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Vienna Lung Transplant Program Winterschool Obergurgl 2012
Chronische Abstoßungsreaktion und Immunsuppression nach Transplantation
Peter JakschMUW Thorax-Chirurgie
Vienna Lung Transplant Program Winterschool Obergurgl 2012
NUMBER OF LUNG TRANSPLANTS REPORTED BY YEAR AND PROCEDURE TYPE
Vienna 1989-2011 (1157 + 95 ReTX)
1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 20110
20
40
60
80
100
120
ReTX
HLuTX
Bilateral/Double Lung
Single Lung
Vienna Lung Transplant Program Winterschool Obergurgl 2012
1989- 1/2012CF vs „non-CF“
1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2004 2006 2007 2008 2009 2010 2011 2012year of TX
0
20
40
60
80
100
120
314 16
23 2520
1320 18
48 4741
33
52 54 50
67 67
53
7767 67
80
110
2 0
1 12
40 5
3 7
47
10 1111
1320
11
23
1927
21
3
CFnonCF
2xkomb mit LTX, 1x NTX
Vienna Lung Transplant Program Winterschool Obergurgl 2012
TX bei CF Patienten(1999-2011)
Austria
Hungary
Greece
Poland
Slowenia
Germany
Italy
Slowakia
Czek Rep
croatia
great brit
ain0
10
20
30
40
50
60
70
80
90
10095
41
22 18 144 4 4 2 1 1
number of TX (n=188)
Vienna Lung Transplant Program Winterschool Obergurgl 2012
Ergebnisse nach LuTX2000-2011
n=726
n=181
p<0.05
days
Vienna Lung Transplant Program Winterschool Obergurgl 2012
Bronchiolitis obliterans (Syndrom)
Unter Bronchiolitis obliterans versteht man eine Entzündung, die sich auf Ebene der Bronchiolen abspielt. Es kommt zu einer Entzündung der kleinen Atemwege, wobei die Bronchiolen durch Granulationsgewebe obstruiert werden.Die Folge ist eine Obstruktion mit expiratorischer Flussbehinderung .
0
20
40
60
80
100
120
140
160
VC%
FEV1%
MEF50%
TLC%
Vienna Lung Transplant Program Winterschool Obergurgl 2012
BOS Grading
04/08/1
998 02:00
29/12/1
998 14:53
25/01/1
999 14:53
18/02/1
999 14:53
30/03/1
999 14:53
11/05/1
999 14:53
04/08/1
999 14:53
15/11/1
999 14:53
28/02/2
000 09:07
17/05/2
000 09:07
04/09/2
000 13:43
29/11/2
000 15:42
14/02/2
001 09:55
30/03/2
001 09:55
25/06/2
001 09:55
19/11/2
001 09:55
10/01/2
002 09:55
02/05/2
002 09:55
24/06/2
002 09:55
25/09/2
002 09:55
20/11/2
002 09:55
02/01/2
003 09:55
11/02/2
003 09:55
23/04/2
003 09:55
01/09/2
003 09:550
20
40
60
80
100
120
FEV1%MEF50%TLC %
Vienna Lung Transplant Program Winterschool Obergurgl 2012
Vienna Lung Transplant Program Winterschool Obergurgl 2012
n=891
Freedom from BOS1989-2010 LuTX Wien
survival >90days
Vienna Lung Transplant Program Winterschool Obergurgl 2012
p=ns
1989-2010 LuTX Wiensurvival >90days
Male (n=473) vs female (n=418)
Vienna Lung Transplant Program Winterschool Obergurgl 2012
p=0.009
1989-2010 LuTX Wiensurvival >90days
CF (n=162) vs non-CF (n=729)
Vienna Lung Transplant Program Winterschool Obergurgl 2012
Freedom from BOS at risk for BOS (surv > 90 days)
D sex/R sex
f-m
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
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
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
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
Vienna Lung Transplant Program Winterschool Obergurgl 2012
Alloimmune Faktoren
• Akute Abstoßung
• Alloreaktivität gegen HLA Antigene
• HLA Mismatch
• Humorale Komponente ?
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 ?
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
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
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
• ???
Vienna Lung Transplant Program Winterschool Obergurgl 2012
• Inhalatives CyA
• Inhalative Steroide
• Rapamycin/Everolimus
• Fundoplicatio
• Azithromycin
• Montelukast
• Ev. Plasmapherese
Therapieansätze bei BOS (2)
Vienna Lung Transplant Program Winterschool Obergurgl 2012
ImmunsuppressionsSwitch
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
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.
Vienna Lung Transplant Program Winterschool Obergurgl 2012
EverolimusSnell et alAm J Transplant 2006 Jan;6(1):169-77
Randomized, prospective, 213 ptsAza (1-3mg/d) vs Everolimus (3mg/d)At 12 months, the everolimus group had significantly
reduced incidences of deltaFEV1 >15%, and acute rejections
Vienna Lung Transplant Program Winterschool Obergurgl 2012
Extrakorporale Phototherapie
Moreel et alJ Heart Lung Transplant 2010;29:424–431
Retrospective 60 patsreduction in the rate of
decline in lung function20% improved
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 )
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
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
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 ?
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
Vienna Lung Transplant Program Winterschool Obergurgl 2012
ReTransplantation
• Selektierte Patienten• Keine relevanten Komorbiditäten• Alter !• Resultate – ca idem zur prim TX• Ethische Frage –
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 -
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– ????????????????????????????????
Vienna Lung Transplant Program Winterschool Obergurgl 2012
Vielen Dank für Ihre Aufmerksamkeit
Fragen ???????????
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
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
Vienna Lung Transplant Program Winterschool Obergurgl 2012
Freedom from BOS at risk for BOS (surv > 6mo)
n=776
Vienna Lung Transplant Program Winterschool Obergurgl 2012
Wichtigste Komplikation im Langzeitverlauf nach LUTX
Hintergrund
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
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
Vienna Lung Transplant Program Winterschool Obergurgl 2012
Ziele und Fragestellung
Prävalenz von BOS nach Lungentransplantation in Wien
Risikofaktoren
Früh (< 2 Jahren) vs Spät (> 2 Jahren)
Graftsurvival
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 und > 2 Jahren post TX
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
Vienna Lung Transplant Program Winterschool Obergurgl 2012
Ergebnisse
Vienna Lung Transplant Program Winterschool Obergurgl 2012
Ergebnisse
Freedom from BOS:5 Jahre: 66,8 %10 Jahre: 53,3 %
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
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 TXWeigt 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
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
Vienna Lung Transplant Program Winterschool Obergurgl 2012
Ergebnisse – BOS vs No BOS
75,6 %
56,7 %
p < 0,05
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”
Vienna Lung Transplant Program Winterschool Obergurgl 2012
ZUSAMMENFASSUNG
Rate von BOS in Wien niedriger als International
Abstoßungen (Lymphozytäre Bronchitis) wichtiger Risikofaktor
Induktion protektiv ???
Immunsuppression
Infekte (CMV, Aspergillus) erkennen und frühzeitig therapieren
Vienna Lung Transplant Program Winterschool Obergurgl 2012
AUSBLICK
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
Vienna Lung Transplant Program Winterschool Obergurgl 2012
Vienna Lung Transplant Program Winterschool Obergurgl 2012
Chronische Abstoßungsreaktion