infection in immunocompromised hosts · infection in immunocompromised hosts. 63 yoman with 2nd...
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InfectioninImmunocompromisedHosts
JayA.Fishman,M.D.Professor ofMedicine,HarvardMedicalSchool
Director,TransplantInfectiousDiseaseandCompromised HostProgram,MassachusettsGeneralHospital
AssociateDirector,MGHTransplantCenter,Boston,MA,USA
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• Moreeffectiveimmunosuppressiveregimenshavereducedratesofacutegraftrejection• Moreatypicalpresentations(humoral)• Persistenceof“ChronicAllograftDysfunction”
• Infectionsarecommon• Presentationsareoftenatypicalwithoutfeverorothersigns• Nowexceedrejectionasacauseofhospitalization.• Prophylaxisiseffectiveindelayinginfection (notindefinitely)• Infectionisincreasinglyrecognizedasariskfactorinprovokinggraftrejection.
• Microbiologicalassays(molecular)areroutinelyusedindiagnosisandmanagement.
KeyConcepts:InfectioninImmunocompromisedHosts
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63yomanwith2nd deceaseddonorrenalgraftfordiabetes,earlyhumoralrejection,baselineCr=2.2,immunosuppressionwithrapamycin andmycophenylatemofetil.Non-healingskinulcer
growingS.aureus.Poorresponsetomultiplecoursesofantibiotics.
AVGraft
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Thispatienthas?1.Ischemiculcer– stealfrom
AVgraft2.ResistantStaphylococcusaureus
infection
3.Fusarium species
4.Nocardia asteroides
5.Rapamycin-inducedpoorwoundhealing
Phaeohyphomycosisà Possibly
No
No
Yes!– onbiopsy
à Likely
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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)
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Diagnosisofinfectionismoredifficultinimmunocompromised hosts:
⇒ Diminishedsignsofinflammation⇒ Dualinfections(orprocesses)arecommon⇒ Infectionisadvancedatpresentation⇒ Antimicrobialresistanceiscommon⇒ Toxiceffectsofdrugs(antimicrobialagents)⇒ Anatomicandsurgicalalterations
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GeneralPrinciples:DiagnosisandTreatmentofinfection
üDemonstrationofAnatomy(CT/MRI)üTissueHistology-- invasiveprocedures(biopsy),specialstainsüDemonstrationofnucleicacidsorproteins(Note:serologictestsarenotgenerallyusefulforacutediagnosis)üEarlyandaggressivetherapy(surgicaldebridement)– cannoteradicateinfectionunlessprimarysourceisresolved(e.g.hematoma)
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GreatVariabilityofRatesofInfection
From:PatelRandPaya C.Clin MicroRev1997,10:1;p86-124.
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Feverisunreliableasasignofinfectioninsolidorganrecipients
• Intransplantrecipients,feverisdefinedasanoraltemperatureof37.8°Corgreateronatleasttwooccasionsduringa24-hourperiod
• Antimetabolites (mycophenolatemofetil,andazathioprine)areassociatedwithsignificantlylowermaximumtemperaturesandleukocytecounts
• Patientswithsignificantinfection(bowelperforation)maylackfeverorlocalizingsigns
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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]
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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.
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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.
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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
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High-ThroughputSequencingMethodG.Palaciosetal,NEJM358:991
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Riskforinfectionisasemiquantitativerelationshipbetween:
Epidemiologicexposures
and“TheNetStateofImmuneSuppression”
(includinglatentinfections)
After:RobertRubin(1970’s)
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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
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“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
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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)
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Single-DoseAlemtuzumableadstoLong-TermT-CellDepletion
0100200300400500600700800900
Pre 0 3 6 9 12
Months post-induction
Cell
coun
t
CD4+CD8+
Coxetal,Eur JImmunol 2005
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CTLA-4IgInhibitors:(Belatacept)
Costimulationblockade(signal2:CD28/B7-CD80/CD86):Costimulatory pathwaysarenormallyrequiredforoptimalandsustainedactivationofnaïveT-cells.Costimulation involvesacomplexarrayofdevelopmentallyregulatedsurfacereceptorsandintracellularpathways.
FigurecourtesyofFlavio Vincente.See:XCLietal,ImmunologicalRev229:271-293,2009
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Coxetal,Eur JImmunol 2005
Blymphocytefunction
Complementactivation
NeutralizationofmicrobePhagocytosis
PlasmapheresisAnti-CD20 antibody
Mycophenylate mofetilCalcineurin inhibitors
Cobra venom Splenectomy
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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
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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
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Measuresof“ImmuneDeficits”Mostpatientshavemixedimmunedeficits– Multipledrugs(changing)– Variablemetabolism– Unknownnative“immunefunction”– Unknownmeaningofdruglevelsinindividual– Differingexposuresandbackgroundimmunity– Fewrelevantassays– lymphocytemarkers
Must individualize immune suppression, but generally lack appropriate assays
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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
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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)
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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
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Beforeweleave…andlestyouthinkwenowwhataredoing…
• Let’sjustplaywithsomenewerconcepts.
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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.
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“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
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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?
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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
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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
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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
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Specific DiagnosisRemainsKey:Fever,CoughTwoYearsPostCardiacTransplant
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NodulewithFaintHaloatOnset
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CavitatedNoduleFiveDaysLater--NoResponsetoAntifungaltherapy
Nocardia
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Summary- InfectionintheImmunocompromisedPatient
• Moredifficulttodiagnose• Advancedatthetimeofdiagnosis• Drugtoxicityiscommon– specificdiagnosisiskey!!
• Theintensityofimmunesuppression(includinganatomicdefects)isasimportantasantimicrobialtherapyincaringforthesepatients