Ppt0000003 [Lecture seule] - HÔPITAL NECKERnephro-necker.org/pdf/2013/04-Merville.pdf · 2013. 6....

CMV INFECTION IN KIDNEY TRANSPLANTATION

PIERRE MERVILLEPIERRE MERVILLEPIERRE MERVILLEPIERRE MERVILLE

CHU BORDEAUX CHU BORDEAUX CHU BORDEAUX CHU BORDEAUX ---- UNIVERSITUNIVERSITUNIVERSITUNIVERSITÉÉÉÉ BORDEAUX SEGALENBORDEAUX SEGALENBORDEAUX SEGALENBORDEAUX SEGALEN

UMRUMRUMRUMR----CNRS 5164CNRS 5164CNRS 5164CNRS 5164

SUMMARY:

1.1.1.1.Epidemiology in kidney transplantationEpidemiology in kidney transplantationEpidemiology in kidney transplantationEpidemiology in kidney transplantation

2.2.2.2.T cell response: T cell response: T cell response: T cell response: αβαβαβαβ and and and and γδγδγδγδ lymphocyteslymphocyteslymphocyteslymphocytes

3.3.3.3.CMV monitoring: Why? How? Should I?CMV monitoring: Why? How? Should I?CMV monitoring: Why? How? Should I?CMV monitoring: Why? How? Should I?

4.4.4.4.Indirects effects: Clinical impact Indirects effects: Clinical impact Indirects effects: Clinical impact Indirects effects: Clinical impact

5.5.5.5.Update on CMV guidelinesUpdate on CMV guidelinesUpdate on CMV guidelinesUpdate on CMV guidelines

6.6.6.6.PerspectivesPerspectivesPerspectivesPerspectives

AT THE ERA OF GENERALIZED PREVENTION, THE AT THE ERA OF GENERALIZED PREVENTION, THE

RISK OF INFECTION DEPENDS ON THE RISK OF INFECTION DEPENDS ON THE

TREATMENTTREATMENT

Universal

Prophylaxis

Universal

Prophylaxis

Preemptive

Therapy

Preemptive

Therapy

Whole blood CMV qPCR: 1/week J0-M3, 1/month M3-M12

No threshold for anti-CMV therapy

Whole blood CMV qPCR

D0 M3 M12M6

MORE CMV INFECTIONS WITH THE

PREEMPTIVE STRATEGY

qPCRD+R- D+R+ D-R+ n

PRO 6 Mths

PRO 3 Mths PREE PRO PREE PRO PREE

Khoury, 2006 44,0 54,0 18,0 54,0 27,0 75,0 98,0

Kliem, 2008 52,0 74,0 10,0 56,0 0,0 25,0 148,0

Reischig, 2007 75,0 83,0 56,0 96,0 60,0 86,0 70,0

Helentera, 2010 37,0 127,0

Humar, 2010 37,4 50,9 326,0

Van der Beek, 2010 52,0 69,0 78,0

Couzi, 2012 34,0 60,0 112,0

Witzke, 2011 15,6 53,8 3,6 22,2 296,0

Atabani, 2012 70,0 53,0 44,0 368,0

Mean (%) 37,2 51,3 68,3 24,9 62,6 22,7 50,4 1623,0

PRO : ProphylacticPREE: Preemptive

SIMILAR INCIDENCE OF CMV DISEASES

qPCRD+R- D+R+ D-R+ n

PRO 6 Mths

Proph 3 Mths PREE PRO PREE PRO PREE

Khoury, 2006 19,0 8,0 5,0 0,0 0,0 0,0 98,0

Kliem, 2008 148,0

Reischig, 2007 9,0 6,0 13,0 0,0 0,0 0,0 70,0

Helentera, 2010 34,0 127,0

Humar, 2010 16,1 36,8 326,0

Van der Beek, 2010 0,0 0,0 78,0

Couzi, 2012 16,0 26,0 112,0

Witzke, 2011 4,4 19,2 3,6 5,6 296,0

Atabani, 2012 32,5 2,5 0,9 368,0

Mean (%) na 20.2 18.1 7,5 5,4 1,2 1,6 1623,0

PRO : ProphylacticPREE : PreemptiveNa : Not applicable

SUMMARY:

1.1.1.1.Epidemiology in kidney transplantationEpidemiology in kidney transplantationEpidemiology in kidney transplantationEpidemiology in kidney transplantation

2.2.2.2.T cell response: T cell response: T cell response: T cell response: αβαβαβαβ and and and and γδγδγδγδ lymphocyteslymphocyteslymphocyteslymphocytes

3.3.3.3.CMV monitoring: Why? How? Should I?CMV monitoring: Why? How? Should I?CMV monitoring: Why? How? Should I?CMV monitoring: Why? How? Should I?

4.4.4.4.Indirects effects: Clinical impact Indirects effects: Clinical impact Indirects effects: Clinical impact Indirects effects: Clinical impact

5.5.5.5.Update on CMV guidelinesUpdate on CMV guidelinesUpdate on CMV guidelinesUpdate on CMV guidelines

6.6.6.6.PerspectivesPerspectivesPerspectivesPerspectives

BROADLY TARGETED CMV SPECIFIC CD4 AND CD8 T CELLS BROADLY TARGETED CMV SPECIFIC CD4 AND CD8 T CELLS BROADLY TARGETED CMV SPECIFIC CD4 AND CD8 T CELLS BROADLY TARGETED CMV SPECIFIC CD4 AND CD8 T CELLS

DOMINATE DOMINATE DOMINATE DOMINATE THE MEMORY COMPARTMENTS OF EXPOSED THE MEMORY COMPARTMENTS OF EXPOSED THE MEMORY COMPARTMENTS OF EXPOSED THE MEMORY COMPARTMENTS OF EXPOSED

SUBJECTSSUBJECTSSUBJECTSSUBJECTS

Sylwester et al, J. Exp. Med., 2005; 5: 673-685

70 % of viral peptides are able to generate a T cell response

IN R+ INDIVIDUALS, ANTIIN R+ INDIVIDUALS, ANTIIN R+ INDIVIDUALS, ANTIIN R+ INDIVIDUALS, ANTI----CMV RESPONSE ENGAGES 4CMV RESPONSE ENGAGES 4CMV RESPONSE ENGAGES 4CMV RESPONSE ENGAGES 4----5 % 5 % 5 % 5 %

OF TOTAL CD4 AND CD8 LYMPHOCYTESOF TOTAL CD4 AND CD8 LYMPHOCYTESOF TOTAL CD4 AND CD8 LYMPHOCYTESOF TOTAL CD4 AND CD8 LYMPHOCYTES

Sylwester et al, J. Exp. Med., 2005; 5: 673-685

CONSEQUENCES OF CMV INFECTION: MEMORY

INFLATION AND IMMUNE SENESCENCE?

Vescovini et al, J. Immunol., 2007; 179: 4283-4291

•« CMV would represent the most

important agent of effector T cell

expansion and probably one of the

most important causes for persistent

immune activation in human aging »

CMV-drivenexpansion of γδ T cells

γδγδγδγδ T CELL : A LYMPHOID STRESS SURVEILLANCE T CELL : A LYMPHOID STRESS SURVEILLANCE T CELL : A LYMPHOID STRESS SURVEILLANCE T CELL : A LYMPHOID STRESS SURVEILLANCE

INVOLVED IN CMV INFECTIONINVOLVED IN CMV INFECTIONINVOLVED IN CMV INFECTIONINVOLVED IN CMV INFECTION

Organ recipients

CMV

MCMV

• γδ protect αβ- mice from death• γδ control virus

Mouse model

Months post-tx1210864

0

5

10

15

20 CMV+

CMV-

2

% γ

δ γδ

γδ

γδ T

lym

phoc

ytes

• massive expansion of Vδδδδ2neg cells• diverse TCR repertoire• high expression of MHC-NKR• high expression of CD16

Innate-like features

(JCI, 1999)

Early γδγδγδγδ expanders Late γδ γδ γδ γδ expanders

0

4

8

12

16

20

Wee

k of

infe

ctio

n p<0.0001 • very specific of CMV • associated to infection resolution• long-term blood signature of CMV• TEMRA phenotype,• concomitant to αβ expansion• more rapid response in secondary infection

Adaptive-like features

(JID, 2001; Blood, 2008; JID, 2009, Blood 2012)(JEM, 2005; JASN, 2010; Cancer Res, 2009)

stressstress

CD69

Patients Isolated T cell clones Reporter cell lines

JRT3

TCR-Ligand

TCR transfer

Lentiviral transduction

γδγδγδγδCMVCMV

mAb screening

TCR ligand

identification

CMV-infected

or tumor cells

CMV INFECTION, A RELEVANT MODEL TO UNDERSTAND γδγδγδγδ T CELLS

STRATEGY TO IDENTIFY NEW STRATEGY TO IDENTIFY NEW STRATEGY TO IDENTIFY NEW STRATEGY TO IDENTIFY NEW γδγδγδγδ TCR LIGANDSTCR LIGANDSTCR LIGANDSTCR LIGANDS

TCR

Immunisation

DISCOVERY OF EPCR AS THE LIGAND OF THE DISCOVERY OF EPCR AS THE LIGAND OF THE DISCOVERY OF EPCR AS THE LIGAND OF THE DISCOVERY OF EPCR AS THE LIGAND OF THE

CLONE CLONE CLONE CLONE ““““LESLESLESLES”””” (V(V(V(Vγγγγ5V5V5V5Vδδδδ5)5)5)5)

� Involved in coagulation (activator of protein C)� MHC-I-like molecule� Crystallization: associated with phospholipids� expressed on endothelial cells (CMV targets)� Increased expression on carcinoma cells

� Antigen-presenting molecule�Glyco- and phospho-lipid presentation to invariant NKT cells

αααα1

αααα2

EPCRPhospholipids

αααα2

αααα1

CD1d

75

37

25

50

20

IgM 2E9

2E9+ line

IgM 2E9

2E9- line (B Willcox’s team)

EndothelialProtein C Receptor

EPCR

Immunoprecipitation with 2E9 and M/MS

sEPCR directly binds to LES sTCR

-60-40-200 20 40 60 800

200

400

600

800TCR LES TCR MAU TCR αβNone

Res

pons

e (R

U)

Time (s)

EPCR

Kd = 100 µM

(Willcox et al, Nat Immunol 2012)

SUMMARY:

1.1.1.1.Epidemiology in kidney transplantationEpidemiology in kidney transplantationEpidemiology in kidney transplantationEpidemiology in kidney transplantation

2.2.2.2.T cell response: T cell response: T cell response: T cell response: αβαβαβαβ and and and and γδγδγδγδ lymphocyteslymphocyteslymphocyteslymphocytes

3.3.3.3.CMV monitoring: Why? How? Should I?CMV monitoring: Why? How? Should I?CMV monitoring: Why? How? Should I?CMV monitoring: Why? How? Should I?

4.4.4.4.Indirects effects: Clinical impact Indirects effects: Clinical impact Indirects effects: Clinical impact Indirects effects: Clinical impact

5.5.5.5.Update on CMV guidelinesUpdate on CMV guidelinesUpdate on CMV guidelinesUpdate on CMV guidelines

6.6.6.6.PerspectivesPerspectivesPerspectivesPerspectives

13

Prophylaxis of CMV infection :

D+/R- patients : Which patients require a prolongati on of prophylaxis? R+ patients : Is a treatment necessary for all pati ents?

Treatment of CMV disease :

Should we treat minor/transitory ADNemia?Following complete treatment of CMV disease, which patients

require viral monitoring?

When this patient is really cured?

WHY TO MONITORE SPECIFIC CMV IMMUNE WHY TO MONITORE SPECIFIC CMV IMMUNE WHY TO MONITORE SPECIFIC CMV IMMUNE WHY TO MONITORE SPECIFIC CMV IMMUNE

RESPONSE?RESPONSE?RESPONSE?RESPONSE?

HOW TO MONITORE SPECIFIC CMV IMMUNE RESPONSE?HOW TO MONITORE SPECIFIC CMV IMMUNE RESPONSE?HOW TO MONITORE SPECIFIC CMV IMMUNE RESPONSE?HOW TO MONITORE SPECIFIC CMV IMMUNE RESPONSE?

= quantiferon

From Sester M, J Lab Med 2008;32:121-130.

SUMMARY OF THE STUDIESSUMMARY OF THE STUDIESSUMMARY OF THE STUDIESSUMMARY OF THE STUDIES

Assays Correlation with ADNemia

Correlation with disease

Clinical impact on treatment decision

QuantiFERON-CMV (N=4) Yes Yes No data

ELISPOT (N=5) Yes Yes No data

Cytométry (N=9) Yes Yes No data

Multimer HLA (N=1) No No No data

Control Rechute

- Limited number of patients (10-134), heterogeneous (R+ and D+R-)

- No clear predictive threshold, weak sensitivity, influence of treatment…

- Probably more a matter of kinetics of the response than an immune threshold.

SUMMARY:

1.1.1.1.Epidemiology in kidney transplantationEpidemiology in kidney transplantationEpidemiology in kidney transplantationEpidemiology in kidney transplantation

2.2.2.2.T cell response: T cell response: T cell response: T cell response: αβαβαβαβ and and and and γδγδγδγδ lymphocyteslymphocyteslymphocyteslymphocytes

3.3.3.3.CMV monitoring: Why? How? Should I?CMV monitoring: Why? How? Should I?CMV monitoring: Why? How? Should I?CMV monitoring: Why? How? Should I?

4.4.4.4.Indirects effects: Clinical impact Indirects effects: Clinical impact Indirects effects: Clinical impact Indirects effects: Clinical impact

5.5.5.5.Update on CMV guidelinesUpdate on CMV guidelinesUpdate on CMV guidelinesUpdate on CMV guidelines

6.6.6.6.PerspectivesPerspectivesPerspectivesPerspectives

INDIRECT EFFECTS OF CMV INFECTIONINDIRECT EFFECTS OF CMV INFECTIONINDIRECT EFFECTS OF CMV INFECTIONINDIRECT EFFECTS OF CMV INFECTION

Fishman, NEJM, 2007 ; 357: 2601-14

Infection (D+R-)

Or Reactivation (R+)

CMV infection

(DNAemia)

INDIRECTS effects of

CMV

DIRECT effects

CMV disease

CMV

Syndrome

Invasive

disease

Hepatitis

Colitis,

Pneumonia,

Etc, …

RejectionIF/TA

↓↓↓↓ Graft

survival

Arterial

stenosis

↓↓↓↓ Patient

survival

↑↑↑↑ PTLD

↑↑↑↑ Opportunistic

infections

CMV AND ACUTE REJECTION : AN OLD DEBATE

PRO :PRO :PRO :PRO :�Sagedal S, et al. The impact of cytomegalovirus inf ection and disease on rejection episodes in renal a llograft recipients. Am J Transplant. 2002;2(9):850-6.

�Toupance O, et al. Cytomegalovirus-related disease and risk of acute rejection in renal transplant rec ipients: a cohort study with case-control analyses. Transpl Int. 2000;13(6) :413-9.

�Reischig T, et al. Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytome galovirus disease after renal transplantation. Am J Transplant. 2008; 8(1):69-77.

�Lowance D, et al. Valacyclovir for the prevention o f cytomegalovirus disease after renal transplantati on. International Valacyclovir Cytomegalovirus Prophylaxis Transplant ation Study Group. N Engl J Med. 1999;340(19):1462- 70.

�Dickenmann MJ, et al. Cytomegalovirus infection and graft rejection in renal transplantation. Transpla ntation. 2001;71(6):764-7.

�Pouteil-Noble C, et al. Cytomegalovirus infection-- an etiological factor for rejection? A prospective study in 242 renal transplant patients. Transplantation. 1993;55(4):85 1-7.

CONTRA :CONTRA :CONTRA :CONTRA :�Couchoud C, et al. Cytomegalovirus prophylaxis with antiviral agents in solid organ transplantation: a meta-analysis. Transplantation. 1998;65(5):641-7.

�Erdbruegger U, et al. Impact of CMV infection on ac ute rejection and long-term renal allograft function : a systematic analysis in patients with protocol biopsies and indicated bi opsies. Nephrol Dial Transplant. 2012;27(1):435-43.

Drawbacks :•Retrospective studies•Timing between CMV and acute rejection•Interplay between these two major events in kidney transplantation

EFFECT OF CMV VIREMIA ON SUBCLINICAL ACUTE

REJECTION AND IFTA

Patients and methods :

118 kidney transplant recipients with • Prophylactic treatment (VACV 3 months)• Preemptive treatment (VGCV) • Protocol biopsy at M3

Résults :

DNAemia incidence : 41 % Subclinical acute rejection : 29 %IFTA : 28 %Subclinical acute rejection :

• Is not associated to DNAemia

IFTA• Is associated to DNAemia > 2000 copies (OR: 3.8, p=0.02)

Reischig et al, Transplantation 2009; 87:436-444

SOME YEARS LATER… LATE EFFECTS OF A PREEMPTIVE

TREATMENT

Patients :

Preemptive (VGCV) : N=34Preventive (VACV 3 mois) : N=36

Better patient survival in the preemptive group

With less late-onset CMV infections

Trend to less IFTA in the preemptive group (19 % vs 38 %)

Reischig et al, J Am Soc Nephrol 2012 23: 1588

EFFECT ON DNAEMIA ON GRAFT DYSFUNCTION AT 2

YEARS

N=55 pediatric kidney transplants

22 % of subclinical CMV DNAemia during the first tw o years

Prophylactic treatment for 3 à 12 months

Smith et al, J Am Soc Nephrol 2010, 21: 1579–1586.

More IFTA on protocol biopsies in viremic patients Unless the prophylactic treatment

INDIRECT EFFECTS AT THE LIGHT OF ECOLOGICAL

IMMUNOLOGY: CONCEPT OF TOLERANCE TO A

PATHOGEN

For each individual, a CMV infection has a fitness cost :

Damage caused by the pathogen : direct effectsDamage caused by host immune system : indirect effects

Tolerance is the magnitude of these direct and indirect effects

In transplantation, immunosuppressive treatment can differently modulate the level of tolerance

Ruslan Medzhitov, Disease Tolerance as a Defense S trategy, Science, 2012 , 335, 936

Ayres and Schneider, Tolerance of Infections, Ann R ev Immunol 2012, 30:271-294

SUMMARY:

1.1.1.1.Epidemiology in kidney transplantationEpidemiology in kidney transplantationEpidemiology in kidney transplantationEpidemiology in kidney transplantation

2.2.2.2.T cell response: T cell response: T cell response: T cell response: αβαβαβαβ and and and and γδγδγδγδ lymphocyteslymphocyteslymphocyteslymphocytes

3.3.3.3.CMV monitoring: Why? How? Should I?CMV monitoring: Why? How? Should I?CMV monitoring: Why? How? Should I?CMV monitoring: Why? How? Should I?

4.4.4.4.Indirects effects: Clinical impact Indirects effects: Clinical impact Indirects effects: Clinical impact Indirects effects: Clinical impact

5.5.5.5.Update on CMV guidelinesUpdate on CMV guidelinesUpdate on CMV guidelinesUpdate on CMV guidelines

6.6.6.6.PerspectivesPerspectivesPerspectivesPerspectives

CMV MANAGEMENT CMV MANAGEMENT CMV MANAGEMENT CMV MANAGEMENT –––– FROM FROM FROM FROM CONSENSUS TO CLINICAL PRACTICECONSENSUS TO CLINICAL PRACTICECONSENSUS TO CLINICAL PRACTICECONSENSUS TO CLINICAL PRACTICE

International consensus guidelines on the management

of cytomegalovirus in solid organ transplantation

Transplantation Society International CMV Consensus Group.

Transplantation. 2010 Apr 15;89(7):779-95

Update October 2012

MANAGEMENT OF CMV INFECTION

CONSENSUS RECOMMENDATIONS I

Both universal prophylaxis and pre-emptive strategi es are viable approaches for prevention of CMV disease (D+R- and R +).

For centers or patients unable to meet the stringen t logistic requirements required with a pre-emptive therapy st rategy, prophylaxis is preferred.

Where possible, 6 months may be preferable for D+/R - kidney recipients

When a prophylaxis strategy is used for prevention in R+ patients (with either D+ or D-), 3 months of antiviral medic ation should be used

When a pre-emptive therapy strategy is used, a suff iciently low threshold for initiation of treatment during pre-em ptive therapy is recommended.

MANAGEMENT OF CMV INFECTION

CONSENSUS RECOMMENDATIONS II

Anti-viral medications used in kidney transplant: v alganciclovir, intravenous ganciclovir, or high dose valacyclovir.

Treatment of rejection (ALG, high dose steroids) sh ould result in reinitiation of prophylaxis or pre-emptive therapy for 1 to 3 months

The routine use of the hybrid strategy is not recom mended at this time in any risk group

Immune monitoring assays should continue to be impr oved for ease of use and standardization.

Kotton CN, et al. Transplantation 2010; 89:779-795.

PERSPECTIVES

WHO international standard +++ (UI/ML)

Clinical studies on immune monitoring are required

Maribavir and new medications (letermovir, cyclopropavir, CMX001)useful in anti-viral resistance

Vaccines (anti-Gb), humanized anti-CMV antibodies

Modulation of immunosuppression: anti-viral effects of mTOR inhibitors.

MERCI POUR VOTRE

ATTENTION