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Latenttuberculosisinfection
Jasmer,RobertMNahid,PayamHopewell,PhilipC.TheNewEnglandJournalofMedicine 347.23 (Dec5,2002):18601866.

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ThecurrentjointrecommendationsoftheAmericanThoracicSocietyandtheCentersforDiseaseControlandPrevention38aredesignedtotargettuberculin testingtopersonsathighriskforthedevelopmentoftuberculosiswho,iftheytestpositive,willbecandidatesfortreatmentoflatenttuberculosisinfection (Table1).6Becausepersonsshouldbetargetedfortreatmentonthebasisoftheirincreasedriskofdevelopmentoftuberculosis,agedoesnotplayapartin thedecisiontotreat.

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Headnote ClinicalPractice Headnote ThisJournalfeaturebeginswithacasevignettehighlightingacommonclinicalproblem.Evidencesupportingvariousstrategiesisthenpresented,followedbya reviewofformalguidelines,whentheyexist.Thearticleendswiththeauthors'clinicalrecommendations. Patient1,a44yearoldmanwhorecentlyimmigratedfromPeru,isfoundtohaveindurationof16mmindiameteronatuberculinskintest.Hereceived bacilleCalmetteGuerin(BCG)vaccineasaninfantandisasymptomatic.Chestradiographyshowsfibronodularopacitiesintheupperlobe.Patient2,a27 yearoldschoolteacherwhowasbornintheUnitedStates,hasindurationof17mmonatuberculinskintest,nosymptoms,andanormalchestradiograph. Shouldthesepatientsreceivetreatmentforlatenttuberculosisinfection? THECLINICALPROBLEM Despiteintensifiedglobalefforts,thenumberofcasesoftuberculosisworldwideisincreasing.TheWorldHealthOrganization(WHO)estimatesthatin1999, therewere8.4millionnewcases,upfrom8.0millionin1997.(1)TheWHOalsoestimatesthattherearenearly2milliondeathsfromtuberculosisannually thus,thediseaserankssecondonlytohumanimmunodeficiencyvirus(HIV)infectionasaninfectiouscauseofdeath.2Approximately1.7billionpeople,nearly onethirdoftheworld'spopulation,arethoughttobeinfectedwithMycobacteriumtuberculosis.3TheUnitedStatesandotherdevelopedcountriesarenot protectedfromtheongoingepidemicoftuberculosisoccurringinthepoorcountriesoftheworld:currentlyintheUnitedStates,about50percentofthenew casesareoccurringinpersonsbornoutsidethecountry.4 Althoughtreatmentofpersonswithactivetuberculosisisthefirstpriorityfortuberculosiscontrol,animportantsecondpriorityincountrieswithalow incidenceisidentificationandtreatmentofpersonswithlatenttuberculosisinfection.AstheInstituteofMedicinehasargued,5"tomakesignificantprogress towardtheeliminationoftuberculosisintheUnitedStates,effortstopreventcasesfromoccurringmustbeamplified." Inmostpersons,infectionwithM.tuberculosisisinitiallycontainedbyhostdefenses,andtheinfectionremainslatent.However,latenttuberculosisinfection hasthepotentialtodevelopintotuberculosisatanytime,andpersonswithactivetuberculosisbecomesourcesofnewinfections.Treatmentoflatentinfection greatlyreducesthelikelihoodthatactivetuberculosiswilldevelop.Thus,ithasthepotentialbothtopreservethehealthofanindividualpersonandtoprotect thehealthofthepublicbyreducingthenumberofpotentialsourcesofinfection.6 STRATEGIESANDEVIDENCE IdentifyingLatentTuberculosisInfection Untilrecently,theonlytesttoidentifylatenttuberculosisinfectionwasthetuberculinskintest.7However,atestmeasuringthereleaseofinterferongamma inwholebloodinresponsetostimulationbypurifiedproteinderivative(PPD)hasbeenapprovedbytheFoodandDrugAdministration.8Bothtestsare discussedbelow.Regardlessofthetestusedtodiagnoselatenttuberculosisinfection,thebasicprinciplesfortheapplicationofthetestandanyactionsthat ensuefromtheresultarethesame. WhoShouldBeTested? Thegoaloftestingforlatenttuberculosisinfectionistoidentifypersonswho,becausetheyareatincreasedriskforthedevelopmentoftuberculosis,would benefitfromtreatmentoftheinfection.Sinceonlypersonswhowouldbenefitfromtreatmentshouldbetested,adecisiontotestpresupposesadecisionto treatifthetestispositive.

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Therearetwobroadcategoriesofcandidatesfortestingforlatenttuberculosisinfection:personswhoarelikelytohavebeeninfectedrecentlyandpersons whoareatincreasedriskfortuberculosisbecauseofcertainclinicalconditions(Table1).Recentinfectionisidentifiedwhentheindurationfromatuberculin skintestincreasesbyatleast10mmwithinatwoyearperiod(aconditiontermed"tuberculinconversion").Theriskoftuberculosisishighestsoonafter infectionhasoccurredthus,personswhohavehadrecentexposuretoapatientwithnewlydiagnosedtuberculosisrepresentahighpriorityfortestingand,if theytestpositive,fortreatment. TheTuberculinSkinTest Thetuberculinskintesthasbeeninusesincethelate1800s,anditsdesignisbasedontheobservationbyRobertKochthat infectionwithM.tuberculosiscausedcutaneousreactivitytotuberculin,aconcentratedfiltratefromculturesofM. tuberculosisthathadbeenheatkilled.7Thestandardtuberculintestconsistsof0.1ml(5tuberculinunits)ofPPD administeredintracutaneously,usuallyinthevolarsurfaceoftheforearm.Thereactionisread48to72hoursafter injection,althoughareadingobtaineduptooneweeklaterisaccurate.9Thesizeofthereactionisdeterminedby measurementoftheinduration(noterythema)acrosstheforearmatthesiteoftheinjection.Thecriterionforinterpreting thereactionaspositive(indicatingthepresenceoftuberculosisinfection)variesdependingoncertaincharacteristicsofthe personbeingtested(Table2).Thegeneralprincipleisthatifasmallerreactionisdefinedasindicatinginfection,the sensitivityofthetestisincreasedinthosewhoareatgreatestriskforthedevelopmentoftuberculosis. Sensitizationtotuberculincanalsobeinducedbyinfectionwithnontuberculousmycobacteria,includingBCG,whichisusedinmanypartsoftheworldasa vaccineagainsttuberculosis.Althoughitisnotpossibletodistinguishbetweenatuberculinreactionthatiscausedbytrueinfectionandareactionthatis causedbyBCG,onestudyshowedthatonly8percentofpersonswhohadreceivedBCGvaccineatbirthhadapositivetuberculintest15yearslater.10 BecausemostpersonswhoreceiveBCGvaccinearefromcountrieswithahighincidenceoftuberculosis,itisrecommendedthatthehistoryofBCGvaccination beignoredwhentuberculintestsareinterpreted.6 Inaddition,thetuberculinskintestisnot100percentsensitiveforinfectionwithM.tuberculosis,andevenamongpatientswithproventuberculosisandno apparentimmunosuppression,10to20percentwillhavenegativeresultsontuberculinskintests.11,12Testingwithcontrolantigenssuchasmumpsand candidawaspreviouslythoughttohelpdeterminewhetherpersonshadtruenegativeratherthanfalsenegativetuberculintests.However,inseveralstudies inHIVinfectedpersons,serialanergytestinghasrevealedthatresponsesvaryovertime.1315SuchtestingisthereforenotrecommendedinHIVinfected persons.Becausetheroleofanergytestinginthediagnosisoflatenttuberculosisinfectionisnotwelldefinedforpatientswithnormalimmunesystemsor conditionscausingimmunocompromiseotherthanHIVinfection,mostcliniciansdonotperformsuchtests. Overtime,delayedhypersensitivityresultingfrommycobacterialinfectionmaywaneinsomepersons,resultinginanonreactivetuberculinskintestdespite thepresenceoftrueinfection.However,thestimulusofthisnegativetuberculintestmay"boost"orincreasethesizeofthereactiontoasecondtest administeredlater,resultinginapositivetuberculintestandmisleadinglysuggestingtuberculinconversion(the"booster"phenomenon).9,16Personswhowill undergoannualtuberculinskintesting(e.g.,healthcareworkers)shouldundergotwosteptestingoninitialevaluation,withasecondtuberculintest administeredoneweekafteranegativeinitialtest. WholeBloodInterferonGammaAssay Aninvitroassayofwholebloodforcellmediatedimmunity,basedonthereleaseofinterferonyfromTlymphocytesin responsetostimulationwithM.tuberculosisPPD,showspromisefortheidentificationoflatenttuberculosisinfection.17Ina multicentertrial,therewasexcellentagreementbetweenthetuberculinskintestandtheassay.8Becausethetuberculin testwasusedasthereferencestandard,thebloodtestcouldnotbeshowntobebetterthanthetuberculintest.Asstudied, theassayseemedtobeconfoundedbyBCGtothesameextentasthetuberculintest.However,anotherassaythatusesthe secretedantigenESAT6,whichisnotpresentinBCG,todetectthereleaseofinterferonyfromTcellsspecifictoM. tuberculosisoffersthepossibilityofdistinguishingbetweentruetuberculosisinfectionandaBCGinducedreaction." RulingoutActiveTuberculosis Thediagnosisoflatenttuberculosisinfectionrequiresnotonlyapositivetuberculinskintest,butalsothatactivetuberculosisberuledout.Thisisusually accomplishedbyacarefulhistorytaking,appropriateevaluationofsymptoms,andradiographicexaminationofthechest(Fig.1).Combinationchemotherapy forpresumptivetuberculosisshouldbeinitiatedpendingcultureifthereisahighclinicalsuspicionofactivetuberculosis.Treatmentforlatentinfectionshould beadministeredonlyafternegativeresultshavebeenobtainedoncultureandactivetuberculosisisnolongerclinicallysuspected. TreatmentRegimensforLatentTuberculosisInfectionIsoniazid Isoniazidhasbeenevaluatedinrandomized,controlledtrialsconductedbytheU.S.PublicHealthServicethatincludedmorethan70,000participantsfroma varietyofpopulations.19Whenallthesestudiesareconsideredtogether,theeffectivenessofthedrug,ascomparedwithplacebo,inreducingtheincidenceof activetuberculosisaveragesabout60percent,witharangeof25to92percent,thehighervaluesbeingassociatedwithbetteradherencetothetreatment regimen.19Inmoststudies,300mgofisoniazidwasgivendailyforoneyear. Intheonlystudythatassesseddifferentdurationsofisoniazidtherapy,6monthsoftreatmentwas65percenteffectiveand12monthsoftreatmentwas75 percenteffective(butnotstatisticallydifferentfrom6months)inpreventingtuberculosisamongpatientswithradiographicabnormalitiessuggestiveof inactivetuberculosis.20Throughtheinterpolationofdatafromrandomizedtrials,theoptimaldurationofisoniazidtreatmentforlatenttuberculosisinfection hasbeendeterminedtobeninemonths.6,21 Themostimportantsideeffectofisoniazidishepatitis.Althoughliverenzymeabnormalitiesarerelatively common,occurringin10to20percentofpersonstakingthedrug,symptomatichepatitisis uncommon.22,23Thefrequencyofisoniazidrelatedhepatitis(definedasbothsymptomsofhepatitisand liverenzymelevelsmorethanfivetimestheupperlimitofnormal)increaseswithincreasingageandwas2.3 percentamongpersonsolderthan50yearsofageinaU.S.PublicHealthServicestudy.24Becauseofthe increasedriskofhepatitisassociatedwithadvancedage,anageofmorethan35yearswaspreviously

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consideredacontraindicationtotreatmentwithisoniazid.However,inamorerecentreport,theincidenceof isoniazidrelatedhepatitiswasdeterminedtobeonly1caseper1000persons,althoughtheincidencewas notanalyzedaccordingtoage.25Alcoholconsumptionisanimportantcofactorforisoniazidrelatedhepatitis thus,patientsshouldbeadvisedtoabstainfromalcoholwhiletakingisoniazid.Anotheradverseeffectof isoniazid,peripheralneuropathy,occursinupto2percentofpatientstakingthedruginthedosesthatare usuallyprescribed.26Itiscausedbyinterferencewiththemetabolismofpyridoxineandcanbeeffectively preventedbypyridoxinesupplementation.27 Rifampin Intheonlystudythatevaluatedtheefficacyofrifampinaloneastreatmentforlatenttuberculosisinfection, rifampingivendailyforthreemonthstopersonswithlatenttuberculosisinfectionandsilicosishadanefficacy thatwassignificantlybetterthanthatofplaceboandequivalenttothatofisoniazidgivendailyforsix months.28Adversereactionstorifampinareuncommon.Thereareseveralimportantdruginteractions,most notablywiththeproteaseinhibitorclassofantiretroviraldrugs,thatlimittheuseofrifampininpatientswith HIVinfection. RifampinandPyrazinamide

Inclinicaltrials,aregimenofrifampinandpyrazinamidewasshowntobeaseffectiveandassafeasisoniazidinHIVinfectedpersonswithlatenttuberculosis infection.2931However,therehasbeenrelativelylittleexperiencewiththisregimeninpersonswithoutHIVinfection,andcasereportsofseverehepatitis, includingeighthepatitisrelateddeaths,havearousedconcernaboutthesafetyoftheregimen.32Arecentmulticenterclinicaltrialinvolvingadultswithout HIVinfectionconfirmedthatrifampinandpyrazinamideareassociatedwithagreaterriskofhepatotoxicitythanisisoniazid.33Inthatstudy,8percentofthe patientswhoreceivedrifampinandpyrazinamidehadliverenzymelevelsmorethanfivetimestheupperlimitofnormal,ascomparedwith1percentofthose whoreceivedisoniazid. AREASOFUNCERTAINTY Althoughstudiessuggestthatisoniazidgivenforninemonthsprovidestheoptimalprotectionagainstactivetuberculosis,thisdurationhasnotitselfbeen studieddirectly,andtheoptimaldurationoftherapyisaparticularlyimportantquestionforHIVinfectedpersons.AnanalysisfromatrialconductedinUganda showedthatisoniazidaloneinitiallyprotectedagainstthedevelopmentoftuberculosisintuberculinpositiveHIVinfectedpersonsbutthatitsbenefitwaslost oneyearaftertreatmentbegan.34,35However,patientstreatedwitheitherisoniazidplusrifampinorisoniazid,rifampin,andpyrazinamideforthreemonths hadsustainedbenefit.Alsouncertainisthefutureroleofthewholebloodinterferongammaassayforthediagnosisoflatenttuberculosisinfection. Finally,adecisionanalysisinthisissueoftheJournal36suggeststhatbecauseofthehighprevalenceofisoniazidresistanttuberculosisinfectioninVietnam, Haiti,andthePhilippines,personsfromthosecountriesintheUnitedStatesshouldbetreatedwitharifampinbasedregimentoobtainmaximalhealthand economicbenefits.37Theseobservationswillneedtobeconfirmedinprospectivestudies. GUIDELINES DeterminingWhomtoTreat ThecurrentjointrecommendationsoftheAmericanThoracicSocietyandtheCentersforDiseaseControlandPrevention38aredesignedtotargettuberculin testingtopersonsathighriskforthedevelopmentoftuberculosiswho,iftheytestpositive,willbecandidatesfortreatmentoflatenttuberculosisinfection (Table1).6Becausepersonsshouldbetargetedfortreatmentonthebasisoftheirincreasedriskofdevelopmentoftuberculosis,agedoesnotplayapartin thedecisiontotreat.Inpersonswiththehighestriskoftuberculosis(Table2),indurationof5mmormoreindiameteronatuberculinskintestisusedto diagnoselatenttuberculosisinfection.ThisgroupincludespersonswithHIVinfection,closecontactsofpersonswithactivetuberculosis,personswithan abnormalchestradiographshowingupperlobefibrosisconsistentwithprevioustuberculosis,andimmunosuppressedpatientswhohavebeenreceivingthe equivalentofatleast15mgofprednisoneperdayforatleastonemonth.Inpersonswithanintermediateriskoftuberculosis,anindurationof10mmor moreshouldbeusedtodefinelatentinfection. ForthefirstseveralyearsaftertheirarrivalintheUnitedStates,foreignbornpersonsfromcountrieswithahighprevalenceoftuberculosishaveratesof tuberculosisthataresimilartothoseintheircountriesoforigin.37Forthisreason,itisrecommendedthatpersonswhohavearrivedwithinthepastfiveyears betreatediflatenttuberculosisinfectionisidentified.PersonswithnoneoftheriskfactorsinTable1shouldnotbetested.Beforetreatmentoflatent tuberculosisinfectionisbegun,itisessentialthatactivetuberculosisberuledout(Fig.1). TreatmentRegimens Thefirstchoicefortreatmentoflatenttuberculosisinfectionisisoniazid(Table3).Currentguidelinesrecommendadurationofatleastsixandpreferablynine monthsinadultsandninemonthsinchildren.Forpersonswithpooradherencetotreatment,directlyobservedtreatmentmaybetheoptimalapproach,with directobservationeitherdailyortwiceweekly.Inpersonswhoarepredisposedtoneuropathy(e.g.,thosewithdiabetes,uremia,malnutrition,orHIV infection),pregnantwomen,andpersonswithseizuredisorders,pyridoxine(25mgperday)shouldbegivenwithisoniazid.Rifampinaloneforfourmonthsis thesecondchoiceandshouldbeusedforpatientswhoareintolerantofisoniazidorwhoarepresumedtohaveinfectionwithisoniazidresistantstrainsofM. tuberculosis. Athirdchoicefortreatmentisrifampinandpyrazinamidefortwomonths.Becauseofthepossibilityofseverehepatotoxicity,thisregimenisgenerallyreserved forpersonswhoarenotlikelytocompletealongertreatmentregimenandwhocanbemonitoredclosely.Itisnotrecommendedforpregnantwomenor children.Beforeanyofthesetreatmentsisinitiated,itisessentialthatpatientsbeeducatedaboutpotentialadverseeffectsofthetreatmentregimenbeing used(Table3). CONCLUSIONSANDRECOMMENDATIONS

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Thegoaloftestingforlatenttuberculosisinfectionistoidentifyinfectedpatientswhowillbenefitfromtreatment.Thepatientswhowillbenefitarethosewho eitherareatincreasedriskforhavingrecentlyacquiredinfectionorhaveamedicalconditionthatincreasestheirriskofprogressiontoactivetuberculosis. Patient1describedinthevignetteshouldbepresumedtohavetuberculosisinfectionhishistoryofBCGshouldbeignored.However,becauseofthe abnormalityonhischestradiograph,treatmentforlatenttuberculosisinfectionshouldnotbestarteduntilsputumculturesarenegativeforM.tuberculosis. Afterculturesarenegative,thepreferredregimenwouldbeisoniazidgivenforninemonths.Patient2isatlowriskforthedevelopmentoftuberculosisand shouldnothavebeentested.Nonetheless,shehaslatenttuberculosisinfection,asevidencedbyhertuberculinreactionofmorethan15mm.However,she shouldnotbetreated,becauseshehasnoconditionsthatincreaseherriskofprogressiontotuberculosisanditisunknownwhenshebecameinfected.One cannotconcludethatshehashadrecenttuberculinconversion,becauseshehasnothadanegativetuberculintestwithinthepasttwoyears. SupportedbygrantsfromtheNationalInstitutesofHealth(AI01549andAI34238). References REFERENCES References 1.Globaltuberculosiscontrol:WHOreport2001.Geneva:WorldHealthOrganization,2001. (WHO/CDS/TB/2001.287) 2.DyeC,ScheeleS,DolinP,PathaniaV,RaviglioneMC.Globalburdenoftuberculosis:estimatedincidence, prevalence,andmortalitybycountry:WHOGlobalSurveillanceandMonitoringProject.JAMA1999282:67786. References 3.DolinPJ,RaviglioneMC,KochiA.Globaltuberculosisincidenceandmortalityduring19902000.BullWorldHealthOrgan199472:21320.4.Tuberculosis mortalityamongU.S.bornandforeignbornpopulationsUnitedStates,2000.MMWRMorbMortalWklyRep200251:1014.5.Advancingtoward elimination.In:GeiterL,ed.Endingneglect:theeliminationoftuberculosisintheUnitedStates.Washington,D.C.:NationalAcademyPress,2000:86121. 6.Targetedtuberculintestingandtreatmentoflatenttuberculosisinfection.AmJRespirCritCareMed2000161:52215247. 7.MenziesRI.Tuberculinskintesting.In:ReichmanLB,HershfieldES,eds.Tuberculosis:acomprehensiveinternationalapproach.2nded.NewYork:Marcel Dekker,2000:279322. 8.MazurekGH,LoBuePA,DaleyCL,etal.ComparisonofawholebloodinterferonyassaywithtuberculinskintestingfordetectinglatentMycobacterium tuberculosisinfections.JAMA2001286:17407. 9.SlutkinG,PerezStableEJ,HopewellPC.Timecourseandboostingoftuberculinreactionsinnursinghomeresidents.AmRevRespirDis1986134:1048 51. 10.MenziesR,VissandjeeB.EffectofbacilleCalmetteGuerinvaccinationontuberculinreactivity.AmRevRespirDis1992145:6215. 11.HoldenM,DubinMR,DiamondPH.Frequencyofnegativeintermediatestrengthtuberculinsensitivityinpatientswithactivetuberculosis. NEnglJMed1971285:15069. 12.NashDR,DouglassJE.Anergyinactivepulmonarytuberculosis: acomparisonbetweenpositiveandnegativereactorsandanevaluationof5TUand250TUskintestdoses.Chest198077:327 13.ChinDP,OsmondD,PageShaferK,etal.ReliabilityofanergyskintestinginpersonswithHIVinfection.AmJRespirCritCareMed1996153:19824. 14.MarkowitzN,HansenNI,WilcoskyTC,etal.TuberculinandanergytestinginHIVseropositiveandHIVseronegativepersons.AnnInternMed 1993119:18593. 15.CaiaffaWT,GrahamNMH,GalaiN,RizzoRT,NelsonKE,VlahovD.Instabilityofdelayedtypehypersensitivityskintestanergyinhumanimmunodeficiency virusinfection.ArchInternMed1995155:21117.16.ThompsonNJ,GlassrothJL,SniderDEJr,FaresLS.Theboosterphenomenoninserialtuberculin testing.AmRevRespirDis1979119:5879717.RothelJS,JonesSL,CornerLA,CoxJC,WoodPR.Asandwichen References zymeimmunoassayforbovineinterferongammaanditsuseforthedetectionoftuberculosisincattle.AustVetJ199067:1347. 18.LalvaniA,PathanAA,DurkanH,etal.EnhancedcontacttracingandspatialtrackingofMycobacteriumtuberculosisinfectionbyenumerationofantigen specificTcells.Lancet2001357:201721. 19.FerebeeSH.Controlledchemoprophylaxistrialsintuberculosis:ageneralreview.BiblTuberc197026:28106. 20.InternationalUnionAgainstTuberculosisCommitteeonProphylaxis.Efficacyofvariousdurationsofisoniazidpreventivetherapyfortuberculosis:fiveyears offollowupintheIUATTrial.BullWorldHealthOrgan198260:55564. 21.ComstockGW.Howmuchisoniazidisneededforpreventionoftuberculosisamongimmunocompetentadults?IntJTubercLungDis19993:84750. 22.MitchellJR,ZimmermanHJ,IshakKG,etal.Isoniazidliverinjury:clinicalspectrum,pathology,andprobablepathogenesis.AnnInternMed197684:181 92. 23.ByrdRB,HornBR,SolomonDA,GriggsGA.Toxiceffectsofisomazidintuberculosischemoprophylaxis:roleofbiochemicalmonitoringin1,000patients.

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24.KopanoffDE,SniderDEJr,CarasGJ.Isoniazidrelatedhepatitis: aU.S.PublicHealthServicecooperativesurveillancestudy.AmRevRespirDis1978117:9911001. 25.NolanCM,GoldbergSV,BuskinSE.Hepatotoxicityassociatedwithisoniazidpreventivetherapy:a7yearsurveyfromapublichealthtuberculosisclinic. JAMA1999281:10148. 26.OestreicherR,DresslerSH,MiddlebrookG.Peripheralneuritisintuberculouspatientstreatedwithisoniazid.AmRevTuberc195470:5048.27.SniderDE Jr.Pyridoxinesupplementationduringisoniazidtherapy.Tubercle198061:1916. 28.HongKongChestService/TuberculosisResearchCentre,BritishMedicalResearchCouncil.Adoubleblindplacebocontrolledclinicaltrialofthree antituberculosischemoprophylaxisregimensinpatientswithsilicosisinHongKong.AmRevRespirDis1992145:3641. 29.HalseyNA,CoberlyJS,DesormeauxJ,etal.RandomisedtrialofisoniazidversusrifampicinandpyrazinamideforpreventionoftuberculosisinHIV1 infection.Lancet1998351:78692. 30.MwingaAG,HospM,GodreyFaussettP,etal.TwiceweeklytuberculosispreventivetherapyinHIVinfectioninZambia.AIDS199812:244757 References 31.GordinFM,ChaissonRE,MartsJP,etal.RifampinandpyrazinamidevsisoniazidforpreventionoftuberculosisinHIVinfectedpersons:aninternational randomizedtrial.JAMA2000283:144550. 32.Update:fatalandsevereliverinjuriesassociatedwithrifampinandpyrazinamideforlatenttuberculosisinfection,andrevisionsinAmericanThoracic Society/CDCrecommendationsUnitedStates,2001.MMWRMorbMortalWklyRep200150:7335. 33.JasmerRM,SaukkonenJJ,BlumbergHM,etal.Shortcourserifampinandpyrazinamidecomparedwithisoniazidforlatenttuberculosisinfection:a multicenterclinicaltrial.AnnInternMed2002137:6407 34.WhalenCC,JohnsonJL,OkweraA,etal.AtrialofthreeregimenstopreventtuberculosisinUgandanadultsinfectedwiththehumanimmunodeficiency virus.NEnglJMed1997337:8018. 35.JohnsonJL,OkweraA,HomDL,etal.DurationofefficacyoftreatmentoflatenttuberculosisinfectioninHIVinfectedadults.AIDS200116:213747 36.KhanK,MuennigP,BehtaM,ZivinJG.GlobaldrugresistancepatternsandthemanagementoflatenttuberculosisinfectioninimmigrantstotheUnited States.NEnglJMed2002347:18509. 37.McKennaMT,McCrayE,OnoratoI.TheepidemiologyoftuberculosisamongforeignbornpersonsintheUnitedStates,1986to1993. NEnglJMed1995332:10716. 38.Targetedtuberculintestingandtreatmentoflatenttuberculosisinfection.NewYork:AmericanThoracicSociety,1999.(AccessedNovember8,2002,at http://www.thoracic.org/adobe/statements/latenttbl27pdf) AuthorAffiliation ROBERTM.JASMER,M.D.,PAYAMNAHID,M.D.,ANDPHILIPC.HOPEWELL,M.D. AuthorAffiliation FromtheDivisionofPulmonaryandCriticalCareMedicine,SanFranciscoGeneralHospital,andtheDepartmentofMedicine,UniversityofCalifornia,San FranciscobothinSanFrancisco.AddressreprintrequeststoDr.JasmerattheDivisionofPulmonaryandCriticalCareMedicine,SanFranciscoGeneral Hospital,Rm.RK1,1001PotreroAve.,SanFrancisco,CA94110,oratrjasmer@itsa.ucsf.edu.

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Title Author Publicationtitle Volume Issue Pages Numberofpages Publicationyear Publicationdate

Latenttuberculosisinfection Jasmer,RobertMNahid,PayamHopewell,PhilipC TheNewEnglandJournalofMedicine 347 23 18601866 7 2002 Dec5,2002

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2002 MassachusettsMedicalSociety Boston UnitedStates MedicalSciences 00284793 NEJMAG ScholarlyJournals English Feature 223933369 http://ezproxy.vccs.edu:2048/login? url=http://search.proquest.com/docview/223933369?accountid=12902 CopyrightMassachusettsMedicalSociety,PublishingDivisionDec5,2002 20100609 ProQuestResearchLibrary

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