Lung Transplantation

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_at_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 1861065
3
New York City Marathon (1998)

• 32 y.o. male patient s/p bilateral lung tx for
  cystic fibrosis.
• Completes marathon in 70850

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
Lung Transplantation

• Unilateral
• Interstitial Fibrosis
• COPD
• Pulmonary Hypertension

• Bilateral, sequential
• Bronchiectasis
• Cystic Fibrosis
• COPD (young patients)
• Pulmonary Hypertension
• Eisenmengers Syndrome (correctable)

7
ISHLT Registry DataSingle versus Bilateral
Plt0.05
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 LTClam 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 (n68) 317 days
• 9/99-present (n25) 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 N70
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 (n32).
• 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 gt 3 months post-transplant 64
Reinchenspurner H, et al. Ann Thorac Surg 1996
62 1467
22

Bronchiolitis Obliterans Syndrome

• Risk Factors
• Acute rejxn RR1.25
• CMV RR1.12
• Recipient age RR1.009/yr
• Antibody induction RR0.84
• Single lung RR1.24
• Incompatible lymphocyte Xmatch RR1.68

• Non-risk Factors
• Pre-LT CMV status, gender, donor age
• High panel reactive antibody (PRA).

plt0.01
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
95C.I. For difference 0.13 to 0.82 plt0.01
Ross DJ, et al. J Heart Lung Transplant 1998
17768-74
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
108547-56.
27
BALF MCP-1 in BOS

• CCR2-/- knock-out murine model ? mononuclear
  recruitment after tracheal transplant
  attenuation of BOS.

P0.01
Plt0.0001
Belperio JA, et al. J Clin Invest 2001
108547-56.
28
Human DefensinsPotential 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
?
? p0.001 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_at_mednet.ucla.edu
• [phone]