Science and Technology Development Plan of Shandong Province (grant 2013G0021820). No conflict of interest existed in the submission of this article. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
There are a few previous articles discussing lobar distribution of emphysema and its connection with pulmonary function tests (PFTs), which reported that the extent of emphysema in the lower lung is more closely correlated with the results of PFTs than is the extent of emphysema in the upper lung zone, even if the upper lung is more severely affected.3,7,8 However, the results of the researchers are not all the same. Saitoh et al,3 who were the first to study quantify emphysema severity in each lobe with computed tomography (CT), reported that the diffusing capacity was more closely correlated with the extent of emphysema in the upper lobes than in the lower lobes. Recently, Matsuo et al8 demonstrated that the pulmonary function results, particularly diffusing capacity for carbon monoxide (DLCO), were primarily affected by the normal lobar volumes (normal lobar volume = total lobar volume − emphysematous lobar volume) of the lower lobes. Thus, more researches are needed. In this study, we compared the extent of emphysema of whole lung, right lung, left lung, and each anatomic lung lobe by quantitative CT measurements with PFT results and determined the capability of quantitative emphysema to assess pulmonary function loss and disease severity in COPD patients.
MATERIALS AND METHODS Subjects The study protocol was approved by our institutional review board for human research; informed consent was obtained from clinical subjects and waived for the healthy check-up subjects. Between June 2012 and June 2013, a total of 95 consecutive patients who were suspected of having COPD underwent noncontrast CT. Then, patients were selected according to the criterion that they had undergone both chest CT imaging and PFTs at approximately the same time. Additional selection criteria included the following: (1) visualized emphysema on CT, (2) no parenchymal destruction due to disease other than emphysema, and (3) adequate CT image quality without motion artifact. Therefore, 49 subjects were excluded, and 46 subjects (37 males, 9 females; mean age, 67.0 ± 10.84 years), who were all smokers, were enrolled in this study. These patients were drawn for each GOLD stage,1 resulting in 8 GOLD 1, 17 GOLD 2, 13 GOLD 3, and 8 GOLD 4. In addition, we selected 30 normal smokers from the healthy check-up subjects with normal lung function tests. Normal lung function was defined as forced expiratory volume in 1 second (FEV1) greater than 80% predicted and ratio of FEV1 to forced vital capacity (FEV1/FVC) of greater than 70%. The characteristics of the subjects are shown in Table 1.
Pulmonary Function Tests Pulmonary function tests were performed while the patients were at rest in a seated position. Spirometry, body plethysmography, and diffusion capacity testing were obtained according to
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TABLE 1. Clinical Data for Patients With Emphysema Parameter
n
Mean
SD
Range
Age, y BMI, kg/m2 FEV1, % predicted FEV1/FVC, % DLCO, % predicted RV/TLC, %
76 76 76 76 34 53
59.92 24.16 72.56 71.25 69.38 52.53
13.46 3.99 31.15 15.59 25.39 11.78
31–88 14.53–34.77 20.10–124.50 42.37–100.00 21.30–118.80 21.38–81.53
European Respiratory Society guidelines9 using CHESTAC-880 (Chest, Tokyo, Japan). Forced vital capacity, FEV1, FEV1/FVC, ratio of residual volume to total lung capacity (RV/TLC), and
DLCO were obtained. Forced expiratory volume in 1 second and DLCO were expressed as percentages of predicted values. The CT and the PFTs were performed at an interval of less than 7 days.
CT Scan Protocols The patients were scanned with a 64-detector-row and 128slice CT scanner (GE Optima CT660; GE Healthcare, Milwaukee, Wis). The scan parameters were as follows: adaptive mA (tube current range 30–120 mA), 120-kVp tube voltage, 380-mm field of view, a scan range from the lung apex to the diaphragm, a pitch of 0.875, a section thickness of 5 mm, a reconstruction interval of 5 mm, a collimator width of 64 0.625 mm, and a gantry rotation speed of 0.8 second. Respiratory gating was not applied; the studies were performed after having adequately instructed the
FIGURE 1. Images of a 60-year-old male COPD patient with GOLD stage 4 disease. A, The volume rendering (VR) image of the lungs. B, The outline of the right lung lobes. C, Coronal image of the lungs. D, Area of the lungs having a CT value of less than −950 HU is shown in blue. E, Percentages of low attenuation volume of whole lung, right lung, left lung, and each lobe were obtained automatically.
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patients, in a single apnea (full inspiration, supine position). No contrast media were used. These CT raw data were reconstructed to 0.625-mm section thicknesses using a standard algorithm.
Image Analysis For our quantitative CT assessments, all images were transferred to an advanced workstation AW4.5 (General Electric Company) for analysis using the Thoracic VCAR software (GE Healthcare, Milwaukee, Wis). Quantitative assessment of lung volumes and the percentage of lung CT voxels below the threshold of −950 Hounsfield units (as a representative value of the presence of lung emphysema) were performed. Percentages of low attenuation volume (%LAVs) were obtained for the whole lung, right lung, left lung, and each lobe (Fig. 1).
Statistical Analysis Computed tomography scan measurements were compared between the 5 groups (ie, normal smokers and the 4 COPD stages) with analysis of covariance, with sex, age, and body mass index (BMI) as covariates. Multivariate linear regression analyses were performed to evaluate the relationship between lung function parameters (dependent variables) and the CT measurements (independent variables), whereas sex, age, and BMI were introduced as correction factors for PFT. Furthermore, multicolinearity and the distribution of residuals was assessed for all models; %LAV were log transformed (log %LAV) as to obtain a normal distribution and warrant symmetrical variance of the errors around zero (ie, homoscedasticity). All statistical analyses were performed using SPSS version 19.0 (SPSS Inc, Chicago, Ill). P < 0.05 was considered statistical significant. Continuous data are given as mean ± SD, unless indicated otherwise.
RESULTS Table 2 shows correlation coefficients between %LAV of the lobes and the PFT results. The %LAV of right upper lobe (RUL), right middle lobe (RML), right lower lobe (RLL), left upper lobe (LUL), left lower lobe (LLL), right lung, left lung, and whole lung all showed moderate, negative correlations with airflow limitation (FEV1 and FEV1/FVC) (r = −0.68 to −0.52, P < 0.001). Except for RML and RLL, all the quantitative CT measurements showed moderate, negative correlations with diffusing capacity (DLCO) (r = −0.63 to −0.54, P ≤ 0.001) and weak to moderate correlations with residual volume (RV/TLC) (r = 0.36 to 0.41, P < 0.01). The %LAV of RML showed no correlation with DLCO (r = 0.34, P > 0.05) and RV/TLC (r = 0.24, P > 0.05). The %LAV of
Assessment of Pulmonary Function by CT
RLL showed weak correlation with DLCO (r = 0.36, P < 0.05) and showed no correlation with RV/TLC (r = 0.26, P > 0.05). Table 3 provides patient characteristics, pulmonary function, and quantitative CT measurements of the 5 groups. As compared with %LAV in control samples, the value of %LAVof whole lung, right lung, left lung, and each lobe was increased in patients with GOLD stages 2, 3, and 4 disease (P < 0.05), the value of %LAVof whole lung, right lung, and RUL was increased in patients with GOLD stage 1 disease (P < 0.05),whereas there were no significant differences in the value of %LAV of left lung, LUL, LLL, RML, and RLL between control group and GOLD stage 1 group (P >0.05). In addition, there were significant differences in the value of %LAV of whole lung, right lung, left lung, and all the lobes except RUL between GOLD stage 1 group and GOLD stage 4 group (P < 0.05). There were significant differences in the value of %LAV of whole lung, right lung, left lung, and all the lobes except RML between GOLD stages 2 and 4 groups (P < 0.05). For the RML, there was significant difference in the value of % LAV between GOLD stages 3 and 4 groups (P < 0.05), between control group and GOLD stage 2 group (P < 0.05), as well as between control group and GOLD stage 4 group (P < 0.01).
DISCUSSION Pulmonary emphysema results from parenchymal tissue destruction induced by chronic inflammatory response after inhalation exposure of cigarette smoke and other noxious particles.1 Quantification of pulmonary emphysema in vivo is important to understand the natural history of the disease, to assess the extent of the disease, and to evaluate and follow-up therapeutic interventions.10–12 Besides, the detection of early emphysema may prevent the occurrence of obstructive ventilatory impairment with smoking cessation or medical intervention. Computed tomography allows for early detection of emphysema. Computed tomography also makes it possible to quantify the total amount of emphysema and provides the precise location of the obstructive ventilatory impairment. While the lung function test, which is the most common method for diagnosing COPD, cannot do it, it only provides the general function. On CT scans, emphysema is characterized by areas of lung with reduced attenuation coefficients. Several studies have discussed the threshold of CT analysis. We used −950 HU in this study, which was first defined on incremental thin-section CT and comparison with pathological specimens.13,14 Zaporozhan et al15 reported that the −950 HU threshold data measured on multi–detector-row correlated well with PFTs. Several clinical studies also used the same threshold of −950 HU.6,16 Our current study confirms significant correlations between CT measurements of emphysema and airflow obstruction parameters
TABLE 2. Correlation Coefficients Between %LAVs and PFT Results FEV1, % Predicted %LAV, Mean ± SD Whole lung (6.95 ± 8.52) Right lung (6.69 ± 8.78) Left lung (7.08 ± 8.65) RUL (7.01 ± 10.17) RML (6.19 ± 8.55) RLL (6.14 ± 9.07) LUL (6.91 ± 8.48) LLL (6.93 ± 9.44)
FEV1/FVC, %
DLCO, % Predicted
RV/TLC, %
r
P
r
P
r
P
r
P
−0.67 −0.63 −0.65 −0.57 −0.53 −0.57 −0.61 −0.62
0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000
−0.68 −0.65 −0.66 −0.61 −0.52 −0.57 −0.63 −0.62
0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000
−0.62 −0.56 −0.62 −0.61 −0.34 −0.36 −0.63 −0.54
0.000 0.000 0.000 0.000 0.052 0.039 0.000 0.001
0.41 0.36 0.41 0.38 0.24 0.26 0.38 0.38
0.002 0.008 0.002 0.005 0.080 0.065 0.005 0.005
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TABLE 3. Patient Characteristics, Pulmonary Function, and Quantitative CT Measurements Controls (n = 30) Male/female, n 26/4 Age, y 48.73 ± 8.16 Pulmonary FEV1, % predicted 101.69 ± 13.79 FEV1/FEV, % 86.53 ± 7.60 90.58 ± 6.97 DLCO, % predicted RV/TLC, % 44.20 ± 8.42 CT parameters (log %LAV) Whole lung −0.02 ± 0.41 Right lung −0.19 ± 0.46 Left lung 0.11 ± 0.41 RUL −0.12 ± 0.14 RML 0.03 ± 0.52 RLL −0.45 ± 0.58 LUL 0.17 ± 0.39 LLL −0.07 ± 0.56
GOLD 1 (n = 8)
GOLD 2 (n = 17)
GOLD 3 (n = 13)
GOLD 4 (n = 13)
6/2 68.38 ± 6.39
13/4 63.18 ± 13.49
10/3 70.54 ± 10.79
8/0 69.25 ± 7.55
89.96 ± 10.18 67.63 ± 6.08 63.40 ± 21.22 44.34 ± 11.50
63.74 ± 7.44 67.22 ± 8.71 74.41 ± 22.98 51.74 ± 10.52
35.89 ± 4.15 53.43 ± 8.25 60.59 ± 27.35 57.33 ± 8.00
24.25 ± 3.55 55.10 ± 9.78 32.87 ± 11.00 66.32 ± 9.33
0.52 ± 0.61 0.52 ± 0.66 0.52 ± 0.56 0.45 ± 0.21 0.44 ± 0.50 0.27 ± 1.01 0.54 ± 0.50 0.34 ± 0.87
0.58 ± 0.50 0.55 ± 0.60 0.57 ± 0.44 0.46 ± 0.14 0.60 ± 0.51 0.34 ± 0.81 0.57 ± 0.51 0.48 ± 0.51
0.90 ± 0.52 0.79 ± 0.57 0.88 ± 0.52 0.70 ± 0.18 0.55 ± 0.71 0.73 ± 0.62 0.86 ± 0.58 0.84 ± 0.50
1.26 ± 0.33 1.24 ± 0.35 1.28 ± 0.31 1.04 ± 0.23 1.16 ± 0.47 1.17 ± 0.37 1.22 ± 0.31 1.29 ± 0.39
in PFT. The correlations were in agreement with some expert narrative review17 and individual studies.18–20 However, other studies reported weaker associations, such as the National Emphysema Treatment Trial study21 and the International COPD Genetics Network study.22 In the National Emphysema Treatment Trial and International COPD Genetics Network, predominantly single-slice CT was used; the reduced strength of the correlations was probably caused by the weak reproducibility and accuracy of single-slice CT.23 Our analysis data suggest that the %LAV of each upper lobe, LLL, right lung, left lung, and whole lung showed weak to moderate correlations with DLCO and RV/TLC. These results are not in conformity with the findings of the previous study. Saitoh et al3 found moderate to strong correlations of DLCO with the %LAV of the right lung, the whole lung, and each upper lobe, whereas the %LAVof the left lung and each lower lobe showed no or only weak correlations with DLCO. They also found moderate correlations of RV/TLC with the %LAVof the right lung, left lung, whole lung, and each lower lobe, whereas the %LAVof each upper lobe showed no or only weak correlations with it. The difference may be partly due to technical factors. Densitometry can be influenced not only by the applied percentile or density threshold, but also by image reconstruction algorithm,24–27 section thickness,24,28 inspiration level,29,30 scanner/study center,29 gravity,31 and radiation dose.32 Group analysis indicated that there existed significant differences in CT quantitative measurements of emphysema between control samples and GOLD stages 2, 3, and 4 diseases. There is also difference in the %LAV of whole lung, right lung, and RUL between control samples and GOLD stage 1 disease, whereas there was no difference in the %LAV of left lung, RML, RLL, LUL, and LLL and no difference between control samples and GOLD stage 1 disease. Thus, it may be inferred that emphysema takes place first in the RUL. Can we interpret it as the right main bronchus is stub and steep, so inflammatory agents are easier to reach the right lung? Mohamed Hoesein et al33 reported that heavy (former) smokers with upper-lobe predominant CT-quantified emphysema have a more rapid decrease in lung function than do those with lower-lobe predominant CT-quantified emphysema. But does the CT-quantified emphysema of RUL reflect a better reduction of lung function? More research is needed.
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This study has certain limitations. First, this study has small number of patients from a single institution, which may influence the results. Further studies with larger numbers of subjects are needed. Another limitation was that the emphysema cohort may have confounded the results. Emphysema restricts lung motion and likely alters the dynamics of breathing when compared with normal subjects. The differences in the degree of emphysema may also simply be reflective of individual differences in respiratory effort and ability.
CONCLUSIONS The present study showed that CT measurements of emphysema are significantly related to airflow obstruction as accessed by FEV1 % predicted and FEV1/FVC in COPD patients. Pulmonary function results, particularly DLCO and RV/TLC, were primarily affected by the % LAV of the upper lobes. Thus, CT provides a quantitative morphological method to investigate lung function impairment by emphysema in COPD. ACKNOWLEDGMENT The authors thank Wu Li of GE Corporation for his technical assistance in this study and also thank Baoguang Hu for his advice regarding the manuscript editing. REFERENCES 1. Vestbo J, Hurd SS, Agustí AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013;187: 347–365. 2. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006;3:e442. 3. Saitoh T, Koba H, Shijubo N, et al. Lobar distribution of emphysema in computed tomographic densitometric analysis. Invest Radiol. 2000;35: 235–243. 4. Gurney JW, Jones KK, Robbins RA, et al. Regional distribution of emphysema: correlation of high-resolution CT with pulmonary function tests in unselected smokers. Radiology. 1992;183:457–463.
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5. Parr DG, Stoel BC, Stolk J, et al. Pattern of emphysema distribution in alpha1-antitrypsin deficiency influences lung function impairment. Am J RespirCrit Care Med. 2004;170:1172–1178.
20. Boschetto P, Quintavalle S, Zeni E, et al. Association between markers of emphysema and more severe chronic obstructive pulmonary disease. Thorax. 2006;61:1037–1042.
6. Martinez FJ, Foster G, Curtis JL, et al. Predictors of mortality in patients with emphysema and severe airflow obstruction. Am J Respir Crit Care Med. 2006;173:1326–1334.
21. Washko GR, Criner GJ, Mohsenifar Z, et al. Computed tomographic–based quantification of emphysema and correlation to pulmonary function and mechanics. COPD. 2008;5:177–186.
7. Chen F, Kubo T, Shoji T, et al. Comparison of pulmonary function test and computed tomography volumetry in living lung donors. J Heart Lung Transplant. 2011;30:572–575.
22. Patel BD, Coxson HO, Pillai SG, et al. Airway wall thickening and emphysema show independent familial aggregation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;178:500–505.
8. Matsuo K, Iwano S, Okada T, et al. 3D-CT lung volumetry using multidetector row computed tomography: pulmonary function of each anatomic lobe. J Thorac Imaging. 2012;27:164–70.
23. Newell JD Jr. Quantitative computed tomography of lung parenchyma in chronic obstructive pulmonary disease: an overview. Proc Am Thorac Soc. 2008;5:915–918.
9. Miller MR, Crapo R, Hankinson J, et al. General considerations for lung function testing. Eur Respir J. 2005;26:153–161. 10. Madani A, Keyzer C, Gevenois PA. Quantitative computed tomography assessment of lung structure and function in pulmonary emphysema. Eur Respir J. 2001;18:720–730. 11. Gierada DS, Yusen RD, Pilgram TK, et al. Repeatability of quantitative CT indexes of emphysema in patients evaluated for lung volume reduction surgery. Radiology. 2001;220:448–454. 12. Newell JD, Hogg JC, Snider GL. Report of a workshop: quantitative computed tomography scanning in longitudinal studies of emphysema. Eur Respir J. 2004;23:769–775. 13. Bankier AA, de Maertelaer V, Keyzer C, et al. Pulmonary emphysema: subjective visual grading versus objective quantification with macroscopic morphometry and thin-section CT densitometry. Radiology. 1999;211:851–858.
24. Gierada DS, Bierhals AJ, Choong CK, et al. Effects of CT section thickness andreconstruction kernel on emphysema quantification relationship to the magnitude of the CT emphysema index. Acad Radiol. 2010;17: 146–156. 25. Ley-Zaporozhan J, Ley S, Weinheimer O, et al. Quantitative analysis of emphysema in 3D using MDCT: influence of different reconstruction algorithms. Eur J Radiol. 2008;65:228–234. 26. Reske AW, Busse H, Amato MB, et al. Image reconstruction affects computer tomographic assessment of lung hyperinflation. Intensive Care Med. 2008;34:2044–2053. 27. Boedeker KL, Nitt-Gray MF, Rogers SR, et al. Emphysema: effect of reconstruction algorithm on CT imaging measures. Radiology. 2004;232:295–301.
14. Gevenois PA, de Vuyst P, de Maertelaer V, et al. Comparison of computed density and microscopic morphometry in pulmonary emphysema. Am J Respir Crit Care Med. 1996;154:187–192.
28. Madani A, de Maertelaer V, Zanen J, et al. Pulmonary emphysema: radiation dose and section thickness at multidetector CT quantification—comparison with macroscopic and microscopic morphometry. Radiology. 2007;243:250–257.
15. Zaporozhan J, Ley S, Eberhardt R, et al. Paired inspiratory/expiratory volumetric thin-slice CT scan for emphysema analysis: comparison of different quantitative evaluations and pulmonary function test. Chest. 2005;128:3212–3220.
29. Bakker ME, Stolk J, Putter H, et al. Variability in densitometric assessment of pulmonary emphysema with computed tomography. Invest Radiol. 2005;40:777–783.
16. Ohno Y, Iwasawa T, Seo JB, et al. Oxygen-enhanced magnetic resonance imaging versus computed tomography: multicenter study for clinical stage classification of smoking-related chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;177:1095–1102. 17. Matsuoka S, Yamashiro T, Washko GR, et al. Quantitative CT assessment of chronic obstructive pulmonary disease. Radiographics. 2010;30:55–66. 18. Orlandi I, Moroni C, Camiciottoli G, et al. Spirometric-gated computed tomography quantitative evaluation of lung emphysema in chronic obstructive pulmonary disease—a comparison of 3 techniques. J Comput Assist Tomogr. 2004;28:437–442. 19. Camiciottoli G, Bartolucci M, Maluccio NM, et al. Spirometrically gated high-resolution CT findings in COPD: lung attenuation vs lung function and dyspnea severity. Chest. 2006;129:558–564.
30. Madani A, van Muylem A, Gevenois PA. Pulmonary emphysema: effect of lung volume on objective quantification at thin-section CT. Radiology. 2010;257:260–268. 31. Wiemker R, Opfer R, Bülow T, et al. Toward computer-aided emphysema quantification on ultralow-dose CT: reproducibility of ventrodorsal gravity effect measurement and correction. Proc SPIE. 2007;6514:65140O-1-65140O-11. 32. Yuan R, Mayo JR, Hogg JC, et al. The effects of radiation dose and CT manufacturer on measurements of lung densitometry. Chest. 2007;132:617–623. 33. Mohamed Hoesein FA, van Rikxoort E, van Ginneken B, et al. Computed tomography–quantified emphysema distribution is associated with lung function decline. Eur Respir J. 2012;40:844–850.
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Quantitative Emphysema Assessment of Pulmonary Function Impairment by Computed Tomography in Chronic Obstructive Pulmonary Disease Guangli Wang, MM, Lin Wang, MM, Zhenshen Ma, MM, Chengqi Zhang, MD, PhD, and Kai Deng, PhD Objective: The objective of this study was to determine the capability of quantitative emphysema by computed tomography (CT) to assess pulmonary function impairment in a population of current smokers with and without airflow limitation. Methods: Seventy-six subjects (30 normal smokers; 8 with mild obstruction; 17 with moderate obstruction; 13 with severe obstruction; 8 with very severe obstruction) underwent CT examinations and pulmonary function tests. For the quantitative assessment, percentages of low attenuation volume (%LAVs) of whole lung, right lung, left lung, and each lobe were obtained. Computed tomography measurements were related to lung function (forced expiratory volume in 1 second [FEV1], ratio of FEV1 to forced vital capacity, diffusing capacity for carbon monoxide [DLCO], ratio of residual volume to total lung capacity [RV/TLC]) by multivariate linear regression analysis. Results: Quantitative CT measurements of emphysema were moderately, negatively correlated to airflow limitation (FEV1 and ratio of FEV1 to forced vital capacity) (r = −0.68 to −0.52, P < 0.001). Except for right middle and lower lobes, all the quantitative CT measurements showed moderate, negative correlations with diffusing capacity (DLCO) (r = −0.63 to −0.54, P ≤ 0.001) and weak to moderate correlations with RV (RV/TLC) (r = 0.36–0.41, P < 0.01). As compared with control samples, the % LAV of whole lung, right lung, left lung, and each lobe was increased in patients with GOLD stages 2, 3, and 4 disease (P < 0.05), and the % LAV of whole lung, right lung and right upper lobe was increased in patients with GOLD stage 1 (P < 0.05). Conclusions: Pulmonary function results, particularly DLCO and RV/ TLC, were primarily affected by the % LAV of the upper lobes. Quantitative CT measurements of emphysema provides a morphological method to investigate lung function impairment in patients with chronic obstructive pulmonary disease. Key Words: pulmonary emphysema, quantitative computed tomography, pulmonary function test, chronic obstructive pulmonary disease (J Comput Assist Tomogr 2015;39: 171–175)
C
hronic obstructive pulmonary disease (COPD), a common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive.1 Currently, COPD is a major public health problem and is associated with significant economic and social burden.2 It is important to qualitatively and quantitatively describe the functional status of the patient with COPD. A functional assessment provides pertinent information related to disease severity, management effectiveness, and the patient’s ability to cope with COPD. In addition, the distribution of emphysema also influences disease severity.3–6
From the Department of Radiology, Qianfoshan Hospital Affiliated to Shandong University, Jinan, People’s Republic of China. Received for publication August 15, 2014; accepted October 17, 2014. Reprints: Chengqi Zhang, MD, PhD, Department of Radiology, Qianfoshan Hospital Affiliated to Shandong University, Jinan, People’s Republic of China 250014 (e‐mail: [email protected]). Funding was provided by the Science and Technology Development Plan of Shandong Province (grant 2013G0021820). No conflict of interest existed in the submission of this article. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
There are a few previous articles discussing lobar distribution of emphysema and its connection with pulmonary function tests (PFTs), which reported that the extent of emphysema in the lower lung is more closely correlated with the results of PFTs than is the extent of emphysema in the upper lung zone, even if the upper lung is more severely affected.3,7,8 However, the results of the researchers are not all the same. Saitoh et al,3 who were the first to study quantify emphysema severity in each lobe with computed tomography (CT), reported that the diffusing capacity was more closely correlated with the extent of emphysema in the upper lobes than in the lower lobes. Recently, Matsuo et al8 demonstrated that the pulmonary function results, particularly diffusing capacity for carbon monoxide (DLCO), were primarily affected by the normal lobar volumes (normal lobar volume = total lobar volume − emphysematous lobar volume) of the lower lobes. Thus, more researches are needed. In this study, we compared the extent of emphysema of whole lung, right lung, left lung, and each anatomic lung lobe by quantitative CT measurements with PFT results and determined the capability of quantitative emphysema to assess pulmonary function loss and disease severity in COPD patients.
MATERIALS AND METHODS Subjects The study protocol was approved by our institutional review board for human research; informed consent was obtained from clinical subjects and waived for the healthy check-up subjects. Between June 2012 and June 2013, a total of 95 consecutive patients who were suspected of having COPD underwent noncontrast CT. Then, patients were selected according to the criterion that they had undergone both chest CT imaging and PFTs at approximately the same time. Additional selection criteria included the following: (1) visualized emphysema on CT, (2) no parenchymal destruction due to disease other than emphysema, and (3) adequate CT image quality without motion artifact. Therefore, 49 subjects were excluded, and 46 subjects (37 males, 9 females; mean age, 67.0 ± 10.84 years), who were all smokers, were enrolled in this study. These patients were drawn for each GOLD stage,1 resulting in 8 GOLD 1, 17 GOLD 2, 13 GOLD 3, and 8 GOLD 4. In addition, we selected 30 normal smokers from the healthy check-up subjects with normal lung function tests. Normal lung function was defined as forced expiratory volume in 1 second (FEV1) greater than 80% predicted and ratio of FEV1 to forced vital capacity (FEV1/FVC) of greater than 70%. The characteristics of the subjects are shown in Table 1.
Pulmonary Function Tests Pulmonary function tests were performed while the patients were at rest in a seated position. Spirometry, body plethysmography, and diffusion capacity testing were obtained according to
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TABLE 1. Clinical Data for Patients With Emphysema Parameter
n
Mean
SD
Range
Age, y BMI, kg/m2 FEV1, % predicted FEV1/FVC, % DLCO, % predicted RV/TLC, %
76 76 76 76 34 53
59.92 24.16 72.56 71.25 69.38 52.53
13.46 3.99 31.15 15.59 25.39 11.78
31–88 14.53–34.77 20.10–124.50 42.37–100.00 21.30–118.80 21.38–81.53
European Respiratory Society guidelines9 using CHESTAC-880 (Chest, Tokyo, Japan). Forced vital capacity, FEV1, FEV1/FVC, ratio of residual volume to total lung capacity (RV/TLC), and
DLCO were obtained. Forced expiratory volume in 1 second and DLCO were expressed as percentages of predicted values. The CT and the PFTs were performed at an interval of less than 7 days.
CT Scan Protocols The patients were scanned with a 64-detector-row and 128slice CT scanner (GE Optima CT660; GE Healthcare, Milwaukee, Wis). The scan parameters were as follows: adaptive mA (tube current range 30–120 mA), 120-kVp tube voltage, 380-mm field of view, a scan range from the lung apex to the diaphragm, a pitch of 0.875, a section thickness of 5 mm, a reconstruction interval of 5 mm, a collimator width of 64 0.625 mm, and a gantry rotation speed of 0.8 second. Respiratory gating was not applied; the studies were performed after having adequately instructed the
FIGURE 1. Images of a 60-year-old male COPD patient with GOLD stage 4 disease. A, The volume rendering (VR) image of the lungs. B, The outline of the right lung lobes. C, Coronal image of the lungs. D, Area of the lungs having a CT value of less than −950 HU is shown in blue. E, Percentages of low attenuation volume of whole lung, right lung, left lung, and each lobe were obtained automatically.
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patients, in a single apnea (full inspiration, supine position). No contrast media were used. These CT raw data were reconstructed to 0.625-mm section thicknesses using a standard algorithm.
Image Analysis For our quantitative CT assessments, all images were transferred to an advanced workstation AW4.5 (General Electric Company) for analysis using the Thoracic VCAR software (GE Healthcare, Milwaukee, Wis). Quantitative assessment of lung volumes and the percentage of lung CT voxels below the threshold of −950 Hounsfield units (as a representative value of the presence of lung emphysema) were performed. Percentages of low attenuation volume (%LAVs) were obtained for the whole lung, right lung, left lung, and each lobe (Fig. 1).
Statistical Analysis Computed tomography scan measurements were compared between the 5 groups (ie, normal smokers and the 4 COPD stages) with analysis of covariance, with sex, age, and body mass index (BMI) as covariates. Multivariate linear regression analyses were performed to evaluate the relationship between lung function parameters (dependent variables) and the CT measurements (independent variables), whereas sex, age, and BMI were introduced as correction factors for PFT. Furthermore, multicolinearity and the distribution of residuals was assessed for all models; %LAV were log transformed (log %LAV) as to obtain a normal distribution and warrant symmetrical variance of the errors around zero (ie, homoscedasticity). All statistical analyses were performed using SPSS version 19.0 (SPSS Inc, Chicago, Ill). P < 0.05 was considered statistical significant. Continuous data are given as mean ± SD, unless indicated otherwise.
RESULTS Table 2 shows correlation coefficients between %LAV of the lobes and the PFT results. The %LAV of right upper lobe (RUL), right middle lobe (RML), right lower lobe (RLL), left upper lobe (LUL), left lower lobe (LLL), right lung, left lung, and whole lung all showed moderate, negative correlations with airflow limitation (FEV1 and FEV1/FVC) (r = −0.68 to −0.52, P < 0.001). Except for RML and RLL, all the quantitative CT measurements showed moderate, negative correlations with diffusing capacity (DLCO) (r = −0.63 to −0.54, P ≤ 0.001) and weak to moderate correlations with residual volume (RV/TLC) (r = 0.36 to 0.41, P < 0.01). The %LAV of RML showed no correlation with DLCO (r = 0.34, P > 0.05) and RV/TLC (r = 0.24, P > 0.05). The %LAV of
Assessment of Pulmonary Function by CT
RLL showed weak correlation with DLCO (r = 0.36, P < 0.05) and showed no correlation with RV/TLC (r = 0.26, P > 0.05). Table 3 provides patient characteristics, pulmonary function, and quantitative CT measurements of the 5 groups. As compared with %LAV in control samples, the value of %LAVof whole lung, right lung, left lung, and each lobe was increased in patients with GOLD stages 2, 3, and 4 disease (P < 0.05), the value of %LAVof whole lung, right lung, and RUL was increased in patients with GOLD stage 1 disease (P < 0.05),whereas there were no significant differences in the value of %LAV of left lung, LUL, LLL, RML, and RLL between control group and GOLD stage 1 group (P >0.05). In addition, there were significant differences in the value of %LAV of whole lung, right lung, left lung, and all the lobes except RUL between GOLD stage 1 group and GOLD stage 4 group (P < 0.05). There were significant differences in the value of %LAV of whole lung, right lung, left lung, and all the lobes except RML between GOLD stages 2 and 4 groups (P < 0.05). For the RML, there was significant difference in the value of % LAV between GOLD stages 3 and 4 groups (P < 0.05), between control group and GOLD stage 2 group (P < 0.05), as well as between control group and GOLD stage 4 group (P < 0.01).
DISCUSSION Pulmonary emphysema results from parenchymal tissue destruction induced by chronic inflammatory response after inhalation exposure of cigarette smoke and other noxious particles.1 Quantification of pulmonary emphysema in vivo is important to understand the natural history of the disease, to assess the extent of the disease, and to evaluate and follow-up therapeutic interventions.10–12 Besides, the detection of early emphysema may prevent the occurrence of obstructive ventilatory impairment with smoking cessation or medical intervention. Computed tomography allows for early detection of emphysema. Computed tomography also makes it possible to quantify the total amount of emphysema and provides the precise location of the obstructive ventilatory impairment. While the lung function test, which is the most common method for diagnosing COPD, cannot do it, it only provides the general function. On CT scans, emphysema is characterized by areas of lung with reduced attenuation coefficients. Several studies have discussed the threshold of CT analysis. We used −950 HU in this study, which was first defined on incremental thin-section CT and comparison with pathological specimens.13,14 Zaporozhan et al15 reported that the −950 HU threshold data measured on multi–detector-row correlated well with PFTs. Several clinical studies also used the same threshold of −950 HU.6,16 Our current study confirms significant correlations between CT measurements of emphysema and airflow obstruction parameters
TABLE 2. Correlation Coefficients Between %LAVs and PFT Results FEV1, % Predicted %LAV, Mean ± SD Whole lung (6.95 ± 8.52) Right lung (6.69 ± 8.78) Left lung (7.08 ± 8.65) RUL (7.01 ± 10.17) RML (6.19 ± 8.55) RLL (6.14 ± 9.07) LUL (6.91 ± 8.48) LLL (6.93 ± 9.44)
FEV1/FVC, %
DLCO, % Predicted
RV/TLC, %
r
P
r
P
r
P
r
P
−0.67 −0.63 −0.65 −0.57 −0.53 −0.57 −0.61 −0.62
0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000
−0.68 −0.65 −0.66 −0.61 −0.52 −0.57 −0.63 −0.62
0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000
−0.62 −0.56 −0.62 −0.61 −0.34 −0.36 −0.63 −0.54
0.000 0.000 0.000 0.000 0.052 0.039 0.000 0.001
0.41 0.36 0.41 0.38 0.24 0.26 0.38 0.38
0.002 0.008 0.002 0.005 0.080 0.065 0.005 0.005
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TABLE 3. Patient Characteristics, Pulmonary Function, and Quantitative CT Measurements Controls (n = 30) Male/female, n 26/4 Age, y 48.73 ± 8.16 Pulmonary FEV1, % predicted 101.69 ± 13.79 FEV1/FEV, % 86.53 ± 7.60 90.58 ± 6.97 DLCO, % predicted RV/TLC, % 44.20 ± 8.42 CT parameters (log %LAV) Whole lung −0.02 ± 0.41 Right lung −0.19 ± 0.46 Left lung 0.11 ± 0.41 RUL −0.12 ± 0.14 RML 0.03 ± 0.52 RLL −0.45 ± 0.58 LUL 0.17 ± 0.39 LLL −0.07 ± 0.56
GOLD 1 (n = 8)
GOLD 2 (n = 17)
GOLD 3 (n = 13)
GOLD 4 (n = 13)
6/2 68.38 ± 6.39
13/4 63.18 ± 13.49
10/3 70.54 ± 10.79
8/0 69.25 ± 7.55
89.96 ± 10.18 67.63 ± 6.08 63.40 ± 21.22 44.34 ± 11.50
63.74 ± 7.44 67.22 ± 8.71 74.41 ± 22.98 51.74 ± 10.52
35.89 ± 4.15 53.43 ± 8.25 60.59 ± 27.35 57.33 ± 8.00
24.25 ± 3.55 55.10 ± 9.78 32.87 ± 11.00 66.32 ± 9.33
0.52 ± 0.61 0.52 ± 0.66 0.52 ± 0.56 0.45 ± 0.21 0.44 ± 0.50 0.27 ± 1.01 0.54 ± 0.50 0.34 ± 0.87
0.58 ± 0.50 0.55 ± 0.60 0.57 ± 0.44 0.46 ± 0.14 0.60 ± 0.51 0.34 ± 0.81 0.57 ± 0.51 0.48 ± 0.51
0.90 ± 0.52 0.79 ± 0.57 0.88 ± 0.52 0.70 ± 0.18 0.55 ± 0.71 0.73 ± 0.62 0.86 ± 0.58 0.84 ± 0.50
1.26 ± 0.33 1.24 ± 0.35 1.28 ± 0.31 1.04 ± 0.23 1.16 ± 0.47 1.17 ± 0.37 1.22 ± 0.31 1.29 ± 0.39
in PFT. The correlations were in agreement with some expert narrative review17 and individual studies.18–20 However, other studies reported weaker associations, such as the National Emphysema Treatment Trial study21 and the International COPD Genetics Network study.22 In the National Emphysema Treatment Trial and International COPD Genetics Network, predominantly single-slice CT was used; the reduced strength of the correlations was probably caused by the weak reproducibility and accuracy of single-slice CT.23 Our analysis data suggest that the %LAV of each upper lobe, LLL, right lung, left lung, and whole lung showed weak to moderate correlations with DLCO and RV/TLC. These results are not in conformity with the findings of the previous study. Saitoh et al3 found moderate to strong correlations of DLCO with the %LAV of the right lung, the whole lung, and each upper lobe, whereas the %LAVof the left lung and each lower lobe showed no or only weak correlations with DLCO. They also found moderate correlations of RV/TLC with the %LAVof the right lung, left lung, whole lung, and each lower lobe, whereas the %LAVof each upper lobe showed no or only weak correlations with it. The difference may be partly due to technical factors. Densitometry can be influenced not only by the applied percentile or density threshold, but also by image reconstruction algorithm,24–27 section thickness,24,28 inspiration level,29,30 scanner/study center,29 gravity,31 and radiation dose.32 Group analysis indicated that there existed significant differences in CT quantitative measurements of emphysema between control samples and GOLD stages 2, 3, and 4 diseases. There is also difference in the %LAV of whole lung, right lung, and RUL between control samples and GOLD stage 1 disease, whereas there was no difference in the %LAV of left lung, RML, RLL, LUL, and LLL and no difference between control samples and GOLD stage 1 disease. Thus, it may be inferred that emphysema takes place first in the RUL. Can we interpret it as the right main bronchus is stub and steep, so inflammatory agents are easier to reach the right lung? Mohamed Hoesein et al33 reported that heavy (former) smokers with upper-lobe predominant CT-quantified emphysema have a more rapid decrease in lung function than do those with lower-lobe predominant CT-quantified emphysema. But does the CT-quantified emphysema of RUL reflect a better reduction of lung function? More research is needed.
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This study has certain limitations. First, this study has small number of patients from a single institution, which may influence the results. Further studies with larger numbers of subjects are needed. Another limitation was that the emphysema cohort may have confounded the results. Emphysema restricts lung motion and likely alters the dynamics of breathing when compared with normal subjects. The differences in the degree of emphysema may also simply be reflective of individual differences in respiratory effort and ability.
CONCLUSIONS The present study showed that CT measurements of emphysema are significantly related to airflow obstruction as accessed by FEV1 % predicted and FEV1/FVC in COPD patients. Pulmonary function results, particularly DLCO and RV/TLC, were primarily affected by the % LAV of the upper lobes. Thus, CT provides a quantitative morphological method to investigate lung function impairment by emphysema in COPD. ACKNOWLEDGMENT The authors thank Wu Li of GE Corporation for his technical assistance in this study and also thank Baoguang Hu for his advice regarding the manuscript editing. REFERENCES 1. Vestbo J, Hurd SS, Agustí AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013;187: 347–365. 2. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006;3:e442. 3. Saitoh T, Koba H, Shijubo N, et al. Lobar distribution of emphysema in computed tomographic densitometric analysis. Invest Radiol. 2000;35: 235–243. 4. Gurney JW, Jones KK, Robbins RA, et al. Regional distribution of emphysema: correlation of high-resolution CT with pulmonary function tests in unselected smokers. Radiology. 1992;183:457–463.
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5. Parr DG, Stoel BC, Stolk J, et al. Pattern of emphysema distribution in alpha1-antitrypsin deficiency influences lung function impairment. Am J RespirCrit Care Med. 2004;170:1172–1178.
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