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J Thorac Cardiovasc Surg 2008;135:594-602
© 2008 The American Association for Thoracic Surgery
Evolving Technology |
a Department of Surgery, University of Virginia, Charlottesville, Va
b Department of Public Health Sciences, University of Virginia, Charlottesville, Va
Received for publication April 24, 2007; revisions received October 12, 2007; accepted for publication October 26, 2007. * Address for reprints: Gorav Ailawadi, MD, Assistant Professor of Surgery, University of Virginia, PO Box 800679, Charlottesville, VA 22908-0679. (Email: gorav{at}virginia.edu).
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Abstract |
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Methods: Consecutive adult lung transplants (n = 163) at the University of Virginia from January 1998 to May 2006 were reviewed. Antithymocyte globulin induction was routinely performed before January 2002 (65 patients), after which all patients received daclizumab (98 patients). Estimates of cumulative event rate of acute rejection, bronchiolitis obliterans, and death were calculated by Kaplan–Meier method and between-group differences compared by log-rank test. Cox proportional hazards models were fitted to assess treatment effects adjusted for covariates.
Results: Groups were similar in demographics and preoperative and intraoperative risk factors. Maintenance immunosuppression changed during the study, and mycophenolate mofetil was more commonly given to patients receiving daclizumab. By Kaplan–Meier method, daclizumab was associated with significantly less acute rejection (P = .002), less bronchiolitis obliterans (P = .02), and improved overall survival (P = .04). Induction agent was highly associated with acute rejection (P = .002), bronchiolitis obliterans (P = .02), and mortality (P = .05); antimetabolite agent was associated only with acute rejection (P = .01). Adjusting for covariates, induction agent remained significantly predictive for acute rejection (P = .02) and bronchiolitis obliterans (P = .05), approaching significance for survival (P = .07).
Conclusion: Lung transplant recipients receiving daclizumab for induction had significantly less acute rejection and bronchiolitis obliterans than those receiving antithymocyte globulin, with possibly improved survival. Improvements in acute rejection may have been confounded by the use of mycophenolate mofetil.
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Introduction |
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According to data from the International Society for Heart and Lung Transplantation (ISHLT), AR affects more than 50% of recipients in the first year after transplantation.2 Centers with aggressive screening programs have found pathologic evidence of AR in 85% of patients.3 It is well documented that AR is a significant risk factor for the development of BOS.4-5 BOS has been found in 45% of patients by 5 years after lung transplantation and is the most common cause (30%) of late death.2 Induction agents have been shown to decrease the number of patients requiring treatment for AR. Routine use of a specific induction regimen has not been universally accepted, however, with approximately 50% of patients receiving no induction immunosuppression.2 The two most common induction strategies are daclizumab (Zenapax), a monoclonal IgG antibody to interleukin 2 receptor (IL-2R), and antithymocyte globulin (AT), a polyclonal horse antibody to human thymus (primarily T lymphocytes). There remains considerable debate regarding which regimen is optimal for preventing AR.6-9 Moreover, no study has evaluated long-term outcomes of BOS and survival with different induction regimens. The purpose of this study was to examine the effects of daclizumab induction and AT induction on the incidences of AR and BOS and on survival. |
Methods |
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All transplant recipients received azathioprine (2.5 mg/kg) and methylprednisolone (1 g) before organ implantation. From 1998 to 2002, all patients (n = 65) underwent induction immunosuppression consisting of methylprednisolone (250 mg every 8 hours for three doses) and AT (15 mg/kg on day 1, 10 mg/kg on day 2, and 7.5 mg/kg on days 3–7; Pharmacia Corp, Kalamazoo, Mich). AT was stopped for hypersensitivity, leukopenia, or thrombocytopenia. Daily triple maintenance immunosuppression included cyclosporine (INN ciclosporin) or tacrolimus (serum trough goal of 10–15 ng/mL), azathioprine (2 mg/kg) or mycophenolate mofetil (MMF, 2 g), and prednisone (20 mg). Beginning in January 2002, all patients (n = 98) received induction with methylprednisolone (as before) and daclizumab (Zenapax, 1 mg/kg on day of surgery, then every 2 weeks for a total of five doses; Hoffmann-LaRoche Inc, Nutley, NJ). Daily maintenance immunosuppression included cyclosporine or tacrolimus, MMF (2 g), and prednisone (20 mg). Patients received cytomegalovirus (CMV) prophylaxis during the study period with ganciclovir sodium (INN ganciclovir, 3 mg/ kg twice daily) or valganciclovir hydrochloride (INN valganciclovir, Valcyte, 900 mg daily; Hoffmann-LaRoche) from day 7 through day 21. After completion of ganciclovir sodium, CMV prophylaxis was maintained with acyclovir (INN aciclovir, 800 mg four times daily). When the donor was positive for CMV and the recipient was negative for CMV, ganciclovir was continued until day 90 and CMV intravenous immune globulin (Cytogam; Genesis Bio-Pharmaceuticals, Hackensack, NJ) was administered (150 mg/kg on day 4 and at weeks 2, 4, 6, and 8, then 100 mg/kg at weeks 12 and 16).
The database contained donor age; recipient characteristics including age, sex, ethnicity, body mass index, diagnosis, and CMV status; operative events including single- versus double-lung transplantation, use of cardiopulmonary bypass, and graft ischemic time; and postoperative variables including oxygenation index, AR, BOS, and survival status. The variable of CMV mismatch was defined as differing donor and recipient CMV statuses. Graft ischemic time for double lung-transplantation was entered into the model as an average of the ischemic time for both lungs. Maintenance immunosuppression regimen was entered into the registry. Outcomes evaluated included AR, BOS, and mortality.
Definitions of AR and BOS
AR was defined by a panel of pulmonologists, thoracic surgeons, and pathologists and was agreed on by protocol; this definition did not change during the study period. Diagnosis was made according to either clinical or pathologic criteria. Clinical criteria included an acute change in symptoms, a new radiographic infiltrate, or a decrease in forced expiratory volume in 1 second of 20% from baseline not explained by infection or other cause. Lung biopsy was conducted if clinical criteria failed to diagnose AR. Pathologic diagnosis of rejection was defined by ISHLT grade A3 or higher histologic grade.10 Treatment included corticosteroids or augmentation of immunosuppression. BOS was determined by a decrease in pulmonary function testing greater than 20% from baseline (current forced expiratory volume in 1 second divided by two highest consecutive postoperative values). Follow-up data were used to derive comparisons between immunosuppression regimens with respect to the incidences of AR and BOS and to survival.
Statistical Analysis
Bivariate analyses between groups and categoric variables were done by either 
2 test or Fisher exact test as appropriate. The 2-sample t test or Wilcoxon rank sum test was used to compare continuous variables. For comparing time to first episode of AR, time to first episode of BOS, and survival, the Kaplan–Meier method was used, and differences between groups were compared by log-rank test. Because median follow-up was 1.8 years in the daclizumab group, AR, BOS, and survival were compared with the 2 test at 2 years after transplantation. The Kaplan–Meier model did not account for repeated episodes of AR for a given patient or for progression of BOS. Cox proportional hazards models were fitted to investigate the effect of induction on AR, BOS, and survival, with adjustment for the covariates of donor age, recipient age, CMV mismatch, and diagnosis. All analyses were performed with SAS version 9.1.3 software (SAS Institute, Inc, Cary, NC).
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Results |
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Table 1. No differences in donor age, recipient age, ethnicity, body mass index, or CMV mismatch were identified. More than half of the transplant recipients undergoing AT induction were women, which was not significantly different from the daclizumab group. Diagnoses were similar between induction treatment groups. Graft ischemic times were significantly longer in the daclizumab group (mean ± SE 295 ± 8.1 minutes) than in the AT group (226.3 ± 10.6 minutes, P = .001). The number of patients undergoing double-lung transplantation significantly increased during the study period, from 12.3% (8/65) during the AT era to 26.5% (26/98) in the daclizumab era (P = .03). Importantly, among patients receiving AT, the median number of doses of the induction agent tolerated was four. Among the 65 patients in the AT group, a total of 61 patients (94%) tolerated two doses of AT and 43 patients (66%) completed four doses of AT. In fact, only 2 patients (3%) were able to tolerate a complete 7-day course per our induction protocol. AT was discontinued because of severe hypersensitivity reactions, leukopenia, thrombocytopenia, or evidence of infection.
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Table 2). In the AT group, 11 patients received cyclosporine, whereas 53 patients received tacrolimus. In this same group, 5 patients received MMF, and 58 patients were treated with azathioprine. The daclizumab group received mainly tacrolimus (93 patients) rather than cyclosporine (5 patients) and MMF (93 patients) rather than azathioprine (5 patients).
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Figure 1, A). AR tended to occur in the first 3 to 6 months after transplantation, irrespective of induction regimen. Beyond 6 months, the Kaplan–Meier estimator curves are parallel, regardless of induction regimen. At 2 years after transplantation, patients receiving daclizumab had less AR (9%, 9/98) than did patients receiving AT (28%, 18/65, P = .002). The time to the first episode of BOS was significantly shorter among patients undergoing AT induction than among those undergoing daclizumab induction (P = .02; Figure 1, B). In the group receiving daclizumab, BOS rarely occurred until 2 years after transplantation, whereas AT induction patients had BOS develop as early as 1 year after transplantation. The two curves have different slopes, suggesting less BOS with time after daclizumab induction. At 2 years after transplantation, BOS was less common among patients who received daclizumab (6.4%, 6/96) than among those who received AT (23%, 14/60, P = .002). Furthermore, daclizumab induction demonstrated improved survival relative to AT induction (P = .04; Figure 1, C). At 2-year follow-up, survival in the daclizumab group was 94%, compared with 83% survival in the AT group (P = .03).
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Table 3). AR was strongly associated with induction regimen (P = .002) and antimetabolite maintenance drug (P = .01). Calcineurin inhibitor was not significantly associated with AR. BOS was associated with induction,(P = .02) but not with other variables, including maintenance immunosuppression. Mortality was significantly associated only with induction (P = .05) and not with recipient or donor age, body mass index, diagnosis, CMV mismatch, or maintenance immunosuppression.
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Table 4). Type of induction regimen was significantly associated with AR, with a hazard ratio (HR) of 2.71 (P = .02). Interestingly, younger recipient age was weakly but significantly associated with AR (HR 0.94, P = .03).
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From our analyses, AR was correlated with BOS, and BOS was correlated with mortality. During the study period, 46% of patients with AR (13/28) had BOS develop, compared with 26% of patients who did not have an episode of AR (35/135) who had BOS develop (P = .04). Similarly, 42% of patients with BOS died during the study period, compared with 18% of patients who died without any antecedent BOS (21/115, P = .002).
The incidence of malignancy and posttransplantation lymphoproliferative disorder (PTLD) was not different between the two induction groups. Five patients in the AT group (7.7%) and 3 patients in the daclizumab group (3.1%) had malignancy develop during follow-up (P = .26). Only 1 patient in the daclizumab group and no patients in the AT group had PTLD develop.
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Discussion |
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The rationale for induction therapy for organ transplantation is to suppress the initial host immune response to the allograft. This strategy has been shown to decrease the incidence of AR in kidney and combined kidney–pancreas transplantation.11-12 In lung transplantation, longitudinal studies indicate that AR primarily occurs within 4 months after transplantation and decreases with time.13 Despite the rationale for induction therapy, according to ISHLT data, more than 50% of lung transplant recipients do not receive any induction agent.2
Specifically, IL-2R antagonists have been shown to affect the development of AR. In kidney as well as heart transplant recipients, induction immunosuppression with daclizumab, a potent IL-2R monoclonal antibody, has been associated with a decrease in the number of episodes of AR.14-15 The efficacy of daclizumab as an induction agent in preventing AR after lung transplant has been studied.6-9 Garrity and colleagues6 demonstrated that the incidence of grade 2 AR significantly decreased from 48% without induction to 18% with daclizumab during the first 6 months after transplantation. Few studies have compared daclizumab with AT as induction immunosuppression for lung transplantation. In a prospective trial, Brock and associates7 demonstrated no differences in AR, BOS, or survival among three induction regimens (OKT3, AT, and daclizumab). Despite a relatively small sample size in each group (total of 87 patients divided into three groups), however, patients receiving daclizumab had significantly fewer infections than did those receiving the other two induction agents. Burton and colleagues8 analyzed over more than lung transplant recipients and documented less AR with AT induction than with daclizumab. In that study, 100% of patients receiving daclizumab induction had AR by 2 years after transplantation, a rate notably higher than in any other study, and outcomes of BOS and mortality were not reported. In a recent report of 25 patients, daclizumab was associated with significantly improved freedom from AR relative to AT.9
Although the effects of induction therapy on AR have been documented, outcomes of BOS and survival have not been well described. Only one previous study attempted to find any differences between daclizumab and AT induction with respect to BOS or survival. This small study (25 patients) did not find significant differences. Larger studies comparing the two induction agents have not evaluated BOS or survival. AR is the most important risk factor for the development of BOS.4,5 BOS is the most common cause of death after lung transplantation.2 In our report, AR was significantly associated with the development of BOS, and BOS in turn was significantly associated with mortality during the study period. Our investigation supports the concept that AR, BOS, and survival are related outcomes.
Despite conflicting data regarding daclizumab versus AT induction, the ISHLT Registry has noted increasing use of IL-2R antibody induction rather than AT.2 In fact, daclizumab induction is used for more than 30% of lung transplant recipients, whereas AT induction has declined to approximately 10%.2 There are several explanations for the increased use of daclizumab. First, AT is not well tolerated, as seen in our study, with a minority of patients in the AT group completing our induction protocol because of significant adverse effects. Second, patients receiving AT induction demonstrate higher infection rates than are seen with daclizumab induction.7 In a study of heart transplant recipients, bacterial infections were three times more likely after AT induction than after daclizumab induction.16 Brock and associates7 reported that viral infections were three times more common after AT induction than after daclizumab induction. Finally, the risk profile of daclizumab is low, and the agent appears to be well tolerated. In our study, no patient required the discontinuation of daclizumab because of an adverse effect.
According to bivariate analysis, only induction agent was a significant predictor for all three outcomes. Importantly, antimetabolite maintenance agent was associated with the outcome of AR but not with BOS or mortality. Antimetabolite maintenance agent would ideally have been added to the multivariate model, because it is a confounding variable. Because of the strong correlation between the use of MMF and daclizumab, however, the two variables (induction and maintenance immunosuppression) could not be put into the model together, as this would render the model statistically invalid. Analysis of antimetabolite agent within each induction group did not show any correlation with AR. This subgroup analysis was limited by type II error because of the small sample sizes of 5 patients in maintenance immunosuppression groups. It is possible that with larger sample sizes, maintenance immunosuppression might correlate with all three outcomes. Patients undergoing double-lung transplantation have been shown to have a survival advantage relative to patients undergoing single-lung transplantation.2 Even though there were significantly more patients undergoing bilateral lung transplantation in the daclizumab group in our study, there was no correlation between double-lung transplantation and the three outcomes according to bivariate analysis. Other clinically important variables were therefore selected for the multivariate model. Data from ISHLT has demonstrated higher mortality after lung transplantation to be associated with donor age, recipient age, CMV mismatch, and diagnosis.2
Our study has several limitations. First, it is a retrospective, single-institution study with inherent biases. Our two patient populations were similar, however, with respect to baseline characteristics and intraoperative data (Table 1). Second, there were notable differences in maintenance immunosuppression during our two study periods. There are conflicting data regarding the effects of specific maintenance regimens on outcomes. In a recent multicenter randomized trial, azathioprine and MMF did not differ with respect to the development of AR or BOS or to survival at 3 years.17 Previous studies have compared tacrolimus and cyclosporine in the treatment of AR and BOS. A retrospective review demonstrated that tacrolimus was superior to cyclosporine for patients with AR or BOS.18 In contrast, a prospective, randomized study demonstrated no differences in associated BOS or survival between tacrolimus and cyclosporine.19 Several multicollinear variables were evaluated in our study. Daclizumab was used most often in conjunction with MMF during a more mature era of our lung transplant program. These variables are difficult to separate because of their collinearity and also the limited sample size. It is likely that some of the effects seen on these three outcomes are due to concomitant effects daclizumab and MMF. Third, although we did not find any differences in the selection, intraoperative management, or postoperative care of these transplant recipients with time, our lung transplant program has matured, with greater experience of our lung transplant surgeons and pulmonologists and greater use of bilateral lung transplantation. Collectively, the improved evolution of our program may have contributed to our improved outcomes in patients who received daclizumab. The ISHLT Registry has reported an improvement in survival in recent transplant recipients relative to earlier eras.2 As such, the improved survival in the later group with the use of daclizumab induction may also be related to improvements in processes of care. Fourth, our median follow-up of 1.8 years in the daclizumab group was short. With longer follow-up, it is possible that the benefits seen after daclizumab induction may be lost. Finally, the seven daily AT doses used in our study differ from previous reports. Burton and colleagues8 administered AT at 12.5 mg/(kg · d) for three doses, whereas the protocol used by Brock and associates7 included a 7-day course of AT starting at 15 mg/(kg · d) and adjusted daily. Neither report documented the number of patients who received all intended doses. Differences in our AT protocol relative to other studies may in part explain our outcomes.
PTLD has been linked to the use of induction agents after renal transplantation.20 In one study, an IL-2R inhibitor as an induction agent was not associated with any increase in PTLD relative to no induction, whereas use of AT induction was associated with a 55% increase in PTLD.20 Because of the relatively low incidence of any type of malignancy in our study, we did not document differences in malignancy after either induction agent.
In conclusion, AR and BOS were improved in patients receiving daclizumab induction immunosuppression relative to AT. In addition, there was a trend toward improved survival among patients receiving daclizumab. Poor tolerance to AT resulted in fewer patients completing the induction protocol. Differences in maintenance immunosuppression during the two different periods, as well as improvements in the evolution of care of our maturing lung transplant program, may also explain these outcomes. This study supports the need for prospective, randomized trials comparing induction agents in lung transplantation.
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Acknowledgments |
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Footnotes |
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Read at the Eighty-seventh Annual Meeting of The American Association for Thoracic Surgery, Washington, DC, May 5–9, 2007.
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