Immunosuppression in pediatric heart transplantation: 2003 and beyond

  • Subash C. Reddy
  • Karen Laughlin
  • Steven A. Webber

Opinion statement

Advances in immunosuppressive therapy have contributed to the improved long-term survival of pediatric heart transplant recipients over the past two decades. The introduction of cyclosporine in the early 1980s (the first oral agent to selectively target T-lymphocyte pathways) led to a dramatic reduction in acute rejection rates and improved graft and patient survival. A combination of cyclosporine, azathioprine, and corticosteroids (“triple therapy”) became the standard of care for pediatric and adult heart transplantation. The introduction of several new agents in the past decade has resulted in an almost infinite number of potential immunosuppressive regimens, none of which have been (or are likely to be) tested in randomized clinical trials in children. Tacrolimus is replacing cyclosporine as the primary calcineurin inhibitor in many programs. Mycophenolate mofetil, despite its increased cost, is likely to replace azathioprine as the adjunctive antimetabolite of choice in heart transplantation. Furthermore, target of rapamycin inhibitors, such as sirolimus, will likely be used in lieu of antimetabolite agents if their known myointimal antiproliferative effects are demonstrated to reduce or prevent graft vasculopathy (chronic rejection) in humans. With the availability of more potent immunosuppressive agents, early steroid withdrawal or complete steroid avoidance will become the standard of care in most pediatric transplant programs. Complete avoidance of steroids can be facilitated by the use of induction therapy with polyclonal anti-T-cell antibodies (eg, rabbit antithymocyte globulin [Thymoglobulin; SangStat Medical Corp., Fremont, CA]) or with the use of nondepleting antibodies that block the interleukin-2 receptor (eg, basiliximab, daclizumab). All these agents appear to have a good safety profile and are likely to lead to a resurgence of interest in induction therapy as a strategy to avoid chronic use of corticosteroids in children. As the elucidation of immunosuppressive pathways continues to advance, many newer immunosuppressive agents will be developed that target specific critical pathways in the immune response to the allograft. These advances should lead to more focused immunosuppression, greater drug synergism, reduction in the doses of individual agents, steroid-sparing regimens, and reduction in end-organ toxicities. The ultimate goal will be to define a perioperative therapeutic regimen that will result in a state of “transplantation tolerance,” in which the patient will indefinitely accept their allograft without the need for chronic immunosuppressive therapy.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Taylor DO: Immunosuppressive therapies after heart transplantation: best, better, and beyond. Curr Opin Cardiol 2000, 15:108–115.PubMedCrossRefGoogle Scholar
  2. 2.
    Boucek RJ, Boucek MM: Pediatric heart transplantation. Curr Opin Pediatr 2002, 14:611–619.PubMedCrossRefGoogle Scholar
  3. 3.
    Pietra B, Boucek M: Immunosuppression for pediatric cardiac transplantation in the modern era. Prog Pediatr Cardiol 2000, 11:115–129. Covers mechanisms of action—pharmacology as well as clinical application of immunosuppressive therapy—in the pediatric heart transplant population.PubMedCrossRefGoogle Scholar
  4. 4.
    Nevins TE: Overview of new immunosuppressive therapies. Curr Opin Pediatr 2000, 12:146–150.PubMedCrossRefGoogle Scholar
  5. 5.
    Shah MB, Schroeder TJ, First MR: Guidelines for immunosuppression management and monitoring after transplantation in children. Transplant Rev 1999, 2:83–97.CrossRefGoogle Scholar
  6. 6.
    Gaber AO, First MR, Tesi RJ, et al.: Results of the double blind, randomized, multi-center phase III clinical trial of thymoglobulin versus ATGAM in the treatment of acute graft rejection episodes after renal transplantation. Transplantation 1998, 66:29–37.PubMedCrossRefGoogle Scholar
  7. 7.
    Kahan BD, Rajagopalan PR, Hall MI: Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric anti-interleukin 2 receptor monoclonal antibody. Transplantation 1999, 67:276–284.PubMedCrossRefGoogle Scholar
  8. 8.
    Beniaminovitz A, Itescu S, Lietz K, et al.: Prevention of rejection in cardiac transplantation by blockade of the interleukin-2 receptor with a monoclonal antibody. N Engl J Med 2000, 342:613–619. This small (55 patients) but important study in adult heart transplant recipients showed that induction therapy with daclizumab safely reduces the frequency and severity of cardiac-allograft rejection during the induction period.PubMedCrossRefGoogle Scholar
  9. 9.
    Vincenti F, Kirkman R, Light S: Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. N Engl J Med 1998, 338:161–165.PubMedCrossRefGoogle Scholar
  10. 10.
    Gilbert EM, Dewitt CW, Eiswirth CC, et al.: Treatment of refractory cardiac allograft rejection with OKT3 monoclonal antibody. Am J Med 1987, 82:202–206.PubMedCrossRefGoogle Scholar
  11. 11.
    Thymoglobulin (antithymocyte globulin [rabbit] [prescribing information]. Menlo Park, CA: SangStat Medical Corporation; 1998.Google Scholar
  12. 12.
    Poston RS, Billingham L, Hoyt EG, et al.: Rapamycin reverses chronic graft vascular disease in a novel cardiac allograft model. Circulation 1999, 100:67–74.PubMedGoogle Scholar
  13. 13.
    Radley-Smith RC, Yacoub MH: Long-term results of pediatric heart transplantation. J Heart Lung Transplant 1992, 11:S227-S281.Google Scholar
  14. 14.
    Au J, Gregory JW, Colquhoun IW, et al.: Paediatric cardiac transplantation with steroid-sparing maintenance immunosuppression. Arch Dis Child 1992, 67:1262–1266.PubMedCrossRefGoogle Scholar
  15. 15.
    Canter CE, Moorhead S, Saffitz JE, et al.: Steroid withdrawal in the pediatric heart transplant recipient initially treated with triple immunosuppression. J Heart Lung Transplant 1994, 13:74–80.PubMedGoogle Scholar
  16. 16.
    Boucek MM, Edwards LB, Keck BM, et al.: The Registry of the International Society for Heart and Lung Transplantation: fifth official pediatric report—2001 to 2002. J Heart Lung Transplant 2002, 21:826–938. This detailed annual report focuses on survival and risk factors for survival after pediatric heart transplantation. Although efficacy of immunosuppressive agents cannot be established from this registry, current use of various immunosuppressive agents is described.Google Scholar
  17. 17.
    Ritschel WA: Microemulsion technology in the reformulation of cyclosporine: the reason behind the pharmacokinetic properties of Neoral. Clinic Transplant 1996, 10:364–373.Google Scholar
  18. 18.
    Hoyer PF, Boekenkamp A, Vester U, et al.: Conversion from Sandimmune to Neoral in pediatric renal transplant recipients. Transplant Proc 1996, 26:2259–2261.Google Scholar
  19. 19.
    Webber SA: Fifteen years of pediatric heart transplantation at the university of Pittsburgh: lessons learned and future prospects. Pediatr Transplant 1997, 1:8–21.PubMedGoogle Scholar
  20. 20.
    Keown P: New concepts in cyclosporine monitoring. Curr Opin Nephrol Hypertens 2002, 11:619–626. Emphasizes the evolving consensus on how to optimally monitor cyclosporine levels. The rationale behind increasing use of C2 monitoring is clearly explained.PubMedCrossRefGoogle Scholar
  21. 21.
    Pirsch JD, Miller J, Deierhoi MH, et al.: A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. Transplantation 1997, 63:977–983.PubMedCrossRefGoogle Scholar
  22. 22.
    A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. The U.S. Multicenter FK506 Liver Study Group [no authors listed]. N Engl J Med 1994, 331:1110–1115.Google Scholar
  23. 23.
    Asante-Korang A, Boyle GA, Webber SA, et al.: Experience of FK506 immune suppression in pediatric heart transplantation: study of long term adverse effects. J Heart Lung Transplant 1996, 15:415–422.PubMedGoogle Scholar
  24. 24.
    Robinson BV, Boyle GJ, Miller SA, et al.: Optimal dosing of intravenous tacrolimus following pediatric heart transplantation. J Heart Lung Transplant 1999, 18:786–791.PubMedCrossRefGoogle Scholar
  25. 25.
    Taylor DO, Barr ML, Radovancevic B, et al.: A randomized, multicenter comparison of tacrolimus and cyclosporine immunosuppressive regimens in cardiac transplantation: decreased hyperlipidemia and hypertension with tacrolimus. J Heart Lung Transplant 1999, 18:336–345.PubMedCrossRefGoogle Scholar
  26. 26.
    McGhee B, McCombs JR, Boyle G, et al.: Therapeutic use of an extemporaneously prepared oral suspension of tacrolimus in pediatric patients. Transplantation 1997, 64:941–942.PubMedCrossRefGoogle Scholar
  27. 27.
    Dipchand AI, Benson L, McCrindle BW, et al.: Mycophenolate mofetil in pediatric heart transplant recipients: a single-center experience. Pediatr Transplant 2001, 5:112–118.PubMedCrossRefGoogle Scholar
  28. 28.
    Kobashigawa J, Miller L, Renlund D, et al.: A randomized active-controlled trial of mycophenolic mofetil in heart transplant recipients. Transplantation 1998, 66:507–515.PubMedCrossRefGoogle Scholar
  29. 29.
    Kahan BD: Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomized multicenter study. The Rapamune US Study Group. Lancet 2000, 356:194–202.PubMedCrossRefGoogle Scholar
  30. 30.
    McAlister VC, Gao Z, Peltekian K, et al.: Sirolimustacrolimus combination immunosuppression [letter]. Lancet 2000, 355:376–377.PubMedCrossRefGoogle Scholar
  31. 31.
    Sindhi R, Webber SA, Venkataramanan R, et al.: Sirolimus for rescue and primary immunosuppression in transplanted children receiving tacrolimus. Transplantation 2001, 72:851–855. One of the first reports of experience with sirolimus in a large (n = 50) cohort of children who have undergone solid-organ transplantation. This report confirmed adult studies showing that sirolimus can be effectively used with tacrolimus-based immunosuppression.PubMedCrossRefGoogle Scholar
  32. 32.
    Paolillo J, Boyle GJ, Law Y, et al.: Post-transplant diabetes mellitus in pediatric thoracic organ recipients receiving tacrolimus-based immunosuppression. Transplantation 2001, 71:252–256.PubMedCrossRefGoogle Scholar
  33. 33.
    Pahl E, Zales VR, Fricker FJ, Addonizzio LJ: Post transplant coronary artery disease in children. A multi-center national survey. Circulation 1994, 90:II56-II60.PubMedGoogle Scholar
  34. 34.
    Schroeder JS, Gao SZ, Alderman EL, et al.: A preliminary study of diltiazem in the prevention of coronary artery disease in heart transplant recipients. N Engl J Med 1993, 328:164–170.PubMedCrossRefGoogle Scholar
  35. 35.
    Kobashigawa JA, Katznelson S, Laks H, et al.: Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995, 10:621–627.CrossRefGoogle Scholar
  36. 36.
    Webber SA, Naftel DC, Parker J, et al.: Late rejection episodes greater than 1 year after pediatric heart transplantation: risk factors and outcomes. J Heart Lung Transplant 2003, in press.Google Scholar
  37. 37.
    Morice MC, Serruys PW, Sousa JE, et al.: A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002, 346:1773–1780.PubMedCrossRefGoogle Scholar
  38. 38.
    Kirklin JK, George JF, McGriffin DC, et al.: Total lymphoid irradiation: is there a role in pediatric heart transplantation? J Heart Lung Transplant 1993, 12:S293-S300.PubMedGoogle Scholar
  39. 39.
    Barr ML, Meiser BM, Eisen HJ, et al.: Photopheresis for the prevention of rejection in cardiac transplantation. N Engl J Med 1998, 339:1744–1751.PubMedCrossRefGoogle Scholar
  40. 40.
    Klupp J, Morris RE: Unapproved non-biologic agents. In Pediatric Solid Organ Transplantation. Edited by Tejani AH, et al. Copenhagen: Munksgaard; 2000:121–134.Google Scholar
  41. 41.
    Kirk A: Immunosuppression without immunosuppression? How to be a tolerant individual in a dangerous world. Transplant Infect Dis 1999, 1:65–75.CrossRefGoogle Scholar

Copyright information

© Current Science Inc 2003

Authors and Affiliations

  • Subash C. Reddy
  • Karen Laughlin
  • Steven A. Webber
    • 1
  1. 1.Transplantation ProgramChildren’s Hospital of PittsburghPittsburghUSA

Personalised recommendations