Tuberculosis in HIV-infected infants, children, and adolescents in Latin America

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

w w w . e l s e v i e r . c o m / l o c a t e / b j i d

Original

Article

Tuberculosis

in

HIV-infected

infants,

children,

and

adolescents

in

Latin

America

Margot

R.

Krauss

_,

_D.

_Robert

_Harris

_,

_Thalita

_Abreu

_,

_Fabiana

_G.

_Ferreira

_,

Noris

Pavia

Ruz

_,

_Carol

_Worrell

_,

_Rohan

_Hazra

_,

_for

_the

_NISDI

_Pediatric

_Study

_Group

b_{InstitutodePuericulturaePediatriaMartagãoGesteira,UniversidadeFederaldoRiodeJaneiro,RiodeJaneiro,RJ,Brazil} c_{UniversidadeFederaldeMinasGerais,BeloHorizonte,MG,Brazil}

d_{HospitalInfantildeMexicoFedericoGomez,MexicoCity,Mexico}

e_{EuniceKennedyShriverNationalInstituteofChildHealthandHumanDevelopment(NICHD),Bethesda,USA}

a

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o

Received11March2014 Accepted2August2014 Availableonline11October2014

Keywords: Tuberculosis HIV Children LatinAmerica

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Objective:Toevaluate theoccurrence,clinicalpresentationsanddiagnosticmethodsfor tuberculosisinacohortofHIV-infectedinfants,childrenandadolescentsfromLatin Amer-ica.

Methods:A retrospectiveanalysis ofchildrenwith tuberculosisandHIVwasperformed withinaprospectiveobservationalcohortstudyconductedatmultipleclinicalsitesinLatin America.

Results:Of1114HIV-infectedinfants,children,andadolescentsfollowedfrom2002to2011, 69thatcouldbeclassifiedashavingconfirmedorpresumedtuberculosiswereincludedin thiscaseseries;52.2%(95%CI:39.8–64.4%)hadlaboratory-confirmedtuberculosis,15.9% (95%CI:8.2–26.7%)hadclinicallyconfirmeddiseaseand31.9%(95%CI:21.2–44.2%)had pre-sumedtuberculosis.Sixty-sixwereperinatallyHIV-infected.Thirty-two(61.5%)childrenhad ahistoryofcontactwithanadulttuberculosiscase;howeverinformationonexposureto activetuberculosiswasmissingfor17participants.Atthetimeoftuberculosisdiagnosis,39 werereceivingantiretroviraltherapy.Sixteenofthesecasesmayhaverepresentedimmune reconstitutioninflammatorysyndrome.

Conclusions: Ourstudyemphasizestheneedforadequatecontacttracingofadult tuber-culosiscasesandscreeningforHIVortuberculosisinLatinAmericanchildrendiagnosed witheithercondition.Preventivestrategiesintuberculosis-exposed,HIV-infectedchildren shouldbeoptimized.

©2014ElsevierEditoraLtda.Allrightsreserved.

∗ _{Correspondingauthor.}

E-mailaddress:Margotkrauss@westat.com(M.R.Krauss).

1 _{ThemembersoftheNISDIPediatricStudyGrouparelistedintheAcknowledgementssection.}

http://dx.doi.org/10.1016/j.bjid.2014.08.007

Introduction

HIV/AIDSisresponsibleforexacerbatingthetuberculosis(TB) epidemicsinbothadultsandchildreninmanylowandmiddle incomecountries.1_{Unfortunately,diagnosingTBinchildren}

isachallengingtaskbecausesymptomsarenon-specificand sputumspecimensareusuallynotaccessible,making bacte-riologicconfirmationdifficult.

Diagnosisinchildrenoftenrequiresreliance onclinical, epidemiological, and radiographic criteria.1 _The

diagno-sis of TB is further complicated in HIV-infected children2

presentingwithadvancedimmune-suppressionwhen Pneu-mocystis jiroveci, disseminated bacterial, fungal and viral infections,or other mycobacterialagents mimicor coexist with TB disease, and treatment is started empirically for more than one etiological agent in severely ill patients.3

Interpretationoftuberculin skintestsisdifficult,withfalse negativeresultsoccurringinHIV-infectedchildrenwho are immunocompromisedandfalsepositiveresultsoccurringin Latin-Americanregionswithmoderatetohighendemicitylike Brazil,whereBCGisroutinelygivenatbirth.4,5

Many investigators have reported on pediatric HIV-TB co-infectioninAfrica,6–9_{butfewsuchstudieshavebeen}

con-ductedinLatinAmerica.10–12_{ThelargestLatinAmericanstudy}

reported29casesofTBinacohortof360HIV-infected chil-drenusingaretrospective,chartabstractionofhospitalization recordsbetween1989and1999.10_{Mostcasesinthisstudyhad}

pulmonarydisease;bacteriologicalconfirmationwasobtained inhalfofthecases,andnodataonantiretroviraltherapy(ART) werereported.

ThemainpurposeofourstudywastodescribecasesofTB occurringinHIV-infectedchildrenandyouthwhowere par-ticipatinginalarge,multicenterobservationalcohortstudy conductedinLatinAmerican countries. Ouraimsincluded describingHIV-TBco-infection,methodsusedtodiagnoseTB cases,clinicalpresentation,thetimingoftheTBdiagnosisin relationtotimingofinitiatingtreatmentforHIV, therapeu-ticresponsetoTBtreatment,andtheassociationbetweenTB clinicalpresentationandpatientimmunologicalstatus(when appropriatedatawereavailable).

Methods

TheEuniceKennedyShriverNationalInstituteofChildHealth andHumanDevelopment(NICHD)InternationalSite Devel-opmentInitiative(NISDI)Pediatricprotocolwasaprospective cohortstudythatenrolledandfollowedHIV-infectedchildren atmultipleclinicalsitesinLatinAmericabetween2002and 2011.Theprimarypurposeofthestudywastodescribethe demographic, clinical,immunological and virologic charac-teristicsofHIV-infectedchildrenand youthatparticipating clinical sites, as well as characterize outcomes related to HIVdisease,includingexposuretoARVtreatment.Adetailed description of this study has been published elsewhere.13

Briefly,HIV-infectedchildrenandyouth<21yearsofagewere enrolledatoutpatientclinicsand treatedwithART accord-ingtoeachcountry’sstandardprotocol.Historicallaboratory andclinicaldataweresystematicallycollectedatenrollment;

protocol evaluations, including medicaland treatment his-toryandclinicalandlaboratoryassessments,wereconducted every six months. The protocol was approved bythe eth-ical review boards at each clinical site, by the sponsoring institution(NICHD),thedatamanagementandstatistical cen-ter (Westat), and the Brazilian National Ethics Committee (CONEP).Informedconsentwasobtainedfromparentsand/or guardians.

Thiscaseserieswasobtainedfromaretrospectivemedical recordreviewofallTBcasesreportedamongHIVinfected sub-jectsparticipatingintheNISDIPediatricprotocol(2002–2007) andprospectivecaseascertainmentafter2007.Participating clinicalsitesinBrazil(elevensites),Argentina(twosites),Peru (twosites),andMexico(twosites)wereaskedto:(1)review the medicalrecords forall subjects witha clinical diagno-sisofTB,oranydiagnosis whereMycobacteriumtuberculosis

was cultured; and (2) complete a TBcase report formfor each case.Datacollected from availablemedicalrecordsat the timeofdiagnosisincludedthe basisfortheTB diagno-sis(laboratory,epidemiological,radiological,clinicalsignsand symptoms); the clinical presentationof TB;receipt of ART priortotheTBdiagnosis;receiptofanti-TBdrugtherapy;and CD4andviralloadnearest(withinsixmonthsbeforeandone monthafter) thetimeofTBdiagnosis.HAART wasdefined asatleastthreeanti-retroviralmedicationsfromatleasttwo classes.

Tobeincludedinthiscaseseries,eachsubjecthadtohave documentationofhavingbeenprescribedanti-TBtherapyand someevidenceofTBobtainedfromthemedicalrecordsatthe timeoftheTBdiagnosis.Caseswereclassifiedinoneofthree ways:laboratory-confirmed,clinicallyconfirmed,orpresumed TB.

ThediagnosisofTBwasconsideredlaboratory-confirmedif oneormoreofthefollowingconditionsweremet:

• IsolationofM.tuberculosisfromaclinicalspecimen. • DemonstrationofM. tuberculosis complexfrom a clinical

specimenbynucleicacidamplificationtest.

• Demonstration ofacid-fast bacilli ina clinical specimen whenaculturehadnotbeenorcouldnotbeobtained. • HistopathologyconsistentwithTB.

Intheabsenceofanylaboratoryevidence,TBwasclassified asclinicallyconfirmedifallofthefollowingconditionsweremet: • Apositivetuberculin skintest(≥5mminduration)forM.

tuberculosis.

• Clinical signs and symptoms (e.g., fever, cough, weight loss),radiologicevidence(e.g.,abnormalchestradiograph [CXR],abnormalchestcomputerizedtomography[CT]scan or ultrasound evidence of hepatomegaly, splenomegaly, and/orlymphadenopathy)compatiblewithTB.

• Treatmentwithtwoormoreanti-TBmedications.

If a case could not be classified as laboratory- or clin-ically confirmed, the case was considered presumed TB if thesubjectwastreatedwiththreeormoreanti-TB medica-tions andtherewasevidenceinatleasttwoofthreebroad categories(epidemiologic,radiologic,clinicalsignsor symp-toms).

Reported TB cases N=103 Medical records available at time of TB diagnosis n=79 (76.7%) No medical records N=24 (23.3%) Treated TB N=76 (96.2%) Radiologic evidence: N=21 (95.5%) Signs/symptoms: N=19 (86.3%) Epidemiologic evidence: N=14 (63.65%) Radiologic evidence: N=23 (63.9%) Signs/symptoms: N=33 (91.7%) Epidemiologic evidence: N=14 (38.9%) Radiologic evidence: N=10 (90.9%) Signs/symptoms: N=8 (72.7%) Epidemiologic evidence: N=4 (36.4%) TB confirmed Laboratory* N=36 (76.6%) Clinical* N=11 (23.4) N=47 (68.1%)

Lack sufficient evidence to classify as confirmed or presumed N=7 (9.2%) M. aviwn (n=1), no TB medication (n=2) N=3 (3.8%) TB presumed* N=47 (68.1%)

* All subjects in the final case series had more than one type of evidence for TB.

Fig.1–DifferentsourcesofevidenceforclassificationofreportedTBcases.

• ReportofclosecontactwithanactiveTBcasewas consid-eredepidemiologicevidence.

• Radiologicalevidenceincluded(1)CXRand/orCT demon-stratingcavitation,hilarlymphadenopathy,aninfiltrate,or findings consistentwithmiliaryTBand/or(2)ultrasound evidence of the following: hepatomegaly, splenomegaly and/orlymphadenopathy.

• Clinical signs/symptoms included a report ofsymptoms compatible with TB (cough, fever, weight loss, lym-phadenopathy,orliverand/orspleenenlargement).

Thosecaseswithinsufficientevidenceforclassificationas outlinedabovewerenotincludedinthefinalcaseseries.

A clinical response to treatment with anti-tuberculosis medicationwasdefinedasareturn tonormaltemperature afterreportedfeverand/orgaining10%ofbodyweightamong thosewhohadpreviouslylost10%oftheirbodyweightone monthpriortothediagnosisofTB.

Results

Ofthe1114HIV-infectedinfants,children,and adolescents enrolled in NISDI, 103 (9.2%) had some mention of TB in their casereport formsand 79 (76.7%) ofthesehad medi-calrecordsavailableatthetimeoftheTBdiagnosis(Fig.1).

Ofthese 79 cases,one wasexcluded fora positiveculture forMycobacteriumaviumandtwowereexcludedastherewas nodocumentationoftreatmentforTB.Oftheremaining76 subjects, sevenlacked sufficient evidence forclassification andwereexcluded,resultingin69TBcasestobedescribed, of which 36 (52.2%; 95% CI: 39.8–64.4) were classified as laboratory-confirmedTB,11(15.9%;95%CI:8.2–26.7)as clin-ically confirmed TB, and 22 (31.9%; 95% CI: 21.2–44.2) as presumedTB.Thus,87.3%(69/79)ofreportedTBcouldbe clas-sifiedbyourchartreview.

AsshowninTable1,amongthese69TBcases,49(71.0%) werefromBrazil,reflectingtheoveralldistributionof enroll-mentsinthecohort;66(95.7%)hadperinatallyacquiredHIV infection,andthemajority(84.1%)hadreceivedBCG vaccina-tion.Ofthe52subjectswithinformationavailableoncontact history,32(61.5%)hadahistoryofcontactwithanadultTB case,with94%ofthesereportingdailycontactwiththis per-son.ThemedianageatTBdiagnosiswas2.5years,ranging from birthto22 yearsofage. Nodeathsfrom TBoccurred amongthese69casesduringstudyfollow-up.

Clinicalfeatures/presentationanddiagnosticmethods Sixtycases(87.0%)hadsymptomsconsistentwithTBrecorded with the remaining nine (13%) subjects missing informa-tionregardingtheirsymptoms(Table1).Feverwasthemost

Table1–Demographicandclinicalfeaturesofthe69 tuberculosis(TB)cases. Variable n(%) Countryoforigin Argentina 3(4.3) Brazil 49(71.0) Mexico 7(10.1) Peru 10(14.5) Gender Male 37(53.6) Female 32(46.4)

ModeofHIVacquisition

Perinatal 66(95.7)

Horizontal 3(4.3)

HistoryofcontactwithadultTBcase

Yes 32(61.5) No 20(38.5) Missing 17 BCGvaccination Yes 58(84.1) Notconfirmed 11(15.9)

Ifyes,ageatBCGvaccination(months)

<12 51(94.4)

≥12 3(5.6)

Missing 4

Ifyes,monthssinceBCGatTBdiagnosis

<12 16(30.2)

12<24 8(15.1)

≥24 29(54.7)

Missing 5a

AgeatTBdiagnosis(years)

<1 20(29.0) 1–4 27(39.1) 5–14 19(27.5) >14 3(4.4) Median 2.5 Range Birthto22

RelationshipofTBdiagnosis(dx)toART

TBdxpriortoanyART 25(36.2)

TBdxwithin3daysofstartinganyART 3(4.3)

TBdxafterbeingonART>3days 39(56.5)

MissingARTdates 2(2.9)

Clinicalpresentation Pulmonary 33(47.8) Miliary 24(34.8) Lymphadenitis 9(13.0) Other 3(4.4) Clinicalfeatures

AnysymptomsconsistentwithTB 60(87.0)

Unknown/missing 9(13.0) Fever Yes 42(70.0) No 18(30.0) Cough Yes 39(65.0) No 21(35.0)

Weightlosswithin1month

Yes 22(36.7) No 38(63.3) Table1(Continued) Variable n(%) Lymphadenopathy Yes 7(11.7) No 53(88.3)

Hospitalizationfor≥28days

Yes 42(60.9)

Noorunknown 27(39.1)

a _{OnecaseofTBoccurredpriortoBCGadministration.}

frequent symptom recorded (70%), with most fevers

last-ing≥14days[24/42(57.1%)],followedbycough(65%),recent

(within1month)weightloss(36.7%),andlymphadenopathy

(11.7%).

PulmonaryTBwasthemostfrequentdiagnosis(47.8%),

fol-lowed bymiliary TB(34.8%),and TB lymphadenitis(13.0%)

(Table1).Table 2showsthe clinicalpresentationoftheTB casesandhow theywere diagnosedanddistributedbyage category.

Amongthe36laboratory-confirmedcases,18(50.0%)had a positive cultureand another 18 (50.0%)had at leastone specimenpositiveforacidfastbacilli(AFB)and/or histopath-ologysuggestiveofTB(onebyhistopathologyalone)(datanot shown).

Among 61 records reporting CXR and/or CT exams, 54 (88.5%) were abnormal; 18 (33.3%) ofthe 54 were read as miliary TB, 15 (27.8%) with local or diffuse infiltrates, 14 (25.9%)withhilar/lymphnodeenlargement,three(5.6%)with cavitation and four (7.4%) other. Eleven (84.6%) of the 13 abdominalultrasoundsperformeddemonstrated hepatomeg-aly,splenomegaly,and/orlymphadenopathy.

Tuberculinskintestswererecorded for37 (53.6%)ofthe 69TBcases,ofwhich16(43.2%)werepositive.Fiveoutof16 (31.3%)testsamongthe36bacteriologicallyconfirmedcases werepositive.

Clinicalresponsetotreatment

Among61caseswithavailableweightandfeverinformation, 72.5%(n=44)demonstratedapositiveresponseafterTB treat-ment;17(27.5%)chartsdocumentedbothanincreaseinbody weight of≥10% anddisappearance offever, and27 (44.9%) documented either anincrease of≥10% in body weightor

disappearanceoffever(datanotshown). TimingofTBandART

Thevastmajority(87.0%)ofTBcaseswerediagnosedprior toenrollmentintoNISDI;onlyninecasesofTB(13.0%)were diagnosedafterstudyenrollment.MostARTstartdatesalso occurredpriortostudyenrollment.Two(2.9%)casesdidnot haveART startdatesavailable,25(36.2%)casesofTBwere diagnosedpriortothestartofART,three(4.3%)hadthe diag-nosisofTBandARTinitiationoccurwithinthreedaysofeach other,and39(56.5%)caseswereonART[26wereon HAART-PI,threeonHAART-NNRTI,andtenondualtherapy]priorto TBdiagnosis(Table1).Elevenofthe39casesonARTpriorto TBdiagnosishadbeenonHAARTforlessthanthreemonths

Table2–Tuberculosis(TB)casesbyageattimeofTBdiagnosis,clinicalpresentation,andtypeofevidenceusedfor diagnosis.

AgeattimeofTBdiagnosis Clinicalpresentation Typeofevidenceusedfordiagnosis Total LaboratoryconfirmedTB ClinicallyconfirmedTB PresumedTB

0≤12mo Lymphadenitis 2 1 0 3 MiliaryTB 5 2 1 8 PulmonaryTB 6 1 1 8 CongenitalTB 1 0 0 1 1–4yr Lymphadenitis 3 0 0 3 MiliaryTB 3 2 6 11 PulmonaryTB 4 2 7 13 5–14yr Lymphadenitis 2 0 1 3 MiliaryTB 2 0 2 4 PulmonaryTB 7 2 2 11 RenalTB(6yr) 0 1 0 1 >14yr Lymphadenitis 0 0 0 0 MiliaryTB 0 0 1 1 PulmonaryTB 0 0 1 1 TBmeningitis(22yr) 1 0 0 1 Total 36 11 22 69

whenTBmanifesteditselfandanotherfivecaseswere diag-nosedbetweenthreeandsixmonthsfollowinginitiationof HIVtreatment(datanotshown).

Immunologicalmarkers

InthemajorityofcasesnoCD4countswereavailableatthe timeofTBdiagnosis.TwentyeightcaseshadCD4results avail-ablewithinsixmonthsbeforeoronemonthafterTBdiagnosis:

11 (39.3%) had CD4% <15%, 12 (42.9%) had CD4% between

15%and25%,andfive(17.9%)hadCD4%>25%.Therewasno

apparentassociationbetweenCD4percentagesandclinical

presentation(datanotshown).

Discussion

Ofthe1114HIV-infectedsubjectsenrolledintheNISDIstudy, 103(9.2%)hadsomementionofTBintheircasereportforms. Thiscrudeprevalenceissimilartothe7.4%(51/689)prevalence

reported amongKenyan childrenenrolled in a prospective

studyfromsixweeksto14yearsofage.14

Ofthe79availablemedicalrecords,69(87.3%)contained sufficientevidencetoclassifythesecasesasfollows:52.2% (95%CI:39.8–64.4)wereclassifiedaslaboratory-confirmedTB, 15.9%(95%CI:8.2–26.7)asclinicallyconfirmedTB,and31.9% (95%CI:21.2–44.2)aspresumedTB.Aspreviouslynoted,the diagnosisofTBinchildrenisachallengingtask,often requir-ing reliance on clinical, epidemiological, and radiographic criteria.

Among218 children with symptoms suggestive of pul-monarytuberculosis(cases)thatenrolledfromAugust,2002, toJanuary,2007attwohospitalsinLima,Peru,only22(10%) hadatleastonepositiveM.tuberculosisculture.15_Incontrast,

inourcaseseries,26%(18/69)ofcaseswerecultureconfirmed, perhapsdue,inpart,tothestrictcriteriautilizedtoclassify cases.

Thirty-nine(56.5%)subjects were receiving ARTatleast threeormoredayspriortoTBdiagnosis,withelevencases

receivingARTforlessthanthreemonthswhenTBwas diag-nosedandfivecasesdiagnosedbetweenthreeandsixmonths followinginitiation ofART. GiventhetimingART initiation inrelationshiptothetimingofTBdiagnosis,these16(23%) cases may represent immune reconstitution inflammatory syndrome(IRIS).ArecentsystematicliteraturereviewofTB IRISfoundonlythirteenpertinentstudies.16_Theyfoundthe

mediantimefromstartofARTtoTBIRISdiagnosis(reportedby eightstudies)rangedfromeightdaysto16weeks.Thisreview includedonlyonestudyfromLatinAmerica,thatreportedon twocasesofdisseminatedBCGinHIVinfectedchildrenless thanoneyearofage.17_{Thus,ourreportof16potentialTBIRIS}

casesfromLatinAmericaisthelargestweareawareof. Therearesomepotentiallimitationsofthisstudythatare worthnotingwheninterpretingtheresults.InLatin Ameri-cancountries,BCGimmunizationisrecommendedinthefirst monthoflifebecauseofitsprovenefficacyinavoidingsevere formsofthedisease.18_{Itishowevernotrecommendedin}

chil-drenwithsymptomaticHIVdiseasebecauseofitspotential tocauseseverelocalorevendisseminateddisease.19,20_Most,

ifnotall,childreninthiscohortwerenotknowntobe HIV-infectedatthetimetheyreceivedBCG,soitisnotpossibleto excludetheMycobacteriumbovisstrainasthecauseofoneor morecasesinthepresentcohort.

In this observational cohort, most cases of TB (87%) occurredpriortoenrollmentintoNISDI,andtherefore,were basedonchartreviewwhichmayhavemissedimportant clin-icalandepidemiologicaldetails.Patientswereenrolledat15 sitesinfourcountriesovernineyears,thusstandardofcarefor diagnosisandtreatmentofTBandHIVcouldhavevaried con-siderablyovertimeandacrosssites.Despitetheselimitations wecouldclassifythemajorityofcasesreported.

Arecent reportbyWHO21 _{showsthatthis regionofthe}

AmericasissecondtoAfricawithrespecttoprevalenceofHIV amongTBpatients;44%ofTBpatientsinAfricafoundtobe HIV-positivecomparedto17%intheregionoftheAmericas. Infact,thediagnosisofTBmayhaveledtotheHIVdiagnosis inourstudy,sinceoverone-thirdoftheTBcaseswerenoton ARTuntilmonthstoyearslater.Therefore,thereisanurgent

needtofind,preventandtreatTBinpeoplelivingwithHIV, andtoscreen forHIVandTBinchildrenupondiagnosisof eithercondition.

Ourfindingthatnearlyhalfofallcases(32)hadahistory ofcontactwithanadultTBcaseemphasestheneedformore aggressivecontacttracingamongadultTBcasesandprovision ofpreventivetherapyforexposedHIVinfectedchildren.

Research on optimizing preventive strategies in TB-exposed,HIV-infectedchildrenisneeded.

Funding

FundedbyEuniceKennedyShriverNationalInstituteofChild HealthandHumanDevelopment,Bethesda,Maryland,NICHD Contract#HHSN267200800001C(NICHDControl# N01-HD-8-0001).

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgements

Wethankthechildrenandfamilieswhoparticipatedinthe NISDIpediatricprojectandthesitestaffinvolvedinthe con-ductofthestudy.

Principalinvestigators,co-principalinvestigators,study coor-dinators,datamanagementcenterrepresentativesandNICHD staffinclude:Brazil:BeloHorizonte:JorgePinto,FláviaFaleiro (UniversidadeFederalde MinasGerais);Caxias do Sul:Rosa DeaSperhacke,Nicole Golin,SílviaMarianiCostamilan (Uni-versidadedeCaxiasdoSul/Servic¸oMunicipaldeInfectologia); NovaIguacu:JosePilotto,BeatrizGrinsztejn,ValdileaVeloso,Luis FelipeMoreira,IveteGomes(HospitalGeralNovadeIguacu–HIV FamilyCareClinic);PortoAlegre: RosaDeaSperhacke,Breno RiegelSantos,RitadeCassiaAlvesLira(UniversidadedeCaxias doSul/HospitalConceic¸ão);RosaDeaSperhacke,MarioFerreira Peixoto,ElizabeteTeles(UniversidadedeCaxiasdoSul/Hospital Fêmina);RosaDeaSperhacke,MarceloGoldani,CarmemLúcia OliveiradaSilva,MargeryBohrerZanetello(Universidadede CaxiasdoSul/HospitaldeClínicasdePortoAlegre);Regis Kre-itchmann,MarceloComerlatoScotta,DeboraFernandesCoelho (IrmandadedaSantaCasadeMisericordiadePortoAlegre); RibeirãoPreto:MarisaM.Mussi-Pinhata,MariaCéliaCervi, Már-cia L. Isaac, Fernanda Tomé Sturzbecher, Bento V. Moura Negrini(HospitaldasClínicas daFaculdadedeMedicinade RibeirãoPretodaUniversidadedeSãoPaulo);RiodeJaneiro: RicardoHugoS.Oliveira,MariaC.ChermontSapia(Instituto dePuericulturaePediatriaMartagãoGesteira);EsauCustodio Joao,MariaLeticiaCruz,AnaPaulaAntunes,JacquelineAnita deMenezes (Hospital dosServidoresdoEstado);São Paulo: ReginaCeliadeMenezesSucci,DaisyMariaMachado(Escola Paulista deMedicina -Universidade Federalde SãoPaulo); MarinellaDellaNegra,WladimirQueiroz,YuChingLian (Insti-tutodeInfectologiaEmilioRibas);Mexico:MexicoCity:Noris Pavía-Ruz,DulceMorales-Pérez,JorgeGamboa-Carde ˜na(Hospital Infantil deMéxico FedericoGómez); Peru:Lima:Jorge Alar-cónVillaverde(InstitutodeMedicinaTropical“DanielAlcides

Carrión”- SeccióndeEpidemiologia,UNMSM),María Castillo Díaz (Instituto Nacional de Salud del Ni ˜no), Mary Felissa Reyes Vega(Instituto de Medicina Tropical “Daniel Alcides Carrión”-SeccióndeEpidemiologia,UNMSM);Data Manage-mentandStatisticalCenter:YolandaBertucci,LauraFreimanis Hance,RenéGonin,D.RobertHarris,RoslynHennessey, Mar-got Krauss,James Korelitz, KathrynMiller, SharonSothern de Sanchez, SoniaK.Stoszek (Westat,Rockville,MD, USA);

NICHD:RohanHazra,LynneM.Mofenson,GeorgeK.Siberry (EuniceKennedyShriverNationalInstituteofChildHealthand HumanDevelopment,Bethesda,Maryland).

Thefindings andconclusionsinthisreportare thoseof theauthorsanddonotnecessarilyrepresenttheviewsofthe NationalInstitutesofHealthortheDepartmentofHealthand HumanServices.

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e

f

e

r

e

n

c

e

s

1.MaraisBJ,SchaafHS.Childhoodtuberculosis:anemerging andpreviouslyneglectedproblem.InfectDisClinNorthAm. 2010;24:727–49.

2.VerhagenLM,WarrisA,vanSoolingenD,etal.Human ImmunodeficiencyVirusandtuberculosisco-infectionin children.PediatrInfectDis.2010;29:e63–70.

3.JeenaPM,PillayP,PillayT,etal.ImpactofHIV-1co-infection onpresentationandhospital-relatedmortalityinchildren withcultureprovenpulmonarytuberculosisinDurban,South Africa.IntJTubercLungDis.2002;6:672–8.

4.WorldHealthOrganizationCountryprofiles2011,Brazil.

http://www.who.int/tb/publications/globalreport/2011/gtbr11 a2.pdf[accessed16.12.13].

5.FejaK,SaimanL.Tuberculosisinchildren.ClinChestMed. 2005;26:295–312.

6.ElengaN,KouakoussuiKA,BonardD,etal.Diagnosed tuberculosisduringthefollow-upofacohortofhuman immunodeficiencyvirus-infectedchildreninAbidjan,Cote d’IvoireANRS1278study.PediatrInfectDisJ.2005;24:1077–82.

7.HesselingAC,WestraAE,WerschkullH,etal.Outcomeof HIV-infectedchildrenwithcultureconfirmedtuberculosis. ArchDisChild.2005;90:1171–4.

8.BraitsteinP,NyandikoW,VreemanR,etal.Theclinical burdenoftuberculosisamonghumanimmunodeficiency virus-infectedchildreninWesternKenyaandtheimpactof combinationantiretroviraltreatment.PediatrInfectDisJ. 2009;28:626–32.

9.ChistiMJ,AhmedT,PietroniMA,etal.Pulmonarytuberculosis inseverely-malnourishedorHIV-infectedchildrenwith pneumonia:areview.JHealthPopulNutr.2013;31:308–13.

10.BertoliniDV,SatoHK,MarquesHHS.Tuberculoseemcrianc¸as comAids.JBrasAIDS.2002;3:17–22.

11.Ramirez-CardichME,KawaiV,OberhelmanRA,etal.Clinical correlatesoftuberculosisco-infectioninHIV-infected childrenhospitalizedinPeru.IntJInfectDis.2006;10:278–81.

12.VianiRM,LopezG,Chacon-CruzE,etal.Pooroutcomeis associatedwithdelayedtuberculosisdiagnosisin

HIV-infectedchildreninBajaCalifornia,Mexico.IntJTuberc LungDis.2008;12:411–6.

13.HazraR,StoszekSK,Freimanis-HanceL,etal.CohortProfile: NICHDInternationalSiteDevelopmentInitiative(NISDI):a prospective,observationalstudyofHIV-exposedand HIV-infectedchildrenatclinicalsitesinLatinAmericanand Caribbeancountries.IntJEpidemiol.2009;38:1207–14.

14.AbuogiLL,MwachariC,LeslieHH,etal.Impactofexpanded antiretroviraluseonincidenceandprevalenceoftuberculosis

inchildrenwithHIVinKenya.IntJTubercLungDis. 2013;17:1291–7.

15.OberhelmanRA,Soto-CastellaresG,GilmanRH,etal. Diagnosticapproachesforpaediatrictuberculosisbyuseof differentspecimentypes,culturemethods,andPCR:a prospectivecase–controlstudy.LancetInfectDis. 2010;10:612–20.

16.Link-GellesR,MoultrieH,SawryS,MurdochD,VanRieA. Tuberculosisimmunereconstitutioninflammatorysyndrome inchildreninitiatingantiretroviraltherapyforHIVinfection: asystematicliteraturereview.PediatrInfectDisJ.

2014;33:499–503.

17.FernandesRC,deAraújoLC,Medina-AcostaE.Reducedrate ofadversereactionstotheBCGvaccineinchildrenexposed

totheverticaltransmissionofHIVinfectionandin

HIV-infectedchildrenfromanendemicsettinginBrazil.EurJ Pediatr.2009;168:691–6.

18.WorldHealthOrganization.BCGVaccinePositionpaper.Wkly EpidemiolRec.2004;79:27–38.

19.HesselingAC,RabieH,MaraisBJ,etal.Bacille

Calmette-Guérinvaccine-induceddiseaseinHIV-infectedand HIV-uninfectedchildren.ClinInfectDis.2006;42:548–58.

20.WorldHealthOrganization.GlobalAdvisoryCommitteeon Vaccinesafety29–30November2006.WklyEpidemiolRec. 2007;82:18–23.

21.WorldHealthOrganizationReport2011.Globaltuberculosis control.http://www.who.int/tb/publications/globalreport/ 2011/gtbr11full.pdf[accessed16.12.13].