InfezionieTrapiantodiCSE

AndreaBacigalupoIstitutodiEmatologiaFondazionePoliclinicoGemelliUniversita’ CattolicadelSacroCuoreRoma

andrea.bacigalupo@unicatt.it

Varese18.maggio.2017

-5000

500100015002000250030003500

-7 0 30 100 200 365

cellu

le /m

mc

PMN CD4

Gv HD

condit

HSCT

HSV

CMV

EBV

CyA + MTX (or FK506 or MMF)

Tx of aGvHD (Pred + other)

B.Inf Fungal infections

enteropathy

1. Infections and GvHD

GvHD (clinical and subclinical) plays a major role in post-transplant infections

GvHD needs to be PREVENTED

1970 1980 1990 2000 2010 2017

MTX

ALG

1970 1980 1990 2000 2010 2017

MTX

Cyclosporin A

TCD ex vivo

ATG /CAMP

MTX

1970 1980 1990 2000 2010 2017

MTX

Cyclosporin A

CyA+MTX

TCD ex vivo

T CD in vivo (ATG /CAMP)

1970 1980 1990 2000 2010 2017

MTX

Cyclosporin A

CyA+MTX

TCD ex vivo

T CD in vivo (ATG /CAMP)

CyA + MMF

FK+ Sirolimus

1970 1980 1990 2000 2010 2017

MTX

Cyclosporin A

CyA+MTX

TCD ex vivo+

T CD in vivo (ATG /CAMP)

CyA + MMF

FK+ Sirolimus

PTCY

36

1611

6 5

05

10152025303540

GvHD III-IV

% o

f pat

ient

s

<80 80-90 90-2000 2000-2010 >2010

P<0.00001

Reduced incidence of severe GvHD

2. Infections and GvHD

Significant reduction of severe GvHD with time

CD4recovery after HSCTmedian counts

CsA+MTX+ATG

CsA+MTX+ATG

CsA+MTX

CsA+MMF+PTCY

3. Infections and GvHD

Immune reconstitution depends on GvHD prophylaxis, and donor

Incidence ? Severity ?

CI of infectionsI-II : non severeIII lethal (with or without other cause GvHD)

Predisposing factors?

Each pre-transplant bacterial infection/yearleads to an additional 2.15 post-HSCT bacterialinfection year (p=0.004)

Pre HSCT Post HSCTInf/year <2 2.3Inf/year >2 4.3 0.01

GvHD increases the incidence of infections

GvHD increases the severity of infections

HR of infectious deathfor GvHD+ vs GvHD-= 2.8

Bacterial infections and acute GVHD

Sayer, Blood 1994

4. Bacterial Infections and GvHD

Risk factors

Pre-Tx bacterial infectionsGvHD (increases the number and severity )

Impact of IFDs in the overall survival at 1-year from transplant 2008-2010

Parameter Pr > ChiSq HazardRatio

95%HazardRatioConfidence

LimitsIFD, time dependent <.0001 3.149 2.526 3.927aGVHD:0-1vs2-4 <.0001 1.432 1.211 1.694Stem cell source:BMvsPERIPH

0.3202 0.910 0.755 1.096

Stem cell source:CBvsPERIPH

0.0420 1.300 1.010 1.674

Donor:Matched relvsunrelated

0.0030 0.769 0.646 0.914

Donor: Mismatchedrel vsunrelated

0.0131 1.475 1.085 2.004

Age,continuous <.0001 1.014 1.008 1.019Disease phase attransplant:CRvsnoCR

<.0001 0.466 0.386 0.561

Disease: ALvsother <.0001 1.630 1.354 1.961

Multivariate analysisCommissione Infezioni

5. Fungal Infections and GvHD

# risk factors areGvHD, age, advanced disease, acute leukemia

# IFI increase mortality

If GvHD promotes infections andinfectiousmortality

Preventing severeGvHD should reduceinfectionrelatedmortality

60

36

221617

1116

695

0

10

20

30

40

50

60

70

Death I+G GvHD III-IV

% o

f pat

ient

s

<80 80-90 90-2000 2000-2010 >2010

P<0.00001

Reduced incidence of severe GvHDn=2455 allogeneic HSCT

6. Infections and GvHD

YES:

Prevention of GvHD decreasesmortality due to infections (+ GvHD)

Newtrends?

Bacterial infections andGVHD:themicrobiota

Manzo,Blood2015

Bacteriodes

Firmicutes

SCFA

Ep cells

TLR

LPS

Defensins

Treg Th 17

AgMcell

IgA

Peyer’s patch

Th 1 Th 17

IL-6

IL-10

TNF

Retinoic acid

Flagellin

IL-10

Bacterial infections andGVHD:themicrobiota

• Fecal analysis from94patients until day +35

Taur,CID2012

CONCLUSIONS

Very strong correlation of GvHD and infections

Effective prevention of GvHD is the secret for successful allogeneicHSCT

Genova BMT UnitE Angelucci AM Raiola,F Gualandi, A Dominietto,R Varaldo, M T Van Lint , S Bregante, C di GraziaT Lamparelli

Commissione InfezioniCorrado Girmenia

Gemelli BMT UnitS Sica, L Laurenti, P Chiusolo, F sora’, S Giammarco, E Metafuni, I Innocenti, F Autore

Nursing team Data ManagerR OnetoG Conti M Daneri

Genova ID UnitC ViscoliM MikulskaV del Bono