LowTransmissibilityofMycobacteriumtuberculosisBasedonTimetoDetec6onfromPa6entswithanIni6alSputumPosi6vebyLiquidCulturebutNega6vebyNucleicAcidAmplifica6onTes6ngandAcid-FastBacilliStainSaahirKhan1,AudreyNakasone2,MinooGhajar3,MariamZhowandai3,SunitaPrabhu3,RickAlexander3,JulieLow4,EllenaPeterson2,andLauriThrupp1,2,5
1DivisionofInfec6ousDiseases,2ClinicalMicrobiologyLaboratory,5EpidemiologyandInfec6onPreven6on,UniversityofCaliforniaIrvineHealth,Orange,California3PublicHealthLaboratory,4TuberculosisControlDivision,OrangeCountyHealthcareAgency,SantaAna,California
Background
Tradi6onalguidelinesforde-isola6onofsuspectedpulmonaryTBcasesrequirethreerespiratoryspecimenscollectedandtestednega6vebyacid-fastbacilli(AFB)staining1,2(basedonstudiesshowingnega6veAFBindicateslowerorganismburdenandtransmissionrisk5,9)butrequirepa6entstospendtwoormoredaysincostlyairborneisola6onrooms3.
Ofconcernwiththisapproach,30-50%ofspecimensfromcultureposi6vepulmonaryTBcaseshavenega6veAFBstain4,and17%ofnewcasetransmissionsareacquiredfromAFB-nega6vecases5.
Recently,useofnucleicacidamplifica6ontests(NAAT)hasincreasedsensi6vityforTBdiagnosis6,promp6ngstudiessugges6ngde-isola6onaaeronespecimenwithnega6veAFBstainandnega6veNAAT5,6,11.
However,thisstrategymays6llmiss10-20%ofculture-posi6veAFBnega6vespecimens,promp6ngrecentguidelinessugges6ngtwospecimenswithnega6veNAATberequiredforde-isola6on7,8.
O’sheaetal.foundthat6metodetec6on(TTD)inliquidcultureof9ormoredaysindicatedlowertransmissionriskbederthanAFBstain10.
Figure1.Transmissionratesandpropor6onofsecondarycasesofac6vediseaseandlatentinfec6on(LTBI)stra6fiedby6me-to-detec6on.ReprintedfromO'Sheaetal.,ClinInfectDis,2014.
TTDhasnotyetbeenexaminedalongwithAFBstainandNAATtodetermineifTTDaddssubstan=vesupporttotheconceptofde-isola=onaAeronespecimennega=vebyAFBandNAAT.
PrincipalAim
ToevaluatewhetherpredictedTTD,incombina=onwithAFBandNAATtoiden=fylowriskcasesofsuspectedpulmonaryTB,supportsthegoalofde-isola=onaAeronespecimennega=veforAFBandNAAT
Methodology
Retrospec6veanalysisofacohortofall117pa6entstestedatU.C.IrvineHealth(UCI)from2013to2014and670pa6entstestedatOrangeCountyHealthCareAgency(OCHCA)in2014iden6fiedatotalof94Mtbculture-posi6vefirstrespiratoryspecimens(34atUCI,60atOCHCA).
EachspecimenwasassessedbyAFBgradewithKinyounstain,TTDinMGITculture,andNAATresultbyCepheidXpertonfresh(OCHCA)orstoredfrozen(UCI)rou6neconcentrates.
Figure2.KinyounstainforAFB(lea),MGITforliquidculture(middle),andCepheidXpertforNAAT(right).
Weanalyzedcorrela6onbetweenAFBgradeandTTDusingPearsoncorrela6oncoefficientwithStudent’st-testforgroupcomparisons.
Results
TimetoDetec=on,AFBGrade,andNAATResultfor94MtbCulture-Posi=veFirst-RespiratorySpecimens
Figure3.Timetodetec6onincultureversusAFBgradeandNAATresultfor94specimensanalyzed,stra6fiedintolowriskoftransmissionwithTTD>9daysandhighriskoftransmissionwithTTD<9days.
Among94totalspecimens,61specimens(65%)wereposi6vebyAFBstainandNAAT,andanaddi6onal21(22%)wereposi6vebyNAATalone,leaving12specimensofinterest(13%)thatwereposi6vebyMtbsolidculturebutnega6vebybothAFBstainandNAAT.
Figure4.94specimensanalyzedbyAFBgrade,NAATresult,andTTDwerestra6fiedintoahightransmissionriskgroup(pink)withposi6veAFBstainorposi6veNAATorTTDlessthan9daysandalowtransmissionrisk
group(blue)withnega6veAFBstain,nega6veNAAD,andTTDgreaterthanorequalto9days.
All12specimenswithnega6veAFBstainandNAAThadTTDof9daysorgreaterindica6nglowerriskofMtbtransmission(seeFigure3onlea).
TTDhasstronginverselinearcorrela6onwithAFBgrade(ρ=0.62).
Figure5.Mean6metodetec6onwithcorrela6ontosputumAFBgrade(errorbarsrepresentSEM)
Discussion/Conclusion
Nega6veAFBstainandNAATpredictTTDof9daysorgreater,allofwhichindicateloworganismburdenpredic6nglowtransmissionrisk.
Thesefindingssupportearlyde-isola6onaaeronespecimenwithnega6veAFBstainandNAATsincetheculture-posi6vesubsetofthesepa6entsallhadTTDof9daysorgreaterindica6nglowtransmissionrisk.
Addi6onally,inves6ga6onsofcontactswithprolongedexposureslikelyoveres6matetransmissionriskinhospitalseongswithbriefexposures.
UCInowallowsremovalofairborneisola6onforsuspectedpulmonaryTBcases(withoutcavi6es,miliarypadern,orimmunosuppression)aaeronespecimennega6vebybothAFBstainandNAAT.
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MtbCulturePosi6ve94(100%)
AFBStainPosi6ve61(65%)
AFBStainNega6ve33(35%)
MtbNAATPosi6ve21(22%)
MtbNAATNega6ve12(13%)
MtbTTD>9Days12(13%)
MtbTTD<9Days
0
Abstract57911
0
10
20
30
40TimetoDetec=o
n(Days)
AFBGrade:negneg1+2+3+4+TotalNAATResult:negposposposposposN=94
higherrisk
lowerrisk
NAAT TTD Smear Total0 1+ 2+ 3+ 4+
Nega6ve <9days 0 0 0 0 0 0 12≥9days 12 0 0 0 0 12
Posi6ve <9days 1 1 3 8 10 23 82≥9days 20 12 15 11 1 59Total 33 13 18 19 11 94
Rela6veRiskofTransmission:TTD>9days=0.4410
AFBnega6ve=0.19-0.225,9
lowerrisk higherrisk
TTD=-3.5*(AFB)+23DoublingTime=25hours
0
5
10
15
20
25
0 1+ 2+ 3+ 4+MeanTimetoDetec=o
n(Days)
SputumAFBGrade
References