Lung Transplantation:Where we are and Where we are going…

Shaf Keshavjee MD MSc FRCSC FACS

Director, Toronto Lung Transplant ProgramSurgeon-in-Chief, University Health NetworkJames Wallace McCutcheon Chair in Surgery

Professor, Division of Thoracic Surgery and Institute of Biomaterials and Biomedical EngineeringUniversity of Toronto

Disclosure

• Vitrolife – Research support and clinical trial

• Astellas Canada – Research Grant

• CIHR/ Wyeth (Pfizer) – Chair in Transplantation Research

• Axela, Xceed Molecular – Research Grant

• Will discuss off label use of devices

2

OVERVIEWLung Transplantation

Overview of Lung Transplantation: Activity, indications outcomes

Changing the practice of clinical lung transplantation Expansion of indications

Bridge to transplant

New Horizons Ex vivo lung perfusion, personalized medicine for the

organ, engineering “super organs”

Adults ILD / IPF

BAC

PAH

CF

Eisenmenger's

COPD /Emphysema

ReTx

Other

Indications for Lung Transplantation Adult (1983-Apr 2012)

N=1245 (96.3 %)

Indications for Transplantation Pediatric (1983-Apr 2012)

N=48 (3.7 %)

6

Number of Transplants / Year 1983-Apr 2012 (YTD)

83

85

87

89

91

93

95

97

99

'01

'03

'05

'07

'09

'11

0

20

40

60

80

100

120HLT

SLT

BLT

Year

No

of T

x /

yr

7

Total Transplants / Year Adult vs. Pediatric

(1983-Apr 2012)-YTD

0

20

40

60

80

100

120'8

3'8

4'8

5'8

6'8

7'8

8'8

9'9

0'9

1'9

2'9

3'9

4'9

5'9

6'9

7'9

8'9

9'0

0'0

1'0

2'0

3'0

4'0

5'0

6'0

7'0

8'0

9'1

0'1

1'1

2

Year

No

of T

x / y

r

Adults Peds

N Peds =48

NUMBER OF LUNG TRANSPLANTS REPORTED BY YEAR AND PROCEDURE TYPE

www.ishlt.org

5 7 38 89204

449

758

972

11601291

13891509 1548 1559

16991783

19712008

2216

2567

2791

3272

2972

1411

2917

0

500

1000

1500

2000

2500

3000

3500

Nu

mb

er

of

tra

ns

pla

nts

Bilateral/Double LungSingle Lung

ISHLT 2011ISHLTJ Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132

n = 38,119

LUNG TRANSPLANTS: Recipient and Donor Age by Year of Transplant

0%

20%

40%

60%

80%

100%

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

Year of Transplant

0

10

20

30

40

50

0-11 12-17 18-34 35-49 50-59 60+ Median Donor Age

% o

f tr

ansp

lan

ts

Med

ian

do

no

r ag

e (y

ears

)

ISHLT 2011ISHLTJ Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132

AVERAGE CENTER VOLUMELung Transplants

54

39

2316

7

28

70

10

20

30

40

50

60

1-4 5-9 10-19 20-29 30-39 40-49 50+

Average number of lung transplants per year

Nu

mb

er

of

ce

nte

rs

0

4

8

12

16

20

24

Number of centers Percentage of transplants

Per

cen

tag

e o

f tr

ansp

lan

ts

ISHLT 2011ISHLTJ Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132

ADULT LUNG TRANSPLANTS (1/1997-6/2009) Risk Factors for 1 Year Mortality

Center Volume

0

0.5

1

1.5

2

5 10 15 20 25 30 35 40 45 50

Center Volume (cases per year)

p < 0.0001

Rel

ativ

e R

isk

of

1 Y

ear

Mo

rtal

ity

ISHLT 2011ISHLTJ Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132

ADULT LUNG TRANSPLANTATIONKaplan-Meier Survival by Era (Transplants: January 1988 – June 2009)

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12

Years

Su

rviv

al (

%)

1988-1994 (N=4,548)1995-1999 (N=6,795)2000-6/2009 (N=20,728)

1988-1994: 1/2-life = 4.7 Years; Conditional 1/2-life = 7.9 Years1995-1999: 1/2-life = 4.8 Years; Conditional 1/2-life = 7.5 Years2000-6/2009: 1/2-life = 5.9 Years; Conditional 1/2-life = 8.0 Years

N at risk =552

N at risk = 702

N at risk = 841

Survival comparisons by era1988-94 vs. 1995-99: p = 0.48581988-94 vs. 2000-6/09: p <0.0001 1995-99 vs. 2000-6/09: p <0.0001

ISHLT 2011ISHLTJ Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132

ADULT LUNG TRANSPLANTATION Kaplan-Meier Survival by Age Group (Transplants: January 1990 – June 2009)

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Years

18-34 (N = 5,523)35-49 (N = 7,980)50-59 (N = 11,389)60-65 (N = 5,685)>65 (N = 1,217)

Survival comparisonsAll p-values significant at p < 0.0001 except 18-34 vs. 35-49: p =0.1708

HALF-LIFE 18-34: 6.4 Years; 35-49: 6.7 Years; 50-59: 5.3 Years; 60-65: 4.4 Years; >65: 3.5 Years

Su

rviv

al (

%)

ISHLT 2011ISHLTJ Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132

ADULT LUNG TRANSPLANTATIONKaplan-Meier Survival By Diagnosis (Transplants: January 1990 – June 2009)

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14Years

Su

rviv

al (

%)

Alpha-1 (N=2,349) CF (N=4,828) COPD (N=10,741)IPF (N=6,478) IPAH (N=1,189) Sarcoidosis (N=756)

HALF-LIFE Alpha-1: 6.3 Years; CF: 7.4 Years; COPD: 5.3 Years; IPF: 4.5 Years; IPAH: 4.9 Years; Sarcoidosis: 5.3 Years

Survival comparisonsAll comparisons with Alpha-1 and CF are statistically significant at < 0.01

COPD vs. IPF: p < 0.0001

ISHLT 2011ISHLTJ Heart Lung Transplant. 2011 Oct; 30 (10): 1071-1132

15

16311498 1557

852953 916 940

175 218 200 220

799837 827

9281116 1171

127114081461

16501766

18921913 18571720

17451676 1683

528456 499 507 536 529 498667

617700 641 686 693 727

765875

926

161133 145 139 151 150 151 150 133 166 128 137 143 153 148 172 200

0

500

1000

1500

2000

25001991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

Waiting List(all) Transplants(all) Ont. Donors©

Waiting List, Transplants and Donors (All Organs-Ontario) (Source: TGLN 1991-2011)

Number

of

Pat

ien

ts

16

Death on Waiting List, Total LTx/yr &

Listed/yr 2004-Jan/2012 (YTD)

Nu

mb

ers

Solutions to Deaths on the Wait List

•Keep the patient alive longer and in better condition Bridge to Transplant

•Increase the supply of donor organs

17

Cypel/Keshavjee ECMO Red Book, 4th edition, 2011.

Selection of ECLS Support Mode /Configuration

NovalungR

Novalung Pumpless A-V Mode: Femoral Artery to Femoral

Vein (extra-corporeal ventilation)

V-V ECLS

CardioHelp Device

Novalung iLAactivve

Dual Lumen Canula (AvalonR)

• One canula inserted through right internal jugular vein

• Drainage from IVC and SVC oxygenated blood returned to right atrium

• Allows mobilisation of extubated patients

Garcia/Griffith et al J Thorac Cardiovasc Surg 2010;139:e137-9

Bridge to Lung Transplant for PAH PatientsSimple Atrial Septostomy is Unsatisfactory

PA LA

RV failure 20 to Pulmonary Vascular Resistance

Atrial Septostomy: provides pressure decompression problem: R-L shunt, hypoxia

Novalung PA to LABridge to Lung Transplant for PAH Patients

“The Oxygenating Septostomy”

PA LA

1. Pumpless

2. Effectively: an oxygenating shunt provides pressure decompression AND gas exchange

Strueber / Keshavjee et al. Am J Transplant 2009; 9: 853-7.

June 2008

Dec 2008

Number of days on PA-LA Novalung

219 14

7 6

30*

69*

174*

0

20

40

60

80

100

120

140

160

180

200

Patients

Day

s o

n P

A-L

A N

ova

lun

g

*Pediatric patients

ECLS decreases wait list mortality in iPAH patients: Toronto experience

0

5

10

15

20

25

1998-2005 2006-2010

Patients listed

Patients transplanted

Died on waiting listp=0.03

Nu

mb

er

of p

atie

nts

de Perrot et al J Heart Lung Transplant 2011

Wait list mortality: 22% 0%

ECLS Toronto Experience2000 – 2012 (10Apr2012)

n = 100

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012(ytd)

0

2

4

6

8

10

12

14

16

18

20

Bridge to recovery (non-Tx)

Bridge to recovery post-transplant

Bridge to lung transplant

Year

Nr

of

EC

LS

IMPROVING SUPPLY:Focus on Organ Recovery and Repair Rather than

Simply Focusing on Slowing Down Death…

Good

Better

Normothermic Ex Vivo Lung

Perfusion (EVLP)• Time to accurately assess - diagnose• Option to treat/repair/recover • Opportunity to reassess - confirm results of treatment

TORONTO EX VIVO LUNG PERFUSION (EVLP) SYSTEM

Perfusion : 40% COVentilation: 7cc/kg, 7BPM, PEEP 5, FiO2 = 21%

J Heart Lung Transplant 2008; 27(12):1319-25.

DEVELOPMENT OF A STABLE AND RELIABLE EX VIVO LUNG PERFUSION TECHNIQUE

Cypel/Keshavjee. Technique for Prolonged Normothermic Ex Vivo Lung Perfusion. J Heart Lung Transplant 2008;27(12):1319-25.

Normothermic Ex vivo Lung Perfusion in Clinical Transplantation – HELP Trial

HELP II TRIAL CLINICAL TRANSPLANTATION OF EX VIVO

PERFUSED LUNGSN=52 transplants to date

Toronto General Hospital OR

Bronchoscopy

LUNG X-Ray

Ex vivo treatment opportunities Donor lung injuries

• 1- Pulmonary Edema

• 2- Brain death associated inflammation

• 3- Infection, Pneumonia

• 4- Aspiration

• 5- Pulmonary emboli

• 6- Ischemia-reperfusion injury

• 7- Immunologic preparation

Su

rviv

al

Survival Days

0.0

0.2

0.4

0.6

0.8

1.0

0 365 730 1095 1460 1825

Low risk group

High risk group

Intermediate risk group

The Wilcoxon testP value: 0.0004

Kaneda H / Keshavjee S et al. Pre-implantation multiple cytokine mRNA expression analysis of donor lung grafts predicts survival after lung transplantation in humans. Am J Transplant 2006 Mar; 6 (3):544-51.

Diagnose Specific Injuries:The expression ratio of IL-6/IL-10 in the donor lung predicts recipient outcome

Ziplex Inflammatory Tip ChipR (Axela)

Pre EVLP Post EVLP

Pre-EVLP sample 1-22 Post-EVLP sample 1-22

Monitoring the Response to Ex Vivo Treatment

Functional Repair of Human Donor Lungs by Ex Vivo IL-10 Gene Therapy

M Cypel, M Liu, M Rubacha, J C Yeung, S Hirayama, M Anraku, M Sato, J Medin, BL Davidson, M de Perrot, TK Waddell, A S Slutsky, S Keshavjee. Sci Trans. Med 1:4ra9; 2009.

PaO2/FiO2

-100

0

100

200

300 *

Cha

nge

from

Bas

elin

e(m

mH

g)

PVR

-600-400-200

0200400600

*

(dyn

es.s

ec.c

m-5

)

EVLP/AdIL-10 EVLP

Delivery of IL-10 by EVLP Ad Gene Therapy to injured human donor lungs resulted in improved lung function

44April 14th 2011, vol. 364, no. 15, pp. 1431-1440.

Resolution of pulmonary edema during EVLP

Donor P/F 230

1h EVLP

3h EVLPRecipient P/F 420

Donor, EVLP and Recipient P/F (n=35)

P/F

Donor 1h 2h 3h 4h ICU

0

100

200

300

400

500

600

EVLP

mm

Hg

Overall Survival

0 200 400 600 800 10000

20

40

60

80

100Control (n=116)EVLP (n=23)

p=0.77

Days after transplantation

Per

cen

t su

rviv

al

median f/u 635 days

48

EVLP Activity /Year 1983-Apr 2012(YTD)

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

'00

'01

'02

'03

'04

'05

'06

'07

'08

'09

'10

'11

'12

0

20

40

60

80

100

120EVLP pre Tx

LuTx-no EVLP

Year

No

of T

x /

yr

53/65 EVLP was successfully Transplanted

49

Operative (30 day) Mortality by year1983-April 2012 (YTD)

0

20

40

60

80

100

120

0 1 1 3 3 1 272 1 2 3 1 4 4 2 3

9 7 4 2 5 5 4 6 18 3 2 11 2

6 615 1314

3627272524

3230313338

5042

59546468

87

100

85

102

84

102

40

Death <=30-d

Number of transplants

Num

ber o

f TX

Year

The Future of Transplantation is here…The “Organ Repair Center”

HeartLung

Kidney Liver

Case Report (April 2011)

• 52 y old male in US• Viral Pneumonia• 7 days ventilator – extubated• Day 14 – re-intubated• Day 22 – VV – ECMO • Day29 – deterioration – bleeding complications• Day 30 urgently listed for LTx

• Day 32 – Donor is identified in another state. • Massive pulmonary edema and P/F 230mmHg

Love R et al. Am J Transplantation 2012. In press

April 2011

Love R et al. Am J Transplantation 2012. In press

Ex vivo Lung Perfusion:The Toronto Experience

• Clinically feasible• Increases the utilization of donor lungs (20% of our current program activity)• Equivalent outcomes trend to improved post transplant lung function• Demonstrated the concept of the “organ repair center”• New era of transplantation:

• “Personalized medicine for the organ”:• More accurate assessment• Treatment specific injuries • Lung transplantation with more predictable outcome

The Toronto Lung Transplant Team

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