1. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Chronische Abstoßungsreaktion und Immunsuppression nach Transplantation Peter Jaksch MUW Thorax-Chirurgie

2. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 NUMBER OF LUNG TRANSPLANTS REPORTED BY YEAR AND PROCEDURE TYPE Vienna 1989-2011 (1157 + 95 ReTX)

3. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 1989- 1/2012 CF vs non-CF 2xkomb mit LTX, 1x NTX

4. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 TX bei CF Patienten (1999-2011)

5. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Ergebnisse nach LuTX 2000-2011 n=726 n=181 p<0.05 days

6. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Bronchiolitis obliterans (Syndrom) Unter Bronchiolitis obliterans versteht man eine Entzündung, die sich auf Ebene der Bronchiolen abspielt.EntzündungBronchiolen Es kommt zu einer Entzündung der kleinen Atemwege, wobei die Bronchiolen durch Granulationsgewebe obstruiert werden. Die Folge ist eine Obstruktion mit expiratorischer Flussbehinderung.

7. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 BOS Grading

8. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012

9. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 n=891 Freedom from BOS 1989-2010 LuTX Wien survival >90days

10. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 p=ns 1989-2010 LuTX Wien survival >90days Male (n=473) vs female (n=418)

11. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 p=0.009 1989-2010 LuTX Wien survival >90days CF (n=162) vs non-CF (n=729)

12. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Freedom from BOS at risk for BOS (surv > 90 days) D sex/R sex f-m

13. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Freedom from BOS at risk for BOS (surv > 90 days) 1989-1999( n=205) vs 2000-2010 (n=686) ns

14. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Freedom from BOS at risk for BOS (surv > 90days) CyA (n=300) vs Tac (n=591) p<o,o5

15. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 BOS (pat 2000-2010) at risk for BOS (surv > 6mo) n=572 Freedom from BOS at risk for BOS (surv > 90days) DLuTX (n=691) vs SLuTX (n=200) ns

16. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 final common pathway" lesion Trauma und Inflammation von Epithelzellen und subepithelialen Strukturen der kleinen Atemwege Exzessive Fibroproliferation als Folge der epithelialen Regeneration und überschießender Gewebsregeneration Alloimmune und nicht-alloimmune Mechanismen

17. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Alloimmune Faktoren Akute Abstoßung Alloreaktivität gegen HLA Antigene HLA Mismatch Humorale Komponente ?

18. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Alloimmune-independent Factors Bakterielle und fungale Infekte CMV pneumonitis Virale non-CMV Infektion PGD Ischämie der Atemwege – Chron Ischämie durch Durchtrennung der Bronchialarterien ? – Kalte Ischämie Reflux ?

19. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012

20. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Beste Therapie = Prävention Früherkennung wichtig Aber wie reagieren ?? – Switch – Phototherapie – Antikörper-Th – Proliferationshemmer – ???? – ? Biopsien Lungenfunktion MS-CT BAL NO im Exhalat

21. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Therapieansätze Ätiologie Akute bzw. rez Abstoßung CMV Infekt Bakt Infekte Entsprechende Therapie Suffiziente Immunsuppression Suffiziente CMV Prophylaxe/Therapie Suffiziente AB Prophylaxe/Therapie Trotzdem ca 40-60% BO(S) 5 Jahre post LuTX

22. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Therapieansätze bei BOS (1) Intensivierung der Immunsuppression Immunmodulation ? CyA Tac Poly-oder monoklonale Antikörper Methotrexat ? Ciclophosphamid ? Extracoporale Photopherese Irradiatio ???

23. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Inhalatives CyA Inhalative Steroide Rapamycin/Everolimus Fundoplicatio Azithromycin Montelukast Ev. Plasmapherese Therapieansätze bei BOS (2)

24. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Immunsuppressions Switch CyA - Tac Sarahrudi et al, J Thorac Cardiovasc Surg. 2004 Apr;127 244 patients - retrospective Conversion from CyA to Tac - reversal of recurrent- ongoing rejection. Conversion for BOS - short-term stabilisation

25. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Sirolimus Cahill et al, J Heart Lung Transplant. 2003 Feb 12 LT recipients with OB/BOS pulmonary function was not affected by the addition of sirolimus.

26. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Everolimus Snell et al Am J Transplant 2006 Jan;6(1):169-77 Randomized, prospective, 213 pts Aza (1-3mg/d) vs Everolimus (3mg/d) At 12 months, the everolimus group had significantly reduced incidences of deltaFEV1 >15%, and acute rejections

27. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Extrakorporale Phototherapie Moreel et al J Heart Lung Transplant 2010;29:424–431 Retrospective 60 pats reduction in the rate of decline in lung function 20% improved

28. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Azithromycin Gerhardt et al.(John Hopkins) Am J Respir Crit Care Med. 2003 Jul 1;168(1) In CF patients azithromycin decreased the number of respiratory exacerbations, improves FEV1, and improves quality of life. 6 LuTX pts received 250 mg orally three times per week for a mean of 13.7 weeks Significant improvement in pulmonary function (range -0.18 to 1.36 L )

29. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vos R et al J Heart Lung Transplant. 2010 Dec;29(12) retrospective, observational 107 patients with BOS treated with azithromycin for 3.1 ±1.9 years. FEV1 increased 10% after 3 to 6 months of treatment in 40% of patients, of whom 33% later redeveloped BOS. FEV1 further declined in 78% and stabilized in 22% of the remaining non-responders. Pre-treatment neutrophilia was higher in responders. Azithromycin

30. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Cantu et al, Ann Thorac Surg. 2004 Oct;78 retrospective of 457 patients Incidence of postoperative reflux was 76% (127 of 167 patients). early fundoplication improved freedom from bronchiolitis obliterans syndrome at 1 and 3 years (100%, 100%). early aggressive surgical treatment of reflux results in improved rates of bronchiolitis obliterans syndrome and survival Gastroesophageal reflux disease

31. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Jaramillo et al Pediatr Transplant. 2005 Feb;9 BOS is the result of humoral and cellular immune responses developed against major histocompatibility complex molecules This process is aggravated by alloimmune-independent mechanisms such as ischemia-reperfusion and infection. Humorale Abstoßung ?

32. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Mögliches diagnostisch-therapeutisches Procedere Bei reproduzierbarem FEV1 Abfall BSK + TBB + BAL Kein Infekt oder Abstoßung MS-CT (In-und Exspiration) Gastroskopie + pH-Metrie – ev Fundoplicatio Azithromycin für mind 3 Monate ECP HLA-spez Antikörper – ev Plasmapherese

33. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 ReTransplantation Selektierte Patienten Keine relevanten Komorbiditäten Alter ! Resultate – ca idem zur prim TX Ethische Frage –

34. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Weitere Zukunft ? Genetische Untersuchungen Micro-Arrays Suche nach upregulierten Genen bei BO(S) Früherkennung – Risiko-Scores Neue Einsichten in Pathogenese Subtypen -

35. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Zukunft BOS Subtypen – early (< 2a post) – late (> 2a) – rapid decline of FEV1 (>20% /6months) – slow – Restriction vs obst ruction (BO) – Combined – Neutrophile vs lymhozytäre BAL – CT Morphologie – ????????????????????????????????

36. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vielen Dank für Ihre Aufmerksamkeit Fragen ???????????

37. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012

38. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Freedom from BOS at risk for BOS (surv > 6mo) n=776

39. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 BOS (pat 2000-2010) at risk for BOS (surv > 6mo) n=572 n.s. Freedom from BOS at risk for BOS (surv > 6mo) n=776

40. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Freedom from BOS at risk for BOS (surv > 6mo) n=776

41. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Wichtigste Komplikation im Langzeitverlauf nach LUTX Hintergrund

42. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Hintergrund Pathogenese: Neutrophile Inflammation/Infiltration Cytokinen (IL17, IL-8) Wachstumsfaktoren } Fibroproliferation und Obliteration Iskander Al-Githmi et al Bronchiolitis obliterans following lung transplantation Eur J Cardiothorac Surg 2006;30:846-851

43. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Hintergrund Sharples LD et al Risk factors for BOS: a systematic review of recent publications J Heart Lung Transplant 2002 Feb;21(2):271-81. Scott AI et al Bronchiolitis obliterans syndrome: risk factors and therapeutic strategies Drugs. 2005;65(6):761-71. Verleden et al Obliterative bronchiolitis following lung transplantation:from old to new concepts?Transpl Int. 2009 Aug;22(8):771-9 Risikofaktoren: Abstoßungen HLA-missmatch GERD Reperfusionsschaden Infektionen (CMV) Ischämiezeit Spender- und Empfängeralter

44. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Ziele und Fragestellung Prävalenz von BOS nach Lungentransplantation in Wien Risikofaktoren Früh ( 2 Jahren) Graftsurvival

45. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Methodik Retrospektive Datenanalyse aller Lungentransplantationen von 1998-2009 Exkludiert: HLTX, verstorben 6 Monaten post TX Einteilung aller Patienten BOS 1 in 2 Gruppen: BOS 1 Beginn 2 Jahren post TX

46. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Methodik Testvariablen: Alter Spender / Empfänger Geschlecht Spender / Empfänger CMV Status Spender / Empfänger Ischämiezeit/Reperfusionsödem DLUTX / SLUTX Aspergillus Infektion post TX Graftsurvival Primäre Immunsuppression Induktionstherapie Abstoßungen MV bei Listung CMV Infektion post TX ICU Zeit Freedom from BOS

47. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Ergebnisse

48. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Ergebnisse Freedom from BOS: 5 Jahre: 66,8 % 10 Jahre: 53,3 %

49. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Ergebnisse f-m vs m-m: p < 0,05 Roberts DH et al Donor-recipient gender mismatch in lung transplantation: impact on obliterative bronchiolitis and survival J Heart Lung Transplant. 2004 Nov;23(11):1252-9

50. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Ergebnisse – BOS vs No BOS p< 0,05: Primare Immunsuppression (CyA vs TAC) Bittner HB et al Preoperative introduction and maintenance immunosuppression therapy of oral-only tacrolimus, mycophenolate mofetil and steroids reduce acute rejection episodes after lung transplantation Eur J Cardiothorac Surg. 2010 Sep;38(3):268-76. Epub 2010 Mar 20 Fan Y et al Tacrolimus versus cyclosporine for adult lung transplant recipients: a meta-analysis Transplant Proc. 2009 Jun;41(5):1821-4 Hachem RR et al A randomized controlled trial of tacrolimus versus cyclosporine after lung transplantation J Heart Lung Transplant. 2007 Oct;26(10):1012-8 Induktion (ATG oder Alemtuzumab vs keine Induktion) Reams BD et al Alemtuzumab in the treatment of refractory acute rejection and bronchiolitis obliterans syndrome after human lung transplantation Am J Transplant. 2007 Dec;7(12):2802-8 Alemtuzumab weniger AR + Stabilisierung BOS Wiebe K et al ATG induction therapy and the incidence of bronchiolitis obliterans after lung transplantation: does it make a difference? Transplant Proc. 1998 Jun;30(4):1517-8 ATG vs keine Induktion kein Unterschied Ailawadi G et al Effects of induction immunosuppression regimen on acute rejection, bronchiolitis obliterans, and survival after lung transplantation J Thorac Cardiovasc Surg. 2008 Mar;135(3):594-602 Induktion besser als keine, Daclizumab besser als ATG Aspergillus Infektion post TX Weigt SS et al Aspergillus colonization of the lung allograft is a risk factor for bronchiolitis obliterans syndrome Am J Transplant. 2009 Aug;9(8):1903-11 Valentine VG et al Effect of etiology and timing of respiratory tract infections on development of bronchiolitis obliterans syndrome. J Heart Lung Transplant. 2009 Feb;28(2):163-9

51. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 p <0,05 Abstoßungen Kumulative A und B scores im 1. Jahr, B scores im 2. Jahr Glanville AR et al Severity of lymphocytic bronchiolitis predicts long-term outcome after lung transplantation Am J Respir Crit Care Med. 2008 May 1;177(9):1033-40 Höherer B-score korreliert mit BOS CMV Infektionen post TX (Virämie und Disease) Sharples LD et al Risk factors for bronchiolitis obliterans: a systematic review of recent publications. J Heart Lung Transplant. 2002 Feb;21(2):271-81 Ergebnisse – BOS vs No BOS

52. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Ergebnisse – BOS vs No BOS 75,6 % 56,7 % p < 0,05

53. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Ergebnisse – Früh vs Spät P< 0,05: Alter Abstoßungen B2 Jahr 1, 2 Aspergillus Infektion post TX Jackson CH et al Acute and chronic onset of bronchiolitis obliterans syndrome (BOS): are they different entities? J Heart Lung Transplant. 2002 Jun;21(6):658-66 Akute Anstoßungen und akute Events

54. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Rate von BOS in Wien niedriger als International Abstoßungen (Lymphozytäre Bronchitis) wichtiger Risikofaktor Induktion protektiv ??? Immunsuppression Infekte (CMV, Aspergillus) erkennen und frühzeitig therapieren

55. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 AK mediierte Abstoßung Radiologie/ Morphologie/ Obstruktion vs Restriktion Neue Therapieformen: Myeloablation Angiogenese + Airway remodelling (CXCR2/VEGF) Belatacept (T-Zell Co-Stimulations Blocker) Bortezomib (Proteasom Inhibitor, depletiert Plasma Zellen) Tasocitinib (Jak Inhibitor) Snell GI, Westall GP The contribution of airway ischemia and vascular remodelling to the pathophysiology of bronchiolitis obliterans syndrome and chronic lung allograft dysfunction. Curr Opin Organ Transplant. 2010 Oct;15(5):558-62. Luznik L, Fuchs EJ High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation. Immunol Res. 2010 Jul;47(1-3):65-77. Everly JJ et al Proteasome inhibition for antibody-mediated rejection Curr Opin Organ Transplant. 2009 Dec;14(6):662-6 Campara M et al Interleukin-2 receptor blockade with humanized monoclonal antibody for solid organ transplantation. Expert Opin Biol Ther. 2010 Jun;10(6):959-69

56. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012

57. Vienna Lung Transplant Program Winterschool Obergurgl 2012 Vienna Lung Transplant Program Winterschool Obergurgl 2012 Chronische Abstoßungsreaktion