Prof Geert M. Verleden UZ Gasthuisberg Leuven

Prof Geert M. Verleden UZ Gasthuisberg Leuven

Patients with chronic end-stage lung disease, such as COPD, CF, PAH, Pulmonary fibrosis Max 50-55 y for HLTx 60-65 y for LTx Failing medical treatment Or no medical treatment exists Need for Information Demonstration of adequate health behavior Willingness to adhere to guidelines Aim of LTx: survival benefit and increase in QOL

Malignancy in the last 2 years, except cutaneous squamous and basal cell tumors Remains questionnable regarding for instance breast cancer, renal cancer. How long tumor free? Untreatable advanced dysfunction of other organs (kidney, liver, ) Unless combined transplantation Untreatable coronary artery disease What is nowadays untreatable? Non-curable chronic extrapulmonary infections (hep B, hep C, HIV) Also questionnable

Significant chest wall/spinal deformity To be discussed with surgeons Documented non-adherence Specific problem in young CF patients Untreatable psychiatric or psychologic condition with inability to comply with medical therapy Absence of social support Difficulties to adhere to strict follow up protocols Substance addiction: tobacco, alcohol, narcotics, drug abuse that is active or within the last 6 months Is six months enough delay?

Age > 65 y Critical or unstable clinical condition (invasive ventilation, ECMO) BMI > 30 Colonization with highly resistant or virulent bacteria, fungi or mycobacteria CF patients specifically Mycobacterial colonization/infection remains problematic arterial hypertension peptic ulcer GER (50% or more pretx) Severe or symptomatic osteoporosis Diabetes Should be adequately treated before Tx

Number of Transplants 3000 2750 2500 2250 2000 1750 1500 1250 1000 750 500 250 0 5 7 36 78 190 1985 1986 1987 1988 1989 Bilateral/Double Lung Single Lung 1990 UZ Leuven 419 704 1629 1693 1357 145214621490 1336 1223 1088 921 1991 1992 1993 1994 1995 1996 1997 1882 1932 2071 2384 2448 J Heart Lung Transplant 2010;29: 1083-1141. 2769 2716 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Number 25 20 Lung Transplantations per year in UZ Leuven 20 15 14 13 12 12 13 13 12 10 7 5 2 0

Increasing number of referrals Increasing number of accepted donors Increasing number of transplant procedures Decreasing waiting list mortality

Lung Transplantations per year in UZ Leuven Number 90 80 70 60 57 53 49 47 58 62 81 56 > 50/y 50 40 30 20 20 32 33 43 39 39 10 0

60 30 50 25 Number of centers 40 30 20 10 0 49 32 25 26 14 5 7 1-4 5-9 10-19 20-29 30-39 40-49 50+ 20 15 10 5 0 Percentage of transplants Average number of lung transplants per year Number of centers Percentage of transplants J Heart Lung Transplant 2010;29: 1083-1141

(HEART)-LUNG Tx IN LEUVEN BY DISEASE (n = 766) 5% 23% 3% 2% 2% 4% 6% 14% 42% alpha1 ATD emphysema cystic fibrosis PH Eisenmenger ReTx Fibrosis Bronchiectasis miscellaneous

350 300 250 200 150 100 50 0 < 20 20-30 31-40 41-50 51-60 >60 age distribution

100 75 1988-1994 (N=4,392) 1995-1999 (N=6,726) 2000-6/2005 (N=9,419) Survival (%) 50 25 0 0 1 2 3 4 5 6 7 8 9 10 ISHLT 2007 Years J Heart Lung Transplant 2007;26: 782-795

100 75 1988-1994 (N=4,392) 1995-1999 (N=6,726) 2000-6/2005 (N=9,419) Leuven Survival (%) 50 25 0 0 1 2 3 4 5 6 7 8 9 10 ISHLT 2007 Years J Heart Lung Transplant 2007;26: 782-795 Verleden et al; Clinical Transplants 2007.

75% 60%

Survival evolution in Leuven 5-y survival

Leuven 100 ISHLT Alpha-1 (N=2,187) CF (N=4,144) COPD (N=9,616) IPF (N=5,459) IPAH (N=1,123) Sarcoidosis (N=660) 75 HALF-LIFE Alpha-1: 6.1 Years; CF: 7.1 Years; COPD: 5.2 Years; IPF: 4.3 Years; IPAH: 4.9 Years; Sarcoidosis: 5.1 Years Survival (%) 50 25 Survival comparisons All comparisons with Alpha-1 and CF are statistically significant at 0.01 0 IPAH vs. IPF: p = 0.0210 COPD vs. IPF: p < 0.0001 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Years P=0.0021

Increasing experience Increase in number of transplantations per year Use of marginal donors Use of non-heart beating donors (DCD donors) Use of euthanasia donors

Age > 45-50 j Smokers (> 10 py) PaO2 < 400 mm Hg Chest X-ray with infiltrates Purulent secretions

Meers et al. Transpl Int. 2010;23: 628-35

NHBD De Vleeschauwer et al. JHLT 2011( n=21) Van de Wauwer et al. Eur J CardioThorac Surg. 2011; (n=27)

Increasing experience Increase in number of transplantations per year Use of marginal donors Use of non-heart beating donors (DCD donors) Shift from single to double lung transplantation

HLTx SLtx SSLTx 45 91% 40 35 30 25 20 15 10 5 0 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Increasing experience Increase in number of transplantations per year Use of marginal donors Use of non-heart beating donors (DCD donors) Shift from single to double lung transplantation Specific follow up in Leuven

Outpatient clinic run by specialized nurses, supervised by staff members of transplant unit Every year global check up during short admission All complications treated in own transplant unit in Leuven (role of experience!!)

Increasing experience Increase in number of transplantations per year Use of marginal donors Use of non-heart beating donors (DCD donors) Shift from single to double lung transplantation Specific follow up in Leuven Cooperation with GP/specialist

Calcineurin inhibitor Ciclosporine or tacrolimus Proliferator inhibitor Azathioprine or mycophenolate corticosteroids

Macrolides clarithomycin Antifungal drugs Itraconazole, voriconazole, fluconazole NSAID Ibuprofen and others Antihistamines Antidepressants

Increasing experience Increase in number of transplantations per year Use of marginal donors Use of non-heart beating donors (DCD donors) Shift from single to double lung transplantation Specific follow up in Leuven Cooperation with GP/specialist Better treatment options for chronic rejection

FEV1, L 4 3,5 3 2,5 2 1,5 1 0,5 0 07/01/2002 07/05/2002 07/09/2002 07/01/2003 07/05/2003 07/09/2003 07/01/2004 07/05/2004 07/09/2004 07/01/2005 07/05/2005 07/09/2005 07/01/2006 Postoperative time

Vos R et al. Eur Respir J 2011; 37:164-72.

active placebo P=0.0025

ESW ratg FK + MMF BOS 2 75% ratg Neutrophils in BAL Time after HLTx Verleden et al. Eur Respir J 2005; 25: 221-224.

ESW FEV1 ratg FK + MMF ratg Time after HLTx

Verleden et al. Transpl Int 2011; 24:651-656.

P=0.028

Freedom from BOS 120 100 80 60 40 20 0 69% 53% 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Months post transplantation ISHLT Leuven

Number of Tx procedures is imperative for good results More SSLTx Use of marginal and NHB donors Results of lung transplantation have significantly increased in recent years Expertise of a whole team is extremely important Close follow up is evenly important Chronic rejection remains the major cause of death Role of azi in prevention/treatment ofchronic rejection (35-40% responders) Trying to stabilize FEV 1 decline with MLK

Medics Robin Vos Lieven Dupont Dirk Van Raemdonck Marion Delcroix Jonas Yserbyt Leuven pulmonology and surgical team Erik Verbeken (pathology) Tx Nurses Kristel Jans Kris Rosseel Veronique Schaevers Mieke Meelberg Annemieke Schoonis E 650 paramedics BOF-ZAP researcher Bart Vanaudenaerde PhD Students Kathleen Blondeau Veerle Mertens Nele Geudens Stéphanie Devleeschauwer Caroline Meers Shana Wouters Stijn Verleden David Ruttens, Elly Vandermeulen