LUNG TRANSPLANTATION FOR CYSTIC FIBROSIS · -FEV1 that has fallen to 30% or a patient with advanced...
Transcript of 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
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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
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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.
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Types of lung transplantations
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• (Heart- lung transplantation)
• Single lung transplantation
• Double lung transplantation
• Lobar transplantation
Adult and Pediatric Lung TransplantsNumber of Transplants by Year and Procedure Type
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Adult Lung TransplantsIndications for Bilateral/Double Lung Transplants
(Transplants: January 1995 – June 2012)
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Adult Lung TransplantsIndications for Single Lung Transplants
(Transplants: January 1995 – June 2012)
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Adult Lung TransplantsMajor Indications By Year (Number)
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Recipient selection: general criteria
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• 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
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Absolute contra-indications
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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
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Relative contra-indications
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• 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
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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
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Allocation rules
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• 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.
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Waiting list mortality Candidates in ET 1995-2005
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% patients listed
Restrictive
VascularCF
Other
COPD
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Transplant window
Cli
nic
al
co
urs
e
Time
Referral
Too lateTW
Crucial time-points
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Surgical technique
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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
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Surgical complications
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• Hemorrhagies
• Primary graft dysfunction
• Phrenic nerve palsy
• Anastomotic complications
Surgical ‘mortality’ 5-10%
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Medical complications
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• Acute rejection
• Chronic allograft dysfunction
• Infections
• Cardio-vascular/metabolic complications
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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
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Degree of immunosuppression after solid organ transplantation
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Immunosuppression after LTx
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• 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
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Bronchiolitis obliterans syndrome: Risk factors
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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
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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
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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
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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.
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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)
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Adult Lung TransplantsKaplan-Meier Survival by Diagnosis(Transplants: January 1990 – June 2011)
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Adult Lung TransplantsFunctional Status of Surviving Recipients
(Follow-ups: March 2005 – June 2012)
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Conclusions: LTx in 2014
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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
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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
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Epreuves fonctionnelles respiratoires
3 semaines, pas d’infection aigue, pas de rejet aigu, pas de problèmes anastomotiques
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31.05.2011 23.09.2011
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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
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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
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Reflux gastro-oesophagien
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Hartwig Ann Thorac Surg 2011; 92: 462.
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Syndrome de bronchiolite oblitérante: Diagnostic
• Fonction respiratoire classique
• ‘Single-breath washout’
• Piégeage aérien sur CT expiratoire
• Neutrophilie alvéolaire
• Condensat exhalé, sputum induit
• …52
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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
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Monitoring thérapeutique de la CsA
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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 ?
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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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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
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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
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88
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1984
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Transplants (n)
Lung transplantation Belgium
Belgium: 9.3 pmpEurope: 2.6 pmpET: 2.2 pmpUSA: 4.4 pmp
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� 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
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� 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
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� 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
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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
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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)
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Sarcoidose + HTAP
67Mars 2013 Shlobin. Eur Respir J 2012; 39: 1520.
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Adult and Pediatric Lung TransplantsAverage Center Volume (Transplants: January 2000 – June 2012)
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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.)
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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 %
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Interprétation
Arcasoy AJT 2011
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� 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
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� 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
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� 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
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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
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Tx bi-pulmonaire
• Risque et durée opératoire
• Réserve fonctionnelle supérieure
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• 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
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Choix de la procédure: mono vs. bi ?
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• 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
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Le poumon natif
• Progression de la fibrose
• Exacerbations aigues
• Infections
• Cancer: prévalence 5.9%
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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 ?
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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
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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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