Advances in Lung Transplantation - Royal Perth Hospital

Advances in Lung
Transplantation
Eli Gabbay MD FRACP
Medical Director
Western Australian Lung Transplant Unit
Royal Perth Hospital

Survival for Solid Organ Transplantation
RPH LungTransplants
RPH Heart Transplants

Why is Lung Transplantation so
difficult?
“We choose to do these things not because
they are easy but because they are hard”
John Fitzgerald Kennedy 1960
– Surgical
– Immediate Post operative (0 -10 days)
– Early Post Operative ( 0 - 90 days)
– Long term (270 days + )

Why is Lung Transplantation so
difficult?
– Surgical
– Immediate Post operative (0 -10 days)
– Early Post Operative ( 0 - 90 days)
– Long term (270 days + )

Protoplasm
Surgical Issues
– late referral
– prolonged wait (improved with increased donor rates)
Need for pneumonectomy
– bleeding ++
Pleural Space Issues
– infection
–air leak
– need for prolonged in situ Intercostal Catheters

Pneumonectomy in already scarred lungs and pleura can be
associated with chest wall bleeding that may be difficult to
control

Donor Availability
1. Impact of Donate West
- 1.5 x increase in lung donors in 5 years
- medical donor co-ordinator at SCGH
- WA second highest organ donation rate
- RPH 3rd busiest hospital in Australia
2. Greater Donor Pool
- marginal donors (increased use with local donors)
- impact of non-heart beating donors
More donors results in more transplants at a more
optimal time

Maximizing the Utilization of Donor
Organs Offered for LTX
Gabbay E et al
Am J of Respiratory and Critical Care Medicine Vol 160 1999
140 transplants
- from January 1st 1995 to May 31st 1998
- from 112 of 219 (51%) lung donor offers
48 (43%) satisfied published criteria for suitable
organ donors (Group 1)
64 (57%) did not (marginal donors Group 2)

Maximizing the Utilization of Donor
Organs Offered for LTX
Gabbay E et al
Am J of Respiratory and Critical Care Medicine Vol 160 1999
o difference between patients transplanted
from ideal (47%) or marginal donors (53%)
- gas exchange at 24hrs
- length of ICU stay
o difference in 30d, 1yr, 2yr and 3yr survival
nly graft ischaemic time predicted recipient
Pa02/Fi02 ratio

Use of Marginal Donors
Marginal donors can be used without
compromising results from transplantation
providing the ischaemic time is low
A greater percentage of local marginal donors
were used because ischaemic times were low
Implications for having a local program

Why is Lung Transplantation so
difficult?
– Surgical
– Immediate Post Operative (0 -10 days)
– Early Post Operative ( 0 - 90 days)
– Long term (270 days + )

Ischemic reperfusion injury
Most frequent cause of early mortality and
prolonged ICU stay
Frequency 10-20 %
Risk factors
- ischaemic time
- poor preservation
Characterised by non cardiogenic pulmonary
odema
Histologically characterised by diffuse alveolar
damage

Treatment
Volume status important - keep dry
Maintain blood pressure with inotropic support
Requires max ventillatory support, independent
lung ventilation (SLTx)
Nitric Oxide - Reduces length of ICU stay
ECMO (extracorporeal membrane oxygenation)
for severe hypoxia

Prevention
inimise Ischaemic Time
- Ischaemic times in WA are low as most local
donors
prove Organ Preservation
- We are considering adopting a low K+
preservation solution

Why is Lung Transplantation so
difficult?
– Surgical
– Immediate Post Operative (0 -10 days)
– Early Post Operative ( 0 - 90 days)
– Long term (270 days + )

Early Post Operative
Balance between infection and rejection
Lung is open to the environment
- recipient lungs are wonderful growth media
- increased risk of infection post transplantation
Large organ, lots of lymphocytes and
receives total cardiac output
- increased risk of rejection
- requires higher levels of calcineurin inhibitors
- combination of greater exposure to infection +
need for higher levels of immunosuppression

Improvements in Treatment and
Prevention of Infection
– Cytomegalovirus
– Respiratory Viral Infections
• improvements with ribavarin and oseltamivir
– Fungal Infections
• improvements with voriconazole and liposomal
amphotericin

CMV Pneumomitis Post Lung Transplant

CMV and Lung Transplantation
CMV disease has important implications
(?unique) to lung transplantation
Incidence pre prophylaxis 53 - 75 %
Highest of any solid organ transplant
D+ / R- 90-100%; D+ / R+ 55 - 60%
Improvements in prophylaxis
- reduced rates of infection and disease
- reduced rates of chronic graft dysfunction

Post Transplant CMV Prophylaxis
Zamora et al Am J of Transplantation 2004;4:1635
90 Post Lung Transplant (donor or recipient CMV
positive)recipients received I.V. Ganciclovir (5
mg/kg/bd, 2weeks) plus CMV Immunoglobulin
followed by Valganciclovir (450 mg bd) for 180 -
365 days
Compared to 140 historical controls who received
high dose oral Aciclovir instead of Valganciclovir

Post Transplant CMV Prophylaxis
Zamora et al Am J of Transplantation 2004;4:1635
Results:
CMV infection: 7.8 % (valgan) v 35%; p

CMV and Lung Transplantation
pre emptive therapy
uantification of Viral Load (and treat based on this)
- CMV Quantitative PCR (serum and lavage)
- CMV antigenemia
arlier treatment of disease if it does develop
- Less severe disease (not seeing CMV
pneumonitis)
- ? Delayed development of BOS

Why is Lung Transplantation so
difficult?
– Surgical
– Immediate Post operative (0 -10 days)
– Early Post Operative ( 0 - 90 days)
– Long term (270 days + )

Improvements Over Time?

Long Term Problems
Thorn in the side of lung transplantation
Obliterative Bronchiolitis
(Bronchiolitis Obliterans Syndrome; BOS)
Active

Typical FEV1 Plot
Start of baseline
End of baseline
BOS 1
BOS 2
BOS 3

The real meaning of BOS…
BOS is a late phenomenon
- diagnosed at least a month after the
physiological effect of a particular pathological
event first becomes apparent.
Healing by secondary intention is already
established
The fibroproliferative response has been active
for (at least) 4-6 weeks!

Anatomy of the Bronchioles
The killing zone

The real meaning of BOS…
• BOS 0 : 0-20% small airways involved
• BOS 0-p :10-30% small airways involved
• BOS 1 : 20-40% small airways involved
• BOS 2 : 30-50% small airways involved
• BOS 3 : 40-80% small airways involved

Potential therapies
• Corticosteroids
• CNI switching
• Cytolytic therapies
• Azithromycin
• Mycophenolate vs Azathioprine
• MTOR inhibitors
• Radiotherapy
• Surgery (especially for GERD)
multiplicity bespeaks lack of efficacy

CNI Switch from CyA to Tacrolimus:
Demographics
n = 144
M: F = 55: 45
Age = 38 ± 13 (M ± SD)
23%
23%
17%
17%
Indications
Indications
for
for
primary
primary
Tx
Tx
5%
5%
25%
25%
30%
30%
CF COPD/Emphysem Fibrosis PH Others
CF COPD/Emphysem Fibrosis PH Others
Number of p atients
60
50
40
30
20
10
0
55
60
RAR OB Side effects Miscellaneus
arahrudi K, Estenne M, Corris P, Niedermayer J, Knoop C, Glanville AR, Chapparo C et al.
nternational experience with conversion from cyclosporine to tacrolimus for acute and chronic lung allograft rejection.
Thorac Cardiovasc Surg, 2004; 127:1126-1132.
21
8

Switch from CyA to Tacrolimus
Rejection episodes 3 months pre and post switch
Mean of nr. of rejections
2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
1.9
0.27
p = 0.001
0.5
RAR OB
prio r to s witc h post switch
p = 0.001
arahrudi K, Estenne M, Corris P, Niedermayer J, Knoop C, Glanville AR, Chapparo C et al.
nternational experience with conversion from cyclosporine to tacrolimus for acute and chronic lung allograft rejection.
Thorac Cardiovasc Surg, 2004; 127:1126-1132.
0.11

hange in FEV1 (% pred) after switch from CyA to Tacrolimus
FEV1% predicted
90
80
70
60
50
40
30
20
10
0
FEV1( % pred) - Time course
Mean monthly loss in
FEV1% = 2.65%
Best value 6 mo. 3 mo. switch 3 mo. 6 mo. 12 mo.
OB RAR Total
Mean monthly loss in
FEV1% = 1.0%
arahrudi K, Estenne M, Corris P, Niedermayer J, Knoop C, Glanville AR, Chapparo C et al.
nternational experience with conversion from cyclosporine to tacrolimus for acute and chronic lung allograft rejection.
Thorac Cardiovasc Surg, 2004; 127:1126-1132.

CNI Switching: Conclusions
ecurrent Acute Rejection
Tacrolimus is is highly effective in in controlling acute rejection. rejection
Lung function stabilises over a time time period of of 1 year year
bliterative Bronchiolitis
Tacrolimus results in in a reduced rate rate of of progression of of OB OB
Influence of of the the natural history of of OB OB is is unknown
ide effects
No No significant difference in in frequency of of infection or or
impairment of of renal function
Klepetko, et al. JTCVS 2004

Azithromycin
Panbronchiolitis and CF model
Early data hold promise
Definitive trial awaited
Multiple mechanisms
- Anti-inflammatory
- ? antifibrotic
- Disrupt biofilm integrity
- Downregulate epithelial IL2

Azithromycin….. Susan G Gerhardt, John F McDyer, Reda
E Girgis, John V Conte, Steve C Yang, Jonathan B
Orens… AJRCCM

SURGERY
Surgery for gastro- esophageal reflux
disease (GERD):
– Effective
Native lung volume reduction for native lung
hyperinflation syndrome:
– Effective if transplanted lung does not have OB
– Less effective if does have OB
Lung retransplantation:
– Selected patients

Fundoplication for GERD
369 LTx
(Davis et al, JTCVS, 2003;125:533-42)
128 pH probes 93 abnormal
43 fundoplication
pre fundoplication post fundoplication
Number BOS 26/43 13/43
Mean FEV1 1.89L 2.19L
routine transplant group post surgery group
3yr survival 71% 86%
5 yr survival 48% 69%

OB: New Therapies are Needed
Rationale
Cause
- unknown but associated with recurrent
and severe rejection
Process
- inflammation / fibroproliferation
Effect
- endstage intraluminal fibrosis

In vitro effect on fibroblasts
from LTX patients..
“Everolimus and mycophenolate mofetil
are potent inhibitors of fibroblast
proliferation after lung transplantation.”
Andrea Azzola , Adrian Havryk, Prashant Chhajed, Katrin Hostettler, Judith Black,
Peter Johnson, Michael Roth, Allan R Glanville, Michael Tamm
Transplantation: 2004; 77:275-280.

Azzola A, Havryk A, Chhajed P, Hostettler K, Black J, Johnson P, Roth M, Glanville AR, Tamm M.
Everolimus and mycophenolate mofetil are potent inhibitors of fibroblast proliferation after lung transplantation.
Transplantation 2004; 77:275-280.
% Growth +/- SE
150
100
50
-50
0
Effect of Methylprednisolone
on stimulated LTX fibroblasts
0.01 0.1 1 10 50 100
Concentration (mg/l)
Azzola et al

Azzola A, Havryk A, Chhajed P, Hostettler K, Black J, Johnson P, Roth M, Glanville AR, Tamm M.
Everolimus and mycophenolate mofetil are potent inhibitors of fibroblast proliferation after lung transplantation.
Transplantation 2004; 77:275-280.
% Growth +/- SE
150
100
50
-50
0
Effect of Everolimus (RAD)
on stimulated LTX fibroblasts
� �
1 -05 1 -04 0.001 0.01 0.1 1
Concentration (mg/l)

Azzola A, Havryk A, Chhajed P, Hostettler K, Black J, Johnson P, Roth M, Glanville AR, Tamm M.
Everolimus and mycophenolate mofetil are potent inhibitors of fibroblast proliferation after lung transplantation.
Transplantation 2004; 77:275-280.
% Growth +/- SE
150
100
50
-50
0
Effect of Mycophenolate mofetil
on stimulated LTX fibroblasts
0.001 0.01 0.1 0.5 1 5
Concentration (mg/l)
�
��

Three Year Analysis of an
International Randomized Study of
MMF vs. Azathioprine in Lung
Transplantation
On Behalf of the International Study Group
Trial Sponsored by Roche

MMF
1.5gm bd
159 patients
40 deaths
Survival
75%
317 Patients
Survival
72%
SLT 33%
HLT 11%
BLT 56%
AZA
1-2mg/kg/day
158 patients
48 deaths
Survival
69%

Post-Hoc Analysis of Composite Endpoint:
BOS, Death, ReTx, Withdrawal for Lack of
Therapeutic Response
% Event
100
80
60
40
20
0
p = 0.07
0 0.5 1 1.5 2 2.5 3
Years after Randomization
MMF
AZA

Randomized, double-blind study of
everolimus
vs AZA to inhibit the decline of
pulmonary function in stable lung
&
heart-lung transplant recipients
- 24 month results -
On behalf of the RAD B159 Study Investigators

imary composite efficacy endpoint
Month 12
Everolimus AZA
(n=101) (n=112) p-value
Primary composite endpoint: 21.8% 33.9% 0.05
- Decline in FEV1 >15% 15.8% 27.7% 0.03
- Graft loss 1.0% 5.4% 0.06
- Patient death 3.0% 8.9% 0.06
Month 24
Primary composite endpoint: 43.6% 44.6% ns
- Decline in FEV1 >15% 34.7% 41.1% ns
- Graft loss 7.9% 8.0% ns
- Patient death 12.9% 13.4% ns

Steering Committee of the Australian
and European Investigators
in Lung Transplantation

Lung Transplantation
at Royal Perth Hospital

Actuarial survival post lung
transplantation (1992 - 2006)
RPH ISHLT Alfred
1 month 98% (n = 68) 88% 94%
1 year 91% (n = 53) 77% 90%
2 year 85% (n = 41) 68% 78%
3 year 82% (n = 35) 61% 73%
5 year 77% (n = 16) 47% 69%
10 year 66% (n = 5) 22% 44%

RPH First 8 Transplants
Who have we done?
patients in 13 months (target 8 / year first 2 yrs)
edian waiting time 8 weeks
- Australian median 11 months
SLTx, 1 Ht-Lung Tx, 2 BSLTx (7 M; median age 59, range
45 - 64)
- 4 emphysema, 3 ILD (1 pt both), 1 alpha 1
antitrypsin
all hypoxic and hypercapnoeic, functional class IV
- 1 congenital heart disease/ PAH
LV and RV failure, functional class IV, implantable

RPH First 8 Transplants
How have they done?
median ischaemic time 3.0 hrs (range 2 - 5 hrs),
3/7 non-ideal donors resulted in 4/8 transplants
Post operative ventilation 2 - 18hrs (median 9 hrs)
ICU stay 1 - 4 days (median 2 days)
1 death, day 16, wound dehiscence
1 reintubation for 12 hours at day 21
median Hospital stay 27 days (14 - 44 days)
7 alive, functional class I -II, nil requirement for
supplemental oxygen
median 6MWT improvement 215 metres (75 - 345 m)