CM-1

Clinical Transplantation Lung

Clinical Transplantation Lung

Howard University Hospital

Department of Transplantation

Clive O. Callender, MD.

Arturo Hernandez, MD

CM-2

Objective

Current Status of Lung Transplantation

CM-3

No of Transplanted Organs vs Waiting List 2004

Recovered Transplanted Waiting List

Total 25,237 26,539 86,378

Kidney 12,575 15,671 (9,025) 57,910 PTA 2,021 132 504 PAK 418 973 K-P 879 2,410 Liver 6,405 5,780 (5,457) 17,133 Intestine 167 52 196 Heart 2,096 1,961 3,237 Lung 1,973 1,168 3,852 Heart-lung 37 171 Source: 2005 OPTN/SRTR Annual Report,

CM-4

Graft SurvivalFollow-up Period 1 Year 10 Years

Tx 2002-2003 Tx 1993-2003 Kidney Deceased Donor Graft Survival 89.0% 40.5% Patient Survival 94.6% 60.7% Kidney: Living Donor Graft Survival 95.1% 56.4% Patient Survival 97.9% 76.4% Kidney-Pancreas Kidney Graft Survival 91.7% 52.5% Pancreas Graft Survival 85.8% 53.6% Liver Deceased Donor Graft Survival 82.2% 52.5% Patient Survival 81.7% 67.0% Intestine Graft Survival 73.8% 22.0% Heart Graft Survival 86.8% 51.1% Lung Graft Survival 81.4% 22.1% Heart-Lung Graft Survival 55.8% 24.6%

UNOS/SRTR, 2003

CM-5

Current Status of Lung Transplantation

Long term survival—50% die by 5 years

Bronchiolitis obliterans (chronic rejection)—primary cause of poor survival

Future of lung transplantation is prevent bronchiolitis obliterans

CM-6

Lung TransplantationPre-Cyclosporine Era, Pre-1983

Time (days)

(4)

(12)

(19)

(28)

(38)

At risk:

0 50 100 150 200 250

0

20

40

60

80

100

% f

ree

fro

m d

eath

CM-7

0

200

400

600

800

1000

1200

1400

1600

1800

85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03

Year

Double lung

Single lung

Worldwide Lung Transplantation Numbers

Source: International Society of Heart and Lung Transplantation (ISHLT); UNOS

Lung transplants performed worldwide, by year

Emphysema/COPDIdiopathic pulmonary fibrosisCystic fibrosisAlpha-1 antitrypsin deficiencyPrimary pulmonary hypertensionSarcoidosisRetransplant/graft failureOther

1.8%2.6%

4.2%

39.0%

10.4%

17.0%16.0%

9.0%

Primary diagnosis, 01/1995 - 06/2003

13421337

14171413

14101508

1537

17061655

12061069

902

685

408

18580471513

CM-8

Comparative Transplantation Survival Rates

0

25

50

75

100

0 1 2 3 4 5 6 7 8 9 10

Time, years

Su

rviv

al,

%

Alpha-1 antitrypsin

Cystic fibrosis

Emphysema/COPD

IPF

PPH

0

25

50

75

100

0 1 2 3 4 5 6 7 8 9 10

Time, years

Kidney—living donor

Liver—cadaveric donor

Heart

Primary lung transplant by underlying diagnosis

Primary kidney, liver, and heart transplant

*Kidney, liver, and heart data extrapolated from OPTN Annual Report, 2003.

Chiron Briefing Document Figure 2.2-1

CM-9

CM-10

Clinical Manifestations of Chronic Rejection

Two methods for the diagnosis of chronic rejection– Histologically through transbronchial biopsy (OB)– Clinically through sustained decline in pulmonary

function (Bronchiolitis Obliterans Syndrome, BOS)– OB and BOS are histologic and clinical

manifestations of the same process Patients develop progressive shortness of breath,

graft failure, airflow obstruction, recurrent pulmonary infections

Once chronic rejection develops, airway damage is progressive and irreversible– Patients die of graft failure/pneumonia

CM-11

Causes of Death Following Lung Transplantation

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 - 30days

31 days -1 year

> 1 - 3years

> 3 - 5years

> 5 years

Bronchiolitis

Infection, non-CMV

Graft failure

Other

Cardiovascular

Acute rejection

Malignancy

Technical

CMV

Lymphoma

CM-12Despite Best Current Systemic Treatment and Patient Management, Chronic Rejection

Eventually Affects Most Patients

0

20

40

60

80

100

0 1 2 3 4 5 6 7

Years from transplant

0

20

40

60

80

100

Calcineurin inhibitors

Anti-metabolites Prednisone

CsACsA

TacTac

AZAAZA

MMFMMF

% ofpatients

Plus induction, plus pulsed intensifications prn

Source: ISHLT, market research

Despite best available therapy

% chronic rejection-free

survival

CM-13

New Concept: Avoid Increasing Systemic Immunosuppression

• Infection• GERD• Others

• Infection• GERD• Others

ImmuneactivationImmune

activation

Increasesystemic immune

suppression

Increasesystemic immune

suppression

BOSBOS

NonNonalloimmunealloimmunefactors:factors:

CM-14

Epithelial injury

Inflammation

Fibroblastic repair

Pathway to Chronic Rejection

Non-alloimmune stimuli Airway ischemia Viruses Bacterial - PSEUDOMONAS Oxidant stress Reflux

Alloimmune stimuli Recurrent acute vascular rejectionRecurrent acute vascular rejectionLymphocytic bronchitis

CM-15

Lymphocytic Bronchitis/Bronchiolitis

CM-16

Acute Rejection

Acute rejection is a perivascular process diagnosed by transbronchial biopsy

CM-17

Separate Interventions for Separate Processes

Systemic immunosuppression

rejection and ongoing injury, inflammation and fibrosis ending in bronchiolitis obliterans

Systemic administration to avert vascular rejection, halting lymphocytic recruitment and activation