LatentInfectionofTuberculosisinChina

HUASHANHOSPITAL,FUDANUNIVERSITY,Shanghai,ChinaWenhongZhang,M.D&PhD.TB:Aleadinginfectiouskiller

-top3infectiouskillerTBkillsabout2millionpeopleeachyear8millionpeoplebecomesickwithTBeachyearTBistheleadingkillerofHIV/AIDSpatients50millionpeopleinfectedwithdrug-resistantTB

TheNewTuberculosisHIVandDrug-resistantTB–AlethalcombinationandamajorthreattoTBcontrol

WHOdeclaredTBaglobalemergencyin1993TBChemotherapy:

THEEffectiveTBControlPre-antibioticera:before1940s(e.g.,codliveroils,bedrest,freshair)DrugsusedtotreatTB:StreptomycinfirstTBdrug(1944),followedbyPAS(1946),isoniazid(1952),pyrazinamide(1952),rifampin(1963) (a)Front-lineDrugs:isoniazid

(INH)rifampicin(RMP),pyrazinamide

(PZA),streptomycin,ethambutol. (b)Second-lineDrugs:PAS,kanamycin,cycloserine,ethionamide,thiacetazone,ciprofloxacin/ofloxacin,rifapentine,amikacin,viomycin,capreomycin.DOTS-TheBestTBTherapy

since1991DOTS:6monththerapy-ThebesttherapyagainstTB(78%-96%curerate).Initialphase(daily,2months)with4drugs:INH,RMP,PZA,Ethambutol.Continuationphase(3timesaweek,4months)with2drugs:INHandRMP.

DOTS-PlusDOTS+second-lineTBdrugs(PAS,ethionamide,cycloserine,kanamycin,amikacinetc.)Tooexpensive(TBcase:$11to$100,costoftreatinganMDR-TBcase:$150,000)MDR-TBrequiresextensivechemotherapy(alsomoretoxictopatients-sideeffects)foruptotwoyears

DOTS-PlusworksasasupplementtotheDOTS,toaddressbothdrug-susceptibleandMDR-TBinareaswithsignificantMDR-TB.DiseaseBurdenofTuberculosisinChina,2000dataPrevalenceofactivepulmonarydiseasesis367／100,000PrevalenceofSearpositivepulmonarydiseasesis122／100,000130,000patientsdiefromtuberculosiseveryyearNodataoflatenttuberculosisinChinauptonowChinaCDC2006PrevalenceofSmearPositiveTuberculosisinChinaIncidenceoftuberculosisaccordingtothereportfromChinaCDCButincidencedonotdecrease!020000040000060000080000010000001200000140000016000002003200420052006ChinaCDC2006FactorscontributetotuberculosisreemerginginChinaMDRTB?HIVincreasing?Latentinfection?Diagnosistoolsaremoreaccuratetofindmorenewcases?HIVinfectedTuberculosisCases<1/100,000populationinChinaLatencyTBbacillicanpersistforlongperiodsoftime(decades)inthehostbeforereactivatingandcausingactivediseaseHostfactors:immunocompromisedconditions,viralinfections(e.g.HIVandmeasles),steroids,anti-TNFantibody(REMICADE?infliximab)aspartofthetreatmentofrheumatoidarthritisBacterialfactors:e.g.isocitratelyase,alpha-crystallin,48-genedormancyregulon,etc.DormantorPersistentBacilli

Cornellmodel:MiceinfectedwithTBbacilliaretreatedfor3monthswithINHandPZA-->Nobacillifoundininfectedorgans(spleens/lungs)byplating-->stoptreatment-->3monthslater,1/3micerelapsewithTB(drugsusceptible)andallmicerelapsewithTBiftreatedwithimmonosuppressingsteroids-->suggestexistenceofdormantbacilliorpersisters(phenotypicresistance).

NewTBcasesaredrivenbythereservoiroflatentlyinfectedpeople.IfwewanttostopactiveTBcases,weneedtoeliminatethisreservoirofinfection.This“hiddenepidemic〞ofpeopleinfectedwithlatentTBisenormous.ThegrowthinlatentTBisbecomingaclinicaltimebomb.Weneedtodefusethisbombbyincreasingoureffortstoidentifyandtreatlatentlyinfectedpeople.LatenttuberculosisisthereservoirofactivetuberculosisActiveTB–8millionnewcasesayear-UnfortunatelyjustthetipoftheicebergLatentTB-the“hiddenepidemic〞-2billionpeopleinfectedEpidemiologyoflatentinfectionintheworldFrothinghamR,etal.InternationalJournalofInfectiousDiseases(2005)9,297—31145%55%InfectedNoinfectionTSTpositiveinChina,2000ShortageofTSTPoorspecificity:antigeniccross-reactivityofPPDwithBCGandenvironmentalmycobacteriaPoorsensitivity:75-90%inactivedisease(lowerindisseminatedTBandHIVinfection;unknownforlatentinfection)FactorsleadingtoFalse-PositiveTSTReactionsNontuberculousmycobacteriaReactionscausedbynontuberculousmycobacteriaareusually10mmofindurationBCGvaccinationReactivityinBCGvaccinerecipientsgenerallywanesovertime;positiveTSTresultislikelyduetoTBinfectionifriskfactorsarepresentTSPOTTMdetectINF-rreleasedbyspecificTcellsCollectwhitecellsusingBDCPTtubeorFicollextraction.AddwhitecellsandTBantigenstowells.Tcellsreleaseinterferongamma.Interferongammacapturedbyantibodies.Incubate,washandaddconjugatedsecondantibodytointerferongamma.Addsubstrateandcountspotsbyeyeorusereader.EachspotisanindividualTcellthathasreleasedinterferongamma.HowdoesT-spotTechnologyWork

PatientWholebloodSample

PBMCESAT-6CFP10

TcellsecretingINF

AbcaptureINF

Bluespot

2commercialKitavailablefordetectinglatentoractivetuberculosisTcell-basedassayforinterferongamma,theenzyme-linkedimmunosorbentspottest(ELISPOT),haspromiseinthediagnosisofMycobacteriumtuberculosisinfectionafterexposuretoaknowntuberculosis(TB)patient.CommercialisationoftwoTcellbasedtestsforthediagnosisofM.tuberculosisinfection(TSpotTBbyOxfordImmunotecandQuantiferon-TBGoldbyCellestis)T-cellbasedassayisrecommendedfordetectinginfectionofM.TbmeasuresindividualreactingTcells:Evenindividualcellscanbedetectedinasample.Thereforeeventhosewhoareseverelyimmunocompromised,ifasinglecellreactsthenitcanbedetected.measuresalltypesofTcells:BothCD4andCD8typeTcellsa