Testing & Treatment for TB Infection: Blood Tests, Skin...
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)