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Lung Transplantation

Lung Transplantation. David J. Ross, M.D. Medical Director, Lung & Heart-Lung Transplant Program Director, Pulmonary Hypertension Program Associate Professor of Medicine U.C.L.A. School of Medicine dross@mednet.ucla.edu. J.D. Hardy (1963): 1 st Human Lung Transplant.

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Lung Transplantation

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  1. Lung Transplantation David J. Ross, M.D. Medical Director, Lung & Heart-Lung Transplant Program Director, Pulmonary Hypertension Program Associate Professor of Medicine U.C.L.A. School of Medicine dross@mednet.ucla.edu

  2. J.D. Hardy (1963):1st Human Lung Transplant • 58 y.o. male patient • (L) mainstem bronchogenic CA & (R) severe COPD • (L) Single lung tx on June 11, 1963. • Immunosuppression: AZA, prednisone, Cobalt irradiation. • Survived 18 days J.D. Hardy, W.R. Webb, M.L. Dalton, et al. JAMA 1963; 186:1065

  3. New York City Marathon (1998) • 32 y.o. male patient s/p bilateral lung tx for cystic fibrosis. • Completes marathon in 7:08:50 Scand J Med & Science in Sports, 2000

  4. Organ Transplants 2001: UNOS UNOS Statistics 5/1/02

  5. UNOS “Waiting List” UNOS Statistics 5/1/02

  6. Unilateral Interstitial Fibrosis COPD Pulmonary Hypertension Bilateral, sequential Bronchiectasis Cystic Fibrosis COPD (young patients) Pulmonary Hypertension Eisenmenger’s Syndrome (correctable) Lung Transplantation

  7. ISHLT Registry Data:Single versus Bilateral P<0.05 Meyer DM, et al. J Heart-Lung Transplant 2002; 20(9):935-41.

  8. SLT vs BLT by Recipient Age Meyer DM, et al. J Heart-Lung Transplant 2002; 20(9):935-41

  9. Bilateral Sequential LT:“Clam Shell” Incision

  10. Single Lung Transplant: IPF

  11. Alpha-1 Anti-trypsin Deficiency: Single Lung Transplant

  12. Median Waiting Times • Introduction of “Expanded Donor Criteria Program” in Sept 1999. • 1995-8 cohort (n=68): 317 days • 9/99-present (n=25): 105 days

  13. 1-year Survival 8 12 • Development of “New Team” in July 1999. • Medicare/HCFA Certification • “Expanded Donor Criteria” Program • “Waiting Time” Issues in Southern Cal 15 (N) 13 10 18 25 12

  14. Median Total Hospital LOS • Median ICU LOS with “Expanded Donor” is 3  4 days. • Acceptable allograft function without prolonged intubation • Inhaled N.O. only for established reperfusion injury. • “Modified reperfusion” CTS protocol

  15. UCLA Lung Transplant Program: Patient Survival Actual Survival, 10/1/97-6/1/02; N=70

  16. Relative Risk of Death for LT versus Continued Waiting Disease 6 mos 12 mos • COPD (163) 0.55 0.32 SLT (92) 0.58 0.38 DLT/HLT (35) 0.54 0.29 • C.F. (174) 0.21 0.15 • Eisenmenger (76) 1.26 0.85 • Bronchiectasis (51) 0.58 0.58 • IPF (100) 0.65 0.46 SLT (63) 0.71 0.54 DLT/HLT (47) 0.57 0.36 • PAH (68) 0.37 0.34 Charman SC, et al. J Heart and Lung Transplant 2002; 21(2):226-32.

  17. Pulmonary Arterial Hypertension in IPF Novel therapies for a serious complication

  18. Bosentan (Tracleer™) • Oral, dual ET-1 receptor antagonist • Class III/IV with either PPH or PSS (n=32). • 12 week placebo-controlled study. • Bosentan vs placebo: • 6-minute walk: +70 vs -6 meters • Cardiac index: +0.5 0.1 vs -0.50.1 L/min/m2 • mPAP: -1.6 1.2 vs +5.12.8 mm Hg • PVR: -22356 vs +19174 dynes/sec/cm-5 • RA: -1.30.9 vs +4.91.5 mm Hg[Mean SE] Channick R, et al. Lancet 2001; 358(9288):1119-23.

  19. Vascular Biology ET-1 AA COX PGI2 ETB ETB ETA BIG ET-1 ECE ET-1 CONTRACTION L-arginine NOS NO (–) cAMP K+/Ca2+ RELAXATION cGMP Smooth muscle cell Endothelium

  20. Bronchiolitis Obliterans Syndrome [BOS] “Constrictive Bronchiolitis”

  21. BOS: Stanford Experience Prevalence of BOS > 3 months post-transplant ~ 64% Reinchenspurner H, et al. Ann Thorac Surg 1996; 62: 1467

  22. Non-risk Factors Pre-LT CMV status, gender, donor age High panel reactive antibody (PRA). Bronchiolitis Obliterans Syndrome Risk Factors • Acute rejxn: RR=1.25* • CMV: RR=1.12* • Recipient age: RR=1.009/yr* • Antibody induction: RR=0.84 • Single lung: RR=1.24 • Incompatible lymphocyte Xmatch: RR=1.68 *p<0.01 Novartis Lung Transplant Database, 1998

  23. U.C.L.A. Immunosuppressive Protocol • Tacrolimus (Prograf) • Mycophenolate mofetil (Cellcept) • Prednisone • rATG (Thymoglobulin ) x 1-3 days • BOS  Methotrexate Sirolimus  rATG

  24. Cellcept [MMF] versus Imuran  [AZA] after Lung Transplantation XSD [95%C.I. For difference: 0.13 to 0.82; p<0.01] Ross DJ, et al. J Heart Lung Transplant 1998; 17:768-74

  25. Collaborative Research U.C.L.A. Lung & Heart-Lung Transplant Program

  26. Role for C-C Chemokine MCP-1/CCR2 in BOS • Chemoattractant for mononuclear phagocytes, CD45RO+ T lymphocytes, B cells, & NK cells. • Involved in chronic inflammatory & fibroproliferative diseases e.g. rheumatoid arthritis. • MCP-1 binds & signals through seven-transmembrane G protein-coupled receptor, CCR2. Belperio JA, et al. J Clin Invest 2001; 108:547-56.

  27. BALF MCP-1 in BOS • CCR2-/- knock-out murine model—  mononuclear recruitment after tracheal transplant & attenuation of BOS. P=0.01 P<0.0001 Belperio JA, et al. J Clin Invest 2001; 108:547-56.

  28. Human Defensins:Potential Effects on Adaptive Immunity • (a-HD)  Neutrophil chemotaxis through epithelial elaboration of IL-8. • (a-HD)  T-cell release of g-IFN, IL-6 & IL-10 • (HbD-2)  Memory helper T-lymphocytes (CD4+/CD45RO+) & progenitor-derived immature dentritic cells (CD34+) through chemokine receptor (CCR6).1 1. Yang D, et al. Science 2000; 286(5439):525

  29. BAL [HBD2]   p=0.001; Kruskal-Wallis ANOVA (MedianSEM) • Ross DJ, et al. J Heart and Lung Transplant 2002; 21(1):A75.

  30. Lung Transplantation David J. Ross, M.D. Medical Director, Lung & Heart-Lung Transplant Program Director, Pulmonary Hypertension Program Associate Professor of Medicine U.C.L.A. School of Medicine dross@mednet.ucla.edu (310) 825-6068

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