Testing & Treatment for TB Infection: Blood Tests, Skin...
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Testing & Treatment for TB Infection: Blood Tests, Skin Tests, Who to Screen & Who to Treat? E. Jane Carter, M.D. Immediate Past President International Union Against TB and Lung Disease Associate Professor Division of Pulmonary, Critical Care and Sleep Warren Alpert School of Medicine at Brown University NECHA 11/4/2016
Transcript of Testing & Treatment for TB Infection: Blood Tests, Skin...
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
0
10
20
30
40
50
60
Posi
tive
rate
StanfordQFT-GITSurveillanceGraphShowingDailyPositiveRate
TBAglotdiscontinuedElevatedrate
noted
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)
