Chronic Respiratory Symptoms Associated With Airway Wall Thickening Measured by Thin-Slice Low-Dose CT

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1 Cardiopulmonary Imaging Original Research Xie et al. CT for Respiratory Symptoms Cardiopulmonary Imaging Original Research Xueqian Xie 1,2,3 Akkelies E. Dijkstra 4 Judith M. Vonk 5 Matthijs Oudkerk 2 Rozemarijn Vliegenthart 1,2 Harry J. M. Groen 4 Xie X, Dijkstra AE, Vonk JM, Oudkerk M, Vliegenthart R, Groen HJM Keywords: airway wall thickening, chronic bronchitis, CT, large airway, respiratory symptoms DOI: /AJR Received July 11, 2013; accepted after revision February 28, Department of Radiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 2 Department of Radiology, Center for Medical Imaging, University of Groningen, University Medical Center Groningen, North East Netherlands, Hanzeplein 1, 9700RB Groningen, The Netherlands. Address correspondence to X. Xie (xiexueqian@hotmail.com). 3 Department of Radiology, Shanghai JiaoTong University School of Medicine, Ruijin Hospital, Shanghai, China. 4 Department of Pulmonary Diseases, GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 5 Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. WEB This is a web exclusive article. AJR 2014; 203:W383 W X/14/2034 W383 American Roentgen Ray Society Chronic Respiratory Symptoms Associated With Airway Wall Thickening Measured by Thin-Slice Low-Dose CT OBJECTIVE. In lung cancer screening, the prevalence of chronic respiratory symptoms is high among heavy smokers. The purpose of this study was to compare CT-derived airway wall measurements between male smokers with and those without chronic respiratory symptoms. MATERIALS AND METHODS. Fifty male heavy smokers with chronic respiratory symptoms (cough, excessive mucus secretion, dyspnea, and wheezing) and 50 without any respiratory symptom were randomly selected from the Dutch-Belgian Randomized Lung Cancer Screening Trial. Thin-slice low-dose CT images were evaluated with dedicated software for airway measurements. Wall area percentage and airway wall thickness were measured from trachea to bronchi in five different pulmonary lobes of airways with a luminal diameter of 5 mm or greater. Association between airway wall measurements and respiratory symptoms was analyzed by multiple linear regression adjusted for age, body mass index, smoking status, emphysema, and pulmonary function. RESULTS. After adjustment for relevant factors, a significant positive association between airway wall measurements and respiratory symptoms was found in airways with a luminal diameter between 5 to 10 mm (p < 0.01), but not in airways measuring 10 mm or greater (p > 0.05). At the airway level between 5 to 10 mm, the mean wall area percentages were 51.5% ± 7.9%. Airway wall thicknesses were 1.54 ± 0.39 mm and 1.37 ± 0.35 mm (p < 0.001). CONCLUSION. Male heavy smokers with chronic respiratory symptoms in lung cancer screening, who are at high-risk of chronic bronchitis, have bronchial wall thickening in airways with a luminal diameter of 5 10 mm but not in larger airways. N early 50% of smokers undergoing lung cancer screening have chronic respiratory symptoms, that is, chronic hypersecretion of mucus combined with chronic cough and often accompanied by dyspnea and wheezing [1]. Smokers with these symptoms are at risk of development of chronic bronchitis, a disease associated with accelerated decline in pulmonary function and an important risk factor for chronic obstructive pulmonary disease (COPD) and all-cause mortality [2, 3]. During their lifetimes, more than 40% of smokers contract chronic bronchitis [2]. The clinical diagnosis of chronic bronchitis is commonly based on a combination of medical history, physical examination findings, and spirometric and laboratory test results [4]. Despite the high prevalence, chronic bronchitis is often underdiagnosed or diagnosed late [5]. Chronic bronchitis is histopathologically found in a range of airways, commonly in large airways [6]. The morphologic basis of chronic bronchitis is bronchial wall thickening and airway luminal narrowing, which result in airflow limitation [7]. The observation of morphologic changes is important to understand pathogenesis and the effect of therapeutic interventions for chronic bronchitis [8]. The development of thin-slice MDCT and dedicated software allows accurate noninvasive quantification of airway dimensions in large bronchi [9 11]. Among participants in a lung cancer screening study, it is important to know whether there are morphologic changes in the airway walls of subjects with chronic respiratory symptoms, because early treatment would be performed in cases of airway remodeling of chronic bronchitis in this highrisk population. Airway wall thickening is AJR:203, October 2014 W383

2 Xie et al. associated with relevant factors such as age, body mass index (BMI), smoking status, emphysema, and pulmonary function [12, 13]. Orlandi et al. [14] found the relation between airway wall thickening on CT images and chronic bronchitis in the COPD population [14]. However, in male heavy smokers, the representative population in lung cancer screening, the adjusted association between CT-derived airway wall quantification and respiratory symptoms is still unclear. The purpose of our study was to retrospectively compare, after adjustment for relevant factors, airway wall thickness (AWT) along the respiratory pathway between male heavy smokers with and those without chronic respiratory symptoms. Fig. 1 Flow diagram shows subject selection. Materials and Methods Sample The study sample was randomly selected from the baseline round at the Groningen center of the population-based multicentric Dutch-Belgian Randomized Lung Cancer Screening Trial (NEL- SON) (Fig. 1). The group with symptoms contained 50 male heavy smokers ( 15 cigarettes/ day during 25 years or 10 cigarettes/day during 30 years) with four chronic respiratory symptoms: chronic cough, chronic mucus hypersecretion, dyspnea, and wheezing lasting for at least 3 months during the last year before inclusion. The group without symptoms contained 50 male smokers without respiratory symptoms. The sample in each group was randomly selected with statistical software (SPSS version 20, IBM SPSS). It has been reported [15] that the wall area percentage (WA%) in large airways is 53.5% in patients with symptoms and 48.0% in patients without symptoms and that the SD is 8.0. Assuming results similar to the reported data, a 50/50 sample size would provide a statistical power greater than 0.90 with a confidence level of 95% in the Student t test in the assessment of WA% in large airways between these two groups. The NELSON trial was approved by the Dutch minister of health and the ethics board at the participating center. All participants gave written informed consent. Detailed inclusion and exclusion criteria and the characteristics of this male population based trial have been described elsewhere [16]. In short, current and former heavy smokers years old were included. Individuals in moderate or poor health who could not climb two flights of stairs were excluded. Information about the presence of respiratory symptoms and smoking behavior (e.g., current or former smoker, pack-years) was obtained by questionnaires. The participants were asked the following question for recording their respiratory symptoms: Have you experienced the following symptoms for at least 3 months during the past year, even when you did not have a cold: cough, sputum expectoration, wheezing, or dyspnea? CT A 16-MDCT scanner (Sensation 16, Siemens Healthcare) was used with a low-dose acquisition protocol [17]. The protocol was spiral acquisition at 120 kv; 20 mas; rotation time, 0.5 second; pitch, 1.5; collimation, mm; FOV, 350 mm; slice thickness, 1 mm; slice increment, 0.7 mm. The effective radiation dose was less than 0.8 msv. Contrast medium was not used. The images were reconstructed to a pixel matrix of with a medium-smooth (B30f) kernel. The CT system was calibrated routinely. Image acquisition was performed during one breath-hold at full inspiration after appropriate instruction. Pulmonary Function Testing On the same day as CT acquisition, standard pulmonary function testing was performed according to the European Respiratory Society guidelines [18]. In this population-based trial, a bronchodilator was not administered. Forced expiratory volume in one second ( ) and forced vital capacity (FVC) were assessed. was presented as percentage of predicted value. Airway Selection We measured the airways from the tracheal, main, and lobar bronchi down to the segmental and subsegmental bronchi with an internal luminal diameter of 5 mm or greater. These airways were subsequently categorized into three categories (luminal diameter 15 mm, between 10 and 15 mm, and between 5 and 10 mm). We selected five bronchi of segmental level, each representing one pulmonary lobe: the apical bronchus (RB1) of the right upper lobe, the lateral bronchus (RB4) of the right middle Enrollment 2018 Subjects screened for lung cancer in one center 1413 With complete data on questionnaire, pulmonary function test and CT on the same day Allocation 676 With respiratory symptoms 737 Without respiratory symptoms Analysis 50 Randomly included 50 Randomly included lobe, the posterior basal bronchus (RB10) of the right lower lobe, the apicoposterior bronchus (LB1+2) of the left upper lobe, and the posterior basal bronchus (LB10) of the left lower lobe. Those bronchi were selected because they are relatively free from cardiac motion artifacts. In the bronchial tree below the segmental level, when more than one bronchus was present in each airway generation, we evaluated only one bronchus in each generation. Thereafter, the bronchial pathway was evaluated from the trachea down to the airway level of 5-mm luminal diameter. After randomization of all included subjects, one radiologist with 9 years experience in thoracic diagnostic radiology selected airways and evaluated the images. This radiologist was blinded to subject information regarding basic characteristics and clinical data during evaluation. The duration of the whole assessment process for each subject was approximately 3 minutes. Quantitative Image Analysis The images were evaluated with dedicated software for airway measurement (Airway Examiner 1.0, Fraunhofer MEVIS), which was based on a 3D algorithm of airway geometry [11] instead of the traditional full width at half-maximum (FWHM) algorithm. Briefly, wall thickness is estimated in 3D space with this algorithm, as opposed to the 2D plane in the FWHM method [11]. For AWT as small as 1 mm, the 3D algorithm had much better accuracy and reproducibility than the FWHM method in phantom studies [11, 19]. This software tool follows two principal steps. First, the software automatically segments the bronchial tree. Second, after the user clicks a bronchus in the bronchial tree, the software automatically quantifies airway dimensions along the trachea to the chosen bronchus, presenting data per 1 mm along this respiratory pathway. A representative figure generated by the software package is shown in Figure 2. To avoid potentially misleading W384 AJR:203, October 2014

3 CT for Respiratory Symptoms segmentation of airway walls in branching points, the airways within 5 mm from the branching point were not included. We collected three airway quantitative measurements: WA%, AWT, and airway luminal diameter. WA% was defined as follows: (wall area) / (wall area + lumen area) 100. Emphysema quantification was performed with dedicated software (ImageXplorer, Image Sciences Institute). This software automatically applies lung segmentation, image noise reduction, and CT attenuation calibration to improve the accuracy and reproducibility of evaluation [20, 21]. The images were recalibrated by shifting CT attenuation so that the attenuation inside the trachea became 1000 HU [22]. We collected three CT quantification parameters: 15th percentile point of lung attenuation, percentage of lung attenuation area less than 950 HU, and lung volume. Larger emphysematous tissues are indicated by lower 15th percentile point or higher percentage area less than 950 HU. Statistics Data were reported as mean ± SD for normally distributed data and as median and 25th and 75th percentiles for nonnormally distributed data. Differences in characteristics between the groups with and without symptoms were assessed by independent samples Student t test for normally distributed continuous data, by Mann-Whitney U test for nonnormally distributed continuous data, and by chi-square test for nominal data. The association between airway wall measurements (WA% and AWT) and potentially associated factors was evaluated by univariate linear regression analysis. The association between airway wall measurements and respiratory symptoms was analyzed by multiple linear regression adjusted for age, BMI, smoking status, 15th percentile point of lung attenuation, and as percentage of predicted value. A value of p < 0.05 was considered statistically significant. Statistical analyses were performed with SPSS software (version 20, IBM SPSS). A Fig year-old male heavy smoker with chronic respiratory symptoms. A, Image generated with dedicated software shows automatic segmentation of bronchial tree. White = tracheal and main airways. Orange = lobar or segmental airways in upper pulmonary lobes. Green = lobar or segmental airways in right middle lobe. Dark gray = lobar or segmental airways in lower lobes. B, Stretched multiplanar reconstruction converted from segmentation in A shows bronchial pathway from trachea to selected bronchus. Results Sample Characteristics The characteristics of the groups with and without symptoms are presented in Table 1. All subjects were men with a mean age of 56.5 ± 5.4 years (range, years). No diseases (e.g., pneumonia, atelectasis) affecting airway wall measurements were detected in review of CT images. No pulmonary fibrosis affecting the observation of large bronchi wall was found. No obstructive diseases (e.g., airway mass or tumor, external compression and bronchial stricture) causing airway wall thickening were found either. Airway walls were successfully evaluated in all 100 subjects, among whom 65,070 TABLE 1: Characteristics of Subjects With and Without Chronic Respiratory Symptoms Characteristic With Symptoms Without Symptoms Sample size (n) Basic characteristics Male sex (no. of subjects) Age (y) 56.0 ± ± Weight (kg) 86.9 ± ± Height (m) 1.79 ± ± Body mass index 27.0 ± ± Smoking behavior Current or former smoker (no. of subjects) 37/13 23/27 < 0.05 Pack-years 42.1 ± ± Smoking duration (y) 8.3 ± ± CT quantification Wall thickness (mm) 1.55 ± ± 0.40 < Wall area percentage 47.0 ± ± 11.1 < Lung volume (L) 7.0 (6.3, 8.0) 6.6 (5.7, 7.5) < th percentile point of lung attenuation (HU) 922 ( 933, 912) 915 ( 928, 898) < Percentage of lung attenuation area less than 950 HU 3.2 (2.1, 5.5) 2.3 (1.0, 4.0) < Pulmonary function test results (% of predicted) 80.3 (65.4, 110.4) (95.6, 108.2) < /FVC (%) 65.5 (51.9, 72.4) 75.3 (69.6, 80.8) < Chronic obstructive pulmonary disease (no. of subjects) < Note Data are mean ± SD for normally distributed data or median with 25th and 75th percentiles in parentheses for nonnormally distributed data. = forced expiratory volume in the first second, FVC = forced vital capacity. p B AJR:203, October 2014 W385

4 Xie et al. cross sections of airways were measured. WA% increased from proximal to distal airway, whereas AWT and luminal diameter decreased. WA% ranged from 14.6% to 75.5%. AWT ranged from 0.7 to 3.2 mm. Airway luminal diameter ranged from 5.0 to 22.9 mm. The group with symptoms had more current smokers than the group without symptoms (74% vs 46%, p < 0.05). No significant differences were found for age, BMI, packyears, or smoking duration between those two groups (p > 0.05). The group with symptoms had significantly worse pulmonary function (, /FVC) than the group without symptoms (p < 0.001). At CT emphysema quantification, the group with symptoms had significantly lower 15th percentile point of lung attenuation and percentage of lung attenuation area less than 950 HU than the group without symptoms (p < 0.001), indicating more emphysematous tissue in the group with symptoms. The median percentages of lung attenuation area less than 950 HU were 3.2% (25th, 75th percentiles, 2.1%, 5.5%) in the group with symptoms and 2.3% (1.0%, 4.0%) in the group without symptoms, indicating mild emphysema in the two groups [9]. Factors Associated With Airway Wall Measurements Univariate linear regression analysis showed that thicker airway walls were positively associated with the presence of respiratory symptoms, higher BMI, current smoking, more pack-years, and longer Wall Thickness (mm) *} Symptoms No symptoms * } 5 Ø < Ø < 15 Ø 15 Luminal Diameter (mm) TABLE 2: Results of Univariate Regression Analysis for Factors Associated With Airway Wall Measurements Characteristic smoking duration (p < 0.05) (Table 2). Conversely, thinner airway walls were positively associated with more advanced age, longer duration of smoking cessation, and better pulmonary function (, / FVC) (p < 0.01). Airway Wall Thickness Wall Area Percentage B p B p Basic characteristics Age (y) < < 0.01 Weight (kg) Height (m) Body mass index < < 0.05 Smoking behavior Current smoking < < Pack-years < < Smoking duration (y) < < 0.01 Duration of smoking cessation (y) < < Chronic respiratory symptoms present < < CT emphysema quantification Lung volume (L) th percentile point of lung attenuation (HU) Percentage of lung attenuation area less than 950 HU Pulmonary function test results (% of predicted) < < /FVC (%) < < Note, = forced expiratory volume in the first second, FVC = forced vital capacity. * } A Wall Area Percentage (%) *} Airway Wall Thickness Differences Between the Groups With and Without Symptoms Without adjustment for relevant factors, the group with symptoms had a higher overall WA% (47.0% ± 12.1% vs 43.3 ± 11.1%, p < 0.001) and higher AWT (1.55 ± 0.44 mm * } Symptoms No symptoms * } 5 Ø < Ø < 15 Ø 15 Luminal Diameter (mm) Fig. 3 Comparisons across luminal diameters (Ø). A and B, Graphs show airway wall area percentage (A) and thickness (B) between groups of subjects with and without chronic respiratory symptoms without adjustment for relevant factors. Asterisk indicates significant difference between groups. B W386 AJR:203, October 2014

5 CT for Respiratory Symptoms TABLE 3: Results of Multiple Linear Regression for the Association Between Airway Wall Measurements and Chronic Respiratory Symptoms Airway Luminal Diameter (mm) 5 Diameter < Diameter < 15 Diameter 15 Characteristic B p B p B p Wall thickness Presence of respiratory symptoms < Age < 0.01 Body mass index < Current smoking < th percentile point of lung attenuation < as percentage of predicted value < < < 0.01 Wall area percentage Presence of respiratory symptoms < Age < 0.05 BMI < Current smoking < th percentile point of lung attenuation < as percentage of predicted value < < < Note Adjusted for age, body mass index, current smoking status, 15th percentile point of lung attenuation, and as percentage of predicted value., = forced expiratory volume in the first second. A B vs 1.42 ± 0.40 mm, p < 0.001) than the group without symptoms. In detail, in all three categories of large airways (luminal diameter 15 mm, between 10 and 15 mm, and between 5 and 10 mm), the group with symptoms had significantly higher WA% and AWT (p < 0.01) (Fig. 3). The representative images of those two groups are shown in Figure 4. Multiple linear regression analysis showed that after adjustment for age, BMI, smoking status, 15th percentile point of lung attenuation, and as percentage of predicted value, a significant positive association between thicker airway walls (WA% and AWT) and the presence of respiratory symptoms was found only in airways with a luminal diameter between 5 and 10 mm (p < 0.01). In the airway level between 5 and 10 mm, mean WA% was 51.5% ± 7.9% in the group with symptoms and 48.1% ± 7.7% the group without symptoms (p < 0.01). AWT was 1.54 ± 0.39 mm in the group with symptoms and 1.37 ± 0.35 mm in the group without symptoms (p < 0.001). No significant associations were found in airways with a luminal diameter of 10 mm or greater (p > 0.05) (Table 3). Discussion Thin-slice CT and automated software are promising tools for quantifying airway walls. Using these techniques, after adjusting for relevant factors, we found that heavy Fig. 4 Cross-sectional CT images perpendicular to long axis of bronchi. A, 59-year-old male heavy smoker with chronic respiratory symptoms. Wall area percentage is 51%, airway wall thickness is 1.4 mm, and luminal diameter is 7 mm. B, 63-year-old male heavy smoker without chronic respiratory symptoms. Wall area percentage is 43%, airway wall thickness is 1.1 mm, and luminal diameter is 7 mm. Yellow lines indicate internal border of airway walls. Orange lines = external border. White dashed lines = computer-estimated border. AJR:203, October 2014 W387

6 Xie et al. smokers with chronic respiratory symptoms had significantly thicker airway walls in airways with a luminal diameter between 5 and 10 mm, but not in the larger airways. Without adjustment, the thicker airway walls were in all 5-mm or larger airways. The group with symptoms had generally thicker airway walls up to the trachea. The common causes of bronchial wall thickening are inflammatory, congenital (e.g., cystic fibrosis, α 1 -antitrypsin deficiency), and obstructive bronchial diseases [23]. Inflammation of the mucous membrane directly results in hypersecretion of mucus, leading to respiratory symptoms, such as cough, dyspnea, and wheezing [24]. Our sample was from a population-based trial, and these congenital bronchial diseases are rare [25]. An experienced radiologist reviewed the CT images and did not observe obstructive bronchial disease. Thus, the primary cause of bronchial wall thickening in our study was likely inflammatory. Chronic bronchitis is associated with long-term inflammatory stimulation [6]. The histologic evidence indicates that the inflammation and airway remodeling associated with chronic bronchitis is located in the more central airways [26]. Using CT quantification in a COPD population rather than a population of heavy smokers, Patel et al. [27] observed a significant positive association between AWT and respiratory symptoms in airways approximately 6 mm in luminal diameter. Mair et al. [15] found a significant positive association in proximal airways (> 11 mm in luminal diameter) but not in distal airways ( 2 4 mm). We therefore investigated bronchial walls with a luminal diameter of 5 mm or greater. On the other hand, thickening of smaller airway walls is important for the pathogenesis of COPD and asthma [28, 29]. Increased CT-derived AWT of more peripheral airways, as small as 2 4 mm in luminal diameter, strongly correlates with airflow limitations in those diseases [22, 30, 31]. Importantly, we adjusted for five relevant factors to determine the adjusted association between thicker airway walls and chronic respiratory symptoms. In a study of the same age group as in our study [32], smokers had thicker bronchial walls than did nonsmokers. Smoking often causes more airway inflammation [33] and is an important potential confounder in investigations of airway wall thickening. Thus it is essential to adjust for smoking behavior. Next, in accordance with previous studies in which age, BMI, and pulmonary function were associated with airway wall thickening [13, 34, 35], we also found by univariate linear regression that thicker airway walls were significantly associated with current smoking, younger age, higher BMI, and worse pulmonary function. Inconsistently with previous studies in which emphysema was associated with airway wall thickening [13, 36], we found a nonsignificant association between CT emphysema quantification and airway wall thickening. That inconsistent finding may be explained by the presence of only mild emphysema in our sample, which was selected from a population-based screening trial. After adjustment for the potential confounders, we found significantly thicker airway walls in airways with a luminal diameter between 5 and 10 mm, but not in the larger airways. We used a 3D algorithm to assess airway walls in this study. With this algorithm, wall thickness is approximated by an integral-based closed-form solution based on the volume conservation property of convolution [11]. In contrast, the traditionally used FWHM algorithm calculates x-ray attenuation values along rays placed from the lumen center to outward directions in 2D cross section [10]. In phantom studies [11, 19], the 3D algorithm has been much more accurate and reproducible than the 2D algorithm for wall thickness as small as 1 mm. The accuracy of bronchial wall quantification in CT depends on other factors, such as image noise. Lutey et al. [37] found that partial volume effects had more influence on bronchial wall measurements in smaller airways than in larger airways. Diaz et al. [38] found that emphysema had more influence on smaller airways. In a phantom study based on the 3D algorithm for thin-slice low-dose CT (slice thickness, mm; tube current as low as 18 mas), the average wall thickness error for a tube (luminal diameter, 3.4 mm; wall thickness, 0.9 mm) was 4.4% [19]. This phantom study simulated thin-slice low-dose settings with considerable image noise and airways as small as 3.4 mm in luminal diameter, which were similar to our methods; thus, we expected that our measurements were accurate. Our results were based on 16-MDCT images of voxels. This image matrix is widely available in current clinical practice. The latest CT technique provides higher spatial resolution and thus improves airway wall assessment [39]. For example, an image matrix of voxels may result in more accurate measurements. CT quantification is associated with pathophysiologic changes of airway remodeling. A number of CT-derived measurements have been used for airway quantification, such as thickness, area, perimeter, CT attenuation, and visual score [12, 27, 40]. We measured WA% and AWT because these two measurements directly indicate and pathologically reflect airway wall thickening [29]. Moreover, we used automated dedicated software to evaluate airway dimensions per 1 mm. Some previous studies were conducted with manual methods of quantifying airway walls. In those methods, airway walls were noncontinuously measured in cross sections between large gaps of up to 20 mm [14, 27]. Mair et al. [15] quantified airway walls as a function of airway generation. In addition to that study, we evaluated airway walls as a function of airway luminal diameter, because the same airway generation in two bronchi may have different sizes. Clinical Implications In lung cancer screening trials, the participants are usually heavy smokers, who have a high prevalence of chronic bronchitis. Despite the high prevalence, chronic bronchitis was often underdiagnosed or diagnosed late [5]. We expect to use CT bronchial wall quantification among smokers in screening, such as the participants in the NELSON trial, which is the important population for early diagnosis and treatment of chronic bronchitis. This screening trial excludes individuals in moderate or poor health, because participants need to have enough cardiopulmonary reserve to undergo surgery. Thus the population in the NEL- SON trial is representative of general heavy smokers. One morphologic manifestation of chronic bronchitis is bronchial wall thickening caused by chronic inflammatory stimulation [6]. We found that heavy smokers with chronic respiratory symptoms had significantly thicker airway walls, which represents airway remodeling in an inflammatory process. Our study shows that this airway remodeling can be detected with thin-slice CT and dedicated software; thus this method has potential benefit for early diagnosis of chronic bronchitis. Clinical symptoms and spirometric findings are commonly used for diagnosis and surveillance of chronic bronchitis [41]. Noninvasive CT quantification of airway walls has potential for regional and morphologic evaluation of the therapeutic response to treatment of chronic bronchitis [8]. In our study, significantly thicker airway walls W388 AJR:203, October 2014

7 CT for Respiratory Symptoms were especially identified in large airways between 5 and 10 mm in luminal diameter in the group with respiratory symptoms. Thus, CT quantification of airway walls may provide additional morphologic information beyond clinical symptoms and spirometric findings. When assessing airway wall thickening in patients with symptoms, airways between 5 and 10 mm in luminal diameter optimally reflect the presence of respiratory symptoms, but the larger airways do not. The absolute increase in airway wall thickening in subjects with symptoms is commonly within 1 mm, which is barely perceptible to the human eye on CT images. Kim et al. [42] found a significant association between visual and quantitative assessments. In screening, a quantitative method is important across different observers and during follow-up of patients, because the small changes have to be recorded accurately and reproducibly. Hence, dedicated software is a good candidate for screening airway walls. Limitations First, inherent to a population-based lung cancer screening trial, histopathologic results on the bronchial wall are extremely difficult to obtain. At the least, our results suggested that chronic respiratory symptoms are associated with airway remodeling caused by an inflammatory process, which is a pathologic basis for chronic bronchitis. In addition, the only participants were male heavy smokers with mild emphysema. Sex was not adjusted for in this study. Worldwide it is estimated that men smoke nearly five times as much as women [43]. Lung cancer has higher incidence and mortality rates among men than among women [44]. Because of the higher prevalence of heavy smoking and lung cancer, male smokers are more often screened and examined with CT. Our study was performed only with men. Whether the results are generalizable to women should be investigated in the future. Second, a pulmonary function test to assess reversibility in airflow limitation a criterion for excluding bronchial asthma was not performed after bronchodilator administration [28]. Our sample was from a population-based trial, and the prevalence of asthma among elderly men is approximately 2% in The Netherlands [45]. Thus, our results might not be substantially influenced by that limitation. Third, five bronchi from different pulmonary lobes, instead of bronchi from all pulmonary lobes, were evaluated because they are relatively free from cardiac motion artifacts. A large number of airway cross sections (650 per subject) were measured. We expected that five bronchi with a large number of measurements would represent the quantification of airway dimensions. Conclusion After adjustment for relevant factors, male heavy smokers with chronic respiratory symptoms from a population-based lung cancer screening trial have significantly thicker bronchial walls in airways with a luminal diameter between 5 and 10 mm but not in larger airways than do smokers without symptoms. Thus, male heavy smokers with chronic respiratory symptoms do have airway remodeling. Thin-slice CT and dedicated software showed potential for evaluating airway remodeling in smokers with chronic respiratory symptoms. References 1. Mets OM, Buckens CF, Zanen P, et al. Identification of chronic obstructive pulmonary disease in lung cancer screening computed tomographic scans. JAMA 2011; 306: Pelkonen M. Smoking: relationship to chronic bronchitis, chronic obstructive pulmonary disease and mortality. Curr Opin Pulm Med 2008; 14: Guerra S, Sherrill DL, Venker C, Ceccato CM, Halonen M, Martinez FD. 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