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Antithymocyte Globulin Induction Therapy Adjusted for Immunologic Risk After Heart Transplantation
Antithymocyte Globulin Induction Therapy Adjusted for Immunologic Risk After Heart Transplantation L.S.C. Czer, A. Phan, A. Ruzza, M. Rafiei, S. Setareh-Shenas, M. Caceres, M. Awad, C. Soliman, J. Mirocha, M. De Robertis, R.M. Kass, and A. Trento ABSTRACT Introduction. The efficacy of antithymocyte globulin (ATG) induction in the therapy of immunologically low- and high-risk patients after heart transplantation is not known. Methods. All patients who received ATG induction from January 2000 through January 2010 were divided into two groups based on the risk of rejection. A higher-risk group (age younger than 60 years, multiparous females, African Americans, panel-reactive antibody >10%, or positive cross-match) received ATG (1.5 mg/kg) for 7 days (ATG7), and the remaining lower-risk group received ATG for 5 days (ATG5), all followed by calcineurin inhibitor, mycophenolate, and prednisone. Endomyocardial biopsies were performed based a standard protocol for up to 3 years after heart transplantation, and for suspected rejection. Results. Of 253 heart transplant recipients, 87 received ATG5 and 166 ATG7. Absolute lymphocyte count <200 per microliter was achieved within 10 days in 88% of ATG5 and 86% of ATG7. Baseline creatinine was 1.3 0.8 pre-transplantation, 1.8 0.9 posttransplantation, and 1.0 0.4 mg/dL at discharge (mean standard deviation [SD]; P < .001, compared with pre-transplantation). Of 3667 biopsies, 33 (0.90%) had 3A/2R cellular rejection (CR). Of 3599 biopsies, 16 (0.44%) had definite antibody-mediated rejection (AMR). At 5 years, freedom from 3A/2R CR (94% 2.8% vs 83% 7.7%; P ¼ .31) and freedom from AMR (95% 2.4% vs 90% 6.4%; P ¼ .98) were similar between ATG5 and ATG7, respectively. Survival for ATG5 and ATG7 was comparable at one year (94% 2.5% vs 93% 2.0%), and at 8 years (61% 6.9% and 61% 4.7%; P ¼ .88). At 5 years, ATG5 and ATG7 were similar in freedom from cytomegalovirus (CMV) infection (92.3% vs 94.3%; P ¼ not significant [NS]), freedom from pneumonia (83.8% vs 82.1%; P ¼ NS), and in rate of malignancy (excluding skin cancer; 8.0% vs 6.0%; P ¼ NS). Conclusions. ATG induction therapy (prospectively dose-adjusted for immunologic risk) in low- and high-risk patients results in excellent and equivalent short- and long-term survival rates, with a low incidence of CR and AMR. The use of ATG does not increase rates of CMV infection with appropriate prophylaxis. ATG may benefit renal function by delaying calcineurin inhibitor exposure, and may have a role in the prevention of AMR.
A
NTITHYMOCYTE globulin (ATG) is a polyclonal antibody preparation that depletes T lymphocytes and has multiple immunologic targets.1 ATG is the most commonly used agent for induction therapy after heart transplantation, although its routine use remains controversial. Guidelines from the International Society for Heart and Lung Transplantation (ISHLT) have not endorsed routine use for ATG after heart transplantation,2 although
From the Divisions of Cardiology (L.S.C.C., A.P., M.R., S.S.-S., M.A., C.S.) and Cardiothoracic Surgery (A.R., M.C., M.D.R., R.M.K., A.T.), Cedars-Sinai Heart Institute, and the Section of Biostatistics (J.M.), Cedars-Sinai Medical Center, Los Angeles, California, USA. Address reprint requests to Lawrence S.C. Czer, MD, Medical Director, Heart Transplant Program, 8700 Beverly Blvd., Los Angeles, CA 90048. E-mail: [email protected]
ª 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.02.114
Transplantation Proceedings, 45, 2393e2398 (2013)
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more than half of adult heart transplant recipients receive induction therapy, including ATG.3 There remains a lack of long-term outcome data on the use of ATG induction therapy in heart transplant recipients. This study was performed to determine the effects of intravenous ATG induction therapy after heart transplantation. A review of our center’s experience was conducted to evaluate the effects on rejection, renal function, lymphocyte depletion and recovery, cytomegalovirus (CMV) infection, malignancy, and survival. METHODS Patients undergoing heart transplantation from January 2000 through January 2010 at our institution who received ATG induction therapy were reviewed. Patients received ATG at a dose of 1.5 mg/kg for either 5 days (ATG5) or 7 days (ATG7), with the dose adjusted for white blood cell (WBC) and platelet counts. Criteria for patients receiving ATG7 were those considered to be at higher risk for rejection, including younger patients (younger than 60 years of age), multiparous females, African Americans, patients with an elevated panel-reactive antibody (PRA) level (>10%), and those with a positive retrospective or prospective donor-recipient crossmatch. Multiorgan transplant recipients were excluded from the study. Heart transplantation was performed using the bicaval technique as described previously.4e13
Maintenance Immunosuppressive Therapy Maintenance immunosuppression included cyclosporine or tacrolimus, mycophenolate mofetil, and corticosteroids. After a 5-day course of ATG, cyclosporine was initiated at 50 mg orally every 12 hours when the creatinine level was <2 mg/dL, and was adjusted to achieve a whole blood level of 200 to 400 ng/mL in the first three months, and 100 to 200 ng/mL thereafter. After a 7-day course of ATG, tacrolimus was initiated at 2 mg orally every 12 hours when the creatinine level was <2 mg/dL, and was adjusted to achieve a whole blood level of 10 to 20 ng/mL in the first three months, and 6 to 10 ng/mL thereafter. Mycophenolate mofetil was started at 250 mg twice daily and increased to a target dose of 1 g twice daily (with cyclosporine) and 500 mg twice daily (with tacrolimus), and adjusted according to the WBC count, platelet count, and gastrointestinal tolerance. In patients who could not tolerate mycophenolate mofetil due to gastrointestinal side effects, azathioprine was given at a dose of 2 mg/kg and adjusted according to the WBC count platelet count. Patients were administered methylprednisolone intravenously during induction therapy (500 mg on the first day, then 125 mg daily), and were transitioned to oral prednisone at 0.5 mg/kg/d, and tapered sequentially over 3e12 months after two negative (0 or 1A-1R) endomyocardial biopsies, until they were off prednisone.14,15
CZER, PHAN, RUZZA ET AL endothelial cell swelling and intravascular macrophage accumulation, with or without interstitial hemorrhage and edema, and positive immunofluorescence or immunoperoxidase staining for a complement component (C1q, C3a, or C4d) with or without an immunoglobulin (IgG, IgM, or IgA). AMR was graded according to published criteria.18e20 CR was treated if it was grade 3A/2R or greater, and occasionally if it was a lower grade in association with hemodynamic compromise. AMR was treated if it was definite or greater. Patients who experienced CR or AMR were administered a pulse of methylprednisolone (10 mg/kg/d for 3 days). If there was CR or AMR with evidence of hemodynamic compromise (systolic blood pressure <90 mm Hg without inotropic support, or requiring inotropic or mechanical support, or cardiac index <1.8), patients also received a 5-day course of ATG (1.5 mg/kg/d, adjusted according to the WBC and platelet counts). Patients with AMR additionally received sucrose-free intravenous immunoglobulin (IVIG) 10% at 1 gm/kg on two consecutive days.21e23
Antiviral Prophylaxis All patients received antiviral prophylaxis.24 CMV seropositive recipients received intravenous ganciclovir (5 mg/kg every 12 hours and adjusted for renal function, WBC count, and platelet count) for 10 days, followed by oral acyclovir until 6 months postoperatively. Seronegative recipients of a seropositive donor (or seronegative recipients with seronegative donors but with unscreened blood; or seropositive recipients with prolonged hospitalization, ventilatordependent for prolonged duration, recurrent or severe rejection, or readmission for complication) received ganciclovir (5 mg/kg every 12 hours and adjusted for renal function, WBC count, and platelet count) for 10 days, followed by oral ganciclovir or valganciclovir until one year after heart transplantation. Seronegative recipients with a seronegative donor (and no unscreened blood products) received oral acyclovir until 6 months post-transplantation. CMV DNA was monitored using polymerase chain reaction (PCR) at periodic intervals during and after completion of prophylaxis, and when recurrence of CMV was suspected.25 Prophylaxis was repeated after treated rejection episodes requiring pulse steroid therapy or ATG.
Statistical Analysis Continuous variable results were presented as mean standard deviation, and were compared using a t test. Categorical variables were presented as frequency, and were compared across groups using chi-square or Fisher exact test. Numerical variables were compared using Wilcoxon rank sum test. Kaplan-Meier curves were constructed for time-related events of rejection or death. Mean followup time was 2.75 years. The log-rank test was used to compare survival across groups. All statistical tests were 2-sided, and P < .05 was considered significant. Statistical analysis was performed using SAS 9.1 software (SAS Institute Inc., Cary, NC, USA).
Endomyocardial Biopsies and Assessment of Rejection Endomyocardial biopsies after heart transplantation were initiated within two to five days after completion of ATG therapy and at weekly intervals for 3 weeks, then every other week twice, then monthly 2, every other month 2, every 4 months 1, every 6 months 2, and yearly up to 3 years, or when clinically indicated for suspected rejection.14,15 Biopsy specimens were assessed for both cellular rejection (CR) and antibody-mediated rejection (AMR) using histology and immunostaining. CR was graded according to the classification of the ISHLT.16,17 AMR was defined as histological evidence of capillary
RESULTS
A total of 253 heart transplant recipients were included in the study, with a mean age of 56.4 11.8 years. Of note, 24% were female, 15% were African American, 58% had an ischemic etiology, 49% had hypertension, 27% had diabetes mellitus, and 67% had positive donor serology for CMV. Baseline creatinine level was 1.3 0.8 mg/dL before heart transplantation, and mean peak creatinine level was 1.8 0.9 mg/dL after heart transplantation. The discharge
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creatinine level was 1.0 0.4 mg/dL. There was a significant difference between baseline and discharge creatinine levels (P < .001). Baseline characteristics are shown in Table 1. A total of 87 heart transplant recipients received ATG for 5 days (ATG5), whereas 166 received ATG for 7 days (ATG7). Patients in the ATG7 group were younger and were more frequently female and African American, and less frequently seropositive for CMV. There was a higher prevalence of hyperlipidemia in the ATG5 group. Evidence of sensitization with a PRA > 10% was found in 19.5% (8/41) of the ATG5 group, and in 28.3% (17/60) of the ATG7 group. Absolute lymphocyte count <200 per microliter was achieved within 10 days in 88% of ATG5 and 86% of ATG7 patients. At 5 years, there was no significant difference between the ATG5 and ATG7 groups in freedom from CMV infection (92.3% vs 94.3%; P ¼ not significant [NS]), freedom from pneumonia (83.8% vs 82.1%; P ¼ [NS]), and rate of malignancy, excluding skin cancer (8.0% vs 6.0%; P ¼ NS). Of 3667 endomyocardial biopsies, 33 (0.90%) had grade 3A/2R CR. At 5 years, the freedom from 3A/2R CR between the ATG5 and ATG7 groups was comparable at 94% 2.8% and 83% 7.7%, respectively (P ¼ .31; Fig 1). Of 3599 biopsies, 16 (0.44%) had definite AMR. The rate of AMR at 5 years was also similar between the ATG5 and ATG7 groups at 95% 2.4% and 90% 6.4% (P ¼ .98; Fig 2). Survival curves are shown in Figure 3. Survival rates at 30 days were 97% 2.0% in the ATG5 group, and 98% 1.2% in the ATG7 group. At one year, survival rates for ATG5 and ATG7 were 94% 2.5% and 93% 2.0% and at 8 years were 61% 6.9% and 61% 4.7%, respectively (log-rank P ¼ .88).
DISCUSSION
There has been an increase in the use of induction therapy from 38% in 1997 to 52% in 2010.3 Early and long-term outcomes in heart transplant recipients treated with induction therapy and, in particular, ATG still remain unclear. The findings in this study reinforce those in other trials where the use of induction therapy resulted in a decreased risk of early rejection.26e28 A study comparing ATG induction therapy to no induction therapy found that patients treated with antithymocyte therapy had a lower rate of early rejection compared with those who did not receive induction therapy.29 Other studies using ATG induction therapy for 5 days showed freedom from rejection to be 80% at one year and 75% at four years.30 A prospective randomized trial comparing an interleukin-2 receptor antagonist and ATG induction therapy found that there was a significantly higher incidence of severe rejection in the group receiving interleukin-2 receptor antagonist over a 10-year follow-up (55% vs 10%; P ¼ .028).28 These results are in contrast with unadjusted data reported by the ISHLT showing a higher rate of rejection with induction therapy, probably related to the selection bias of patients at a higher risk of rejection to receive induction therapy and the multiplicity of agents included in the category of induction therapy (such as Orthoclone-OKT3 [Ortho Biotech, Raritan, NJ, USA] and interleukin-2 receptor antagonists). Immunologic effects of ATG therapy may also be more long-lasting than the acute phase after heart transplantation, with effects on lymphocyte populations lasting 6 months to one year.14 The current study by our group demonstrated that CR remained low at five years in patients who received ATG induction therapy, with a freedom from CR of 94% 2.8% in the ATG5 group and 83% 7.7% in the ATG7 group at 5 years (P ¼ .31; Fig 1). Furthermore,
Table 1. Clinical Characteristics of the Patients Characteristic
Recipient age, y Donor age, y Recipient female, % (n) Donor female, % (n) Gender mismatch, % (n) Race AA, % (n) Donor race AA, % (n) Ischemic etiology, % (n) UNOS Status, % (n) 1A 1B 2 Hypertension, % (n) Cholesterol, % (n) Diabetes mellitus, % (n) Recipient CMV, % (n) Donor CMV, % (n) Dialysis, % (n) Creatinine
All Patients (n ¼ 253)
ATG5 (n ¼ 87)
ATG7 (n ¼ 166)
P
<.0001 .065 .002 .008 .006 .026 .015 .069 .41
56.4 11.8 33.6 12.4 24.1 (61) 23.7 (60) 25.7 (65) 15.0 (38) 7.9 (20) 57.7 (146)
60.1 31.7 12.6 13.8 14.9 8.1 2.3 65.5
10.4 12.0 (11) (12) (13) (7) (2) (57)
54.4 12.0 34.6 12.5* 30.1 (50) 28.9 (48) 31.3 (52) 18.7 (31) 10.8 (18) 53.6 (89)
31.6 (80) 35.2 (89) 33.2 (84) 48.6 (123) 54.2 (137) 27.0 (68/252) 58.5 (148) 66.8 (145/217) 7.9 (20) 1.29 0.78
26.4 39.1 34.5 55.2 69.0 29.9 67.8 68.4 4.6 1.19
(23) (34) (30) (48) (60) (26) (59) (54/79) (4) 0.40
34.3 (57) 33.1 (55) 32.5 (54) 45.2 (75) 46.4 (77) 25.5 (42/165) 53.6 (89) 65.9 (91/138) 9.6 (16) 1.34 0.91
Abbreviations: AA, African American; UNOS, United Network for Organ Sharing.
.146 .0008 .45 .029 .72 .22 .064
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Fig 1. Freedom from CR. The ATG5 day group is depicted with a solid line, and the ATG7 day group with a dashed line. In the inset box are the rates of freedom from CR at 1, 2, 3, and 5 years in the ATG5 and ATG7 day groups. There was no significant difference between the ATG5 and ATG7 day groups in the freedom from CR (P ¼ .31).
Fig 3. Survival. The ATG5 day group is depicted with a solid line, and the ATG7 day group with a dashed line. In the inset box are the survival rates at 30 days, 1, 2, 3, 5, and 8 years in the ATG5 and ATG7 day groups. There was no significant difference between the ATG5 and ATG7 day groups in survival (P ¼ .88).
less than 1% of post-transplantation biopsies (33/3667 or 0.90%) had grade 3A/2R CR, a very low rate of biopsyproven rejection. Few studies have addressed the effects of induction therapy and, in particular, ATG on AMR. In the current study, AMR remained low at five years in patients who received ATG induction therapy, with a freedom from AMR of 95% 2.4% in the ATG5 group and 90% 6.4% in the ATG7 group at 5 years (P ¼ .98; Fig 2). Moreover,
less than 1% of post-transplantation biopsies (16/3599 or 0.44%) had definite AMR. This occurred despite sensitization with a PRA > 10% in 19.5% of the ATG5 group, and in 28.3% of the ATG7 group. The current study is the first to document a low incidence of AMR with ATG induction therapy and implies that ATG may have a role in preventing AMR. In the current study, immunologically high-risk patients were included in the ATG7 group, including younger patients (younger than 60 years of age), multiparous females, African Americans, patients with an elevated panel-reactive antibody level (>10%), and those with a positive retrospective or prospective donor-recipient cross-match. Despite this preponderance of higher-risk patients in the ATG7 group, the rates of CR and AMR (Fig 1 and Fig 2) and the short- and long-term survivals were similar in the ATG5 and ATG7 groups, implying that the longer course of ATG had an effect to “level the playing field” between the immunologically low- and high-risk patients in the ATG5 and ATG7 groups, respectively. Registry data report about an 80% and 70% survival rate at one and five years, respectively, after heart transplantation, and a median survival of 11 years.3 Our study demonstrates that ATG induction therapy does not have unfavorable effects on long-term survival with at least 72% of patients alive after 5 years in the ATG5 and ATG7 groups. A prospective randomized controlled trial to evaluate ATG-Fresenius and ATG-ThymoglobulinMerieux induction therapy in heart transplant recipients did not find a significant difference between the two agents, with an actuarial survival rate of 84.6% and 87.5% at one year, respectively.27 Higgins et al reviewed a multiinstitutional database to evaluate the impact of induction
Fig 2. Freedom from AMR. The ATG5 day group is depicted with a solid line, and the ATG7 day group with a dashed line. In the inset box are the rates of freedom from AMR at 1, 2, 3, and 5 years in the ATG5 and ATG7 day groups. There was no significant difference between the ATG5 and ATG7 day groups in the freedom from AMR (P ¼ .98).
ATG INDUCTION THERAPY
therapy on heart transplantation and found that over a 10-year period there was a higher survival rate in patients who did not receive induction therapy, with the difference in survival occurring during the first year after heart transplantation.31 In contrast, we found that the survival rate after one year was greater than 93% in both the ATG5 and ATG7 groups. The discrepancy between our findings and those reported by Higgins et al may be due to differences in induction therapy agents, because the majority of their patients who received induction therapy were treated with OKT3 in the Higgins study. Calcineurin inhibitors are now commonly used as part of triple drug immunosuppressive therapy regimens, although their nephrotoxic effects may cause complications in newly transplanted heart recipients. We have demonstrated that the use of ATG for induction therapy is effective in reducing absolute lymphocyte counts to allow adequate immunosuppression while delaying initiation of calcineurin inhibitors. This may prove to have significant effects on renal function because a significant decrease from baseline to discharge creatinine was demonstrated in patients treated with ATG. This is in agreement with a recent large-scale study demonstrating the renal-sparing effects of ATG induction therapy.32 Concern with the use of induction therapy includes not only increased rate of infection but also malignancies such as lymphoproliferative disorders. In our study, we were able to demonstrate that over the ten-year timeframe, the rate of CMV infection remained relatively low, affecting less than 8% of the transplanted population at five years. This may be due to the relatively aggressive prophylaxis for CMV (including treated rejection episodes) in the current study and the use of CMV monitoring using PCR.25 With regard to malignancy in posteheart transplantation recipients, a retrospective study performed by Yagdi et al33 found that 15.1% of patients developed a malignancy after heart transplantation, whereas in our study the use of ATG induction therapy resulted in 8% of patients developing a malignancy (excluding skin cancers). Choice of induction therapy may also affect the rate of malignancy, as Swinnen et al34 found an increased risk of post-transplantation lymphoproliferative disorder in patients treated with OKT3 (11.4% vs 1.3%). The purpose of this study was to present the outcomes of a contemporary group of heart transplant recipients receiving induction therapy with ATG during the last decade. The outcomes presented are favorable in a group of patients traditionally considered to have higher rates of rejection and decreased survival. However, limitations to this study have to be noted, particularly related to the inherent nature of a retrospective study. All patients were treated with ATG induction therapy and therefore, a control group without induction therapy was not available for a matched comparison. There were baseline clinical characteristic differences between the ATG5 and ATG7 groups due to the intentional selection of high-risk patients to receive ATG7.
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In conclusion, ATG induction therapy after heart transplantation resulted in excellent and equivalent short- and long-term survival rates, with a low incidence of CR and AMR. The use of ATG did not result in increased rates of CMV infection with appropriate prophylaxis. ATG may benefit renal function by delaying calcineurin inhibitor exposure during the early postoperative period after heart transplantation. REFERENCES 1. Preville X, Flacher M, LeMauff B, et al. Mechanisms involved in antithymocyte globulin immunosuppressive activity in a nonhuman primate model. Transplantation. 2001;71(3):460e468. 2. Costanzo MR, Dipchand A, Starling R, et al. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2010;29(8):914e956. 3. Stehlik J, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Twenty-eighth Adult Heart Transplant Reporte2011. J Heart Lung Transplant. 2011;30(10):1078e1094. 4. Blanche C, Czer LS, Valenza M, Trento A. Alternative technique for orthotopic heart transplantation. Ann Thorac Surg. 1994;57(3):765e767. 5. Blanche C, Valenza M, Aleksic I, Czer LS, Trento A. Technical considerations of a new technique for orthotopic heart transplantation. Total excision of recipient’s atria with bicaval and pulmonary venous anastomoses. J Cardiovasc Surg. 1994;35(4): 283e287. 6. Blanche C, Valenza M, Czer LS, et al. Orthotopic heart transplantation with bicaval and pulmonary venous anastomoses. Ann Thorac Surg. 1994;58(5):1505e1509. 7. Czer LS, Cohen MH, Gallagher SP, et al. Exercise performance comparison of bicaval and biatrial orthotopic heart transplant recipients. Transplant Proc. 2011;43(10):3857e3862. 8. Trento A, Czer LS, Blanche C. Surgical techniques for cardiac transplantation. Semin Thorac Cardiovasc Surg. 1996;8(2): 126e132. 9. Trento A, Takkenberg JM, Czer LS, et al. Clinical experience with one hundred consecutive patients undergoing orthotopic heart transplantation with bicaval and pulmonary venous anastomoses. J Thorac Cardiovasc Surg. 1996;112(6):1496e1502. 10. Doering LV, Dracup K, Moser DK, Czer LS, Peter CT. Hemodynamic adaptation to orthostatic stress after orthotopic heart transplantation. Heart Lung. 1996;25(5):339e351. 11. Doering LV, Dracup K, Moser DK, Czer LS, Peter CT. Evidence of time-dependent autonomic reinnervation after heart transplantation. Nurs Res. 1999;48(6):308e316. 12. Freimark D, Czer LS, Aleksic I, et al. Improved left atrial transport and function with orthotopic heart transplantation by bicaval and pulmonary venous anastomoses. Am Heart J. 1995;130(1):121e126. 13. Freimark D, Silverman JM, Aleksic I, et al. Atrial emptying with orthotopic heart transplantation using bicaval and pulmonary venous anastomoses: a magnetic resonance imaging study. J Am Coll Cardiol. 1995;25(4):932e936. 14. Goland S, Czer LS, Coleman B, et al. Induction therapy with thymoglobulin after heart transplantation: impact of therapy duration on lymphocyte depletion and recovery, rejection, and cytomegalovirus infection rates. J Heart Lung Transplant. 2008;27(10): 1115e1121. 15. Daneshvar D, Czer LS, Phan A, et al. Heart transplantation in patients aged 70 years and older: a two-decade experience. Transplant Proc. 2011;43(10):3851e3856. 16. Billingham ME, Cary NR, Hammond ME, et al. A working formulation for the standardization of nomenclature in the
2398 diagnosis of heart and lung rejection: Heart Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant. 1990;9(6):587e593. 17. Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant. 2005;24(11):1710e1720. 18. Kobashigawa J, Crespo-Leiro MG, Ensminger SM, et al. Report from a consensus conference on antibody-mediated rejection in heart transplantation. J Heart Lung Transplant. 2011;30(3): 252e269. 19. Tan CD, Baldwin WM 3rd, Rodriguez ER. Update on cardiac transplantation pathology. Arch Pathol Lab Med. 2007;131(8): 1169e1191. 20. Lones MA, Czer LS, Trento A, Harasty D, Miller JM, Fishbein MC. Clinical-pathologic features of humoral rejection in cardiac allografts: a study in 81 consecutive patients. J Heart Lung Transplant. 1995;14(1 Pt 1):151e162. 21. Goland S, Czer LS, Siegel RJ, et al. Intravenous immunoglobulin treatment for acute fulminant inflammatory cardiomyopathy: series of six patients and review of literature. Can J Cardiol. 2008;24(7):571e574. 22. Jordan SC, Quartel AW, Czer LS, et al. Posttransplant therapy using high-dose human immunoglobulin (intravenous gammaglobulin) to control acute humoral rejection in renal and cardiac allograft recipients and potential mechanism of action. Transplantation. 1998;66(6):800e805. 23. Jordan SC, Tyan D, Czer L, Toyoda M. Immunomodulatory actions of intravenous immunoglobulin (IVIG): potential applications in solid organ transplant recipients. Pediatric Transplant. 1998;2(2):92e105. 24. Czer LS, Ruzza A, Vespignani R, et al. Prophylaxis of cytomegalovirus disease in mismatched patients after heart transplantation using combined antiviral and immunoglobulin therapy. Transplant Proc. 2011;43(5):1887e1892. 25. Toyoda M, Carlos JB, Galera OA, et al. Correlation of cytomegalovirus DNA levels with response to antiviral therapy in
CZER, PHAN, RUZZA ET AL cardiac and renal allograft recipients. Transplantaion. 1997;63(7): 957e963. 26. Carlsen J, Johansen M, Boesgaard S, et al. Induction therapy after cardiac transplantation: a comparison of anti-thymocyte globulin and daclizumab in the prevention of acute rejection. J Heart Lung Transplant. 2005;24(3):296e302. 27. Schnetzler B, Leger P, Volp A, Dorent R, Pavie A, Gandjbakhch I. A prospective randomized controlled study on the efficacy and tolerance of two antilymphocytic globulins in the prevention of rejection in first-heart transplant recipients. Transplant Int. 2002;15(6):317e325. 28. Bonaros N, Dunkler D, Kocher A, et al. Ten-year follow-up of a prospective, randomized trial of BT563/bb10 versus antithymocyte globulin as induction therapy after heart transplantation. J Heart Lung Transplant. 2006;25(9):1154e1163. 29. Carrier M, Jenicek M, Pelletier LC. Value of monoclonal antibody OKT3 in solid organ transplantation: a meta-analysis. Transplant Proc. 1992;24(6):2586e2591. 30. Chien NC, Lin FL, Chou NK, et al. Rabbit antithymocyte globulin induction immunosuppression in heart transplantation. Transplant Proc. 2000;32(7):2380e2382. 31. Higgins R, Kirklin JK, Brown RN, et al. To induce or not to induce: do patients at greatest risk for fatal rejection benefit from cytolytic induction therapy? J Heart Lung Transplant. 2005;24(4): 392e400. 32. Emin A, Rogers CA, Thekkudan J, Bonser RS, Banner NR; Steering Group UKCTA. Antithymocyte globulin induction therapy for adult heart transplantation: a UK national study. J Heart Lung Transplant. 2011;30(7):770e777. 33. Yagdi T, Sharples L, Tsui S, Large S, Parameshwar J. Malignancy after heart transplantation: analysis of 24-year experience at a single center. J Cardiac Surg. 2009;24(5):572e579. 34. Swinnen LJ, Costanzo-Nordin MR, Fisher SG, et al. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients. N Engl J Med. 1990;323(25): 1723e1728.
A
NTITHYMOCYTE globulin (ATG) is a polyclonal antibody preparation that depletes T lymphocytes and has multiple immunologic targets.1 ATG is the most commonly used agent for induction therapy after heart transplantation, although its routine use remains controversial. Guidelines from the International Society for Heart and Lung Transplantation (ISHLT) have not endorsed routine use for ATG after heart transplantation,2 although
From the Divisions of Cardiology (L.S.C.C., A.P., M.R., S.S.-S., M.A., C.S.) and Cardiothoracic Surgery (A.R., M.C., M.D.R., R.M.K., A.T.), Cedars-Sinai Heart Institute, and the Section of Biostatistics (J.M.), Cedars-Sinai Medical Center, Los Angeles, California, USA. Address reprint requests to Lawrence S.C. Czer, MD, Medical Director, Heart Transplant Program, 8700 Beverly Blvd., Los Angeles, CA 90048. E-mail: [email protected]
ª 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.02.114
Transplantation Proceedings, 45, 2393e2398 (2013)
2393
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more than half of adult heart transplant recipients receive induction therapy, including ATG.3 There remains a lack of long-term outcome data on the use of ATG induction therapy in heart transplant recipients. This study was performed to determine the effects of intravenous ATG induction therapy after heart transplantation. A review of our center’s experience was conducted to evaluate the effects on rejection, renal function, lymphocyte depletion and recovery, cytomegalovirus (CMV) infection, malignancy, and survival. METHODS Patients undergoing heart transplantation from January 2000 through January 2010 at our institution who received ATG induction therapy were reviewed. Patients received ATG at a dose of 1.5 mg/kg for either 5 days (ATG5) or 7 days (ATG7), with the dose adjusted for white blood cell (WBC) and platelet counts. Criteria for patients receiving ATG7 were those considered to be at higher risk for rejection, including younger patients (younger than 60 years of age), multiparous females, African Americans, patients with an elevated panel-reactive antibody (PRA) level (>10%), and those with a positive retrospective or prospective donor-recipient crossmatch. Multiorgan transplant recipients were excluded from the study. Heart transplantation was performed using the bicaval technique as described previously.4e13
Maintenance Immunosuppressive Therapy Maintenance immunosuppression included cyclosporine or tacrolimus, mycophenolate mofetil, and corticosteroids. After a 5-day course of ATG, cyclosporine was initiated at 50 mg orally every 12 hours when the creatinine level was <2 mg/dL, and was adjusted to achieve a whole blood level of 200 to 400 ng/mL in the first three months, and 100 to 200 ng/mL thereafter. After a 7-day course of ATG, tacrolimus was initiated at 2 mg orally every 12 hours when the creatinine level was <2 mg/dL, and was adjusted to achieve a whole blood level of 10 to 20 ng/mL in the first three months, and 6 to 10 ng/mL thereafter. Mycophenolate mofetil was started at 250 mg twice daily and increased to a target dose of 1 g twice daily (with cyclosporine) and 500 mg twice daily (with tacrolimus), and adjusted according to the WBC count, platelet count, and gastrointestinal tolerance. In patients who could not tolerate mycophenolate mofetil due to gastrointestinal side effects, azathioprine was given at a dose of 2 mg/kg and adjusted according to the WBC count platelet count. Patients were administered methylprednisolone intravenously during induction therapy (500 mg on the first day, then 125 mg daily), and were transitioned to oral prednisone at 0.5 mg/kg/d, and tapered sequentially over 3e12 months after two negative (0 or 1A-1R) endomyocardial biopsies, until they were off prednisone.14,15
CZER, PHAN, RUZZA ET AL endothelial cell swelling and intravascular macrophage accumulation, with or without interstitial hemorrhage and edema, and positive immunofluorescence or immunoperoxidase staining for a complement component (C1q, C3a, or C4d) with or without an immunoglobulin (IgG, IgM, or IgA). AMR was graded according to published criteria.18e20 CR was treated if it was grade 3A/2R or greater, and occasionally if it was a lower grade in association with hemodynamic compromise. AMR was treated if it was definite or greater. Patients who experienced CR or AMR were administered a pulse of methylprednisolone (10 mg/kg/d for 3 days). If there was CR or AMR with evidence of hemodynamic compromise (systolic blood pressure <90 mm Hg without inotropic support, or requiring inotropic or mechanical support, or cardiac index <1.8), patients also received a 5-day course of ATG (1.5 mg/kg/d, adjusted according to the WBC and platelet counts). Patients with AMR additionally received sucrose-free intravenous immunoglobulin (IVIG) 10% at 1 gm/kg on two consecutive days.21e23
Antiviral Prophylaxis All patients received antiviral prophylaxis.24 CMV seropositive recipients received intravenous ganciclovir (5 mg/kg every 12 hours and adjusted for renal function, WBC count, and platelet count) for 10 days, followed by oral acyclovir until 6 months postoperatively. Seronegative recipients of a seropositive donor (or seronegative recipients with seronegative donors but with unscreened blood; or seropositive recipients with prolonged hospitalization, ventilatordependent for prolonged duration, recurrent or severe rejection, or readmission for complication) received ganciclovir (5 mg/kg every 12 hours and adjusted for renal function, WBC count, and platelet count) for 10 days, followed by oral ganciclovir or valganciclovir until one year after heart transplantation. Seronegative recipients with a seronegative donor (and no unscreened blood products) received oral acyclovir until 6 months post-transplantation. CMV DNA was monitored using polymerase chain reaction (PCR) at periodic intervals during and after completion of prophylaxis, and when recurrence of CMV was suspected.25 Prophylaxis was repeated after treated rejection episodes requiring pulse steroid therapy or ATG.
Statistical Analysis Continuous variable results were presented as mean standard deviation, and were compared using a t test. Categorical variables were presented as frequency, and were compared across groups using chi-square or Fisher exact test. Numerical variables were compared using Wilcoxon rank sum test. Kaplan-Meier curves were constructed for time-related events of rejection or death. Mean followup time was 2.75 years. The log-rank test was used to compare survival across groups. All statistical tests were 2-sided, and P < .05 was considered significant. Statistical analysis was performed using SAS 9.1 software (SAS Institute Inc., Cary, NC, USA).
Endomyocardial Biopsies and Assessment of Rejection Endomyocardial biopsies after heart transplantation were initiated within two to five days after completion of ATG therapy and at weekly intervals for 3 weeks, then every other week twice, then monthly 2, every other month 2, every 4 months 1, every 6 months 2, and yearly up to 3 years, or when clinically indicated for suspected rejection.14,15 Biopsy specimens were assessed for both cellular rejection (CR) and antibody-mediated rejection (AMR) using histology and immunostaining. CR was graded according to the classification of the ISHLT.16,17 AMR was defined as histological evidence of capillary
RESULTS
A total of 253 heart transplant recipients were included in the study, with a mean age of 56.4 11.8 years. Of note, 24% were female, 15% were African American, 58% had an ischemic etiology, 49% had hypertension, 27% had diabetes mellitus, and 67% had positive donor serology for CMV. Baseline creatinine level was 1.3 0.8 mg/dL before heart transplantation, and mean peak creatinine level was 1.8 0.9 mg/dL after heart transplantation. The discharge
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creatinine level was 1.0 0.4 mg/dL. There was a significant difference between baseline and discharge creatinine levels (P < .001). Baseline characteristics are shown in Table 1. A total of 87 heart transplant recipients received ATG for 5 days (ATG5), whereas 166 received ATG for 7 days (ATG7). Patients in the ATG7 group were younger and were more frequently female and African American, and less frequently seropositive for CMV. There was a higher prevalence of hyperlipidemia in the ATG5 group. Evidence of sensitization with a PRA > 10% was found in 19.5% (8/41) of the ATG5 group, and in 28.3% (17/60) of the ATG7 group. Absolute lymphocyte count <200 per microliter was achieved within 10 days in 88% of ATG5 and 86% of ATG7 patients. At 5 years, there was no significant difference between the ATG5 and ATG7 groups in freedom from CMV infection (92.3% vs 94.3%; P ¼ not significant [NS]), freedom from pneumonia (83.8% vs 82.1%; P ¼ [NS]), and rate of malignancy, excluding skin cancer (8.0% vs 6.0%; P ¼ NS). Of 3667 endomyocardial biopsies, 33 (0.90%) had grade 3A/2R CR. At 5 years, the freedom from 3A/2R CR between the ATG5 and ATG7 groups was comparable at 94% 2.8% and 83% 7.7%, respectively (P ¼ .31; Fig 1). Of 3599 biopsies, 16 (0.44%) had definite AMR. The rate of AMR at 5 years was also similar between the ATG5 and ATG7 groups at 95% 2.4% and 90% 6.4% (P ¼ .98; Fig 2). Survival curves are shown in Figure 3. Survival rates at 30 days were 97% 2.0% in the ATG5 group, and 98% 1.2% in the ATG7 group. At one year, survival rates for ATG5 and ATG7 were 94% 2.5% and 93% 2.0% and at 8 years were 61% 6.9% and 61% 4.7%, respectively (log-rank P ¼ .88).
DISCUSSION
There has been an increase in the use of induction therapy from 38% in 1997 to 52% in 2010.3 Early and long-term outcomes in heart transplant recipients treated with induction therapy and, in particular, ATG still remain unclear. The findings in this study reinforce those in other trials where the use of induction therapy resulted in a decreased risk of early rejection.26e28 A study comparing ATG induction therapy to no induction therapy found that patients treated with antithymocyte therapy had a lower rate of early rejection compared with those who did not receive induction therapy.29 Other studies using ATG induction therapy for 5 days showed freedom from rejection to be 80% at one year and 75% at four years.30 A prospective randomized trial comparing an interleukin-2 receptor antagonist and ATG induction therapy found that there was a significantly higher incidence of severe rejection in the group receiving interleukin-2 receptor antagonist over a 10-year follow-up (55% vs 10%; P ¼ .028).28 These results are in contrast with unadjusted data reported by the ISHLT showing a higher rate of rejection with induction therapy, probably related to the selection bias of patients at a higher risk of rejection to receive induction therapy and the multiplicity of agents included in the category of induction therapy (such as Orthoclone-OKT3 [Ortho Biotech, Raritan, NJ, USA] and interleukin-2 receptor antagonists). Immunologic effects of ATG therapy may also be more long-lasting than the acute phase after heart transplantation, with effects on lymphocyte populations lasting 6 months to one year.14 The current study by our group demonstrated that CR remained low at five years in patients who received ATG induction therapy, with a freedom from CR of 94% 2.8% in the ATG5 group and 83% 7.7% in the ATG7 group at 5 years (P ¼ .31; Fig 1). Furthermore,
Table 1. Clinical Characteristics of the Patients Characteristic
Recipient age, y Donor age, y Recipient female, % (n) Donor female, % (n) Gender mismatch, % (n) Race AA, % (n) Donor race AA, % (n) Ischemic etiology, % (n) UNOS Status, % (n) 1A 1B 2 Hypertension, % (n) Cholesterol, % (n) Diabetes mellitus, % (n) Recipient CMV, % (n) Donor CMV, % (n) Dialysis, % (n) Creatinine
All Patients (n ¼ 253)
ATG5 (n ¼ 87)
ATG7 (n ¼ 166)
P
<.0001 .065 .002 .008 .006 .026 .015 .069 .41
56.4 11.8 33.6 12.4 24.1 (61) 23.7 (60) 25.7 (65) 15.0 (38) 7.9 (20) 57.7 (146)
60.1 31.7 12.6 13.8 14.9 8.1 2.3 65.5
10.4 12.0 (11) (12) (13) (7) (2) (57)
54.4 12.0 34.6 12.5* 30.1 (50) 28.9 (48) 31.3 (52) 18.7 (31) 10.8 (18) 53.6 (89)
31.6 (80) 35.2 (89) 33.2 (84) 48.6 (123) 54.2 (137) 27.0 (68/252) 58.5 (148) 66.8 (145/217) 7.9 (20) 1.29 0.78
26.4 39.1 34.5 55.2 69.0 29.9 67.8 68.4 4.6 1.19
(23) (34) (30) (48) (60) (26) (59) (54/79) (4) 0.40
34.3 (57) 33.1 (55) 32.5 (54) 45.2 (75) 46.4 (77) 25.5 (42/165) 53.6 (89) 65.9 (91/138) 9.6 (16) 1.34 0.91
Abbreviations: AA, African American; UNOS, United Network for Organ Sharing.
.146 .0008 .45 .029 .72 .22 .064
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Fig 1. Freedom from CR. The ATG5 day group is depicted with a solid line, and the ATG7 day group with a dashed line. In the inset box are the rates of freedom from CR at 1, 2, 3, and 5 years in the ATG5 and ATG7 day groups. There was no significant difference between the ATG5 and ATG7 day groups in the freedom from CR (P ¼ .31).
Fig 3. Survival. The ATG5 day group is depicted with a solid line, and the ATG7 day group with a dashed line. In the inset box are the survival rates at 30 days, 1, 2, 3, 5, and 8 years in the ATG5 and ATG7 day groups. There was no significant difference between the ATG5 and ATG7 day groups in survival (P ¼ .88).
less than 1% of post-transplantation biopsies (33/3667 or 0.90%) had grade 3A/2R CR, a very low rate of biopsyproven rejection. Few studies have addressed the effects of induction therapy and, in particular, ATG on AMR. In the current study, AMR remained low at five years in patients who received ATG induction therapy, with a freedom from AMR of 95% 2.4% in the ATG5 group and 90% 6.4% in the ATG7 group at 5 years (P ¼ .98; Fig 2). Moreover,
less than 1% of post-transplantation biopsies (16/3599 or 0.44%) had definite AMR. This occurred despite sensitization with a PRA > 10% in 19.5% of the ATG5 group, and in 28.3% of the ATG7 group. The current study is the first to document a low incidence of AMR with ATG induction therapy and implies that ATG may have a role in preventing AMR. In the current study, immunologically high-risk patients were included in the ATG7 group, including younger patients (younger than 60 years of age), multiparous females, African Americans, patients with an elevated panel-reactive antibody level (>10%), and those with a positive retrospective or prospective donor-recipient cross-match. Despite this preponderance of higher-risk patients in the ATG7 group, the rates of CR and AMR (Fig 1 and Fig 2) and the short- and long-term survivals were similar in the ATG5 and ATG7 groups, implying that the longer course of ATG had an effect to “level the playing field” between the immunologically low- and high-risk patients in the ATG5 and ATG7 groups, respectively. Registry data report about an 80% and 70% survival rate at one and five years, respectively, after heart transplantation, and a median survival of 11 years.3 Our study demonstrates that ATG induction therapy does not have unfavorable effects on long-term survival with at least 72% of patients alive after 5 years in the ATG5 and ATG7 groups. A prospective randomized controlled trial to evaluate ATG-Fresenius and ATG-ThymoglobulinMerieux induction therapy in heart transplant recipients did not find a significant difference between the two agents, with an actuarial survival rate of 84.6% and 87.5% at one year, respectively.27 Higgins et al reviewed a multiinstitutional database to evaluate the impact of induction
Fig 2. Freedom from AMR. The ATG5 day group is depicted with a solid line, and the ATG7 day group with a dashed line. In the inset box are the rates of freedom from AMR at 1, 2, 3, and 5 years in the ATG5 and ATG7 day groups. There was no significant difference between the ATG5 and ATG7 day groups in the freedom from AMR (P ¼ .98).
ATG INDUCTION THERAPY
therapy on heart transplantation and found that over a 10-year period there was a higher survival rate in patients who did not receive induction therapy, with the difference in survival occurring during the first year after heart transplantation.31 In contrast, we found that the survival rate after one year was greater than 93% in both the ATG5 and ATG7 groups. The discrepancy between our findings and those reported by Higgins et al may be due to differences in induction therapy agents, because the majority of their patients who received induction therapy were treated with OKT3 in the Higgins study. Calcineurin inhibitors are now commonly used as part of triple drug immunosuppressive therapy regimens, although their nephrotoxic effects may cause complications in newly transplanted heart recipients. We have demonstrated that the use of ATG for induction therapy is effective in reducing absolute lymphocyte counts to allow adequate immunosuppression while delaying initiation of calcineurin inhibitors. This may prove to have significant effects on renal function because a significant decrease from baseline to discharge creatinine was demonstrated in patients treated with ATG. This is in agreement with a recent large-scale study demonstrating the renal-sparing effects of ATG induction therapy.32 Concern with the use of induction therapy includes not only increased rate of infection but also malignancies such as lymphoproliferative disorders. In our study, we were able to demonstrate that over the ten-year timeframe, the rate of CMV infection remained relatively low, affecting less than 8% of the transplanted population at five years. This may be due to the relatively aggressive prophylaxis for CMV (including treated rejection episodes) in the current study and the use of CMV monitoring using PCR.25 With regard to malignancy in posteheart transplantation recipients, a retrospective study performed by Yagdi et al33 found that 15.1% of patients developed a malignancy after heart transplantation, whereas in our study the use of ATG induction therapy resulted in 8% of patients developing a malignancy (excluding skin cancers). Choice of induction therapy may also affect the rate of malignancy, as Swinnen et al34 found an increased risk of post-transplantation lymphoproliferative disorder in patients treated with OKT3 (11.4% vs 1.3%). The purpose of this study was to present the outcomes of a contemporary group of heart transplant recipients receiving induction therapy with ATG during the last decade. The outcomes presented are favorable in a group of patients traditionally considered to have higher rates of rejection and decreased survival. However, limitations to this study have to be noted, particularly related to the inherent nature of a retrospective study. All patients were treated with ATG induction therapy and therefore, a control group without induction therapy was not available for a matched comparison. There were baseline clinical characteristic differences between the ATG5 and ATG7 groups due to the intentional selection of high-risk patients to receive ATG7.
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In conclusion, ATG induction therapy after heart transplantation resulted in excellent and equivalent short- and long-term survival rates, with a low incidence of CR and AMR. The use of ATG did not result in increased rates of CMV infection with appropriate prophylaxis. ATG may benefit renal function by delaying calcineurin inhibitor exposure during the early postoperative period after heart transplantation. REFERENCES 1. Preville X, Flacher M, LeMauff B, et al. Mechanisms involved in antithymocyte globulin immunosuppressive activity in a nonhuman primate model. Transplantation. 2001;71(3):460e468. 2. Costanzo MR, Dipchand A, Starling R, et al. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2010;29(8):914e956. 3. Stehlik J, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Twenty-eighth Adult Heart Transplant Reporte2011. J Heart Lung Transplant. 2011;30(10):1078e1094. 4. Blanche C, Czer LS, Valenza M, Trento A. Alternative technique for orthotopic heart transplantation. Ann Thorac Surg. 1994;57(3):765e767. 5. Blanche C, Valenza M, Aleksic I, Czer LS, Trento A. Technical considerations of a new technique for orthotopic heart transplantation. Total excision of recipient’s atria with bicaval and pulmonary venous anastomoses. J Cardiovasc Surg. 1994;35(4): 283e287. 6. Blanche C, Valenza M, Czer LS, et al. Orthotopic heart transplantation with bicaval and pulmonary venous anastomoses. Ann Thorac Surg. 1994;58(5):1505e1509. 7. Czer LS, Cohen MH, Gallagher SP, et al. Exercise performance comparison of bicaval and biatrial orthotopic heart transplant recipients. Transplant Proc. 2011;43(10):3857e3862. 8. Trento A, Czer LS, Blanche C. Surgical techniques for cardiac transplantation. Semin Thorac Cardiovasc Surg. 1996;8(2): 126e132. 9. Trento A, Takkenberg JM, Czer LS, et al. Clinical experience with one hundred consecutive patients undergoing orthotopic heart transplantation with bicaval and pulmonary venous anastomoses. J Thorac Cardiovasc Surg. 1996;112(6):1496e1502. 10. Doering LV, Dracup K, Moser DK, Czer LS, Peter CT. Hemodynamic adaptation to orthostatic stress after orthotopic heart transplantation. Heart Lung. 1996;25(5):339e351. 11. Doering LV, Dracup K, Moser DK, Czer LS, Peter CT. Evidence of time-dependent autonomic reinnervation after heart transplantation. Nurs Res. 1999;48(6):308e316. 12. Freimark D, Czer LS, Aleksic I, et al. Improved left atrial transport and function with orthotopic heart transplantation by bicaval and pulmonary venous anastomoses. Am Heart J. 1995;130(1):121e126. 13. Freimark D, Silverman JM, Aleksic I, et al. Atrial emptying with orthotopic heart transplantation using bicaval and pulmonary venous anastomoses: a magnetic resonance imaging study. J Am Coll Cardiol. 1995;25(4):932e936. 14. Goland S, Czer LS, Coleman B, et al. Induction therapy with thymoglobulin after heart transplantation: impact of therapy duration on lymphocyte depletion and recovery, rejection, and cytomegalovirus infection rates. J Heart Lung Transplant. 2008;27(10): 1115e1121. 15. Daneshvar D, Czer LS, Phan A, et al. Heart transplantation in patients aged 70 years and older: a two-decade experience. Transplant Proc. 2011;43(10):3851e3856. 16. Billingham ME, Cary NR, Hammond ME, et al. A working formulation for the standardization of nomenclature in the
2398 diagnosis of heart and lung rejection: Heart Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant. 1990;9(6):587e593. 17. Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant. 2005;24(11):1710e1720. 18. Kobashigawa J, Crespo-Leiro MG, Ensminger SM, et al. Report from a consensus conference on antibody-mediated rejection in heart transplantation. J Heart Lung Transplant. 2011;30(3): 252e269. 19. Tan CD, Baldwin WM 3rd, Rodriguez ER. Update on cardiac transplantation pathology. Arch Pathol Lab Med. 2007;131(8): 1169e1191. 20. Lones MA, Czer LS, Trento A, Harasty D, Miller JM, Fishbein MC. Clinical-pathologic features of humoral rejection in cardiac allografts: a study in 81 consecutive patients. J Heart Lung Transplant. 1995;14(1 Pt 1):151e162. 21. Goland S, Czer LS, Siegel RJ, et al. Intravenous immunoglobulin treatment for acute fulminant inflammatory cardiomyopathy: series of six patients and review of literature. Can J Cardiol. 2008;24(7):571e574. 22. Jordan SC, Quartel AW, Czer LS, et al. Posttransplant therapy using high-dose human immunoglobulin (intravenous gammaglobulin) to control acute humoral rejection in renal and cardiac allograft recipients and potential mechanism of action. Transplantation. 1998;66(6):800e805. 23. Jordan SC, Tyan D, Czer L, Toyoda M. Immunomodulatory actions of intravenous immunoglobulin (IVIG): potential applications in solid organ transplant recipients. Pediatric Transplant. 1998;2(2):92e105. 24. Czer LS, Ruzza A, Vespignani R, et al. Prophylaxis of cytomegalovirus disease in mismatched patients after heart transplantation using combined antiviral and immunoglobulin therapy. Transplant Proc. 2011;43(5):1887e1892. 25. Toyoda M, Carlos JB, Galera OA, et al. Correlation of cytomegalovirus DNA levels with response to antiviral therapy in
CZER, PHAN, RUZZA ET AL cardiac and renal allograft recipients. Transplantaion. 1997;63(7): 957e963. 26. Carlsen J, Johansen M, Boesgaard S, et al. Induction therapy after cardiac transplantation: a comparison of anti-thymocyte globulin and daclizumab in the prevention of acute rejection. J Heart Lung Transplant. 2005;24(3):296e302. 27. Schnetzler B, Leger P, Volp A, Dorent R, Pavie A, Gandjbakhch I. A prospective randomized controlled study on the efficacy and tolerance of two antilymphocytic globulins in the prevention of rejection in first-heart transplant recipients. Transplant Int. 2002;15(6):317e325. 28. Bonaros N, Dunkler D, Kocher A, et al. Ten-year follow-up of a prospective, randomized trial of BT563/bb10 versus antithymocyte globulin as induction therapy after heart transplantation. J Heart Lung Transplant. 2006;25(9):1154e1163. 29. Carrier M, Jenicek M, Pelletier LC. Value of monoclonal antibody OKT3 in solid organ transplantation: a meta-analysis. Transplant Proc. 1992;24(6):2586e2591. 30. Chien NC, Lin FL, Chou NK, et al. Rabbit antithymocyte globulin induction immunosuppression in heart transplantation. Transplant Proc. 2000;32(7):2380e2382. 31. Higgins R, Kirklin JK, Brown RN, et al. To induce or not to induce: do patients at greatest risk for fatal rejection benefit from cytolytic induction therapy? J Heart Lung Transplant. 2005;24(4): 392e400. 32. Emin A, Rogers CA, Thekkudan J, Bonser RS, Banner NR; Steering Group UKCTA. Antithymocyte globulin induction therapy for adult heart transplantation: a UK national study. J Heart Lung Transplant. 2011;30(7):770e777. 33. Yagdi T, Sharples L, Tsui S, Large S, Parameshwar J. Malignancy after heart transplantation: analysis of 24-year experience at a single center. J Cardiac Surg. 2009;24(5):572e579. 34. Swinnen LJ, Costanzo-Nordin MR, Fisher SG, et al. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients. N Engl J Med. 1990;323(25): 1723e1728.