Tony T. Tahan , Betina M.A. Gabardo , Andrea M.O. Rossoni different perspectives childhood and in Tuberculosis adolescence: a viewfrom REVIEW ARTICLE

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www.jped.com.br

REVIEW ARTICLE

Tuberculosis in childhood and adolescence: a view from different perspectives ^夽,夽夽

Tony T. Tahan

^a^,^b

, Betina M.A. Gabardo

^a^,^b

, Andrea M.O. Rossoni

^a^,^b^,∗

aUniversidadeFederaldoParaná(UFPR),DepartamentodePediatria,Curitiba,PR,Brazil

bRedeBrasileiradePesquisasemTuberculose(REDETB),Brazil

Received19August2019;accepted4November2019 Availableonline18December2019

KEYWORDS Child;

Diagnosis;

Treatment;

Prevention

Abstract

Objective: Todescribetheepidemiologicalsituationoftuberculosisinchildrenunder19years ofageinBrazilandtoreviewthelatestpublicationsondiseaserisk,diagnosis,treatment,and prevention.

Sourceofdata: NotiﬁableDiseasesInformationSystem(2018),WorldHealthOrganizationesti- mates,andPubMedarticlesselectedusingthedescriptor‘‘Tuberculosis,’’delimitedbytypeof study,period,age,andlanguage.

Synthesisofdata: In2018,inBrazil,9.4%ofnotificationswereinchildrenunder19years.The pulmonaryformpredominatedin80.1%ofthecases.Thecureratewas76.8%,lethalitywas 0.8%,andabandonmentwas10.4%.Theprevalenceofdrug-resistanttuberculosis(2011---2016) was0.5%.Ithasbeenfoundthattheriskofdiseasecanreachupto56%inchildrenunder5 years,influencedbyhelminthco-infections,malaria,chronicviralinfections,liveattenuated virusvaccines,andhypovitaminosisD.Exposuretoabacilliferouspatientforperiodsshorter than30minutesissufficientforthedevelopmentofinfectionand/ordisease.InBrazil,micro- biologicalscreeningisrecommended,buttheuseofthescoringsystem,modifiedin2019,has beenmaintained.Studiesoninfectiondetectionhavesupportedtheuseofthetuberculinskin test.In thetreatment, thegreatadvancewas theintroductionofdispersible formulations, adjustmentoftherecommendeddoses,andshortenedregimensforlatentinfection.Several vaccinestudies(stages1---3)areongoing,butnoBCG-licensedsubstitutehasbeenimplemented yet.

Conclusions: Therehasbeenprogressintreatment,butmajorchallengesneedtobeovercome toimprovediagnosis,monitoring,andoutcomeofcases,aimingtoeliminatetuberculosis.

4.0/).

夽 Please citethis articleas: TahanTT, GabardoBM, RossoniAM. Tuberculosis in childhood and adolescence: a viewfrom different perspectives.JPediatr(RioJ).2020;96(S1):99---110.

夽夽Institutionorservicethestudyisassociatedwithforindexing:IndexMedicus/MEDLINE:DepartmentofPediatrics,UniversidadeFederal doParaná,BrazilianNetworkofTuberculosisResearch(REDETB---RedeBrasileiradePesquisasemTuberculose).

∗Correspondingauthor.

E-mail:dearossoni@gmail.com(A.M.Rossoni).

https://doi.org/10.1016/j.jped.2019.11.002

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100 TahanTTetal.

PALAVRAS-CHAVE Crianc¸a;

Diagnóstico;

Tratamento;

Prevenc¸ão

Resumo

Objetivo: Descrever a situação epidemiológica da tuberculosenos menores de 19 anosno Brasil erevisarasúltimaspublicaçõessobreriscode adoecimento,diagnóstico,tratamento eprevenção.

Fontedosdados: BancodenotificaçãoBrasil(2018),estimativasdaOrganizaçãoMundialda SaúdeeartigosdoPubMed selecionadospelodescritorTuberculosis,delimitaram-setipode estudo,período,idadeelíngua.

Síntesedosdados: Em2018,noBrasil,9,4%dasnotiﬁcac¸ões foramnosmenoresde19anos.

Predominouaformapulmonarem 80,1%dos casos.Ataxade curafoide76,8%, letalidade 0,8%eabandono10,4%.Aprevalênciadetuberculosedrogarresistente(2011a2016)foi0,5%.

Encontrou-sequeoriscodeadoecimentopodechegaraté56%,nosmenoresdecincoanos, influenciadoporcoinfecçõescomhelmintos,malária,infecçõesviraiscrônicas,vacinasdevírus vivosatenuadosehipovitaminoseD.Aexposiçãoaodoentebacilíferoporperíodosmenoresde 30minutosésuficienteparaodesenvolvimentodeinfecçãoe/oudoença.NoBrasil,recomenda- seapesquisamicrobiológica,porémmantem-se ousodoSistemadePontuação,modificado em2019. Estudossobredetecçãodainfecçãorespaldaramousodaprovatuberculínica.No tratamento, ogrande avanço foi aintrodução dasformulações dispersíveis,adequaçãodas dosespreconizadaseesquemas encurtadospara infecçãolatente.Váriosestudosdevacinas (fasesde1a3)estãoemandamento,masaindasemsubstitutolicenciadoparaaBCG.

Conclusões: Observaram-seprogressosnotratamento,porémaindahágrandesdesaﬁospara melhorarodiagnóstico,monitoramentoedesfechodoscasosembuscadaeliminac¸ãodatuber- culose.

0/).

Introduction

Fortheﬁrst timein history, in September 2018, tuberculosis(TB)wasacentraltopicatahigh-levelUnitedNations meeting,aimedatoutliningstrategiesfortheeliminationof TBby2030.Thismeetinghighlighted theneedtoimprove measures of prevention, diagnosis, and treatment of this disease,whichcontinuestohavehighmortalityratesworld- wide. At the age range of children and adolescents, the importanceofimprovingdiagnostictoolstoreducethenum- berofundiagnosedcases,theso-called‘missingcases,’was alsoreiterated, aswell astheneed for moreappropriate medications,especiallyforchildren.¹

The World Health Organization (WHO) estimated 1000,000newcasesoftuberculosisinchildrenunder14in 2017.Ofthese,55%wentundiagnosedand/orunreported.

Inchildrenunder5years,thispercentagewas69%,while in the others it was 40 %. When assessing the number of deaths, 80 % occurred in children under 5 years; in 96 % of these, children did not have access to anti-TB treatment.²

Aimingtoimprove theseindicators, the WHO haspub- lished the ‘‘Roadmap towards ending TB in children and adolescents.’’ItguidesthenarrowingofTBcontrolprogram actionswithinthechildhealthcarenetwork,includingpri- maryhealthcare,nutrition,HIV,andimmunization,among others.Theobjectiveistoemphasizenewprevention,diagnosis,andtreatmenttools,especiallydispersibledrugsfor children.² It also emphasizes the empowerment of and partnership with civil society, communities, and families affectedbyTBtogiverelevancetothediseaseandreduce itsstigma,whichisasoldasthehistoryofmankind.

Considering the abovementioned facts, this review described the epidemiological situation of TB in children under19years,aswellasthelatestpublicationsontherisk ofthedisease,diagnosis,andtreatmentofactiveandlatent disease.Thus,thisstudyaimedtoanalyzeTBinchildhood andadolescencefromdifferentperspectives.

Method

TodescribetheepidemiologicalsituationofTB inchildren under18yearsold,theBrazilianNotiﬁableDiseasesInforma- tionSystem database (2017---2018), unpublished data,and WHO²estimateswereused.

Asearch wascarriedoutinthePubMeddatabaseusing thedescriptor‘‘Tuberculosis’’andatotalof253,156articles were found. After reﬁningthe search tooriginal articles, clinical studies,or meta-analyses,publishedfromJanuary 01,2018toJune30,2019,inchildrenunder18yearsold, humanbeings,inEnglish,Spanish,orPortuguese,atotalof 104articlesremained.Aftertheevaluationofallabstracts, 26 articlesrelated totuberculosisin children andadoles- cents were selected. While reading these articles, other articles mentioned in these references and recommenda- tionsforTBcontrolbytheBrazilianMinistryofHealth(MoH) andtheWHOwereincluded.

ThisstudywasapprovedbytheHumanResearchEthics CommitteeofHospitaldeClínicasofUniversidadeFederal doParanáunderCAENo.17876919.8.0000.0096.

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Number of cases(%)

< 1 year 1 to 4 years

pulmonary extrapulmonary and mixed

5 to 9 years 10 to 14 years 15 to 19 years 335 (4.7)

90 (1.3) 413 (5.8)

177 (2.5) 364 (5.1) 173 (2.4)

710 (9.9) 269 (3.8)

709 (9.9) 3902 (54.6)

Fig. 1 Distribution of new cases of pulmonary, extrapulmonary,ormixedtuberculosisinthepediatricagegroup,Brazil, 2018.

Source:NotiﬁableDiseasesInformationSystem,HealthSurveil- lanceSecretariat,MinistryofHealth,Brazil.

TBepidemiologyinchildrenandadolescentsin Brazil

The WHO’s overall estimates show that Brazil failed to detect approximately12,000 TB cases in 2017. Of these, 8500(71%)werein childrenunder14years,namely3500 inchildrenunder4and5000inchildrenbetween5and14 years.³Onepossibilityforthisunder-detectionisthedifﬁ- cultyin TB diagnosis. These datashow theimportanceof prioritizingactionsforthisagegroup,expandingdecentral- ization,andtrainingprofessionalsfromprimaryhealthcare servicesinthediagnosisandtreatmentofthesecases.⁴

In2018,Brazilreported75,709newcasesofTB,including 1552(3.3%)inchildrenunder14years.Itisnoteworthythat theWHOestimatesthepercentageofcasesinthisagegroup wouldbe10%ofthetotalreportedcasesforthe30countries withhighburdenofthedisease,includingBrazil.³However, theseareglobalestimatesandtherearenonationalstudies onthesedata,whichdeservecautionintheirinterpretation.

The distribution ofnew casesnotiﬁed in Brazil (2018), accordingtotheagegroupandfederatedunits,isshownin Table1.

The pulmonary form predominated in those under 19 years, accounting for 80.1 % of cases. Fig. 1 shows the distribution, by type of TB, per age group. The distribu- tionofthelessfrequentextrapulmonaryformsvariedwith age.Inchildrenunder1year,themeningealandganglionic formsshowedsimilarnumberofcases,whileintheothers, therewasapredominanceoftheganglionicform,excluding adolescents,in whom the pleural formwas predominant.

The distribution of extra pulmonary and/or mixed cases (pulmonary associated withextra pulmonary) is shown in Table2.

Regardingtheclosureofcasesreportedin2017,children under1yearofagehadacurerateof65%,abandonment of7%,andlethalityof2%.Itisnoteworthythatthelethal- ityat thisage is doublewhencomparedtothe otherage groupsofchildhoodandadolescence,showingtheseverity ofthediseaseinthisgroup.Itisimportanttoobservethat abandonmentshoweditshighestrateinadolescents,which was12.7%,evenabovethatattheagerangeof20years;

thisreﬂectstheimportanceofthedirectlyobservedtreat- ment(DOT)inthispopulation.Otheroutcomesareshownin Table3.

TB exposure

Routine immunizations(↑ IgG) Infections that cause ↑Th2, T reg,and ↓Th1 Chronic infections: CMV, EBV, Hep B, C, andHIV Severe infections: malaria

Measles

Respiratory virus (influenza, adenovirus, others) Helminthiases

“Healthy” microbioma Older age

,

No infection TB infection

Th2 and T reg (lL4, IL13, TGF , IL10) (lFN

TB disease

H. pylori

β

Th2 and T reg (lL4, IL13, TGF , IL10)β

Th2 and T reg (lL4, IL13, TGF , IL10)β γTNFα)

Th1

(lFN Th1γ,TNFα)

Fig.2 Factorsthatinﬂuencetuberculosisimmuneresponse.

TB,tuberculosis;IgG,immunoglobulinG;Th,Thelperlympho- cyte;Treg,Tregulatorycells;IL,interleukin;IFN,interferon;

TNF,tumornecrosisfactor;CMV,cytomegalovirus;EBV,Epstein- Barrvirus;Hep,hepatitis.

AdaptedfromWhittakeretal.⁹

Thepreventionofactivetuberculosisthroughthetreat- ment of latent tuberculosis infection (LTBI) is one of the mainstrategies for reducingthe incidenceof tuberculosis andachievingthegoalsoftheEndTBStrategy.³

TheglobalburdenofLTBIisnotknownandisestimated atuptoaquarteroftheworld’spopulation;however,there iswidevariationbycountryandagegroup.^5,6InBrazil,its treatment is not subjectto compulsory notification in all federatedunits,butitisrecommendedtonotifyinaspecific national form.⁷ Recently, the LTBI Treatment Notification Systemwasimplemented inthe countrytomonitor, evaluate,andsurveilthesecases,whichwillprovideknowledge ofthemagnitudeofthisproblem.

The WHO estimates that in 2014, 25,000 children and adolescents up to 15 years of age became ill with drug- resistant TB (DRTB) and less than 10 % had access to treatment.Anothermatterofconcernisthatthereareno dataonDRTBstratiﬁedbyageinthepediatricandadoles- centagegroupsreportedtotheWHO,makingitdifﬁcultto knowtherealextentofthisdisease.²

BrazilhashadtheTuberculosisSpecialTreatmentInfor- mation System (Sistema de Informação de Tratamentos EspeciaisdaTuberculose[SITETB]) since2013.The assess- mentofnotifiedcasesinchildrenunder19years,from2011 to2016, reported 181 cases of DRTB, correspondingto a prevalence of 0.5% of all reportedTB casesin the same age group and period. It is noteworthy that the cases of DRTBaccountedfor67%ofSITETBnotificationsinchildren under19 years and,among thecases of resistance, most weremultiresistant(88%).⁸

Riskofillness

It is known that not every child with a latent infection will develop active TB. Children under 5 years or those withimmunodeﬁciency have an increased risk of disease progression, butthe understanding of risk factorsfor this occurrence is limited. Whittaker etal. described that an infectionbyanotherpathogen(viruses,bacteria,fungi,or parasites)is themost often involved processfor thispro- gression,by dysregulating the Th1, Th2, and T-regulatory immune responses (Fig. 2). Many of these diseases have geographic distributions overlapping TB, making it difﬁ-

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102 TahanTTetal.

Table1 DistributionofnewcasesoftuberculosisinBrazil,byagegroupandstate,2018.

FederatedUnit <1year(%) 1to4(%) 5to9(%) 10to14(%) 15to19(%) ≥20(%) Total(%)

North 55 (0.7) 88 (1.1 66 (0.8) 151 (1.8) 654 (7.8) 7325 (87.8) 8339 (11.0)

AC 0 (0.0) 3 (0.7) 2 (0.5) 5 (1.2) 35 (8.4) 373 (89.2) 418 (0.6)

AP 0 (0.0) 1 (0.5) 1 (0.5) 3 (1.4) 15 (6.8) 202 (91.0) 222 (0.3)

AM 17 (0.6) 46 (1.5) 35 (1.1) 71 (2.3) 251 (8.2) 2629 (86.2) 3049 (4.0)

PA 30 (0.8) 36 (0.9) 22 (0.6) 59 (1.5) 310 (8.0) 3409 (88.2) 3866 (5.1)

RO 3 (0.5) 0 (0.0) 5 (0.9) 6 (1.1) 27 (4.9) 509 (92.5) 550 (0.7)

RR 5 (2.1) 2 (0.9) 1 (0.4) 7 (3.0) 16 (6.8) 203 (86.8) 234 (0.3)

Northeast 140 (0.7) 127 (0.6) 125 (0.6) 257 (1.3) 1152 (5.8) 18,122 (91.0) 19,923 (26.3)

AL 9 (0.8) 7 (0.7) 8 (0.8) 15 (1.4) 71 (6.7) 952 (89.6) 1062 (1.4)

BA 37 (0.8) 16 (0.4) 24 (0.5) 49 (1.1) 263 (6.0) 4012 (91.2) 4401 (5.8)

CE 18 (0.5) 21 (0.6) 19 (0.5) 54 (1.5) 218 (6.1) 3267 (90.8) 3597 (4.8)

MA 19 (0.8) 8 (0.4) 7 (0.3) 37 (1.6) 145 (6.5) 2031 (90.4) 2247 (3.0)

PB 5 (0.4) 15 (1.3) 10 (0.8) 13 (1.1) 67 (5.6) 1081 (90.8) 1191 (1.6)

PE 37 (0.8) 37 (0.8) 43 (0.9) 65 (1.4) 261 (5.7) 4167 (90.4) 4610 (6.1)

PI 4 (0.6) 4 (0.6) 5 (0.7) 5 (0.7) 23 (3.2) 679 (94.3) 720 (1.0)

RN 9 (0.7) 15 (1.2) 7 (0.5) 13 (1.0) 51 (3.9) 1202 (92.7) 1297 (1.7)

SE 2 (0.3) 4 (0.5) 2 (0.3) 6 (0.8) 53 (6.6) 731 (91.6) 798 (1.1)

Midwest 20 (0.5) 49 (1.3) 36 (0.9) 53 (1.4) 148 (3.9) 3503 (92.0) 3809 (5.0)

DF 1 (0.3) 3 (0.8) 3 (0.8) 2 (0.5) 13 (3.5) 347 (94.0) 369 (0.5)

GO 5 (0.5) 3 (0.3) 3 (0.3) 13 (1.3) 40 (4.0) 941 (93.6) 1005 (1.3)

MT 5 (0.5) 22 (2.0) 17 (1.5) 11 (1.0) 38 (3.5) 1007 (91.5) 1100 (1.5)

MS 6 (0.5) 19 (1.7) 8 (0.7) 22 (1.9) 46 (4.1) 1029 (91.1) 1130 (1.5)

TO 3 (1.5) 2 (1.0) 5 (2.4) 5 (2.4) 11 (5.4) 179 (87.3) 205 (0.3)

Southeast 141 (0.4) 265 (0.8) 268 (0.8) 427 (1.2) 2121 (6.1) 31,600 (90.7) 34,823 (46.0)

ES 2 (0.2) 5 (0.4) 5 (0.4) 12 (1.0) 73 (5.9) 1143 (92.2) 1240 (1.6)

MG 27 (0.7) 27 (0.7) 30 (0.8) 42 (1.2) 154 (4.3) 3321 (92.2) 3601 (4.8)

RJ 51 (0.4) 73 (0.6) 91 (0.8) 157 (1.3) 855 (7.3) 10,515 (89.6) 11,742 (15.5)

SP 61 (0.3) 160 (0.9) 142 (0.8) 216 (1.2) 1040 (5.7) 16,621 (91.1) 18,240 (24.1)

South 68 (0.8) 60 (0.7) 41 (0.5) 89 (1.0) 534 (6.1) 7969 (91.0) 8761 (11.6)

PR 12 (0.5) 16 (0.7) 12 (0.5) 20 (0.9) 104 (4.5) 2142 (92.9) 2306 (3.0)

SC 14 (0.8) 17 (1.0) 10 (0.6) 16 (0.9) 112 (6.4) 1571 (90.3) 1740 (2.3)

RS 42 (0.9) 27 (0.6) 19 (0.4) 53 (1.1) 318 (6.7) 4256 (90.3) 4715 (6.2)

Unknown 1 (1.9) 1 (1.9) 1 (1.9) 2 (3.7) 1 (1.9) 48 (88.9) 54 (0.1)

Total 465 (0.6) 590 (0.8) 537 (0.7) 979 (1.3) 4611 (6.1) 68,567 (90.6) 75,709 (100) Source:NotiﬁableDiseasesInformationSystem(SINAN),HealthSurveillanceSecretariat,MinistryofHealth,Brazil.

Table2 Distributionofnewcasesofextrapulmonaryandmixedtuberculosisbyagegroup,Brazil,2018.

Types >1year(%) 1to4(%) 5to9(%) 10to14(%) 15to19(%) ≥20(%) Total(%) Pleural 16 (0.3) 19 (0.4) 42 (0.8) 103 (2.0) 386 (7.6) 4521 (88.9) 5087 (40.5) Ganglionary 22 (0.9) 84 (3.3) 94 (3.7) 100 (4.0) 153 (6.1) 2067 (82.0) 2520 (20.1)

Others 8 (0.5) 18 (1.2) 11 (0.8) 21 (1.4) 63 (4.3) 1343 (91.7) 1464 (11.7)

Miliary 14 (1.3) 13 (1.2) 5 (0.5) 10 (0.9) 42 (3.9) 1000 (92.3) 1084 (8.6)

Meningoencephalic 22 (3.0) 32 (4.4) 6 (0.8) 17 (2.3) 27 (3.7) 624 (85.7) 728 (5.8)

Ocular 1 (0.2) 0 (0.0) 2 (0.4) 4 (0.8) 13 (2.4) 513 (96.2) 533 (4.2)

Bone 3 (0.6) 6 (1.2) 6 (1.2) 10 (1.9) 12 (2.3) 477 (92.8) 514 (4.1)

Genitourinary 2 (0.8) 0 (0.0) 0 (0.0) 0 (0.0) 5 (2.0) 243 (97.2) 250 (2.0)

Skin 2 (0.9) 5 (2.2) 6 (2.6) 4 (1.8) 7 (3.1) 204 (89.5) 228 (1.8)

Laryngeal 0 (0.0) 0 (0.0) 1 (0.7) 0 (0.0) 1 (0.7) 137 (98.6) 139 (1.1)

Ignored 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) 1 (0.0)

Total 90 (0.7) 177 (1.4) 173 (1.4) 269 (2.1) 709 (5.7) 11,130 (88.7) 12,548 (100) Source:NotiﬁableDiseasesInformationSystem(SINAN),HealthSurveillanceSecretariat,MinistryofHealth,Brazil.

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Table3 Treatmentoutcomeofnewcasesoftuberculosisbyagegroup,Brazil,2017.

Agerange Cure n(%)

Death fromTB n(%)

Deathfrom othercausen (%)

Transferred n(%)

Abandonment n(%)

Ignored n(%)

Total n(%)

<1yr 233 (65.4) 8 (2.2) 16 (4.5) 37 (10.4) 25 (7.0) 37 (10.4) 356 (0.5)

1to4 421 (79.0) 6 (1.1) 7 (1.3) 34 (6.4) 28 (5.3) 37 (6.9) 533 (0.7)

5to9 348 (77.9) 4 (0.9) 5 (1.1) 36 (8.1) 25 (5.6) 29 (6.5) 447 (0.6)

10to14 717 (79.6) 5 (0.6) 8 (0.9) 64 (7.1) 50 (5.5) 57 (6.3) 901 (1.2)

15to19 3476 (76.7) 33 (0.7) 37 (0.8) 196 (4.3) 576 (12.7) 212 (4.7) 4530 (6.3)

≤19 5,195 (76.8) 56 (0.8) 73 (1.1) 367 (5.4) 704 (10.4) 372 (5.5) 6767 (9.4)

≥20 46,361 (70.7) 2545 (3.9) 2997 (4.6) 3376 (5.2) 6867 (10.5) 3406 (5.2) 65,552 (90.6) Total 51,556 (71.3) 2601 (3.6) 3070 (4.2) 3743 (5.2) 7571 (10.5) 3778 (5.2) 72319 (100) Source:NotiﬁableDiseasesInformationSystem(SINAN),HealthSurveillanceSecretariat,MinistryofHealth,Brazil.

cult toestablisha causalcorrelation.Vaccines, especially thoseusingliveattenuatedviruses,cancollaborateinredu- cing the risk of disease by stimulating the production of immunoglobulinsandinterferongamma.⁹

The time of disease evolution is described as 5%---10%

throughoutlife,with50%ofcasesconcentratedintheﬁrst twotoﬁveyearsafter theinfection, withmoreincidents inchildrenunder5years.¹⁰Traueretal.proposedthatthe riskofactiveTBafterinfectionishigherthanthetradition- allyacceptedestimates,especiallyamongchildrenunder5 years,andmaybeashighas56%insomeprojections.¹¹

Studies that assessed the disease risk among contacts fromcountrieswithdifferentincomesshowedvaryingrates ofactiveTB.Inlow/middle-incomecountries,thepercent- agewas3.1%,whileinhigh-incomecountriesitwas1.4%.

However,in both situations, the percentages were higher (10.0%and4.7%,respectively)inchildrenunder5years.¹² Another issue questioned in relation to the disease is relatedtothe risk ofinfection. Howlong wouldthe time ofcontacthavetobeforanindividualtobecomeinfected?

Normallytheguidelinesdonothavethisanswer.Eachcase shouldbeanalyzedbyobservingthesourcecase’sbacillary loadand the environment:ventilation, size of the space, proximity of the case, and duration of contact. This last itemisthemost difficulttoestablish,becauseit depends directly on the previous ones. The Australian guideline (2015)assignedeighthoursastheminimumtimeforanindi- vidual to become infected, and a shorter time should be considered when moresusceptiblepeople areinvolved or whentherearehigh-exposureprocedures(coughinduction orintubation).¹³TheWHO’s2013recommendationsconsider theperiodofriskduringflightsinthoselastingmorethan eight hours.¹⁴ However, in 2017, Luzzati et al. described theinvestigation ofan outbreakinTrieste, Italy,withthe identification ofsecondary casesinchildren, inwhich the contactwiththesourcecasewasoccasional,withinaperiod oflessthan30min.¹⁵Thisleadsustoquestiontheneedfor long-lastingcontactsfortheindividualtobecomeinfected.

Anothertopicof studyis thecorrelationbetween vita- minDdeficiencyandTB.^16,17Suchanassociationhasalready been established, but studies are required to determine whether the deficiency would be the cause or the con- sequence, as well as whether vitamin D supplementation wouldinfluence disease progressionavoidanceor improve patientresponsetotreatment.

DiagnosisofpulmonaryTB

TB is classiﬁed as pulmonary, extrapulmonary, and/or mixed,⁷sothediagnostictoolsvaryaccordingtoitslocation.

PulmonaryTBisthemostprevalentformand,therefore,will bethefocusofthisreview.

The pathophysiology and clinical presentation of TB differaccordingtoage.TheWHOclassifiesaschildrenindi- vidualsagedupto14years,whileinBrazil,basedonthese differences,considersupto10years.Thisagecutoffdefines theresearchflowsandtherapeuticconducts.Childrenhave a nonspecific clinical picture similar to usual childhood infectionsandarepaucibacillary.Asforadolescents(older than10years),theydevelopdiseasesimilartothatinadults, andcanhavebacilliferouspictures.Therefore,accordingto theMoHguideline,thediagnosisofpulmonaryTBinBrazil variesaccordingtoage.⁷

In children under 10 years of age, due to paucibacil- laryformandsputumcollectiondifﬁculties,thediagnosisis basedonascoringsystem,whichevaluatestheclinicaland epidemiologicalhistory,tuberculinskintest(TST)response, chestX-ray,andthe patient’snutritional status(Table4).

Thisscoreisdynamicandevaluatesthecaseevolution,with differentscoresaccordingtotimeofevolutionandresponse totherapies for usual infections; it has been adopted in Brazilsince2002.Itisthebest-studied,most-validatedreg- imen,withconsistentsensitivities andspeciﬁcities among thevariousexistingsystemsintheworld.¹⁸However,asthe TSTscores change,furtherstudiesshouldbedevelopedto assessitscurrentsensitivityandspeciﬁcity.

Thoseover10yearsold,withsimilarradiologicalclinical picturestoadults,havetheirdiagnosisestablishedbymicro- biologicaltests.However,intheabsenceofbacteriological conﬁrmation,the recommendationofthe MoHis thatthe diagnosisshouldbebasedonthescoringsystem.

The WHO advises, wheneverpossible, to seekbacteri- ological conﬁrmation through smear microscopy, culture, or rapid molecular test and does not recommend the

‘‘therapeutic test,’’ which consists of trying to estab- lishthe diagnosis of TB by performingthe treatment and awaiting clinical improvement.¹⁹ Forthe MoH, the use of the score provides early diagnosis and therapeutic inter- vention, even in basic health units, without the need formore sophisticatedcomplementaryexamsand/or spe- cializedprofessionals.⁷Bacteriologicalconﬁrmationshould

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104TahanTTetal.

Table4 Diagnosisofpulmonarytuberculosisinchildrenandadolescentswithnegativesmearorundetectedrapidmoleculartestfortuberculosis(RMT-TB).

Clinical-radiologicalpicture Contactwithadultwith

Tuberculosis

Tuberculinskintest(TST) Nutritionalstatus Feverorsymptomssuchas

cough,adynamia,

expectoration,weightloss, sweatingfortwoweeksor more

15points

Hilarormiliarypattern adenomegalyand/or condensationorinﬁltrate (withorwithout

excavation)unalteredfor twoweeksormoreand/or condensationorinﬁltrate (withorwithout

excavation)fortwoweeks ormore,progressingto worseningorno improvementwith antibioticsforcommon microorganisms 15points

Close,inthelasttwoyears 10points

TT≥10mm 10points

Severemalnutrition(weight below10^thpercentile) 5points

TTbetween5---9mm 5points

Asymptomaticorwith symptomsforlessthantwo weeks

0points

Respiratoryinfection improvedafterantibiotic useforcommon

microorganismsorwithout antibiotics

−10points

Condensationorinﬁltrateof anykindforlessthantwo weeks

5points

Occasionalornegative 0points

TT<5mm 0points

Weightequaltoorgreater thanthe10^thpercentile 0points

PlainX-ray

−5points Interpretation:

≥40points(verylikelydiagnosis):itisrecommendedtostarttreatment.

30to35points(possiblediagnosis):indicativeoftuberculosis;itisadvisedtostarttreatmentatthecliniciansdiscretion.

<25points(unlikelydiagnosis):Investigationshouldcontinue.Differentialdiagnosisshouldbemadewithotherlungdiseasesandcomplementarydiagnosticmethodscanbeemployed, suchassputumsmearsandcultureofinducedsputum,orgastriclavage,bronchoscopy,puncturehistopathology,andotherrapidtests.⁷

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always be attempted, although this should not delay the startofthetreatment.

Despitetherelevanceofthetopic,littlehasbeenpub- lished in thelastyear regarding thisspeciﬁc point.Other clinical collectionoptions, suchasinducedsputum, string test,ororal swab,arebeingevaluated,buttherearestill manychallengesandcontroversies,asrecentlydiscussedby Rauteretal.²⁰

The technique of induced sputum collection consists of performing hypertonic inhalation of an airway irritant priorto thecollectionof thematerial. Inindividuals who can spontaneously expectorate, sputum is collected, but in children the material is collected by nasal aspiration.

Theaccuracy ofthesesamplesissimilartothatofgastric lavage,²⁰butithasthedisadvantageofgeneratingaerosols and, therefore, a biosecure site suitable for collectionis needed.

The efﬁcacy of the string test or Corda Dulce has yet tobeestablished. Inthis methodology,the childrenswal- low acapsule containinga ‘‘string’’that remains for one hour in the stomach and it is then removed. This string adsorbsmycobacteriaandissenttothelaboratoryforrou- tineexaminations suchassmear microscopy,culture, and rapidmoleculartesting.Thistechniquehassomeadvantages becauseitdoesnotrequirehospitalizationorbiosecurecon- ditions forcollection. Itsdrawbackisthatnotallchildren canswallowthecapsules.However,furtherstudiesneedto beperformedtodemonstratethetolerabilityandaccuracy ofthemethod.²¹Theoralswabhasbeenstudiedasapromis- ingalternative,butthestudieshaveonlybeencarriedout inadults.^22---24

Microbiologically, the rapid molecular test has not yet been able tosurpass theculture for the diagnosis of pulmonary tuberculosis in childhood, but due to the rapid culture result, when available, it should always be per- formed. This technique has now been modiﬁed with the productionofthenewGeneXpertULTRAcartridge(Xpert^®, CA, USA), which has been shown to be more sensitive, improving diagnosis, especially in populations with HIV, children under 10 years, and cases of extrapulmonary tuberculosis.²⁵

The TSThas severallimitations,suchasadministration technique,reader-dependentresult,needfortwovisitsto performthetest,differentreferencevaluesintheliterature toconsiderthetestpositive,possibilityofinterferencewith othermycobacteria,especiallytheM.bovisvaccinalstrain and,inrecentyears,thelackofsupplies,PPD-RT23(Puriﬁed ProteinDerivatite,RT:ResetTuberculin,23.StatensSerum, Copenhagen,Denmark).Therefore,moresensitiveandspe- ciﬁc tests are under study. Currently, interferon-gamma releaseassays(IGRA)arethemostpromising,butwithlim- itationsofuseinchildrenfrom2to5yearsoldduetothe lowrateofagreementwithTSTandhighratesofindetermi- natecases.Moreover,theyhaveahighcost,requirebetter laboratory infrastructure,andhave showed nosuperiority inanystudywhencomparedwithTST.Velasco-Arnaizetal.

comparedthetestsinchildren under5yearsoldandcon- cludedthatthereisnoneedtoperformbothinunvaccinated populations, due to the high agreement between them.

Among vaccinated children, the disagreement was higher (␬=0.190),anditwasnotpossibletoestablishwhetherthe caseswereinfectedwithothermycobacteriaorbyM.tuber-

culosis.Thus,inthepresenceofdisagreement,theauthors suggestconsideringthechildasbeinginfected.Inthatstudy, there was no difference in the results between infected patientsandthosewiththedisease,norwastheregreater sensitivityofIGRAinrelationtoTSTinpatients.²⁶

In 2018, Aggerbeck et al. published a phase-3 study with a new C-Tb tuberculin test (Statens Serum Institut---Copenhagen,Denmark).It is askin test proposed forLTBIdiagnosis,aimedatovercomingsomedifﬁcultiesof theusualTSTwithPPD-RT23andIGRAs.Itisadministered andreadinthesamewayastheTST,butconsistsofthemore speciﬁcantigens,ESAT-6andCFP-10,thesameasofIGRAs.

Thepositivitycutoffisuniversal,with5-mmskininduration.

Theresultsshowedasafetestwithpositivityrates similar tothatofTSTandIGRA(83%agreement),eveninchildren under5yearsandinHIV-positivepatients.However,inHIV- positiveindividuals withCD4<100 cells/␮L,the positivity ratesweredecreasedinallthreetests.²⁷

Evidenceof inﬂammatory activity is classically investi- gatedinassociationwithTB.Velasco-Arnaizetal.evaluated theassociationofprocalcitoninandC-reactiveproteinwith TBinchildrenunder6yearsofageanddescribedthenor- mality of this marker in cases of pulmonary TB, and an increase in both procalcitonin and C-reactive protein in pneumococcalpneumonia. Thus,it is suggested thatchil- drenwithTBcontactswhohaveincreasedprocalcitoninand C-reactiveproteinlevelsshouldbeevaluatedfor thepos- sibility of treatment for bacterial pneumonia and further re-evaluationforTBintwotothreeweeks.²⁸

Treatmentofactivedisease

The recommended TB treatment regimens in Brazil, as well as the diagnosis, follow the same age cutoffs. The latest guideline showed a change in the dose ranges for children, according to the WHO recommendations, so that the indicated serum concentrations of these drugs could be reached. Rifampicin should be prescribed at a dose of 15mg/kg (10---20mg/kg) and isoniazid 10mg/kg (7---15mg/kg),whilepyrazinamidewasmaintainedatadose of35mg/kg(30---40mg/kg).⁷

The recommended treatment time is two months for pyrazinamideandsixmonthsfor theother drugs.⁷Specif- ically, in relation to the meningeal form, it is extended to12months,followingastandardizedWHOregimen.The importanceof isoniazid and pyrazinamide is emphasized, duetotheirexcellentpenetrationandhighconcentration, withpotentCSFbactericidalactivity,whereasrifampicinhas lowerpenetrationandconcentrationinthissite.²⁹Asforthe formswithboneinvolvement,therecommendedtreatment timeissixto12months,atclinicaldiscretion.⁷

AreviewbyDonaldetal.showedthattheuseofetham- butolatadoseof20mg/kg(15---25mg/kg)issafeinchildren andcanbeusedinthepediatricagerange.Inthisreview, with3811children,opticneuritiswasattributedtoetham- butolinonly0.05%ofchildrenusingthisdrugatadoseof 15---30mg/kg/day.³⁰ InBrazil,itsuse is stillrecommended onlyin childrenover 10 yearsold,butwhen necessary,it canbesafelyusedinyoungerchildren.⁷

Another important advancementfor children has been thedevelopmentofthecombinedﬁxeddosesince2015,in

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106 TahanTTetal.

Table 5 Therapeutic regimen for tuberculosis, with friendlyformulations,accordingtodifferentweightranges.

Weightrange Intensivephase(RHZ 75/50/150)

Maintenancephase (RH75/50)

4−7kg 1 1

8-11kg 2 2

12-15kg 3 3

16-24kg 4 4

≥25kg Doserecommended foradults

Doserecommended foradults

R,rifampicin;H,isoniazid;Z,pyrazinamide.

AdaptedfromtheWorldHealthOrganization.³¹

theformofdispersibletablets:child-friendly,fruit-ﬂavored formulations,whichmakesthetreatmentmuchmorepalat- ableandpleasant forchildren, in linewiththe newWHO recommendations.Eachtabletcontains75mgofrifampicin, 50mgofisoniazid,and150mgofpyrazinamidefortheinten- sivephase;tabletswith75mgrifampicinand50mgisoniazid areusedfor thetreatment maintenancephase (Table5).

Dispersible tablets with isolated doses of pyrazinamide, ethambutol,isoniazid, and other drugs used for TB³¹ are underpreparation.

ItisnoteworthythatBrazilisinthephaseofacquisitionof pediatricdispersibleformulations,showingitscommitment toprioritizingTBcontrolinthisagegroup.

Childrenarestillgrowingand developing,and because of this, the drugs have a wide pharmacokinetic variabil- ity and may have serum concentrations that are below thetherapeutic level. Astudy carriedout in Africafound that rifampicin and pyrazinamide, at the new doses recommended by the WHO, do not reach adequate serum concentrations in children under 12kg. Notably, serum rifampicinlevelsinchildren,regardlessoftheweight,were lower than those in adults. New studies are underway to evaluate the bioavailability of drugs in different geo- graphicregions,takingintoaccountpossiblegeneticfactors, weight,age,andformulationused.³²

AstudycarriedoutinIndiaevaluatedtheserumconcen- trationsreached byisoniazid(10mg/kg) andpyrazinamide (35mg/kg)andcomparedtheminchildrenunderandover 3 years of age, as well as with nutritional status. The concentrationofpyrazinamidewaslowerinchildrenunder threeyearsoldandin childrenwithlow bodymass index, whileisoniazidshowednosigniﬁcantdifferenceswhenthese variableswereevaluated.³³

InBrazil,theregimensusedandmadeavailableforthe treatment of DRTB inchildren are the sameas in adults, extendingfrom18to24months.⁷TheWHOrecommendsthe possibilityofashortenedregimen,fromnineto12months, butwithlittleevidenceinthepediatricpopulation.³⁴

Kumaretal.evaluatedthepharmacokineticsofsecond- linemedicationsusedtotreatMDR-TB(multidrug-resistant tuberculosis) in Indian children and adolescents, with a median age of 16 years, and showed that levoﬂoxacin reachedhigher serumconcentrationsin females,³⁵ similar to a study by Denti et al. with South African children.³⁶ Thelatterstudyusedmaceratedlevoﬂoxacintabletsinchil- drenandshowedlowerserumconcentrationsthaninadults,

despite equivalent doses,suggesting theneed for further studiestoevaluatetheeffectsofdifferentformulationsand presentations.³⁶

Kumar et al. alsoshowed that ethionamide had lower serumconcentrations in children under12 yearsand that theserumconcentrationsofpyrazinamideweredecreased inchildrenandadolescentswithlowweight.³⁵

Thesedifferencesindrugpharmacokineticsaccordingto gender,age,andweightshouldbeconsideredwhenfacing unfavorableoutcomes,evenwhenusingappropriatedoses andwithgoodtreatmentadherence.

New drugs are being tested and released for use in pediatrics,suchasbedaquilineanddelamanidinlong-term regimens. Bedaquiline can be usedin patients aged 6---17 yearsanddelamanidinpatientsfrom3yearsofage.³⁴Pre- tomanid, a new drug recently approved by the FDA, still requiresstudiesbeforebeingusedinchildren.³⁷

Follow-upoftreatmentinchildrenandadolescents

Childrenandadolescentsshouldbemonitoredasdescribed inTable6.

Children,usuallypaucibacillaryandwithoutbacteriolog- icalconﬁrmation,willnotundergocontrolsmearandshould be followed periodically (at least once a month) according to their clinical and radiological evolution. Follow-up atreferraloutpatientclinicswithspecialistpediatriciansis recommended in cases of greater complexity,considering that bettertreatment outcomes,such asreducedmortal- ity,wereobservedinthefollow-upwithprofessionalsfrom theseservices.³⁸

A study with Paraguayan children showed that the rifampicinandpyrazinamidedosebydrybloodspotonﬁlter papercouldbeawayofmonitoringtheplasmaconcentra- tionsof thesedrugs,³⁹ especiallywhengoodadherenceto treatmentiscertainandprogressisunfavorable.

Childrenrarely have adverse events;thus, biochemical testsarerecommendedbasedonlyonindividualclinicalcri- teriaatthebeginningorduringtherapy.

TheimportanceofDOTatallagesisreiterated,guiding thefamilyandthepatient,accordingtotheirunderstand- ing, about the consequences of irregular adherence and treatmentabandonment.⁷

Treatmentoflatentinfection

LTBI is defined asa state of persistent immune response withoutactivedisease.Thegroupsthatwouldbenefitfrom the identification of this status and the need for treat- mentshouldbedefined.Whetherthediagnosiswillbemade throughTSTorIGRA,theTSTvalueconsideredpositive,and theprioritypopulationsfortreatmentmayvaryindifferent countries,accordingtotheprevalence ofTBintheregion andlocalguidelines.⁵

ThepharmacologicaltreatmentofLTBIisthemaininter- vention capable of preventing its progression to active tuberculosis.Itsindicationdependsontheoutcomeofthe TSTorIGRA,age,likelihoodofinfection,andriskofillness.

In Brazil, the TST is considered positive with a skin induration ≥ 5mm, regardless of age, immunologicaland vaccinationstatus,ortimeelapsedsinceBCGvaccination.⁷

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Table6 Clinicalconsultationsandfollow-upexamsfortuberculosistreatmentinchildrenandadolescents.

Procedures 1^stmonth 2^ndmonth 3^rdmonth 4^thmonth 5^thmonth 6^thmonth Observations Monthly

consultation^a

X X X X X X Performmoreoften

accordingtoclinical criterion.

OfferHIV diagnostictest

X Ifnotpossibleinthe

ﬁrstmonth,perform duringtreatment.

Assessmentof adherenceand adverseevents

X X X X X X

Controlsmear microscopy (sputum)

X X X X X X Onlyforbacilliferous

pulmonarycases, whencollectionis easy.

ChestX-ray X X Repeatatclinical

discretion;ifﬁrst controlisnormal, thereisnoneedto repeat.

AdaptedfromtheMinistryofHealth,Brazil.⁷

a Evaluateimprovementofclinicalsymptoms,weightgain.

RecentstudieshaveshownthattheinfluenceofBCGonTST dependsmore ontheageat which BCGwasadministered thantheintervalbetweentheseadministrations.Thiseffect decreasesovertime,especiallyifthevaccinewasadminis- teredbeforetheageof2,theperiodwhenitisperformedin theBrazilianpopulation.⁴⁰Seddonetal.confirmedthisfind- ing,showingthatin thisscenario(children under2years, vaccinated),theTSTwasnegativeinmostcases.⁴¹

Patientswithahistoryofcontactortuberculinconversion in thepast year,those immunosuppressed bymedication, or thosewithan underlying diseasewould bethe priority groupstoinvestigateLTBIandassesstheneedfortreatment.

At-risk groups such as children with HIV infection, those pre-organ transplantation, or those who will start immunosuppressivetherapy shouldbeevaluatedwithTST, regardlessofcontactwithTB.IftheTSTispositive,theLTBI mustbe treated.However,ifthereis ahistory ofcontact withabacilliferous case,theindividualshouldbe treated eveniftheTSTisnegative.⁷

If the treatment of LTBI is necessary, the diagnosis of activediseaseshouldbepreviouslyruledout,withclinical evaluationandchestX-ray.⁷

Currently, several therapeutic regimens are available (Table7).⁴²

Isoniazidreducestheriskofthediseaseby60%---90%.This variationisduetothetreatmentdurationandadherence.

It is noteworthy that the number of doses, not the time oftreatment,isthemostimportantfactorfortherapeutic effectiveness.Itis recommendedthat270 dosesbetaken fromnineto12monthsor180dosesbetweensixandnine months.⁷

Studiesinchildrenhaveshowntheadherence,efﬁcacy, and safety advantages of a four-month treatment with rifampicin,whencomparedtoninemonthsofisoniazid.^43,44 Consideringthisevidence,Brazilrecommendsrifampicin inchildrenunder10andadultsover50yearsold,individuals

withliverdisease,andthosewhoareisoniazid-intolerant, with120dosestakenbetweenfourandsixmonths.⁷

The most promising treatment regimen is rifapentine associatedwithisoniazid,forwhichstudieshaveshownno inferioritytoninemonthsofisoniazidalone.

Theadvantages ofthisregimenaregreateradherence, lowerorsimilartoxicity,andeasy posology.Therearetwo forms of prescription: weekly doses for three weeks (12 doses)⁴⁵ ordailydosesforfourweeks(30doses).⁴⁶

In Brazil, the treatment of LTBI is not compulsorily reported,but notiﬁcationusingaspeciﬁc nationalformis recommended.⁷

ForcontactswithDRTB,thereisinsufficientevidencefor treatment.Theirevaluationisrecommendedtoidentifypos- siblecasesofactiveorlatent TB.WhenLTBIisidentified, periodicfollow-upforatleasttwoyearsisrecommendedto identifyearlysignsofdiseaseprogression.Levofloxacinhas beenstudiedasaprophylacticalternativeforthesecases.⁴⁷ Primarychemoprophylaxis

Newborns(NBs)exposed tocasesof bacillaryor laryngeal pulmonaryTBmaydevelopsevereformsofthediseaseand should be monitored and investigated. In the prevention strategyforthispopulationinBrazil,theuseofrifampicin hasrecentlybeenincorporated asanoption tothe useof isoniazid.⁷

The recommendation is maintained to not vaccinate withBCGatbirthandtostartchemoprophylaxisfor three months;afterthisperiod,theTSTisperformed.IftheTST resultispositive,thechosenregimeniscompleted(isoniazid 180dosesorrifampicin120doses)andthenewbornshould not be vaccinated with BCG. If the TST is negative,dis- continuetreatmentandvaccinate.Ifexposednewbornsare inadvertentlyvaccinated, it is recommendedto complete thetreatmentwithouttheneedforTST.⁷

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108 TahanTTetal.

Table7 Therapeuticregimenfortreatmentoflatenttuberculosisinfection.

Regimen Timeoftreatment Posology Maximumdose

Isoniazid,daily 6to9months (180---270doses)

Adult:5mg/kg Child:10(7---15)mg/kg

300mg Rifampicin,daily 3to4months

(90---120doses)

Adult:10mg/kg Child:15(10---20)mg/kg

600mg Isoniazid+rifampicin,

daily

3to4months (90---120doses)

Samedoseofindividualdrugs Rifapentine+isoniazid,

weekly

3months(12doses) Isoniazid:

≥12years:15mg/kg 2---11years:25mg/kg Rifapentine:

10.0---14.0kg=300mg 14.1---25.0kg=450mg 25.1---32.0kg=600mg 32.1---50.0kg=750mg

>50kg=900mg

Isoniazid:900 mg

Rifapentine:

900mg

Rifapentine+isoniazid, daily^a

Studiedonlyin≥18 years

1month(30doses) Isoniazid:

300mg Rifapentine:

<35kg=300mg 35.0---45.0kg=450mg

>45kg=600mg

Isoniazid:300 mg

Rifapentine:

600mg

AdaptedfromtheWorldHealthOrganization.³⁴

aSwindellsetal.⁴⁶

Table8 Clinicalphasesofongoingstudiesfortuberculosisvaccines.

Vaccineunderstudy Classiﬁcationregardingthetypeofvaccine Clinicalphase

Vaccae Mycobacteriumvaccae.Inactivatedwholecellvaccine 3

MIP Mycobacteriumindicuspranii.Inactivatedwholecellvaccine 3

VPM1002 RecombinantBCGvaccine 2b

M72+AS01E Subunitvaccine 2b

H56+IC31b Subunitvaccine 2b

DAR-901 Nontuberculousmycobacterium.Inactivatedwholecellvaccine 2b

MTBVAC AttenuatedMycobacteriumtuberculosis 2a

H4+IC31b Subunitvaccine 2a

ID93+GLASEc Subunitvaccine 2a

TB-FLU-04L Subunitvaccine 2a

H1+IC31b Subunitvaccine 2a

RUTI Mycobacteriumtuberculosis.Inactivatedwholecellvaccine 2a

Ad5Ag85A Subunitvaccine 1

ChAdOX/85A/MVA85A Subunitvaccine 1

AdaptedfromMéndez-Samperio.⁴⁸

When thesource case isthemother,evaluate thepos- sibilityofcongenitalTB.Therearenocontraindicationsto breastfeedingaslongasthe motherdoes nothave tuber- culousmastitis.Theuseofasurgicalmaskisrecommended whenbreastfeedingandcaringfor thechildwhile sputum smearresultsremainpositive.⁷

Activeimmunization

Inthelast twodecades,greatprogresshas been madein searchforamoreeffectivetuberculosisvaccine,butthere isstillnosubstituteforthelicensedBCGvaccine.Thereare approximately14vaccinesforTBunderstudyandtheyarein

differentphasesofclinicaltrials,beingtestedpre-andpost- exposure.Theyconsistofvaccinesubunits(associatedwith attenuated viralvectorsor adjuvantproteins), whole-cell vaccines(geneticallyattenuatedwithM.tuberculosis,BCG recombinants,ordeadM.vaccaeorM.tuberculosis).^48,49

Twovaccinesareinphase3,i.e.,thephasethatdemon- stratesthevaccine’sefﬁcacyandreinforcesitssafetybefore it use is approvedfor thepopulation. Moststudies are in phase 2,which aimsto assess immunogenicity.Two other vaccines are in phase 1, in which vaccine safety is studied.Asummaryofvaccinesandtheirstudiesisdescribedin Table8.

Despitethewidespreaduse ofBCG,thisvaccine isstill the subject of many studies. In February 2018, the WHO

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questionedthebeneﬁtsofrepeatingtheBCG,duetolackof scientiﬁcevidenceinvaccinatedchildrenwhohadnotdevel- opeda vaccine scar, even witha negativeTST or IGRA.⁵⁰ FollowingtheWHOrecommendations,theBrazilianMinistry of Healthhasnot recommendedrevaccination ofchildren whodid notdevelop the vaccine scar aftersix monthsof itsadministrationandwithouttheneedforfurthertesting (InformativeNoteNo.10/2019-CGPNI/DEVIT/SVS/MS).

Finalconsiderations

ThisreviewlookedatTBfromadifferentviewpointinchild- hoodandadolescence.Itisimportantthatgreaterrelevance isgiventothisdisease,thuscausingchildren,adolescents, family, professionals, and civil society to feelthat some- oneislisteningtothem,makingthisepidemicnotsosilent anymore. Advances in management have been observed.

However,thereismuchtobedone...morethanjustalook, akeenerear,givinganevengreatervoicetochildrenand adolescents;tasteandsmell,sothatnewchild-friendlyfor- mulascanbedeveloped;andacaringtouchthatmobilizes andresultsinmoreeffective actions.Onlywiththe union oftheﬁvesenses,childrenandadolescentswillbeableto replacethesuffering, onceimposedby TB,by afutureof greateracceptance,ofassertivenessindiagnosisandtreat- ment,aswellaspreventionandperhapsTBeliminationin thenearfuture.

Conﬂicts of interest

Theauthorsdeclarenoconﬂictsofinterest.

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