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Testing&TreatmentforTBInfection:BloodTests,SkinTests,Whoto

Screen&WhotoTreat?E.JaneCarter,M.D.

ImmediatePastPresidentInternationalUnionAgainstTBandLungDisease

AssociateProfessorDivisionofPulmonary,CriticalCareandSleep

WarrenAlpertSchoolofMedicineatBrownUniversity

NECHA11/4/2016

Disclosures• Grant Funding

– USAID AMPATH, CFAR• Boards

– Immediate Past President, The Union (Paris, France)– Vital Strategies (NYC, NY)

• Committees– Advisory Panel -TB Modeling and Analysis Consortium– Global Fund- Committee on Tuberculosis– Proposal Review Committee, TB Reach, UNOPS, Geneva

• Consulting– Consultant, Global TB Institute, New Jersey, USA– Consultant, JSI: Project – Linking Primary Care Sites to TB Control in

Massachusetts ( Completed May 2015)• No financial relationship with a commercial entity producing health-care

related products and/or services as well as no tobacco relatedassociations.

Outline• 2Cases- Notcollegestudentsbutusefultounderstandconcepts

• TBEpidemiology• TargetedTestingRecommendations

– TBInfectionTestingOptions– IGRA(InterferonGammaReleaseAssays)OperationCharacteristics

– NationalTBControllers(Draft)GuidelinesforInterpretation

• TBTreatmentOptions• CirclebacktotheCases

Case1

• 44yo FbornintheUS(RI)• JRAsinceage8- nowonHumira for3years

– AllpastTSThavebeennegative• WorksasRTinalocalhospital• RoutinevisittoRheum

• 6weeksearliersherememberedcaringforsomeone“coughingalot”(outoftheordinary)

– PatientwasnotdiagnosedwithTBduringhospitalstay- notpartofacontactinvestigation

• SentforaQuantiferon Goldtest– Reportedas“positive”

Case2

• 74yo F• Septemberjawpain– treatedwithshortcourseofsteroids

• Octoberstartedhavingfeversandnightsweats• Totalbodyscanning– Abd/pelvisnormal;Chestthickeningofthewallsofaorta/brachiocephalicandcarotidsc/w arteritis

• DevelopedSOB– echorevealsasmalleffusion• Quantiferon goldordered- reported“negative”

GlobalTBBurden• 1/3oftheworld’spopulationisinfected• 8-9millioncasesofTBdiseaseregistered/year• 2milliondeaths/year

– In2014TBbecametheleadingcauseofdeathfromaninfectiousdisease

– LeadingcauseofdeathinthoselivingwithHIV/AIDS– Leadingcauseofdeathinwomenofchild-bearingyears– 1/6Tbcaseswilldie– 1/3ofTbcasesgloballynotdiagnosedornotreported

• Worldwideanewinfectionoccursonce/second

Reported TB Cases United States, 1982–2014*

*UpdatedasofJune5,2015.

0

5,000

10,000

15,000

20,000

25,000

30,000

No.ofC

ases

Year

9,421cases

Tuberculosis• Importantonaglobalscale• Importantlocally?

– IfwereallywanttogettoTBelimination,ithastostayontheradarscreen

– TBdiseasewhenitdoeshappen,causesalotofworkandcostsalotofmoney

• Contactinvestigations:Oneindexcaseatalocalhospitalledto739contacts,49%ofwhomwerereportedasevaluatedforTB

• Patientshavebeenhospitalizedformonthswhenappropriatehousingnotavailable

– Whileweareinalowincidencesetting,wedoalotofworrying• Isolationrooms:TMHrangefrom2-7permonthforthelast8months• Andalotofscreening…

– 400Quantiferon goldtestsdoneeachmonthintheLifespansystem

Reported TB Cases United States, 1982–2014*

*UpdatedasofJune5,2015.

0

5,000

10,000

15,000

20,000

25,000

30,000

No.ofC

ases

Year

9,421cases

Bayes Theorem

• Sensitivityandspecificityoftheavailabletestsareinherentinthetests

• However,thepositiveandnegativepredictivevaluesareinherentinthepopulationonwhomthetestsareused

• Therefore,alltestsaremoreaccuratewhenusedonthosewithahighindexofsuspicion– epidemiologyrisk=targetedtesting

WhyScreenforLTBI?

• CriticaltothestrategytoeliminateTB• Patientbenefit

– SimplerregimenthanactiveTB– AvoidslongtermcomplicationsofTBdisease(lungdestructionasthemostcommon)

• Societalbenefit– Treatspatientpriortotheirbecomingcontagious– Transmissionisthereforeavoided

Whodowetargettoscreen?Personsatincreasedriskforinfection

• Closecontactsofinfectiouscases

• ForeignbornfromTBendemicareas

• Residentsandemployeesofhighriskcongregatesettings

• HCWers exposedtoactiveTBpatients

• LocallyepidemiologicalpopulationswithincreasedTBrisk

• Someelderlygrowingupinaneraofhighprevalence

Personsatincreasedriskforprogressionwhomay nothaveincreasedexposurerisk• HIV/AIDS• Personsbeingconsideredfor

immunosuppressive/modulatingtherapy– TNFalphaantagonists– SystemicSteroids>15mgperday– Immunesuppressionfollowing

organtransplantation• Pre-transplantation• Silicosis• EndStageDisease• Diabetes(NotaclearUS

recommendation)

WhodowetargettoscreenForcollegematriculation?

Personsatincreasedriskforinfection

• Closecontactsofinfectiouscases

• ForeignbornfromTBendemicareas

• Residentsandemployeesofhighriskcongregatesettings

• HCWers exposedtoactiveTBpatients

• LocallyepidemiologicalpopulationswithincreasedTBrisk

• Someelderlygrowingupinaneraofhighprevalence

Personsatincreasedriskforprogressionwhomay nothaveincreasedexposurerisk• HIV/AIDS• Personsbeingconsideredfor

immunosuppressive/modulatingtherapy– TNFalphaantagonists– SystemicSteroids>15mgperday– Immunesuppressionfollowing

organtransplantation• Pre-transplantation• Silicosis• EndStageDisease• Diabetes(NotaclearUS

recommendation)

ForeignbornfromTBendemicareas

• Easiertothinkoftheexclusioncriteriathantolisteveryhighburdencountry

• Exclusions:Canada,AustraliaandNewZealand,CountiesofWesternEurope

Whattestsareavailable?

TuberculinSkinTests

– TUBERSOL®(TuberculinPurifiedProteinDerivative)-Mantoux – Sanofi Pasteur,Canada

– Aplisol (TuberculinPurifiedProteinDerivative)– JHPPharmaceuticalsLLC

BloodTests

– QuantiFERON-TBGoldIn-Tube(QFT-GIT)– CellestisLimited,Carnegie,Australia–nowQiagen,HildenGermany

– T-SPOT.TB – OxfordImmunotec,Abingdon,UnitedKingdom

TuberculinSkinTests

Pro• Testmaterialsarerelatively

inexpensive• Doesnotrequirealaboratory• Doesnotrequire

transportationofviablesamples

• Wellstudiedandpublichealthfamiliarity

• Recommendedforchildrenunder5

Con• Cannotbeusedtodiagnoseorruleout

activeTB• Requires2visits(toapplytestandread

results)• Patientcompliancecanbeaproblem• Placement,readingandinterpretation

oftheresultissubjecttohumanerror• Threecutpointsmaycauseconfusion• False-positivetestsmayoccur(inBCG-

vaccinatedpersonsandnon-tuberculous mycobacteria (NTM)infection)

• Establishingbaselineforserialtestingmayrequireatwo-stepTST(4visits)

• Testvariability,particularlyinlow-riskpopulations

IGRAInterferonGammaReleaseAssays

Pro• Requireasingle

encounter**• NocrossreactionwithBCG-

vaccineandmost NTMs• Mayhavebetteracceptance

oftheresultsinsomepopulations

• Standardizedlaboratorytestwithcontrols

• “Objective”results

Con• Cannotbeusedtodiagnose

orruleoutactiveTB• Relativelyexpensive• Requiresphlebotomy• Requiresalaboratorythat

performsthetest• Requiresspecificspecimen

collection,handling,transportandlaboratoryprocessing– Leadingtofalsepositiveor

falsenegativeresults• Testvariability,particularlyin

low-riskpopulations

TuberculinSkinTesting• Testcharacteristics

– TSTis“planted”– SizeMeasurementoftheinduration isrecordedat48-72hours

• Testinterpretation

Epidemiologicriskassessment

Threecutoffs– 5,10,15mm

TwotypesofIGRA

• T-spot– Elispot– MeasuresInterferonGammaperstimulatedTcell

• Quantiferon Gold– Elisa– MeasurestotalInterferonGammaproducedbystimulatedTcells

5.Softwarecalculatesresultsandprintsreport.

4.Washandaddsubstrate.Readabsorbanceafter30min.

3.AddplasmaandconjugatetoELISAplate.Incubatefor120minutesatRoomTemperature.

1.Collect1mLofblood(X3).Incubateat37ºCfor16-24hrs.

2.Centrifugetubesfor5minutes.

IFN-g stablerefrigeratedforatleast4weeks.

StageOne– BloodIncubationandHarvesting

StageTwo– HumanIFN-γELISA

ESAT-6CFP-10TB7.7(p4)

TheELISAstageiseasilyautomatedonexistingmachines

QuantiFERON-TBGoldInTube

NilControl

MitogenControl

Testvariability

Pre-analytical• Manufacturingissues• Improperstorageoftubes• Timeofdayofdraw• Inadequatecleansingofthe

skin• Improperbloodvolume• Variabilityinmixingof

Ag/mitogen (shakingissue)• Specimentempandtransport

timetoprocessing(evenwithinthemanufacturer’sspecification)

Analytical• Imprecisepipetting• Variableincubationtimes

andtemps(evenwithinthemanufacturer’sspecification)

• WithinAssayvariability

EffectofShakingonTBResponse

GauretalJCM2013

Forthoseintheaudienceplanningalargeemployeescreeningprogram,hereissomethingtothinkabout……..

• StanfordExperience• >10,000TSTperyearsowenttoIGRAimmediately

• OngoingQualityAssessmentProgramrequired

Niaz Banaei

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10

20

30

40

50

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Posi

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StanfordQFT-GITSurveillanceGraphShowingDailyPositiveRate

TBAglotdiscontinuedElevatedrate

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Niaz BanaeiJClin Micro2012(50)9:3105

HowaretheIGRAresultsreported?

• Threetubes– TBNil(ControltoverifythattheimmunesystemisnotoverproducingInterferongamma)

• Mustbe<8IU/ml

– TBMitogen (ControltoverifythattheimmunesystemcanworkandproduceinterferonGamma)

– TbAntigen(ThetesttoseeifthepatientproducesinterferongammaagainstTBantigens)

• TBAntigen– TBNilmustbe>0.35IU/ml

HowaretheQuantiferon resultsreported?

Quantitive• Nil• TBAntigen• Mitogen• TBAntigenminusNi

– >0.35IU/mldefinespositivity

• Mitogen minusNil

Qualitative• Positive• Negative• Indeterminate

PerCDCguidelines,labshouldreportthequalitativetestinterpretation,thequantitativeassaymeasurementsandthecriteriafortestinterpretation.MMWR2010/Vol.59/noRR5

Whatarethecausesofanindeterminatetest?

Qualitative• Positive• Negative• Indeterminate

PatientFactors:

CompromisedimmunestateAge<2yearsCertainimmunosuppresive drugs

(TNFalphablockersandimmunomodulators)

ImmunosuppressantconditionsHIV,Cancer,posttransplant)

Recentliveviralvaccination Specimen/laboratoryfactors:

Transportationorstorageoutsideofrecommendedrange

Improperincubation,InsufficientmixingofthebloodcollectiontubesCompromisedMitogens

Whattodowithanindeterminatetest?

• Thisiswhereyouneedtolookatthenumbers– AhighNil(>8.0),irrespectiveoftheTBAntigenresults,suggestsanerrorwiththeNegativecontrol- YoucanrepeattheQuantiferon

– Alowmitogen control(<0.5)intheabsenceofaTBantigenresponsesuggestsaproblemwiththepatient’simmunesystem- hereiswhereyouhavetoreturntothepatient’sepidemiologicriskhistory.

DoesBoostingoccurwithIGRA?

• Boosting- rememberthishastodowithcellmemory……

• DrawinganIGRAdoesnotcausetheresultsofasubsequentTSTorIGRA

• PlacementofaTST>72hourspriortotheIGRAcanaffecttheIGRAforupto6months(usuallylowpositivebut……..)

CantreatmentforTBinfection(ordisease)impact(meaningrevert)the

test?• NO• NO• NO• DonotdrawanIGRA(orperformaTST)toseeiftreatmentwassufficientinthepast

• Ifapatienthasbeentreatedinthepast(andneedtobeinascreeningprogramsuchasaHCW),theydoNOTNEEDeitheraTSToraIGRAbutratherasymptomsscreenchecklist.

AretheretimeswhentheIGRAshouldberepeated?

• RepeatingtheIGRAmay beusefulwhentheinitialIGRAis– Indeterminate– Lowpositive(0.35-1.0IU/ml)

• Inlowriskindividuals,repeattestingrevertstonegative70%ofthetime

– Anunexpectedpositiveornegativeresult• Inlowriskindividuals,repeatingtheQTFwillincreasespecificityofthetesting(2negatives,99%accuracy)

WhenshouldapatienthavebothanIGRAandaTST?

• UseofbothtestsmayincreasesensitivityforTbinfectionandthereforemightbeconsideredinpatientsathighriskofTBinfectionandprogressionorforpooroutcome(HIVinfected,children<2yearsofage)

• InsituationswhereuseofbothmayenhancecompliancewithLTBItreatment– Typicalscenarioissomeone(usuallyBCGvaccinatedand/oraHCW)witha+TSTwhoasksforanIGRAbeforeconsideringtreatment

• RetestingwithaTSTpostanindeterminateIGRAtestisNOTrecommended

WhatshouldIdoifmypatienthasdiscordantresultsfromdifferenttypes

oftestsforTBinfection?• Verycarefulconsiderationshouldbedonepriortousingasecondtestorsecondtestingmethod.

• AsecondtestshouldNOT bedonetosearchfortheanswerthatyouwanted.ThisisNOT anindicationforadifferenttest.

• Bestadvice- trytostayawayfromthesituationinthefirstplace- don’tswitchtestswhenyouareconfusedby(orjustunhappywith)thefirsttest!– Don’tenterthesharkpoolwithoutthinkingaboutitfirst!

Howareunexpectedresultsbestaddressed?

• UnexpectedPositiveResults:– Healthyindividuals

• Mostwillbeafalsepositive• Assurenosymptomsandthenrepeat

– IfTST,doTSTorIGRA– IFIGRA,doanIGRA– If2nd test+,treatas+– If2nd test-,nothingfurtherdone(includingaCXR- don’tdoit!)

– IndividualswithRiskFactorsforprogression• ModerateRisk– sameasaboveunlesslocalepi suggestsdifferently

• HighRisk– backtoweighingriskandbenefits

TreatmentofLatentTBInfection

Intenttoscreenshouldbecoupledwithintentiontotreat

RecommendedRegimensforTreatmentofLTBI

TreatmentIssues

• SideEffectMonitoring– INHorRIF- Hepatitisrateslow,particularlyinayoungpopulation

– RiforRifapentine- DrugDrugInteractionsandredsecretions

– 3HPregimen- nausea,ImmunologicSideEffectmonitoringpriortonextdose

• AdherenceMonitoring– Numberofdosesiswhatmatters– Cleardocumentationoftreatmentatendoftherapy

Case1

• 44yo FbornintheUS(RI)• JRAsinceage8- nowonHumira for2-3years

– AllpastTSThavebeennegative• WorksasRTinalocalhospital• RoutinevisittoRheum

• 6weeksearliersherememberedcaringforsomeone“coughingalot”(outoftheordinary)

– PatientwasnotdiagnosedwithTBduringhospitalstay- notpartofacontactinvestigation

• SentforaQuantiferon Goldtest– Reportedas“positive”

Case1

• ShewenttoemployeehealthwhereanotherTSTwasplanted(buttheydecidednottoreadit….Patientsaiditwas“negative”andlookedlikeitalwayshad)

• ShethenwenttotheERwhereaCXRwasdone

• CXRabnormalsowastakenoutofwork– Fridayafternoon

• Pulmonaryconsult

Case1

• CalltoDOH- noinfectiouscasesdiagnosedduringthetimeperiodofinterest

• Extensivequestioning– noepi risk– Notravel– Nooneillinfamily– Noexposures

• CXRfindings– benignThymic cyst• HerQuantiferon reportonlygavethequalitativeresults

IGRAtesting

#1• TBNil0.03• TBMitogen 18.19• TBAntigen0.43

#2• TBNil0.006• TBMitogen <10• TBAntigen0.03

NoepidemiologicriskNegativerepeattestingwiththesametest

PatientdeemednotinfectedatthistimeClearedtorestartherhumira andtoreturntowork

2½weeksoutofwork2IGRACXR,CT,MRIPulmonaryconsult

Case2

• 74yo F• Septemberjawpain– treatedwithshortcourseofsteroids

• Octoberstartedhavingfeversandnightsweats• Totalbodyscanning– Abd/pelvisnormal;Chestthickeningofthewallsofaorta/brachiocephalicandcarotidsc/w arteritis

• DevelopedSOB– echorevealsasmalleffusion• Quantiferon goldordered- reported“negative”

Case2- TBhistory• BorninIceland• Atage10,herauntandherGFdiedofTB• ShewasthoughttohaveTBandplacedatbedrestformonths

• ShebecameanurseandworkedinthelastTBsanitariuminIcelanduntilitwasclosed.

• OncomingtotheUS,sheworkedinahospitalinNYC

• TSTtherewasverylargeandshewastoldnottohaveTSTtestingagain(Nevertreated)

Case2

• Quantiferon Gold:Negative– TBNil0.120IU/ml– Mitogen 0.544IU/ml– TBAntigen0.134IU/ml

• TreatedwithINHandRifampin– Unabletoruleoutactivediseasecausingherpericardialeffusion

– Goingonsteroidsfor?PMR

Isabloodtest“better”?

• IGRAhasmorespecificitythanTST(takesoutthenoisefromBCGandmostNTMS)

• Bothtestshaveperformancelimitations• Bothtests,whenappliedinalowincidencesetting,willhavefalsepositives

• Notabettertest,justadifferenttest• Westillneedabettertest

IntenttoscreenshouldbecoupledwithintentiontoTHINK

……abouttheTBhistory,thepretestprobabilityofTBinfection,abouttheinherentlimitationsandvariabilityofthetestyouareusing,etc,etcetc

Questions?

NationalTBControllersAssociationhttp://www.tbcontrollers.org

TBGlobalInstituteMedicalConsultationLine1-800-4TBDOCS(1-800-482-3627)