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Thoracic Imaging |
1 From the Departments of Radiology (E.S.L., M.B.G., G.P.R., W.R.W.) and Cardiothoracic Surgery (F.M.K.) and the Division of Pulmonary and Critical Care Medicine (J.A.G.), University of California, San Francisco; the Department of Radiology, Hallym University School of Medicine, Seoul, South Korea (E.S.L.); and the Department of Radiology, Thoracic Imaging Section, San Francisco General Hospital, Rm 1X 55A, Box 1325, 1001 Potrero Ave, San Francisco, CA 94110 (M.B.G.). Received August 18, 1999; revision requested October 7; revision received December 20; accepted January 12, 2000. Address correspondence to M.B.G. (e-mail: michael.gotway@radiology.ucsf.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Thin-section CT scans were reviewed by two observers blinded to the diagnoses in seven consecutive lung transplant recipients with histopathologically proved bronchiolitis obliterans (group A) and 21 with normal biopsy findings (group B). All patients had normal biopsy and stable pulmonary function test (PFT) results 2–36 weeks prior to CT. Patients with normal biopsy results were placed into subgroups based on abnormal (group B1) or stable (group B2) PFT results. Air-trapping extent on expiratory scans was scored on a 24-point scale.
RESULTS: The mean air-trapping score in group A (6.6) was not significantly different from that in group B (4.5, P = .17). The air-trapping score was significantly higher in groups A and B1 than in group B2 (6.2 and 2.6, respectively; P = .03). The frequency of an air-trapping score of 3 or more in groups A and B1 was significantly higher than that in group B2 (P = .03). By using a score of 3 or more to indicate air trapping, the sensitivity of expiratory CT was 74%, specificity was 67%, and accuracy was 71%.
CONCLUSION: Thin-section CT, including expiratory scans, is of limited accuracy in diagnosing early bronchiolitis obliterans after lung transplantation.
Index terms: Bronchi, CT, 60.12118 • Bronchiolitis obliterans, 60.2191 • Lung, biopsy, 60.1262 • Lung, transplantation, 60.458
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although transbronchial biopsy results may be diagnostic of bronchiolitis obliterans, transbronchial biopsy is insensitive because of the patchy distribution of this disease in most patients (5,7). A clinical diagnosis of bronchiolitis obliterans, termed "bronchiolitis obliterans syndrome," may be made on the basis of alterations in PFT results in the absence of positive lung biopsy results (8). Recent studies in which the use of inspiratory (6,9,10) and expiratory (6,10) thin-section CT was assessed for the diagnosis of bronchiolitis obliterans after lung transplantation have shown that inspiratory scan findings of bronchial dilatation, bronchial wall thickening, mosaic perfusion, and the demonstration of air trapping on expiratory scans correlate with biopsy results positive for bronchiolitis obliterans.
However, these studies were performed in limited numbers of patients with expiratory scans (10); in selected groups of patients, including control patients without lung transplants (10) and patients examined a number of years following transplantation with a mean duration of known bronchiolitis obliterans that was unspecified (10) or more than 1 year (6); or in patients with only heart-lung or bilateral lung transplants (6). Furthermore, patients with pulmonary function abnormalities in the absence of positive biopsy results were not included in these studies (6,10), whereas such patients are common in clinical practice. In our experience, the initial diagnosis of bronchiolitis obliterans by means of thin-section CT may be difficult in lung transplant recipients, with obvious air trapping often being absent. Furthermore, air trapping shown at expiratory thin-section CT may be the result of abnormalities other than bronchiolitis obliterans.
The aim of this study was to assess the accuracy of inspiratory and expiratory thin-section CT findings in the initial diagnosis of bronchiolitis obliterans in consecutive patients with lung transplants who had recent stable PFT and normal transbronchial lung biopsy results. Also, because of the difficulties inherent in diagnosing bronchiolitis obliterans by using either a positive biopsy result or an abnormal PFT result as an absolute criterion, both were assessed relative to thin-section CT findings.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Among the seven patients (age range, 39–63 years; mean, 50 years) with bronchiolitis obliterans, there were five women and two men. Five patients had a single lung transplant, and two patients had bilateral lung transplants. The diagnosis of bronchiolitis obliterans in these patients was proved by means of transbronchial biopsy (n = 6) or open lung biopsy (n = 1). In each, the biopsy procedure was the first that was diagnostic of bronchiolitis obliterans. All patients had normal biopsy and stable PFT results 2–27 weeks (mean, 13 weeks) before this study was performed. The 21 transplant recipients (age range, 36–67 years; mean, 52 years) without biopsy findings of bronchiolitis obliterans included 12 men and nine women. Nine had a single lung transplant, and 12 had bilateral lung transplants. All had normal biopsy and stable PFT results 7–36 weeks (mean, 19 weeks) before this study was performed.
PFTs included forced expiratory volume in 1 second (FEV1) and forced expiratory flow rate in the middle half of the forced vital capacity (FEF25%–75%). PFT results were considered abnormal if (a) FEV1 decreased by more than 20% from previous baseline values obtained at least 1 month earlier (8), (b) FEF25%–75% was less than 70% of that predicted in patients with bilateral lung transplants (3,11), or (c) FEF25%–75% decreased by more than 20% from previous baseline values in patients with a single lung transplant.
On the basis of the biopsy and PFT results, the study subjects were assigned to one of three groups (Table 1). Seven patients with biopsy-proved bronchiolitis obliterans formed group A. Five patients in group A had abnormal PFT results. In the two patients with bilateral lung transplants, FEV1 was reduced from baseline in two (mean reduction, 26%). In the five patients with single lung transplants, two had reduced FEV1 (mean reduction, 37%), one had FEF25%–75% reduced 27% from baseline, and two had stable PFT results.
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Thin-section CT scans were obtained by using 1.0- or 1.5-mm collimation, 1–2-second scanning times, 120–140 kVp, and 280–340 mAs (9800 or HiSpeed Advantage scanners; GE Medical Systems, Milwaukee, Wis) and were reconstructed by using a high spatial frequency (bone) algorithm. The inspiratory scans were obtained from the thoracic inlet to the lung base. Scans were obtained at 20-mm intervals with the patient in both the supine and the prone positions. Postexpiratory scans were obtained at three levels—aortic arch, tracheal carina, and above the diaphragm—with the patient in the supine position; for expiratory scans, the patient was instructed to forcefully exhale and then stop breathing. All the images were photographed at a window width of 1,000–1,500 HU and a window level of -700 HU.
Two chest radiologists (M.B.G., G.P.R., or W.R.W.) reviewed the thin-section CT scans by means of consensus without knowledge of clinical or histopathology data, other than the age and sex of the patient. The range of experience of the chest radiologists was 2–24 years. For each patient, the inspiratory scans were reviewed first, followed immediately by review of the expiratory scans in the same patient. The inspiratory thin-section CT scans were evaluated for the presence of bronchial dilatation, or a bronchoarterial ratio of more than 1; bronchial wall thickening; and mosaic perfusion, or heterogeneous lung attenuation associated with a reduction in size of pulmonary arteries (Table 2).
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Differences in air-trapping scores between groups were assessed by using both the Mann-Whitney U test for nonparametric data and the Student t test (one tailed). Differences in frequency were tested by using the Fisher exact test. A P value of less than .05 was considered statistically significant.
Overall, 17 of the 21 patients in group B were followed up with repeat biopsy. Nine of 12 patients in group B1 underwent follow-up biopsy, and two of these had bronchiolitis obliterans diagnosed 4 and 7 months following the thin-section CT examination evaluated for this study. Eight of the nine patients in group B2 underwent follow-up biopsy, and bronchiolitis obliterans was not diagnosed in any of them.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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An air-trapping score of 3 or more was found in five of seven patients in group A (Fig 1), nine of 12 patients in group B1 (Fig 2), and three of nine patients in group B2 (Fig 3). The difference in frequency of air trapping between groups A and B1 and group B2 was significant (P = .03, Fisher exact test). Grouping patients together with positive biopsy and abnormal PFT results, the sensitivity of an air-trapping score of 3 or more was 74% (14 of 19), specificity was 67% (six of nine), and accuracy was 71% (20 of 28). If groups having only positive biopsy results (group A) and patients with negative biopsy and PFT results (group B2) are considered, sensitivity was 71% (five of seven), specificity was 67% (six of nine), and accuracy was 69% (11 of 16).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In accordance with definitions proposed by the International Society for Heart and Lung Transplantation, or ISHLT, the term "bronchiolitis obliterans" is reserved for patients with a biopsy diagnosis of this condition (8). The term "bronchiolitis obliterans syndrome," as recently defined, is used to refer to a progressive deterioration of graft function secondary to airway disease but not explained by other factors such as infection, acute rejection, or anastomotic complications (8). By using criteria established by the International Society of Heart and Lung Transplantation, the diagnosis of bronchiolitis obliterans syndrome is established by a decrease in FEV1 of 20% or more from previous baseline PFTs performed at least 1 month earlier (8). A decrease in FEF25%–75% to less than 70% of predicted values also has been suggested as a more sensitive criterion in patients with bilateral lung transplants (3,4,11). However, in patients with a single lung transplant for emphysema, isolated FEF25%–75% values are usually abnormal regardless of graft function, owing to abnormalities in the remaining native lung, which makes this criterion difficult to apply.
In our study, in patients with a single lung transplant, we used a decrease in FEF25%–75% of more than 20% from baseline to indicate graft dysfunction; this definition was applied in three of eight patients with single lung transplants in group B1. This definition allows graft function to be referenced to a baseline value and thereby avoids the difficulties inherent in interpreting PFT abnormalities in patients with healthy single lung transplants but diseased native lungs.
Results of two prior reports (6,10) showed that air trapping on expiratory scans is sensitive (80%–91%) and specific (80%–94%) in diagnosing bronchiolitis obliterans in lung transplant recipients. In our study, the sensitivity and specificity of expiratory scans were lower. The sensitivity (74%), specificity (67%), and accuracy (71%) of an air-trapping score of 3 or more was highest when patients with positive biopsy results (group A) and those with abnormal PFT results (group B1) were both considered to have bronchiolitis obliterans. When patients with positive biopsy results (group A) and those with negative biopsy and PFT results (group B2) were considered as study groups, sensitivity (71%), specificity (67%), and accuracy (69%) were nearly the same.
In the study by Worthy et al (10), 15 patients with biopsy-proved bronchiolitis obliterans were compared with 13 healthy control subjects and five patients with transplants with normal biopsy and stable PFT results; however, only eight patients with transplants underwent expiratory CT, five of these with bronchiolitis obliterans. On inspiratory scans, 13 (87%) of 15 patients with bronchiolitis obliterans had at least one inspiratory scan abnormality, most commonly bronchiectasis. Air trapping, diagnosed on expiratory scans if a total area of more than one segment appeared abnormal, was seen in four (80%) of five patients with bronchiolitis obliterans who had expiratory scans, and none of the three with negative biopsy results. In their analysis, which included healthy control subjects, who did not have lung transplants, the sensitivity of air trapping in diagnosing bronchiolitis obliterans was 80% (four of five), with a specificity of 94% (17 of 18).
In a study by Leung et al (6), air trapping was found in 10 of 11 patients with biopsy-diagnosed bronchiolitis obliterans compared with two of 10 patients without a biopsy diagnosis of bronchiolitis obliterans or PFT abnormalities. Air trapping had a sensitivity of 91% (10 of 11), a specificity of 80% (eight of 10), and an accuracy of 86% (18 of 21) for diagnosing bronchiolitis obliterans. However, the mean time from lung transplantation to CT was 4.8 years in their study (6), and the mean duration of known bronchiolitis obliterans was 1.3 years.
Our study differed substantially from those reported by Worthy et al (10) and Leung et al (6). First, all of the patients in our study had normal biopsy and stable PFT results from 2–36 weeks (mean, 18 weeks) prior to the PFT, biopsy, and thin-section CT examinations evaluated as part of our study. In the previous reports, the time from biopsy to diagnosis was unspecified (10) or averaged 1.3 years (6). It should be noted that the relatively high prevalence of inspiratory scan abnormalities found in their patients likely reflected the duration of bronchiolitis obliterans. In the study by Worthy et al (10), 87% (13 of 15) of patients with bronchiolitis obliterans showed an inspiratory scan abnormality, whereas in the study by Leung et al (6), bronchiectasis was visible in 36% (four of 11) of patients and mosaic attenuation in 64% (seven of 11). In our study, only about 30% of unhealthy patients showed an inspiratory scan abnormality.
Second, in addition to a group of patients with abnormal biopsy results and a group with normal biopsy and stable PFT results, consecutive patients with normal biopsy and abnormal PFT results were included in our study. Although this makes analysis more difficult, it better reflects the clinical mix of patients examined. Also, in our study, half of the patients had single lung transplants, whereas a majority (10) or all (6) patients in prior studies had heart-lung or bilateral lung transplants. Third, although the extent of air trapping necessary to diagnose the presence of an abnormality in our study was similar to that required by previous authors for an abnormal diagnosis, expiratory scans were obtained at only three levels in our study, as opposed to five in theirs (6,10).
Although expiratory thin-section CT scans demonstrate limited accuracy for the diagnosis of early bronchiolitis obliterans following lung transplantation, expiratory thin-section CT is not without benefit in this patient population. Expiratory thin-section CT scans may depict air trapping in some patients with bronchiolitis obliterans who may have false-negative transbronchial biopsy results owing to the patchy distribution of this disease. In addition, expiratory thin-section CT scans obtained prior to transbronchial biopsy may allow the biopsy procedure to be directed to the most abnormal lung regions.
Finally, expiratory thin-section CT scans are not acquired in isolation; rather, they are obtained as part of a complete examination that also includes inspiratory scans. Thin-section CT examinations, including expiratory scans, are valuable for the detection of subtle parenchymal abnormalities in lung transplant patients, and early detection of subtle disease is vitally important in patients with immunosuppression.
Air trapping at expiratory thin-section CT has limited sensitivity, specificity, and accuracy for the diagnosis of early bronchiolitis obliterans following lung transplantation. However, thin-section CT, including expiratory scans, will continue to play an important role in the evaluation of complications related to and the surveillance of graft function in lung transplants. Awareness of the limited accuracy of air trapping for the diagnosis of bronchiolitis obliterans in this setting may prompt more aggressive evaluation in patients who fail to demonstrate evidence of air trapping but are at high risk for bronchiolitis obliterans.
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FOOTNOTES |
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Author contributions: Guarantor of integrity of entire study, M.B.G.; study concepts, M.B.G., E.S.L., W.R.W., J.A.G.; study design, E.S.L., W.R.W.; definition of intellectual content, E.S.L., M.B.G., G.P.R., J.A.G., W.R.W.; literature research, E.S.L., W.R.W.; clinical studies, J.A.G., F.M.K.; data acquisition, E.S.L., M.B.G., G.P.R., W.R.W.; data analysis, E.S.L., M.B.G., W.R.W.; statistical analysis, E.S.L., W.R.W.; manuscript preparation and editing, E.S.L., M.B.G., W.R.W.; manuscript review, E.S.L., W.R.W., M.B.G., J.A.G.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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