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(Radiology. 2001;220:455-462.)
© RSNA, 2001

Pediatric Imaging

Post–Lung Transplantation Bronchiolitis Obliterans Syndrome: Usefulness of Expiratory Thin-Section CT for Diagnosis1

Marilyn J. Siegel, MD, Sanjeev Bhalla, MD, Fernando R. Gutierrez, MD, Charles Hildebolt, DDS, PhD and Stuart Sweet, MD

1 From the Mallinckrodt Institute of Radiology (M.J.S., S.B., F.R.G., C.H.) and Department of Pediatrics, Division of Pulmonary Medicine (S.S.), Washington University School of Medicine, 510 S Kingshighway Blvd, St Louis, MO 63110. Received October 20, 2000; revision requested December 12; revision received February 16, 2001; accepted March 16. Address correspondence to M.J.S. (e-mail: siegelm@mir.wustl.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To assess the usefulness of thin-section expiratory computed tomography (CT), as compared with that of thin-section inspiratory CT, in detecting airway obstruction and air trapping in pediatric lung transplant recipients with bronchiolitis obliterans syndrome (BOS).

MATERIALS AND METHODS: Thin-section CT scans were obtained at full inspiration and end expiration in 21 pediatric lung transplant recipients with proved BOS and in 41 transplant recipients with normal airways. True diagnosis was based on pulmonary function test results. Inspiration CT scans were scored for extent of decreased attenuation of the lung parenchyma; expiration CT scans were scored for extent of air trapping.

RESULTS: The sensitivity of inspiratory CT for enabling diagnosis of BOS was 71%; the specificity, 78%; the positive predictive value, 62%; and the negative predictive value, 84%. The sensitivity of expiratory CT for enabling diagnosis of BOS was 100%; the specificity, 71%; the positive predictive value, 64%; and the negative predictive value, 100%. Expiratory CT scores correlated more strongly ({rho} = 0.75, P < .01) with pulmonary function test–based scores than did inspiratory CT scores ({rho} = 0.48, P < .01). Nominal logistic regression analysis revealed that expiratory CT was a more powerful predictor of true diagnosis (P < .01) than was inspiratory CT (P = .10).

CONCLUSION: Expiratory CT is sensitive for depicting BOS-related airway abnormalities and may be more useful than inspiratory CT for diagnosis of small airway obstruction.

Index terms: Bronchiolitis obliterans, 60.219 • Lung, abnormalities, 60.219, 60.26, 60.744 • Lung, air trapping, 60.219, 60.26 • Lung, CT, 60.1211, 60.12118 • Lung, transplantation, 60.458


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Over the past 16 years, substantial improvements in lung transplantation have made it an accepted treatment option for patients with end-stage lung disease. With operative mortality rates lower than 10%, bronchiolitis obliterans remains the major cause of long-term complications and death (1,2). On the basis of definitions proposed by the International Society for Heart and Lung Transplantation, the term bronchiolitis obliterans is used to refer to histologically proved chronic rejection with scarring and fibrosis of airways (3,4). The term bronchiolitis obliterans syndrome (BOS) is used to refer to the deterioration of graft function secondary to progressive airway disease of which there is no other cause, such as infection, acute rejection, or anastomotic complications (3,4). This clinical staging was proposed because of the lack of parallelism between the clinical and pathologic findings.

Although bronchiolitis obliterans and BOS are irreversible, early diagnosis and initiation of treatment can improve the survival of transplant recipients with these conditions. Therefore, these patients frequently undergo transbronchial biopsy, pulmonary function tests (PFTs), and imaging studies, including computed tomography (CT). The diagnosis may be established clinically when PFTs are abnormal in the absence of other disease processes. Although transbronchial biopsy can be performed to diagnose BOS, it is insensitive because of the patchy distribution of this disease (5,6).

Thin-section CT at inspiration and expiration has been used increasingly to diagnose obstructive small airway disease after lung transplantation and to obtain physiologic information about regional obstruction. Expiratory air trapping, which is the paradigm of small airway disease, has been reported to be a strong predictor of airflow obstruction in adults (7–9). However, the value of this diagnostic sign in pediatric lung transplant recipients has not been fully evaluated. Virtually all reports of thin-section CT studies in this population have involved only mosaic attenuation or bronchial abnormalities at inspiratory CT (10,11).

The purpose of this study was to assess the usefulness of thin-section expiratory CT, as compared with that of thin-section inspiratory CT, in detecting airway obstruction and air trapping in pediatric lung transplant recipients with BOS.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Subjects
Our retrospective study included 62 children who underwent lung transplantion from 1991 to 1999: 21 children who had BOS on the basis of PFT results and 41 children who had had no clinical evidence of small airway obstruction for at least 1 year after transplantation. The 21 patients with BOS were seven boys and 14 girls (mean age ± SD, 13 years ± 3.5). The median postoperative time until the onset of BOS was 18 months (range, 12–36 months). The 41 transplant recipients without PFT findings of BOS were 18 boys and 23 girls (mean age, 15 years ± 3.3). The final clinical diagnoses in these patients included bronchitis or normal airways. Informed consent and institutional review board approval were not required by our institution at the time the study was performed.

Study entry criteria included the availability of inspiratory and expiratory thin-section CT scans obtained at least 12 months after transplantation and PFTs performed within 7 days after CT. Twelve months was selected as the earliest date for review of the CT findings to minimize the possibility of seeing early postoperative complications, such as acute graft rejection or infection. At our institution, lung transplant recipients routinely undergo CT at 3, 6, 9, and 12 months after transplantation and then every 6 months thereafter. The timing of CT studies is designed to correspond with the timing of pulmonary function measurements.

Patients who received unilateral lung transplants or heart-lung transplants were excluded from the study. Children younger than 5 years also were excluded because of their inability to reliably comply with breathing instructions (11). Although 68 patients met the criteria for inclusion (bilateral lung transplantation and age older than 5 years), six were excluded because of inadequate follow-up, absent corroborative pulmonary function measurements, absent CT studies, or all three factors.

Pulmonary Function Tests
Patients underwent PFTs within 1 week of CT (usually on the same day). Because many of our patients come from far distances, the clinical setup at our institution requires a patient to present for pulmonary function testing at the same time that he or she presents for CT. Of 161 PFTs, 121 were performed the same day as the CT examination. The 40 remaining tests were performed 2–6 days after the corresponding CT examinations. In no case were pulmonary function measurements performed prior to CT. Spirometry was performed with a mass flow sensor spirometer or a dry rolling seal spirometer (Sensor Medics, Yorba Linda, Calif). Routine PFTs included percentage of predicted forced expiratory volume in the 1st second (FEV1), forced vital capacity, residual volume, total lung capacity, and ratio of residual volume to total lung capacity. However, the diagnosis of BOS was based on the FEV1 according to standards of the International Society for Heart and Lung Transplantation (3). After the exclusion of other conditions that could reduce the FEV1, such as airway infection or acute graft rejection, a fractional decline in FEV1 of 20% from the FEV1 at previous baseline studies performed at least 1 month apart was considered to be diagnostic of BOS.

CT Scanning
CT scans were obtained (Somatom Plus 4 scanner; Siemens, Erlangen, Germany), according to our routine protocol, with a scan acquisition time of 1 second. First, routine scans with contiguous 4- or 8-mm thickness were obtained at 4- or 8-mm/sec table feed from the lung apex to the diaphragm. Next, full-inspiration thin-section CT was performed by using 1.5-mm collimation from the lung apex to the diaphragm, and the images were reconstructed by using a high-spatial-frequency (ie, bone) algorithm. Scans were obtained at four levels—aortic arch, tracheal carina, subcarinal area (level of pulmonary venous confluence), and 1 cm above the right diaphragm—with the patient in the supine position. Postexpiratory scans were then obtained at the same four levels by using the same technical parameters. The patient was instructed to forcefully exhale and then stop breathing. Breath holding at full inspiration and expiration was rehearsed with each patient prior to the CT examination. Lung images were obtained at a window width of 1,000–1,500 HU and a window level of -700 to -500 HU. No contrast medium was used.

Two chest radiologists (M.J.S., F.R.G.), who were unaware of the clinical and histopathologic data, reviewed the thin-section CT scans independently. For each patient, the inspiratory scans were reviewed first, and immediately after, the expiratory scans were reviewed.

Inspiration CT.—The inspiratory thin-section CT scans were evaluated for the presence of (a) mosaic lung attenuation, which was defined as heterogeneous lung attenuation; (b) bronchial dilatation, which was considered to be present when there was a bronchoarterial ratio of more than 1 or a bronchial lumen seen within 1 cm of the costal pleura or abutting the mediastinal pleura; and (c) bronchial wall thickening. Mosaic attenuation was assessed semiquantitatively so that comparison could be made to the attenuation seen on expiratory scans. The extent of abnormal low attenuation, which was believed to be representative of small airway disease, was scored by using a five-point scale: 0 indicated no low-attenuating areas; 1, 1%–25% of the cross-sectional area of the lung affected; 2, 26%–50% affected; 3, 51%–75% affected; and 4, 76%–100% affected. A separate score was determined for each lung at each level and summed to provide a total score per examination. The potential total score per examination, then, could range from 0 to 32 (or 4 x 4 x 2). The diagnosis of bronchial wall thickening was determined subjectively.

Expiration CT.—The expiratory chest CT scans were evaluated for the presence of air trapping. Air trapping was defined as areas of lung that failed to increase in attenuation after full expiration, as compared with the attenuation at full inspiration. The reviewers disregarded spurious areas of decreased attenuation, including the bare area in the region of the minor fissure, the relatively low-attenuating apical segments of the lower lobes and the air trapping in single secondary lobules seen in some healthy individuals (12), and beam hardening due to the effect of the adjacent ribs.

On expiratory CT scans, the area of relative attenuation difference between the areas of air trapping and the surrounding lung parenchyma was assessed semiquantitatively. The extent of air trapping at each of the four levels and for each lung was scored by using a five-point scale: 0 indicated no air trapping visible; 1, 1%–25% of the cross-sectional area of the lung affected; 2, 26%–50% affected; 3, 51%–75% affected; and 4, 76%–100% affected (Figs 1, 2). As with the inspiratory CT scans, a separate score for each lung at each level was determined and then summed to obtain a total score that could range from 0 to 32.



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  		Figure 1a. Normal (a) full-inspiration and (b) suspended end-expiration transverse thin-section CT scans of the upper lobes of the lungs in a 17-year-old girl. The arrow in b points to flattening of the trachea at expiratory CT. No mosaic attenuation is seen in a, and no air trapping is seen in b. Both observers scored this level as 0.

 


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  		Figure 1b. Normal (a) full-inspiration and (b) suspended end-expiration transverse thin-section CT scans of the upper lobes of the lungs in a 17-year-old girl. The arrow in b points to flattening of the trachea at expiratory CT. No mosaic attenuation is seen in a, and no air trapping is seen in b. Both observers scored this level as 0.

 


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  		Figure 2a. Air trapping in BOS. (a) Full-inspiration transverse thin-section CT scan of the lower lobes of the lungs in a 15-year-old boy shows linear atelectasis in the right middle lobe. The streak artifacts across this scan are due to the metallic wires in the sternal area. (b) Suspended end-expiration transverse thin-section CT scan obtained at the same level as in a in the same patient. Both observers considered air trapping (arrows) to be present in the right lower lobe, and both scored this level as a 2 at expiration CT.

 


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  		Figure 2b. Air trapping in BOS. (a) Full-inspiration transverse thin-section CT scan of the lower lobes of the lungs in a 15-year-old boy shows linear atelectasis in the right middle lobe. The streak artifacts across this scan are due to the metallic wires in the sternal area. (b) Suspended end-expiration transverse thin-section CT scan obtained at the same level as in a in the same patient. Both observers considered air trapping (arrows) to be present in the right lower lobe, and both scored this level as a 2 at expiration CT.

 
Statistical Analyses
The 62 children in the study underwent 161 PFTs and CT examinations. Because the inclusion of results from the repeated examinations as independent samples would have artificially increased the sample size and violated the assumption of independence required for statistical analyses, one CT examination and one PFT for each patient, performed within 7 days of each other, were randomly selected using statistical software (JMP; SAS Institute, Cary, NC). The results for this single-examination set were entered into analyses. Although only the results for the reduced data set are the focus of this article, analyses of the full data set also were performed to determine whether the findings for the full data set were comparable to those for the reduced data set.

{kappa} statistics were used as measures of observer diagnostic agreement. The data obtained by each observer were analyzed separately. In addition, the scores for the two observers were averaged and the average scores were analyzed. Sensitivities, specificities, positive predictive values, and negative predictive values (and the corresponding 95% CIs) for inspiration and expiration CT were calculated. Nominal logistic regression analysis was performed to test the strengths of the associations between the true diagnoses (BOS or normal airway, as determined with PFTs) and the inspiration and expiration CT scores and to construct probability plots for inspiration and expiration CT scores. Odds ratios and the profile likelihood CIs were used to evaluate the various diagnostic results based on inspiration and expiration CT scores. Analyses were performed with statistical software (JMP; SAS Institute).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PFT and CT Results
In the 21 children with BOS, the mean FEV1 was 58% of that predicted (range, 29%–77%). None of the 41 control patients had evidence of airflow obstruction. Bronchiectasis and bronchial wall thickening were seen on the inspiration CT scans obtained in two (10%) of 21 patients with BOS and in two (5%) of 41 control patients. Bronchial wall thickening without bronchiectasis was present in two (10%) of 21 patients with BOS and in one (<3%) of 41 control patients.

Statistical Analysis of Mosaic Attenuation and Air Trapping
Observer diagnostic agreement.—For both inspiration and expiration CT, the maximum possible score per lung was 16 and the maximum possible score per patient was 32. The scores for inspiration and expiration CT for both observers were nonnormally distributed, with the minimum number of zeros recorded by an observer for inspiration or expiration CT being 34. Spearman nonparametric correlation coefficients indicated significant (P < .01) but only moderate correlations (inspiration CT, {rho} = 0.46; expiration CT, {rho} = 0.75) between the two observers’ scores.

Two thresholds were used to establish the diagnosis of BOS. For the first threshold, scores greater than 0 were considered to be positive for BOS. For the second threshold, scores of 3 or greater were considered to be positive for BOS. The second threshold was used because air trapping scores of 2 may be seen in healthy subjects (12,13). For inspiration CT, the mean {kappa} value (± SEM) was 0.44 ± 0.12 with the 0 threshold and 0.37 ± 0.15 with the greater than or equal to 3 threshold. For expiration CT, the corresponding {kappa} values were 0.64 ± 0.10 and 0.63 ± 0.10. Observer diagnostic agreement was therefore fair for inspiration CT and moderate for expiration CT. These results, however, did not vary substantively when individual observer scores were used or when average scores were used; therefore, to minimize the presentation and discussion of results, only the average scores are considered in this article. Average inspiratory and expiratory CT scores are listed in Table 1.


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  		TABLE 1. Inspiration and Expiration CT Scores

 
Inspiration and expiration CT scores.—All expiration CT scores for the 21 patients with PFT-confirmed BOS, except those for one patient, who had a score of 4.0 for both expiration and inspiration CT (Table 1), were greater than 0 and higher than the corresponding inspiration CT scores. Six patients with BOS had inspiration CT scores of 0. Twenty-seven of the 41 patients with normal airways had a score of 0 for both inspiration and expiration CT. Among the 14 remaining patients with normal airways, five had inspiration CT scores of 0; two, expiration CT scores of 0; three, inspiration CT scores of 3 or greater; and four, expiration CT scores of 3 or greater. Scatterplots of the inspiration and expiration CT scores are shown in Figure 3. There was a fair amount of overlap in the scores for patients with BOS and normal airways, although the overlap was less pronounced with the expiration scores. In none of the patients with BOS was mosaic attenuation seen only on the inspiration CT scans, and in six patients, heterogeneous lung attenuation was seen only on the expiration CT images.



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  		Figure 3. Scatterplots of inspiration and expiration CT scores. In 27 of the 62 patients, both the inspiration and expiration CT scores were 0. These patients had normal airways, and their score points are not displayed. True diagnosis was based on PFT results.

 
Diagnostic performance of inspiration and expiration CT.—The diagnostic performance rates for inspiration and expiration CT are shown in Table 2. When PFTs were used to determine the true diagnosis for the presence of BOS and a score greater than 0 was used as the threshold for a positive diagnosis of BOS, the sensitivity of inspiratory CT scan scores was 71% (15 of 21 patients); the specificity, 78% (32 of 41 patients); the positive predictive value, 62% (15 of 24 patients); the negative predictive value, 84% (32 of 38 patients); and the odds ratio, 8.9. The values for expiratory CT scan scores were sensitivity, 100% (21 of 21 patients); specificity, 71% (29 of 41 patients); positive predictive value, 64% (21 of 33 patients); negative predictive value, 100% (29 of 29 patients); and odds ratio, greater than 48.3. This is a conservative odds ratio. It was not possible to calculate the actual odds ratio, because with 100% sensitivity, a division by 0 would be required. The odds ratio of 48.3 is based on a sensitivity of 95% (ie, one false-negative case). When a score of greater than or equal to 3 was used as the threshold for a positive diagnosis of BOS, the diagnostic performance of both inspiration and expiration CT decreased (odds ratio at inspiration CT, 4.0; at expiration CT, 39.0). The biggest decrease was in the sensitivity of inspiration CT (24% [five of 21 patients]).


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  		TABLE 2. Diagnostic Success Rates

 
Association between PFT and CT scores.— To better understand how well inspiration and expiration CT scores predict the true diagnosis, nominal logistic regression analysis was performed. Likelihood ratio {chi}2 test results indicated that inspiration CT scores were not significant predictors of the true diagnosis (P = .10). The r2 measure of fit (in which a scale of 0%–100% is used) was only 0.03 for inspiration CT. Expiration CT scores, however, were highly significant (P < .01) predictors, with an r2 of 0.26. Cumulative probability plots were constructed to show how the probability of having BOS varied with changes in inspiration and expiration CT scores (Fig 4). In such plots, the steeper the probability curve, the better the predictive value of the variable. The slope for the inspiration CT curve was 0.17 and not significant (P = .11); that for the expiration CT curve was 0.43 and highly significant (P < .01).



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  		Figure 4. Cumulative probability plots of the relationships between the diagnoses based on PFT results and the observer scores for inspiration and expiration CT. The line of fit partitions the whole probability into the response categories. The probability of a patient having BOS can be read directly from the vertical axis. The probability of a patient having a normal airway is the distance from the line to the top of the graph, which is 1 minus the axis reading. For instance, if the inspiration CT score was 4, the patient would have a 45% chance of having BOS and a 55% chance of having a normal airway. If the expiration CT score was 4, the patient would have a 50% chance of having BOS and a 50% chance of having a normal airway.

 
The inspiration and expiration CT scores plus the interaction of inspiration and expiration CT scores were entered into a logistic regression analysis to determine whether the combination of these variables would result in improved diagnostic performance. Although the resulting model was highly significant (P < .01) and had improved diagnostic success, the prediction formula resulted in values that made no sense, other than the values for this specific data set. For instance, an inspiration CT score of 11.0 and an expiration CT score of 20.5 resulted in a diagnosis of a normal airway. Diagnoses of a normal airway were also obtained with inspiration and expiration CT scores of 11.0 and 5.5, respectively, and 5.0 and 2.5, respectively. As indicated by the data in Table 1, these are correct diagnoses for this data set, but for general use, a prediction formula would be expected to classify patients with high inspiration and expiration CT scores as having BOS. In this prediction model, inspiration CT scores were not significant predictors (P = .79, Wald {chi}2 test), and the interaction term was largely responsible for the aberrant values that were produced by the prediction formula. A prediction model that contained only inspiration and expiration CT scores was therefore tried. Again, inspiration CT scores were not significant predictors (P = .06, Wald {chi}2 test). Moreover, the sensitivity for this model was only 62% (13 of 21 patients) (Table 2).

Spearman nonparametric correlation coefficients suggested that the association between expiration CT and PFT scores (which were used to establish the true diagnosis) was stronger ({rho} = 0.75, P < .01) than that between inspiration CT and PFT scores ({rho} = 0.48, P < .01).

Finally, the analyses were repeated by using values from all the CT and PFT examinations rather than those from randomly selected examinations. The mean difference (± SD) between the sensitivities and specificities reported in Table 2 and those that resulted from using all the recall appointments was 3.8% ± 3.9 (range, 0.0%–12.0%).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
BOS is the major late complication of lung transplantation, occurring in 41% of transplant recipients, although some believe that all such patients eventually develop some form of BOS (1,2). It affects the terminal and respiratory bronchioles and is believed to be a form of chronic airway rejection. The clinical diagnosis of BOS has been limited by the lack of noninvasive diagnostic tests that are both sensitive and specific and by the lack of a reliable invasive diagnostic tool (eg, transbronchial biopsy) (5,6). A decrease in FEV1 by more than 20% is considered to be a reliable predictor of BOS, but such alterations in pulmonary function do not have the specificity required to discriminate between infection and rejection. In a retrospective study of 77 patients with BOS after lung transplantation, Sundaresan et al (1) observed that only 48% of patients had pathologically proved bronchiolitis obliterans. Conversely, a small percentage of patients with pathologically proved bronchiolitis obliterans never experienced a decline in FEV1. These observations have led to the theory that BOS is an independent clinical entity with prognostic implications that differ from those of bronchiolitis obliterans (1–4).

Early diagnosis is important, as prompt initiation of therapy may help to preserve lung function. Consequently, there has been increasing use of thin-section CT to diagnose small airway disease in lung transplant recipients. Prior studies involving children with posttransplantation bronchiolitis obliterans have largely involved the evaluation of anatomic indexes of airflow obstruction (ie, lung heterogeneity and bronchial abnormalities) at inspiration CT. Results of two prior reports (10,11) of inspiratory CT in children have shown relatively poor sensitivity for the detection of mosaic attenuation. In the study of Medina et al (10), the sensitivity of mosaic attenuation was 67% (four of six patients) and the sensitivity of bronchial dilatation was 17% (one of six patients) in children with biopsy-diagnosed bronchiolitis obliterans following lung transplantation. That study addressed the acute pulmonary complications following transplantation, with the mean time between transplantation and CT being 6 months, and it did not include a control population.

In a study by Lau et al (11), the inspiration CT results in six infants and young children with proved bronchiolitis obliterans were compared with those in 15 control subjects of similar age without obstructive airway disease. The sensitivity and specificity of mosaic attenuation for the diagnosis of bronchiolitis obliterans were 83% (five of six patients) and 60% (nine of 15 patients), respectively. The sensitivity and specificity of bronchial dilatation were 50% (three of six patients) and 100% (15 of 15 patients), respectively. In our study of older children, the sensitivity and specificity of lung heterogeneity at inspiration CT were 71% (15 of 21 patients) and 78% (32 of 41 patients), respectively, when inspiration CT scores greater than 0 were considered to be positive for BOS. Bronchial dilatation and wall thickening occurred infrequently, and the numbers were too small to analyze.

A major aim of our study was to determine the usefulness of expiratory thin-section CT findings in the diagnosis of BOS in older children and adolescents with lung transplants. Thin-section CT during suspended end expiration is the most widely used technique to visualize expiratory air trapping. In healthy individuals, the cross-sectional lung area decreases and attenuation increases during expiration. When air trapping is present, the cross-sectional lung area fails to decrease and lung attenuation fails to increase (13,14). This technique has been used to demonstrate air trapping in patients with bronchopulmonary dysplasia (15,16), Swyer-James syndrome (17), asthma (18), bronchiectasis (19), hypersensitivity pneumonitis (20,21), and Langerhans cell histiocytosis (22). Furthermore, the results of a study by Arakawa et al (23) showed that the use of suspended end-expiration scanning substantially improved diagnostic accuracy in patients with inhomogeneous areas of attenuation on inspiratory CT scans.

In our study, the sensitivity of air trapping at expiratory CT was 100% (21 of 21 patients) and the specificity was 71% (29 of 41 patients) when expiration CT scores greater than 0 were considered to be positive for BOS. The results of three prior studies involving adults (7–9) showed that the sensitivity of air trapping at expiratory CT ranged from 74% to 91% and the specificity ranged from 67% to 94%.

In the study by Worthy et al (9), 15 lung transplant recipients with biopsy-proved bronchiolitis obliterans were compared with five patients with normal biopsy and PFT results; however, only eight patients underwent expiratory CT, five of whom had bronchiolitis obliterans. Air trapping (diagnosed as the total area of more than one abnormal-appearing segment) was seen in four (80%) of the five patients with bronchiolitis obliterans who underwent expiratory CT and in none of the control subjects. In the study by Leung et al (8), air trapping was found in 10 of 11 lung transplant recipients with biopsy-diagnosed bronchiolitis obliterans compared with two of 10 control subjects without a diagnosis of bronchiolitis obliterans. Air trapping had a sensitivity of 91% (10 of 11 patients) and a specificity of 80% (eight of 10 patients) for enabling the diagnosis of bronchiolitis obliterans. In the study by Lee et al (7), air trapping was found at expiratory CT in five of seven lung transplant recipients with biopsy-diagnosed bronchiolitis obliterans compared with 12 of 21 control subjects without a diagnosis of bronchiolitis obliterans, for a sensitivity of 74% and specificity of 67%.

Our study differed substantially from those reported by Worthy et al (9) and Leung et al (8). First, the true diagnoses in all the patients in our study were based on PFT rather than biopsy results. As mentioned previously, biopsy is relatively insensitive because of the patchy distribution of bronchiolitis obliterans. Second, all of our study patients had bilateral lung transplants, whereas half of the patients reported on by Lee et al (7) had single-lung transplants. Diagnosing bronchiolitis obliterans in single-lung transplant recipients may be difficult because changes in pulmonary function may be hard to diagnose owing to disease in the native lung.

A second goal of our study was to compare the value of inspiratory and expiratory CT scans in the diagnosis of BOS. In our study, expiratory CT was superior to inspiratory CT, with sensitivities of 100% (21 of 21 patients) and 71% (15 of 21 patients), respectively. At thin-section inspiratory CT, the pattern of mosaic lung attenuation in BOS represents areas of normal lung intermixed with areas of obstructed lung that retain air. The regions of obstructed lung manifest as areas of lower attenuation. A decrease in the number and size of pulmonary vessels is often present in the regions of lower attenuation and likely results from the physiologic shunting of blood. During expiration, the attenuation differences between the normal and obstructed lungs increase in conspicuity as the normal lung increases in attenuation and the abnormal lung maintains a low attenuation.

Of note, both inspiratory and expiratory CT scans have only moderate specificity for the diagnosis of BOS when PFT results are used as the true diagnoses. In our study, 12 of 41 patients with areas of air trapping at expiratory CT did not have BOS at pulmonary function testing. The importance of this patient population has yet to be determined. In a recent study by Bankier et al (24), five of six patients with initial false-positive findings (abnormal CT study, FEV1 > 80%) later developed BOS. CT, then, may have a role in detecting BOS before PFTs. Preliminary data suggest that it is in this population that immunosuppression may stabilize or reverse BOS (25).

A potential limitation of our study was the subjective quantification of the intensity of air trapping by using a relative contrast score. Because of the retrospective nature of the study, we could not use regions of interest to quantify the contrast differences between the areas of air trapping and the surrounding lung parenchyma. However, in standard clinical examinations, lung attenuation abnormalities are evaluated chiefly by using subjective analysis.

In conclusion, air trapping on expiratory CT scans showed a significant correlation with BOS in a transplantation population and was more sensitive than inspiratory CT in depicting BOS. Of equal importance is the finding that subjects with normal expiratory CT findings are likely to have normal pulmonary function measurements. However, the results of our study also show that both expiratory and inspiratory thin-section CT scans demonstrate limited specificity for the diagnosis of BOS and that observers may have difficulty in detecting subtle differences in attenuation of the lung parenchyma. Nevertheless, we believe that dynamic expiratory CT is sensitive for detecting abnormalities of ventilation and may be a useful adjunct to inspiration CT and PFTs in the diagnosis of small airway disease.

Our study results show that expiratory CT has a sensitivity similar to that of pulmonary function testing in detecting BOS but is no more specific in distinguishing infection from rejection as a cause of air trapping. Currently, this distinction relies on culture results. Air trapping at CT may be from infection—with or without a decrease in pulmonary function. On the basis of our study results, normal expiratory CT may be used (in conjunction with normal surveillance chest CT) to obviate simultaneous pulmonary function testing. Thus, at routine follow-up, the two studies may be performed alternatively rather than concomitantly.


   FOOTNOTES
 
Abbreviations: BOS = bronchiolitis obliterans syndrome, FEV1 = forced expiratory volume in the 1st second, PFT = pulmonary function test

Author contributions: Guarantor of integrity of entire study, M.J.S.; study concepts, M.J.S., S.B., F.R.G.; study design, M.J.S., S.B., S.S.; literature research, S.B.; clinical studies, M.J.S., S.S.; data acquisition, M.J.S., S.B.; data analysis/interpretation, M.J.S., S.B., F.R.G.; statistical analysis, C.H.; manuscript preparation, M.J.S., S.B., C.H.; manuscript definition of intellectual content, M.J.S., S.B.; manuscript editing, M.J.S.; manuscript revision/review and final version approval, all authors.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

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