Lung Transplantation in Patients with Cystic Fibrosis

David Weill, M.D.Director, Lung and Heart -Lung TransplantationDirector, Adult Cystic Fibrosis ProgramStanford University Medical Center

NUMBER OF LUNG TRANSPLANTS REPORTED BY YEAR AND PROCEDURE TYPE

5 7 36 78190

419

704

921

10881223

1336145214621490

16291693

188219322071

23842448

2769

1357

2716

0

250

500

750

1000

1250

1500

1750

2000

2250

2500

2750

3000

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

Nu

mb

er o

f Tr

ansp

lan

ts

Bilateral/Double LungSingle Lung

NOTE: This figure includes only the lung transplants that are reported to the ISHLT Transplant Registry. As such, this should not be construed as representing changes in the number of lung transplants performed worldwide.

ADULT LUNG RECIPIENTSCross-Sectional Analysis

Functional Status of Surviving Recipients(Follow-ups: April 1994 – June 2009)

0%

20%

40%

60%

80%

100%

1 Year (N = 6,845) 3 Year (N = 4,381) 5 Year (N = 2,516) 10 Years (N = 430)

No Activity Limitations Performs with Some Assistance Requires Total Assistance

Lung Transplantation Procedure Options

• Double-lung transplantation – Donor hearts could serve other patients– Avoids risk of accelerated atherosclerosis

• Heart-lung transplantation – Less commonly performed in the US– Fewer airway complications

• Bilateral living lobar transplantation – Reduced incidence and intensity of rejection– Circumvents the donor shortage problem– Considerable risk to donors

• Split-lung transplantation– Single donor can serve multiple recipients– Technically difficult procedure

Shennib H. Arch Intern Med. 1992.Starnes VA, et al. J Thorac Cardiovasc Surg. 1994.

Boehler A. Swiss Med Wkly. 2003.

Double-Lung Transplantation

Photos courtesy of Woo MS.

CF and Lung Transplant

• The course of CF is very unpredictable, and that makes the timing for transplant more difficult

• About 1600 CF recipients since 1991• 120-150 recipients each year • Second largest group to get transplanted• CF recipients do better in general than

non-CF recipients

Transplantation Window of Opportunity—in an Ideal World

Time

Cli

nic

al c

ou

rse

TOO SOON TOO LATE

Marshall SE, et al. Chest. 1990.

“Transplant window”

Transplantation Window of Opportunity—in Reality

Time

Cli

nic

al c

ou

rse

TOO SOON? TOO LATE?

“Transplant window??”

Difficult Questions to Ask Before Organ Transplantation

• When should a patient be referred for evaluation?

• When should a patient be placed on the waiting list?

• When should a patient have a transplant?

Referral for Lung Transplant

• Patient readiness

• Transplant team readiness and comfort level

• Local transplant center culture

• Wait times (less important now because of LAS)

Lung Allocation Score

• New scoring system since May 2005

• “How bad you need it + How well you’ll do with it”

• Applies to transplant candidates > 12 yrs

• Scores range from 0-100

• Scores can be updated

Lung Allocation Score: Clinical Information

• Diagnosis• Age• Height and Weight

(BMI)• Diabetes• Use of supplemental

oxygen• Six minute walk

distance

• PASP• PCWP• FVC• Serum Creatinine• Functional Status• Assisted Ventilation

Lung Allocation Score:CF Variables That Are Not Included

• FEV1

• pCO2

• Infections

• Antibiotic Sensitivity of Infections

• Hemoptysis

• Frequency of Exacerbations

The Kerem Survival Model

Significant predictors of 2-year survival

Single covariate analysis Multiple covariate analysis

FEV1 and FVC FEV1

Female gender Female gender

Low arterial pO2 Age

High arterial pCO2

Low weight-for-height

Kerem E, et al. N Engl J Med. 1992.

Consensus Guidelines for Referral of Lung Transplant Candidates with CF

• FEV1 ≤30% of predicted with rapid, progressive respiratory deterioration– Increasing number of hospitalizations– Massive hemoptysis– Recurrent pneumothorax– Increasing cachexia– Rapid fall in FEV1

• Hypoxemia: PaO2 <55 mm Hg• Hypercapnia: PaCO2 >50 mm Hg• <50% survival in 2 years• Early referral is recommended for young female patients,

who have particularly poor prognosis

American Thoracic Society. Am J Respir Crit Care Med. 1998.Boehler A. Swiss Med Wkly. 2003.

The Validated Predictive 5-Year Survival Model of CF

FEV1 % equivalency*

Increased survival:

• Pancreatic sufficiency +12

• Higher weight-for-age z-score +10

• Staphylococcus aureus infection +6

• Higher FEV1% +1

Decreased survival:

• Burkholderia cepacia infection –48

• Diabetes mellitus –13

• Acute pulmonary exacerbation –12

• Female gender –6

• Increasing age –0.7*Difference in FEV1 (% predicted) required for equivalent effect on survival

Liou TG, et al. Am J Epidemiol. 2001.

Equivocal Survival Benefit of Lung Transplantation in Patients with FEV1 ≤30%

Liou TG, et al. JAMA. 2001.

ControlLung Transplant

0

20

40

60

80

100

0 1 2 3 4 5Time (yr)

Su

rviv

al (

%)

Predicting the “Right Time” for Transplant

• Study to look at who was listed too late

• Evaluated who was listed for transplant but died before receiving new lungs

• Rationale is that there are things that the transplant centers integrate with the variables collected by the CFF Registry and UNOS

• Four transplant centersBelkin et al. AJRCCM 2006

Predicting the “Right Time” for Transplant

Variables that increased risk of death• FEV1 < 30% predicted• Shorter height• PaCO2 > 50mmHg• Need for nutritional intervention

Variables that decreased risk of death• Referral from a CF Center • Listing after 1996

Belkin et al. AJRCCM 2006

International Guidelines for the Selection of Lung Transplant Candidates: 2006 Update

• Guidelines for referral:– FEV1 below 30% predicted or a rapid decline in FEV1

– in particular young female patients– Exacerbation of pulmonary disease requiring ICU stay– Increasing frequency of exacerbations requiring abx– Refractory/recurrent pneumothorax– Recurrent hemoptysis not controlled by embolization

International Guidelines for the Selection of Lung Transplant Candidates: 2006 Update

• Guidelines for transplant:– Oxygen-dependent respiratory failure– Hypercapnia– Pulmonary hypertension

Absolute Contraindications to Lung Transplantation

Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic Fibrosis. 1997.American Thoracic Society. Am J Respir Crit Care Med. 1998.

LungTransplant

Other major organ dysfunction

Infections affectinglong-term survival

Cardiovascular diseaseHIV

Liver disease: hepatitis CHepatitis B or C

Tuberculosis

Active malignancy <5 years

Renal failure: ClCr <50 mL/min

Other organ damage

Relative Contraindications to Lung Transplantation

Symptomatic osteoporosis

Substance addiction

Psychosocial problems

Nutritional status (<70% or >130% IBW)

High-dose corticosteroid use

Kyphoscoliosis

Invasive ventilation

Fungi or atypical mycobacteria

Pan-resistant organisms

American Thoracic Society. Am J Respir Crit Care Med. 1998.

LungTransplant

CF-relatedarthropathy

Postoperative Issues specific to CF Lung Transplant Recipients

Excess Mortality Associated with Preoperative B cepacia Infection

Chaparro C, et al. Am J Respir Crit Care Med. 2001.

0

20

40

60

80

100

0 1 3 4 5Year

2

Pro

po

rtio

n s

urv

ivin

g (

%)

No infection

B cepacia

P = 0.003

Post-transplant Survival Influenced by B cepacia Genomovar Type

Aris RM, et al. Am J Respir Crit Care Med. 2001.De Soyza A, et al. Lancet. 2001.

Deaths (N) in patients infected with

Study Genomovar III Non-genomovar III P value*

Aris 5 0 0.035

De Soyza 4 0 0.007

*Genomovar III vs non-genomovar III

Lung Transplantation in Adult CF Patients with History of Acute Respiratory Failure

n = 17 (40%) Received lung transplants

n = 14 (82%) Alive at 1 year postoperation

N = 42 Admitted to ICU with hypercapnic respiratory failure

n = 19 (45%) Died in ICU

n = 3 (7%) Died within 6 months

of ICU discharge

n = 3 (7%) Alive at 1 year

without lung transplant

Sood N, et al. Am J Respir Crit Care Med. 2001.

Potential Surgical Complications of Lung Transplantation

Zuckerman JB, et al. Clin Chest Med. 1998.Trulock EP. Am J Respir Crit Care Med. 1997.

Akindipe OA, et al. Chest. 2000.

Complication Prevalence (%)

Most serious

•Primary graft failure due to ischemia-reperfusion injury/diffuse alveolar damage

15-35

•Anastomotic complications: vascular or airway

7

Most common

•Phrenic/vocal cord paresis 3-30

•Gastroparesis 25-30

Potential Medical Complications Following Lung Transplantation

• Obliterative bronchiolitis (BOS/chronic rejection)• Acute rejection• Infection: viral, bacterial, fungal, protozoal• Toxicity of immunosuppressives

– Nephrotoxicity– Hypertension– Hirsutism, gingival hyperplasia

• Diabetes• Hyperlipidemia• Post-transplant lymphoproliferative disease (EBV)

Zuckerman JB, et al. Clin Chest Med. 1998.Kurland G, et al. Curr Opin Pediatr. 1994.

Recommended Follow-up of Transplant Recipients

• Regular monitoring of PFTs, chest x-rays, and blood tests – Creatinine, complete blood count, liver function tests,

CMV infection

• Post-transplant bronchoscopy; surveillance with BAL and transbronchial biopsy following:– Decline in PFTs – Change in chest x-ray– Onset of new symptoms– Acute rejection

Photo courtesy of Woo MS.

Special Issues for the CF Patient

• Colonization vs. infection• Sinus disease• GI Issues:

– GERD– Pancreatic Insufficiency– Nutrition– DIOS

• CFRD• Osteoporosis• Psychosocial

French Lung Transplant Experience for CF

• Compared two five year periods (2000-2005 and 2005-2010)– Improved one year survival (75% to 88%) due

to: extensive use of thoracic epidurals leading to increased early extubations

Mordant et al. European Journal of Cardiothoracic Surgery. 2010

Survival of Transplant Recipients by Procedure Type

Trulock EP, et al. J Heart Lung Transplant. 2004.

0

20

40

60

80

100

Su

rviv

al (

%)

0 2 4 6 8 10 12 14 16 18 20

Years

Bilateral lung (N = 6686)

Single lung (N = 8581)

All lungs (N = 15,267)

Causes of Death in Lung Transplant Recipients

Trulock EP, et al. J Heart Lung Transplant. 2004.

0

10

20

30

40

50

60

70

80

90

0-30 days 31 days-1 year >1-3 years >3-5 years >5 years

Time after transplantation

Pe

rce

nt

of

de

ath

s

Technical complication Graft failure Cardiovascular disease

Infection – Non-CMV Chronic rejection Malignancy – Non-lymphoma

Early complications Late complications

Summary

• CF is the third most common indication for lung transplant

• Decision of transplantation is derived from a comprehensive evaluation that MUST take into account several indicators of disease severity: FEV1, increase in O2 need, hypercapnia, need for non-invasive ventilation, functional status & pulmonary hypertension.

Summary

• Post-transplant survival of CF patients is similar or even greater than survival of patients w/ other conditions