Ann Thorac Surg 2000;69:1529-1531
© 2000 The Society of Thoracic Surgeons
Original articles: General thoracic
The anatomic distribution of acute cellular rejection in the allograft lung
Tsuyoshi Hasegawa, MDa,
Aldo T. Iacono, MDb,
Samuel A. Yousem, MDa
a Departments of Department of Pathology, University of Pittsburgh Medical Center, Presbyterian University Hospital, Pittsburgh, Pennsylvania, USA
b Department of Pulmonary Medicine, University of Pittsburgh Medical Center, Presbyterian University Hospital, Pittsburgh, Pennsylvania, USA
Address reprint requests to Dr Yousem, Department of Pathology, A610, University of Pittsburgh Medical Center, Presbyterian University Hospital, 200 Lothrop St, Pittsburgh, PA 15213
e-mail: yousemsa{at}msx.upmc.edu
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Abstract
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Background. Transbronchial lung biopsy (TBLB) is used for routine monitoring and diagnosing of acute cellular rejection (ACR) in the lung allograft, and yet the optimal anatomic site for lung biopsy has not been investigated. We examined our clinical data to clarify the distribution of ACR in the lung allograft monitored by TBLB.
Methods. A retrospective case-series study was done reviewing the pathology files and slides of TBLB performed on lung allograft recipients. In 73 patients, transbronchial biopsies were taken from more than one lobe.
Results. Identical grades of ACR were seen in 33 of 73 (45%) patients, and a single-grade difference in ACR was noted 34 of 73 (47%) patients. Six cases demonstrated two or more grade differences on biopsies taken from two separate lobes. Among cases with different grades of ACR, the "upper" lobes had a higher grade in 35% (14/40) and the "lower" lobes had a higher grade in 65% (26/40).
Conclusions. If limitations on the site for transbronchial biopsy exist, biopsies of the lower lobes appear more informative.
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Introduction
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Lung transplantation and heart-lung transplantation are established therapeutic modalities for end-stage pulmonary disease. Advances in surgical technique, organ preservation, postoperative care, and immunosuppressive regimens have led to improvements in survival, especially short-term survival [1]. At the University of Pittsburgh, 1-year survival rate for single lung transplantation is 78%, for double lung transplantation is 74%, and for heart-lung transplantation is 55% for the period of 1991 to 1997 [2]. Major causes of short-term death were infection, graft failure, and acute cellular rejection (ACR). Because ACR is also a major risk factor of bronchiolitis obliterans, the identification and treatment of ACR is essential [3]. Transbronchial lung biopsy (TBLB) is the invasive technique used most frequently for routine monitoring and diagnosing of ACR in the lung allograft [4].
The number of biopsy pieces that are needed for adequate TBLB diagnosis of ACR has been assessed in animal models by Tazelaar and colleagues [5]. They found that three to five pieces of lung tissue obtained at transbronchial biopsy were adequate for the diagnosis of acute pulmonary rejection after lung transplantation, but they did not address the lobar distribution of the rejection process. Scott and associates [6] reported that 18 TBLB biopsy specimens were required to have 95% confidence in diagnosing rejection. Meanwhile the Lung Rejection Study Group [7] recommended that at least five pieces of alveolated lung parenchyma, each containing bronchioles and greater than 100 air sacs, were necessary to confidently grade acute and chronic rejection. In all instances, a specific biopsy site was not suggested.
Recently, on the basis of a multiinstitutional questionnaire, Kukafka and associates [8] reported that 90% of transplant centers felt that biopsy specimens should be taken from more than one lobe of the lung. Their report, however, did not attempt to identify the optimal site of biopsy. We investigated our clinical data retrospectively to clarify the distribution of ACR and to propose some suggestions for TBLB management of lung transplant recipients.
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Material and methods
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The pathology files of transbronchial biopsies from 1984 to 1998 were reviewed. Approximately 380 lung transplants and 4,500 transbronchial biopsies were performed during this period. All patients were treated with standard immunosuppressive regimens described earlier [2]. Surveillance fiberoptic bronchoscopy was performed routinely just after operation and within the first 10 days after operation, and when indicated by clinical deterioration or suspicion of lung rejection. In later periods, bronchoscopy was done every 3 to 4 months routinely within the first 2 posttransplant years. The majority of biopsies of more than one lobe was performed during a 6-month period on patients being evaluated for acute rejection. In the case of double lung and combined heart-lung transplant, biopsy was performed on one lung. Generally, five or six adequate biopsy specimens were taken from each lobe (average 6.1, range 5.0 to 11.0) and histologic diagnosis was performed using the revised working formulation from the lung rejection study group [7]. Patients were excluded from this study if there was a localized process in one lobe, eg, lung cancer or posttransplant lymphoproliferative disorders, if submitted specimens were too small for diagnosis, or if infection was suspected. We found 73 (73 of 4,500 [1.6%]) cases where multiple lobes were biopsied and separately designated, and we analyzed them in terms of the degree of ACR at each site. For the purpose of comparison, we used the word "upper" and "lower" as a relative relationship. If specimens originated from both right upper lobe and right middle lobe, we classified the middle lobe as the "lower" lobe. If they were taken from right middle lobe and lower lobe, the middle lobe was classified as the "upper" lobe. Bronchiolitis obliterans was not studied here due to the rarity of its histologic diagnosis.
Statistical analysis was done by Student’s t test with significance reflected in p values less than 0.05.
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Results
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There were 73 instances (1.6%) where biopsies for rejection evaluation were taken from more than one lobe and designated as such. Biopsies were performed from postoperative days 6 to 1,718 (average 389, median 252). Identical grades of ACR in the specimens taken from different lobes was seen in 33 of 73 (45%) patients and a single-grade difference in ACR was noted 34 of 73 (47%) patients. A two-grade difference of ACR in different lobes was observed in four cases (5.5%) and a difference of three grades was seen in only two cases (2.7%) (Table 1). Eight of 73 (11%) biopsy sessions showed an A0/A1 difference in biopsy grade, a clinically insignificant difference because both grades are not treated by augmented immunosuppression. Thirteen cases (18%) had an A1 ACR in one lobe and A2 in another. In another 13 cases (18%), there was A2 in one lobe and A3 in the second (Table 2).
Six cases demonstrated a two or more grade difference on biopsies taken from two lobes. Among them, the "lower" lobe had a higher grade in five cases.
Among cases with different grades of ACR, the "upper" lobes had a higher grade in 35% (14/40) and the "lower" lobes had a higher grade in 65% (26/40) (Table 3).
All results were independent of type of procedure, postoperative day on which the biopsy was taken, and history of bronchiolitis obliterans and infection (Student’s t test; p < 0.05).
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Comment
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It has been reported that most transplant programs utilize TBLB for surveillance and the diagnosis of ACR. TBLB is an established and valuable method for diagnosing acute cellular rejection of lung allograft [4]. Recently, Kukafka and associates [8] reported that most active lung transplant centers perform surveillance transbronchial lung biopsy and do so on a regular basis. According to their data, 90% of transplant centers agreed they should take biopsy specimens from more than one lobe per TBLB session; 59% took six to 10 biopsy specimens per session, 33% took three to five biopsy specimens, and 7% took more than 10 biopsy specimens per session [8].
Several reports have discussed the appropriate number of biopsy specimens required to diagnose acute cellular rejection. Tazelaar and associates [5] reported five pieces of lung tissue were needed to yield a sensitivity of 92% to identify mild acute rejection in the entire lung with transbronchial biopsy in a mongrel dog model. Scott and associates [6] mentioned 18 biopsy specimens are required to have 95% confidence of diagnosing rejection in human lung allograft. Trulock and associates [9] obtained a good yield with an average of 10 biopsy specimens per procedure. No study has tackled the problem of which lobe to biopsy for transbronchial monitoring. If identical yield was obtained from biopsies of a single lobe, the procedure could be shortened and the complications further reduced.
Our data demonstrated that only 45% of biopsy sessions with two lobe biopsies had identical grades of ACR in both lobes, and 34 cases (47%) showed one grade difference of ACR. Only six cases (9%) showed a two or more grade difference of ACR. If one accepts a one-degree margin of error in grading, almost 90% of single-lobe biopsy specimens would be satisfactory for diagnosis. Of the discrepancies, an A1-A2 difference was seen in 13 cases (18%), as was an A2-A3 difference (13 cases [18%]). According to Kukafka’s report, if the threshold for initiating treatment for ACR based on histologic grading is an A2 biopsy, 74% of patients would obtain an adequate diagnosis from a single-lobe biopsy. If the treatment threshold was an A3 grade on biopsy, 22% of patients (16 of 73; 13 cases of A2-A3 difference and three cases of more than two-grade difference) would be undertreated. These data suggest that multiple lobes should be biopsied at one transbronchial biopsy session. If restrictions exist, biopsies of the lower lobes appear more informative.
The distribution of ACR suggests a tendency for the "lower" lobe to show higher grade of ACR than the "upper" lobe. The reason for this difference is not clear. Physiologically, the "lower" lobe receives greater blood flow than "upper" lobe [10], and this hemodynamic state may play some role in predisposing to the perivascular mononuclear infiltration of ACR.
This paper has several limitations. It is a retrospective rather than prospective study. Data were not available for the indications for TBLB, so that we could not dissect those biopsy sessions done for symptomatic (vs asymptomatic) indications. Finally, the number of alveolated fragments obtained per session were variable, although averaging 6.1 fragments (range 5.0 to 11.0).
This small case-series study is very limited, but we believe some suggestions may be valuable for bronchoscopists treating lung transplant recipients: (a) over 90% of biopsy specimens taken from two lobes showed an ACR grade difference of 0 or 1; (b) only 18% of biopsy specimens taken from two lobes showed an A1-A2 difference that may affect decisions for augmented immunosuppressive therapy; and (c) the "lower" lobe tended to show higher degrees of ACR than the "upper" lobe.
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References
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Accepted for publication October 14, 1999.
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Abstract
Introduction
) of ACR Between Lobes of the Allograft Lungs