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Ann Thorac Surg 1995;60:111-116
© 1995 The Society of Thoracic Surgeons

Seventy-two Pulmonary Retransplantations for Obliterative Bronchiolitis: Predictors of Survival

Departments of Surgery, Epidemiology, and Biostatistics, University Hospital, the Robarts Research Institute, and the University of Western Ontario, London, Ontario, Canada; Hannover, Germany; Clichy, France; Vienna, Austria; Pittsburgh, Pennsylvania; Houston, Texas; St. Louis, Missouri; and participating centers in the pulmonary retransplant registry

	Abstract

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Background. Obliterative bronchiolitis (OB) occurs in up to 40% of patients in the intermediate term after lung transplantation. In recent years an increasing number of recipients with end-stage OB have been treated with retransplantation.

Methods. Seventy-two patients with OB underwent retransplantation at 26 North American and European centers a median of 590 days after their first transplant operation. The predictors of survival were determined using life table and Cox proportional hazards methods, and the recurrence rate of OB was determined in survivors.

Results. The actuarial survival rate was 71% ± 5% at 1 month, 43% ± 6% at 1 year, and 35% ± 6% at 2 years; nonetheless, of the 90-day postoperative survivors, 63% ± 7% were alive 2 years after retransplantation. Institutional experience with more than three pulmonary retransplantations (p = 0.008), reoperation in Europe (p = 0.013), donor–recipient ABO blood group identity (p = 0.018), and more recent year of retransplantation (p = 0.03) were associated with survival. On multivariate analysis, reoperation after 1989 (p < 0.001), retransplantation performed in Europe (p = 0.017), and being ambulatory immediately before reoperation (p = 0.022) were found to be predictive of a positive outcome. Pulmonary function test analyses confirmed that the forced expiratory volume in 1 second decreased from postoperative baseline values by 11% ± 9% at 1 year and 27% ± 10% at 2 years (p = 0.02; year 2 versus baseline). Fourteen percent of patients were in stage 3 of the bronchiolitis obliterans syndrome at 1 year postoperatively, with 33% affected at 2 years.

Conclusions. The results of pulmonary retransplantation for OB are improving. Current evidence indicates that OB does not recur in an accelerated manner after retransplantation, although pulmonary function does worsen again by 2 years. Pulmonary retransplantation is appropriate only in selected patients with OB who are ambulatory and are operated on at experienced centers.

	Introduction

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Despite increasing experience in the postoperative care of lung transplant recipients, obliterative bronchiolitis (OB) develops in as much as 40% of patients in the intermediate term postoperatively [1, 2]. Although some patients with this condition respond to increased immunosuppression [1, 3], in many others chronic allograft dysfunction is resistant to therapy and ultimately causes death as the result of progressive respiratory failure or opportunistic infection. Since 1988 an increasing number of lung transplant recipients with OB have been treated by retransplantation [4–12]. The pulmonary retransplant registry was established in 1991 to document the results and determine the predictors of survival after pulmonary retransplantation [5, 11]. Recently, after increased patient accrual, the registry data were updated to document the determinants of outcome after retransplantation for the treatment of OB.

	Patients and Methods

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
The pulmonary retransplant registry currently contains complete data on 142 retransplantation patients from 35 North American and European centers. Patients who have undergone repeat heart-lung transplantation or a heart-lung transplantation after a previous pulmonary transplantation have been excluded [5, 11]. The status of all study patients was updated in July 1994 through the use of standardized follow-up questionnaires. Only patients who underwent retransplantation because of end-stage OB were included in the study cohort.

The 15 parameters listed in Table 1 were analyzed in each patient. The main outcome variables included the survival interval after retransplantation, the cause of death, and the functional status and pulmonary function test data in survivors. Questionnaire responses were tabulated on the FoxPro database system (Microsoft Corporation, Redmond, WA) on a 486 DX2/66 MHz computer. Statistical analysis was performed with the Statistical Analysis System package (version 6.04; SAS Institute, Cary, NC). All data were expressed as the mean ± the standard error of the mean. Actuarial survival was calculated by the Kaplan-Meier method [13], and the statistical difference between survival curves was determined by the Wilcoxon [14] and log-rank tests. Furthermore, Cox proportional hazards methods [15] were used to determine which variables were associated with and which subset of variables were predictive of survival after pulmonary retransplantation for OB. The risk ratio of each variable was expressed as a comparison of survival between groups, with a value of 1.00 indicating no survival difference. A p value of less than 0.05 was deemed significant.

	Results

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Twenty-six lung transplantation centers participating in the pulmonary retransplantation registry had performed reoperations for OB as of July 1994. A total of 72 patients with this condition had undergone retransplantation, and this consisted of 37 patients in 13 North American centers and 35 patients in 13 European centers. The study cohort comprised 43 women and 29 men with a median age of 39 years (range, 5 to 62 years). Before receiving their first transplant 32% had had emphysema, 26% primary pulmonary hypertension or Eisenmenger's syndrome, 17% cystic fibrosis, 17% restrictive lung disease, and 8% miscellaneous conditions. The median interval between the transplant procedures was 590 days (range, 195 to 2358 days). Twenty-seven patients underwent redo single-lung transplantation for OB, 11 on the ipsilateral side and 16 on the contralateral side. Ten patients underwent redo double-lung transplantation, 14 underwent double-lung transplantation after a previous single-lung transplantation, and 21 underwent single-lung transplantation after a previous double-lung or heart-lung transplantation.

Survival
The actuarial survival rates for all patients after retransplantation for OB are shown in Figure 1. Of the 72 retransplant recipients, 44 have died and 28 are still living. Despite the high early postoperative attrition, a separate actuarial analysis of 90-day postoperative survivors showed that 63% ± 7% were alive 2 years after retransplantation. The median follow-up in current survivors is 429 days (range, 188 to 1337 days). Twenty-one patients have reached the first anniversary, 12 the second anniversary, and 5 the third anniversary of their retransplantation.

View larger version (13K): [in this window] [in a new window]   Fig 1. . Actuarial survival rates in 72 patients undergoing pulmonary retransplantation for obliterative bronchiolitis.

View larger version (17K): [in this window] [in a new window]   Fig 2. . Actuarial survival rates according to year of retransplantation (p < 0.001).

View larger version (18K): [in this window] [in a new window]   Fig 3. . Actuarial survival rates according to institutional experience with pulmonary retransplantation for obliterative bronchiolitis (p = 0.008).

View larger version (18K): [in this window] [in a new window]   Fig 4. . Actuarial survival rates according to whether retransplantation was performed in a European or North American center (p = 0.01).

Impact of the Type of Retransplantation Procedure on Survival
The actuarial survival rate after the five different types of retransplantation procedures did not differ (p = 0.78). An old, retained contralateral graft remained in situ after retransplantation in 51% of patients, whereas all old grafts were completely explanted in 49%. In contradistinction to our last report [11], the actuarial survival rate did not differ according to whether an old graft remained in situ after retransplantation (Fig 5).

View larger version (18K): [in this window] [in a new window]   Fig 5. . Actuarial survival rates according to whether an old contralateral graft remained in situ after retransplantation (p = 0.52).

View larger version (18K): [in this window] [in a new window]   Fig 6. . Actuarial survival rates according to the presence or absence of a cytomegalovirus (CMV) serologic donor–recipient mismatch at reoperation (p = 0.09).

Predictors of Survival Shown by Multivariate Analysis
As shown in Table 1, reoperation after 1989, retransplantation performed in Europe, and being ambulatory immediately before reoperation were predictive of survival according to multivariate analysis. ABO blood group identity and institutional experience with retransplantation for OB, which univariate analysis showed to be significant, did not enter the multivariate model.

Functional Status, Pulmonary Function, and Recurrence of OB in Retransplantation Survivors
Of the 28 current survivors, 12 (43%) are in functional class I, 11 (39%) are in functional class II, 3 (11%) are in functional class III, and 2 (7%) are in functional class IV. The BOS stages of retransplant recipients at yearly postoperative intervals are shown in Table 2. Of note is the fact that the prevalence of stage 3 (ie, severe) BOS was 14% at 1 year, 33% at 2 years, and 40% at 3 years after retransplantation. Absolute FEV₁ values decreased from postoperative baseline values by 11% ± 9% at 1 year and by 27% ± 10% at 2 years (p = 0.02; year 2 versus baseline). There were no significant differences in the BOS stages or the rate of FEV₁ decrease between single-lung and double-lung transplant recipients undergoing retransplantation.

	Comment

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

The pulmonary retransplant registry was established in 1991 to document the outcome and predictors of survival after redo lung transplantation [5]. There are limitations to this and previously published papers from the registry [5, 11] that may make it difficult to draw definitive conclusions from the data presented. These studies have included data collected retrospectively from 26 institutions in North America and Europe, each of which has different preoperative and postoperative protocols and varying experience in the performance of primary and redo lung transplantation. The optimal approach, consisting of a prospective randomized trial of pulmonary retransplantation versus the best alternative therapy in patients with severe OB, will likely never be realized, however. Fortunately, the high rate of participation by North American and European transplant centers in the retransplantation registry ensures that the study cohort and reported outcomes are representative. Furthermore, as the registry has become better known, data are increasingly being collected prospectively. The sizable number of patients in the registry has augmented the statistical power of the outcome analyses and enabled multivariate analyses to be performed to determine those factors that reliably predict survival after pulmonary retransplantation [22]. Despite the increasing numbers of patients, the dynamic nature of the data set increases the probability that the predictors of outcome may change from year to year as experience in the operative and postoperative care of pulmonary retransplantation patients continues to grow.

The most important finding of this study is that the results of pulmonary retransplantation for OB are improving. The 1-year actuarial survival rate in patients undergoing retransplantation in recent years has approached 50%. As in patients undergoing primary lung transplantation, infection was a major cause of morbidity and mortality, both early and late postoperatively [23]. Of the 90-day postoperative survivors, 63% ± 7% were alive 2 years after retransplantation. These data indicate that, with proper patient selection and minimization of early infectious complications, patient survival after pulmonary retransplantation for OB can approach that in patients who undergo primary lung transplantation.

In this series, better results were noted for centers with experience in the performance of at least four pulmonary retransplantations for OB. The 1-year actuarial survival rate in patients operated on at these centers was 54% ± 8% compared with 25% ± 10% in patients undergoing retransplantation at centers with less experience. Furthermore, patients undergoing retransplantation in Europe appeared to fare better than did those reoperated on in North America, with increased survival in European patients revealed by both the life table and univariate Cox analyses. The improved results in patients reoperated on in Europe do not appear to be due solely to increased operative experience, as only three of 13 of the European centers, as opposed to five of 13 of the North American centers, had performed four or more retransplantations. Moreover, a detailed comparison of the other covariates listed in Table 1 in European versus North American patients did not readily reveal the reasons for the differing outcome. This fact and the finding that reoperation in Europe was also noted to be a significant independent predictor of survival in the multivariate analysis indicates that other factors, perhaps involving patient selection, may play a role.

Although the donor CMV status at reoperation appeared to play a less important predictive role than that noted in our first study [5], there was a trend toward decreased survival after pulmonary retransplantation in those patients in whom there was a donor–recipient CMV mismatch (p = 0.09). In a large series of patients who underwent primary lung transplantation, donor–recipient CMV matching was found to have no influence on the prevalence of biopsy-proven OB or the BOS stage [1]. Furthermore, in the most recent report from the St. Louis International Lung Transplant Registry, no significant difference in survival was noted for any of the CMV donor–recipient combinations [24]. In our series a significant number of deaths resulting from infection occurred within the first 90 days postoperatively; CMV was a major offending organism, in concert with resistant gram-negative bacteria and fungi. Perhaps the increased doses of immunosuppressive drugs at retransplantation and a more precarious patient condition before retransplantation were responsible for accentuating the morbidity resulting from CMV infection in this series.

As noted in previous reports concerning the retransplantation registry [5, 11], ventilator dependence before retransplantation does not bias postoperative survival. In a recently reported single-center experience with pulmonary retransplantation, preoperative ventilator dependence also was not found to adversely affect survival but was associated with a markedly prolonged postoperative intensive care unit stay [12]. Results of other studies have confirmed that primary lung transplantation can be performed with a reasonable expectation of success in patients who have been on the ventilator for less than 3 weeks [25]. Other factors such as preoperative nutritional and ambulatory status are probably more important than ventilatory status in determining survival after retransplantation. As more patients have been added to the retransplantation registry, being ambulatory immediately preoperatively has become predictive of survival according to multivariate analysis. Further follow-up of a larger number of patients is necessary to confirm the importance and predictive value of ambulatory status in terms of survival after retransplantation for OB.

Whether OB recurs in an accelerated manner after retransplantation for this complication is a major issue. The actuarial data on the prevalence and severity of OB after primary lung transplantation are sparse. In a single-center experience the freedom from stage 3 BOS was found to be identical in both the primary and secondary lung transplant recipients at 1 year [12]. After 2 years, however, 72% of the recipients of primary lung grafts were free of stage 3 BOS, as opposed to only 27% of the pulmonary retransplant recipients. In the larger number of OB patients followed in the retransplantation registry, 86% were free of stage 3 BOS at 1 year and 67% were free of stage 3 BOS at 2 years. Furthermore, the absolute FEV₁ decreased from postoperative baseline values by only 27% ± 10% at 2 years, similar to the Washington University experience in patients who underwent primary lung transplantation [1]. It is thus evident that, although rapidly progressive OB develops in some patients after retransplantation for this condition, the majority have acceptable pulmonary function in the intermediate term postoperatively. There is therefore no evidence at present that OB occurs in an accelerated manner after a secondary, as opposed to a primary, lung transplant operation.

Until such time as the number of lung grafts available for primary transplantation increases, the practice of pulmonary retransplantation will continue to raise ethical dilemmas [11, 26]. In recognition of the experimental nature of pulmonary retransplantation, it is imperative that only those patients most likely to survive be offered the option of reoperation. Current evidence indicates that pulmonary retransplantation should be performed only in highly selected patients with OB who are ambulatory and are operated on at experienced centers. It is hoped that further research will yield information that clarifies the pathogenesis of OB and leads to the development of therapies to prevent chronic graft dysfunction in primary lung transplant recipients, thus reducing the number of patients who must be considered for pulmonary retransplantation.

	Acknowledgments

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
We thank the contributing thoracic surgeons, pulmonary medicine physicians, and recipient coordinators who have participated in the pulmonary retransplant registry. We also acknowledge the assistance of Heather Motloch in manuscript preparation and of Theresa Novick, MSc, in data collection and analysis. This study was supported by a block-term grant from the Ontario (Canadian) Thoracic Society.

	Footnotes

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Presented at the Poster Session of the Thirty-first Annual Meeting of The Society of Thoracic Surgeons, Palm Springs, CA, Jan 30–Feb 1, 1995.

Address reprint requests to Dr Novick, Division of Cardiothoracic Surgery, PO Box 5339, University Hospital, London, Ontario, Canada N6A 5A5.

	References

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Richard J. Novick Hans-Joachim Schäfers Bernard Andréassian Walter Klepetko Robert L. Hardesty G. Alexander Patterson Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Novick, R. J. Articles by Patterson, G. A. Search for Related Content PubMed PubMed Citation Articles by Novick, R. J. Articles by Patterson, G. A.