lung transplantation for cystic fibrosis · -fev1 that has fallen to 30% or a patient with advanced...

LUNG TRANSPLANTATION FOR CYSTIC FIBROSIS

C. Knoop, I. Etienne, I. Wellemans, M. Ruiz,

Y. Sokolow, M. Cappello

Unité de Tx cardiaque et pulmonaire

Hôpital Universitaire Erasme, Bruxelles

[email protected]

1

2

Lung Homotransplantation in Man: Report of the Initial CaseJames D. Hardy, MD; Watts R. Webb, MD;

Martin L. Dalton, MD; George R. Walker, MD

JAMA. 1963;186(12):1065-1074.

1963

25th South Eastern European Cystic Fibrosis Conference

3

1982-1983

COMBINED HEART-AND-LUNG TRANSPLANTATION FOR LYMPHANGIOLEIOMYOMATOSISEstenne M, de Francquen P, Wellens F,

Leclerc JL, Vanderhoeft P, Yernault JC,

Primo G.

The Lancet 1984; 323: 275.

3

Types of lung transplantations

4

• (Heart- lung transplantation)

• Single lung transplantation

• Double lung transplantation

• Lobar transplantation

Adult and Pediatric Lung TransplantsNumber of Transplants by Year and Procedure Type

JHLT. 2013 Oct; 32(10): 965-978

2013

Adult Lung TransplantsIndications for Bilateral/Double Lung Transplants

(Transplants: January 1995 – June 2012)

JHLT. 2013 Oct; 32(10): 965-978

2013

Adult Lung TransplantsIndications for Single Lung Transplants

(Transplants: January 1995 – June 2012)

JHLT. 2013 Oct; 32(10): 965-978

2013

Adult Lung TransplantsMajor Indications By Year (Number)

JHLT. 2013 Oct; 32(10): 965-978

2013

Recipient selection: general criteria

9

• End-stage respiratory disease, symptomatic

(NYHA III-IV class), progressive, irreversible

• Ambulatory patient with a potential for rehabilitation

• Well-informed, motivated and compliant

• Reduced life expectancy

Primary goal = survival benefit


Absolute contra-indications

10

Few today

• Cancer (exception for skin cancers, (no melanoma !)

• Active hepatitis B or C infection with histologically significant

tissue damage

• HIV (?)

• Active smoking, drug or alcohol abuse

• Severe mental illness

• Non-compliance

• No social network or support system


Relative contra-indications

11

• Age > 65 yrs, no fixed age limit

• Renal or hepatic insufficiency

• Obesity – Malnutrition

• Medical comorbidities– Atheromatosis, especially if coronary involvement

– (GERD)

– (Diabetes)

– Osteoporosis with fractures

– Multiplicity of co-morbidities

• Pleurodesis

• Mechanical ventilation – ECMO

• CF: Bcc – Mycobacterium abscessus


J Heart Lung Transplant 2006; 25(7):745-55

Timing of referral- FEV1 that has fallen to 30% or a patient with advanced disease with a rapidly falling

FEV1 despite optimal therapy (particularly if female), infected with NTM or Bccand/or diabetes.

- a 6-minute walk distance of < 400 m.- Development of pulmonary hypertension in the absence of a hypoxic exacerbation,

(systolic PAP >35 mmHg on echocardiography or a mean PAP >25 mmHg on right heart catheterization)

- Clinical decline characterized by increasing frequency of exacerbations associatedwith any of the below: - An episode of acute respiratory failure requiring NIV. - Increasing antibiotic resistance and poor clinical recovery from exacerbations. - Worsening nutritional status despite supplementation.- Pneumothorax. - Life-threatening hemoptysis despite bronchial embolization.

J Heart Lung Transplant 2006; 25(7):745-55

Timing of listing- Chronic respiratory failure.- With hypoxia alone PaO2 > 60 mm Hg.- With hypercapnia PaCO2 > 50 mm Hg.- Chronic non-invasive ventilation therapy.- Pulmonary hypertension.- World Health Organization Functional Class IV.

Waiting time


Allocation rules

15

• Allocation is patient-specific

• Allocation based on time waited, ABO blood group, and size

compatibility

• No prioritization according to disease/medical urgency

• Urgent organ request strictly limited

• LAS applicable in Germany

• The LAS has had a positive impact on the majority of wait-listed patients in the U.S.

Chen AJRCCM 2009;180: 468.


Waiting list mortality Candidates in ET 1995-2005

16

% patients listed

Restrictive

VascularCF

Other

COPD


Transplant window

Cli

nic

al

co

urs

e

Time

Referral

Too lateTW

Crucial time-points

17

18

Surgical technique

19

ECLS pre-, peri- and post-operatively

Primary Lung Transplantation After Bridge With Extracorporeal Membrane

Oxygenation: A Plea for a Shift in Our Paradigms for Indications.Lang Transplantation 2012; 93: 729.

Bridge &&&& IMPROVE


Surgical complications

20

• Hemorrhagies

• Primary graft dysfunction

• Phrenic nerve palsy

• Anastomotic complications

Surgical ‘mortality’ 5-10%


Medical complications

21

• Acute rejection

• Chronic allograft dysfunction

• Infections

• Cardio-vascular/metabolic complications


22GLEM 12/2013 - CHU du Sart Tilman

CD4+

DIRECTRECOGNITIONof alloantigens

INDIRECTRECOGNITIONof alloantigens

IL-4IL-5

Mf

CD8+

CD4+CD8+ CD4+

CD4EFF.

CD4EFF.

CD4EFF.

Donor DC Recipient DC

Help

Y

CD4

B

CD4

:Allo-MHC class I

:Allo-MHC class II

:Recipient-MHC class IIwith allo-peptides

: Granules with perforin and granzyme

Le Moine Transplantation 2002

CD4EFF.

CD8CD8

CD8

CD8

IFN-g

Eo

PMN

23

Degree of immunosuppression after solid organ transplantation

24

Immunosuppression after LTx

25

• INDUCTION therapy

• MAINTENANCE therapy

1) Calcineurin Inhibitors

Tac = Prograft or CsA = Neoral

2) Cell cycle Inhibitors

Mycophenolate mofetil = Cellcept or Azathioprine = Imuran

3) Steroïds

• Treatment of ACUTE REJECTION


Bronchiolitis obliterans syndrome: Risk factors

28

Probable:

1) Acute rejection (severe, persistant, recurrent)

2) Lymhocytic bronchitis/bronchiolitis

3) CMV pneumonia

4) Incompliance !

Potential:

1) Respiratory infections (viral, bacterial, fungal)

2) Older donor and prolonged ischemia time

3) GERD


29

FibrosisNormal

InjuryInflammatory response

Repair response withfibroblast proliferationand extracellular matrix

depositionInnate immune response(PMN, macrophages,

dendritic cells)

Adaptive immune response

(T-/B-lymphocytes)

Primary damage to the airway epithelium

(rejection, ischemia-reperfusion injury, infection, aspiration)

Adult Lung TransplantsFreedom from Bronchiolitis Obliterans Syndrome

N at risk at 5 years = 2,614

Adult Lung Transplants Relative Incidence of Leading Causes of Death

(Deaths: January 1992 – June 2012)

Time-table for the occurrence of infection after solid organ transplantation

Time (months)

Bacterial pneumonia

2 4 6 8 10 12

Wound infection

Bacterial

Viral

Listeriosis

KT-related sepsis

HSV, HHV-6

CMV

EBV

Rubin 2002

Fungal

Aspergillus

1

Pneumocystis jirovecii

32

CF-specifics

– Pre-tx colonisation with Aspergillus fumigatus does not increase the incidence

of invasive aspergillosis

– Pre-tx colonisation with pan-resistantfungi remains a problem

(e.g.Scedosporium apiospermum)

Flume et al. 1994

THE PECULIAR ANATOMIC SITUATION OF THE TRANSPLANTED LUNG

17 novembre 2014 34

X

X

X

� NO BRONCHIAL ARTERIAL BLOOD SUPPLY

� Bronchial anastomosis

THE PECULIAR ANATOMIC SITUATION OF THE TRANSPLANTED LUNG

17 novembre 2014 35

17 novembre 2014 36

CF SINUS DISEASE: IMPACT ON GRAFT SURVIVAL

CFpathogens

EFFECTS OF CYCLOSPORINE ON GLOMERULAR CIRCULATION IN THE RAT1

Vasoconstricted arteriole (arrow) after14 days of oral cyclosporine therapy

Control

1. English et al. Transplantation 1987; 44: 135-141.

37

Adult Lung TransplantsCumulative Morbidity Rates in Survivors within 1 and 5 Years

Post-Transplant (Follow-ups: April 1994 – June 2012)

Outcome Within 1 Year

Total number

with known response

Within 5 Years

Total number

with known response

Hypertension 51.7% (N = 15,267) 82.4% (N = 4,503)

Renal Dysfunction 23.3% (N = 17,291) 55.4% (N = 5,571)

Abnormal Creatinine ≤ 2.5 mg/dl 16.2% 36.5%

Creatinine > 2.5 mg/dl 5.2% 15.0%

Chronic Dialysis 1.7% 3.2%

Renal Transplant 0.1% 0.7%

Hyperlipidemia 25.5% (N = 15,975) 58.4% (N = 4,856)

Diabetes 24.6% (N = 17,227) 40.5% (N = 5,498)

Bronchiolitis Obliterans Syndrome 9.5% (N = 16,264) 39.7% (N = 4,701)

JHLT. 2013 Oct; 32(10): 965-978

2013

Adult Lung TransplantsKaplan-Meier Survival by Diagnosis(Transplants: January 1990 – June 2011)

JHLT. 2013 Oct; 32(10): 965-978

2013

Adult Lung TransplantsFunctional Status of Surviving Recipients

(Follow-ups: March 2005 – June 2012)

JHLT. 2013 Oct; 32(10): 965-978

2013

Conclusions: LTx in 2014

41

1) Surgical technique ‘under control’

2) Important life-long immunosuppression

3) BOS = 1st cause of death (medium-term)

4) Infectious and metabolic complications have an

impact on medium- and long-term survival

5) Scrupuluous follow-up is mandatory

6) Actuarial survival is progressively improving

7) Some patients achieve very good quality of life


Message # 2


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Syndrome de bronchiolite oblitérante: Définition

• Bronchiolite oblitérante histologique

Biopsies transbronchique

Sensibilité médiocre (15 - 93%)

• Syndrome de bronchiolite oblitérante (BOS)

se définit par des altérations du VEMS et du

DEM25-75 comparées aux 2 meilleures valeurs

post-opératoires obtenues dans un intervalle

> 3 semaines45

SBIP 12/2011GLEM 12/2013 - CHU du Sart

Tilman

46

Epreuves fonctionnelles respiratoires

3 semaines, pas d’infection aigue, pas de rejet aigu, pas de problèmes anastomotiques

GLEM 12/2013 - CHU du Sart Tilman

31.05.2011 23.09.2011


47

Syndrome de bronchiolite oblitérante: Présentation clinique

• Présentation hétérogène (phénotype ?, vitesse)• Début insidieux ou aigu• Altération asymptomatique fonction

pulmonaire →→→→ symptômes d’<infection respiratoire>

• Dyspnée progressive• Auscultation normale →→→→ râles sous-

crépitants aux bases

• Intervalle depuis tx: à tout momentPic d’incidence: 16 - 22 mois après tx

48SBIP 12/2011


49Basseri Ann Thorac Surg 2010; 90: 1630.GLEM 12/2013 - CHU du Sart Tilman

Reflux gastro-oesophagien

• Présence pepsine/acides biliaires au

niveau LBA →→→→ aspiration ?D’Ovidio J Thorac Cardiovasc Surg 2005, Blondeau Eur Respir J 2008

• Fundoplicature précoce ↓ risque de BOS et ↑↑↑↑

survieDavies J Thorac Cardiovasc Surg 2003, Cantu Ann Thorac Surg 2004

• BOS →→→→ fundoplicature: amélioration

fonctionnelle 16/26Davies J Thorac Cardiovasc Surg 2003

50SBIP 12/2011


50

Reflux gastro-oesophagien

51

Hartwig Ann Thorac Surg 2011; 92: 462.


Tilman51

Syndrome de bronchiolite oblitérante: Diagnostic

• Fonction respiratoire classique

• ‘Single-breath washout’

• Piégeage aérien sur CT expiratoire

• Neutrophilie alvéolaire

• Condensat exhalé, sputum induit

• …52


Tilman

Prévention: Stratégies d’immunosuppression

1) Stratégies de monitoring thérapeutique

d’IS couramment utilisés

2) Nouveaux régimes de maintenance• Tac à la place de CsA

• MMF à la place de aza

• Inhibiteurs mTOR

3) IS inhalées

4) Détection/traitement précoce épisodes

de rejet aigu

53SBIP 12/2011


Monitoring thérapeutique de la CsA

54

CF non-CF

Knoop Transplantation 2003; 76: 683.GLEM 12/2013 - CHU du Sart Tilman

Prévention: Autres stratégies

1) Prévention infections virales

2) Traitement agressif de toutes les épisodes

d’infection respiratoire

3) Traitement agressif du reflux gastro-

oesophagien

4) Azi dès le départ ?

55SBIP 12/2011


BOS et azi: Prévention

Pas de différence:– rejet aigu

– bronchiolite lymphocytaire

– infections pulmonaires

– prévalence colonisation bactérienne greffon

– reflux

56Vos Eur Respir J 2011; 37: 164.GLEM 12/2013 - CHU du Sart Tilman

Yates et al. AJRCCM 2005; 172:772.

BOS and azithromycin

Verleden et al. AJRCCM 2006; 174: 566.

N = 20

N = 14

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Tilman

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BOS et azi: Etudes ‘pilote’

• 6 patients

• Azi 250 mg/j 5 j puis 3 x/sem

• Amélioration 5/6: ∆∆∆∆VEMS +0.5 L, ∆∆∆∆CVF +0.4 L, +17%

Gerhardt AJRCCM 2003;168: 121.

• 8 patients

• Amélioration 4/8: ∆∆∆∆VEMS +0.33 L, +18% Verleden Transplantation 2004; 77: 1465.

• 20 patients

• Amélioration 10/20: ∆∆∆∆VEMS +0.11 L, +14% Yates AJRCCM 2005; 172: 775.

• 11 patients

• Amélioration 0/11 Shitrit JHLT 2005; 24: 144.

42% patients se sont améliorés, ∆∆∆∆VEMS moyen +15%58GLEM 12/2013 - CHU du Sart Tilman

59Finlen Copeland AJRCCM 2010; 182: 784.GLEM 12/2013 - CHU du Sart Tilman

The concept of net state of immunosuppression

60GLEM 12/2013 - CHU du Sart Tilman

1) Immunosuppressive regimen

(type, magnitude, duration)

+

2) Damage to muco-cutaneous barriers/foreign bodies

3) Neutropenia

4) Hypogammaglobulinemia

5) Metabolic abnormalities such as protein mal-

nutrition, uremia, hyperglycemia

6) Infection with immuno-modulating viruses

(CMV, EBV, HIV, hepatitis B and C)

1 20 0

24 5

7

21

30

2527

35

30

3538

33

42

4749

65 65 64

88

93

81

0

10

20

30

40

50

60

70

80

90

1001983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

Transplants (n)

Lung transplantation Belgium

Belgium: 9.3 pmpEurope: 2.6 pmpET: 2.2 pmpUSA: 4.4 pmp


61

� 1963 Jackson (Hardy): First Human Lung transplant

� 1968 Gent (Derom): Successful lung transplant

� 1981 Stanford (Reitz): HLT for PPH

� 1983 Toronto (Cooper): SLT for Pulmonary fibrosis

� 1986 Toronto (Patterson): DLT for emphysema

� 1989 St Louis (Pasque): SSLT (BLT) for emphysema

� 1994 Los Angeles (Starnes): Lobar/Living-related LT

� 1996 Paris (Couetil): Split lung transplant

Lung transplantation History


62

� Timing of referral: physician’s impression of limited

survival prospects and altered QOL, and patient’s desire

for information

� Timing of listing: when life expectancy is reduced, but

greater than expected waiting time

� Timing of transplantation: when expected survival with

Tx is greater than expected survival without Tx (survival

benefit)

Timings


63

� UIP associated with worst survival (only 15-20%

respond to treatment)

� Well-preserved spirometry should not preclude

referral

� Deterioration of FVC or O2 saturation at rest, and

fall in saturation during 6-MWT in UIP/NSIP is

associated with higher mortality

Disease-specific selection criteriaIdiopathic Interstitial Pneumonia


64

IPF: Mortalité sur liste

• Maladie dévastatrice

• Survie médiane 3 ans

• Mortalité élevée sur liste ~ 20-25%

• Facteurs de mauvais pronostic:– Age avancé

– Sexe masculin

– CVF ↓↓↓↓, DLCO ↓↓↓↓

– HTAP

– Test de marche de 6’ < 200 m RR x 5

→ Lung allocation score (LAS)

Net transplant benefit (1-yr survival with tx – 1-yr survival w/o tx) - medical urgency (1-yr

survival w/o tx)65

Mars 2013GLEM 12/2013 - CHU du Sart

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Sarcoidose

• Europe: Irelande, Scandinavie: caucasiens

• EU: Afro-américains

• ~ 5% maladie fibro-kystique

• Evolution fréquemment sur des décades (Mémoire S. Reckelbus, Milman Sarcoidosis Vasc Diff Lung Dis 2005)

• Complications multiples– Bronchiectasies symptomatiques, aspergillomes, hémoptysies

– Maladie multi-systémique extra-pulmonaire (cardiaque, …)

• HTAP fréquente et multi-factorielle (3/4)

66Mars 2013


66

Sarcoidose + HTAP

67Mars 2013 Shlobin. Eur Respir J 2012; 39: 1520.


67

Adult and Pediatric Lung TransplantsAverage Center Volume (Transplants: January 2000 – June 2012)

JHLT. 2013 Oct; 32(10): 965-978

2013

Rejet vasculaire aigu: Incidence et facteurs de risque

� « the lung is more susceptible to rejection than other solid organ transplants »

� 315 patients, CsA, Aza vs. MMF, mpds,

Incidence 54 % à 1 an comparé à ≤≤≤≤ 40 % chez Tx rénaux

Glanville J Heart Lung Transplant 2003

� Mismatch HLA

� Taille de l’organe, importante population de cellules du système

immunitaire

� Exposition permanente à l’environnement extérieur (Inhalation

pathagènes, fumée, reflux, etc.)

Formation UTCP 2011GLEM 12/2013 - CHU du Sart

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Rejet aigu: Diagnostic

� Cliniquement / Fonctionnellement évident

� Cliniquement / Fonctionnellement silencieux

→ Biopsies trans-bronchiques de surveillance et

en cas de symptômes/signes

(gold standard)

→ pas de marqueur non-invasif sensitif / spécifique à l’heure actuelle

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Considérations techniques

1) 219 TBB (6 – 56 biopsies, médiane 17)• Sensibilité 94 %, spécificité 90 %• 95 % confidence finding rejection = 18 samples‘

2) Kukafka 1997• 13/39 (33%) 3 – 5 TBB• 23/39 (59%) 6 – 10 TBB• 3/39 (8 %) > 10 TBB• ‘keep in mind loss of diagnostic sensitivity if small number

of biopsies’

3) TBB diagnostic OB trop peu de sensibilité ~ 20 %


71

Interprétation

Arcasoy AJT 2011


72

73Mars 2013


73

� Overall survival is acceptable in advanced emphysema

� Rate of decline in FEV1=50-75 ml/yr=2-3% pred

value/yr

� NOTT: 70% survival at 3 years

� Burrows et al (NEJM 1987): 40% survival at 10 years

� Seersholm et al (AJRCCM 1995): median survival time

for patients with FEV1<25% pred: 6.3 year

Life expectancy in emphysema


74

� COPD: emphysema has worse prognosis than “chronic asthmatic

bronchitis” (Burrows et al NEJM 1987)

� In patients with severe COPD and LTOT, survival at 5 years is

64% if PAP<30mmHg and 15% if PAP>30mmHg (Oswald-

Mammoser Chest 1995)

� Low BMI and Pimax are predictors of mortality (Gray-Donald et al

AJRCCM 1995)

� 2-year survival in COPD patients admitted for acute exacerbation

with PaCO2>50mmHg is only 51% (Connors et al AJRCCM 1996)

� BODE index (Celli et al NEJM 2004)

Prognostic factors in COPD


75

� Histologic or radiographic evidence of UIP

� Histologic evidence of fibrotic NSIP

� Histologic or radiographic evidence of UIP and any of the following:

� DLco < 39% pred

� A 10% or greater decrement in FVC during last 6 months

� A decrease in pulse oxymetry < 88% during a 6-MWT

� Histologic or radiographic evidence of NSIP and any of the following:

� DLco < 35% pred

� A 10% or greater decrement in FVC or 15% decrement in DLco during last 6

months

Guideline for referral/Listing

Guideline for Transplantation


76

Choix de la procédure: mono vs. bi

Tx mono-pulmonaire• Risque et durée opératoire moindres

• Réserve fonctionnelle moindre

• HTAP 2ndaire sévère – risque

d’œdème de reperfusion majoré

• Problème du poumon natif

• Justice distributive

77Mars 2013

Tx bi-pulmonaire

• Risque et durée opératoire

• Réserve fonctionnelle supérieure


77

• 2 études mono-centriques– Mason Ann Thorac Surg 2007 DLTx > SLTx

– Meyers J Thorac Cardiovasc Surg 2000 SLTx > DLTx

• 3 études utilisant les régistres – Meyer Ann Thorac Surg 2005

821 patients survie SLTx > DLTx pour receveurs < 60 ans

– Whelan J Heart Lung Transplant 2005

830 patients mortalité 30 j > avec DLTx

– Thabut Ann Intern Med 2009

3327 patients survie SLTx = DLTx, survie post-op initiale moindre avec DLTx puis survie à long-terme supérieure

• Nathan J Heart Lung Tx 2010 temps d’attente et mortalité sur liste > avec DLTx

78Mars 2013

Choix de la procédure: mono vs. bi ?


78

• ISHLT guidelines for lung transplantation

APC

31

CMH

IL-12

Calcineurin

NFAT

Cytokine genes e.g. IL-2

CD3ATG - OKT3

Steroids

CSA - FK506

CD4 CD28

B7

CD45

Cell cycle

Aza - MMF

CD40L

CD40

TCR

MHC

CD2

mRNA

CD4

CD4+

Inhibitory effect


80

Le poumon natif

• Progression de la fibrose

• Exacerbations aigues

• Infections

• Cancer: prévalence 5.9%

81Mars 2013


81


82

Syndrome de bronchiolite oblitérante: Traitement

1) Changement de l’immunosuppression maintenance ?

2) Majoration de l’immunosuppression = non

3) Immunosuppression inhalée ?

4) Azithromycine ?

5) Immunomodulation ?

6) Retransplantation ?

83SBIP 12/2011


84

0,64

1,3

1,6

1,8 1,8 1,8

0,53

0

1

2

3

6 mo. 3 mo. switch 3 mo. 6 mo. 12 mo. last

BO

BOS stage

Sarahrudi J Thorac Cardiovasc Surg 2004; 127: 1126.

Effet changement CsA →→→→ Tac sur stade de BOS


Iacono et al. N Engl J Med 2006;354:141.

Kaplan-Meier Estimates of Chronic Rejection on the Basis of BO Identified by Spirometric and Histologic Analyses

14 deaths

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85

lung transplantation for cystic fibrosis · -fev1 that has fallen to 30% or a patient with advanced...

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