Comparison of the validity of smear and culture conversion as a prognostic marker of treatment PDF
Preview Comparison of the validity of smear and culture conversion as a prognostic marker of treatment
RESEARCHARTICLE Comparison of the validity of smear and culture conversion as a prognostic marker of treatment outcome in patients with multidrug-resistant tuberculosis KefyalewAddisAlene1,2*,KerriViney1,3,HengzhongYi4,EmmaS.McBryde5, KunyunYang4,LiqiongBai6,DarrenJ.Gray1,ZuhuiXu7,ArchieC.A.Clements1 1 ResearchSchoolofPopulationHealth,CollegeofHealthandMedicine,TheAustralianNationalUniversity, Canberra,AustralianCapitalTerritory,Australia,2 InstituteofPublicHealth,CollegeofMedicineandHealth Sciences,UniversityofGondar,Gondar,Ethiopia,3 DepartmentofPublicHealthSciences,Karolinska a1111111111 Institutet,Stockholm,Sweden,4 DepartmentofMDR-TB,InternalMedicine,HunanChesthospital, a1111111111 Changshacity,HunanProvince,China,5 AustralianInstituteofTropicalHealthandMedicine,JamesCook a1111111111 University,Townsville,Queensland,Australia,6 DepartmentofDirector’sOffice,TuberculosisControl InstituteofHunanProvince,Changshacity,HunanProvince,China,7 DepartmentofTuberculosisControl, a1111111111 TuberculosisControlInstituteofHunanProvince,Changshacity,HunanProvince,China a1111111111 *[email protected] Abstract OPENACCESS Citation:AleneKA,VineyK,YiH,McBrydeES, YangK,BaiL,etal.(2018)Comparisonofthe Background validityofsmearandcultureconversionasa TheWorldHealthOrganization(WHO)hasconditionallyrecommendedtheuseofsputum prognosticmarkeroftreatmentoutcomein patientswithmultidrug-resistanttuberculosis. smearmicroscopyandcultureexaminationforthemonitoringofmultidrug-resistanttubercu- PLoSONE13(5):e0197880.https://doi.org/ losis(MDR-TB)treatment.Weaimedtoassessandcomparethevalidityofsmearandcul- 10.1371/journal.pone.0197880 tureconversionatdifferenttimepointsduringtreatmentforMDR-TB,asaprognostic Editor:SeyedEhteshamHasnain,IndianInstitute markerforend-of-treatmentoutcomes. ofTechnologyDelhi,INDIA Received:February13,2018 Methods Accepted:May10,2018 WeundertookaretrospectiveobservationalcohortstudyusingdataobtainedfromHunan ChestHospital,ChinaandGondarUniversityHospital,Ethiopia.Thesensitivityandspecific- Published:May23,2018 ityofcultureandsputumsmearconversionforpredictingtreatmentoutcomeswereana- Copyright:©2018Aleneetal.Thisisanopen lysedusingarandom-effectsgeneralizedlinearmixedmodel. accessarticledistributedunderthetermsofthe CreativeCommonsAttributionLicense,which permitsunrestricteduse,distribution,and Results reproductioninanymedium,providedtheoriginal Atotalof429bacteriologicallyconfirmedMDR-TBpatientswithacultureandsmearpositive authorandsourcearecredited. resultwereincluded.Overall,345(80%)patientshadasuccessfultreatmentoutcome,and84 DataAvailabilityStatement:Allrelevantdataare (20%)patientshadpoortreatmentoutcomes.Thesensitivityofsmearandcultureconversion withinthepaperanditsSupportingInformation files. topredictasuccessfultreatmentoutcomewere:77.9%and68.9%at2monthsafterstarting treatment(differencebetweentests,p=0.007);95.9%and92.7%at4months(p=0.06); Funding:Theauthorsreceivednospecificfunding forthiswork. 97.4%and96.2%at6months(p=0.386);and99.4%and98.9%at12months(p=0.412), respectively.Thespecificityofsmearandculturenon-conversiontopredictapoortreatment Competinginterests:Theauthorshavedeclared thatnocompetinginterestsexist. outcomewere:41.6%and60.7%at2months(p=0.012);23.8%and48.8%at4months PLOSONE|https://doi.org/10.1371/journal.pone.0197880 May23,2018 1/17 ComparisonofthevalidityofsmearandcultureconversionasaprognosticmarkerofMDR-TBtreatmentoutcome (p<0.001);and20.2%and42.8%at6months(p<0.001);and15.4%and32.1%(p<0.001)at 12months,respectively.Thesensitivityofcultureandsmearconversionincreasedasthe monthofconversionincreasedbutatthecostofdecreasedspecificity.Theoptimumtime pointsafterconversiontoprovidethebestprognosticmarkerofasuccessfultreatmentout- comewerebetweentwoandfourmonthsaftertreatmentcommencementforsmear,and betweenfourandsixmonthsforculture.Thecommonoptimumtimepointforsmearandcul- tureconversionwasfourmonths.Atthistimepoint,cultureconversion(AU curve=0.71) ROC wassignificantlybetterthansmearconversion(AU curve=0.6)inpredictingsuccessful ROC treatmentoutcomes(p<0.001).However,thevalidityofsmearconversion(AU curve= ROC 0.7)wasequivalenttocultureconversion(AU curve=0.71)inpredictingtreatmentout- ROC comeswhendemographicandclinicalfactorswereincludedinthemodel.Thepositiveand negativepredictivevaluesforsmearconversionwere:57.3%and65.7%attwomonths, 55.7%and85.4%atfourmonths,and55.0%and88.6%atsixmonths;andforcultureconver- sionsitwas:63.7%and66.2%attwomonths,64.4%and87.1%atfourmonths,and62.7% and91.9%atsixmonths,respectively. Conclusions Thevalidityofsmearconversionissignificantlylowerthancultureconversioninpredicting MDR-TBtreatmentoutcomes.WesupporttheWHOrecommendationofusingbothsmear andcultureexaminationratherthansmearaloneforthemonitoringofMDR-TBpatientsfor abetterpredictionofsuccessfultreatmentoutcomes.Theoptimumtimepointstopredicta futuresuccessfultreatmentoutcomewerebetweentwoandfourmonthsaftertreatment commencementforsputumsmearconversionandbetweenfourandsixmonthsforculture conversion.Thecommonoptimumtimesforcultureandsmearconversiontogetherwas fourmonths. Introduction Multidrug-resistanttuberculosis(MDR-TB)isapublichealthcrisisthatisathreattotubercu- losis(TB)controlprogramsinseveralpartsoftheworld[1].Thenumberofpatientsbeing enrolledontoMDR-TBtreatmenthasbeenincreasingglobally,from45,881in2010to125,000 in2015[2,3].TreatmentforMDR-TBtakesfromnineto24monthsandtheresponseto MDR-TBtreatmentisoftenslow[4].Anoutcomeoftreatmentisassignedtoeachpatientat theendofeachtreatmentcourse;theseoutcomesareusuallyalignedwithrecommendations fromtheWorldHealthOrganization(WHO)[5].Globally,only,half(52%)oftheMDR-TB patientswhostartedtreatmentin2013weresuccessfullytreated[2].PatientswithMDR-TB aremonitoredduringthecourseoftreatmentbymonthlylaboratorytests(usuallybyprovid- ingsputum,whichisusedtoassesssmearandculturestatus,aimingforconversiontonegative forconfirmedpulmonarycases).Basedonpublishedevidencethisisviewedasbeingthebest strategytoevaluateinterimandfinalresponsestotreatment,determineinfectiousness,provide informationforclinicianswhomaybeconsideringachangeinoradjustmenttothetreatment regimen,andisalsousedtoassignfinaltreatmentoutcomes[6]. DespitemajorrecentdevelopmentsinTBdiagnostictests,includingtheintroductionofan automatedmoleculartest,MDR-TBtreatmentresponseisstillevaluatedusingmicrobiological techniquessuchassputumsmearexaminationandculture[7,8].ThenewWHOMDR-TBtreat- mentguideline,releasedinOctober2016,recommendstheuseofsputumsmearmicroscopyand PLOSONE|https://doi.org/10.1371/journal.pone.0197880 May23,2018 2/17 ComparisonofthevalidityofsmearandcultureconversionasaprognosticmarkerofMDR-TBtreatmentoutcome cultureratherthansputumsmearmicroscopyaloneforthemonitoringofpatientswithMDR-TB duringtreatment[5].Thisrecommendationhasbeendescribedasaconditionalrecommendation withverylowqualityevidence;anditwillberevisedbasedonfutureavailableevidence[5]. Sputumcultureisresourceintensive,requiresspecialisedlaboratories,equipmentandtra- inedstaff,takestimetoobtainaresultandiscostly[9,10].Therefore,itisnotreadilyavailable inresourceconstrainedsettings,orifitis,itmayonlybeavailableatreferencelaboratories,at referralhospitalsorincapitalcities[9,11].Ontheotherhand,sputumsmearmicroscopyisrel- ativelyinexpensive,providesrapidresults,iseasytoperform,doesnotrequirecomplexlabora- toryequipmentandisthereforeverysuitableforperipheralhealthcentresandlow-resource settings[9,12–14].However,thevalidity(i.e.thesensitivity,specificity)andthepredictivevalue (i.e.thepositiveandnegativepredictivevalue)ofsputumsmearconversion(frompositiveto negative)atdifferenttimepointshasnotbeensystematicallystudiedasaproxymarkerfora successfulMDR-TBtreatmentoutcome,ascomparedtocultureconversion.Inaddition,the optimumtimesofbothcultureandsmearconversiontopredictafinalsuccessfulTBtreatment outcomeisnotwellknown.Therearefewstudiesthathaveexaminedthevalidityofculture conversionatdifferenttime-pointstopredictendoftreatmentoutcomes[15–17].Thestudies thathavebeenidentifiedreportthatcultureconversionatsixmonthsisbetterthanculturecon- versionattwomonthsinpredictingsuccessfulMDR-TBtreatmentoutcomes[16,17].Alimita- tionofthecurrentstudiesisthattheyhavenotassessedandcomparedthevalidityofculture andsmearconversionasprognosticmarkersofMDR-TBtreatmentoutcomesatdifferenttime- points.Thus,weuseddatafromtwohighMDR-TBburdencountries,ChinaandEthiopia,to assessandtocomparethevalidityandpredictivevalueofcultureandsmearconversionstatus atdifferenttimepointsasprognosticmarkersforasuccessfulMDR-TBtreatmentoutcome. Methods Studydesignandsettings AretrospectiveobservationalcohortstudywasconductedusingdataobtainedfromHunan ChestHospital,ChinaandGondarUniversityHospital,Ethiopia.HunanChestHospitalis locatedinChangsha,thecapitalcityofHunanprovince,andGondarUniversityHospitalis locatedinNorthwestEthiopia.TheHunanChestHospitalandtheGondarUniversityHospital establishedMDR-TBtreatmentcentersin2011and2010,respectively.Thesehospitalsprovide comprehensivediagnosticandtreatmentservicesforallpersonswithpresumptivedrugresistant TBwholiveintheircatchmentarea.Aspartofroutinecare,sputumsmearmicroscopyandcul- tureareperformedmonthlyforthefirstsixmonthsoftreatment,andthereaftereverysecond monthuntiltheendofthetreatment.AtGondarUniversityHospital,sputumspecimensare senttothenationalorregionallaboratoryforculture;whereasattheHunanChestHospital, solidandliquidcultureisperformedinthehospital’slaboratory.Thetreatmentregimensand thediagnosticproceduresofMDR-TBpatientsinHunanChestHospitalandinGondarUniver- sityHospitalhavebeendescribedindetailelsewhere[18,19].SmearmicroscopywithZiehl- NeelsenstainingandfluorescencemicroscopyareusedinbothHunanChestHospitalandGon- darUniversityHospital(1,2)forboththediagnosisandmonitoringofTB.Sincecultureisnot availableatGondarUniversityHospital,sputumspecimensaresenttothenationalorregional laboratoriesforcultureanddrugsusceptibilitytesting(DST).Solid(Lo¨wenstein-Jensen)andliq- uidculture(BACTEC460,MGIT960)areperformedatthenationalandregionallaboratories. AllMDR-TBpatientsincludedinourstudywerediagnosedandmonitoredusingsolidculture. Whereas,attheHunanChestHospital,liquid(BACTEC460,MGIT960)andsolidcultures (Lo¨wenstein-Jensen)areperformedinthehospital’slaboratory.Inourstudy,almostallcases (98%)fromHonanChestHospitalwerediagnosedandmonitoredusingsolidculture. PLOSONE|https://doi.org/10.1371/journal.pone.0197880 May23,2018 3/17 ComparisonofthevalidityofsmearandcultureconversionasaprognosticmarkerofMDR-TBtreatmentoutcome Inclusionandexclusioncriteria ThisstudyincludedallMDR-TBpatientswhowereregisteredatbothHospitalssincetheestab- lishmentoftheirMDR-TBtreatmentcentresthroughuntil31stofDecember,2014.Thisperiod waspurposelyselectedinordertoobtaintreatmentoutcomesofthepatients(astreatmentis24 monthsinduration).AllbacteriologicallyconfirmedMDR-TBpatients(i.e.sputumsmearand culturepositive)atthecommencementofthetreatmentwereeligible.Patientswhowerediag- nosedwithMDR-TBbutwhodidnotstarttreatmentwereexcluded.Inaddition,patientswho werelosttofollow-upandpatientswhowerediagnosedwithXDR-TBwereexcluded. Definitions WereferredtoWHOguidelineswhendefiningsmearandcultureconversionandtreatment outcomes[7,8].Wedefinedcultureconversionastwoconsecutivenegativesputumcultures takenatleast30daysapartfollowinganinitialpositiveculture[7].Similarly,wedefinedsmear conversionastwoconsecutivenegativesputumsmearstakenatleast30daysapartfollowingan initialpositivesputumsmear[7].Wedefinedtimetoinitialsputumsmearconversionasthe timeinmonthsfromthedateofstartofMDR-TBtreatmenttothedateofspecimencollection forthefirstoftwoconsecutivenegativesputumsmearresults,irrespectiveofwhethertherewas asubsequentsputumsmearpositiveresult.Wedefinedsmearreversiontopositivewhenat leastonesubsequentpositivesputumsmearwasrecordedafterinitialconversion.Wedefined sustainedsputumsmearconversionasanabsenceofanysubsequentpositivesputumsmear afterconversion.Wealsodefinedpersistentsputumsmearpositivityasnosputumsmearcon- versioninpatientswithabaselinepositivesputumsmear.Weusedsimilardefinitionsfortime toinitialcultureconversion,culturereversionandpersistentculturepositivity(S1Table). AllconfirmedMDR-TBpatientsareassignedamutuallyexclusivetreatmentoutcomeatthe endoftheirtherapy,byahealthprofessional,basedontheWHOdefinitions[8].Specifically, curewasdefinedassomeonewhocompletedtreatmentwithoutevidenceoftreatmentfailureand whohadthreeormoreconsecutivenegativeculturestakenatleast30daysapart,aftertheinten- sivephase[8].Treatmentcompletionwasdefinedassomeonewhocompletedtreatment,without evidenceoffailurebutwithnorecordthatthreeormoreconsecutivenegativeculturestakenat least30daysapartaftertheintensivephase.Treatmentfailurewasdefinedastreatmenttermi- natedoraneedforpermanentregimenchangeofatleasttwoanti-TBdrugsduetolackofculture conversionbytheendoftheintensivephase,orbacteriologicalreversioninthecontinuation phaseafterconversiontonegativeaftertheintensivephase,orevidenceofadditionalacquired resistancetofluoroquinolonesorsecond-lineinjectabledrugs.Losttofollow-upwasdefinedasa patientwhosetreatmentwasinterruptedfortwoconsecutivemonthsormore.Deathwasdefined assomeonewhodiedforanyreasonduringthecourseoftreatment.Treatmentsuccesswas definedasthesumofthosewhowerecuredandwhocompletedtreatment.Apoortreatmentout- comewasdefinedasthesumofthetreatmentoutcomes:treatmentfailureordeath. Wecalculatedthesensitivityandspecificityofconversiontopredictasuccessfulandpoor treatmentoutcome.Inourstudy,sensitivityreferstotheproportionofMDR-TBpatientswith asuccessfultreatmentoutcomewhohadsputumconversionatagivenmonth.Specificity referstotheproportionofMDR-TBpatientswithapoortreatmentoutcomewhodidnothave sputumconversionatagivenmonth.Wedefinedpositivepredictivevalue(PPV)asthepro- portionofMDR-TBpatientsinwhomtreatmentwassuccessfulamongallthosewithsputum conversionatagivenmonth.Negativepredictivevalue(NPV)wasdefinedastheproportion ofMDR-TBpatientsinwhomtreatmentoutcomewaspooramongallthosewithnosputum conversionatagivenmonth.Amoredetaileddefinitionofvariablesincludedinthisstudyis presentedinthesupplementaryinformation(S1Table). PLOSONE|https://doi.org/10.1371/journal.pone.0197880 May23,2018 4/17 ComparisonofthevalidityofsmearandcultureconversionasaprognosticmarkerofMDR-TBtreatmentoutcome Statisticalanalysis TimetoinitialsputumcultureandsmearconversionwasanalysedusingtheKaplan-Meier estimateanddifferencesbetweengroupswerecomparedusingthelog-ranktest.Forpatients whosesputumcultureorsmearresultdidnotconvertatall,timetoinitialconversionwascon- sideredtobecensoredonemonthbeforetheirlastsputumspecimendate. Weusedbivariateandmultivariaterandom-effectslogisticregressionmodelstodetermine theassociationbetweensputumconversionandtreatmentoutcomeatdifferentmonths(i.e.at 2,4,6,and12months),andoddsratioswiththeir95%confidenceintervals(CI)werecalcu- lated.Sputumconversionwasincludedinthemodelasthemainindependentvariable;and demographicvariablessuchasage,sexandoccupation,aswellasclinicalvariablessuchas HIVstatus,historyofprevioustreatmentwithsecondlineTBdrugs,resistancetoafluoro- quinoloneorsecondlineinjectableTBdrugs,andstudysetting,wereincludedintheadjusted modelsascofoundingfactors.Significancewasdeterminedat5%. Wecalculatedsensitivityandspecificityalongwiththeir95%CIsatdifferentmonthssince commencementoftreatment(i.e.2,4,6,and12months)usingabivariaterandom-effectsgen- eralizedlinearmixedmodel.Wepreferredthismodelbecauseitcanhandlecorrelationsthat occurasaresultofrepeatedobservationsineachindividualanditcanaccommodateheteroge- neitybetweenstudysettingsandgroups[20].Wecalculatedcoefficientsthatdemonstratedthe magnitudeandsignificanceofassociationbetweeneachfactorandtheprobabilityofcorrect predictionoftreatmentsuccess(i.e.sensitivity)andpoortreatmentoutcome(i.e.specificity) byconversionstatus. Sincepositiveandnegativepredictivevaluesdependsontheprevalenceoftheevents,we assumedthattheoverallprevalenceofMDR-TBtreatmentsuccessis50%(basedonthe MDR-TBtreatmentsuccessratereportedinWHO’sGlobalTBReport2015)[21].Weper- formedaseriesofsensitivityanalysesforpositiveandnegativepredictivevaluesofsputumcon- versioninwhichweconsideredsuccessfultreatmentoutcomesof40%,60%and80%(S2Table). Weusedreceiveroperatingcharacteristic(ROC)curvestopresentthesensitivityandspeci- ficityofsputumconversionatdifferentmonths.TheAreaundertheROCcurve(AUC)and Youden’sindex(i.e.sensitivity+specificity-1)wereusedtodeterminetheoptimaltimepoints ofsputumconversionasamarkerofasuccessfulMDR-TBtreatmentoutcome.Theindex closesttoonewasusedasthecriterionfordeterminingthebestpredictoroftreatmentout- comes.AllanalyseswereperformedusingSTATAversion14.1[22]. Ethicsclearance EthicsapprovalwasobtainedfromtheAustralianNationalUniversityHumanResearchEthics Committee(protocolnumber2016/218)andfromtheInstitutionalReviewBoardoftheUni- versityofGondar.PermissionwasgrantedtoaccessthesecondarydatafromTuberculosis ControlInstituteofHunanProvinceandthiswasdocumentedinaletter.Thestudywascon- ductedincollaborationwithresearchersfromGondarUniversityandHunanChestHospital. Results Demographicandclinicalcharacteristics Atotalof721patientswerediagnosedwithMDR-TBinthetwohospitals,490fromHunan ChestHospital,Chinaand231fromGondarUniversityHospital,Ethiopia,fortheperiod 2011–2014forHunanChestHospitaland2010–2014forGondarUniversityHospital.Of these,120werecultureorsputumsmearnegativeatthecommencementoftreatmentand12 werediagnosedwithextensivelydrugresistant(XDR)-TB,andtheywereexcludedfromthe PLOSONE|https://doi.org/10.1371/journal.pone.0197880 May23,2018 5/17 ComparisonofthevalidityofsmearandcultureconversionasaprognosticmarkerofMDR-TBtreatmentoutcome study.Therewereanadditional19caseswhowereexcludedfromthestudy(i.e.10patients whowerediagnosedwithMDR-TBbutdidnotstarttreatment,and9patientswhosetreat- mentoutcomeswerenotrecorded).Fromatotalof570bacteriologicallyconfirmedMDR-TB patientswhohadatreatmentoutcomerecorded,92(16%)werefromGondarUniversityHos- pitaland478(84%)werefromHunanChestHospital.Morethantwothirds,(239;69%)were male,and407(71%)werefarmers.Themedianagewas38years(range,15to87years).A totalof539(94%)patientshadahistoryofpreviousTBtreatment,and138(24%)hadreceived second-lineTBdrugsbeforetheinitiationofthecurrentMDR-TBtreatment.Thebaseline demographicandclinicalcharacteristicsofthepatientsarepresentedinsupplementaryinfor- mation(S3Table). Smearandcultureconversionandtreatmentoutcomes Overall,325(57%)patientswerecured,20(3%)patientscompletedtreatment,18(3%)died duringthetreatment,66(12%)experiencedtreatmentfailure,and141(25%)patientswere losttofollow-up.Afterexcludingthe141patientswhowerelosttofollowup,therewere429 patientswithMDR-TB.Amongthispatientgroup,345(80%)hadasuccessfultreatmentout- comeand84(20%)hadapooroutcome(Fig1). Theprobabilityofapoortreatmentoutcome(i.e.deathortreatmentfailure)bytheendof6 monthswas4%,bytheendofoneyearwas7%,andbytheendofthreeyearswas30%(Fig2). Thetimetoinitialcultureconversionwasshorterinthosewhohadasuccessfultreatment outcomewhencomparedtothosewhohadapoortreatmentoutcome(p<0.001,Fig3). Similarly,thetimetoinitialsmearconversionwasshorterinthosewhohadasuccessful treatmentoutcomecomparedtopatientswithapoortreatmentoutcome(p<0.001,Fig1).Ini- tialsmearconversionoccurredfor417(97%)patients.Ofthosewithasuccessfultreatment outcome,345(99%)experiencedinitialsmearconversion;thisfigurewas84%amongthose withapoortreatmentoutcome.Atotalof76%ofinitialsmearconversionsoccurredwithin twomonthsoftreatmentcommencement.Initialcultureconversionoccurredin401patients (93%);onethird(67%)ofcultureconversionsoccurredwithintwomonthsoftreatmentcom- mencement(Fig1). Fig1.Numberofpatientswithsputumsmearandcultureconversionafter2,4,6,and12monthsoftreatmentformultidrugresistanttuberculosis,amongpatients fromHunanChestandGondarUniversityHospitals,2010to2014,stratifiedbysuccessfulandpoortreatmentoutcomes. https://doi.org/10.1371/journal.pone.0197880.g001 PLOSONE|https://doi.org/10.1371/journal.pone.0197880 May23,2018 6/17 ComparisonofthevalidityofsmearandcultureconversionasaprognosticmarkerofMDR-TBtreatmentoutcome Fig2.Overallprobabilityofapoortreatmentoutcome,andnumberofcorrectsputumsmearandcultureresultsattime-pointsin patientswithmultidrugresistanttuberculosisinHunanChestandGondarUniversityHospital,2010to2014. https://doi.org/10.1371/journal.pone.0197880.g002 Amongthosepatientswhohadaninitialsmearconversion,75patients(18%)subsequently hadatleastonepositivesmearresult(i.e.smearreversion).Themediantimeofsmearrever- sionfromthedateoftreatmentcommencementwas6.5months(IQR:5–12months).Among patientswhohadhadaninitialculturereversion,72patients(17%)hadculturereversion,ata mediantimeof8months(IQR:5–12months)afterthecommencementoftreatment. Associationbetweencultureandsmearconversion,andMDR-TBtreatmentout- comes. Patientswhohadinitialsmearconversionattwomonthshadahigheroddsoftreat- mentsuccesscomparedtothosewithnosmearconversionattwomonths(crudeoddsratio (COR):2.53;95%CI:1.53–4.18)(Table1).Similarly,patientswhohadinitialcultureconver- sionattwomonthshadahigheroddsoftreatmentsuccessthanthosewithoutevidenceofcul- tureconversionattwomonths(COR:3.43;95%CI:2.09–5.63).Whenwecomparedthe strengthofassociationbetweentreatmentsuccussandcultureconversionwiththatoftreat- mentsuccessandsmearconversionateachmonthintheadjustedmodels,theoddsoftreat- mentsuccesswashigherforcultureconversionthanforsmearconversion(Table2).The strengthofassociationbetweensuccessfultreatmentoutcomeandcultureandsmearconver- sionincreasedwithincreasedmonthsofconversion(Table2).Havingahistoryofprevious, second-lineTBtreatmentandhavingbaselineresistancetoafluoroquinoloneweresignifi- cantlyassociatedwithpoortreatmentoutcomes(Table2). PLOSONE|https://doi.org/10.1371/journal.pone.0197880 May23,2018 7/17 ComparisonofthevalidityofsmearandcultureconversionasaprognosticmarkerofMDR-TBtreatmentoutcome Fig3.TimetoinitialsputumsmearandcultureconversioninpatientswithmultidrugresistanttuberculosisbytreatmentoutcomesfromHunanChestand GondarUniversityHospitals,2010–2014. https://doi.org/10.1371/journal.pone.0197880.g003 Validityofcultureandsmearconversion. Forthepredictionofasuccessfultreatment outcome,theoverallsensitivityofsmearconversionattwomonthswas77.9%(95%CI:73.3–82.6) withastatisticallysignificantdifference(i.e.p<0.05)acrossthetwostudysettings(86.8%in HunanChestHospitalvs46.6%inGondarUniversityHospital),agegroup(72.7%amongpati- entsagedlessthan35yearsvs82.5%inpeopleaged35yearsandabove),historyofprevious,sec- ond-lineTB-treatment(86.6%withhistoryofprevious,second-lineTBtreatmentvs75.3%with nohistoryofprevious,second-lineTBtreatment),andresistancetoanyinjectablesecond-lineTB Table1. Associationofsputumsmearandcultureconversionstatusatdifferentmonthswithtreatmentoutcomeinpatientswithmultidrugresistanttuberculosis fromHunanChestandGondarUniversityHospitals,2010–2014. Monthsontreatment Sputumsmear Sputumculture Successfuloutcome Poor Crudeoddsratio Successfuloutcome Poor Crudeoddsratio outcome outcome 2months Converted 269 35 2.53(1.53,4.18) 238 33 3.43(2.09,5.63) Didnotconvert 76 49 1.00 107 52 1.00 4months Converted 331 64 7.39(3.55,15.38) 320 43 12.20(6.76,22.03) Didnotconvert 14 20 1.00 25 41 1.00 6months Converted 336 67 9.47(4.05,22.15) 332 48 19.15(9.48,38.67) Didnotconvert 9 17 1.00 13 36 1.00 12months Converted 343 71 31.4(6.93,142.21) 341 57 40.38(13.62,119.73) Didnotconvert 2 13 1.00 4 27 1.00 Successfuloutcome:Thesumofthetreatmentoutcomescuredandtreatmentcompleted.Pooroutcome:Thesumofthetreatmentoutcomesdeathandtreatment failure. https://doi.org/10.1371/journal.pone.0197880.t001 PLOSONE|https://doi.org/10.1371/journal.pone.0197880 May23,2018 8/17 ComparisonofthevalidityofsmearandcultureconversionasaprognosticmarkerofMDR-TBtreatmentoutcome Table2. Associationofinitialsputumsmearandcultureconversionatdifferentmonthswithtreatmentsuccessinpatientswithmultidrugresistanttuberculosis fromGondarUniversityandHunanChestHospital,2010–2014,andadjustedoddsrationwith95%confidenceinterval. Initialsmearconversion Initialcultureconversion 2months 4months 6months 12months 2months 4months 6months 12months 2months 3.54(1.96, ... ... ... 5.55(3.06, ... ... ... 6.38) 10.07) 4months ... 9.84(4.25, ... ... ... 32.19(13.36, ... ... 22.83) 77.52) 6months ... ... 13.56(5.06, ... ... ... 34.57(13.79, .... 36.30) 86.70) 12months ... ... ... 37.03(7.75, ... ... .... 55.56(17.34, 176.88) 177.94) Age(inyears) <35 1.83(1.03, 1.74(0.97, 1.84(1.02, 1.72(0.95, 1.92(1.06, 1.91(0.98,3.69) 1.98(1.03, 1.87(0.98, 3.26) 3.14) 3.33) 3.10) 3.49) 3.81) 3.56) >=35 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 Malesex 0.83(0.46, 0.84(0.46, 0.850.47, 0.87(0.48, 0.81(0.44, 0.83(0.43,1.63) 0.86(0.44, 0.86(0.45, 1.49) 1.53) 1.56) 1.58) 1.47) 1.66) 1.65) Occupation Farmer 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 Employed(cid:3) 1.52(0.58, 1.970.70, 1.84(0.66, 2.05(0.72, 1.69(0.63, 1.74(0.58,5.25) 1.90(0.64, 1.93(0.63, 3.99) 5.52) 5.13) 5.88) 4.56) 5.66) 5.87) Other^ 0.69(0.33, 0.65(0.31, 0.65(0.31, 0.71(0.34, 0.73(0.34, 0.48(0.22,1.07) 0.59(0.27, 0.52(0.24, 1.44) 1.36) 1.35) 1.49) 1.54) 1.33) 1.12) Yearofenrolment 2010–2011 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 2012 0.73(0.13, 1.45(0.25, 1.69(0.29, 1.18(0.21, 0.54(0.09, 1.15(0.18,7.06) 2.01(0.32, 1.55(0.27, 3.95) 8.30) 9.83) 6.61) 3.07) 12.73) 8.93) 2013 0.83(0.15, 1.39(0.24, 1.61(0.27, 2.25(0.23, 0.89(0.15, 1.83(0.28,11.71) 2.89(0.44, 2.28(0.38, 4.62) 8.09) 9.39) 7.62) 5.15) 18.94) 13.59) 2014 1.40(0.24, 2.24(0.37, 2.75(0.46, 2.25(0.38, 1.32(0.22, 2.41(0.37, 4.58(0.68, 3.12(0.52, 8.02) 13.31) 16.46) 13.13) 7.83) 15.55) 30.72) 18.93) EnrolledinGondarUniversity 2.37(0.76, 2.11(0.66, 2.150.67, 1.27(0.42, 3.06(0.99, 9.47(2.44, 4.94(1.26, 1.51(0.46, Hospital 7.39) 6.71) 6.90) 3.85) 9.44) 36.72) 19.29) 4.98) HIVpositive 0.83(0.14, 0.60(0.09, 0.71(0.10, 1.28(0.17, 1.06(0.17, 0.41(0.05,3.08) 0.43(0.05, 1.07(0.13, 4.94) 3.92) 4.73) 9.40) 6.29) 3.39) 8.56) Historyofprevioussecond-line 0.48(0.27, 0.48(0.27, 0.49(0.28, 0.500.27, 0.54(0.30, 0.63(0.33,1.23) 0.690.36,1.34) 0.55(0.29, TBtreatment 0.85) 0.87) 0.88) 0.90) 0.98) 1.05) Resistancetoethambutol 0.71(0.41, 0.81(0.46, 0.78(0.44, 0.75(0.42, 0.85(0.48, 0.89(0.46,1.68) 0.96(0.51, 0.91(0.49, 1.23) 1.43) 1.37) 1.34) 1.50) 1.82) 1.72) Resistancetofluoroquinolones 0.32(0.14, 0.22(0.09, 0.24(0.11, 0.20(0.09, 0.36(0.16, 0.27(0.10,0.67) 0.24(0.09, 0.17(0.08, 0.73) 0.49) 0.52) 0.45) 0.83) 0.59) 0.41) Resistancetoany2ndline 0.88(0.50, 0.92(0.51, 0.88(0.49, 0.93(0.518, 0.85(0.48, 0.99(0.52,1.90) 0.87(0.45, 0.82(0.43, injectabledrugs 1.55) 1.65) 1.58) 1.68) 1.53) 1.65) 1.56) (cid:3)Employedincludesprivateandgovernmentemployeesaswellasdailylabourers; ^otherincudespeoplewhoareunemployedandunknownoccupations;thereferencegroupforsputumconversionateachmonthsis“didnotconverssputum” https://doi.org/10.1371/journal.pone.0197880.t002 drug(82.5%forbaselineresistancetoanysecond-lineinjectableTBdrugvs72.4%withnobase- lineresistancetoanysecondlineinjectableTBdrug). Theoverallsensitivityofsmearconversionatsixmonthswas97.3%(95%CI:95.5–99.2), withsignificantvariationacrossthetwohospitalsonly(p<0.05;Table3).Theoverallsensitiv- ityofcultureconversionattwomonthswas68.9%(95%CI:64.3–73.6),withsignificant PLOSONE|https://doi.org/10.1371/journal.pone.0197880 May23,2018 9/17 ComparisonofthevalidityofsmearandcultureconversionasaprognosticmarkerofMDR-TBtreatmentoutcome sistanttuber- Specificity%(95%CI) 42.8(33.2–52.4) 40.7(29.7–51.8) 62.5(28.4–96.5) 44.2(31.8–56.6) 39.1(18.9–59.3) 44.0(24.6–63.3) 42.3(29.7–54.9) 44.2(32.3–56.1) 74.9(28.0–100) 20(0.4–44.0) 42.6(31.9–53.3) 50.0(18.5–100) 43.3(32.7–53.9) 0.9(0.009–96.5) 52.9(36.5–69.3) 36.0(22.4–49.5) 44.4(31.2–57.6) 40.0(22.3–57.6) 51.5(34.7–68.2) 37.2(23.8–50.7) 35.2(11.8–58.7) 44.7(32.9–56.5) e hmultidrugr 6months Sensitivity%(95%CI) 96.2(94.3–98.0) (cid:3)(cid:3)98.1(95.9–100) 89.3(85.1–93.5) 96.4(94.0–98.9) 95.7(92.2–99.1) 95.0(92.1–97.9) 97.2(94.5–100) 96.9(94.5–99.4) 95.0(87.2–100) 94.1(88.9–99.3) 96.3(94.2–98.4) 94.1(85.0–100) 96.0(93.9–98.0) 100(91.6–100) 95.8(91.5–100) 96.3(94.0–98.5) 98.4(95.7–100) 93.5(90.6–96.5) 95.2(91.6–98.9) 96.6(94.2–99.0) 94.1(85.0–100) 96.3(94.2–98.4) npatientswit ureconversion Specificity%(95%CI) 48.8(38.8–58.7) 46.0(34.9–57.1) 75.0(40.8–100) 47.5(35.0–60.0) 52.1(31.7–72.5) 48.0(28.4–67.5) 49.1(36.3–61.9) 49.1(37.2–61.1) (cid:3)87.4(39.4–100) 26.6(2.5–50.7) 48.7(39.9–59.5) 50.0(19.0–100) 49.3(38.7–60.0) 0.08(0.009–97.4) 55.8(39.1–72.5) 44.0(30.2–57.7) 50.0(36.6–63.3) 46.6(28.7–64.5) 54.5(37.5–71.5) 45.0(31.4–58.7) 47.0(23.3–70.8) 49.2(37.2–61.2) entoutcomesi Initialsputumcult 4months Sensitivity%(95%CI) 92.7(90.3–95.1) (cid:3)(cid:3)97.7(94.9–100) 74.6(69.2–80.1) 92.5(89.1–95.9) 93.1(88.4–97.8) (cid:3)89.5(85.5–93.4) 95.6(91.8–99.3) 93.5(90.2–96.8) 88.5(77.9–98.2) 94.1(87.0–100) 93.3(90.4–96.0) 82.3(70.0–94.2) 92.3(89.4–95.1) 100(88.6–100) 95.8(89.9–100) 91.9(88.8–94.9) 95.2(91.5–98.9) 89.7(85.6–93.7) 91.5(86.5–96.4) 93.3(90.0–96.5) 94.1(81.7–100) 92.6(89.8–95.4) m kersfortreat Specificity%(95%CI) 60.7(50.2–71.2) 56.5(45.9–67.1) (cid:3)100(67.3–100) 55.7(43.6–67.8) 73.9(54.2–93.5) 64.0(44.8–83.1) 59.3(46.8–71.7) 60.6(48.6–72.6) (cid:3)87.4(40.3–100) 46.6(22.4–70.8) 59.7(49.2–70.2) 100(32.8–100) 60.2(49.7–70.7) 100(4.6–100)) (cid:3)73.5(57.5–89.5) 52.0(38.7–30.7) 61.1(48.0–74.1) 60.0(42.5–77.4) 63.6(46.9–80.2) 58.8(45.4–72.2) 64.7(41.5–87.9) 59.7(48.0–71.3) prognosticmar 2months Sensitivity%(95%CI) 68.9(64.3–73.6) (cid:3)(cid:3)80.7(75.9–85.5) 26.6(17.4–35.8) 67.9(61.9–73.9) 70.9(62.5–79.3) 62.3(55.2–69.4) (cid:3)74.8(68.2–81.5) 75.9(70.2–81.6) (cid:3)(cid:3)42.6(24.3–60.9) 68.6(56.4–80.8) (cid:3)(cid:3)71.3(66.4–76.2) 23.5(20.0–44.9) 68.3(63.3–73.3) 80.0(59.7–100) 79.4(68.9–89.9) 66.1(60.7–71.6) (cid:3)74.6(68.0–81.1) 62.1(59.9–69.3) 65.0(56.3–73.8) 70.7(64.8–76.5) 58.8(36.8–80.7) 69.5(64.5–74.5) ntmonthsas Specificity%(95%CI) 20.2(10.5–25.6) 18.4(9.4–27.3) 37.5(9.9–65.0) 22.9(12.9–32.9) 13.0(3.2–29.3) 20.0(4.2–35.7) 20.3(10.0–30.5) 19.6(9.9–29.3) (cid:3)49.9(11.7–88.2) 6.6(1.2–26.2) 19.5(10.8–28.1) 50.0(5.3–100) 20.4(11.8–29.1) 0.06(0.00778.6) 20.5(7.0–34.0) 20.0(8.8–31.1) 18.5(7.8–29.2) 23.3(8.9–37.6) 18.1(4.4–31.8) 21.5(10.5–32.5) 11.7(7.2–30.5) 22.3(12.8–31.95) e r ersionatdiffe 6months Sensitivity%(95%CI) 97.4(95.5–99.2) (cid:3)98.5(96.6–100) 93.3(89.7–96.9) 97.3(95.2–99.4) 97.4(94.5–100) 97.5(95.0–99.9) 97.2(94.9–99.5) 97.4(95.3–99.4) 96.7(90.1–95.6) 98.0(93.6–100) 97.2(95.5–98.9) 100(92.4–100) 97.2(95.4–98.9) 100(93.0–100) 100(93.0–100) 98.6(94.9–100) 97.8(95.6–100) 96.7(94.2–99.2) 95.2(92.2–98.3) 98.3(96.3–100) 100(92.4–100) 97.2(95.5–98.9) dcultureconv2010–2014. mearconversion Specificity%(95%CI) 23.8(13.8–33.7) 21.0(11.6–30.4) 50.0(21.0–78.9) 26.2(15.5–36.8) 17.3(0.5–34.3) 24.0(7.3–40.6) 23.7(12.8–34.5) 22.9(12.8–33.0) (cid:3)62.9(22.7–99.1) 6.6(1.3–27.0) 23.1(13.9–32.2) 50.0(8.5–100) 24.0(14.95–33.2) 0.01(0.008–83.3) 20.5(6.2–34.8) 26.0(14.2–37.7) 22.2(10.8–33.5) 26.6(11.4–41.8) 24.2(9.7–38.7) 23.5(11.8–35.2) 11.7(0.8–31.8) 26.8(16.7–26.9) y)ofsmearansityHospitals, Initialsputums 4months Sensitivity%(95%CI) 95.9(93.5–98.3) (cid:3)97.0(94.6–99.3) 92.0(87.5–96.4) 95.6(93.0–98.1) 96.5(93.0–100) 96.9(93.8–99.9) 95.0(92.2–97.9) 96.1(93.6–98.6) 95.0(87.0–100) 96.0(90.6–100) 95.7(93.5–97.8) 100(90.6–100) 95.6(93.5–97.8) 100(91.3–100) 95.8(91.3–100) 95.9(93.6–98.3) 95.7(92.9–98.5) 96.1(93.0–99.2) (cid:3)92.4(88.7–96.1) 97.4(95.0–99.9) 100(90.6–100) 95.7(93.5–97.8) Table3.Thevalidity(i.e.sensitivity,specificitculosisfromHunanChestandGondarUniver 2months Sensitivity%Specificity(95%CI)%(95%CI) Overall77.9(73.3–82.6)41.6(31.1–29.8) Studyarea (cid:3)China86.8(82.1–91.2)38.1(27.3–48.9) (cid:3)Ethiopia46.6(38.0–55.2)75.0(41.6–100) Sex Male76.7(71.3–82.1)40.9(28.6–53.3) Female80.3(72.8–87.8)43.4(23.3–63.6) Age(inyears) (cid:3)<3572.8(66.5–72.1)36.0(16.7–55.2) >=3582.5(76.5–88.4)44.0(31.5–55.6) Occupation ƧFarmer82.4(77.1–87.6)40.9(28.7–53.2) (cid:3)Employed69.6(44.9–77.3)61.9(14.3–100) Others78.4(60.9–95.9)33.3(8.6–58.0) HIVstatus Negative78.6(74.1–83.1)40.2(29.7–50.7) Positive64.7(45.0–84.3)100(32.8–100) Historyofprevioustreatment Yes77.5(73.0–82.0)42.1(31.6–52.7) No85.0(66.8–100)0.005(0.01–96.2) HistoryofprevioussecondlineTB-treatment Yes86.6(78.2–97.1)41.1(24.6–57.7) (cid:3)No75.3(70.4–80.2)42.0(28.3–55.6) Resistancetoasecondlineinjectabledrug (cid:3)Yes82.5(76.6–88.4)42.5(29.4–55.7) No72.4(65.9–78.8)40.0(22.3–57.6) Resistancetoethambutol Yes76.4(68.5–84.3)33.3(16.6–49.9) No78.6(73.4–83.9)47.0(33.6–60.4) Resistancetoafluoroquinolone Yes76.4(58.7–96.1)52.9(29.6–76.2) No78.0(73.5–82.5)38.8(27.0–50.5) (cid:3)P-value<0.05; (cid:3)(cid:3)p-value<0.001;ƧReferencegroup https://doi.org/10.1371/journal.pone.0197880.t003 PLOSONE|https://doi.org/10.1371/journal.pone.0197880 May23,2018 10/17
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