Tuberculosis in childhood and adolescence: a view from different perspectives

Tahan, Tony T.; Gabardo, Betina M.A.; Rossoni, Andrea M.O.
doi:10.1016/j.jpedp.2019.11.002
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e tamb&#233;m medicamentos mais adequados&#44; especialmente para as crian&#231;as&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">A OMS estimou 1&#46;000&#46;000 de casos novos de tuberculose nos menores de 14 anos em 2017&#46; Desses&#44; 55&#37; n&#227;o foram diagnosticados e&#47;ou notificados&#46; Nos menores de 5 anos&#44; esse percentual foi de 69&#37;&#44; enquanto nos demais foi de 40&#37;&#46; Ao avaliar os &#243;bitos&#44; 80&#37; ocorreram em menores de 5 anos e em 96&#37; desses as crian&#231;as n&#227;o tiveram acesso ao tratamento anti&#8208;TB&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Com intuito de melhorar esses indicadores&#44; a OMS publicou o <span class="elsevierStyleItalic">Roadmap towards ending TB in children and adolescents&#46;</span> Esse orienta o estreitamento das a&#231;&#245;es dos programas de controle da TB com a rede de cuidado de sa&#250;de da crian&#231;a&#44; aten&#231;&#227;o prim&#225;ria &#224; sa&#250;de&#44; nutri&#231;&#227;o&#44; HIV&#44; imuniza&#231;&#227;o&#44; entre outros&#46; O objetivo &#233; dar &#234;nfase a novas ferramentas de preven&#231;&#227;o&#44; diagn&#243;stico e tratamento&#44; com destaque aos medicamentos dispers&#237;veis para as crian&#231;as&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">2</span></a> Enfatiza tamb&#233;m a parceria com a sociedade civil&#44; comunidades e fam&#237;lias afetadas pela TB para dar relev&#226;ncia e diminuir o estigma dessa doen&#231;a t&#227;o antiga quanto a hist&#243;ria da humanidade&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Diante do exposto&#44; descreveu&#8208;se a situa&#231;&#227;o epidemiol&#243;gica da TB nos menores de 19 anos&#44; bem como as &#250;ltimas publica&#231;&#245;es a respeito do risco de adoecimento&#44; diagn&#243;stico&#44; tratamento da doen&#231;a ativa e latente&#46; Procurou&#8208;se&#44; assim&#44; olhar a TB na inf&#226;ncia e adolesc&#234;ncia sob perspectivas diferentes&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Metodologia</span><p id="par0025" class="elsevierStylePara elsevierViewall">Para descrever a situa&#231;&#227;o epidemiol&#243;gica da TB em menores de 19 anos foi avaliado o banco de notifica&#231;&#227;o do Brasil &#40;2017&#8211;2018&#41;&#44; dados n&#227;o publicados&#44; e usadas estimativas feitas pela OMS&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">2</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Foi feita uma busca no PubMed com o descritor <span class="elsevierStyleItalic">Tuberculosis</span>&#44; encontraram&#8208;se 253&#46;156 artigos&#46; Ao delimitar a pesquisa com artigos originais&#44; estudos cl&#237;nicos ou metan&#225;lises&#44; publicados de 01&#47;01&#47;2018 a 30&#47;06&#47;2019&#44; nos menores de 18 anos&#44; humanos&#44; em ingl&#234;s&#44; espanhol ou portugu&#234;s&#44; resultaram 104 artigos&#46; Ap&#243;s avalia&#231;&#227;o de todos os resumos&#44; selecionaram&#8208;se 26 artigos que se referiam a tuberculose em crian&#231;as e adolescentes&#46; Durante a leitura desses&#44; inclu&#237;ram&#8208;se alguns artigos citados nessas refer&#234;ncias e recomenda&#231;&#245;es para o Controle da TB do Minist&#233;rio da Sa&#250;de &#40;MS&#41; do Brasil e da OMS&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Esse trabalho foi aprovado pelo Comit&#234; de &#201;tica em Pesquisa em Seres Humanos do Complexo Hospital de Cl&#237;nicas da Universidade Federal do Paran&#225; sob n&#176; do CAE 17876919&#46;8&#46;0000&#46;0096&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Epidemiologia da TB nas crian&#231;as e nos adolescentes no Brasil</span><p id="par0040" class="elsevierStylePara elsevierViewall">Estimativas gerais da OMS mostram que o Brasil n&#227;o detectou em 2017 aproximadamente 12 mil casos&#46; Desses&#44; 8&#46;500 &#40;71&#37;&#41; entre os menores de 14 anos&#44; a saber&#44; 3&#46;500 abaixo de 4 anos e 5&#46; 000 entre 5 e 14 anos&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">3</span></a> Uma das possibilidades para essa subdetec&#231;&#227;o &#233; a dificuldade no diagn&#243;stico&#46; Esses dados mostram a import&#226;ncia de priorizar a&#231;&#245;es para essa faixa et&#225;ria&#44; expandir a descentraliza&#231;&#227;o e capacitar os profissionais dos servi&#231;os de aten&#231;&#227;o prim&#225;ria &#224; sa&#250;de&#44; no diagn&#243;stico e tratamento desses casos&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">4</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Em 2018&#44; o Brasil notificou 75&#46;709 casos novos de TB&#44; entre eles 1&#46;552 &#40;3&#44;3&#37;&#41; nos menores de 14 anos&#46; Destaca&#8208;se que a OMS estima que o percentual de casos nessa faixa et&#225;ria seria de 10&#37; do total de casos notificados&#44; para os 30 pa&#237;ses de alta carga da doen&#231;a&#44; inclusive o Brasil&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">3</span></a> Entretanto&#44; s&#227;o estimativas globais e n&#227;o h&#225; estudos nacionais sobre esses dados&#44; o que merece cautela na sua interpreta&#231;&#227;o&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">A distribui&#231;&#227;o dos casos novos notificados no Brasil &#40;2018&#41;&#44; conforme faixa et&#225;ria e unidades federadas&#44; encontra&#8208;se na <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Nos menores de 19 anos&#44; predominou a forma pulmonar&#44; respons&#225;vel por 80&#44;1&#37; dos casos&#46; A <a class="elsevierStyleCrossRef" href="#fig0005">figura 1</a> mostra a distribui&#231;&#227;o&#44; segundo tipo de TB&#44; por faixa et&#225;ria&#46; A distribui&#231;&#227;o das formas extrapulmonares&#44; menos frequentes&#44; variou conforme a idade&#46; Nos menores de um ano&#44; as formas men&#237;ngea e ganglionar apresentaram n&#250;mero de casos semelhantes&#44; enquanto nas demais h&#225; predom&#237;nio de forma ganglionar&#44; exclu&#237;dos os adolescentes em que a forma pleural &#233; a principal&#46; A distribui&#231;&#227;o dos casos extrapulmonares e&#47;ou mistos &#40;pulmonar associado a extrapulmonar&#41; encontra&#8208;se na <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Quanto &#224;s situa&#231;&#245;es de encerramento dos casos notificados em 2017&#44; os menores de um ano apresentaram cura de 65&#37;&#44; abandono de 7&#37; e letalidade de 2&#37;&#46; Destaca&#8208;se que a letalidade nessa idade &#233; o dobro quando comparada &#224;s demais faixas et&#225;rias da inf&#226;ncia e adolesc&#234;ncia&#44; mostra a gravidade da doen&#231;a nesse grupo&#46; Ressalta&#8208;se que o abandono apresentou sua maior taxa nos adolescentes&#44; de 12&#44;7&#37;&#44; inclusive acima dos maiores de 20 anos&#44; e reflete a import&#226;ncia do tratamento diretamente observado &#40;TDO&#41; nessa popula&#231;&#227;o&#46; Demais desfechos encontram&#8208;se na <a class="elsevierStyleCrossRef" href="#tbl0015">tabela 3</a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">A preven&#231;&#227;o da tuberculose ativa por meio do tratamento da infec&#231;&#227;o latente de tuberculose &#40;ILTB&#41; &#233; uma das principais estrat&#233;gias para a redu&#231;&#227;o da incid&#234;ncia da doen&#231;a e o alcance das metas da Estrat&#233;gia pelo Fim da Tuberculose&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">3</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">A carga global da ILTB n&#227;o &#233; conhecida e &#233; estimada em at&#233; um quarto da popula&#231;&#227;o mundial&#46; No entanto&#44; h&#225; grande varia&#231;&#227;o por pa&#237;s e faixa et&#225;ria&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">5&#44;6</span></a> No Brasil&#44; seu tratamento n&#227;o &#233; de notifica&#231;&#227;o compuls&#243;ria em todas as unidades federadas&#44; por&#233;m &#233; recomendado notificar em ficha espec&#237;fica nacional&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a> Recentemente&#44; implantou&#8208;se no pa&#237;s o Sistema da Notifica&#231;&#227;o de Tratamento da ILTB&#44; para monitoramento&#44; avalia&#231;&#227;o e vigil&#226;ncia desses casos&#44; o que permitir&#225; conhecer a magnitude desse agravo&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">A OMS estima que em 2014&#44; 25&#46;000 crian&#231;as e adolescentes at&#233; 15 anos adoeceram por TB drogarresistente &#40;TBDR&#41; e que menos de 10&#37; tiveram acesso ao tratamento&#46; Outra quest&#227;o preocupante &#233; que n&#227;o h&#225; dados de TBDR&#44; desagregados por idade na faixa et&#225;ria pedi&#225;trica e adolesc&#234;ncia reportados a OMS&#44; o que dificulta o conhecimento da real extens&#227;o dessa doen&#231;a&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">2</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">No Brasil existe o Sistema de Informa&#231;&#227;o de Tratamentos Especiais da Tuberculose &#40;Sitetb&#41; desde 2013&#46; A avalia&#231;&#227;o dos casos notificados&#44; em menores de 19 anos&#44; de 2011 a 2016&#44; informou 181 casos de TBDR&#44; o que corresponde uma preval&#234;ncia de 0&#44;5&#37; do total de casos notificados de TB na mesma faixa et&#225;ria e no mesmo per&#237;odo&#46; Ressalta&#8208;se que os casos de TBDR foram respons&#225;veis por 67&#37; das notifica&#231;&#245;es no Sitetb entre os menores de 19 anos e entre os casos de resist&#234;ncia a maioria era multirresistente &#40;88&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Risco de adoecimento</span><p id="par0085" class="elsevierStylePara elsevierViewall">Sabe&#8208;se que nem toda crian&#231;a com infec&#231;&#227;o latente desenvolver&#225; TB ativa&#46; Os menores de cinco anos ou portadores de imunodefici&#234;ncia apresentam um risco aumentado de progress&#227;o para doen&#231;a&#44; por&#233;m a compreens&#227;o dos fatores de risco para que isso ocorra &#233; limitada&#46; Whittaker et al&#46; descreveram que a infec&#231;&#227;o por outro pat&#243;geno &#40;v&#237;rus&#44; bact&#233;rias&#44; fungos e parasitas&#41; &#233; o processo mais implicado&#44; para essa progress&#227;o&#44; ao desequilibrar a resposta imunol&#243;gica tipo Th<span class="elsevierStyleInf">1</span>&#44; Th<span class="elsevierStyleInf">2</span> e T reguladores &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>&#41;&#46; Muitas dessas doen&#231;as t&#234;m distribui&#231;&#245;es geogr&#225;ficas sobrepostas &#224; TB&#44; o que dificulta estabelecer a correla&#231;&#227;o de causalidade&#46; As vacinas&#44; principalmente de v&#237;rus vivo atenuado&#44; por estimular a produ&#231;&#227;o de imunoglobulinas e interferon gama&#44; podem colaborar e diminuir o risco de adoecimento&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">9</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">O tempo de evolu&#231;&#227;o para doen&#231;a &#233; descrito como de 5&#37; a 10&#37; durante toda a vida&#44; 50&#37; dos casos se concentram nos primeiros 2 a 5 anos ap&#243;s a infec&#231;&#227;o&#44; s&#227;o mais incidentes nos menores de 5 anos&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">10</span></a> Trauer et al&#46; prop&#245;em que o risco de TB ativa ap&#243;s a infec&#231;&#227;o &#233; maior do que as estimativas tradicionalmente aceitas&#44; principalmente entre os menores de cinco anos&#44; pode chegar em algumas proje&#231;&#245;es a at&#233; 56&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">11</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Estudos que avaliaram risco de doen&#231;a dentre os contatos de pa&#237;ses de diferentes rendas mostraram variadas taxas de TB ativa&#46; Nos pa&#237;ses de baixa&#47;m&#233;dia renda o percentual foi 3&#44;1&#37;&#44; enquanto nos de alta renda foi de 1&#44;4&#37;&#46; Por&#233;m&#44; em ambos&#44; nos menores de cinco anos&#44; os percentuais foram superiores &#40;10&#44;0&#37; e 4&#44;7&#37; respectivamente&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">12</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Outro ponto questionado em rela&#231;&#227;o ao adoecimento est&#225; relacionado com o risco de infe&#231;&#227;o&#46; Quanto tempo de contato seria necess&#225;rio para um indiv&#237;duo se infectar&#63; Normalmente os <span class="elsevierStyleItalic">guidelines</span> n&#227;o tem essa resposta&#46; Deve&#8208;se analisar cada caso&#44; observarem&#8208;se carga bacilar do caso fonte e o ambiente&#58; a ventila&#231;&#227;o&#44; o tamanho do espa&#231;o&#44; a proximidade do caso e a dura&#231;&#227;o do contato&#46; Esse &#250;ltimo item &#233; um dos mais dif&#237;ceis de se estabelecer&#44; pois depende diretamente dos anteriores&#46; O <span class="elsevierStyleItalic">guideline a</span>ustraliano &#40;2015&#41; atribuiu 8 horas como o tempo m&#237;nimo para um indiv&#237;duo se infectar&#44; deve ser considerado um per&#237;odo menor quando pessoas mais suscet&#237;veis est&#227;o envolvidas ou participam de procedimentos de alta exposi&#231;&#227;o &#40;indu&#231;&#227;o de tosse ou intuba&#231;&#227;o&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">13</span></a> As recomenda&#231;&#245;es da WHO &#40;2013&#41; consideram o per&#237;odo de risco em voos&#44; aqueles com dura&#231;&#227;o acima de 8 horas&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">14</span></a> Por&#233;m&#44; em 2017&#44; Luzzati et al&#46; descreveram a investiga&#231;&#227;o de um surto ocorrido em Trieste&#44; na It&#225;lia&#44; com identifica&#231;&#227;o de casos secund&#225;rios em crian&#231;as&#44; nos quais o contato com o caso fonte foi ocasional&#44; num per&#237;odo menor de 30 minutos&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">15</span></a> Isso nos leva a questionar a necessidade de contatos duradouros para que o indiv&#237;duo se infecte&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Outro tema de estudo &#233; a correla&#231;&#227;o da defici&#234;ncia de vitamina D e TB&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">16&#44;17</span></a> Essa associa&#231;&#227;o j&#225; est&#225; estabelecida&#44; por&#233;m estudos s&#227;o necess&#225;rios para definir se a defici&#234;ncia seria causa ou consequ&#234;ncia&#44; como tamb&#233;m se a suplementa&#231;&#227;o da vitamina D influenciaria em evitar a progress&#227;o para doen&#231;a ou melhoraria a resposta ao tratamento dos doentes&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Diagn&#243;stico da TB pulmonar</span><p id="par0110" class="elsevierStylePara elsevierViewall">A TB &#233; classificada em forma pulmonar&#44; extrapulmonar e&#47;ou mista&#44;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a> assim as ferramentas diagn&#243;sticas variam de acordo com sua localiza&#231;&#227;o&#46; A TB pulmonar &#233; a mais prevalente e&#44; portanto&#44; ser&#225; o foco desta revis&#227;o&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">A fisiopatologia e a apresenta&#231;&#227;o cl&#237;nica da TB diferem de acordo com a idade&#46; A OMS classifica como crian&#231;as at&#233; 14 anos&#44; enquanto&#44; no Brasil&#44; por se basear nessas diferen&#231;as&#44; considera&#8208;se at&#233; 10 anos&#46; Esse corte de idade define os fluxos de investiga&#231;&#227;o e as condutas terap&#234;uticas&#46; As crian&#231;as apresentam quadro cl&#237;nico inespec&#237;fico&#44; semelhante a infec&#231;&#245;es habituais da inf&#226;ncia&#44; e s&#227;o paucibacilares&#46; J&#225; os adolescentes &#40;maiores de 10 anos&#41; desenvolvem doen&#231;a similar aos adultos&#44; podem ter quadros bacil&#237;feros&#46; Dessa forma&#44; de acordo com a diretriz do MS&#44; o diagn&#243;stico da TB pulmonar&#44; no Brasil&#44; varia conforme a idade&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Nos menores de 10 anos&#44; pelas paucibacilaridade e dificuldade de coleta de escarro&#44; o diagn&#243;stico &#233; baseado num sistema de escore&#44; que avalia a hist&#243;ria cl&#237;nica&#8208;epidemiol&#243;gica&#44; resposta a prova tubercul&#237;nica &#40;PT&#41;&#44; radiografia de t&#243;rax e estado nutricional do paciente &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">tabela 4</a>&#41;&#46; Esse escore &#233; din&#226;mico e avalia evolutivamente o caso&#44; com pontua&#231;&#245;es diferentes de acordo com tempo de evolu&#231;&#227;o e a resposta &#224;s terap&#234;uticas para infec&#231;&#245;es habituais&#44; adotado no Brasil desde 2002&#46; &#201; o esquema mais bem estudado&#44; validado e com consistentes sensibilidades e especificidades dentre os diversos existentes no mundo&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">18</span></a> Por&#233;m&#44; com a mudan&#231;a da pontua&#231;&#227;o da PT&#44; novos estudos devem ser desenvolvidos para avaliar suas atuais sensibilidade e especificidade&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">Os maiores de 10 anos&#44; com quadros cl&#237;nicos radiol&#243;gicos similares aos adultos&#44; t&#234;m seu diagn&#243;stico estabelecido por exames microbiol&#243;gicos&#46; Por&#233;m&#44; na aus&#234;ncia da confirma&#231;&#227;o bacteriol&#243;gica&#44; a recomenda&#231;&#227;o do MS &#233; que o diagn&#243;stico deva ser baseado no sistema de escore&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">A OMS orienta&#44; sempre que poss&#237;vel&#44; buscar a confirma&#231;&#227;o bacteriol&#243;gica atrav&#233;s da baciloscopia&#44; cultura ou teste r&#225;pido molecular e n&#227;o recomenda o &#8220;teste terap&#234;utico&#8221;&#44; que seria tentar estabelecer o diagn&#243;stico da TB com a implanta&#231;&#227;o do tratamento e o aguardo da melhoria cl&#237;nica do paciente&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">19</span></a> Para o MS&#44; o uso do escore propicia diagn&#243;stico e interven&#231;&#227;o terap&#234;utica precoces&#44; mesmo em unidades b&#225;sicas de sa&#250;de&#44; sem a necessidade de exames complementares mais sofisticados e&#47;ou profissionais especializados&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a> A confirma&#231;&#227;o bacteriol&#243;gica deve sempre ser tentada&#44; embora isso n&#227;o deva retardar o in&#237;cio do tratamento&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Apesar da relev&#226;ncia do tema&#44; pouco se publicou no &#250;ltimo ano em rela&#231;&#227;o a esse ponto espec&#237;fico&#46; Outras op&#231;&#245;es de coletas cl&#237;nicas&#44; como o escarro induzido&#44; <span class="elsevierStyleItalic">string test</span> o <span class="elsevierStyleItalic">swab</span> oral&#44; s&#227;o avaliadas&#44; por&#233;m ainda existem muitos desafios e controv&#233;rsias&#44; como discutidos recentemente por Reuter et al&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">20</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">A t&#233;cnica da coleta de escarro induzido consiste na inala&#231;&#227;o hipert&#244;nica&#44; como irritante das vias a&#233;reas&#44; previamente &#224; coleta do material&#46; Em indiv&#237;duos que conseguem expectorar espontaneamente&#44; faz&#8208;se a coleta do escarro&#44; por&#233;m em crian&#231;as o material &#233; coletado por aspirado nasal&#46; A acur&#225;cia dessas amostras &#233; similar &#224; do lavado g&#225;strico&#44;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">20</span></a> por&#233;m apresenta a dificuldade de gerar aeross&#243;is e por isso necessita de local com biosseguran&#231;a adequada para sua coleta&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">O <span class="elsevierStyleItalic">string test</span> ou <span class="elsevierStyleItalic">Corda Dulce</span> ainda apresenta sua efic&#225;cia n&#227;o estabelecida&#46; Nessa metodologia as crian&#231;as engolem uma c&#225;psula com uma &#8220;corda&#8221; que permanece por uma hora no est&#244;mago e depois &#233; retirada&#46; Essa corda absorve as micobact&#233;rias e &#233; enviada ao laborat&#243;rio para os exames rotineiros&#44; como baciloscopia&#44; cultura e teste r&#225;pido molecular&#46; Essa t&#233;cnica apresenta algumas vantagens por n&#227;o precisar de interna&#231;&#227;o hospitalar&#44; nem de condi&#231;&#245;es de biosseguran&#231;a para coleta&#46; Seu inconveniente &#233; que nem todas as crian&#231;as conseguem engolir as c&#225;psulas&#46; Por&#233;m novos estudos precisam ser feitos a esse respeito para demonstrar a tolerabilidade e acur&#225;cia do m&#233;todo&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">21</span></a> O <span class="elsevierStyleItalic">swab</span> oral tem sido estudado como uma op&#231;&#227;o promissora&#44; por&#233;m com estudos apenas em adultos&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">22&#8211;24</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Microbiologicamente o teste r&#225;pido molecular ainda n&#227;o conseguiu superar a cultura para diagn&#243;stico da tuberculose pulmonar na inf&#226;ncia&#44; por&#233;m&#44; pela rapidez do resultado em rela&#231;&#227;o &#224; cultura&#44; quando dispon&#237;vel&#44; sempre deve ser feito&#46; Essa t&#233;cnica foi atualmente modificada com a produ&#231;&#227;o do novo cartucho&#44; o GeneXpert Ultra&#44; que se demonstrou mais sens&#237;vel e melhorou o diagn&#243;stico principalmente em popula&#231;&#245;es com HIV&#44; crian&#231;as menores de 10 anos e na tuberculose extrapulmonar&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">25</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">A PT apresenta v&#225;rias limita&#231;&#245;es&#44; como t&#233;cnica de aplica&#231;&#227;o&#44; resultado leitor dependente&#44; necessidade de duas visitas para o teste&#44; valores de refer&#234;ncia diferentes na literatura para considerar o exame positivo&#44; possibilidade de interfer&#234;ncia com outras micobact&#233;rias&#44; principalmente o <span class="elsevierStyleItalic">M&#46; bovis</span> vacinal&#44; e nos &#250;ltimos anos&#44; a falta do insumo &#40;PPD&#8208;RT 23&#41;&#46; Diante disso&#44; testes mais sens&#237;veis e espec&#237;ficos est&#227;o em estudo&#46; Atualmente&#44; os ensaios de libera&#231;&#227;o de interferon gama &#40;IGRA&#41; s&#227;o os mais promissores&#44; por&#233;m com limita&#231;&#245;es de uso nos menores de 2 a 5 anos pela baixa taxa de concord&#226;ncia com a PT e altos &#237;ndices de indeterminados&#46; Al&#233;m disso&#44; apresenta alto custo&#44; necessidade de maior infraestrutura laboratorial e n&#227;o mostrou superioridade em qualquer na compara&#231;&#227;o com a PT&#46; Velasco&#8208;Arnaiz et al&#46; confrontaram os testes em menores de 5 anos e conclu&#237;ram que em popula&#231;&#245;es n&#227;o vacinadas n&#227;o h&#225; necessidade de se fazer ambos&#44; pela alta concord&#226;ncia entre eles&#46; Entre as crian&#231;as vacinadas&#44; a discord&#226;ncia foi maior &#40;&#954;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;190&#41;&#44; n&#227;o se conseguiu estabelecer se os casos eram infectados por outras micobact&#233;rias ou pelo <span class="elsevierStyleItalic">M&#46; tuberculosis</span>&#46; Dessa forma&#44; na presen&#231;a de discord&#226;ncia&#44; os autores sugerem considerar a crian&#231;a como infectada&#46; Nesse estudo n&#227;o se evidenciou diferen&#231;a nos resultados entre pacientes infectados e doentes&#44; nem houve sensibilidade maior do IGRA&#44; em rela&#231;&#227;o a PT&#44; nos doentes&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">26</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Aggerbeck et al&#46;&#44; em 2018 publicaram um estudo de fase 3 com um novo teste tubercul&#237;nico&#44; o C&#8208;Tb &#40;<span class="elsevierStyleItalic">Statens Serum Institut&#44;</span> Copenhagem&#44; Dinamarca&#41;&#46; &#201; um teste de pele proposto para diagn&#243;stico da ILTB&#44; para superar algumas dificuldades da PT habitual com o PPD RT 23 e os IGRAs&#46; &#201; aplicado e lido da mesma forma que a PT&#44; composto pelos ant&#237;genos mais espec&#237;ficos&#44; ESAT&#8208;6 e CFP&#8208;10&#44; os mesmos do IGRAs&#46; O corte de positividade &#233; universal&#44; de 5<span class="elsevierStyleHsp" style=""></span>mm de endura&#231;&#227;o&#46; Os resultados mostraram um teste seguro e com taxas de positividade similares a PT e ao IGRA &#40;concord&#226;ncia de 83&#37;&#41;&#44; mesmo em menores de 5 anos e pacientes HIV positivos&#46; Por&#233;m nos HIV positivos com CD4 &#60;<span class="elsevierStyleHsp" style=""></span>100 c&#233;lulas&#47;&#956;L a positividades foi diminu&#237;da em todos os tr&#234;s testes&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">27</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">Provas de atividade inflamat&#243;ria s&#227;o classicamente investigadas em associa&#231;&#227;o com a TB&#46; Velasco&#8208;Arnaiz et al&#46; avaliaram a associa&#231;&#227;o da procalcitonina e prote&#237;na C reativa com a TB em menores de seis anos e descreveram uma normalidade desse marcador nos casos de TB pulmonar e um aumento&#44; tanto da procalcitonina como da prote&#237;na C reativa&#44; nos quadros de pneumonia pneumoc&#243;cica&#46; Dessa forma&#44; sugerem que crian&#231;as contatos de TB&#44; com n&#237;vel de procalcitonina e prote&#237;na C reativa aumentados&#44; avalia&#8208;se a possibilidade de tratamento para pneumonia bacteriana e posterior reavalia&#231;&#227;o para TB em duas a tr&#234;s semanas&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">28</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Tratamento da doen&#231;a ativa</span><p id="par0170" class="elsevierStylePara elsevierViewall">Os esquemas de tratamento da TB recomendados&#44; no Brasil&#44; da mesma forma que no diagn&#243;stico&#44; seguem os mesmos cortes de idade&#46; Na &#250;ltima diretriz houve mudan&#231;a nas faixas de doses para as crian&#231;as&#44; de acordo com recomenda&#231;&#245;es da OMS&#44; para que se atingissem as concentra&#231;&#245;es s&#233;ricas indicadas desses f&#225;rmacos&#46; A rifampicina deve ser prescrita na dose de 15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg &#40;10&#8208;20<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; e a isoniazida 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg &#40;7&#8208;15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41;&#44; enquanto a pirazinamida foi mantida na dose de 35<span class="elsevierStyleHsp" style=""></span>mg&#47;kg &#40;30&#8208;40<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">O tempo de tratamento preconizado &#233; de 2 meses para a pirazinamida e 6 para as demais drogas&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a> Especificamente em rela&#231;&#227;o &#224; forma men&#237;ngea&#44; se estende para 12 meses&#44; segue esquema padronizado pela OMS&#46; Reitera&#8208;se a import&#226;ncia da isoniazida e da pirazinamida&#44; pela excelente penetra&#231;&#227;o e elevada concentra&#231;&#227;o com potente atividade bactericida no l&#237;quor&#44; enquanto que a rifampicina tem penetra&#231;&#227;o e concentra&#231;&#227;o menores nesse local&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">29</span></a> Enquanto para as formas com acometimento &#243;sseo o tempo de tratamento recomendado &#233; de 6 a 12 meses&#44; a crit&#233;rio cl&#237;nico&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Revis&#227;o feita por Donald et al&#46; mostrou que o uso do etambutol na dose de 20<span class="elsevierStyleHsp" style=""></span>mg&#47;kg &#40;15&#8208;25<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; &#233; seguro em crian&#231;as e pode ser aplicado na faixa et&#225;ria pedi&#225;trica&#46; Nesta revis&#227;o&#44; com 3&#46;811 crian&#231;as&#44; a neurite &#243;ptica foi atribu&#237;da ao etambutol&#44; em apenas 0&#44;05&#37; das crian&#231;as que usaram essa droga na dose de 15&#8208;30<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;dia&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">30</span></a> No Brasil&#44; o seu uso ainda &#233; recomendado apenas nos maiores de 10 anos&#44; mas&#44; quando necess&#225;rio&#44; pode ser usada com seguran&#231;a nos menores&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Outro avan&#231;o importante para as crian&#231;as foi o desenvolvimento da dose fixa combinada desde 2015&#44; na forma de comprimidos dispers&#237;veis&#58; formula&#231;&#245;es amig&#225;veis &#40;<span class="elsevierStyleItalic">child&#8208;friendly formulations</span>&#41;&#44; com sabor de fruta&#44; o que torna o tratamento muito mais palat&#225;vel e agrad&#225;vel &#224;s crian&#231;as&#44; al&#233;m de estarem adequadas &#224;s novas recomenda&#231;&#245;es da OMS&#46; Cada comprimido cont&#233;m 75<span class="elsevierStyleHsp" style=""></span>mg de rifampicina&#44; 50<span class="elsevierStyleHsp" style=""></span>mg de isoniazida e 150<span class="elsevierStyleHsp" style=""></span>mg de pirazinamida para a fase intensiva e comprimidos com 75<span class="elsevierStyleHsp" style=""></span>mg de rifampicina e 50<span class="elsevierStyleHsp" style=""></span>mg de isoniazida para a fase de manuten&#231;&#227;o do tratamento &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">tabela 5</a>&#41;&#46; Encontram&#8208;se em elabora&#231;&#227;o comprimidos dispers&#237;veis com doses isoladas de pirazinamida&#44; etambutol&#44; isoniazida e outros medicamentos usados para TBMR&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">31</span></a></p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0190" class="elsevierStylePara elsevierViewall">Destaca&#8208;se que o Brasil se encontra em fase de aquisi&#231;&#227;o das formula&#231;&#245;es dispers&#237;veis infantis&#44; o que mostra seu compromisso de priorizar o controle da TB nessa faixa et&#225;ria&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">As crian&#231;as encontram&#8208;se em crescimento e desenvolvimento e&#44; devido a isso&#44; as drogas apresentam ampla variabilidade farmacocin&#233;tica&#44; podem apresentar concentra&#231;&#245;es s&#233;ricas abaixo do n&#237;vel terap&#234;utico&#46; Observou&#8208;se em estudo feito na &#193;frica que a rifampicina e a pirazinamida&#44; nas novas doses preconizadas pela OMS&#44; n&#227;o atingem a concentra&#231;&#227;o s&#233;rica adequada nos menores de 12<span class="elsevierStyleHsp" style=""></span>kg&#46; Notadamente&#44; o n&#237;vel s&#233;rico da rifampicina nas crian&#231;as&#44; independentemente do peso&#44; foi inferior ao dos adultos&#46; Novos estudos est&#227;o em condu&#231;&#227;o para avaliar a biodisponibilidade das drogas em diferentes regi&#245;es geogr&#225;ficas&#44; se levarmos em considera&#231;&#227;o poss&#237;veis fatores gen&#233;ticos&#44; peso&#44; idade e formula&#231;&#227;o usada&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">32</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Estudo conduzido na &#205;ndia avaliou as concentra&#231;&#245;es s&#233;ricas atingidas pela isoniazida &#40;10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; e pirazinamida &#40;35<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; e as comparou em menores e maiores de 3 anos&#44; bem como com o estado nutricional&#46; Observou&#8208;se que a concentra&#231;&#227;o da pirazinamida foi mais baixa nos menores de tr&#234;s anos e em crian&#231;as com baixo &#237;ndice de massa corporal&#44; enquanto que para isoniazida n&#227;o houve diferen&#231;a significativa ao se avaliarem essas vari&#225;veis&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">33</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">No Brasil&#44; os esquemas usados e oferecidos no tratamento da TBDR nas crian&#231;as s&#227;o os mesmos dos adultos&#44; estendem&#8208;se de 18 a 24 meses&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a> A OMS orienta a possibilidade do esquema encurtado de 9 a 12 meses&#44; por&#233;m com pouca evid&#234;ncia na popula&#231;&#227;o pedi&#225;trica&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">34</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">Kumar et al&#46; avaliaram a farmacocin&#233;tica das medica&#231;&#245;es de segunda linha usadas no tratamento de TBMR&#44; em crian&#231;as e adolescentes indianas&#44; com mediana de 16 anos&#44; e mostraram que a levofloxacino atingiu concentra&#231;&#245;es s&#233;ricas maiores no g&#234;nero feminino&#44;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">35</span></a> valor semelhante a estudo conduzido por Denti et al&#46; com crian&#231;as sul&#8208;africanas&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">36</span></a> Essa &#250;ltima pesquisa usou comprimidos de levofloxacino macerado nas crian&#231;as e mostrou concentra&#231;&#227;o s&#233;rica inferior &#224; dos adultos&#44; apesar das doses equivalentes&#44; sugeriu a necessidade de novos estudos para avaliar o efeitos das diferentes formula&#231;&#245;es e manipula&#231;&#245;es&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">36</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">Kumar et al&#46; ainda demonstraram que a etionamida apresentou concentra&#231;&#227;o s&#233;rica mais baixa nos menores de 12 anos e para a pirazinamida&#44; em crian&#231;as e adolescentes com peso baixo&#44; a concentra&#231;&#227;o s&#233;rica desse f&#225;rmaco encontrou&#8208;se diminu&#237;da&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">35</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Essas diferen&#231;as na farmacocin&#233;tica das drogas conforme g&#234;nero&#44; idade e peso devem ser consideradas quando nos deparamos com evolu&#231;&#245;es desfavor&#225;veis&#44; mesmo em uso de doses adequadas e boa ades&#227;o ao tratamento&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Novas drogas est&#227;o sendo testadas e liberadas para uso na pediatria&#44; como bedaquilina e delamanid nos esquemas longos&#46; A bedaquilina pode ser usada para pacientes entre 6 a 17 anos e o delamanid a partir dos 3 anos&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">34</span></a> O pretomanid&#44; uma nova droga aprovada recentemente pelo FDA&#44; ainda necessita de estudos para seu uso nas crian&#231;as&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">37</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Seguimento do tratamento das crian&#231;as e adolescentes</span><p id="par0230" class="elsevierStylePara elsevierViewall">As crian&#231;as e adolescentes devem ser seguidos conforme descrito na <a class="elsevierStyleCrossRef" href="#tbl0030">tabela 6</a>&#46;</p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><p id="par0235" class="elsevierStylePara elsevierViewall">As crian&#231;as&#44; geralmente paucibacilares e sem confirma&#231;&#227;o bacteriol&#243;gica&#44; n&#227;o far&#227;o baciloscopia de controle e ser&#227;o acompanhadas periodicamente &#40;pelo menos uma vez por m&#234;s&#41; conforme sua evolu&#231;&#227;o cl&#237;nica e radiol&#243;gica&#46; O acompanhamento em ambulat&#243;rios de refer&#234;ncia com pediatras especialistas seria o recomendado em casos de maior complexidade&#44; vistos os melhores desfechos de tratamento&#44; como a redu&#231;&#227;o da letalidade&#44; observados no acompanhamento com profissionais desses servi&#231;os&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">38</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">Estudo feito com crian&#231;as paraguaias mostra que a dosagem de rifampicina e pirazinamida por meio de gota sangu&#237;nea seca em papel de filtro poderia ser uma forma de monitoramento das concentra&#231;&#245;es plasm&#225;ticas desses f&#225;rmacos&#44;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">39</span></a> principalmente quando h&#225; certeza de boa ades&#227;o ao tratamento e a evolu&#231;&#227;o est&#225; desfavor&#225;vel&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">As crian&#231;as raramente apresentam eventos adversos&#44; portanto exames bioqu&#237;micos s&#227;o recomendados apenas a partir de crit&#233;rios cl&#237;nicos individuais&#44; no in&#237;cio ou durante a terapia&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Reitera&#8208;se a import&#226;ncia do TDO em todas as idades&#44; orienta&#231;&#227;o &#224; fam&#237;lia e ao paciente&#44; conforme seu entendimento&#44; sobre as consequ&#234;ncias da ades&#227;o irregular e do abandono de tratamento&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Tratamento da infec&#231;&#227;o latente</span><p id="par0255" class="elsevierStylePara elsevierViewall">A ILTB &#233; definida como um estado de resposta imune persistente sem a doen&#231;a ativa&#46; Devem&#8208;se definir os grupos que seriam beneficiados com a identifica&#231;&#227;o desse <span class="elsevierStyleItalic">status</span> e a necessidade do tratamento&#46; A forma de diagn&#243;stico com PT ou IGRA&#44; valor da PT considerado positivo&#44; popula&#231;&#245;es priorit&#225;rias para o tratamento&#44; podem variar nos diversos pa&#237;ses&#44; de acordo com a preval&#234;ncia de TB na regi&#227;o e as diretrizes locais&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">5</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">O tratamento farmacol&#243;gico da ILTB &#233; a principal interven&#231;&#227;o capaz de prevenir a progress&#227;o para tuberculose ativa&#46; A sua indica&#231;&#227;o depende do resultado da PT ou do IGRA&#44; da idade&#44; da probabilidade de infec&#231;&#227;o e do risco de adoecimento&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">No Brasil&#44; a PT &#233; considerada positiva com endura&#231;&#227;o &#8805; 5<span class="elsevierStyleHsp" style=""></span>mm&#44; independentemente de idade&#44; situa&#231;&#227;o imunol&#243;gica e vacinal ou tempo decorrido da vacina&#231;&#227;o com BCG&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a> Estudos recentes apontaram que a influ&#234;ncia da BCG na PT depende mais da idade em que o BCG foi aplicado&#44; do que o intervalo entre essas aplica&#231;&#245;es&#46; Esse efeito reduz com o passar do tempo&#44; principalmente se a vacina foi feita antes de dois anos&#44; per&#237;odo no qual &#233; feita na popula&#231;&#227;o brasileira&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">40</span></a> Seddon et al&#46; confirmaram esse achado&#44; mostraram que nesse cen&#225;rio &#40;menores de 2 anos vacinados&#41; na maioria dos casos a PT foi negativa&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">41</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">Os pacientes com hist&#243;ria de contato ou convers&#227;o tubercul&#237;nica no &#250;ltimo ano&#44; imunossuprimidos por medicamentos ou doen&#231;a de base seriam os grupos priorit&#225;rios a se investigar ILTB e avaliar necessidade do tratamento&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">Grupos de risco&#44; como crian&#231;as com infec&#231;&#227;o pelo HIV&#44; pr&#233;&#8208;transplante de &#243;rg&#227;os ou que iniciar&#227;o terapia imunossupressora devem ser avaliadas com PT&#44; independentemente do contato com TB&#46; Em caso PT positiva&#44; fazer o tratamento da ILTB&#46; Por outro lado&#44; se hist&#243;ria de contato com bacil&#237;fero&#44; tratar&#44; mesmo que PT negativa&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall">Caso seja necess&#225;rio&#44; o tratamento da ILTB deve afastar&#44; previamente&#44; o diagn&#243;stico de doen&#231;a ativa com avalia&#231;&#227;o cl&#237;nica e radiografia de t&#243;rax&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a></p><p id="par0285" class="elsevierStylePara elsevierViewall">Atualmente&#44; v&#225;rios esquemas terap&#234;uticos est&#227;o dispon&#237;veis &#40;<a class="elsevierStyleCrossRef" href="#tbl0035">tabela 7</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">42</span></a></p><elsevierMultimedia ident="tbl0035"></elsevierMultimedia><p id="par0290" class="elsevierStylePara elsevierViewall">A isoniazida reduz em 60&#37; a 90&#37; o risco de adoecimento&#46; Essa varia&#231;&#227;o se deve &#224; dura&#231;&#227;o e &#224; ades&#227;o ao tratamento&#46; Destaca&#8208;se que o n&#250;mero de doses&#44; e n&#227;o o tempo de tratamento&#44; &#233; o mais importante para a efetividade terap&#234;utica&#46; Recomendam&#8208;se 270 doses a serem tomadas de 9 a 12 meses ou 180 doses&#44; entre 6 e 9 meses&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a></p><p id="par0295" class="elsevierStylePara elsevierViewall">Estudos em crian&#231;as mostraram as vantagens de ades&#227;o&#44; efic&#225;cia e seguran&#231;a de 4 meses de rifampicina comparados com 9 meses de isoniazida&#46;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">43&#44;44</span></a></p><p id="par0300" class="elsevierStylePara elsevierViewall">O Brasil&#44; diante dessas evid&#234;ncias&#44; recomenda a rifampicina nos menores de 10 e maiores de 50 anos&#44; hepatopatas e intolerantes &#224; isoniazida&#44; com 120 doses tomadas entre 4 e 6 meses&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a></p><p id="par0305" class="elsevierStylePara elsevierViewall">O esquema de tratamento mais promissor &#233; com a rifapentina associada &#224; isoniazida&#44; cujos estudos mostraram n&#227;o inferioridade a nove meses de isoniazida isolada&#46; As vantagens desse esquema s&#227;o maior ades&#227;o&#44; toxicidade menor ou similar e facilidade posol&#243;gica&#46; H&#225; duas formas de prescri&#231;&#227;o&#58; doses semanais por 3 semanas &#40;12 doses&#41;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">45</span></a> ou di&#225;rias por 4 semanas &#40;30 doses&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">46</span></a></p><p id="par0310" class="elsevierStylePara elsevierViewall">No Brasil&#44; o tratamento da ILTB n&#227;o &#233; de notifica&#231;&#227;o compuls&#243;ria&#44; por&#233;m recomenda&#8208;se a notifica&#231;&#227;o em ficha espec&#237;fica nacional&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a></p><p id="par0315" class="elsevierStylePara elsevierViewall">Para os contatos com TBDR&#44; n&#227;o h&#225; evid&#234;ncia suficiente para o tratamento&#46; Recomenda&#8208;se a avalia&#231;&#227;o desses para a identifica&#231;&#227;o de poss&#237;veis casos de TB ativa ou latente&#46; Quando ILTB for identificada&#44; recomenda&#8208;se o acompanhamento peri&#243;dico por pelo menos dois anos&#44; a fim de se identificarem precocemente sinais de progress&#227;o para doen&#231;a&#46; A levofloxacina tem sido estudada como uma op&#231;&#227;o profil&#225;tica para esses casos&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">47</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Quimioprofilaxia prim&#225;ria</span><p id="par0320" class="elsevierStylePara elsevierViewall">Rec&#233;m&#8208;nascidos &#40;RN&#41; expostos a casos de TB pulmonar bacil&#237;fera ou lar&#237;ngea podem desenvolver formas graves da doen&#231;a&#44; devem ser acompanhados e investigados&#46; No fluxo de preven&#231;&#227;o dessa popula&#231;&#227;o&#44; no Brasil recentemente foi incorporado o uso da rifampicina como op&#231;&#227;o ao uso da isoniazida&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a></p><p id="par0325" class="elsevierStylePara elsevierViewall">A orienta&#231;&#227;o se mant&#233;m&#44; de n&#227;o vacinar com a BCG ao nascimento e iniciar a quimioprofilaxia por tr&#234;s meses&#46; Ap&#243;s esse per&#237;odo&#44; faz&#8208;se a PT&#46; Se o resultado da PT for positiva&#44; completar o esquema terap&#234;utico escolhido &#40;isoniazida 180 doses ou rifampicina 120 doses&#41; e o RN n&#227;o dever&#225; ser vacinado com BCG&#46; Caso a PT seja negativa&#44; interromper o tratamento e vacinar&#46; Se o RN exposto for inadvertidamente vacinado&#44; recomenda&#8208;se completar a terap&#234;utica&#44; sem necessidade da PT&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a></p><p id="par0330" class="elsevierStylePara elsevierViewall">Quando o caso fonte for a m&#227;e&#44; avaliar a possibilidade de TB cong&#234;nita&#46; N&#227;o h&#225; contraindica&#231;&#245;es &#224; amamenta&#231;&#227;o&#44; desde que a m&#227;e n&#227;o seja portadora de mastite tuberculosa&#46; &#201; recomend&#225;vel o uso de m&#225;scara cir&#250;rgica ao amamentar e ao cuidar da crian&#231;a enquanto a baciloscopia do escarro se mantiver positiva&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Imuniza&#231;&#227;o ativa</span><p id="par0335" class="elsevierStylePara elsevierViewall">Nas &#250;ltimas duas d&#233;cadas&#44; houve um grande progresso na busca por uma vacina mais eficaz contra a tuberculose&#44; mas ainda n&#227;o h&#225; substituto para a vacina BCG licenciada&#46; Existem em torno de 14 vacinas contra a tuberculose em estudo e est&#227;o em diferentes fases de ensaios cl&#237;nicos&#44; s&#227;o testadas em pr&#233; e p&#243;s&#8208;exposi&#231;&#227;o&#46; S&#227;o compostas por subunidades vacinais &#40;associadas a vetores virais atenuados ou prote&#237;nas adjuvantes&#41;&#44; vacinas de c&#233;lulas inteiras &#40;geneticamente atenuadas com o <span class="elsevierStyleItalic">M&#46; tuberculosis</span>&#44; recombinantes de BCG ou <span class="elsevierStyleItalic">M&#46; vaccae</span> ou <span class="elsevierStyleItalic">M&#46; tuberculosis</span> mortos&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">48&#44;49</span></a></p><p id="par0340" class="elsevierStylePara elsevierViewall">Duas vacinas encontram&#8208;se em fase 3&#44; ou seja&#44; a que demonstra a efic&#225;cia da vacina e refor&#231;a a seguran&#231;a&#44; antes de se obter o registro sanit&#225;rio para liberar seu uso na popula&#231;&#227;o&#46; A maioria dos estudos encontra&#8208;se em fase 2&#44; que tem por objetivo avaliar a imunogenicidade&#46; E duas vacinas est&#227;o em fase 1&#44; que &#233; a da seguran&#231;a vacinal&#46; Um resumo das vacinas e dos estudos encontra&#8208;se na <a class="elsevierStyleCrossRef" href="#tbl0040">tabela 8</a>&#46;</p><elsevierMultimedia ident="tbl0040"></elsevierMultimedia><p id="par0345" class="elsevierStylePara elsevierViewall">Apesar do uso consagrado da BCG&#44; essa vacina ainda &#233; motivo de muitos estudos&#46; Em fevereiro de 2018&#44; a OMS questionou os benef&#237;cios de se repetir a BCG&#44; por aus&#234;ncia de evidencias cient&#237;ficas&#44; em crian&#231;as vacinadas e que n&#227;o tenham desenvolvido a cicatriz vacinal&#44; mesmo com PT ou IGRA negativos&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">50</span></a> Por orienta&#231;&#227;o da OMS&#44; o MS do Brasil passou a n&#227;o recomendar a revacina&#231;&#227;o de crian&#231;as que n&#227;o desenvolveram a cicatriz vacinal ap&#243;s seis meses da aplica&#231;&#227;o e sem necessidade de testes complementares &#40;Nota Informativa n&#176; 10&#47;2019&#8208;CGPNI&#47;DEVIT&#47;SVS&#47;MS&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Considera&#231;&#245;es finais</span><p id="par0350" class="elsevierStylePara elsevierViewall">Buscou&#8208;se dar um novo olhar &#224; TB na inf&#226;ncia e adolesc&#234;ncia&#46; Um olhar que se deparou com maior relev&#226;ncia dada a essa doen&#231;a e&#44; assim&#44; fazer com que crian&#231;as&#44; adolescentes&#44; parentes&#44; profissionais e sociedade fossem mais ouvidos&#44; propiciar que essa epidemia deixe de ser t&#227;o silenciosa&#46; Observaram&#8208;se avan&#231;os no seu manejo&#46; Entretanto h&#225; muito a trilhar&#46;&#46;&#46; Associar ao olhar um ouvir mais agu&#231;ado&#44; dar ainda maior voz &#224;s crian&#231;as e aos adolescentes&#59; paladar e olfato para que desenvolvam novas f&#243;rmulas amigas da crian&#231;a e um tato que mobilize e resulte em a&#231;&#245;es mais efetivas&#46; Somente com a uni&#227;o dos cinco sentidos as crian&#231;as e os adolescentes conseguir&#227;o substituir o sofrimento&#44; outrora imposto pela TB&#44; por um futuro de maior acolhimento&#44; assertividade no diagn&#243;stico&#44; tratamento&#44; bem como preven&#231;&#227;o e qui&#231;&#225; sua elimina&#231;&#227;o num futuro pr&#243;ximo&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflitos de interesse</span><p id="par0360" class="elsevierStylePara elsevierViewall">Os autores declaram n&#227;o haver conflitos de interesse&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To describe the epidemiological situation of tuberculosis in children under 19 years of age in Brazil and to review the latest publications on disease risk&#44; diagnosis&#44; treatment&#44; and prevention&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Source of data</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Notifiable Diseases Information System &#40;2018&#41;&#44; World Health Organization estimates&#44; and PubMed articles selected using the descriptor &#8220;Tuberculosis&#44;&#8221; delimited by type of study&#44; period&#44; age&#44; and language&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Synthesis of data</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">In 2018&#44; in Brazil&#44; 9&#46;4&#37; of notifications were in children under 19 years&#46; The pulmonary form predominated in 80&#46;1&#37; of the cases&#46; The cure rate was 76&#46;8&#37;&#44; lethality was 0&#46;8&#37;&#44; and abandonment was 10&#46;4&#37;&#46; The prevalence of drug&#8208;resistant tuberculosis &#40;2011 to 2016&#41; was 0&#46;5&#37;&#46;It has been found that the risk of disease can reach up to 56&#37; in children under 5 years&#44; influenced by helminth co&#8208;infections&#44; malaria&#44; chronic viral infections&#44; live attenuated virus vaccines&#44; and hypovitaminosis D&#46; Exposure to a bacilliferous patient for periods shorter than 30 minutes is sufficient for the development of infection and&#47;or disease&#46; In Brazil&#44; microbiological screening is recommended&#44; but the use of the scoring system&#44; modified in 2019&#44; has been maintained&#46; Studies on infection detection have supported the use of the tuberculin skin test&#46; In the treatment&#44; the great advance was the introduction of dispersible formulations&#44; adjustment of the recommended doses&#44; and shortened regimens for latent infection&#46; Several vaccine studies &#40;stages 1&#8211;3&#41; are ongoing&#44; but no BCG&#8208;licensed substitute has been implemented yet&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">There has been progress in treatment&#44; but major challenges need to be overcome to improve diagnosis&#44; monitoring&#44; and outcome of cases&#44; aiming to eliminate tuberculosis&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Descrever a situa&#231;&#227;o epidemiol&#243;gica da tuberculose nos menores de 19 anos no Brasil e revisar as &#250;ltimas publica&#231;&#245;es sobre risco de adoecimento&#44; diagn&#243;stico&#44; tratamento e preven&#231;&#227;o&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Fonte dos dados</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Banco de notifica&#231;&#227;o Brasil &#40;2018&#41;&#44; estimativas da Organiza&#231;&#227;o Mundial da Sa&#250;de e artigos do PubMed selecionados pelo descritor <span class="elsevierStyleItalic">Tuberculosis</span>&#44; delimitaram&#8208;se tipo de estudo&#44; per&#237;odo&#44; idade e l&#237;ngua&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">S&#237;ntese dos dados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Em 2018&#44; no Brasil&#44; 9&#44;4&#37; das notifica&#231;&#245;es foram nos menores de 19 anos&#46; Predominou a forma pulmonar em 80&#44;1&#37; dos casos&#46; A taxa de cura foi de 76&#44;8&#37;&#44; letalidade 0&#44;8&#37; e abandono 10&#44;4&#37;&#46; A preval&#234;ncia de tuberculose drogarresistente &#40;2011 a 2016&#41; foi 0&#44;5&#37;&#46; Encontrou&#8208;se que o risco de adoecimento pode chegar at&#233; 56&#37;&#44; nos menores de cinco anos&#44; influenciado por coinfec&#231;&#245;es com helmintos&#44; mal&#225;ria&#44; infec&#231;&#245;es virais cr&#244;nicas&#44; vacinas de v&#237;rus vivos atenuados e hipovitaminose D&#46; A exposi&#231;&#227;o ao doente bacil&#237;fero por per&#237;odos menores de 30 minutos &#233; suficiente para o desenvolvimento de infec&#231;&#227;o e&#47;ou doen&#231;a&#46; No Brasil&#44; recomenda&#8208;se a pesquisa microbiol&#243;gica&#44; por&#233;m mantem&#8208;se o uso do Sistema de Pontua&#231;&#227;o&#44; modificado em 2019&#46; Estudos sobre detec&#231;&#227;o da infec&#231;&#227;o respaldaram o uso da prova tubercul&#237;nica&#46; No tratamento&#44; o grande avan&#231;o foi a introdu&#231;&#227;o das formula&#231;&#245;es dispers&#237;veis&#44; adequa&#231;&#227;o das doses preconizadas e esquemas encurtados para infec&#231;&#227;o latente&#46; V&#225;rios estudos de vacinas &#40;fases de 1 a 3&#41; est&#227;o em andamento&#44; mas ainda sem substituto licenciado para a BCG&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclus&#245;es</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Observaram&#8208;se progressos no tratamento&#44; por&#233;m ainda h&#225; grandes desafios para melhorar o diagn&#243;stico&#44; monitoramento e desfecho dos casos em busca da elimina&#231;&#227;o da tuberculose&#46;</p></span>"
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          "pt" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Fatores que influenciam a resposta imune da tuberculose&#46;</p> <p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">TB&#44; tuberculose&#59; IgG&#44; imunoglublinas G&#59; Th&#44; Linf&#243;cito T helper&#59; Treg&#44; T regulador&#59; IL&#44; interleucina&#59; IFN&#44; Interferon&#59; TNF&#44; fator de necrose tumoral&#59; CMV&#44; citomegalov&#237;rus&#59; EBV&#44; Epstein&#8208;Barr&#59; Hep&#44; hepatite&#46;</p> <p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Adaptado de Whittaker et al&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">9</span></a></p>"
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