The Cerebrospinal Fluid TPPA for Neurosyphilis Diagnosis Christina Marra, Shelia Dunaway, Lauren Tantalo, Sharon Sahi, University of Washington, Seattle, WA, USA
Christina M. Marra, MD [email protected] Phone: 206-897-5400 Fax: 206-897-5401
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Background Thereisnosinglesensitiveandspeci2ictestfordiagnosisofneurosyphilis(NS).Whilethecerebrospinal2luid(CSF)-VenerealDiseaseResearchLaboratory(VDRL)testisspeci2ic,itlackssensitivity.Incontrast,theCSF-2luorescenttreponemalantibody-absorption(FTA-ABS)testissensitive,butlacksspeci2icity.Inaddition,theCSF-FTA-ABSisnotavailableinmanyareas.TheCSF-Treponemapallidumparticleagglutinationassay(TPPA)isanalternativetotheCSF-FTA-ABS,butlittleinformationisavailableregardingitsdiagnosticperformance.Atitercut-offof≥1:320improvestheNSdiagnosticperformanceoftheCSF-Treponemapallidumhemagglutinationtest(TPHA)(1,2),atreponemaltestthatissimilartotheTPPA,buttheNSdiagnosticutilityofaCSF-TPPAcut-offhasnotbeendetermined.
Methods ParticipantswereHIV-infectedandHIV-uninfectedindividualsenrolledinastudyofCSFabnormalitiesinsyphilis.Studyeligibilitycriteriaincludedclinicalorserologicalevidenceofsyphilis,andassessmentbythereferringproviderthatthepatientwasatriskforneurosyphilis.Reasonsforreferraltothestudyincluded1)neurological2indings,particularlyvisionorhearingloss;2)serumRapidPlasmaReagin(RPR)titer>1:32,or3)inHIV-infectedindividuals,peripheralbloodCD4+Tcellcount<350/ul.
CSF-FTA-ABSandCSF-TPPAreactivityweredeterminedinaresearchlaboratoryusingstandardmethodsforaconveniencesampleof192participantsenrichedforreactiveCSF-VDRL(trainingdataset).CSF-TPPAtitersweredeterminedforCSF-TPPAreactivesamples.Subsequently,CSF-FTA-ABSreactivity,CSF-TPPAreactivity,andforCSF-TPPAreactivesamples,CSF-TPPAreactivityata1:320dilution,weredeterminedforallavailablesamplesfromstudyparticipantsenrolledafterthelasttrainingsamplewascollected(n=337,validationdataset).CSFwhitebloodcell(WBC)concentrationandCSF-VDRLreactivityweredeterminedinahospitalclinicallaboratory.PersonnelwhoconductedtheCSF-FTA-ABSandCSF-TPPAtestswereblindedtootherclinicalandlaboratory2indings.
DifferencesincharacteristicsofstudyparticipantsinthetrainingcomparedtovalidationdatasetswereassessedbyChi-squareorMannWhitneyUtests.Kappastatistic,sensitivityandspeci2icitywerecalculatedusingstandardformulas.Differencesinsensitivityandspeci2icitywereestimatedbytwosampletestofproportionusingStataversion11.2.P-values<0.05wereconsideredtobestatisticallysigni2icant.
References 1.LugerAFetal.IntJSTDAIDS.2000;11(4):224-34.2.LevchikNetal.SexTransmDis.2013;40(12):917-22.
Results Comparedtoparticipantsinthevalidationdataset,thoseinthetrainingdatasetwereyounger,weremorelikelytohaveCSFabnormalitiesandmorelikelytobetreatedforNS.
Table1.Par+cipantCharacteris+csTraining
Dataset,n=192Valida+on
Dataset,n=337P-value
Male 186(97) 330(98) NSHIV-infected 159(83) 267(79) NSAge 37(32-43) 42(32-48) .0021/SerumRPR+ter
64(32-256) 64(16-128) NS
Earlysyphilis 134(70) 251(75) NSReac+veCSF-VDRL
61(32) 42(13) <.001
>20WBCs/ulCSF 69(36) 54(16) <.001Visionorhearingloss
40(22),n=183 80(24) NS
TreatedforNS 106(55) 106(32) <.001Resultsareexpressedasnumber(n),percent(%)ormedian(IQR)
Figure1.PercentofsampleswithreactiveCSFtreponemaltests
Results • Signi2icantlymoretrainingsampleshadreactiveCSF-TPPAandsigni2icantlymorewerereactiveatatiterof1:320orgreater
• AgreementbetweentheCSF-FTA-ABSandCSF-TPPAinthetrainingdatasetwasgood(kappa=0.68)andinthevalidationdatasetwasmoderate(kappa=0.58)
• Overall,speci2icityandsensitivityoftheCSF-FTA-ABS,CSF-TPPAandCSF-TPPA≥1:320usingCSF-VDRLreactivityasthegoldstandardwassimilarinthetrainingandvalidationdatasets
• However,speci2icitywashigherandsensitivitywaslowerinthevalidationdatasetwhenvisionorhearinglosswasusedasthegoldstandard
Figure2.Speci2icityandsensitivityofCSFtestsforNSdiagnosisinthetraining(lightblue)andvalidation(darkblue)datasets
Table2.SpecificityandSensi+vityofCSFTestsforNSDiagnosisintheCombinedDatasets
NS=Reac+veCSF-VDRL NS=VisionorHearingLossSpecificity%(95%CI)
Sensi+vity%(95%CI)
Specificity%(95%CI)
Sensi+vity%(95%CI)
CSF-FTA-ABS 59(55-64) 99(97-100) 53(48-58) 68(60-77)CSF-TPPA 69(65-74)* 95(91-99) 61(56-66)** 58(49-66)CSFTPPA≥1:320
89(86-92) 67(58-76) 82(78-86) 34(26-43)
CSF-VDRL -- -- 86(82-89) 36(27-44)95%CI,95%confidenceinterval;*P=.003comparedtoCSF-FTA-ABS;**P=0.02comparedtoCSF-FTA-ABS
Summary • WeexaminedthediagnosticutilityofthreeCSFtreponemaltestsforNSdiagnosisusingalaboratoryandaclinicalgoldstandardintwogroupsofparticipantswhowereenrolledinastudyofCSFabnormalitiesinsyphilis
• AconveniencesampleenrichedforNS(trainingdataset,n=192)
• Successiveindividualsenrolledafterthelastparticipantenrolledinthetrainingdataset,regardlessofCSForclinicalabnormalities(validationdataset,n=337)
• Diagnosticperformancewassimilarinthetwodatasetsusingthelaboratorygoldstandard,butdifferedinthetwodatasetswhentheclinicalgoldstandardwasused
• Overall,theCSF-FTA-ABSandtheCSF-TPPAhadhighdiagnosticsensitivityforlaboratory(95-99%),butnotclinicallydeOinedneurosyphilis(53-61%).WhilediagnosticspeciOicitywaslower,thespeciOicityoftheCSF-TPPA(61-69%)wassigniOicantlybetterthantheCSF-FTA-ABS(53-59%),regardlessofthegoldstandard
• ThediagnosticspeciOicityoftheCSF-VDRLandtheCSF-TPPA≥1:320werehigh(82-86%)andwerenotsigniOicantlydifferent;diagnosticsensitivitywasquitelowforboth(34-36%)
• Inthecombineddatasets,speci2icityoftheCSF-TPPAwasbetterthantheCSF-FTA-ABSusinglaboratoryandclinicalNSde2initions;sensitivitydidnotdifferbetweenthetwotests
• Thediagnosticspeci2icityofCSF-TPPA≥1:320wascomparabletotheCSF-VDRLtestusingaclinicalNSde2inition
Results
Financial Support ThisworkwassupportedbyNIH/NINDSNS34235.
