carina marquez … · tuberculoma /ntm syphilis fungal cryptococcoma histoplasma parasitic...

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]


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


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


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


MAC CD4<50 andnoactiveMAC*sendAFBBcxfirst

Azithro1200mgqweek • Azithro600mgpotwice/week• Rifabutin300mgpodaily(watchfordruginteractions,r/oTB)



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

carina marquez … · tuberculoma /ntm syphilis fungal cryptococcoma histoplasma parasitic...

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