Tuberculosis Disease in Children

10/8/2016
Tuberculosisdiseaseinchildren
OfficialreprintfromUpToDate
www.uptodate.com2016UpToDate
Authors
LisaVAdams,MD
JeffreyRStarke,MD
SectionEditors
CFordhamvonReyn,MD
MorvenSEdwards,MD
DeputyEditor
ElinorLBaron,MD,DTMH
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jul2016.|Thistopiclastupdated:Jun13,2016.
INTRODUCTIONFormalpoliciesandcontroleffortsaddressingtuberculosis(TB)inchildrenhavebeenlimited,in
partduetolackofastandardizedcasedefinitionanddifficultiesassociatedwithestablishingadefinitivediagnosis[1].
However,sincediagnosticandtreatmenttoolsforTBinchildrenhavebeguntoimprovesignificantly,TBinchildren
hasreceivedincreasingattentionbyresearchers,clinicians,andpolicymakers.
IssuesrelatedtoTBdiseaseinchildrenwillbereviewedhere.IssuesrelatedtodiagnosisandtreatmentoflatentTB
infectioninchildrenarediscussedindetailseparately.(See"Latenttuberculosisinfectioninchildren".)
EPIDEMIOLOGY
GlobalepidemiologyEstimatingtheglobalburdenoftuberculosis(TB)diseaseinchildrenischallengingduetothe
lackofastandardcasedefinition,thedifficultyinestablishingadefinitivediagnosis,thefrequencyofextrapulmonary
diseaseinyoungchildren,andtherelativelylowpublichealthprioritygiventoTBinchildrenrelativetoadults[2].
TheWorldHealthOrganization(WHO)publishesglobalTBdataincludingnewandrelapsecasesbyage.Inits2014
report,theWHOestimatesthat,oftheninemillionincidentcasesofTBin2013,approximately550,000occurred
amongchildrenunderage15[3].Additionally,itestimatedthattherewere80,000pediatricdeathsduetoTB(among
HIVuninfectedchildren).Approximately75percentofthesecasesoccurredinthe22highestTBburdencountries
(table1)[3].Inmanydevelopingcountries,childrencomposemorethanonehalfofthepopulation,suggestingthatthe
reportedcasesofchildhoodTBarelikelyunderestimated.
ChildrenunderagefiverepresentanimportantdemographicgroupforunderstandingTBepidemiology,sinceTB
frequentlyprogressesrapidlyfromlatentinfectiontodisease,andseverediseasemanifestations,suchasmiliaryTB
andmeningitis,aremorecommoninthisagegroup.Therefore,thesechildrenserveassentinelcases,indicating
recentand/orongoingtransmissioninthecommunity.
MostchildrenareinfectedbyhouseholdcontactswithTBdisease,particularlyparentsorothercaretakers.Evenin
circumstanceswhenadultindexcasesaresputumsmearnegative,transmissiontochildrenhasbeendocumentedin
30to40percentofhouseholds[4].
Ithasbeenestimatedthat,ofnearlyonemillionchildrenwhodevelopedtuberculosisdiseasein2010,32,000had
multidrugresistantTB[5].AdditionaleffortisneededtoimprovedetectionofdrugresistantTBamongchildren.
UnitedStatesepidemiologyRiskfactorsforpediatricTBintheUnitedStatesincludebeingforeignborn,havinga
parentwhoisforeignborn,orhavinglivedoutsidetheUnitedStatesformorethantwomonths[6].IntheUnited
States,TBamongchildrenisrelativelyrare.In2012,therewere486casesofTBinchildrenandadolescentsunder15
yearsofagereportedbytheUnitedStatesCentersforDiseaseControlandPrevention(CDC)thisnumber
represented5percentofthetotal9945casesreportedthatyear[7,8].However,TBinchildrenandadolescentsis
pronetobothunderandoverreportingduetothedifficultiesrelatedtodiagnosis.Nonetheless,intheUnitedStates,
TBinchildrenandadolescentsappearstobedeclining.Between2008and2012,TBannualcasenotificationsinthose
underage15yearsdecreasedfrom786(in2008)to486cases(in2012)[6].
In2012,mostchildrenandadolescentswithTBintheUnitedStateswerebornintheUnitedStates(79percent).In
contrast,mostadultswithTBintheUnitedStateswereborninendemicareas(table2).Nearlyhalfofallpatients
underage15diagnosedwithTBin2012(42percent)wereyoungchildrenbetweentheagesof1and4[6].[6]
In2012,among471childrenandadolescentswithTBintheUnitedStates,40percentwereHispanic,27percentwere
black,22percentwereAsianorPacificIslander,8percentwerewhite,and4percentwereAmericanIndianorNative
Alaskan[6].Between1993and2011,HIVstatuswasknownfor24percentofthepediatricpatientsreported(n=
19,354)ofthese,3.7percentwereHIVinfected[7].Drugsusceptibilitytestingdatafrom2011revealthattheisolates
from17percentofpediatricTBcaseshaddetectableresistancetooneormoredrugs,and3percentweremultidrug
resistantTB[6].
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CLINICALMANIFESTATIONS
PulmonarytuberculosisPulmonarydiseaseandassociatedintrathoracicadenopathyarethemostfrequent
presentationsoftuberculosis(TB)inchildren[9,10].CommonsymptomsofpulmonaryTBinchildreninclude[11]:
Chronic,unremittingcoughthatisnotimprovingandhasbeenpresentformorethanthreeweeks
Feverofmorethan38Cforatleasttwoweeks,othercommoncauseshavingbeenexcluded
Weightlossorfailuretothrive(basedonchild'sgrowthchart)
However,thesesymptomsarefairlynonspecific.InonestudycomparingsymptomsofchildrenwithcultureprovenTB
withchildrenwithotherlungdiseases,therewasnodifferencebetweenthetwogroupswithrespecttoweightloss,
chroniccough,anddurationofsymptoms[12].Theonlyfactorsdifferentiatingthegroupswerehistoryofcontactwith
aninfectiousTBcaseandapositivetuberculinskintest(TST).Inastudyofmorethan1000HIVuninfectedinfantsin
SouthAfrica,cough>2weeks'duration(presentin17percent)wastheonlydiagnosticsymptomassociatedwith
severepulmonaryTBdiseasethissymptomwastwiceascommoninsevereTBcomparedwithnonsevereTB[13].
Physicalexamfindingsmaysuggestthepresenceofalowerrespiratoryinfection,buttherearenospecificclinical
signsorfindingstoconfirmthatpulmonaryTBisthecause.Childrenages5to10maypresentwithclinicallysilent
(butradiographicallyapparent)disease,particularlyinthesettingofcontactinvestigation[9].Incontrast,infantsare
morelikelytopresentwithsignsandsymptomsoflungdisease.Commonradiographicfindingsarediscussedbelow.
(See'Chestradiography'below.)
ExtrapulmonarytuberculosisTheclinicalpresentationofextrapulmonaryTBdependsonthesiteofdisease.The
mostcommonformsofextrapulmonarydiseaseinchildrenareTBofthesuperficiallymphnodesandofthecentral
nervoussystem(CNS)[14].NeonateshavethehighestriskofprogressiontoTBdiseasewithmiliaryandmeningeal
involvement[14].SomeformsofTBandtheircommonphysicalsignsareasfollows[15]:
Tuberculousmeningitismeningitisnotrespondingtoantibiotictreatment,withasubacuteonset,communicating
hydrocephalus,stroke,and/orelevatedintracranialpressure(see"Centralnervoussystemtuberculosis")
PleuralTBPleuraleffusion(see"TuberculouspleuraleffusionsinHIVuninfectedpatients")
PericardialTBPericardialeffusion(see"Tuberculouspericarditis")
AbdominalTBDistendedabdomenwithascites,abdominalpain,jaundice,orunexplainedchronicdiarrhea(see
"Tuberculousenteritis"and"Tuberculousperitonitis")
TBadenitisPainless,fixed,enlargedlymphnodes,especiallyinthecervicalregion,withorwithoutfistula
formation(see"Tuberculouslymphadenitis")
TBofthejointNontenderjointeffusion(see"Skeletaltuberculosis")
VertebralTBBackpain,gibbusdeformity,especiallyofrecentonset(rarelyseen)(see"Skeletaltuberculosis")
SkinWartylesion(s),papulonecroticlesions,lupusvulgariserythemanodosummaybeasignoftuberculin
hypersensitivity
RenalSterilepyuria,hematuria(see"Renaldiseaseintuberculosis")
EyeIritis,opticneuritis,phlyctenularconjunctivitis(see"Tuberculosisandtheeye")
InthecontextofexposuretoTB,presenceofthesesignsshouldpromptfurtherinvestigationofextrapulmonaryTB.
PerinatalinfectionPerinatalTBcanbealifethreateninginfectionthemortalityinthesettingofcongenitaland
neonatalTBisabout50percent[1618]:
CongenitalTBisrareandmostoftenisassociatedwithtuberculousendometritisordisseminatedTBinthe
mother.Itcanbeacquiredhematogenouslyviatheplacentaandumbilicalveinorbyfetalaspiration(oringestion)
ofinfectedamnioticfluid[16,18].
ClinicalmanifestationsofcongenitalTBincluderespiratorydistress,fever,hepatomegaly,splenomegaly,poor
feeding,lethargy,irritability,andlowbirthweight[17].Clinicalevaluationoftheinfantinthesettingofsuspected
congenitalTBshouldincludeTST,HIVtesting,chestradiograph,lumbarpuncture,cultures(bloodandrespiratory
specimens),andevaluationoftheplacentawithhistologicexamination(includingacidfastbacilli[AFB]staining
culture).TheTSTinnewbornsisusuallynegative,butaninterferongammareleaseassaytestmaybepositivein
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somecases.
NeonatalTBdevelopsfollowingexposureofaninfanttohisorhermother'saerosolizedrespiratorysecretions.
ThisismorecommonthancongenitalTB,anddiagnosisofneonatalTBcanleadtoidentificationofpreviously
unrecognizeddiagnosisofTBinthemother[19].
InthesettingofcongenitalorneonatalTB,themothershouldbeevaluatedasoutlinedindetailseparately.(See
"DiagnosisofpulmonarytuberculosisinHIVuninfectedpatients".)
AdolescentinfectionAdolescentswithTBcanpresentwithfeaturescommoninchildrenoradults.Inonereview
including145casesofadolescentTB,thefollowingfeatureswerenoted[20]:
Mostadolescentspresentedwithclinicalsymptoms.
RatesofextrathoracicTBwerehigh,includingsiximmunocompetentadolescentswithTBmeningitis.
MostcaseswereAFBsputumsmearnegative.
OnlyhalfofpatientswithintrathoracicTBhadpositivecultures.
Antituberculousmedicationsweregenerallywelltolerated.
DIAGNOSISTuberculosis(TB)inchildrenisoftendiagnosedclinically.BecausepulmonaryTBinchildrentypically
presentswithpaucibacillary,noncavitarypulmonarydisease,bacteriologicconfirmationisachievableinlessthan50
percentofchildrenand75percentofinfantsinsuchcases,pulmonaryTBisdiagnosedbyotherclinicalcriteria[21].
Obtainingsputumsamplesfromyoungchildrenischallengingduetolackofsufficienttussiveforcetoproduce
adequatesputumsamplesbyexpectorationalone[22].Forthesereasons,gastricaspirationistheprincipalmeansof
obtainingmaterialforculturefromyoungchildreninducedsputummayalsobecollectediffeasible.Inaddition,most
expertsrecommendthatchildren<12monthswhoaresuspectedofhavingpulmonaryorextrapulmonaryTBundergo
lumbarpuncture,regardlessofwhetherneurologicalsymptomsarepresent[21].
FordiagnosisofextrapulmonaryTB,specimensforcultureshouldbecollectedfromanysitewhereinfectionis
suspected.Eachspecimenshouldbeculturedregardlessofacidfastbacilli(AFB)smearresults[21].Themost
commonextrapulmonaryspecimensincludewholeblood,bonemarrow,tissuespecimens(suchaslymphnodeor
bone),cerebrospinalfluid,urine,andpleuralfluid.Diagnosticyieldisvariable.InpleuralTB,adenosinedeaminase
(ADA)levelsover40units/Linthepleuralfluidareobservedinthemajorityofpatients[9].(See"Tuberculouspleural
effusionsinHIVuninfectedpatients".)
AdiagnosisofTB(pulmonaryorextrapulmonary)inachildisoftenbasedonthepresenceoftheclassictriad:(1)
recentclosecontactwithaninfectiouscase,(2)apositivetuberculinskintest(TST)orinterferongammarelease
assay(IGRA),and(3)suggestivefindingsonchestradiographorphysicalexamination[15].
TheapproachoutlinedbytheWorldHealthOrganization(WHO)forevaluationofachildsuspectedofhavingTB
includes[11]:
Carefulhistory(includinghistoryofTBcontactandsymptomsconsistentwithTB)
Clinicalexamination(includinggrowthassessment)
TSTand/orIGRA(bothtests,ifavailable,toincreasesensitivity)
Bacteriologicalconfirmationwheneverpossible
InvestigationsrelevantforsuspectedpulmonaryandextrapulmonaryTB
HIVtesting(eg,inhighHIVprevalenceareas)
Alldata,includingthoroughhistory,physicalexam,anddiagnostictesting,mustbeconsideredcarefully.Ahistoryof
recentclosecontactwithaninfectious(sputumsmearpositive)caseofTBisacriticalfactorinmakingthediagnosis
ofTBinchildren,especiallyforthoseundertheageoffiveyears.However,theilladultmayhavenotyetbeen
diagnosed,soaskingaboutillcontactsandfacilitatingevaluationforilladultscanalsoexpeditediagnosisforchildren.
InmanycasesofTBinchildren,laboratoryconfirmationisneverestablished(particularlyamongchildrenunderfive
yearsofage).Insuchcases,apresumptivediagnosismaybemadebasedonclinicalandradiographicresponseto
empirictreatment.Treatmentisoftenguidedbythecultureanddrugsusceptibilityresultsfromtheindexcase(eg,the
adult'sTBcontact).
Screeningtests
TuberculinskintestApositiveTSTmaybepresentinbothcontainedlatentTBinfection(LTBI)andinactive
TBdisease.Thus,althoughapositiveTSTmayhelpsupportadiagnosisofactivedisease,thisfindingaloneisnot
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diagnosticofactivediseaseitmustbeconsideredtogetherwithotherdiagnosticcriteria.TheTSTishelpfulfor
diagnosisofTBinchildrenonlyincircumstanceswhenitispositive.CriteriaforpositiveTSTareoutlinedintheTable
(table3)[15].ApositiveTSTmaybefalselypositiveduetopriorvaccinationwithBacilleCalmetteGurin(BCG),
infectionwithnontuberculousmycobacteria,andimproperadministrationorinterpretation(table4).
AnegativeTSTdoesNOTruleoutTBdisease,sincefalsenegativeresultscanoccurinavarietyofcircumstances
(eg,incorrectadministrationorinterpretationoftheTST,agelessthansixmonths,immunosuppressionbyHIV,other
diseaseormedication,certainviralillnessesorrecentlivevirusimmunization,overwhelmingTBinfection)[15,23].
(See"Diagnosisoflatenttuberculosisinfection(tuberculosisscreening)inHIVuninfectedadults",sectionon'False
negativetests'.)
BecausetheTSTcannotdistinguishbetweenTBdisease,latentMycobacteriumtuberculosisinfection,andinfection
duetonontuberculousmycobacteria,theresultmustbeinterpretedinthecontextoftheclinicalfeaturesandhistoryof
TBexposure[24].Overall,upto40percentofimmunocompetentchildrenwithcultureconfirmedTBdiseasemayhave
anegativeTST[21,25].TSTpositivityratesvarybyformofdiseaseinpulmonaryandextrapulmonaryTB,theTSTis
typicallypositive(90and80percent,respectively),whileinmiliaryTBandTBmeningitis,theTSTisusuallypositive
inonly50percentofcases[2628].
InterferongammareleaseassaysIGRAsareinvitrobloodtestsofcellmediatedimmuneresponse.These
assayshavegreaterspecificitythanTSTfordiagnosisofLTBIandaremostusefulforevaluationofLTBIinBCG
vaccinatedindividuals[29].AswiththeTST,IGRAscannotdistinguishLTBIfromactivedisease.IGRAsmayprovea
usefultooltoimprovethediagnosisofTB,althoughevidenceforuseofIGRAsinchildrenislimited[3034].Useof
bothTSTandIGRAmayincreasesensitivityforevaluationofchildrenwithsuspectedTB.Additionalissuesrelatedto
useofIGRAsarediscussedfurtherseparately.(See"Interferongammareleaseassaysfordiagnosisoflatent
tuberculosisinfection".)
Imaging
ChestradiographyFrontalandlateralchestradiographycanbeaveryusefultoolfordiagnosisofTBinchildren
(image1AK)[35,36].ThemostcommonchestradiographfindinginachildwithTBdiseaseisaprimarycomplex,
whichconsistsofopacificationwithhilarorsubcarinallymphadenopathy,intheabsenceofnotableparenchymal
involvement[11].Whenadenopathyadvances,consolidationorasegmentallesionmayoccur,leadingtocollapsein
thesettingofinfiltrateandatelectasis.
Inastudyof326tracedcontactsunderfiveyearsofage,9percentofchildrendiagnosedwithintrathoracicTBwere
asymptomaticandhadradiographicfindingsonlyoftheprimarycomplex[37].Amiliarypatternofopacificationis
highlysuspiciousforTB,asisopacificationthatdoesnotimproveorresolvefollowingacourseofantibiotics[11].
AdolescentswithTBgenerallypresentwithtypicaladultdiseasefindingsofupperlobeinfiltrates,pleuraleffusions,
andcavitationsonchestradiograph[11].(See"DiagnosisofpulmonarytuberculosisinHIVuninfectedpatients".)
ComputedtomographyscanComputedtomography(CT)scanofthechestmaybeusedtofurtherdelineate
theanatomyforcasesinwhichradiographicfindingsareequivocal.Endobronchialinvolvement,bronchiectasis,and
cavitationsmaybemorereadilyvisualizedonCTscansthanchestradiographs[38].However,thereisnorolefor
routineuseofCTscansintheevaluationofanasymptomaticchildsincetreatmentregimensarebasedonchest
radiographyfindings[9].
Inthesettingoftuberculousmeningitis,CTscanoftheheadisuseful.Hydrocephalusandbasilarmeningeal
enhancementareobservedin80and90percentofcases,respectivelychestradiographymaybenormal[9].
LaboratorystudiesThelikelihoodofachievingbacteriologicalconfirmationdependsontheextentofdiseaseand
thetypeofspecimen.TheinitialapproachfordiagnosisofTBinchildrenconsistsofsputumexamination:
expectorated(foradolescents),swallowedandcollectedasgastriccontents(youngchildren),orinduced.Gastric
aspirationistheprimarymethodofobtainingmaterialforacidfastbacilli(AFB)smearandculturefromyoungchildren.
Sputumspecimensshouldbesentforexaminationbysmearmicroscopyandmycobacterialculture.Nucleicacid
amplification(NAA)testingcanbeusedforrapiddiagnosisofanorganismbelongingtotheM.tuberculosiscomplex
(24to48hours)inpatientsforwhomthesuspicionforTBismoderatetohigh[39].(See"Diagnosisofpulmonary
tuberculosisinHIVuninfectedpatients",sectionon'Diagnosticmicrobiology'.)
Acidfastbacillismearandculture
SputumObtainingexpectoratedsputumfromchildrenfordetectionofAFBisdifficultanditsexaminationis
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oflowyield(15percentorlessformicroscopicexaminationand30percentorlessforculture)[40,41].However,most
adolescentscanproduceexpectoratedsputumspontaneously.
Sputuminductionhashigheryieldthanexpectoratedsputuminchildren,andtheuseofsputuminductionforobtaining
TBdiagnosticspecimensinchildrenisincreasing.Sputuminductionisperformedviaadministrationofaerosolized
heatedsalinecombinedwithsalbuterol(orsimilardrugtominimizewheezing),followedbysuctioningtocapturethe
expectoratedsputum.Inastudyof250children(medianage13months),sputuminductionwasfoundtobeasafeand
effectiveprocedureinchildrenasyoungasonemonthofage[40].Intwostudies,outpatientsputuminductionyielded
cultureresultscomparabletoorbetterthaninpatientgastricaspiration[25,40].Minimaladverseeffectsassociatedwith
theprocedureincludedcoughing,epistaxis,vomiting,andwheezing.Childrenwithunderlyingreactiveairwaysdisease
shouldreceivepretreatmentwithabronchodilatortopreventbronchospasmduringorfollowingtheprocedure[40].
GastricaspirateEarlymorninggastriccontentscollectedfromafastingchildcontainsputumswallowed
duringthenight.Gastricaspirationspecimensmaybeobtainedintheinpatientoroutpatientsetting[42,43].Ideally,
threeearlymorningsamplescollectedondifferentdaysbeforethechildeatsorambulatesoptimizespecimenyield
[44].
Gastricaspirationremainsthemostcommonmethodforobtainingrespiratorysamplesfromchildren(infacilitieswhere
thisproceduremaybeperformed).Ingeneral,culturesofgastricaspiratespecimensarepositiveforTBinonly30to
40percentofcases[45].Smearsareevenlessreliable,withpositiveresultsinfewerthan10percentofcases[45]in
addition,falsepositivesmearresultscausedbythepresenceofnontuberculousmycobacteriacanoccur[21].Similar
yieldshavebeenreportedwithnasopharyngealaspiration,alessinvasivetechniquethatcanbeperformedinthe
outpatientsetting[46].
OtherspecimensOtherbodyfluidand/ortissuesamplesmaybenecessaryinsomecircumstances,
dependingonsuspicionforextrapulmonaryTB.Theapproachtothesediagnostictoolsisoutlinedseparately.(See
"DiagnosisofpulmonarytuberculosisinHIVuninfectedpatients",sectionon'Pleuraleffusion'and"Diagnosisof
pulmonarytuberculosisinHIVuninfectedpatients",sectionon'Tissuebiopsy'.)
DiagnosisofTBshouldpromptHIVtesting.(See"ScreeninganddiagnostictestingforHIVinfection".)
RapidtestingTheXpertMTB/RIFassayisanautomatednucleicacidamplificationtestthatcan
simultaneouslyidentifyM.tuberculosisanddetectrifampinresistance.Thistestperformssubstantiallybetterthan
smearmicroscopy[47,48].Inarandomizedtrialincluding452childreninSouthAfricawithsuspectedpulmonaryTB,6
percenthadapositivesputumsmear,16percenthadapositivesputumculture,and13percenthadapositivesputum
XpertMTB/RIFresult[47].TheinitialXpertMTB/RIFtestdetected100percentofculturepositivecasesthatwere
smearpositivebutonly33percentofthosethatweresmearnegativeasecondXpertMTB/RIFtestimprovedthe
detectionofsmearnegativecasesto61percent.Overall,withinducedsputumspecimens,thesensitivityand
specificitywere59and99percent,respectively,foroneXpertMTB/RIFtestand76and99percentfortwoXpert
MTB/RIFtests.TestperformancewasunaffectedbypatientHIVstatus.ResultsforXpertMTB/RIFwereavailable
withinamedianofoneday(versus12daysforculture).Detectionofrifampinresistancewaslesspromising:1of3
rifampinresistantisolateswasnotdetected,and4of74rifampinsensitiveisolateshadan"indeterminate"result.A
multicountrystudyfoundthatXpertMTB/RIFtestingofbothanasopharyngealaspirateandstoolsamplehadahigh
yield(sensitivityof75percentandspecificity>97percent)inHIVinfectedchildrenandposesapromisingalternative
[49].
WhiletheXpertMTB/RIFtestappearstobehighlyspecific,itssensitivityforsputumsmearnegativeTBinchildren
remainslow.Sinceculturewasusedasthegoldstandardinbothstudiesdescribedabove,thesensitivityofXpert
MTB/RIFisexpectedtobeevenlowerinsputumculturenegative,clinicallyconfirmedcases.Therefore,itcannot
replacecurrentmethodsusedtosuspectanddiagnoseTBininfantsandchildren.Mostchildreninthestudypresented
withsymptomaticpulmonaryTBandextensivedisease.TheXpertMTB/RIFtestismeanttobearapiddiagnostictest
thatmaytaketheplaceofsputummicroscopybutnotmycobacterialculture[50].AnegativeXpertMTB/RIFtest
shouldbeinterpretedinthecontextofthechild'sclinicalandradiographicfindings.Sputumcultureremainsamore
sensitivetestandisrequiredtodetectthefulldrugsusceptibilityprofileoftheinfectingorganism.Furtherstudyofthe
assayisneededinareaswithhighandlowprevalenceofTB.(See"DiagnosisofpulmonarytuberculosisinHIV
uninfectedpatients",sectionon'XpertMTB/RIFassay'.)
UseoftheXpertMTB/RIFtestongastriclavageandnasopharyngealspecimensmaybebeneficialinsettingswhere
inducedsputumandmycobacterialculturearenotfeasible.InonestudyinZambia,sensitivityandspecificitywere
foundtobesimilarforsputumandgastriclavageaspirates(sensitivity90and69percent,respectivelyspecificity99
percentforboth)[51].Amongover900childreninSouthAfrica,thesensitivityofXpertMTB/RIFwassimilarfor
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inducedsputumandnasopharyngealaspiratespecimens(71and65percent,respectively)specificitywas>98percent
[52].
MolecularlineprobeassaysarerapidteststhatcanbeusedtodetectthepresenceofM.tuberculosisaswellas
geneticmutationsthatconferrifampinresistancealoneorincombinationwithisoniazidresistance.Theseassayshave
highsensitivity(90to97percent)andspecificity(99percent)comparedwithdrugsusceptibilitytesting[53].(See
"Naturalhistory,microbiology,andpathogenesisoftuberculosis",sectionon'Drugsusceptibilitytests'.)
DrugresistanceMycobacterialculturewithsecondlinedrugsusceptibilitytesting(DST)shouldbeperformed
wheneverpossible[54,55].Concertedeffortshouldbemadetoobtainmultiplehighqualityspecimensfromthemost
accessiblesite(s)ofdisease[55].
Rapidmoleculartestsareusefulforprovidingsomeinformationregardingsusceptibilityintheabsenceofculturedata.
TheseincludeXpertMTB/RIF(anautomatednucleicacidamplificationtestthatprovidesinformationregarding
susceptibilitytorifampin)andMTBDRsl(alineprobeassaythatprovidesinformationregardingsusceptibilityto
fluoroquinolonesandinjectableantituberculousagents).
In2016,theWorldHealthOrganizationrecommendeduseofMTBDRslforidentifyingpatientswithMDRTBor
rifampicinresistantTBwhoarecandidatesfortreatmentwithashortenedtreatmentregimen[56].Theassaymaybe
usedaninitialdiagnostictesthowever,phenotypicculturebaseddrugsusceptibilitytestingisrequiredtodetect
resistancetootherdrugsandtomonitorforemergenceofadditionalresistanceduringtreatment.Issuesrelatedto
diagnosisofdrugresistancearediscussedfurtherseparately.(See"Diagnosis,treatment,andpreventionofdrug
resistanttuberculosis".)
Pendingdefinitivediagnosticinformation,insomecircumstancesitmaybereasonabletopresumepresenceofdrug
resistantTBbasedonclinicalcriteriaincludingsignsandsymptoms,radiographicfindings,historyofcontactwitha
presumedorconfirmedsourcecasewithdrugresistantTB,andfailuretorespondtofirstlineTBdrugs[55].
InvestigationaldiagnosticmethodsBecauseofthedifficultyinachievingmicrobiologicconfirmationofclinically
suspectedTBinchildren,interesthasgrowninalternatemethodsoflaboratorydiagnosis.Onecandidatemethodis
microarrayanalysisofbloodsamplestoidentifyapatternofRNAexpressionthatisassociatedwithactiveTB
infection.OnestudyidentifiedanRNAexpressionriskscorethatdistinguishedwithhighsensitivityandspecificity
cultureconfirmedTBfromlatentTBanddiseasesotherthanTBamongchildreninsubSaharanAfrica.However,the
riskscoredidnotperformaswellamongchildrenwithclinicallydiagnosed,culturenegativeTB[57].Moreover,inorder
tobeapracticaltoolinresourcelimitedsettings,whereitsusewouldbemostrelevant,thetechnologywouldrequire
substantialmodificationtoreducecostandcomplexity.
TREATMENT
SusceptiblediseaseGuidelinesendorsedbytheUnitedStatesCentersforDiseaseControlandPrevention(CDC)
andtheWorldHealthOrganization(WHO)forthetreatmentoftuberculosis(TB)inchildrenemphasizetheuseof
shortcoursemultidrugregimensunderdirectlyobservedtherapy[15].Ingeneral,thepediatrictreatmentregimens
outlinedbytheWHOarecomparablewiththeadultregimens(table5)[21,58].BecauseTBinyoungchildrencan
rapidlydisseminatewithserioussequelae,promptinitiationoftherapyiscritical.Appropriatedosingisoutlinedinthe
Table(table6).Forinfantsandyoungchildren,isoniazid(INH)tabletsandcanbepulverized,andthecontentsof
rifampincapsulescanbesuspendedinaflavoredliquidorsprinkledonsemisoftfoods.(See"Treatmentofpulmonary
tuberculosisinHIVuninfectedadults".)
PyridoxinesupplementationisnotroutinelyrecommendedforchildrenreceivingINHbutshouldbeconsideredfor
exclusivelybreastfedinfants,malnourishedchildrenorthosewithdietspoorinpyridoxine,andHIVinfectedchildren
[21,59].
InmanycasesofTBinchildren,laboratoryconfirmationisneverestablished(particularlyamongchildrenunderfive
yearsofage).Insuchcases,apresumptivediagnosismaybemadebasedonclinicalandradiographicresponseto
empirictreatment.Iftheculturesarenegative,theisolatesofcontacts(ifknownoravailable)shouldguidedecisions
abouttreatmentwithrespecttosusceptibility.Duringandfollowingtreatment,radiographicabnormalitiessuchashilar
adenopathymaypersisttherefore,anormalradiographisnotnecessarytodiscontinuetreatment,andfollowup
radiographsbeyondtheterminationofsuccessfultherapyareusuallynotnecessaryunlessclinicaldeteriorationoccurs
[21].
Drugsusceptibilitytesting(DST)shouldbeperformedoninitialisolatesfromeachsiteofdisease.Susceptibility
testingshouldberepeatedifthepatientremainsculturepositiveafterthreemonthsoftherapyorpositiveculturesare
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detectedafternegativecultureshavebeendocumented.
InHIVinfectedchildrennotonantiretroviraltherapy(ART),ARTshouldbeinitiatedwithineightweeksofstarting
antituberculoustherapyorwithintwotofourweeksiftheCD4countis<50cells/mm3.ChildrenwithTBmeningitis
maybetheonlyexception.EmergingevidencesuggeststhatthereisnosurvivalbenefittostartingARTbeforetwo
monthsofantituberculoustherapy,and,infact,delayingARTuntilthattimemayreduceadverseevents[60].
SelectionofanoptimalARTregimenshouldbemadeinconsultationwithapediatricHIVspecialist.
Unexplaineddeteriorationamongimmunocompetentchildrenreceivingappropriatetherapyforpulmonaryand/or
extrapulmonaryTBhasbeendescribed[61,62].Inonestudyof110children,clinicalorradiographicdeteriorationwas
observedin14percentofcasesafterinitiatingtherapy(range10to181daysmean80days)[61].Themostcommon
complicationwasenlargingintrathoraciclymphadenopathy,oftencausingairwaycompromise.Deteriorationwasmore
likelyamongchildrenwithweightforage25thpercentileandmultiplesitesofdisease.Allchildrenachievedclinicalor
radiographiccurecorticosteroidswereadministeredin60percentofcases.Inanotherstudyof115immunocompetent
children,12developedparadoxicalworseningwithin15to75days(median39days)ofstartingTBtherapychildren
withparadoxicalreactionstendedtobeyounger(medianageatdiagnosisof26monthsversus66months)andhad
neverreceivedBCGvaccination[62].Themostcommonmanifestationwasworseningofpreexistingpulmonary
lesions,observedin75percent,while25percenthadnewdiseasepresentinnewanatomiclocations.
DrugresistantTBIngeneral,theapproachfortreatmentofdrugresistantTBinchildrenissimilartotheapproach
foradults.Childrenmaybetreatedwithaconventionalregimenor,iftheymeetappropriatecriteria,ashortened
regimen[63].However,theapproachtoselectionofantituberculousagentsforchildrenmaydifferfromthatofadultsin
somecircumstancesthisisdiscussedfurtherbelow,andpediatricdosingofsecondlineantituberculousdrugsis
summarizedintheTable(table7).IssuesrelatedtotreatmentofdrugresistantTBarediscussedindetailseparately.
(See"Diagnosis,treatment,andpreventionofdrugresistanttuberculosis",sectionon'Generalprinciples'.)
Ingeneral,useofsecondlineantituberculousagentsinchildreniscomplicatedbytheabsenceofpediatric
formulationsformostofthesedrugs,whichcanleadtounderoroverdosing.Childrenwithnonseverediseaseshould
notbetreatedwithinjectableagents,sincetheharmofthesedrugsclassoutweighsthepotentialbenefits.Inaddition,
althoughtherelativelynewagentsbedaquilineanddelamanidhavebeenapprovedforuseinadults,thereareno
safety,tolerability,efficacy,orpharmacokineticdataforchildren[21,56,64].
Individualizedtreatmentinchildrenhasbeenassociatedwithgenerallygoodoutcomes.Inaretrospectivestudyof149
childrenunder15yearsofage(medianage36months)withdocumentedorsuspecteddrugresistantTBinSouth
Africa,treatmentregimensincludedatleastfouractivedrugs,includedaninjectableagentin66percentofpatients,
andweregivenforamedianof13months[65].Cureorprobablecurewasachievedin92percent.Similaroutcomes
werereportedinaseriesof38childreninPeruwhoreceived18to24monthsofasupervisedindividualizedtreatment
regimen(fivetosevendrugs)basedonsusceptibilityresultsoftheirM.tuberculosisisolateorthesourcecase's
isolate(usuallyahouseholdcontact)[66].
DrugtoxicityiscommoninonemetaanalysisofchildrentreatedformultidrugresistantTB,itwasreportedin39
percentofcases[67].Similarly,intheseriesfromPeru,adverseeffectsoccurredin42percentofcases,althoughno
eventsrequiredsuspensionoftherapyfor>5days[66].ChildrenontreatmentfordrugresistantTBshouldbe
monitoredatleastmonthlyforadherence,responsetotreatment(eg,sputumanalysisforthosewithpulmonaryTB),
andpotentialadverseevents.
PREVENTIONMeasuresforpreventionoftuberculosis(TB)includeinfectioncontrolinterventionsandprompt
identificationandtreatmentoflatentTBinfection(LTBI).SuspicionofTBdiseaseinachildshouldbereportedtothe
healthdepartmentsothataninvestigationcanbestartedrightaway.(See"Latenttuberculosisinfectioninchildren"
and"Tuberculosistransmissionandcontrol".)
IssuesrelatedtotreatmentofLTBIfollowingcontactwithasourcecasearediscussedseparately.(See"Latent
tuberculosisinfectioninchildren".)
IncountrieswhereTBisendemic,routinechildhoodBacilleCalmetteGurin(BCG)immunizationisanimportant
preventivemeasure.IssuesrelatedtouseofBCGindevelopedcountriesarediscussedseparately.(See"BCG
vaccination",sectionon'Developedcountries'.)
SUMMARYANDRECOMMENDATIONS
Estimatingtheglobalburdenoftuberculosis(TB)diseaseinchildrenischallengingduetothelackofastandard
casedefinition,thedifficultyinestablishingadefinitivediagnosis,thefrequencyofextrapulmonarydiseasein
10/8/2016
youngchildren,andtherelativelylowpublichealthprioritygiventoTBinchildrenrelativetoadults.Asaresult,
thereislikelysignificantunderreportingofchildhoodTBfromhighprevalencecountries.(See'Epidemiology'
above.)
ChildrenundertheageoffiveyearsrepresentanimportantdemographicgroupforunderstandingTB
epidemiologyinthisgroup,TBfrequentlyprogressesrapidlyfromlatentinfectiontoTBdisease.Therefore,these
childrenserveassentinelcases,indicatingrecentand/orongoingtransmissioninthecommunity.(See
'Epidemiology'above.)
CommonsymptomsofpulmonaryTBinchildrenincludecough(chronic,withoutimprovementformorethanthree
weeks),fever(morethan38Cformorethantwoweeks),andweightlossorfailuretothrive.Physicalexam
findingsmaysuggestthepresenceofalowerrespiratoryinfection,buttherearenospecificfindingstoconfirm
thatpulmonaryTBisthecause.(See'Pulmonarytuberculosis'above.)
TheclinicalpresentationofextrapulmonaryTBdependsonthesiteofdisease.Themostcommonformsof
extrapulmonarydiseaseinchildrenareTBofthesuperficiallymphnodesandofthecentralnervoussystem.
InfantshavethehighestriskofprogressiontoTBdiseasewithdissemination(miliaryTB)andmeningeal
involvement.(See'Extrapulmonarytuberculosis'above.)
FormsofperinatalTBincludecongenitalandneonataldisease.CongenitalTBisveryrareandmostoftenis
associatedwithmaternaltuberculousendometritisormiliaryTB.NeonatalTBismorecommonanddevelops
followingexposureofaninfanttohisorhermother'saerosolizedrespiratorysecretions.(See'Perinatalinfection'
above.)
TBinchildrenisoftendiagnosedclinicallyinmanycases,laboratoryconfirmationisneverestablished
(particularlyamongchildrenunderfiveyearsofage).Diagnosisisoftenbasedonthepresenceoftheclassic
triad:(1)recentclosecontactwithaninfectiouscase,(2)apositivetuberculinskintest(TST)orinterferon
gammareleaseassay(IGRA),and(3)suggestivefindingsonchestradiographorphysicalexamination.(See
'Diagnosis'above.)
Inchildren,theTSTorIGRAmaybeusedasatoolfordiagnosisofTBdiseaseorlatentTBinfection(LTBI
although,inadults,theTSTorIGRAmaybeusedonlyfordiagnosisofLTBI,notTBdisease).TheTSTorIGRA
ishelpfulfordiagnosisofTBinchildrenonlyincircumstanceswhenitispositive(table3).(See'Tuberculinskin
test'above.)
ThemostcommonchestradiographfindinginachildwithTBdiseaseisaprimarycomplex,whichconsistsof
opacificationwithhilarorsubcarinallymphadenopathy,intheabsenceofnotableparenchymalinvolvement.(See
'Imaging'above.)
Gastricaspirationistheprimarymethodofobtainingmaterialforacidfastbacillismearandculturefromyoung
children,sincethesepatientslacksufficienttussiveforcetoproduceadequatesputumsamplesbyexpectoration
alone.Alternativeapproachesincludesputuminductionorexpectoration(forolderchildren).Fordiagnosisof
extrapulmonaryTB,specimensforcultureshouldbecollectedfromanysitewhereinfectionissuspected.
DiagnosisofTBshouldalsopromptHIVtesting.(See'Laboratorystudies'above.)
ThepediatrictreatmentregimensforTBareoutlinedintheTables(table5andtable6).BecauseTBinyoung
childrencanrapidlydisseminatewithserioussequelae,promptinitiationoftherapyiscritical.
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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Topic8007Version40.0
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GRAPHICS
The22highesttuberculosisburdencountries
Afghanistan
Bangladesh
Brazil
Cambodia
China
DemocraticRepublicoftheCongo
Ethiopia
India
Indonesia
Kenya
Mozambique
Myanmar
Nigeria
Pakistan
Philippines
RussianFederation
SouthAfrica
Tanzania
Thailand
Uganda
Vietnam
Zimbabwe
Datafrom:WorldHealthOrganization.GlobalTuberculosisReport2014.Availableat:
http://www.who.int/tb/country/en/index.html(AccessedonJuly9,2015).
Graphic68082Version6.0
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Countrieswithhighratesoftuberculosis
Afghanistan
DominicanRepublic
Lithuania
Rwanda
Algeria
Ecuador
Madagascar
SaoTomeandPrincipe
Angola
EquatorialGuinea
Malawi
Senegal
Azerbaijan
Eritrea
Malaysia
SierraLeone
Bangladesh
Ethiopia
Mali
SolomonIslands
Belarus
Fiji
MarshallIslands
Somalia
Benin
Gabon
Mauritania
SouthAfrica
Bhutan
Gambia
Micronesia(Federated
SouthSudan
Statesof)
Bolivia(Plurinational
Stateof)
Georgia
Mongolia
SriLanka
Botswana
Ghana
Morocco
Sudan
BruneiDarussalam
Greenland
Mozambique
Swaziland
BurkinaFaso
Guatemala
Myanmar
Tajikistan
Burundi
Guinea
Namibia
Thailand
Coted'Ivoire
GuineaBissau
Nepal
TimorLeste
CaboVerde
Guyana
Nicaragua
Togo
Cambodia
Haiti
Niger
Turkmenistan
Cameroon
Honduras
Nigeria
Tuvalu
CentralAfricanRepublic
India
NorthernMariana
Uganda
Islands
Chad
Indonesia
Pakistan
Ukraine
China
Kazakhstan
PapuaNewGuinea
UnitedRepublicof
Tanzania
China,HongKongSAR
Kenya
Peru
Uzbekistan
China,MacaoSAR
Kiribati
Philippines
Vanuatu
Congo
Kyrgyzstan
RepublicofKorea
Vietnam
DemocraticPeople's
RepublicofKorea
LaoPeople'sDemocratic
Republic
RepublicofMoldova
Zambia
DemocraticRepublicof
Lesotho
Romania
Zimbabwe
Liberia
RussianFederation
theCongo
Djibouti
Reproducedwithpermissionfrom:WorldHealthOrganization,GlobalTuberculosisControl:Estimatedburden
ofTBin2013.http://www.who.int/tb/country/data/download/en/Copyright2013WorldHealth
Organization.
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Definitionsofpositivetuberculinskintest(TST)resultsininfants,
children,andadolescents*
Induration5mmorgreater
Childreninclosecontactwithknownorsuspectedcontagiouspeoplewithtuberculosisdisease
Childrensuspectedtohavetuberculosisdisease:
Findingsonchestradiographconsistentwithactiveorprevioustuberculosisdisease
Clinicalevidenceoftuberculosisdisease
Childrenreceivingimmunosuppressivetherapy orwithimmunosuppressiveconditions,including
humanimmunodeficiency(HIV)infection
Childrenatincreasedriskofdisseminatedtuberculosisdisease:
Childrenyoungerthanfouryearsofage
Childrenwithothermedicalconditions,includingHodgkindisease,lymphoma,diabetesmellitus,
chronicrenalfailure,ormalnutrition
Childrenwithlikelihoodofincreasedexposuretotuberculosisdisease:
Childrenborninhighprevalenceregionsoftheworld
Childrenwhotraveltohighprevalenceregionsoftheworld
ChildrenfrequentlyexposedtoadultswhoareHIVinfected,homeless,usersofillicitdrugs,residents
ofnursinghomes,incarcerated,orinstitutionalized
Childrenagefouryearsorolderwithoutanyriskfactors
*ThesedefinitionsapplyregardlessofpreviousBacilleCalmetteGurinimmunizationerythemaaloneat
TSTsitedoesnotindicateapositivetestresult.Testsshouldbereadat48to72hoursafterplacement.
Evidencebyphysicalexaminationorlaboratoryassessmentthatwouldincludetuberculosisintheworking
differentialdiagnosis(eg,meningitis).
Includingimmunosuppressivedosesofcorticosteroidsortumornecrosisfactoralphaantagonists.
From:AmericanAcademyofPediatrics.Tuberculosis.In:RedBook:2012ReportoftheCommitteeon
InfectiousDiseases,29thed,PickeringLK(Ed),AmericanAcademyofPediatrics,ElkGroveVillage,IL2012.
UsedwiththepermissionoftheAmericanAcademyofPediatrics.Copyright2012.Thecontentsofthis
tableremainunchangedintheRedBook:2015ReportoftheCommitteeonInfectiousDiseases,30thed.
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Potentialcausesoffalsenegativetuberculintests
Technical(potentiallycorrectable)
Tuberculinmaterial:
Improperstorage(exposuretolightorheat)
Contamination,improperdilution,orchemicaldenaturation
Administration:
Injectionoftoolittletuberculinortoodeeply(shouldbeintradermal)
Administrationmorethan20minutesafterdrawingupintothesyringe
Reading:
Inexperiencedorbiasedreader
Errorinrecording
Biologic(notcorrectable)
Infections:
Activetuberculosis(especiallyifadvanced)
Otherbacterialinfection(typhoidfever,brucellosis,typhus,leprosy,pertussis)
HIVinfection(especiallyifCD4count<200)
Otherviralinfection(measles,mumps,varicella)
Fungalinfection(SouthAmericanblastomycosis)
Recentlivevirusvaccination(measles,mumps,polio)
Immunosuppressivedrugs(corticosteroids,tumornecrosisfactorinhibitors,andothers)
Metabolicdisease(chronicrenalfailure,severemalnutrition,stress[surgery,burns])
Diseasesoflymphoidorgans(lymphoma,chroniclymphocyticleukemia,sarcoidosis)
Age(infants<6months,olderadults)
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ClassicGhoncomplexinachildinfectedwith
Mycobacteriumtuberculosis
ThisradiographshowsaclassicGhoncomplexinachildinfectedwith
Mycobacteriumtuberculosisaboutsixmonthspreviously,basedon
resultsofacontactinvestigation.Thereisacalcifedparenchymal
lesionandcalcificationoftheregionalhilarlymphnode.Althougha
Ghoncomplexcontainsliveorganisms,thenumberissmall(asseen
ininfectionratherthandisease),somanagementwithisoniazidalone
asforlatentinfectionissufficient.
CourtesyofJeffreyRStarke,MD.
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Expansilepneumoniacausedbytuberculosis
Thistwoyearoldtoddler,infectedbyhismother,hasanexpansile
pneumoniacausedbytuberculosisand,perhaps,asecondary
infection.Thechildpresentedwithhighfever,cough,andweightloss.
Theclinicalsymptomsimprovedwithconventionalantibiotics,but
culturesofthegastricaspiratesgrewMycobacteriumtuberculosis.A
subsequentcomputedtomographyscanofthechestrevealed
extensiverightsidedhilaradenopathywithobstructionofthemain
bronchustotherightupperlobe.
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Extensivemiliarypulmonarylesionsin
disseminatedtuberculosis
Extensivemiliarypulmonarylesionsinayoungchildwith
disseminatedtuberculosis.Thechildpresentedinashocklikestate
withextremerespiratorydistress,weightloss,andfever.After
appropriatetreatment,thechildhadafullrecoveryandanormal
chestradiograph.
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Extensivepulmonarytuberculosisinapre
adolescentchild
Extensivepulmonarytuberculosisinapreadolescentchild.Thereis
advanceddiseaseintheleftlung,withdiseaseintherightlung
occurring,perhaps,vialymphaticspread.
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Progressiveprimarytuberculosisinatoddler
Progressiveprimarytuberculosisinatoddler.Thereisextensivehilar
adenopathywithsubsequentcollapseconsolidationintheleftlung
andamiliarylikepresentationintherightlung.
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Cavitarytuberculosisinanadolescentmale
Cavitarytuberculosisinanadolescentmale.Thereisinfiltrateanda
cavityalongthehorizontalfissureontheright.Notetheabsenceof
hilaradenopathy,whichistypicalofsocalledreactivationoradult
typetuberculosisinadolescents.
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Enlargedrightsidedhilarlymphnodeswithlocal
infiltrateandatelectasis
Enlargedrightsidedhilarlymphnodeswithlocalinfiltrateand
atelectasiscausedbytuberculosis.Thischildwasasymptomatic,this
lesionhavingbeendiscoveredduringacontactinvestigation
conductedafterthischild'sunclewassuspectedofhavingpulmonary
tuberculosis.
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Leftupperlobeinfiltrateandpossiblecavityin
pulmonarytuberculosis
Leftupperlobeinfiltrateandpossiblecavityinanadolescentwith
sputumsmearpositivepulmonarytuberculosis.Thispatienthadaone
monthhistoryofcough,eightpoundweightloss,andnightsweats.
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Partiallycalcifiedprimarytuberculouscomplexina
threeyearold
Thisisapartiallycalcifiedprimarytuberculouscomplexinathree
yearoldgirl.Thereisrightsidedhilaradenopathywithsome
atelectasisalongthehorizontalfissure.
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Culturepositivetuberculouspleuraleffusionina
nineyearoldpatient
Thisisaculturepositivetuberculouspleuraleffusioninanineyear
oldgirl.Thesourcecasewasaschooljanitor.Thechildcomplained
onlyofamildcoughandwasdiscoveredthroughacontact
investigationoftheschoolcase.
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Extensiveprimarytuberculosisinatoddler
Thisisextensiveprimarytuberculosisinatoddler.Thereisrightsided
hilaradenopathy,narrowingoftherightmainstembronchus,and
collapseconsolidationoftherightlowerlobe.
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Treatmentoftuberculosisinchildren
Regimen
(dailyorthreetimesweekly)*
Diagnosticcategory
Newcases
Intensivephase
Continuationphase
NewsmearpositivepulmonaryTB
INH
INH
NewsmearnegativepulmonaryTBwith
extensiveparenchymalinvolvement
RIF
RIF
PZA
(4months)
SevereformsofextrapulmonaryTB(not
includingmeningitisorosteoarticulardisease)
SevereconcomitantHIVdisease
TBmeningitis(seetext)
EMB
(2months)
INH
INH
RIF
RIF
PZA
(7to10months) [1]
SMorAMorEto
(2months)
OsteoarticularTB
INH
INH
RIF
RIF
PZA
(7to10months) [1]
EMB
(2months)
NewsmearnegativepulmonaryTB(otherthan
abovecategories)
LesssevereformsofextrapulmonaryTB
INH
INH
RIF
RIF
PZA
(4months)
(2months)
Previouslytreatedcases
SmearpositivepulmonaryTB
Relapse
Treatmentafterinterruption
Treatmentfailure
INH
INH
RIF
RIF
PZA
EMB
EMB
(5months)
SM
(2months)
Followedby
INH
RIF
PZA
EMB
(1month)
ChronicandMDRTB
Individualizedregimens
TB:tuberculosisINH:isoniazidRIF:rifampin(rifampicin)PZA:pyrazinamideEMB:ethambutolSM:
streptomycinAM:amikacinEto:ethionomideHIV:humanimmunodeficiencyvirusMDRTB:multidrug
resistantTB.
*Directobservationofdrugadministrationisrecommended.Intermittenttherapy(twoorthreetimes
weekly)isnotrecommendedforchildrenwithHIVinfection.
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Fortreatmentofmeningitis,EMBisreplacedbySMorAmorEto.Thedecisionaboutwhichdrugtouse
maybeguidedbydrugsusceptibilitydataoftheindexcaseifavailableorcountrylevelratesofspecificdrug
resistance.
EMBmaybeomittedduringtheinitialphaseoftreatmentforpatientsinthefollowingcategories:
Patientswithnoncavitary,smearnegativepulmonaryTBandknowntobeHIVnegative
Patientsknowntobeinfectedwithfullydrugsusceptiblebacilli
Reference:
1.RapidAdvice:Treatmentoftuberculosisinchildren.WorldHealthOrganization,Geneva,2010.
(WHO/HTM/TB/2010.13).
Reproducedwithpermissionfrom:WorldHealthOrganization,ChildhoodTBSubgroup.Guidancefornational
tuberculosisprogrammesonthemanagementoftuberculosisinchildren,Geneva.Availableat
http://whqlibdoc.who.int/hq/2006/WHO_HTM_TB_2006.371_eng.pdf.Copyright2006WorldHealth
Organization.
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Drugdosingforthetreatmentoftuberculosisinchildren
Drugs
Ethambutol
Daily
dose,
mg/kg
Dose
forms
Tablets:
20
Twicea
week
dose,
mg/kg
perdose
50
Maximum
dose
2.5g
Adverse
reactions
Opticneuritis
(usually
reversible),
100mg
400mg
decreasedred
greencolor
discrimination,
gastrointestinal
tractdisturbances,
hypersensitivity
Isoniazid*
Scored
10to15
20to30
tablets:
Daily,300mg
Twiceaweek,
100mg
900mg
300mg
Mildhepatic
enzymeelevation,
hepatitis,
peripheralneuritis,
hypersensitivity
Syrup:
10mg/mL
Pyrazinamide*
Scored
30to40
50
2g
Hepatotoxic
tablets:
effects,
500mg
hyperuricemia,
arthralgia,
gastrointestinal
tractupset
Rifampin*
Capsules:
10to20
150mg
10to20
600mg
Orange
discolorationof
300mg
secretionsor
urine,stainingof
Syrup
contactlenses,
formulated
vomiting,
capsules
hepatitis,
influenzalike
reaction,
thrombocytopenia,
pruritusoral
contraceptives
maybeineffective
*Rifamateisacapsulecontaining150mgofisoniazidand300mgofrifampin.Twocapsulesprovidethe
usualadult(>50kg)dailydosesofeachdrug.Rifater,intheUnitedStates,isacapsulecontaining50mgof
isoniazid,120mgofrifampin,and300mgofpyrazinamide.Isoniazidandrifampinalsoareavailablefor
parenteraladministration.
Whenisoniazidinadoseexceeding10mg/kgperdayisusedincombinationwithrifampin,theincidenceof
hepatotoxiceffectsmaybeincreased.
From:AmericanAcademyofPediatrics.Tuberculosis.In:RedBook:2012ReportoftheCommitteeon
InfectiousDiseases,29thed,PickeringLK,BakerCJ,KimberlinDW,LongSS(Eds),AmericanAcademyof
Pediatrics,ElkGroveVillage,IL2012.UsedwiththepermissionoftheAmericanAcademyofPediatrics.
Copyright2012.ThecontentsofthistableremainunchangedintheRedBook:2015Reportofthe
29/33
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CommitteeonInfectiousDiseases,30thed.
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Dosingofsecondlineantituberculosisdrugsinchildren
Drug
Levofloxacin*
Daily
pediatric
dose
Age5years:7.5
Maximum
dailydose
750mg*
to10mg/kgorally
Age<5years:15
to20mg/kgorally
intwodivided
7.5to10mg/kg
400mg*
orally*
Ofloxacin*
15to20mg/kg
Pregnancy
GItoxicity,sleep
Potentialchoice
disturbance,
whenthereareno
arthritis,CNS
suitable
headache,
peripheral
alternatives
neuropathy,QT
doses*
Moxifloxacin*
Mainadverse
affects
prolongation
(moxifloxacin>
levofloxacin)
800mg*
orallyintwo
divideddoses*
Capreomycin
15to30mg/kg
1g
IMorIV
Auditoryand
Avoid
vestibulartoxicity,
nephrotoxicity,
electrolyte
disturbances
Kanamycin
15to30mg/kg
IMorIV
1g
Ototoxicity,
nephrotoxicity
Avoid
Amikacin
15to22.5mg/kg
1g
Ototoxicity,
Avoid
IMorIV
Streptomycin
15to30mg/kg
nephrotoxicity
1g
IMorIV
Vestibularand
Avoid
ototoxicity,
neurotoxicity,
nephrotoxicity
Ethionamide
15to20mg/kg
orallyintwo
1g
divideddoses
GIandhepatic
toxicity,
Potentialchoice
whenthereareno
neurotoxicity,
suitable
hypothyroidism,
alternatives
opticneuritis,
metallictaste
Pyridoxine50to
100mgorallyper
daymaybeuseful
inpreventingor
reducing
neurotoxicity
Cycloserine
10to20mg/kg
orallyintwo
divideddoses
1g
Psychiatric
symptoms,
Potentialchoice
whenthereareno
headaches,
suitable
seizures
alternatives
Pyridoxine50mg
(orallyonceper
day)forevery250
mgofcycloserine
maybeusefulin
preventingor
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reducing
neurotoxicity
Paraaminosalicylic
150mg/kgorally
GItoxicity,
Potentialchoice
acid
intwoorthree
12g
malabsorption,
whenthereareno
divideddoses
hypersensitivity,
hepatitis,
suitable
alternatives
hypothyroidism
TB:tuburculosisIM:intramuscularIV:intravenousGI:gastrointestinalCNS:centralnervoussystem
max:maximum.
*AccordingtotheAmericanAcademyofPediatrics,althoughfluoroquinolonesaregenerallycontraindicated
inchildren<18yearsold,theirusemaybejustifiedincertaincircumstances,suchasmultidrugresistant
tuberculosis.Theoptimaldoseisnotknown.
Generallygivenfivetoseventimesperweek(15mg/kgoramaximumof1gperdose)foraninitialtwoto
fourmonthsandthen(ifneeded)twotothreetimesperweek(20to30mg/kgoramaximumof1.5gper
dose).Doseshouldbedecreasedifrenalfunctionisdiminished.
Forpatientswhoareoverweightorobese,doseisbasedonidealbodyweightordosingweight(see
UpToDatecalculator).Whenavailable,serumdrugmonitoringisadvisedtoestablishoptimaldosing.
Whenavailable,serumdrugmonitoringisadvisedtoestablishoptimaldosing.Recommendedpeak(twoto
fourhourspostdose)levelisnothigherthan30microg/mL.
Datafrom:
1.SeddonJ,etal.Caringforchildrenwithdrugresistanttuberculosis:practicebasedrecommendations.
AmJRespirCritCareMed2012186:953.
2.Guidelinesfortheprogrammaticmanagementofdrugresistanttuberculosis.Geneva,WorldHealth
Organization,2008.
Adaptedwithspecialpermissionfrom:TreatmentGuidelinesfromTheMedicalLetter,April2012Vol.10
(116):29.www.medicalletter.org.
32/33
10/8/2016
ContributorDisclosures
LisaVAdams,MDNothingtodisclose.JeffreyRStarke,MDOtherFinancialInterest:OtsukaPharmaceuticals
[Datasafetymonitoringboard(delamanid)].CFordhamvonReyn,MDNothingtodisclose.MorvenSEdwards,MD
Grant/Research/ClinicalTrialSupport:PfizerInc.[GroupBStreptococcus].ElinorLBaron,MD,DTMHNothingto
disclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressed
byvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthe
content.AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsof
evidence.
Conflictofinterestpolicy
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Tuberculosis Disease in Children

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