Abstract
Patients with asthma COPD overlap syndrome (ACOS) are an important but poorly characterized group. This study sought to explore the distinct characteristics of ACOS on CT densitometry. The study population was randomly selected from communities via questionnaires. All participants underwent low-dose volumetric chest CT both before and after bronchodilator administration. Each CT scan was performed at full-inspiration and full-expiration for CT densitometry. Emphysema index (EI), air trapping (AT), mean lung density (MLD) and total lung volume (TLV) were measured and compared between the ACOS and COPD groups. The distributions of both EI and AT were compared between patients with ACOS and COPD. The variations between the pre- and post-BD measurements observed in patients with ACOS were compared with those in patients with COPD. A total of 71 patients completed the study, including 32 patients with COPD and 39 patients with ACOS. The patients with ACOS exhibited lower EI and more upper-zone-predominant EI distributions, compared with the patients with COPD. No significant differences were exhibited in AT and its distribution. Following bronchodilator administration, the variations in AT and expiratory MLD were greater in patients with ACOS than in patients with COPD. No differences were observed in the variations of EI and inspiratory MLD. Our results indicate that patients with ACOS have lower extent of emphysema and different emphysema distribution, as well as greater post-BD variations in air trapping, compared with patients with COPD. These findings suggest that CT densitometry characterizes ACOS as a distinct phenotype from COPD.
Abbreviations
| COPD | = | chronic obstructive pulmonary disease |
| ACOS | = | asthma COPD overlap syndrome |
| BD | = | bronchodilator; EI, emphysema index |
| AT | = | air trapping; MLD, mean lung density |
| TLV | = | total lung volume |
| FEV1 | = | forced expiratory volume in 1 second |
| FVC | = | forced vital capacity |
| sRaw | = | specific airway resistance |
| RV | = | residual volume |
| DLCO | = | diffusing capacity for carbon monoxide |
| VA | = | alveolar volume |
| PEF | = | peak expiratory flow |
Introduction
Chronic obstructive pulmonary disease (COPD) is characterized by persistent chronic airflow limitations, with high heterogeneity among patients. Asthma and COPD are considered different diseases; however, distinguishing COPD from asthma with chronic airflow limitation in adults is often problematic, particularly after 40 years of age (Citation1). Furthermore, a significant proportion of patients exhibit clinical manifestations of both COPD and asthma, which is broadly recognized but poorly characterized (Citation2, 3) and makes the diagnosis more complex. Patients with asthma and COPD overlap syndrome (ACOS) experience more frequent exacerbations, more rapid declines in lung function and higher mortality rates compared with patients suffering from either asthma or COPD alone (Citation4–6). Patients with ACOS make up a large percentage of the individuals suffering from obstructive lung disease (Citation5) and may require distinct clinical management (Citation3).
Computed tomography (CT) is often used in patients with COPD to visualize the destruction of the lung parenchyma, as well as airway remodeling and concomitant infections. However, subjective visual assessments are insensitive with respect to the identification of chronic airflow limitation, as is the case with hyperinflation and air trapping. CT densitometry provides both quantitative lung density information and volumetric data and is a more reliable objective method of diagnosing diseases characterized by airflow limitation (Citation7) and may therefore help in phenotyping specific chronic airway diseases. Quantitative CT analyses in the setting of both COPD and asthma have attracted significant attention (Citation8–12); however, few studies have investigated the characteristics of ACOS via CT. In particular, the different manifestations of ACOS and COPD on CT densitometry have not been thoroughly discussed, and whether the characteristics of ACOS as visualized by CT densitometry are consistent with the disease's clinical manifestations and pathophysiologic change is unknown. Therefore, we performed both pre- and post-bronchodilator (BD) low-dose volumetric CT imaging studies during the inspiratory and the expiratory phases in patients with COPD and ACOS to visualize the distinct characteristics of ACOS on CT densitometry.
Materials and methods
Subjects
The protocol for this prospective clinical study was approved by the Human Research Ethics Board of Beijing Chao-Yang Hospital (study Citation10-ke-65). A signed written informed consent document was obtained from each patient prior to participation. The study population was randomly selected from communities in Beijing between June 2012 and March 2015 via questionnaires using the following inclusion criteria: (Citation1) age 40–75 years; (Citation2) a history of chronic respiratory symptoms, including wheeze, cough, expectoration and dyspnea; (Citation3) a pre-BD FEV1/FVC ratio < 70%. The participants (n = 236) were in stable clinical condition (). Both CT imaging and pulmonary function tests (PFT) were performed before and after BD (salbutamol) administration.
Figure 1. A flowchart of this study.
Subjects were excluded if (Citation1) post-BD FEV1/FVC ratio ≥70%; (Citation2) they were unable to cooperate with respiration; (Citation3) they were diagnosed of respiratory disease other than COPD and asthma that may affect lung function or (Citation4) they were diagnosed of congenital heart disease or congestive heart failure. The final study population was separated into the following 2 groups, according to the criteria determined by a joint statement released by the Global Initiative for Asthma and the Global Initiative for Chronic Obstructive Lung Disease (Citation13): (Citation1) COPD: based on a post-BD FEV1/FVC ratio < 70% and persistent respiratory symptoms related to noxious particles or gases; (Citation2) ACOS: if patients fulfilled both diagnosis criteria for COPD and asthma (Citation3, Citation6). Asthma was diagnosed when patients had clinical history compatible of asthma plus variable expiratory airflow limitation in PFT: post-BD improvement in FEV1 > 12% and > 200 ml, as well as average daily diurnal peak expiratory flow (PEF) variability >10% over 2 weeks.
CT protocols
Whole-lung volumetric CT examinations were acquired using a 64-MDCT system (LightSpeed VCT, GE Healthcare). Each patient was examined before and after BD administration of Salbutamol (Ventolin Aerosol, 400 μg, Glaxosmithkline) within 3 hours. Pre-BD CT was performed within 60 minutes of each patient's PFT. After BD administration, PFT was performed within 30 minutes and CT was performed within 90 minutes. Each CT scan was performed at full inspiration and full expiration with the patient in the supine position, without contrast medium administration. Before the CT examination, each patient was carefully instructed on how to breathe. Inspiratory status was not monitored by spirometry. The scans were obtained at a 120 kV tube voltage, 50 mAs tube current, 1.0 pitch and 280 to 350 mm display field of view. The data were reconstructed with a 1.25-mm reconstruction slice thickness and a 1.25-mm reconstruction interval using a standard algorithm. The CT system was calibrated routinely.
CT densitometry
All CT images were analyzed using GE ADW 4.5 workstation densitometry (Thoracic-VCAR, GE Healthcare), a program that automatically excludes structures other than the lung segments. The trachea and the main bronchi were also eliminated. Manual modification was performed if necessary to correct for the erroneous inclusion of non-pulmonary structures and the exclusion of lung regions. The emphysema index (EI) was defined as the percentage of lung voxels below the CT attenuation value of -950 HU on an inspiratory CT scan. Air trapping (AT) was defined as the percentage of lung voxels with a CT attenuation value below -856 HU on an expiratory CT scan. A histogram analysis of the segmented lungs was subsequently performed to determine mean lung attenuation (MLD) and the total lung volume (TLV).
EI, AT, MLD and TLV for the entire lung were measured and compared between the COPD and ACOS groups. The right and left lung were then divided into the following three zones: upper, middle and lower, based on the level of the carina and the inferior right pulmonary vein. The EI and AT of each zone were measured. The distributions of EI and AT were classified as follows: (Citation1) upper-lung-zone predominance (U): the presence of the peak EI or AT within the upper zone of the lung combined with a reduction in EI or AT toward the middle and lower zone, plus the difference between the upper and lower zone was greater than 10%; (Citation2) lower-lung-zone predominance (L): the presence of the peak EI or AT within the lower zone of the lung combined with a reduction in EI or AT toward the middle and upper zone, plus the difference between the upper and lower zone was greater than 10%; and (Citation3) middle/homogeneous distribution (M): the CT measurements in the middle zone were larger or smaller than both the upper and the lower zones, or the difference between the upper and lower zones was less than 10% (Citation14, 15).
PFT technique
Lung function was assessed via spirometry and plethysmography (Jaeger MasterScreen, Viasys Healthcare, Höchberg, Germany) according to European Respiratory Society (ERS)/American Thoracic Society (ATS) Guidelines (Citation16). For each subject, the following functional parameters were assessed both before and after the administration of salbutamol: forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), the FEV1/FVC ratio and FEV1% predicted; specific airway resistance (sRaw); residual volume/total lung capacity (RV/TLC); and lung diffusion capacity corrected for alveolar ventilation (DLCO/VA). The PFT parameters of the COPD and ACOS groups are summarized in .
Table 1. The characteristics of the subjects.
Table 2. The physiologic parameters of the subjects.
Statistical analysis
The CT measurements for the whole lung, including pre- and post-BD EI, AT, MLD and TLV, were compared between the COPD and ACOS groups using the 2-tailed independent Student's t test. The distributions of EI and AT between the COPD and ACOS groups were compared using the chi-square test. The variations in the pre- and post-BD whole-lung CT measurements were compared between the patients with COPD and ACOS using a 2-tailed independent Student's t-test. All statistical analyses were performed using SPSS, version 17.0 (SPSS Inc, Chicago, Illinois, USA). The results are presented as means ± SDs. A P-value less than 0.05 was considered statistically significant.
Results
The study population consisted of 71 subjects, including 32 subjects with COPD and 39 subjects with ACOS, with a mean age of 63.0 ± 7.0 years. The clinical characteristics of the subjects in each group are presented in . There were no significant differences in sex, age, body mass index (BMI) and smoking status between the patients with COPD and ACOS. The four non-smoke COPD patients all reported noxious particles or gases exposure in their work.
The physiologic parameters of the subjects are presented in . There were no significant differences in pre-BD FEV1%, FEV1% predicted, FEV1/FVC ratio, sRAW, RV/TLC between the patients with COPD and ACOS. There were significant differences in post-BD FEV1, FEV1% predicted and RV/TLC between the patients with COPD and ACOS.
The patients with ACOS exhibited lower EI than the patients with COPD, whereas no significant differences were exhibited in AT (). Furthermore, the patients with ACOS exhibited more upper-zone-predominant distributions of EI, compared with the patients with COPD. The distribution of AT showed no difference between the COPD and ACOS groups ().
Table 3. A comparison of whole-lung CT measurements between the patients with COPD and ACOS.
Table 4. A comparison of the EI and AT distributions between the patients with COPD and ACOS.
Following BD administration, the variations in AT and expiratory MLD were significantly larger in the ACOS group than in the COPD group. There were no significant differences in the variations in either EI or inspiratory MLD between the two groups. The variations in TLV were not statistically significant ().
Table 5. A comparison of the variations in pre- and post-BD whole-lung CT measurements between the patients with COPD and ACOS.
Discussion
In this study, we demonstrated the characteristics of ACOS using CT densitometry and observed that patients with ACOS exhibited lower EI and different EI distributions, as well as greater post-BD variations in expiratory AT and MLD, compared to patients with COPD.
ACOS is characterized by persistent airflow limitation and identified by the features that it shares with both asthma and COPD (Citation13). Recent publications have attempted to characterize ACOS based on different clinical features, radiographic findings, and diagnostic tests (Citation17, 18). However, there exist no generally defining features for this category of chronic airflow limitation. Guidelines generally recommend a serial approach to assessment.
If asthma–COPD overlap is confirmed, the initiation of corticosteroid (ICS) irrespective of the severity of COPD, together with a long-acting β2 agonist (LABA) is recommended (Citation19). In this study, CT densitometry characterized the airflow limitation of ACOS. The quantitative data of emphysema and its distribution contributed to identify ACOS from COPD. The post-BD variations of air trapping and expiratory MLD indicate the possible diagnosis of ACOS and prompt the treatment for reversible airflow limitation.
EI and inspiratory MLD are reflective of decreased CT attenuation because of either emphysematous lung destruction or hyperinflation during the inspiratory phase. The patients with ACOS exhibited lower EI in both pre-BD and post-BD CT compared to the patients with COPD. Patients with ACOS derived from long-standing asthma have functional small airways disease but no significant emphysema in HRCT (Citation20), which may explain the lower extent of emphysema in ACOS patients. The post-BD difference of EI may be exaggerated, because post-BD improvement of functional data may also result in lower EI in patients with ACOS.
On expiratory CT scans, air trapping, defined as the retention of air in the distal portions of the lung, reflects pathologic changes in the small airways which cannot be directly measured (Citation21, 22). In this present study, no significant differences in AT were observed between COPD and ACOS subjects. The small airway disease in ACOS may have both the character of that of COPD and asthma. COPD is characterized by obstruction of small airway. However, in asthmatic patients, the change of airway dimension was found throughout the entire bronchial path (Citation19). In bronchi with external diameter larger than 2.0 mm, the bronchial walls were thicker in asthmatics than in patients with COPD (Citation23). The structural and functional changes of distal airway in these two diseases require further study.
COPD is characterized by a large amount of heterogeneity. Spirometry does not reflect the range of pathophysiologic abnormalities associated with this heterogeneous condition, although it is essential for making a diagnosis and provides a useful description of COPD severity (Citation24, 25).
Lung densitometry with CT has yielded valuable data for the measurement of regional airflow limitations via the determination of the zonal or lobar distributions of emphysema and bronchitis (Citation15, Citation26, Citation27). To the best of our knowledge, this was the first study to observe the different distributions of emphysema and air trapping between ACOS and COPD. It is difficult to identify the cause underlying the variety of emphysema distributions observed (Citation26). Recently, unsuspected microscopic mild centrilobular emphysema that responsible for loss of lung elastic recoil was found in asthmatics with persistent expiratory airflow limitation (Citation28). Centrilobular emphysema also predominates in the upper lung field, while pan-lobular emphysema predominates in the lower lung field (Citation15).
Previous studies demonstrated that patients with upper-lobe-predominant CT-quantified emphysema experienced a more rapid decline in lung function compared with patients suffering from lower-lobe-predominant CT-quantified emphysema (Citation29,30). This finding is consistent with the clinical manifestation of ACOS, as patients with ACOS suffer frequent exacerbations and experience a more rapid decline in lung function than do patients with COPD. It is reported that hyperinflation and the loss of elastic recoil is more prominent in the upper lobe and zone as the disease progresses (Citation28, 29); therefore, in patients with ACOS, the rapid progress of disease is speculated to be the reason of heavier upper-zone elastic recoil destruction and upper-zone predominant distribution. On the other hand, whether upper-zone-predominant COPD is prone to devolving into ACOS requires confirmation via longitudinal studies.
Previous studies revealed an upper zone predominance of emphysema in smokers (Citation26, Citation31), whereas chronic inflammatory responses in both the airways and the lungs were predominant in the lower zones (Citation32). In this study, smoking was not the underlying explanation for the different distribution, as the smoking status in COPD and ACOS group had no significant difference.
No significant differences were observed in AT distribution. As Come et al. explained, the pattern of gas trapping is relatively uniform across all lung zones in COPD, likely because gas trapping is influenced not only by emphysema but also by airway disease (Citation33).
This study also demonstrated that post-BD variations in whole-lung CT measurements are different in patients with ACOS and COPD. The improvements in AT and expiratory MLD were greater in the ACOS group than in the COPD group, whereas EI and inspiratory MLD were not significantly different between the two groups. This finding indicates that ACOS presents characteristics of asthma, which is characterized by variable expiratory airflow limitation and is sensitive to BD treatment (Citation34). COPD is characterized by persistent airflow limitation. Neither EI nor AT was significantly improved in COPD patients in our study.
The post-BD variations in CT measurements were also consistent with the changes noted in the PFT parameters. Mohamed Hoesein FA et al. reported the contribution of CT measurements on pulmonary function (Citation35). Emphysema was the most contributing structural lung change for FEV1/FVC, while air trapping was most contributive for RV, RV/TLC and FEV1% predicted (Citation22, Citation35, Citation36), which may reflect the extent of expiratory airway obstruction and improve significantly following the administration of BD in asthmatic patients. Our results also indicated that the expiratory scan is important in the utilization of CT densitometry when characterizing airflow limitation diseases.
Our study had several limitations. First, the results of our current study were limited by the small number of patients enrolled; thus, future studies with larger sample sizes may obtain more information about ACOS via quantitative CT. Second, patients with varying disease severities were included because we aimed to study the overall differences between COPD and ACOS. Additionally, inspiratory status was not monitored by spirometry. Madani et al. demonstrated that submaximal inspiration results in the underestimation of the extent of pulmonary emphysema (Citation37). Therefore, in clinical practice, we suggest actively encouraging patients to reach full inspiration and expiration when undergoing a CT scan.
Conclusion
This study demonstrates that patients with ACOS exhibited lower extent of emphysema and different emphysema distributions, as well as greater post-BD variations in air trapping, compared to patients with COPD. Together, these results suggest that CT densitometry characterizes ACOS as a distinct phenotype from COPD.
Declaration of interest statement
Yanli Gao is a fulltime employee of Department of Radiology, Beijing Chao-Yang Hospital, Capital Medical University. Xiaoli Zhai is a fulltime employee of Department of Radiology, Beijing Chao-Yang Hospital, Capital Medical University. Kun Li is a fulltime employee of Department of Radiology, Beijing Chao-Yang Hospital, Capital Medical University. Hong Zhang is a fulltime employee of Department of Pulmonary and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Institute of Respiratory Medicine. Ying Wang is a postgraduate student of Department of Pulmonary and Critical Care Medicine, Beijing Chao-Yang Hospital.
Yong Lu is a fulltime employee of Department of Pulmonary and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Institute of Respiratory Medicine. Zhenyu Pan is a fulltime employee of Department of Radiology, Beijing Chao-Yang Hospital, Capital Medical University. Lei Zhang is a fulltime employee of Department of Radiology, Beijing Chao-Yang Hospital, Capital Medical University. Kewu Huang is a fulltime employee of Department of Pulmonary and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Institute of Respiratory Medicine. Renyou Zhai is a fulltime employee of Department of Radiology, Beijing Chao-Yang Hospital, Capital Medical University. The authors alone are responsible for the content and writing of the article.
This study was supported by grants from the following sources: the Capital Health Development of Scientific Research (Shou-Fa: 2011-1004-01), the Projects in the National Science & Technology Pillar Program During the Twelfth Five-Year Plan Period (2012BAI05B01, 2012BAI05B02, 2013BAI06B02, 2014BAI08B04), the National High Technology Research and Development Program of China (2012AA02A511), and the Program of Beijing Municipality Health System Program for High-Level Talent (Citation2011-2-04).
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