InfectioninImmunocompromisedHosts

JayA.Fishman,M.D.Professor ofMedicine,HarvardMedicalSchool

Director,TransplantInfectiousDiseaseandCompromised HostProgram,MassachusettsGeneralHospital

AssociateDirector,MGHTransplantCenter,Boston,MA,USA

• Moreeffectiveimmunosuppressiveregimenshavereducedratesofacutegraftrejection• Moreatypicalpresentations(humoral)• Persistenceof“ChronicAllograftDysfunction”

• Infectionsarecommon• Presentationsareoftenatypicalwithoutfeverorothersigns• Nowexceedrejectionasacauseofhospitalization.• Prophylaxisiseffectiveindelayinginfection (notindefinitely)• Infectionisincreasinglyrecognizedasariskfactorinprovokinggraftrejection.

• Microbiologicalassays(molecular)areroutinelyusedindiagnosisandmanagement.

KeyConcepts:InfectioninImmunocompromisedHosts

63yomanwith2nd deceaseddonorrenalgraftfordiabetes,earlyhumoralrejection,baselineCr=2.2,immunosuppressionwithrapamycin andmycophenylatemofetil.Non-healingskinulcer

growingS.aureus.Poorresponsetomultiplecoursesofantibiotics.

AVGraft

Thispatienthas?1.Ischemiculcer– stealfrom

AVgraft2.ResistantStaphylococcusaureus

infection

3.Fusarium species

4.Nocardia asteroides

5.Rapamycin-inducedpoorwoundhealing

Phaeohyphomycosisà Possibly

No

No

Yes!– onbiopsy

à Likely

Consider…NewRenalTransplantrecipientswithdischargeserumcreatinine1.8and

falling– similarpresentations

Time Cr U/A WBC Fever? DX

1week 1.4 5-10wbc 2200 no Drugeffect

1week 2.6 neg 6100 no Lymphocele

3months 2.6 5-10 6100 no BKpolyomavirus

6months 2.6 neg 2000 Low grade CMV/rejection(offprophylaxis)

9months 2.6 5-10wbc 2200 LowGrade EBV-PTLD(ingraft)

Diagnosisofinfectionismoredifficultinimmunocompromised hosts:

⇒ Diminishedsignsofinflammation⇒ Dualinfections(orprocesses)arecommon⇒ Infectionisadvancedatpresentation⇒ Antimicrobialresistanceiscommon⇒ Toxiceffectsofdrugs(antimicrobialagents)⇒ Anatomicandsurgicalalterations

GeneralPrinciples:DiagnosisandTreatmentofinfection

üDemonstrationofAnatomy(CT/MRI)üTissueHistology-- invasiveprocedures(biopsy),specialstainsüDemonstrationofnucleicacidsorproteins(Note:serologictestsarenotgenerallyusefulforacutediagnosis)üEarlyandaggressivetherapy(surgicaldebridement)– cannoteradicateinfectionunlessprimarysourceisresolved(e.g.hematoma)

GreatVariabilityofRatesofInfection

From:PatelRandPaya C.Clin MicroRev1997,10:1;p86-124.

Feverisunreliableasasignofinfectioninsolidorganrecipients

• Intransplantrecipients,feverisdefinedasanoraltemperatureof37.8°Corgreateronatleasttwooccasionsduringa24-hourperiod

• Antimetabolites (mycophenolatemofetil,andazathioprine)areassociatedwithsignificantlylowermaximumtemperaturesandleukocytecounts

• Patientswithsignificantinfection(bowelperforation)maylackfeverorlocalizingsigns

SourcesofFever• Feverisduetoinfectioninupto80%ofepisodesandtononinfectiouscausesin22%.– 40%ofinfectionswerenotaccompaniedbyfever,particularlyinfungaldiseases.– Febrileviralinfectionswereoftenduetovirusesotherthancytomegalovirus(HHV6,EBV,recurrenthepatitis)• Rejectionaccountsfor4-6%oftheepisodes.• Highestrateswereinheartandlungrecipients(30-60%)

R.G.Sawyer,T.D.Crabtree,T.G.Gleason,etal.Clin Transpl,13(3)(1999),pp.260–265F.Y.Chang,N.Singh,T.Gayowski,etClin InfectDis,26(1)(1998),pp.59–65J.G.Montoya,L.F.Giraldo,B.Efron,etal Clin InfectDis,33(5)(2001),pp.629–640[Epub 2001Aug6]

CommonInfections

§ Bloodstream infectionsinimmediatepost-opperiod– ~18episodesper100patientyears(Year1)

§ Pneumonia accountsfor30%to80%ofinfectionssufferedbySOTrecipientsandforagreatmajorityofepisodesoffever.§ Highestintheearlypostoperativeperiod(especiallywithintubation)§ Crudemortalityofbacterialpneumoniainsolidorgantransplantation>40%

§ Increasedover4-foldvs.normals infirstyearafterrenaltransplantation

§ Gastrointestinalsymptomsarecommonandoftenignored§ Peritonitis,intra-abdominalinfections,andClostridiumdifficilecolitiscommonafterlivertransplantationintheICU

§ CMVandCdifficile arethemostcommoncausesofinfectiousdiarrheainsolidorganrecipients.

N.Singh,T.Gayowski,M.M.Wagener,etal. Transplantation,67(8)(1999),pp.1138–1144L.A.Mermel,D.G.MakiSemin Respir Infect,5(1)(1990),pp.10–29;USRDS2002,KCAbbott etal,AmJNephrol.2001;DJTveit etal,J.Nephrol 2002;MJHanaway etal.NEJM,364:1909,2011.

NewerPathogensinTransplantation

• Bacteria:Non-TBmycobacteria,AntimicrobialResistance:VRE,MRSA,Carbapenem-ResistantGNR(CRE)

• Fungi:Azole-resistantCandidaspp.Candidaauris,Mucor, Scedosporium, Dematiaceousmoulds.

• Viruses:Zika,multidrug-resistantCMV,adenovirusvectors,parainfluenza inHSCT,SARS,HHV6,-7,-8,

• Parasites:Cryptosporidium,T.cruzi,Leishmania,Strongyloides.

Whynew(er)pathogens?ØProlongedpatientsurvivalØBroadgeographicexposures (endemicinfections,travel,employment)

Ø Shiftsinnosocomial flora withprolongedhospitalizations,organshortageü Routineprophylaxis(fluconazole,vancomycin,cephalosporins,antivirals)à antimicrobialresistance

ü Renal,hepatic,pulmonarydysfunction(sickerpatients)

Ø IntensifiedImmunosuppressionØ Improveddiagnosticassays

High-ThroughputSequencingMethodG.Palaciosetal,NEJM358:991

Riskforinfectionisasemiquantitativerelationshipbetween:

Epidemiologicexposures

and“TheNetStateofImmuneSuppression”

(includinglatentinfections)

After:RobertRubin(1970’s)

CarefulMedicalHistory:EpidemiologicExposuresMayBeRecentorDistant

Recent• Nosocomialflora• Catheter-related• ComplexSurgery• Communityacquired• Urinarytractinfection• Aspiration• Cryptococcus• Legionella• Donor-derived*

Distant• Tuberculosis• Colonization(remote)• Non-tuberculousmycobacteria• Strongyloides• Herpesviruses• Toxoplasmosis• Leishmania,T.cruzi• Histoplasmosis,Coccidioides• HTLV,HIV,HCV,HBV

HTLV,humanT-celllymphotrophic virus;HIV,humanimmunodeficiency virus.

*e.g.,Dengue,Chikungunya, LCMV,Rabies,VRE,MDRO,Candida,TB

“Net State of Immune Suppression”�ImmunosuppressiveTherapy: Type/TemporalSequence/Intensity -- “AUC”

�Priortherapies(Chemotherapy,Antimicrobials)�RoleofdisruptedMicrobiome?�Alteredcolonizationpatterns,C.difficile

�Mucocutaneous BarrierIntegrity(catheters)�Neutropenia,Lymphopenia (depth,duration)�UnderlyingImmuneDeficiency&Metabolicconditions:Uremia,Malnutrition,Diabetes,Alcoholism/cirrhosis,Anatomy(leaks,COPD/bronchiectasis)

�ViralCo-Infection(CMV,HepatitisBandC,RSV):ImmuneModulation/Rejection/Cancer

SelectedTypesofImmunosuppressionandInfection:“Biologic”Agents

• Antilymphocyte globulins – depletelymphocytes(Tand/orBcells,possiblyNKanddendriticcellsdependingondrug)– Usuallyusedin“induction”therapyortreatmentofrejection

• T-celldepletionpredisposestoviralinfection,mimicsalloimmune response&activateslatent(herpes)viruses,TNFαàfeverà cytokines– Rabbit(Thymoglobulin),horse,humanizedmonoclonal– Reconstitutionwitheffector/memoryphenotypesunderCNI’s

• B-celldepletion(anti-CD20,notplasmacells):�antibodies(encapsulatedbacteria,yeasts?)

• Co-stimulatoryblockade:feweffectsbutlateEBV-PTLD?(Belatacept)

Single-DoseAlemtuzumableadstoLong-TermT-CellDepletion

0100200300400500600700800900

Pre 0 3 6 9 12

Months post-induction

Cell

coun

t

CD4+CD8+

Coxetal,Eur JImmunol 2005

CTLA-4IgInhibitors:(Belatacept)

Costimulationblockade(signal2:CD28/B7-CD80/CD86):Costimulatory pathwaysarenormallyrequiredforoptimalandsustainedactivationofnaïveT-cells.Costimulation involvesacomplexarrayofdevelopmentallyregulatedsurfacereceptorsandintracellularpathways.

FigurecourtesyofFlavio Vincente.See:XCLietal,ImmunologicalRev229:271-293,2009

Coxetal,Eur JImmunol 2005

Blymphocytefunction

Complementactivation

NeutralizationofmicrobePhagocytosis

PlasmapheresisAnti-CD20 antibody

Mycophenylate mofetilCalcineurin inhibitors

Cobra venom Splenectomy

NewerAgents• Signaltransductioninhibitors blocktheactivitiesofmoleculesthatparticipate

in signaltransduction, theprocessbywhichacellresponds tosignalsfrom itsenvironment.

• Geneexpressionmodulatorsmodify thefunctionofproteins thatplayaroleincontrollinggeneexpression.

• Apoptosisinducers causecancercellstoundergo aprocessofcontrolledcelldeath=apoptosis.

• Angiogenesisinhibitors (smallmolecules)blockthegrowthofnew bloodvessels totumors(aprocesscalledtumorangiogenesis) e.g.,vascularendothelialgrowthfactor (VEGF).

• Immunotherapies includingmonoclonalantibodiesthatdelivertoxicmolecules.• Checkpointinhibitors:autoimmunedisorders• Car-Tcells:Neurologic syndromes

DrugorDrugClass(Mechanismofpossibleeffect)

PlasmaExposure toCNI/mTOR

PlasmaExposure toDrug

(Mechanism)RecommendedApproach+

Azoleantifungalagents(CYP2C9,CYP2C19, CYP3A4 Inhibition)

Increased Increased TDMessential,dependsondrug

Warfarin PT/INRincreased(CYP2C9 Inhibition)

TDM,evaluateforriskforbleeding

Omeprazole(proton-pump inhibitors)

increased(gastricpHwithCYP2C19/CYP3A4

Inhibition)

Increased(CYP2C19/CYP3A4

Inhibition)TDM,avoidifpossible

HMG-CoAReductaseInhibitors (statins) Increased(CYP3A4 Inhibition)

Monitor forsideeffects

CalciumChannel Blockers(Dihydropyridine)

Increased Increased(CYP3A4 Inhibition)

Doseadjustment,avoid

OralContraceptives (ethinylestradiol,norethindrone)

(CYP3A4 Inhibition)Increased

Increased(CYP2C19Inhibition)

TDM

Corticosteroids Increased(CYP3A4 Inhibition)

Increased? Monitor forefficacy,steroid levelsmayincrease

Rifampin,Rifabutin(CYP450 Induction)

Reduced Increased(CYP3A4 Inhibition)

TDM,avoidifpossible(contraindicated)

HAARTMayincreaseCNIlevelsbutdropHIV

meds

Increased(CYP450 Induction)

Reduced(CYP2C9and

CYP2C19 induction)

TDM,avoidifpossible(contraindicated),monitor for

antiviraleffectiveness

Terfenadine,astemizole,cisapride,Quinidine, Pimozide

Increased(CYP3A4andP-gP

Inhibition)Varies

Potential forQTprolongation,arrhythmias,contraindicated.Elevatedquinidine levels.

Fishman,2015

Measuresof“ImmuneDeficits”Mostpatientshavemixedimmunedeficits– Multipledrugs(changing)– Variablemetabolism– Unknownnative“immunefunction”– Unknownmeaningofdruglevelsinindividual– Differingexposuresandbackgroundimmunity– Fewrelevantassays– lymphocytemarkers

Must individualize immune suppression, but generally lack appropriate assays

TheTimelineofPost-TransplantInfections

COMMONVARIABLES inIMMUNESUPPRESSION:LMANYDIFFERENTREGIMENS(steroid-free,CNI-free,AntibodyInduction,costimulatoryblockade)L TREATMENTOFREJECTION-- “Resetsclock”L NEUTROPENIA(virusordrug-induced)L VIRALINFECTIONS(CMV,HCV,EBV,RSV…)

TRANSPLANT4WEEKS

~6-12MOS.LONGTERM

NOSOCOMIALTECHNICAL

OPPORTUNISTIC,RELAPSED,RESIDUAL

FromCOMMONTOZEBRAS*

HSV,CMV,HBV,HCV,LISTERIA,PCP,TOXO

Periodofmostintensive

immunesuppression

Exposure to nosocomial pathogens

Donor or Recipient

Impactofroutineprophylaxis:Whatinfectionsdon’ttheyhave?

• Surgicalprophylaxis forcommonpathogens(e.g.,UTI– renal;fungi- liver,bowel,pancreasorlung)orknowncolonizersoftheindividualpatient(VRE,Aspergillus)

• Pneumocystis carinii (jirovecii)– Note:TMP-SMXhasactivityvs.commonurinary-GI-Respiratorypathogens,mostNocardia,Listeria (6monthstolife)

• Cytomegalovirus (HSV,VZV):3-6months(basedonrisk)– usuallyganciclovir orvalganciclovir (Note:notFDAapprovedforlivertransplantation)

TheTimelineofPost-BMT/HSCTInfections

VARIABLES:L Greatervariabilityintiming;EngraftmentsyndromeL Centralrolesofneutropenia &GVHDL ANYTIME:CMV,VZV,EBV,PCP,Adenovirus,HHV6,

MYCOBACTERIA,LEGIONELLA,NOCARDIA

TRANSPLANT1-4WEEKS DAY100 LONGTERM

NOSOCOMIAL,Pre-EngraftmentNEUTROPENIA OPPORTUNISTIC,RELAPSED,

RESIDUALFromCOMMONTO

ZEBRAS*

Bacteria,VZV,CMV,BKAspergillus,LISTERIA,PCP,

Toxo,FUO

AcuteGVHDwithintensive

immunesuppression

Candida, HSV, VRE, MRSA

ChronicGVHD

Post-Engraftment

GVHD&GVLEffect

Beforeweleave…andlestyouthinkwenowwhataredoing…

• Let’sjustplaywithsomenewerconcepts.

Relevant Financial Relationship Disclosure StatementMicrobialShiftsinTransplantation

•CanGImicrobiomebemanipulatedtoproducesustainableimmunechangesthatallowreductionoreliminationofexogenousimmunosuppression?•Canmicrobiomestudiesbeusedasabiomarkerforgraftrejectionandtolerance?

See:FishmanJA. ImmuneReconstitutionSyndromes:HowDoWe“Tolerate”ourMicrobiome?ClinInfectDis,(2015)60(1):45-47.NelloreA, Fishman,JA.TheMicrobiome,SystemicImmuneFunctionandAllotransplantation.ClinMicrobiolRev,29:191–199.

“NormalMicrobiome”PreventsChronicRejection:GoodPseudomonasintheLungs?

• MicrobialcommunitiesinCFlungtransplantpatientsfallintotwomutuallyexclusivegroups– DominatedbyPseudomonas(donotcontainAspergillus)– DominatedbyStreptococcusandVeillonella (Gram+)

• RecolonizationoftheallograftbyPseudomonasinindividualswithcysticfibrosisisnotassociatedwithBOS.

• Ingeneral,reestablishmentofpre-transplantlungmicrobiomes intheallograftseemstohaveaprotectiveeffectagainstBOS

• Denovoacquisitionofmicrobialpopulations oftenbelongingtothesamegeneramayincreasetheriskofBOS.

Willner DLetal.AmJRespir Crit CareMed.2013Mar15;187(6):640-7

InfectionwithTLR-ligationcanblocktoleranceinduction(Innateimmunefunction)

• Tissueinflammation(infection,surgery)andinjuryàincreasedtraffickingofT-cells

• Listeria monocytogenes (intracellularbacterium)à IFNβblocksheartandskintolerance(TWangetal,AJT,10:1524,2010)

• Staphylococcusaureus (butnotPseudomonasaeruginosa)àIL-6(EBAhmedetal,AJT,11:936,2011)

• Newcastlediseasevirusà IFNα bydendriticcells(DC)andmacrophages(YKumagi etal,Immunity,27:240,2007)

Mechanism:Non-specificstimulation(cytokines,chemokines)ofT-cellsorincreasedantigenpresentationbyAPCs?

Thecompositionofthemicrobiotamodulatesallograftrejection(LeiYMetal.JClin Invest.2016Jul 1;126(7):2736-44)

• Theinfluenceofhostanddonormicrobiotaonskinandcardiactransplantrejection• Pretreatmentofdonorsandrecipientswithbroad-spectrumantibiotics(Abx)oruseofgerm-free

(GF)donorsandrecipientsresultedinprolongedsurvivalofminorantigen-mismatchedskingrafts.IncreasedgraftsurvivalcorrelatedwithreducedtypeIIFNsignalinginantigen-presentingcells(APCs)anddecreasedprimingofalloreactive Tcells.

• ColonizationofGFmicewithfecalmaterialfromuntreatedconventionalmice(butnotABXtreatedmice)increasedAPCprimingofalloreactive Tcellsandacceleratedgraftrejectionà Alloimmunityismodulatedbythecompositionofmicrobiotaratherthanthequantityofbacteria.

• à Targetingmicrobialconstituentsisapotentialtherapeuticstrategyforenhancinggraftacceptance.

Skin:MinorAgMismatch Abx pretreatmentdelaysrejectionofmajorantigen–mismatched skin(BALB/cà B6) andMHCclassII–mismatched cardiac(Bm12à B6)allografts

ClostridiaandmixturesofClostridiaspeciesavailabletothisprojectfromVedantainduceTreg accumulationincoloniclaminapropria.

(A) GFBALB/corIQImicewerecolonizedwithsegmentedfilamentous bacteria(SFB), 16strainsof Bacteroides (Bactero.),3strainsof Lactobacillus (Lacto.),or46strainsof Clostridium (Clost.) for3weeks.ThepercentageofFoxp3+ cellswithin theCD4+ cellpopulation inthecolonandSIofindividual micewasanalyzedbyflowcytometry (n ≥5micepergroup).(B)Electronmicrographshowing theproximalcolonofClost.-colonizedB6mice.(Arpaia Netal.Nature.2013;504:451-455)

K Atarashi etal.Nature 1-5 (2013)doi:10.1038/nature12331

Infection,ImmunityandTransplantation

Pre-Transplantation•Organdysfunction•Colonization (ICU)• Antimicrobials• Infections• Vaccination

TransplantSurgery• Infection(technical)• Tissueinjury• Organdysfunction

Post-Transplantation•DepletionandImmunereconstitution•Immunosuppression•Communityexposures•Opportunistic infection

Immunememory• Heterologous orcross-reactiveepitopes• Vaccination• Latentorpersistentinfections• Microbiome

•Commensals•Colonization

ImmuneStimulation• Innate:LigandsforPRRàcytokines, chemokines• Microbialderivedantigens• AllograftDamage-associatedmolecularpatternmolecules• Enhancedantigenpresentation• Adaptive:Alloimmunestimulationà⇓ tolerance,⇑rejection

Heterologous orcross-reactivememory

• Acute/Chronic Rejection•Failedcostimulatory blockade•Narrowedimmuneresponses(infections)• Stimulation bynewor“persistentinfections” (graftinjury)à cytokines,chemokines• IncreasedeffectoroverTregs

TransplantPhaseIm

muneEffects

Specific DiagnosisRemainsKey:Fever,CoughTwoYearsPostCardiacTransplant

NodulewithFaintHaloatOnset

*

*

*

CavitatedNoduleFiveDaysLater--NoResponsetoAntifungaltherapy

Nocardia

Summary- InfectionintheImmunocompromisedPatient

• Moredifficulttodiagnose• Advancedatthetimeofdiagnosis• Drugtoxicityiscommon– specificdiagnosisiskey!!

• Theintensityofimmunesuppression(includinganatomicdefects)isasimportantasantimicrobialtherapyincaringforthesepatients

If I can help: jfishman@mgh.harvard.edu

Thank you!!