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Chronic Obstructive Pulmonary Disease: Thin-Section CT Measurement of Airway Wall Thickness and Lung Attenuation¹

¹ From the Radiodiagnostic Section, Department of Clinical Physiopathology (I.O., C.M., M.B., N.V., M.M.), and Respiratory Medicine Unit, Department of Critical Care (G.C., M.P.), University of Florence, Viale Morgagni 85, Florence 50134, Italy. Received January 13, 2004; revision requested March 16; revision received March 31; accepted May 17. Address correspondence to M.M. (e-mail: m.mascalchi@dfc.unifi.it).

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To prospectively evaluate airway wall thickness and lung attenuation at spirometrically gated thin-section computed tomography (CT) in patients with chronic obstructive pulmonary disease (COPD) and to correlate gated CT findings with pulmonary function test (PFT) results.

MATERIALS AND METHODS: The ethical committee approved the study, and all patients gave informed consent. Forty-two consecutive patients with COPD (20 with and 22 without chronic bronchitis [CB]) underwent gated thin-section CT and PFTs on the same day. The percentage wall area (PWA) and the thickness-to-diameter ratio (TDR) for all depicted bronchi that were round and larger than 2 mm in diameter, the mean lung attenuation (MLA), and the pixel index (PI) at –950 HU were determined. The reproducibility of the airway measurements was preliminarily tested by performing a five-trial examination in a patient with COPD and in a control patient. Differences in airway and lung attenuation measurements between the patients with and those without CB were evaluated at Mann-Whitney U testing. Simple and multiple regression analyses were used to assess the correlation between thin-section CT and PFT measurements.

RESULTS: The mean intraoperator coefficient of variation for airway measurements was 7.8% (range, 3.8%–13.4%). An average of nine bronchi per patient were assessed. Patients with CB had significantly higher PWAs, TDRs, and MLAs and significantly lower PIs than patients without CB (P < .05 for all values). The combination of PWA, TDR, and PWA normalized to body weight correlated significantly (P < .05) with the forced expiratory volume in 1 second–to–slow vital capacity ratio and the diffusing capacity of the lung for carbon monoxide in patients with but not in patients without CB. PFT results correlated better with MLA and PI in patients without CB.

CONCLUSION: Bronchial wall measurements differ between patients who have COPD with CB and those who have COPD without CB. The correlation between airway dimensions and indexes of airway obstruction in patients with COPD and CB indicates that the bronchial tree is the site of anatomic-functional alterations in this patient group.

© RSNA, 2005

	INTRODUCTION

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Chronic obstructive pulmonary disease (COPD), including chronic bronchitis (CB), emphysema, and forms of CB combined with emphysema, is characterized by progressive airway obstruction and airflow limitation that do not reverse with the administration of bronchodilator drugs (1).

Computed tomography (CT) is an established tool for in vivo assessment of pulmonary emphysema, which appears as areas of decreased lung attenuation (2–5). In several studies (6–8), investigators have reported a correlation between the airway wall thickness measured on CT scans and the severity and duration of disease in patients with asthma (6–8). In one study (9), the apical bronchus of the right upper lobe of the lung in patients with COPD was assessed.

Spirometric gating enables the acquisition of CT scans at predefined levels of the patient’s vital capacity (VC), which obviates the variability in lung attenuation (10–14) and presumably in airway size (15) caused by different degrees of lung inflation during scanning. Thus, the purpose of our study was to prospectively evaluate airway wall thickness and lung attenuation by using spirometrically gated thin-section CT in patients with COPD and to correlate the gated CT findings with the pulmonary function test (PFT) results.

	MATERIALS AND METHODS

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Patients and CT Scans
We examined 42 consecutive outpatients (37 men, five women; mean age, 63 years; age range, 42–73 years) who had received a diagnosis of COPD (1) and were undergoing periodic clinical and functional evaluations. Eighteen patients were current smokers who smoked a mean of 60 packs per year ± 46 (standard deviation) (range, 7–320 packs per year). The mean disease duration (since the first PFT evaluation) was 84 months ± 37 (range, 24–180 months). Twenty patients fulfilled the criteria for having CB—namely, a history of productive cough on most days for at least 3 months for 2 successive years (16)—and 22 did not. Our hospital’s ethical committee approved the study, and all patients gave informed consent to being participants in the investigation.

The patients underwent PFTs and spirometrically gated thin-section CT (herein also referred to as gated CT) on the same day. In the first 10 patients enrolled in the study (six with and four without CB), conventional inspiratory thin-section CT (ie, nongated CT) scans also were obtained. On the basis of the results of our comparison of the gated and nongated CT data obtained in these 10 patients, we obtained only gated CT scans in the remaining 32 patients enrolled in the study.

To assess the reproducibility of the airway wall measurements, we randomly selected the nongated CT scans obtained in one of the first 10 patients with COPD who satisfied the criteria for CB and the nongated CT scans obtained in a 34-year-old man with systemic sclerosis (control patient) who was examined for diagnostic purposes and whose PFT and CT examination revealed no abnormalities. After the aims of the study were explained to this patient, he gave consent for his CT scans to be used in this context.

PFT Procedure
PFTs were performed by using a constant-volume body plethysmograph (V6200 Autobox Body Plethysmograph; Sensor Medics, Yorba Linda, Calif). Forced VC maneuvers were performed with use of a mass flow sensor (part of V6200 plethysmograph) before and after the patients inhaled 400 µg of salbutamol (Ventolin; GlaxoSmithKline, Liverpool, England) from a metered dose inhaler. A postbronchodilation increase in forced expiratory volume in 1 second (FEV₁) of less than 12% or of less than 200 mL from the baseline value indicated nonreversible airway obstruction (1). The functional residual capacity at end-tidal expiration was measured while the patient panted against a closed shutter at a frequency of approximately 0.5 Hz. After the shutter was opened, the expiratory reserve volume and the VC were measured and the residual volume and the total lung capacity were calculated. The single-breath diffusing capacity of the lung for carbon monoxide (DLCO) was measured by using a multigas analyzer (part of V6200 plethysmograph). All of the above parameters were expressed as percentages of the predicted values according to reference equations (1).

CT Examinations
Thin-section CT examinations were performed by using a Somatom Plus scanner (Siemens, Erlangen, Germany) and consisted of sequential acquisitions of 1-mm-thick sections at 140 kVp and 146 mA. No intravenous contrast material was administered. Spirometric gating was performed by using the "Spiro" option on the Somatom Plus scanner (13). This option was used with a small open spirometer (Micro Medical, Rochester, England) equipped with a shutter to interrupt the airflow at user-selected percentages of the VC for the duration of the CT examination. Before each CT examination, the spirometer was quality tested with a 3-L volume calibrator.

Before the CT examination, each patient was instructed to breathe through a mouthpiece and perform respiratory maneuvers while lying on the CT table so that the VC could be measured. In addition, he or she experienced at least one episode of apnea that was induced by the shutting of the spirometer valve while a respiratory maneuver (without ensuing CT scan acquisition) was being performed. We selected a trigger level of 90% of the VC, which can be considered representative of the maximum inspiration (11).

Then, the patient was asked to perform a VC maneuver and airflow was automatically inhibited when 90% of the VC was reached. In each of the 42 patients, four triggered CT scans were obtained: a scout view and three transverse scans 5 cm above and 5 cm below the carina (11–13). In the first 10 patients enrolled in the study, a nongated CT examination was performed after the gated CT examination. For this examination, eight to 12 1-mm-thick CT sections with a 20-mm gap were obtained from the apex to the diaphragm at end inspiration by using the peak voltage and amperage values used to perform the gated examination. The duration of the gated CT examination was 8–10 minutes, and that of the nongated CT examination was 10–15 minutes.

Image Analysis
Airway evaluation.—For airway evaluation, all gated and nongated CT scans were reconstructed by using a thin-section algorithm and were visualized by using a window width of 1500 HU and a window level of –450 HU (17–19). One radiologist (I.O.) who had 5 years experience interpreting chest CT scans and was blinded with regard to which patients had CB and which did not, to the PFT results, and to the lung attenuation measurements (detailed in following text) selected all of the bronchi that were depicted as being round and had an external diameter of greater than 2 mm (17,20) and a maximum diameter–to–minimum diameter ratio of less than 1.5 (17) on the three gated CT scans obtained in each of 42 patients and on the eight to 12 nongated CT scans obtained in each of 10 patients. To compute the thickness-to-diameter ratio (TDR) and the percentage wall area (PWA) (Fig 1) (7–9) for all selected bronchi, we measured the internal and external bronchial diameters by using an electronic caliper. For each patient, the mean TDR and the mean PWA were calculated and the mean PWA was normalized to the body weight.

View larger version (61K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Schematic drawing of airway measurements. The formulas used to calculate the TDR and the PWA on the basis of wall thickness (T), bronchial external diameter (D), and bronchial lumen diameter (L) are as follows: TDR = T/D and where (D/2)2 is the total area and (L/2)2 is the endoluminal area. B = bronchial wall area.

Lung attenuation evaluation.—Another radiologist (C.M.) who had 7 years experience interpreting chest CT scans and was blinded with regard to which patients had CB and which did not, to the PFT results, and to the airway wall measurements evaluated the gated and nongated CT scans by using a software program (Pulmo; Siemens) provided by the CT scanner manufacturer (13). Each lung attenuation evaluation session was preceded by a quality test that was performed by using a phantom. The boundaries of each lung were automatically determined by using attenuation-discriminating software (Pulmo).

Traced lung contours usually needed to be manually corrected on scans obtained at the carina owing to the irregular shape of bronchovascular structures at this level. In addition, pulmonary nodules, areas of pleural thickening, and fibrous scarring were manually excluded from the regions of interest. Then, relative frequency histograms of lung attenuation values were obtained (13). With use of the data on each CT section, the inspiratory mean lung attenuation (MLA) and the pixel index (PI), defined as the percentage of lung area with attenuation values lower than –950 HU (3,4), were measured. The lung attenuation evaluation was performed at the end of each CT examination and required about 15 minutes with the three gated scans and about 45 minutes with the nongated scans.

Statistical Analyses
We used the Student t test for paired data to compare PWAs, TDRs, MLAs, and PIs between the gated and nongated CT scans obtained in 10 patients with COPD. In addition, Bland and Altman plots (21) were used to compare the PWAs and TDRs measured on the gated and nongated CT scans obtained in the same set of patients.

The Mann-Whitney U test was used to evaluate differences in airway measurements, lung attenuation data, and PFT results between the 20 patients with COPD and CB and the 22 patients with COPD without CB who were examined with gated CT. Simple and multiple regression analyses were used to investigate the relationship between the morphologic airway data and the PFT results in the entire group of patients with COPD and in each of the two subsets of patients with COPD (those with and those without CB). Specifically, multiple regression analysis was performed to further analyze the contributions of PWA, TDR, and PWA per kilogram of body weight, as independent variables, to the relationship between airway wall changes and PFT results. To reach this goal, the FEV₁, FEV₁-to–slow VC ratio (FEV₁/VC), DLCO, and functional residual capacity, all expressed in percentages, were in turn considered dependent variables. Finally, we used simple regression analysis to investigate the relationship between lung attenuation data and PFT results in all of the patients with COPD as a whole and in the two subsets of patients with COPD (those with and those without CB). Results were considered significant at P < .05.

Power analysis of the airway and lung attenuation measurements (22) was performed, and assuming a measurement difference of 8% between the subsets of patients with and those without CB, the power was 0.99 for PWA, 0.91 for TDR, and 0.99 for MLA but only 0.10 for PI. All statistical analyses were performed with computer software (SPSS, version 11.5 for Windows, 2001; SPSS, Chicago, Ill).

	RESULTS

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Reproducibility of Measurements
To assess the reproducibility of airway measurements, 63 bronchi in the control patient and 38 bronchi in the patient with COPD were measured. The mean coefficient of variation (standard deviation/mean) for the internal and external bronchial diameters measured during five trial examinations with these two patients was 7.8%, with values ranging between 3.8% for the internal diameter in the control patient to 13.4% for the external diameter in the patient with COPD.

Gated and Nongated Thin-Section CT
The average number of bronchi measured in the 10 patients examined with nongated CT was 26 (range, 15–44). The average number of bronchi measured in the 42 patients examined with gated CT was nine (range, 2–20). No significant difference in airway and lung attenuation measurements was observed between the nongated and gated CT scans obtained in the 10 patients with COPD (Table 1). Bland and Altman plots showed substantial agreement between the airway data derived at gated CT and the corresponding data derived at nongated CT (Fig 2).

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Figure 2a. Bland and Altman plots show substantial agreement between the (a) PWA and (b) TDR values calculated from gated thin-section CT findings and the corresponding values calculated from nongated thin-section CT findings in 10 patients with COPD. Lines above and below averages line illustrate the 95% confidence interval.

View larger version (17K): [in this window] [in a new window] [Download PPT slide]   Figure 2b. Bland and Altman plots show substantial agreement between the (a) PWA and (b) TDR values calculated from gated thin-section CT findings and the corresponding values calculated from nongated thin-section CT findings in 10 patients with COPD. Lines above and below averages line illustrate the 95% confidence interval.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

In our study, the patients with COPD and clinically diagnosed CB had significantly different morphologic airway findings, lung attenuation data, and functional impairment severity at PFT evaluation compared with the patients without CB.

Because of the small number of observations, we cannot establish whether the lack of a correlation between the PFT results and the morphologic airway measurements at univariate analysis was due to the small sample size or to a nonexistent relationship. Nevertheless, at multivariate analysis, correlations between FEV₁/VC and the combined morphologic airway data and between DLCO and the combined morphologic airway data were observed in the entire group of patients with COPD. Moreover, when the patients were divided into those with and those without CB, the correlation remained—and higher coefficients were observed—only for the patients with CB.

Our study results vary in part from those obtained by Nakano et al (9), who did not observe significant differences in bronchial wall thickness, PWA, or TDR between smokers who did and smokers who did not have CB. They did, however, observe a correlation between the PFT results and the morphologic airway data in the entire group of smokers. Several factors can explain these discrepancies. First, Nakano et al (9) examined smokers regardless of whether they did or did not have an obstructive syndrome, whereas we included patients with a definite clinical-functional diagnosis of COPD. Second, they evaluated only the wall of the bronchus in the apical segment of the right upper lung lobe depicted on 3-mm-thick sections acquired with a spiral technique without gating, whereas we measured the walls of all of the bronchi detected on three CT scans acquired at three anatomic levels with spirometrically gated thin-section CT. In fact, we analyzed a larger number of bronchi, including many bronchi that were smaller than the bronchus of the apical segment of the right upper lobe, in each patient. In addition, by evaluating sections acquired at different anatomic levels, we performed a more extensive evaluation of airway abnormalities, which can show heterogeneous distribution in COPD.

The different bronchial wall thicknesses that we measured in patients who had COPD with CB and in those who had COPD without CB support the view that distinct mechanisms underlie the limited airflow in these two patient groups. In patients with CB, the airflow obstruction is due to intrinsic bronchial changes associated with a reduced lumen. In patients without CB, the airflow limitation is presumably the result of complex mechanical relationships between the bronchial lumen size, the lung volume, and the elastic recoil properties of the lung (23). In fact, the peribronchial connective tissue connects the bronchial walls to the alveolar ducts, and the size of the bronchial lumen is determined not only by the intrinsic bronchial wall properties but also by the radial and longitudinal traction forces (24). This relationship accounts for the physiologic modifications in airway size that correlate with the changes in lung volume. In patients who have COPD with or without CB, the relationship between airway size and lung size is altered and the airway size increases less than the volume size owing to both the greater rigidity of the bronchial walls due to bronchitis and the reduced radial traction secondary to emphysema (24,25).

The greater alterations in FEV₁, static volume (ie, functional residual capacity), and diffusing capacity in the patients without clinical evidence of CB indicate that the mechanisms that characterize severe lung destruction—namely, marked reductions in lung elastic recoil and in radial traction forces on the bronchial wall—might be the main factors of airflow obstruction in these patients. This theory was confirmed by the lower severity of the airway changes, as indicated by the lower PWA and the lower TDR, and the more extensive and severe destructive changes, as indicated by the lower MLA and the higher PI, in the patients without CB as compared with these values in the patients with CB.

For the aforementioned reasons, the correlation at multiple regression analysis between airway wall changes and FEV₁/VC in the patients with CB was not unexpected. In fact, in this group of patients, the intrinsic bronchial wall alterations, which were indicated by increased airway morphologic values, were in line with the obstructive pattern detected at PFT evaluation. On the other hand, the correlation between airway changes and DLCO in the same patients at multiple regression analysis deserves some explanation. Although reduced DLCO is often considered to be caused only by destructive changes in the alveolar and vascular beds, in patients with CB, DLCO impairment actually is assumed to be due to inflammatory and remodeling changes in the vessels adjacent to the bronchi rather than to the destruction of the vessels themselves (as occurs in emphysema) (26). The correlation between PFT results and inspiratory lung attenuation measurements obtained at gated CT in our study is in line with prior observations (11).

We recognize some limitations of our study. First, we lacked normal reference values of airway and lung attenuation measurements in age-matched subjects. However, it would be difficult to justify exposing healthy subjects to the radiation dose required to perform CT for these purposes. Second, we had no pathologic correlation of the airway and lung attenuation changes that we measured. However, the lung attenuation measurements that we obtained have been validated in previous CT-pathologic studies (2).

Moreover, although semiautomatic and automatic software has been developed for use in combination with volume (spiral) acquisition techniques (27) to assess airway walls, this software was not used in our study. Finally, we admit that spirometrically gated CT is a rather sophisticated technique that is associated with very limited diffusion. Although we believe that the same information that we extracted from three gated thin-section CT scans theoretically could have been extracted from three nongated thin-section CT scans, and although this finding undoubtedly would have increased the influence of our results in clinical practice, this assumption was not tested in our study.

In conclusion, our study results indicate that airway measurements derived from three spirometrically gated thin-section CT scans obtained at defined anatomic levels can enable the differentiation of patients who have COPD with CB from those who have COPD without CB, which is a distinction that correlates with pulmonary functional impairment.

	FOOTNOTES

 
Abbreviations: CB = chronic bronchitis, COPD = chronic obstructive pulmonary disease, DLCO = diffusing capacity of the lung for carbon monoxide, FEV₁ = forced expiratory volume in 1 second, MLA = mean lung attenuation, PFT = pulmonary function test, PI = pixel index, PWA = percentage wall area, TDR = thickness-to-diameter ratio, VC = vital capacity

Authors stated no financial relationship to disclose.

Author contributions: Guarantor of integrity of entire study, M.M.; study concepts, M.M., M.P.; study design, M.M.; literature research, I.O., C.M.; clinical studies, G.C., M.B., C.M.; data acquisition, G.C., M.B., C.M.; data analysis/interpretation, I.O., C.M., M.M., G.C.; statistical analysis, C.M., G.C.; manuscript preparation, M.M., C.M.; manuscript definition of intellectual content and final version approval, M.M.; manuscript editing, M.P.; manuscript revision/review, N.V.

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