Maintenance immunosuppression following lung transplantation
- Sangeeta Bhorade, MD
Sangeeta Bhorade, MD
- Professor of Medicine, Medical Director, Lung Transplant Program
- Northwestern University Feinberg School of Medicine
- Robert M Kotloff, MD
Robert M Kotloff, MD
- Chairman, Department of Pulmonary Medicine
- Respiratory Institute Cleveland Clinic
Maintenance immunosuppressive therapy is administered to all lung transplant recipients to help prevent acute and chronic rejection and the loss of the lung allograft. . Substantial progress has been made in developing immunosuppressive regimens to prevent acute and chronic rejection, while trying to reduce the side effects of immunosuppression . However, despite improvements in immunosuppressive therapy, acute and chronic transplant rejection remain important obstacles to successful lung transplantation.
The protocols for immunosuppressive therapy following lung transplantation can be divided into three general categories: induction, maintenance, and treatment of rejection. Strategies for maintenance of immunosuppression in the lung transplant recipient will be reviewed here. The role of induction agents in immunosuppression, general issues related to lung transplantation, the immunology of sold organ transplantation, and the diagnosis and treatment of acute and chronic lung transplant rejection are discussed separately. (See "Induction immunosuppression following lung transplantation" and "Lung transplantation: An overview" and "Transplantation immunobiology" and "Evaluation and treatment of acute lung transplant rejection" and "Chronic lung transplant rejection: Bronchiolitis obliterans".)
Three general principles underlie immunosuppressive therapy following lung transplantation:
●The first principle is that immune reactivity and the tendency toward graft rejection are highest early (within the first three to six months) after graft implantation and decrease with time. Thus, most regimens employ the highest intensity of immunosuppression immediately after surgery and decrease the intensity of therapy over the first year, eventually settling on the lowest maintenance levels of immunosuppression that are compatible with preventing graft rejection while minimizing drug toxicities.
●The second principle is to use low doses of several drugs with non-overlapping toxicities in preference over higher (and more toxic) doses of fewer drugs whenever feasible. Combination regimens are also better able to block the complex immunological cascade that leads to allograft rejection.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Blumenstock DA, Lewis C. The first transplantation of the lung in a human revisited. Ann Thorac Surg 1993; 56:1423.
- Chambers DC, Yusen RD, Cherikh WS, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-fourth Adult Lung And Heart-Lung Transplantation Report-2017; Focus Theme: Allograft ischemic time. J Heart Lung Transplant 2017; 36:1047.
- Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N Engl J Med 2005; 353:1711.
- Barnes PJ. How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol 2006; 148:245.
- Bhorade SM, Stern E. Immunosuppression for lung transplantation. Proc Am Thorac Soc 2009; 6:47.
- Shitrit D, Bendayan D, Sulkes J, et al. Successful steroid withdrawal in lung transplant recipients: result of a pilot study. Respir Med 2005; 99:596.
- Borro JM, Solé A, De la Torre M, et al. Steroid withdrawal in lung transplant recipients. Transplant Proc 2005; 37:3991.
- Keenan RJ, Konishi H, Kawai A, et al. Clinical trial of tacrolimus versus cyclosporine in lung transplantation. Ann Thorac Surg 1995; 60:580.
- Treede H, Klepetko W, Reichenspurner H, et al. Tacrolimus versus cyclosporine after lung transplantation: a prospective, open, randomized two-center trial comparing two different immunosuppressive protocols. J Heart Lung Transplant 2001; 20:511.
- Zuckermann A, Reichenspurner H, Birsan T, et al. Cyclosporine A versus tacrolimus in combination with mycophenolate mofetil and steroids as primary immunosuppression after lung transplantation: one-year results of a 2-center prospective randomized trial. J Thorac Cardiovasc Surg 2003; 125:891.
- Hachem RR, Yusen RD, Chakinala MM, et al. A randomized controlled trial of tacrolimus versus cyclosporine after lung transplantation. J Heart Lung Transplant 2007; 26:1012.
- Sarahrudi K, Carretta A, Wisser W, et al. The value of switching from cyclosporine to tacrolimus in the treatment of refractory acute rejection and obliterative bronchiolitis after lung transplantation. Transpl Int 2002; 15:24.
- Bhorade SM, Jordan A, Villanueva J, et al. Comparison of three tacrolimus-based immunosuppressive regimens in lung transplantation. Am J Transplant 2003; 3:1570.
- Toronto Lung Transplant Group. Unilateral lung transplantation for pulmonary fibrosis. N Engl J Med 1986; 314:1140.
- Kahan BD. Cyclosporine: a revolution in transplantation. Transplant Proc 1999; 31:14S.
- Parekh K, Trulock E, Patterson GA. Use of cyclosporine in lung transplantation. Transplant Proc 2004; 36:318S.
- Knoop C, Haverich A, Fischer S. Immunosuppressive therapy after human lung transplantation. Eur Respir J 2004; 23:159.
- Monchaud C, Marquet P. Pharmacokinetic optimization of immunosuppressive therapy in thoracic transplantation: part I. Clin Pharmacokinet 2009; 48:419.
- Briffa N, Morris RE. New immunosuppressive regimens in lung transplantation. Eur Respir J 1997; 10:2630.
- Kahan BD. Cyclosporine. N Engl J Med 1989; 321:1725.
- Kahan BD, Dunn J, Fitts C, et al. Reduced inter- and intrasubject variability in cyclosporine pharmacokinetics in renal transplant recipients treated with a microemulsion formulation in conjunction with fasting, low-fat meals, or high-fat meals. Transplantation 1995; 59:505.
- International Society for Heart Lung Transplantation, Adult lung transplantation statistics, 2014. https://www.ishlt.org/registries/slides.asp?slides=heartLungRegistry.
- Valapour M, Skeans MA, Heubner BM, et al. OPTN/SRTR 2013 Annual Data Report: lung. Am J Transplant 2015; 15 Suppl 2:1.
- Scott LJ, McKeage K, Keam SJ, Plosker GL. Tacrolimus: a further update of its use in the management of organ transplantation. Drugs 2003; 63:1247.
- Watkins KD, Boettger RF, Hanger KM, et al. Use of sublingual tacrolimus in lung transplant recipients. J Heart Lung Transplant 2012; 31:127.
- Doligalski CT, Liu EC, Sammons CM, et al. Sublingual administration of tacrolimus: current trends and available evidence. Pharmacotherapy 2014; 34:1209.
- Collin C, Boussaud V, Lefeuvre S, et al. Sublingual tacrolimus as an alternative to intravenous route in patients with thoracic transplant: a retrospective study. Transplant Proc 2010; 42:4331.
- Penninga L, Penninga EI, Møller CH, et al. Tacrolimus versus cyclosporin as primary immunosuppression for lung transplant recipients. Cochrane Database Syst Rev 2013; :CD008817.
- Treede H, Glanville AR, Klepetko W, et al. Tacrolimus and cyclosporine have differential effects on the risk of development of bronchiolitis obliterans syndrome: results of a prospective, randomized international trial in lung transplantation. J Heart Lung Transplant 2012; 31:797.
- Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: twenty-seventh official adult lung and heart-lung transplant report--2010. J Heart Lung Transplant 2010; 29:1104.
- Palmer SM, Baz MA, Sanders L, et al. Results of a randomized, prospective, multicenter trial of mycophenolate mofetil versus azathioprine in the prevention of acute lung allograft rejection. Transplantation 2001; 71:1772.
- McNeil K, Glanville AR, Wahlers T, et al. Comparison of mycophenolate mofetil and azathioprine for prevention of bronchiolitis obliterans syndrome in de novo lung transplant recipients. Transplantation 2006; 81:998.
- Allison AC. Mechanisms of action of mycophenolate mofetil. Lupus 2005; 14 Suppl 1:s2.
- Morris RE, Hoyt EG, Murphy MP, et al. Mycophenolic acid morpholinoethylester (RS-61443) is a new immunosuppressant that prevents and halts heart allograft rejection by selective inhibition of T- and B-cell purine synthesis. Transplant Proc 1990; 22:1659.
- Kobashigawa JA, Renlund DG, Gerosa G, et al. Similar efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS, myfortic) compared with mycophenolate mofetil (MMF) in de novo heart transplant recipients: results of a 12-month, single-blind, randomized, parallel-group, multicenter study. J Heart Lung Transplant 2006; 25:935.
- Taylor AL, Watson CJ, Bradley JA. Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy. Crit Rev Oncol Hematol 2005; 56:23.
- Poppe D, Tiede I, Fritz G, et al. Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-APC conjugation through inhibition of Vav guanosine exchange activity on Rac proteins. J Immunol 2006; 176:640.
- Tiede I, Fritz G, Strand S, et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest 2003; 111:1133.
- Zuckermann A, Klepetko W, Birsan T, et al. Comparison between mycophenolate mofetil- and azathioprine-based immunosuppressions in clinical lung transplantation. J Heart Lung Transplant 1999; 18:432.
- Ross DJ, Waters PF, Levine M, et al. Mycophenolate mofetil versus azathioprine immunosuppressive regimens after lung transplantation: preliminary experience. J Heart Lung Transplant 1998; 17:768.
- Speich R, Schneider S, Hofer M, et al. Mycophenolate mofetil reduces alveolar inflammation, acute rejection and graft loss due to bronchiolitis obliterans syndrome after lung transplantation. Pulm Pharmacol Ther 2010; 23:445.
- Sehgal SN. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem 1998; 31:335.
- Kelly PA, Gruber SA, Behbod F, Kahan BD. Sirolimus, a new, potent immunosuppressive agent. Pharmacotherapy 1997; 17:1148.
- Formica RN Jr, Lorber KM, Friedman AL, et al. The evolving experience using everolimus in clinical transplantation. Transplant Proc 2004; 36:495S.
- Neumayer HH. Introducing everolimus (Certican) in organ transplantation: an overview of preclinical and early clinical developments. Transplantation 2005; 79:S72.
- Sehgal SN. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc 2003; 35:7S.
- Iverson M, Corris PA. Immunosuppression. Eur Respir Mon 2009; 45:147.
- Snell GI, Levvey BJ, Chin W, et al. Sirolimus allows renal recovery in lung and heart transplant recipients with chronic renal impairment. J Heart Lung Transplant 2002; 21:540.
- King-Biggs MB, Dunitz JM, Park SJ, et al. Airway anastomotic dehiscence associated with use of sirolimus immediately after lung transplantation. Transplantation 2003; 75:1437.
- Groetzner J, Kur F, Spelsberg F, et al. Airway anastomosis complications in de novo lung transplantation with sirolimus-based immunosuppression. J Heart Lung Transplant 2004; 23:632.
- Santacruz JF, Mehta AC. Airway complications and management after lung transplantation: ischemia, dehiscence, and stenosis. Proc Am Thorac Soc 2009; 6:79.
- Snell GI, Valentine VG, Vitulo P, et al. Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double-blind clinical trial. Am J Transplant 2006; 6:169.
- Bhorade S, Ahya VN, Baz MA, et al. Comparison of sirolimus with azathioprine in a tacrolimus-based immunosuppressive regimen in lung transplantation. Am J Respir Crit Care Med 2011; 183:379.
- Andoh TF, Lindsley J, Franceschini N, Bennett WM. Synergistic effects of cyclosporine and rapamycin in a chronic nephrotoxicity model. Transplantation 1996; 62:311.
- Ahya VN, McShane PJ, Baz MA, et al. Increased risk of venous thromboembolism with a sirolimus-based immunosuppression regimen in lung transplantation. J Heart Lung Transplant 2011; 30:175.
- Morelon E, Stern M, Israël-Biet D, et al. Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients. Transplantation 2001; 72:787.
- Lennon A, Finan K, FitzGerald MX, McCormick PA. Interstitial pneumonitis associated with sirolimus (rapamycin) therapy after liver transplantation. Transplantation 2001; 72:1166.
- McWilliams TJ, Levvey BJ, Russell PA, et al. Interstitial pneumonitis associated with sirolimus: a dilemma for lung transplantation. J Heart Lung Transplant 2003; 22:210.
- Lindenfeld JA, Simon SF, Zamora MR, et al. BOOP is common in cardiac transplant recipients switched from a calcineurin inhibitor to sirolimus. Am J Transplant 2005; 5:1392.
- Vlahakis NE, Rickman OB, Morgenthaler T. Sirolimus-associated diffuse alveolar hemorrhage. Mayo Clin Proc 2004; 79:541.
- Vos R, Vanaudenaerde BM, Verleden SE, et al. A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation. Eur Respir J 2011; 37:164.
- Wieland E, Olbricht CJ, Süsal C, et al. Biomarkers as a tool for management of immunosuppression in transplant patients. Ther Drug Monit 2010; 32:560.
- Johnson BA, Iacono AT, Zeevi A, et al. Statin use is associated with improved function and survival of lung allografts. Am J Respir Crit Care Med 2003; 167:1271.
- Floreth T, Bhorade SM, Ahya VN. Conventional and novel approaches to immunosuppression. Clin Chest Med 2011; 32:265.
- GENERAL PRINCIPLES
- AGENTS FOR MAINTENANCE THERAPY
- Calcineurin inhibitors
- - Cyclosporine
- - Tacrolimus
- - Tacrolimus versus cyclosporine
- Nucleotide blocking agents
- - Mycophenolate mofetil
- - Azathioprine
- - Mycophenolate mofetil versus azathioprine
- mTOR inhibitors
- - Sirolimus/everolimus
- - Azathioprine versus sirolimus/everolimus
- MONITORING AND ADJUSTING MAINTENANCE THERAPY
- TREATMENT OF REJECTION
- PREVENTION OF OPPORTUNISTIC INFECTION
- FUTURE DIRECTIONS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS