Post on 29-Jul-2019
OpportunisticInfections4ThingsYouNeedToKnow
CarinaMarquez,MD,MPHAssistantProfessor
UniversityofCalifornia,SanFranciscoDivisionofHIV,ID,andGlobalMedicine
ZuckerbergSanFranciscoGeneralHospital
Objectives
• IdentifyandmanagecommonOIsintheHIV-infectedpatients
• IdentifyandmanageImmuneReconstitutionInflammatorySyndrome(IRIS)
OffLabelDisclosures
• None
KeyFact#1:CD4countcorrelateswithriskofspecificOIsinuntreatedHIVdisease
CD4countcorrelateswithriskofspecificOI’sinuntreatedHIVdisease
0
100
200
300
400
500
600
700
800
>500 200-500 100-200 50-100 <50
PCP,PML,Histoplasmosis, MAC
CMV,PrimaryCNSlymphoma
Recurrentbacterialpneumonia,TB,HSV,VZV/Zoster,NHL,Kaposis Sarcoma,
oropharyngealcandidiasis
Toxoplasmosis,CryptococcosisCryptopsoridiosis
CD4Co
unt
CD4CountCategoryAdaptedfromBartlettJG,GalantJE,PhamPA.MedicalManagementofHIV.2012
44y/oMwithHIV(CD494,notonARVsorprophylaxis)presentswith1monthofprogressiveSOB,non-productivecough,fevers,nightsweats,andweightloss.
• Exam:Afebrile,90%RA.Diffusecrackles,thrush,bilaterallyandmildwheezing.
• Labs:WBC8.3.LDH386,BDG>500.
• ABG:7.44/35/59 onRA
Case#1
Case#1:continued
A. Heshouldbestartedonempirictreatmentforcommunityacquiredpneumonia,TMP/SMX,andprednisone
B. Ifthispatienthasaseptra allergyyoushouldconsiderseptradesensitization
C.Pneumocystiscarinii causespneumoniainrats
D. Thespecificityofbetad-glucanwithPCPis92%
ARS:WhichofthefollowingisNOT true
• Subacutepresentationofcough:oftenpresentwithdrycough,DOE• HypoxemiawithnormalCXR(possibleinearlydisease)• Desaturationwithexertion
• CD4<200• >90%ofcasesoccurwithCD4<200
• CXRandchestimaging-• Diffusebilateralsymmetricinfiltrates,seenin60%ofcases• HRCTforgroundglass(Sensitivity~100%,specificity89%)• Pneumothrorax common,35%incysticPCP• Lymphadenopathy,cavitations andeffusionareNOTcommon
WhentosuspectPCP
• NoculturesystemforP.jirovecii
• Sensitivityofstainedrespiratorysecretions• Inducedsputum:<50-90%• BAL:95-100%
• ElevatedLDH• Sensitivity83-100%,specificity25-85%
• BetaDGlucan• (1→3)-β-D-glucan isacomponentofthecellwallofmostfungi(includingPjirovecii)• Sensitivity92%,specificity65%forPCPusingacutoffof80pg/ml• MedianlevelinPCPwas408• OtherfungalcausesofpositiveBDG:candidiasis,histo,cryptococcus• Mostusefulifnegative
Grover,ClinInvestMed1992.Sax,CID2011.
PCP:LaboratoryDiagnostics
• TMP-SMXisfirst-linetherapy• Dosing:
• TMP/SMX(TMP15–20mg/kgandSMX75-100mg)/kg/daydividedq6h-q8h• UseIVTMP/SMXformoderatetoseverediseaseandmayswitchtoPOafterclinicalimprovement• PatientswhogetPCPdespiteTMP-SMXprophylaxisstillrespondtostandarddosing
• Desensitizationprotocolsavailableforpatientswithallergy
• Steroidswithin72hoursinseveredisease:RAPaO2<70mmHgorA-agradient>35mmHg• Prednisone40mgbidx5dthen• Prednisone40mgqd x5dthen• Prednisone20mgqd x11d
• Durationoftherapy: 21daysthenstartsecondaryprophylaxis
• AdverseeffectsarecommoninHIV+patients• Rash,fever,leukopenia,thrombocytopenia,azotemia,hepatitis,hyperkalemia• Tryto“treatthrough”common(non-lifethreatening)reactionsifpossible
DHHSOIGuidelines2016
PCPTreatment
• Moderatetoseveredisease(PaO2<70,A-agrad>35):• Pentamidine(IV)4mg/kgIVdaily
• Historicallypreferredasthe2nd lineagentforseveredisease(A-agradient>45)becauseofmoreefficacydata
• Serioussideeffects(irreversiblerenalandpancreaticisletcelltoxcity,orthostatichypotension,profoundhypoglycemia,cytopenias)
• Clindamycin(IV:600mgQ6hor900mgQ8h.PO:450mgQ8h)+Primaquine (30mgPOdaily;checkG6PD)
• Milddisease(PaO2>70,A-agrad<35):• Clindamycin(450mgq6hror600mgq8hr)+primaquine 30mg(base)POdaily• Atovaquone 750mgPOBIDwithfood• Dapsone 100mgPOdaily+TMP15mg/kg/dayPO[3divideddoses]
DHHSOIGuidelines2016
AlternativeRxforFailureorToxicity
• StartedonempiricCTX/doxy+TMP-SMX/prednisone.
• Couldnotgetinducedsputum.
• BAL:• AFBsmearandcxneg• Bacterial:oralflora• PCPpositive
• AfterBALreturned:CTX/doxystopped,TMP-SMX/prednisonecontinued.
BacktoCase1
37y/oMwithHIV(CD428)presentswithfever,AMS,andseizure.
ARS#2:Whatdoyourecommend?
A. BrainbiopsyB. StartempirictoxoplasmosistherapyC. StartRIPEtotreatempiricallyforTB
Case#2
LongDifferential
Skiest DJFocalNeurologicDiseaseInpatientswithacquiredimmunodeficiencysyndrome.CID2002.
SelectedDdx ofCNSSpaceOccupyingLesionsinAIDS
ShortDifferential
• Toxoplasmagondii
• PrimaryCNSlymphoma
BacterialPyogenicabscess
NocardiaRhodacoccus
Tuberculoma/NTMSyphilis
FungalCryptococcomaHistoplasma
ParasiticToxoplasmagondii
Chagasdisease/chagoma
MalignancyPrimaryCNSlymphoma
• OccursatCD4<100,buthighestriskifCD<50
• Almostexclusivelyduetoreactivationoflatentinfection
• Transmissionoccursbyingestingoocystsexcretedincatfeces(incatlitterorsoil)orbyingestingundercookedmeat(porkandlamb)orrawshellfishcontainingtissuecysts
• Subacutepresentationoverseveralweeks:HA,fever,behavioralchanges,confusion,hemiparesis,seizures,ataxia,CNpalsies,diffuseencephalitis.
Skiest,CID2002.
ToxoplasmaEncephalitis:EpiandClinical
• Lesionsaremostcommonlylocatedintheparietalorfrontallobesandatthecorticomedullaryjunction,basalganglia,thalamus,andpituitarygland
• Lesionscanbesingleormultiple:• Classicfindingis≥2ring-enhancinglesionswithsurroundingedema• Butupto27%–43%ofpatientshaveasinglelesion
• Inrarecasespatientscanhavediffuseencephalitiswithnofocallesions
Skiest,CID2002.
CNSToxoplasmosis:Imaging
Imagingfindingsfor2otherpatientswithtoxoplasmosis
• SerumtoxoIgG:ifnegativethenvirtuallyexcludesinfectionbecause<3%–6%ofpatientswithTEhavenegativeIgG
• CSFstudies:• Chemistriesmaybenormalorshowmildincreaseinprotein,lymphocyticpleocytosis,lowglucose• Toxo CSFPCR:sensitivityonly50%althoughspecificity96-100%.Anegativetestdoesnotruleoutdisease.
• ItisverydifficulttodistinguishbetweenToxoandprimaryCNSlymphomabasedonclinicalfindingsalone
Skiest,CID2002.
CNSToxoplasmosis:LaboratoryDiagnosis
• UsuallytreatempiricallybasedonpositiveserumIgG• FollowMRIin2weeks• Shouldseeradiographicimprovementwithin2weeks– ifnotthenconsideralternativediagnosis,pursuebiopsytoruleoutothercauses
• Firstchoiceregimen:Pyrimethamine plussulfadiazineplusleucovorin x6weeks• Thensecondaryppx:pyrimethamine plussulfadiazineplusleucovorin• Pyrimethamine:rash,nausea,andbonemarrowsuppression(canreversebyincreasingleucovorin dose)
• Sulfadiazine:rash,fever,leukopenia,hepatitis,nausea,vomiting,diarrhea,andcrystalluria(encouragehydration)
• Alternativeregimen(fortoxicityorclinicalfailure)• Pyrimethamineplusclindamycin• Pyrimethamine free:TMP/SMXaloneorAtovaquone+/-sulfadiazine• OtherpossibleregimenslistedinCDCguidelines,especiallyifneedIVoptions
• Avoidsteroids(ifpossible)iftreatingempiricallybecausethiswilltreatlymphomaaswell
DHHSOIGuidelines2016
CNSToxoplamsosis:Treatment
• OccursusuallyatCD4<50,subacutepresentation
• Imaging:• Lesionscanbesingleormultifocal,oroftensingle• Usuallyenhancehomogenously,butcanalsoberim-enhancing• Locatedinthecerebrum,basalganglia,cerebellum,brainstem• CharacteristicfindingistobenexttoCSF(egperiventricular,meningeal,subependymal)
• CSFfindings:• Mildelevatedproteinandpleocytosis• EBVPCR:sensitivity>80%,specificity94-100%
Skiest,CID2002.
PrimaryCNSLymphoma
Case#3• CC:51Mp/wshortnessofbreath
• HPI:• Dyspnea&reducedexercisetolerancex1mo• Sweats,fevers,10lb weightlossx1-2mo
Labs/Studiesatpresentation• HIVAntibody(+),CD439
• SputumAFBsmears(-)x3
!
SerumCrAg (+)1:32,768
LP:OP26cm,WBC2 (N0,L93,M7),RBC2,Glu 47,Prot 42
CSFCrAg 1:128,CSFcxCneoformans
Inducedsputum+BALCneoformans
BloodcxCneoformans
• MostcasesoccurwhenCD4<100
• Clinical:• Presentsassubacutemeningitisormeningoencephalitis• Canalsoseeencephalopathicsigns/sxduetoelevatedICP
• Diagnosis:• SerumandCSFCrAgarealmostalwayspositive• CSFstudies:lymphocyticpleocytosisornocells,mildlyelevatedprotein,glucosenormaltolow,elevatedOP
• LowCSFWBCportendsapoorerprognosis
DHHSOIGuidelines2016
CryptococcusMeningitis
• Induction(14days):• Amphotericin0.7mg/kg/dorliposomalamphotericin3-4mg/kg/dplus• Flucytosine(5-FC)100mg/kg/din4divideddoses
• Consolidationtherapy(8weeks):• Fluconazole400mg(6mg/kg)POdaily
• Chronicmaintenancetherapy:• Fluconazole200mgPOdaily• ConsiderstoppingwhenCD4>200andVLsuppressedfor6mo
DHHSOIGuidelines2016;IDSAGuidelines,CID2010.
Cryptococcal Meningitis:Treatment
• ElevatedICPistheleadingcauseofdeathfromCMinthefirst2wksafterdiagnosis
• Managementstrategy:• MeasureOPatdiagnosisIfOPiselevatedandpthassx:dailyLPstoremovevolume(~20-30cc)inordertobringtheOPdowntonormalorby50%ifveryhigh• Aimforatleast2daysofstablepressures• Ifsymptomspersistorcan’tdodailyLPs,thenconsiderEVD/lumbardrain• VPshuntcanbedoneinthesettingofanti-fungals ifothermeasuresfail
DHHSOIGuidelines2016.IDSAGuidelines,CID2010.
Cryptococcal Meningitis:ManagementofElevatedICP
ARS#3:Whendoyoustartantiretroviraltherapy?
A. Within2weeks
B. 5weeksfromstartofanti-fungaltherapy
C. 8weeksfromstartofanti-fungaltherapy
Case#3continued
Advantages• SometimesARVsarethebesttreatmentfortheOI• PML,cryptosporidiosis,KS,microsporidiosis
• PreventionofasecondOI• Restorepathogen-specificimmunity(morerapidclearanceofOI)• SlowHIVprogression
Disadvantages• RiskofIRIS (especiallyifoccursinCNS
StartingARVsduringanAcuteOI
ARTTiminginCryptococcal MeningitisCOATStudy,2013(trialhalted)
Cryptococcal Optimal ARTTiming(COAT)StudyRCT(UG+S.Af.),2013(Boulware,CROIAtlanta,3/6/13)
EarlyART(n=88) LaterART(n=89)
Ampho/Fluc8002w,thenFluc800untilCSFsterile,thenFluc 400x8wks
PLAN: <48hà 7d (5-10)
PLAN: >4wksà 32d(28-36)
MedianCD4+count 19/uL (9-69) 28/uL (11-76)
DeathCSFWBC<5cells/mm3
45%deathby6mo.HR2.21(0.91-5.34)
30%deathby6mo.ref
p=0.03p=0.008
CCM-IRIS(definite/probable/possible) 16.2% 10.1% p=0.347
• Ingeneral,delayARTfor4-5weeks
• Patientswith<5CSFWBChaveahigherriskofmortalityandhavemoretogainwithdelayedART.
SummaryCryptococcal Meningitis
• CMVretinitis:Wewait14days.Limiteddata.
• InflammatoryCNSlesion: Forthosewhohaveevidenceofbrainedema,masseffect,orneurologicdeficitwerecommendwaitingatleast14daysofOIantimicrobialtherapy.Thereisnoavailablerelevantevidence.
• Cryptococcal Meningitis
WhenNOTtoimmediatelystartARTinthesettingofanOI:theZuckerbergSanFranciscoGeneralHospitalExperience
W86clinicalguidelines:http://hivinsite.ucsf.edu/InSite?page=md-ward86-art-oi
KeyFact#2:OIscanbepreventedwithARTandprimaryprophylaxis
OI Indications forPrimaryppx
RegimenofChoice Alternative Regimens Whentostopppx
PCP CD4<200orCD4<12%orh/o thrushorAIDSdefiningillness
TMP-SMX 1DSdailyor1SS
• TMP-SMX1SSdailyor1DStiw• Dapsone (checkG6PD)• Dapsone+pyrimethamine+leucovorin• Aerosolizedpentamidine• Atovaquone
CD4>200for >3mo,HIVRNA<40
Toxoplasmagondii
ToxoIgGpositiveANDCD4<100
TMP-SMX1DSdaily • TMP-SMX1DStiw• Dapsone+pyrimethamine+leucovorin• Atovaquone 1500mgdaily
CD4>200for >3mo,HIVRNA<40
MAC CD4<50 andnoactiveMAC*sendAFBBcxfirst
Azithro1200mgqweek • Azithro600mgpotwice/week• Rifabutin300mgpodaily(watchfordruginteractions,r/oTB)
CD4>100for >3mo,HIVRNA<40
DHHSOIGuidelines2016
PrimaryProphylaxisofOIs:TheBasics
KeyFact#3.Ockham’sRazordoesnotapplytoOIsandAIDS
40yo M,withHIV(lastCD4420andundetectableVL,oneandhalfyearsago,losstofollow-up)presentstourgentcarewithcachexia,fever,diarrhea(10xaday),andabdominalpain
• PMH:• HIVdiagnosed2yearsago,CD4380VL80K.• Startedontruvada anddolutegravir,suppressedfor6months,butthenlosttofollowup
• SH:immigratedfromMexico20yearsago,marginallyhoused
• Labs:Hgb 7,CD448(6%),VL200K,nl LFTsandCr1.0
Case#4
AbdominalCT ChestCT
Imaging
NumerouspulmonarynodulesULandRML- largest1.8cm.
Bulkymesenteric,retroperitoneal,andportacavallymphadenopathy.Non-dilatedfluidfilledloopsofsmallbowelandcolonsuggestiveofileus.
SyndromicDifferentialCanHelpPredictPathogensinPatientswithaCD4<50
ShortDDx:AIDS+Fever+Wasting+LAD
DisseminatedMACTuberculosis
DisseminatedFungal(Crypto,Histo,Cocci)Malignancy
ShortDDx:AIDS+PulmonaryNodules
TuberculosisKaposi'sSarcoma
Fungal(Cryptococcus,Coccidioidomycosis)
Lymphoma
ShortDDx:AIDS+ChronicDiarrheaParasites (cryptosporidium,microsporidium)
Bacterial (salmonella,shigella),mycobacterial (MACcolitis,TBileitis)Viral:CMVcolitis,Kaposi’sSarcoma(HHV8)
Fungal:histoplasmosisOther:HIVenteropathy.
• StoolculturesandO&P- giardiaagpositive,entamoeba histolytica,cryptosporidium.
• SerumCrAG-negative
• Urinehisto Ag-negative
• Violaceouslesiononbaseoftongue
Case4(cont.)
Colonoscopy
ColonoscopyCytopathic changes consistent with CMV
NucleomegallyandSmudgy chromatin
ColonoscopyGranulomatous inflammation with AFB
Lung Biopsy- Kaposi’s Sarcoma
Stains for HHV-8
H&E- spindle cells
Case4-FinalDiagnosis
1.DisseminatedKS:Tongue,skin,andlungs
2.CMVesophagitisandcolitis
3.DisseminatedMAC– MAConLNandcolonbiopsies;bloodculturesgrewMAC
WhentosuspectMycobacteriumAvium ComplexClinical:• Fever,weightloss,wasting,+/- diarrhea,+/- abdominalpain
Laboratory:• CD4<50• ElevatedAlkPhos• Oftenwithanemiaorpancytopeniaduetobonemarrowinfiltration
Diagnostics:• AFBBloodCultures(importanttodrawpriortogivenazithromycin)
• Sensitivity91%for1AFBbloodcultures• Sensitivity98%for2AFBbloodcultures
• CTabdomenoftenrevealshepatosplenomegally andintrabdominallymphadenopathy
• Mayneedtissuebiopsy
Drug1 Drug2 +/- Drug3Clarithro (moredata)
Or
Azithro (bettertolerated,lessdruginteractions)*
Ethambutol Rifabutin
Karakousis,LancetID2004.CDC,MMWR2013.*DunneCID2000**BensonCID2003
MACTreatment:AtLeast2Drugs
• Considera3rd drugwhen:v Highburdenofdiseasev NotonARVsv **mortalitybenefitwith3drugsvs.
2drugs,butpreHAARTera
• Monitoring:• CheckAFBcxat4-6weeks• Considertreatmentfailure,if
noimprovementinsx andstillbacteremic after4-8wks
• UsuallyoccurswhenCD4<50
• CMVinAIDSmanifestsas(inorderoffrequency):• Retinitis:beforeHAART,30-40%developedthis• Screeningeyeexamsinpatients
withCD4<50recommended
• GI:colitis(5-10%),esophagitis(<5-10%)
• Neuro:encephalitis,polyradiculomyelopathy
• Pneumonitis:veryrare,usuallybystanderinBALandnotcauseofpulmonarydisease
CMVandAIDS
CMVretinitis-ImageNIHhttp://www.nei.nih.gov/photo/eyedis/index.asp
Diagnostics• CMVPCRnothelpful,exceptforin
settingofCNSinvolvement• Needtissue(asidefromocular
disease)
KeyFact#4:ThereisanincreasedriskofIRISwithCD4<50-100
5weeksafterstartingARVs,thepatientwasreadmittedwithnewfeverto39.4,CTshowedmildincreaseinsizeofmediastinal/intra-abdominalnodes.
CD4wentfrom46->85,andVL200Kà 110
What’sonyourddx?
Case#4continued
• Immunereconstitutioninflammatorysyndrome(IRIS)
• Adversemedeffect
• Treatmentfailure(noncompliance,resistance,poorabsorptionofmeds)
• NewOI,malignancy,autoimmuneprocess
DDx:WorseningofOIAfterStartingARVs
ARS#4:WhichstatementisINCORRECT?
A. NSAIDScanbeusedtotreatmildIRIS
B. Mortalityofcryptococcus IRISisover20%
C. ThispatientcouldhaveKSIRIS
D. PCPIRISiscommon
• Broadlydefinedasasyndromeofanexaggeratedimmuneresponsetoantigensafter startingARVs• TopersistentantigensofanOIthatisbeingtreated(paradoxicalIRIS)• Toviablepathogensthatweresubclinicalandnotbeingtreated(unmaskingIRIS)
• Timing:RecentinitiationofARVs(usuallywithin3mo)withdecreaseinVLand/orincreaseinCD4
• Usuallyinfectionsbutcanalsobemalignancy(KS-IRIS).
• Littleisknownaboutpathogenesis
WhatisImmuneReconstitutionInflammatorySyndrome(IRIS)?
Mülleretal,LancetID2010.
MAC LocalizedDisease(eg lymphadenitis,abscesses)Bacteremiaabsent
Cryptococcus Recurrenceofmeningitisfrequentlyassociatedw/increasedICPLymphadenitisCryptococcomas
TB Fever,lymphadenitis,coldabscesses,worseningpulmonarydisease
CMV Immunerecoveryuveitis,canbesightthreatening
KS RapidprogressionofKSlesion
ClassicIRISPresentations
Maraisetal,Curr HIV/AIDSReports2009.
• PCPIRIShasbeendocumented,butrare
• OverallincidenceofIRISis~15-30%
• é riskifstartingARVsatalowCD4(<50)orhighVL(>100K)
• ~5%mortalityinIRIS:• 3%withTB-IRIS• 20%withCCM-IRIS
IRISIncidenceandOutcome
Mülleretal,LancetID2010.Novaketal,AIDS2012.
• Step1:OptimizeorinitiatetreatmentoftheOI
• Step2:Supportiveandsymptom-directedtherapy(mostcasesareself-limiting).Mostcasesresolveinseveralweeks.
• Step3:Consideranti-inflammatorytherapies• NSAIDsforlessseveresymptoms• Corticosteroidsmostcommonlyusedformoderatetoseveredisease.Oftenstartprednisone1mg/kgandtaperbasedonclinicalresponse(doseforTBIRIS).
• Don’tStopART!
IRIS:Treatment
Maraisetal,Curr HIV/AIDSReports2009.
• LikelyparadoxicalIRIS
• AFBbloodculturesnegative
• ThepatientwasstartedonNSAIDSandsymptomsresolved.WeavoidedsteroidsbecausepatienthadknownKaposi’sSarcoma.
• Onemonthlater,imagingshowedimprovementinabdominalLAD,andpulmonarylesions.
Case#4:Follow-Up
KeyReferences
• DHHS2016OIGuidelines:https://aidsinfo.nih.gov/contentfiles/lvguidelines/Adult_OI.pdf
• AIDSEducationandTrainingCenters’NationalResourceCenter:www.aidsetc.org
• HIVInsite andWard86ManagementRecommendations:http://hivinsite.ucsf.edu