Pneumologie 2011; 65(2): 94-102
DOI: 10.1055/s-0030-1255762
Serie: Lungentransplantation

© Georg Thieme Verlag KG Stuttgart · New York

Immunsuppression und Infektionsprophylaxe nach Lungentransplantation

Immunosuppression and Infection Prophylaxis after Lung TransplantationC.  Neurohr1 , J.  Behr1
  • 1Schwerpunkt Pneumologie (Leiter Prof. Dr. J. Behr), Medizinische Klinik und Poliklinik I – Campus Großhadern (Direktor Prof. Dr. G. Steinbeck), Klinikum der Universität München
Further Information

Publication History

eingereicht 13. 7. 2010

akzeptiert 16. 7. 2010

Publication Date:
19 October 2010 (online)

Zusammenfassung

Die Lungentransplantation (LTX) ist ein etabliertes Therapieverfahren für Lungenerkrankungen im Endstadium. Hauptursachen für die unbefriedigenden Langzeitüberlebensraten sind Infektionen und das Bronchiolitis-obliterans-Syndrom (BOS). Für beide Komplikationen spielt eine optimale immunsuppressive Strategie eine entscheidende Rolle. Über 60 % der Organempfänger erhalten eine Induktionstherapie, ohne dass bisher ein signifikanter Vorteil bezüglich Langzeitüberleben in kontrollierten Studien demonstriert wurde. Die große Mehrheit der Patienten wird lebenslang mit einer dreifach immunsuppressiven Erhaltungstherapie, bestehend aus einem Calcineurin-Inhibitor, einem Zellzyklus-Inhibitor und einem oralen Kortikosteroid, behandelt. Eine eindeutige Überlegenheit in Bezug auf Langzeitüberleben konnte bisher jedoch für keine der spezifischen Immunsuppressiva-Kombination gezeigt werden. Ob die neueren Proliferations-Signal-Inhibitoren Sirolimus und Everolimus signifikante Vorteile bieten, ist noch nicht abschließend zu beurteilen. Zur Therapie des BOS werden eine Umstellung der Erhaltungstherapie, eine erneute Induktionstherapie, inhalatives Cyclosporin A sowie u. a. Azithromyzin, extrakorporale Photopherese und Lymphsystembestrahlung angewendet. Die Infektionsprophylaxe nach LTX spielt eine entscheidende Rolle bei der Vermeidung von akuten Komplikationen und auch in der Verhinderung des BOS. Insbesondere zur Prophylaxe einer Pneumocystis- und Cytomegalievirus-Erkrankung stehen effektive medikamentöse Optionen zur Verfügung. Darüber hinaus wurde auch die Kolonisierung mit Pseudomonas aeruginosa und Aspergillus-Spezies als Risikofaktor für BOS erkannt. Entsprechende prophylaktische bzw. prä-emptive Therapieansätze finden daher in unterschiedlichem Ausmaß in den meisten Transplantationszentren Anwendung.

Abstract

Lung transplantation (LTX) is an established therapeutic option for end-stage lung diseases. The main reasons for limited long-term survival rates are infections and bronchiolitis obliterans syndrome (BOS). An optimal immunosuppressive regimen is of critical importance for the prevention of both complications. Induction therapy is used in approximately 60 % of recipients. However, there are no controlled trials demonstrating a significant long-term survival benefit. The vast majority of patients receive a triple maintenance immunosuppressive therapy consisting of a calcineurin-inhibitor, a cell cycle inhibitor and corticosteroids. So far, no specific immunosuppressive drug combination has proven superiority regarding long-term survival rates. The potential benefits of the proliferation signal inhibitors sirolimus and everolimus remain to be elucidated. Therapeutic options for BOS encompass a switch in maintenance therapy, renewed induction therapy, aerolised cyclosporine, azithromycine, extracorporeal photopheresis and total lymphoid irradiation. Infection prophylaxis after LTX plays a pivotal role to guard against acute complications and for the prevention of BOS. In particular, prophylaxis for pneumocystis and cytomegalovirus disease is very effective. Moreover, colonisation with Pseudomonas aeruginosa and Aspergillus spp. was identified as risk factor for BOS. Consequently, in most transplant centres prophylactic and pre-emptive therapeutic approaches are applied in varying degrees.

Literatur

  • 1 Christie J D, Edwards L B, Aurora P et al. The Registry of the International Society for Heart and Lung Transplantation: Twenty-sixth Official Adult Lung and Heart-Lung Transplantation Report-2009.  J Heart Lung Transplant. 2009;  28 1031-1049
  • 2 Palmer S M, Miralles A P, Lawrence C M et al. Rabbit antithymocyte globulin decreases acute rejection after lung transplantation: results of a randomized, prospective study.  Chest. 1999;  116 127-133
  • 3 Wiebe K, Harringer W, Wahlers T et al. ATG induction therapy and the incidence of bronchiolitis obliterans after lung transplantation: does it make a difference?.  Transplant Proc. 1998;  30 1517-1518
  • 4 Wain J C, Wright C D, Ryan D P. Induction immunosuppression for lung transplantation with OKT3.  Ann Thorac Surg. 1999;  67 187-193
  • 5 Brock M V, Borja M C, Ferber L et al. Induction therapy in lung transplantation: a prospective, controlled clinical trial comparing OKT3, anti-thymocyte globulin, and daclizumab.  J Heart Lung Transplant. 2001;  20 1282-1290
  • 6 Abramowicz D, Schandene L, Goldman M et al. Release of tumor necrosis factor, interleukin-2, and gamma-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients.  Transplantation. 1989;  47 606-608
  • 7 Ding I B, Baumgartner R A, Schwaiblmair M, Behr J. Administration of anti-interleukin-2Ralpha monoclonal antibody in bronchiolitis obliterans syndrome after lung transplantation.  Transplantation. 2003;  75 1767-1769
  • 8 Burton C M, Andersen C B, Jensen A S et al. The incidence of acute cellular rejection after lung transplantation: a comparative study of anti-thymocyte globulin and daclizumab.  J Heart Lung Transplant. 2006;  25 638-647
  • 9 Garrity Jr. E R, Villanueva J, Bhorade S M et al. Low rate of acute lung allograft rejection after the use of daclizumab, an interleukin 2 receptor antibody.  Transplantation. 2001;  71 773-777
  • 10 McCurry K R, Iacono A, Zeevi A et al. Early outcomes in human lung transplantation with Thymoglobulin or Campath-1H for recipient pretreatment followed by posttransplant tacrolimus near-monotherapy.  J Thorac Cardiovasc Surg. 2005;  130 528-537
  • 11 van Loenhout K C, Groves S C, Galazka M et al. Early outcomes using alemtuzumab induction in lung transplantation.  Interact Cardiovasc Thorac Surg. 2010;  10 190-194 [Epub 2009 Nov 25]
  • 12 Hoffmeyer F, Hoeper M M, Spiekerkotter E et al. Azathioprine withdrawal in stable lung and heart/lung recipients receiving cyclosporine-based immunosuppression.  Transplantation. 2000;  70 522-525
  • 13 Korom S, Boehler A, Weder W. Immunosuppressive therapy in lung transplantation: state of the art.  Eur J Cardiothorac Surg. 2009;  35 1045-1055 [Epub 2009 Apr 5]
  • 14 Borel J F, Feurer C, Gubler H U, Stahelin H. Biological effects of cyclosporin A: a new antilymphocytic agent.  Agents Actions. 1976;  6 468-475
  • 15 Levy G, Thervet E, Lake J, Uchida K. Consensus on Neoral C(2): Expert Review in Transplantation (CONCERT) Group. Patient management by Neoral C(2) monitoring: an international consensus statement.  Transplantation. 2002;  73 (9 Suppl) 12-18
  • 16 Nemati E, Einollahi B, Taheri S et al. Cyclosporine trough (c0) and 2-hour postdose (c2) levels: which one is a predictor of graft loss?.  Transplant Proc. 2007;  39 1223-1224
  • 17 Glanville A R, Morton J M, Aboyoun C L et al. Cyclosporine C2 monitoring improves renal dysfunction after lung transplantation.  J Heart Lung Transplant. 2004;  23 1170-1174
  • 18 Glanville A R, Aboyoun C L, Morton J M et al. Cyclosporine C2 target levels and acute cellular rejection after lung transplantation.  J Heart Lung Transplant. 2006;  25 928-934
  • 19 Taylor J L, Palmer S M. Critical care perspective on immunotherapy in lung transplantation.  J Intensive Care Med. 2006;  21 327-344
  • 20 Ragette R, Kamler M, Weinreich G et al. Tacrolimus pharmacokinetics in lung transplantation: new strategies for monitoring.  J Heart Lung Transplant. 2005;  24 1315-1319
  • 21 Knoop C, Thiry P, Saint-Marcoux F et al. Tacrolimus pharmacokinetics and dose monitoring after lung transplantation for cystic fibrosis and other conditions.  Am J Transplant. 2005;  5 1477-1482
  • 22 Reichenspurner H. Overview of tacrolimus-based immunosuppression after heart or lung transplantation.  J Heart Lung Transplant. 2005;  24 119-130
  • 23 Keenan R J, Konishi H, Kawai A et al. Clinical trial of tacrolimus versus cyclosporine in lung transplantation.  Ann Thorac Surg. 1995;  60 580-584
  • 24 Treede H, Klepetko W, Reichenspurner H. et al.; Munich and Vienna Lung Transplant Group . Tacrolimus versus cyclosporine after lung transplantation: a prospective, open, randomized two-center trial comparing two different immunosuppressive protocols.  J Heart Lung Transplant. 2001;  20 511-517
  • 25 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;  125 891-900
  • 26 Reichenspurner H, Glanville A, Christina A. et al. and European and Australian Investigators in Lung Transplantation . Complete 3 Year Analysis of a Prospective Randomized International Multi-Center Investigator Driven Study Comparing Tacrolimus and Cyclosporin A, Both in Combination with MMF and Steroids after Lung Transplantation in 249 Patients.  J Heart Lung Transplant. 2008;  27 S205-S206
  • 27 Hachem R R, Yusen R D, Chakinala M M et al. A randomized controlled trial of tacrolimus versus cyclosporine after lung transplantation.  J Heart Lung Transplant. 2007;  26 1012-1018
  • 28 Starnes V A. Heart-lung transplantation: an overview.  Cardiol Clin. 1990;  8 159-168
  • 29 Azzola A, Havryk A, Chhajed P et al. Everolimus and mycophenolate mofetil are potent inhibitors of fibroblast proliferation after lung transplantation.  Transplantation. 2004;  77 275-280
  • 30 Kobashigawa J, Miller L, Renlund D et al. A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Mycophenolate Mofetil Investigators.  Transplantation. 1998;  66 507-515
  • 31 Mathew T H. A blinded, long-term, randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation: results at three years. Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group.  Transplantation. 1998;  65 1450-1454
  • 32 Palmer S M, Baz M A, 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 1772-1776
  • 33 McNeil K, Glanville A R, Wahlers T et al. Comparison of mycophenolate mofetil and azathioprine for prevention of bronchiolitis obliterans syndrome in de novo lung transplant recipients.  Transplantation. 2006;  81 998-1003
  • 34 Wali R K, Mohanlal V, Ramos E et al. Early withdrawal of calcineurin inhibitors and rescue immunosuppression with sirolimus-based therapy in renal transplant recipients with moderate to severe renal dysfunction.  Am J Transplant. 2007;  7 1572-1583
  • 35 Fairbanks K D, Eustace J A, Fine D et al. Renal function improves in liver transplant recipients when switched from a calcineurin inhibitor to sirolimus.  Liver Transpl. 2003;  9 1079-1085
  • 36 Snell G I, Levvey B J, Chin W et al. Sirolimus allows renal recovery in lung and heart transplant recipients with chronic renal impairment.  J Heart Lung Transplant. 2002;  21 540-546
  • 37 Groetzner J, Wittwer T, Kaczmarek I et al. Conversion to sirolimus and mycophenolate can attenuate the progression of bronchiolitis obliterans syndrome and improves renal function after lung transplantation.  Transplantation. 2006;  81 355-360
  • 38 Venuta F, De Giacomo T, Rendina E A et al. Recovery of chronic renal impairment with sirolimus after lung transplantation.  Ann Thorac Surg. 2004;  78 1940-1943
  • 39 Snell G I, Levvey B J, Chin W et al. Rescue therapy: a role for sirolimus in lung and heart transplant recipients.  Transplant Proc. 2001;  33 1084-1085
  • 40 Ussetti P, Laporta R, de Pablo A et al. Rapamycin in lung transplantation: preliminary results.  Transplant Proc. 2003;  35 1974-1977
  • 41 King-Biggs M B, Dunitz J M, Park S J et al. Airway anastomotic dehiscence associated with use of sirolimus immediately after lung transplantation.  Transplantation. 2003;  75 1437-1443
  • 42 Groetzner J, Kur F, Spelsberg F. et al.; Munich Lung Transplant Group . Airway anastomosis complications in de novo lung transplantation with sirolimus-based immunosuppression.  J Heart Lung Transplant. 2004;  23 632-638
  • 43 Chhajed P N, Dickenmann M, Bubendorf L et al. Patterns of pulmonary complications associated with sirolimus.  Respiration. 2006;  73 367-374
  • 44 Bhorade S M, Ahya V, Kotloff R et al. Long Term Follow-Up in the AIRSAC Trial, a Multicenter Randomized Clinical Trial in Lung Transplant Recipients.  J Heart and Lung Transplant. 2009;  28 S119-S120
  • 45 Neumayer H H. Introducing everolimus (Certican) in organ transplantation: an overview of preclinical and early clinical developments.  Transplantation. 2005;  79 S72-S75
  • 46 Snell G I, Valentine V G, Vitulo P. et al.; RAD B159 Study Group . Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double-blind clinical trial.  Am J Transplant. 2006;  6 169-177
  • 47 Strueber M, Stefan F, Simon A R et al. Everolimus Versus Mycophenolatemofetil in De Novo Immunosuppression after Lung Transplantation – Interims Analysis of a Prospective, Randomized, Clinical Trial.  J Heart and Lung Transplant. 2008;  27 205
  • 48 Gullestad L, Iversen M, Mortensen S A et al. Everolimus with reduced calcineurin inhibitor in thoracic transplant recipients with renal dysfunction: a multicenter, randomized trial.  Transplantation. 2010;  89 864-872
  • 49 Otton J, Hayward C S, Keogh A M et al. Everolimus-associated pneumonitis in 3 heart transplant recipients.  J Heart Lung Transplant. 2009;  28 104-106 [Epub 2008 Dec 12]
  • 50 Pratap B, Abraham G, Srinivas C N, Bhaskar S. Post-renal transplant hemolytic uremic syndrome following combination therapy with tacrolimus and everolimus.  Saudi J Kidney Dis Transpl. 2007;  18 609-612
  • 51 Morton J M, Williamson S, Kear L M et al. Therapeutic drug monitoring of prednisolone after lung transplantation.  J Heart Lung Transplant. 2006;  25 557-563
  • 52 Borro J M, Solé A, De la Torre M et al. Steroid withdrawal in lung transplant recipients.  Transplant Proc. 2005;  37 3991-3993
  • 53 Shitrit D, Bendayan D, Sulkes J et al. Successful steroid withdrawal in lung transplant recipients: result of a pilot study.  Respir Med. 2005;  99 596-601
  • 54 Keogh A M, Arnold R H, Macdonald P S et al. A randomized trial of tacrolimus (FK506) versus total lymphoid irradiation for the control of repetitive rejection after cardiac transplantation.  J Heart Lung Transplant. 2001;  20 1331-1334
  • 55 Diamond D A, Michalski J M, Lynch J P, Trulock E P. Efficacy of total lymphoid irradiation for chronic allograft rejection following bilateral lung transplantation.  Int J Radiat Oncol Biol Phys. 1998;  41 795-800
  • 56 Fisher A J, Rutherford R M, Bozzino J et al. The safety and efficacy of total lymphoid irradiation in progressive bronchiolitis obliterans syndrome after lung transplantation.  Am J Transplant. 2005;  5 537-543
  • 57 Verleden G M, Lievens Y, Dupont L J et al. Efficacy of total lymphoid irradiation in azithromycin nonresponsive chronic allograft rejection after lung transplantation.  Transplant Proc. 2009;  41 1816-1820
  • 58 Astor T L, Weill D. Extracorporeal photopheresis in lung transplantation.  J Cutan Med Surg. 2003;  7 20-24
  • 59 Morrell M R, Despotis G J, Lublin D M et al. The efficacy of photopheresis for bronchiolitis obliterans syndrome after lung transplantation.  J Heart Lung Transplant. 2010;  29 424-431 [Epub 2009 Oct 22]
  • 60 Benden C, Speich R, Hofbauer G F et al. Extracorporeal photopheresis after lung transplantation: a 10-year single-center experience.  Transplantation. 2008;  86 1625-1627
  • 61 Williams T J, Verleden G M. Azithromycin: a plea for multicenter randomized studies in lung transplantation.  Am J Respir Crit Care Med. 2005;  172 657-659
  • 62 Verleden G M, Dupont L J. Azithromycin therapy for patients with bronchiolitis obliterans syndrome after lung transplantation.  Transplantation. 2004;  77 1465-1467
  • 63 Vanaudenaerde B M, Meyts I, Vos R et al. A dichotomy in bronchiolitis obliterans syndrome after lung transplantation revealed by azithromycin therapy.  Eur Respir J. 2008;  32 832-843
  • 64 Gottlieb J, Szangolies J, Koehnlein T et al. Long-term azithromycin for bronchiolitis obliterans syndrome after lung transplantation.  Transplantation. 2008;  85 36-41
  • 65 Vos R, Vanaudenaerdea B M, Schoonisa A et al. Azithromycin for Bronchiolitis Obliterans Syndrome after Lung Transplantation.  J Heart and Lung Transplant. 2010;  29 S94
  • 66 Iacono A T, Corcoran T E, Griffith B P et al. Aerosol cyclosporin therapy in lung transplant recipients with bronchiolitis obliterans.  Eur Respir J. 2004;  23 384-390
  • 67 Iacono A T, Johnson B A, Grgurich W F et al. A randomized trial of inhaled cyclosporine in lung-transplant recipients.  N Engl J Med. 2006;  354 141-150
  • 68 Ide N, Nagayasu T, Matsumoto K et al. Efficacy and safety of inhaled tacrolimus in rat lung transplantation.  J Thorac Cardiovasc Surg. 2007;  133 548-553
  • 69 Behr J, Zimmermann G, Baumgartner R. et al.; Munich Lung Transplant Group . Lung deposition of a liposomal cyclosporine A inhalation solution in patients after lung transplantation.  J Aerosol Med Pulm Drug Deliv. 2009;  22 121-130
  • 70 Sarahrudi K, Estenne M, Corris P et al. International experience with conversion from cyclosporine to tacrolimus for acute and chronic lung allograft rejection.  J Thorac Cardiovasc Surg. 2004;  127 1126-1132
  • 71 Jordan S C, Quartel A W, Czer L S 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;  66 800-805
  • 72 Bhorade S M, Stern E. Immunosuppression for lung transplantation.  Proc Am Thorac Soc. 2009;  6 47-53
  • 73 Fishman J A. Infection in solid-organ transplant recipients.  N Engl J Med. 2007;  357 2601-2614
  • 74 Remund K F, Best M, Egan J J. Infections relevant to lung transplantation.  Proc Am Thorac Soc. 2009;  6 94-100
  • 75 Avery R K, Michaels M. Update on immunizations in solid organ transplant recipients: what clinicians need to know.  Am J Transplant. 2008;  8 9-14 [Epub 2007 Dec 18]
  • 76 Green H, Paul M, Vidal L, Leibovici L. Prophylaxis of Pneumocystis pneumonia in immunocompromised non-HIV-infected patients: systematic review and meta-analysis of randomized controlled trials.  Mayo Clin Proc. 2007;  82 1052-1059
  • 77 Hodson E M, Craig J C, Strippoli G F, Webster A C. Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients.  Cochrane Database Syst Rev. 2008;  16 CD003774
  • 78 Fishman J A, Emery V, Freeman R et al. Cytomegalovirus in transplantation – challenging the status quo.  Clin Transplant. 2007;  21 149-158
  • 79 Weigt S S, Elashoff R M, Huang C et al. Aspergillus colonization of the lung allograft is a risk factor for bronchiolitis obliterans syndrome.  Am J Transplant. 2009;  9 1903-1911 [Epub 2009 May 13]
  • 80 Solé A, Salavert M. Fungal infections after lung transplantation.  Curr Opin Pulm Med. 2009;  15 243-253
  • 81 Campos S, Caramori M, Teixeira R et al. Bacterial and fungal pneumonias after lung transplantation.  Transplant Proc. 2008;  40 822-824
  • 82 Hafkin J, Blumberg E. Infections in lung transplantation: new insights.  Curr Opin Organ Transplant. 2009;  14 483-487

Dr. med. Claus Neurohr

Medizinische Klinik und Poliklinik I
Klinikum der Universität München – Großhadern

Marchioninistr. 15
81377 München

Email: claus.neurohr@med.uni-muenchen.de

    >