Mycobacterium tuberculosis latent infection in healthcare students: systematic review of prevalence / Infecção latente por Mycobacterium tuberculosis em estudantes da área da saúde: revisão sistemática de prevalência / Infección latente por Mycobacterium tuberculosis en estudiantes de la salud: revisión sistemática de la prevalencia

ABSTRACT Objective: The aim of this study was to synthesize the evidence on the prevalence of latent Mycobacterium tuberculosis infection (LTBI) among undergraduate health care students. Methods: A systematic review of prevalence with meta-analysis was conducted. Prospective and retrospective cohorts and cross-sectional studies involving probable exposure to M. tuberculosis during undergraduate education, along with the tuberculin skin test (TST) or interferon-γ release assay (IGRA) for investigation of latent tuberculosis were searched. Searches were conducted in MEDLINE, CINAHL, EMBASE, LILACS, Scopus, and Web of Science databases. Independent reviewers were responsible for the selection and inclusion of studies. Data were extracted, critically appraised, and synthesized using the JBI approach. PRISMA was used to report the study. Results: Twenty-two studies were analyzed. The overall prevalence in healthcare undergraduate students was 12.53%. Conclusion: The prevalence of LTBI in undergraduate health students was high for such a highly educated population. Screening with TST and/or IGRA and chemoprophylaxis, when necessary, should be provided to undergraduate health students when in contact with respiratory symptomatic patients.

RESUMO Objetivo: O objetivo deste estudo foi sintetizar as evidências sobre a prevalência de infecção de Mycobacterium tuberculosis (ILTB) entre estudantes de graduação da área da saúde. Método: Foi realizada uma revisão sistemática de prevalência com metanálise. Coortes prospectivas e retrospectivas e estudos transversais envolvendo provável exposição a M. tuberculosis durante a graduação, juntamente com o teste tuberculínico (TT) ou ensaio de liberação de interferon-γ (IGRA) para investigação de tuberculose latente foram pesquisados. As buscas foram realizadas nas bases de dados MEDLINE, CINAHL, EMBASE, LILACS, Scopus e Web of Science. Revisores independentes foram responsáveis pela seleção e inclusão dos estudos. Os dados foram extraídos, avaliados criticamente e sintetizados utilizando a abordagem JBI. PRISMA foi usado para relatar o estudo. Resultados: Vinte e dois estudos foram analisados. A prevalência geral em estudantes de graduação da área da saúde foi de 12,53%. Conclusão: A prevalência de ILTB em estudantes de graduação em saúde foi alta para uma população com alto nível de escolaridade. Triagem com TT e/ou IGRA e quimioprofilaxia, quando necessária, deve ser fornecida aos estudantes de graduação da área da saúde quando em contato com pacientes sintomáticos respiratórios.

RESUMEN Objetivo: El objetivo de este estudio fue sintetizar la evidencia sobre la prevalencia de infección latente por Mycobacterium tuberculosis (ILTB) entre estudiantes universitarios de la salud. Métodos: Se realizó una revisión sistemática de la prevalencia con metanálisis. Cohortes prospectivas y retrospectivas y estudios transversales que involucran exposición probable a M tuberculosis durante la educación universitaria, junto con la prueba cutánea de tuberculina (TST) o el ensayo de liberación de interferón-γ (IGRA) para la investigación de tuberculosis latente. Las búsquedas se realizaron en las bases de datos MEDLINE, CINAHL, EMBASE, LILACS, Scopus y Web of Science. Revisores independientes fueron responsables de la selección e inclusión de los estudios. Los datos se extrajeron, se evaluaron críticamente y se sintetizaron utilizando el enfoque JBI. Se utilizó PRISMA para informar el estudio. Resultados: Se analizaron veintidós estudios. La prevalencia global en estudiantes universitarios en salud fue del 12,53%. Conclusión: La prevalencia de LTBI en estudiantes universitarios de salud fue alta para una población con un nivel educativo tan alto. Se debe proporcionar tamizaje con TST y/o IGRA y quimioprofilaxis, cuando sea necesario, a los estudiantes universitarios en salud cuando estén en contacto con pacientes sintomáticos respiratorios.

Prevalencia de infección tuberculosa latente e incidencia de viraje tuberculínico en contactos escolares mayores de 5 años en la Ciudad Autónoma de Buenos Aires / Prevalence of latent tuberculosis infection and incidence of tuberculin conversion among school contacts older than 5 years in the City of Buenos Aires

Introducción. La tuberculosis continúa siendo un problema frecuente en contextos de vulnerabilidad socioeconómica. El objetivo principal fue establecer la prevalencia de infección latente y viraje tuberculínico en contactos escolares de casos de tuberculosis. Población y métodos. En un área programática del sur de la ciudad, se evaluó la prevalencia de infección y viraje tuberculínico de 691 niñas, niños y adolescentes utilizando la prueba cutánea de tuberculina. Se investigó la asociación entre pérdida de seguimiento por parte del equipo de salud y características demográficas, escolares y asistencia inicial, y se describió el grado de adherencia cuando la quimioprofilaxis con isoniacida fue indicada. Resultados. Según las definiciones consideradas, la prevalencia de infección latente fue entre el 3,4 % (IC95 %: 2,3-5,2) y el 11,6 % (IC95 %: 9,3-14,4) de los 610 contactos con al menos una prueba cutánea aplicada. La incidencia de viraje tuberculínico se encontró entre el 0,3 % y el 6,8 % de los 294 evaluados. La edad mayor de 18 años, la mayor prevalencia de necesidades básicas insatisfechas en la comuna escolar, la pertenencia al turno escolar vespertino, la negatividad en la baciloscopia del caso índice y la ausencia de aplicación de la prueba cutánea inicial se asociaron con pérdida de seguimiento del contacto. Conclusiones. La incidencia de viraje tuberculínico en contactos escolares fue baja. La adherencia a isoniacida continúa siendo limitada. Se identificaron factores asociados con la pérdida de seguimiento de contactos que podrían orientar estrategias necesarias para mejorar este proceso.

Introduction. Tuberculosis continues to be a common problem in settings of socioeconomic vulnerability. Our primary objective was to establish the prevalence of latent infection and tuberculin conversion among school contacts of tuberculosis cases. Population and methods. In a programmatic area in the south of the City of Buenos Aires, the prevalence of latent infection and tuberculin conversion was assessed in 691 children and adolescents using the tuberculin skin test. The association between loss to follow-up by the health care team and the demographic, school, and baseline care characteristics was studied, and the level of adherence when isoniazid chemoprophylaxis was indicated was described. Results. According to established definitions, the prevalence of latent infection was between 3.4% (95% confidence interval [CI]: 2.3­5.2) and 11.6% (95% CI: 9.3­14.4) in the 610 contacts with at least one skin test. The incidence of tuberculin conversion was between 0.3% and 6.8% in the 294 assessed participants. Age older than 18 years, a higher prevalence of unmet basic needs in the school district, attending the afternoon school shift, negative sputum smear results in the index case, and absence of baseline skin test were associated with contact lost to follow-up. Conclusions. The incidence of tuberculin conversion among school contacts was low. Adherence to isoniazid treatment remains limited. Factors associated with loss of contact tracing were identified, which may guide strategies necessary to improve this process.

Research progress in transcriptional and immunological biomarkers associated with tuberculosis infection / 中华预防医学杂志

Tuberculosis (TB) is an infectious disease that poses a serious threat to human health. About a quarter of the world's population were infected with Mycobacterium tuberculosis in 2020, and the majority of them were latently infected. Approximately 5%-10% of the population with latent tuberculosis infection may progress to active TB disease. Identifying latent TB infection from active TB by biomarkers and screening people with latent TB infection at high risk of progression for preventive treatment by biomarkers that can reliably predict the progression is one of the most effective strategies to control TB. This article reviews the progress of research on transcriptional and immunological biomarkers for identifying TB infection and predicting the progression from latent infection to active TB, with the aim of providing new ideas for tuberculosis control.

Progress in research of prophylactic therapy in contacts of rifampicin-resistant tuberculosis patients / 中华流行病学杂志

Tuberculosis (TB) prophylactic therapy for latent infection, which can reduce the risk for the development of active TB, is an important measure in TB control. China recommends prophylactic therapy for latent tuberculosis infection (LTBI) in some key populations to reduce the risk for TB. Contacts of patients with multi-drug and rifampicin-resistant TB (MDR/RR-TB) are at high risk for the infection with drug-resistant pathogen, however, no unified prophylactic therapy regimen has been recommended for LTBI due to exposure to MDR/RR-TB patients. This paper summarizes the current MDR/RR-TB prophylactic therapy regimen and its protection effect based on the results of the retrieval of literature, guidelines, expert consensus and technical specifications to provide reference for the prevention and control of LTBI.

Reativação de Tuberculose Pulmonar em uma Paciente com Câncer de Orofaringe Tratada com Nivolumabe: Relato de Caso / Reactivation of Pulmonary Tuberculosis in a patient with Oropharyngeal Cancer Treated with Nivolumab: Case Report

Os inibidores de checkpoints imunológicos (ICI) são uma classe de medicamentos cada vez mais utilizados para tratar o câncer. No entanto, eles têm sido associados a um risco aumentado de reativação da tuberculose (TB) em pacientes com infecção tuberculosa latente (ILTB). Relato do caso: Mulher, 61 anos, com câncer de orofaringe desenvolveu reativação de TB pulmonar enquanto recebia nivolumabe. Acredita-se que a reativação da TB em pacientes em ICI seja em virtude da inibição da via PD-1 que desempenha um papel no controle da ILTB. A incidência de reativação da TB em pacientes em ICI é maior do que na população geral. Conclusão: O uso crescente de ICI provavelmente levará a um aumento no número de casos de reativação da TB. Sugere-se proceder ao rastreamento rotineiro para ILTB nos pacientes que estão sendo considerados para tratamento com ICI, especialmente em países com alta incidência de TB.

Avances en tuberculosis en el 54° Congreso Chileno de enfermedades respiratorias. 3a parte: Prevención de la tuberculosis activa mediante el tratamiento de la tuberculosis latente / Advances in tuberculosis at the 54th Chilean Congress of Respiratory Diseases. Part 3: prevention of active tuberculosis by treating latent tuberculosis

La infección tuberculosa latente (ITL) es un estado asintomático de la infección por Mycobacterium tuberculosis incapaz de transmitir la infección a otros, pero con el potencial de originar una tuberculosis (TBC) activa en el infectado, especialmente ante la presencia de factores de riesgo inmunológico. Es importante en personas de riesgo de desarrollar TBC reconocer la ITL utilizando test como la reacción a la tuberculina (PPD o TST) y los ensayos de liberación de Interferón-γ (IGRAs). Sin embargo, estos tests tienen limitaciones en su capacidad de predicción de riesgo de evolución de infección a enfermedad lo que conlleva a tener que tratar muchas personas para evitar algún caso de enfermedad. Nuevos tests se encuentran en desarrollo para mejorar la sensibilidad de reconocimiento de la ITL, distinguir infecciones recientes (que tienen el mayor riesgo de progresión a enfermedad) e incluso con la capacidad de detectar enfermedad subclínica o inicial. Para reducir la probabilidad de enfermar por TBC se utilizan tratamientos preventivos con fármacos, pero la cobertura mundial de esta terapia es reducida y la adherencia a terapias auto-administradas, como en el caso del uso de isoniazida diaria oral, es también baja. Otro problema de esta terapia son los riesgos de reacciones adversas (hepatitis, erupciones cutáneas) aunque no frecuentes. La recomendación de terapia actual de la ITL incluye el uso de rifamicinas y sus derivados. La asociación de isoniazida con rifapentina en una dosis semanal durante tres meses, administrada bajo supervisión, es la terapia de primera línea para mayores de 2 años, mostrando menos riesgo de hepatotoxicidad y mayor adherencia.

Latent Tuberculosis infection (LTBI) is the asymptomatic state of infection caused by Mycobacterium tuberculosis. Although untransmissible, LTBI can progress to active tuberculosis (TB), especially in people with immune risk factors. It is important to recognize LTBI in people at risk of developing TB; tuberculin skin test (PPD or TST) or interferon-γ release assays (IGRAs) are current diagnostic tests. However, these tests have limitations in their ability to predict subjects who will evolve from infection to disease; consequently, a large number of people with LTBI need treatment to avoid a reduced number of future TB disease cases. Newer tests are under development to improve the sensitivity in recognizing LTBI, distinguish recent infections with highest risk of progression to disease, and even be able to detect initial subclinical disease. Antimicrobial preventive treatment effectively reduces the probability of getting sick with TB, but worldwide availability of TB preventive therapy is limited, and adherence to self-administered therapies, as in the case of the use of daily oral isoniazid, is low. Adverse reactions risk (hepatitis, skin rash) although infrequent, is another problem with these therapies. Currently, LTBI management guidelines include regimens with use of rifamycins and their derivatives. The combination of isoniazid and rifapentine in a weekly dose for three months administered under supervision is the first line choice for LTBI therapy in those over 2 years of age, showing less hepatoxicity risk and greater adherence.

Progress on diagnosis and treatment of latent tuberculosis infection / 浙江大学学报·医学版

One fourth of the global population has been infected with Mycobacterium tuberculosis, and about 5%-10% of the infected individuals with latent tuberculosis infection (LTBI) will convert to active tuberculosis (ATB). Correct diagnosis and treatment of LTBI are important in ending the tuberculosis epidemic. Current methods for diagnosing LTBI, such as tuberculin skin test (TST) and interferon-γ release assay (IGRA), have limitations. Some novel biomarkers, such as transcriptome derived host genes in peripheral blood cells, will help to distinguish LTBI from ATB. More emphasis should be placed on surveillance in high-risk groups, including patients with HIV infection, those using biological agents, organ transplant recipients and those in close contact with ATB patients. For those with LTBI, treatment should be based on the risk of progression to ATB and the potential benefit. Prophylactic LTBI regimens include isoniazid monotherapy for 6 or 9 months, rifampicin monotherapy for 4 months, weekly rifapentine plus isoniazid for 3 months (3HP regimen) and daily rifampicin plus isoniazid for 3 months (3HR regimen). The success of the one month rifapentine plus isoniazid daily regimen (1HP regimen) suggests the feasibility of an ultra-short treatment strategy although its efficacy needs further assessment. Prophylactic treatment of LTBI in close contact with MDR-TB patients is another challenge, and the regimens include new anti-tuberculosis drugs such as bedaquiline, delamanid, fluoroquinolone and their combinations, which should be carefully evaluated. This article summarizes the current status of diagnosis and treatment of LTBI and its future development direction.

Comparison of the effectiveness, safety, compliance, and cost of the 6-month isoniazid vs 3-month isoniazid-rifampicin regimen for latent tuberculosis in children

Background@#Tuberculosis remains to be a major cause of morbidity in children and treatment of latent tuberculosis is important to prevent children from developing active tuberculosis. This study aimed to compare the effectiveness, safety, compliance, and cost of the currently available Latent Tuberculosis Infection treatment regimens, 6 months isoniazid (6H) and 3 months isoniazid plus rifampicin (3HR), based on the 2020 Department of Health National Tuberculosis Control Program Tuberculosis Preventive Treatment guidelines for children.@*Methodology@#In this open label randomized controlled trial pilot study, 30 participants were assigned to receive either 6H or 3HR. Medications were administered daily by either participants (with direct supervision of treatment supporters) or treatment supporters (for younger participants). Data on outcome measures in terms of effectiveness, safety, and compliance were obtained. Direct cost of treatment was computed per patient’s weight category. Independent Z-test for proportion (for effectiveness, safety, and compliance) and mean (for cost) at 5% level of significance was used to compare the outcomes for each treatment group.@*Results@#Twelve subjects (67%) in the 6H group completed per-protocol therapy, compared to 10 subjects (87%) in the 3HR group. The proportion of adverse events was higher in the 6H group (22%) compared to the 3HR group (8%), but statistical tests showed no significant difference for both compliance and frequency of adverse events. No participant developed active TB disease in both groups. The cost of the 6H treatment regimen was 2,180.18 Php while the cost of the 3HR treatment regimen was 1,526.41 Php, with a p-value of 0.0470 which was statistically significant.@*Conclusions@#Both 6H and 3HR are effective treatments for latent TB infection in patients 0-18 years old. Both treatments were comparable in terms of safety and ease of compliance, but overall cost was higher in the 6H treatment regimen.

Infecção latente da tuberculose em pessoas vivendo com HIV no Paraná: caracterização do perfil clínico-epidemiológico / Infección tuberculosa latente en personas que viven con VIH en Paraná: caracterización del perfil clínico-epidemiológico / Latent tuberculosis infection in people living with HIV in Paraná: characterization of clinical-epidemiological profile

Objetivo: caracterizar perfil clínico-epidemiológico das pessoas vivendo com HIV com registro de tratamento da Infecção Latente pelo Mycobacterium tuberculosis no Estado do Paraná em 2019 e 2020. Método: estudo descritivo, com dados do Sistema de Informação Nacional para notificação das pessoas em tratamento para tuberculose, disponibilizados pela Secretaria Estadual de Saúde do Paraná. A análise dos dados foi descritiva. Resultados: houve redução significativa do número de pessoas em tratamento, com perfil predominante de homens brancos com idade média de 41 anos, com radiografia de tórax normal, imunizados contra tuberculose, sem realização de prova tuberculínica, em uso de isoniazida, sem histórico de contato de tuberculose e com tratamento da fase latente. Conclusões: evidencia-se a importância da ação conjunta entre Programas de Controle de HIV e tuberculose, com foco na ampliação do tratamento preventivo e na educação em saúde para conscientização, em especial de homens adultos.(AU)

Objective: to characterize clinical-epidemiological profile of people living with HIV with a record of treatment for Latent Infection by Mycobacterium tuberculosis in the State of Paraná in 2019 and 2020. Method: descriptive study, with data from the National Information System for notifying people undergoing treatment for tuberculosis, made available by the State Department of Health of Paraná. Data analysis was descriptive. Results: there was a significant reduction in the number of people undergoing treatment, with a predominant profile of white men with a mean age of 41 years, with normal chest X-rays, immunized against tuberculosis, without tuberculin skin testing, using isoniazid, no history of contact with tuberculosis and, with treatment of the latent phase. Conclusions: the importance of joint action between HIV and Tuberculosis Control Programs is evident, with a focus on expanding preventive treatment and health education for awareness, especially for adult men.(AU)

Objetivo: caracterizar perfil clínico-epidemiológico de personas que viven con VIH con registro de tratamiento para Infección Latente por Mycobacterium tuberculosis en el Estado de Paraná en 2019 y 2020. Método: estudio descriptivo, con datos del Sistema Nacional para notificar personas en tratamiento por tuberculosis, puesto a disposición por la Secretaría de Estado de Salud de Paraná. El análisis fue descriptivo. Resultados: hubo una reducción significativa en el número de personas en tratamiento, con perfil predominante de hombres blancos, edad media de 41 años, con radiografías de tórax normales, inmunizados contra la tuberculosis, sin prueba cutánea de la tuberculina, usando isoniazida, sin antecedentes de contacto de tuberculosis y con tratamiento de la fase latente. Conclusiones: se evidencia la importancia de la acción conjunta entre Programas de Control del VIH y la Tuberculosis, con foco en ampliar el tratamiento preventivo y la educación en salud para la concientización, especialmente de hombres adultos.(AU)

Tuberculosis latente: diagnóstico y tratamiento actual / Latent tuberculosis: current diagnosis and treatment

Resumen La infección tuberculosa latente (TL) afecta al 23% de la población y constituye un reservorio de tuberculosis (TBC) ya que 10% progresa hacia una TBC. La TL se reconoce por pruebas como la tuberculina (PPD o TST) y los ensayos de liberación de Interferón gama (IGRAs). La sensibilidad de IGRAs (versión Quantiferon TB Gold plus) es 94% y del PPD 77%. La especificidad del Quantiferon TB Gold Plus es 97% y del PPD 68%. El valor predictivo de progresión a TBC activa de estas pruebas es bajo (PPD: 1,5%, IGRAs: 2,7%) pero mejora en personas de alto riesgo de contraer TBC (PPD: 2,4%, IGRAs: 6,8%). Las personas con pruebas negativas que posteriormente presentan viraje (prueba positiva) tienen mayor riesgo de progresión a TBC activa. Estas pruebas son útiles en el seguimiento de contactos intradomiciliarios, extranjeros de países con altas tasas de TBC, inmunosuprimidos, enfermedad renal crónica, diabetes, silicosis y secuelas pulmonares de TBC no tratada. En la terapia de TL se utiliza isoniazida (H) auto-administrada por plazos de 6 a 12 meses con eficacia protectora de 60% y riesgo de toxicidad hepática de 2% pero con baja adherencia (50-70%). La asociación de H con rifapentina en dosis única semanal durante 12 semanas tiene eficacia de 81%, adherencia de 82% y baja toxicidad hepática (0,4%). Nuevos biomarcadores de TL y vacunas que mejoren la inmunidad en TL se encuentran en estudio. El tratamiento de la TL puede reducir la incidencia de TBC a largo plazo.

Latent tuberculosis infection (LT) affects 23% of the population and constitutes a reservoir of tuberculosis (TB) as 10% progresses to TB. LT is recognized by tests such as tuberculin (PPD or TST) and Interferon gamma release assays (IGRAs). The sensitivity of IGRAs (Quantiferon TB Gold plus version) is 94% and PPD 77%. The specificity of Quantiferon TB Gold Plus is 97% and PPD 68%. The predictive value of progression to active TB of these tests is low (PPD: 1.5%, IGRAs: 2.7%) but improves in people at high risk of contracting TB (PPD: 2.4%, IGRAs: 6.8%). People with negative tests who subsequently turn around (positive) have a higher risk of progression to active TB. These tests are useful in the follow-up of intra-household contacts, foreigners from countries with high rates of TB, immunosuppressed, chronic kidney disease, diabetes, silicosis and pulmonary sequelae of untreated TB. In LT therapy, self-administered isoniazid (H) is used for periods from 6 to 12 months with protective efficacy of 60% and risk of liver toxicity of 2%, but with low adherence (50-70%). The association of H with rifapentine in a single weekly dose for 12 weeks has efficacy of 81%, adherence of 82% and low liver toxicity (0.4%). New LT biomarkers and vaccines that improve immunity in LT are under study. Treatment of LT may reduce the incidence of TB in the long term.

Eritema indurado de Bazin como una reactivación de una tuberculosis latente en una paciente con tratamiento biológico anti-factor de necrosis tumoral / Erythema induratum of Bazin as a reactivation of latent tuberculosis infection in a patient receiving anti-tumor necrosis factor treatment

Resumen El eritema indurado de Bazin es una tuberculosis cutánea rara, considerada una tuberculide o reacción de hipersensibilidad a Mycobacterium tuberculosis. El tratamiento con agentes biológicos es un factor de riesgo conocido para la reactivación de tuberculosis, especialmente en áreas de alta incidencia como Latinoamérica, por lo que existen protocolos de búsqueda y tratamiento antes del inicio de este tipo de terapias. Se presenta un caso clínico de eritema indurado de Bazin como reactivación de una infección tuberculosa latente en una paciente con artritis reumatoide que recibía tratamiento con golimumab.

Abstract Erythema induratum of Bazin is a rare form of cutaneous tuberculosis, considered as part of the spectrum of tuberculids or hipersensitivity reactions to Mycobacterium tuberculosis. Treatment with biologic agents is a known risk factor for tuberculosis reactivation, especially in areas of high incidence like Latin America, which is why screening and treatment protocols must be followed before these therapies are initiated. We present a case of erythema induratum of Bazin as a reactivation of latent tuberculosis infection in a patient with rheumatoid arthritis treated with golimumab.

Novas ferramentas para o diagnóstico de infecção latente por Mycobacterium tuberculosis / New tools for the diagnostics of latent Mycobacterium tuberculosis infection

Esta tese objetivou identificar estratégias de triagem para infecção latente por Mycobacterium tuberculosis (Mtb) ­ ILTB em profissionais de saúde que viabilizem o uso mais eficiente dos recursos disponíveis. No Brasil, recomenda-se que os profissionais de saúde, um dos grupos de risco para a ILTB, realizem triagem periódica para detecção da infecção e aqueles que apresentarem conversão aos testes de diagnóstico, indica-se o tratamento preventivo da tuberculose (TB) ­ TPT uma vez que pessoas com conversão recente apresentam elevada chance de progressão para a doença. Desenvolvemos, no primeiro artigo, um modelo preditivo para identificar profissionais de saúde com maior probabilidade de resultado negativo para dois testes de diagnóstico da ILTB a partir de uma análise secundária de dados publicados anteriormente de 708 profissionais de saúde da atenção primária, de cinco capitais brasileiras, submetidos à prova tuberculínica (PT) e ao Quantiferon®-TB Gold in-tube (QFT-IT®). Construímos um modelo preditivo utilizando árvore de classificação e regressão (CART, classification and regression tree). A avaliação do desempenho foi realizada por meio da análise receiver operating characteristics (ROC) e area under the curve (AUC). Utilizou-se o mesmo banco de dados para validação cruzada do modelo. Entre os 708 profissionais de saúde, 247 (34,9%) apresentaram resultado negativo para os testes. A CART identificou que os médicos e agentes comunitários de saúde apresentaram chances duas vezes maior de testes negativos (probabilidade = 0,60) do que os enfermeiros e técnicos/auxiliares de enfermagem (probabilidade = 0,28) naqueles com menos de 5,5 anos de atuação na atenção primária. Na validação cruzada, a acurácia do modelo preditivo foi de 68% [intervalo de confiança de 95% (IC95%) 65 ­ 71) ], AUC de 62% (IC95% 58 ­ 66), especificidade de 78% (IC95% 74 ­ 81) e sensibilidade de 44% (IC95% 38 ­ 50). Apesar do baixo poder preditivo do modelo, a CART permitiu identificar subgrupos com maior probabilidade de terem ambos os testes negativos. No segundo artigo, analisou-se a razão de custo-efetividade de dois testes de sensibilidade cutânea baseados em antígenos específicos do Mtb -Diaskintest® e C-TST® - e a do QFT-Plus® para o diagnóstico da ILTB comparadas com a estratégia diagnóstica atual (PT) entre profissionais de saúde. Desenvolveu-se um modelo analítico de decisão, representado por coorte hipotética de 100.000 profissionais de saúde, de ambos os sexos, com resultado negativo para a PT no ano anterior, horizonte temporal de cinco anos, na perspectiva do Sistema Único de Saúde. Avaliaram-se três regimes de tratamento para a ILTB: três meses de doses semanais de rifapentina (900 mg) e isoniazida (900 mg) (3HP), seis e nove meses de doses diárias de isoniazida (300 mg) (6H e 9H, respectivamente). Aplicou-se taxa de desconto de 5% na efetividade, medida em casos de TB ativa evitados, e nos custos das estratégias de triagem e de tratamento avaliados, estimados em dólares americanos (US$) com taxa média anual de 2021 de acordo com o Banco Central (US$ 1 = 5,39 reais). Foram realizadas análises de sensibilidade determinística univariada e probabilística. Os testes Diaskintest®, C-TST® e QFT-Plus® apresentam maior especificidade (0,98, 0,98 e 0,97, respectivamente). Os custos com QFT-Plus® foram maiores devido aos equipamentos, mão de obra e ao custo do kit. O Diaskintest® foi o teste mais econômico (US$ 7.042, US$ 5.781 e US$ 18.892 por caso de TB ativa evitado para os regimes de tratamento com 3HP, 6H e 9H, respectivamente), inclusive nas análises de sensibilidade. No cenário nacional, o Diaskintest® foi o teste de melhor custo-efetividade para avaliação anual dos profissionais de saúde.

This thesis aimed to identify screening strategies for tuberculosis infection (TBI) in healthcare workers (HCW) that enable the most efficient use of available resources. Investigation of TBI in HCWs is recommended in Brazil as part of the worker's pre-employment and periodic (annual) health visits. HCWs with a first tuberculin skin test (TST) induration < 10 mm are invited to repeat the test in one to three weeks to assess the booster effect (induration size increment of 10 mm). Those with a persistent TST < 10 mm will undergo a one-step TST every 12 months. TPT is recommended when conversion (10 mm increment over latest induration size) occurs. We developed, in the first manuscript, a predictive model to identify HCWs best targeted for TBI screening. We carried out a secondary analysis of previously published results of 708 HCWs working in primary care services in five Brazilian State capitals who underwent two TBI tests: tuberculin skin test and Quantiferon®-TB Gold in-tube. We used a classification and regression tree (CART) model to predict HCWs with negative results for both tests. The performance of the model was evaluated using the receiver operating characteristics (ROC) curve and the area under the curve (AUC), cross-validated using the same dataset. Among the 708 HCWs, 247 (34.9%) had negative results for both tests. CART allowed us to identify that physicians or a community health agents were twice more likely to be uninfected (probability = 0.60) than registered or aid nurse (probability = 0.28) when working less than 5.5 years in the primary care setting. In cross validation, the predictive accuracy was 68% [95% confidence interval (95%CI): 65 ­ 71], AUC was 62% (95%CI 58 ­ 66), specificity was 78% (95%CI 74 ­ 81), and sensitivity was 44% (95%CI 38 ­ 50). Despite the low predictive power of this model, CART allowed to identify subgroups with higher probability of having both tests negative. In the second manuscript, we analyzed the cost-effectiveness of two TB antigen-based skin tests (TBST) using the recombinant ESAT-6 and CFP-10 immunogens (Diaskintest® and C-TST®) and of QFT-Plus® for TBI diagnosis compared with the current standard of care, TST, among HCWs in Brazil. A state-transition Markov model was created, simulating a cohort of 100,000 HCWs (five annual cycles) for TBI treatment scenarios with 3 months of weekly doses of rifapentine (900 mg) and isoniazid (900 mg) (3HP). We adopted the Brazilian public health system perspective. Effects [tuberculosis disease (TBD) averted) and costs for screening and treating TBI were discounted at 5%. Incremental cost-effectiveness per TBD averted was calculated. Hypothetical cohort of 100,000 HCWs of both sexes with a negative result of TST in the previous year. Diaskintest®, C-TST® and QFT-Plus® tests have higher specificity (0.98, 0.98 and 0.97, respectively). Costs with QFT-Plus® were higher due to equipment, human labor and cost of the kit by test. Diaskintest® was the most cost-effective test (US$ 7,042, US$ 5,781, and US$18,892 per case of TBD averted for the 3HP, 6H, and 9H treatment regimens, respectively), including sensitivity analyses. In the Brazilian scenario, Diaskintest® is the most cost-effective test for sequential testing of HCWs.

Terapias biológicas y tuberculosis en pediatría / Biological therapies and tuberculosis in pediatrics

En los últimos años, ha habido un aumento sostenido del uso de terapias inmunomoduladoras como las terapias biológicas y en un período más reciente, de las terapias con moléculas pequeñas. Estos tratamientos constituyen un factor de riesgo más para enfermar de tuberculosis en adultos y aunque en menor grado, también en niños, especialmente con el uso de anti TNF-α, por lo que antes de iniciar una terapia biológica, hay que descartar la tuberculosis activa y la latente. En el tratamiento de una tuberculosis activa producida por un biológico se debe prolongar la etapa de continuación a 9 meses. Es importante el seguimiento clínico prolongado en años de quienes usan o han completado el uso de estas terapias. Hay que posponer la vacunación BCG en los hijos de madres que usaron terapias biológicas durante la gestación hasta la edad 6 a 12 meses de los niños. El foco de esta revisión está centrado en la tuberculosis por progresión de una forma latente a una activa o por un contacto estrecho con una persona con tuberculosis pulmonar en pacientes que reciben terapias biológicas anti TNF alfa de uso inmunoreumatológico.

In recent years, there has been a sustained increase in the use of immunomodulatory therapies such as biologic therapies and, more recently, small molecule therapies. Those therapies have become another risk factor for tuberculosis in adults and, although to lesser degree, also in children, especially some of them, such as anti-TNF α. Before starting biological therapy, active tuberculosis and latent tuberculosis must be ruled out. In the treatment of active tuberculosis caused by a biologic, the continuation stage should be extended to 9 months. Long-term clinical follow-up in years of those who use them or have completed their use, is important. BCG vaccine should be postponed in children of mother who used biologic therapies during pregnancy until the children ́s age 6 to 12 months. The focus of this review is centered on tuberculosis due to progression from a latent to an active form or due to close contact with a person with pulmonary tuberculosis in patients receiving anti-TNF alpha biological therapies for immunorheumatology use.

Prevalence of latent tuberculosis infection among patients with interstitial lung disease requiring immunosuppression / Prevalência de infecção latente por tuberculose em pacientes com doença pulmonar intersticial com necessidade de imunossupressão

ABSTRACT Objective To characterize the prevalence of latent tuberculosis infection (LTBI) in patients with interstitial lung diseases (ILDs) requiring immunosuppression. Only 5 to 10% of individuals infected with Mycobacterium tuberculosis develop tuberculosis, and certain groups of patients have an increased risk of illness, such as the immunocompromised. Patients with ILDs are frequently treated with immunosuppressants and, therefore, might have a higher risk of developing the disease. Methods Prospective study conducted at the ILD reference center of the Federal University of Paraná from January 2019 to December 2020. The screening of LTBI was performed with the use of the tuberculin skin test (TST). Results The sample consisted of 88 patients, of whom 64.8% were women, with a mean age of 61.4 years. The most frequent diagnoses were autoimmune rheumatic disease ILD (38.6%) and hypersensitivity pneumonitis (35.2%). The most common immunosuppressant in use at the time of the TST was prednisone, either in combination with mycophenolate (19.3%) or alone (17.1%). The majority of participants had fibrotic lung disease, characterized by a reticular interstitial pattern on chest computed tomography (79.5%) and moderate to severe functional impairment (mean FVC 69.2%). A prevalence of LTBI of 9.1% (CI 95%, 2.1%-15.1%) was found, with a TST median of 13. Conclusion Patients with ILD who are treated with immunosuppressants are not commonly screened for LTBI, despite being under a greater risk of progression to active disease. This study suggests the need for a more cautious approach to these patients.

RESUMO Objetivo Caracterizar a prevalência de Infecção Latente por Tuberculose (ILTB) em pacientes com Doenças Pulmonares Intersticiais (DPIs) que necessitam de imunossupressão. Apenas 5 a 10% dos indivíduos infectados pelo Mycobacterium tuberculosis desenvolvem tuberculose, sendo que certos grupos de pacientes apresentam maior risco de doença, tais como os imunocomprometidos. Pacientes com DPIs são frequentemente tratados com imunossupressores, portanto, podem apresentar maior risco de desenvolver a doença. Métodos Estudo prospectivo conduzido no Centro de Referência para DPI da Universidade Federal do Paraná (UFPR), entre Janeiro de 2019 e Dezembro de 2020. O rastreio de ILTB foi realizado por meio da Prova Tuberculínica (PT). Resultados A amostra foi composta por 88 pacientes, dos quais 64,8% eram mulheres, com, em média, 61,4 anos de idade. Os diagnósticos mais frequentes foram DPI associada a doença reumática autoimune (DRAI) (38,6%) e pneumonite de hipersensibilidade (35,2%). Prednisona foi o imunossupressor mais comumente utilizado à época da PT, em combinação com micofenolato (19,3%) ou isoladamente (17,1%). A maioria dos participantes tinha doença pulmonar fibrótica, caracterizada por infiltrado reticular em tomografia computadorizada de tórax (79,5%), bem como comprometimento funcional moderado a grave (Capacidade Vital Forçada (CVF) média de 69,2%). Observou-se uma prevalência de ILTB de 9,1% (Intervalo de Confiança (IC) 95%, 2,1%-15,1%), com mediana da PT de 13. Conclusão Não é comum que pacientes com DPI tratados com imunossupressores sejam avaliados quanto à presença de ILTB, apesar de estarem sob um maior risco de progressão para doença ativa. Este estudo sugeriu a necessidade de uma abordagem mais cuidadosa em relação a esses pacientes.

Latent tuberculosis infection in family members in household contact with active tuberculosis patients in Semarang City, Central Java, Indonesia

A quarter of the world's population is infected with Mycobacterium tuberculosis (M.tb), 10% of cases develop active tuberculosis (TB), and 90% have a latent TB infection. Family members of TB patients have the highest potential for latent TB infection. This study aims to identify latent TB infection and risk factors in family members within the household contacts of active TB patients. This study used a crosssectional study design with a contact tracing method. The selected subjects were 138 people from 241 total family members of 112 active TB patients. Subjects underwent a tuberculin skin test (TST), using 2 units of tuberculin (TU) purified protein derivative (PPD) 0.1 mL (PT. Bio Farma Persero, Bandung, Indonesia). Data risk factors were collected during home visits. Data were analyzed using the chi-square test and multiple logistic regression. A total of 63.8% (88/138) of family members of active TB patients' household contacts had latent TB infection. The type of occupation of laborers/ farmers/fishers is the most dominant risk factor associated with latent TB infection (AOR: 7.04; 95% CI: 1.70­29.02), followed by unqualified bedroom density (<8 m2/2 people) (AOR: 5.33; 95% CI: 2.44­ 12.71) and contact duration ≥5 hours/day (AOR: 4.70; 95% CI:1.33­16.66). Latent TB infection in family members of active TB patients' household contacts was quite high. Occupation type, contact duration, and bedroom density were simultaneously confirmed as the main risk factors related to latent TB infection. Therefore, it is recommended to identify and prevent latent TB infection in family members in household contact with active TB patients.

Conversión de prueba cutánea de derivado proteico purificado durante el tratamiento con anti-TNF / Skin test conversion of purified protein derivative during treatment with anti-TNF

Introducción: los anti-TNF-α se asocian con mayor riesgo de desarrollar tuberculosis (TB). La prueba del derivado proteico purificado (purified protein derivative, PPD) se emplea para diagnosticar infección de tuberculosis latente (ITL). Se recomienda el cribado para TB previo al inicio de terapia anti-TNF-α y el seguimiento para evaluar la posible conversión de la PPD durante el tratamiento. El tratamiento de la ITL puede reducir el riesgo de desarrollar enfermedad activa en un 90%. Objetivos: actualmente los resultados de conversión de la PPD y su interpretación durante el tratamiento anti-TNF-α son variables, por tal motivo nos propusimos conocer la frecuencia de conversión de la PPD en este grupo de pacientes de nuestro medio. Materiales y métodos: realizamos un estudio descriptivo, observacional y retrospectivo que incluyó pacientes >18 años, diagnosticados con enfermedad reumática, tratados con anti-TNF-α. Resultados: se incluyeron 54 pacientes (46,7 ± a 12 años), de los cuales 36, presentaron diagnóstico de artritis reumatoidea, seis de artritis idiopática juvenil, cinco de espondilitis anquilosante, tres de artritis psoriásica, tres de uveítis y uno de queratitis intersticial. Los tratamientos fueron: 30 adalimumab, 17 certolizumab, siete etanercept, 44 metotrexato, 19 leflunomida, nueve hidroxicloroquina, dos sulfasalazina, dos azatioprina, uno mofetil micofenolato y glucocorticoides (28 de 54); la conversión de la PPD ocurrió en un solo paciente. Conclusiones: en el presente trabajo la seroconversión fue baja en contraste con otras series. La prueba de PPD es un método accesible, ampliamente disponible, adecuado y sensible para diagnosticar ITL.

Introduction: anti-TNF-α are associated with an increased risk of developing tuberculosis (TB). Purified protein derivative (PPD) is used to demonstrate a latent TB infection (LTBI). Screening is recommended for TB prior to the onset of anti-TNF-α and monitoring evaluating possible conversion of PPD during treatment. Treatment of LTBI can reduce the risk of active disease development by up to 90%. Objectives: currently the results of PPD conversion and its interpretation during anti-TNF-α treatment are variable and that is why we set out to know the frequency of conversion of PPD in this group of patients in our environment. Materials and methods: a descriptive, analytical, observational, retrospective study was conducted. Including patients >18 years old, diagnosed with rheumatic disease, treated with anti-TNF-α. Results: 54 patients were included (46.7 ± to 12 years), of which 36 presented a diagnosis of rheumatoid arthritis, 6 juvenile idiopathic arthritis, 5 ankylosing spondylitis, 3 psoriatic arthritis, 3 uveitis, 1 interstitial keratitis. The treatments were: 30 adalimumab, 17 certolizumab, 7 etanercept, 44 methotrexate, 19 leflunomide, 9 hydroxychloroquine, 2 sulfasalazine, 2 azathioprine, 1 mycophenolate mofetil and glucocorticoids (28/54). PPD conversion took place in 1 patient. Conclusions: in the present study, seroconversion was low in contrast to other series. The PPD test is an accessible, widely available, adequate and sensitive method for diagnosing LTBI, which the rheumatologist should use in his daily practice.

Latent tuberculosis screening before kidney transplantation in the South of Brazil / Rastreamento de tuberculose latente antes do transplante renal no Sul do Brasil

Abstract Background: Tuberculosis (TB) is a prevalent infection after kidney transplantation (KT) in high-burden countries. Latent tuberculosis infection (LTBI) screening includes previous TB history, chest radiograph findings, and tuberculin test (TST) and/or interferon-gamma release assays (IGRAs) results. We aimed to compare our routine LTBI screening of KT candidates and living donors (LD) with their IGRA results, and evaluate if this would improve isoniazid (INH) treatment referral. Methods: We evaluated adult KT candidates and LD with complete routine LTBI screening and QuantiFERON-TB® Gold In-Tube (QFT) testing. Blood samples were collected from April 4th, 2014 to October 31st, 2018, with follow-up until October 31st, 2019. Results: There were 116 KT recipients, with 30% QFT-positive results. Positive QFT was associated with past TB history (p=0.007), positive TST (p<0.0001), residual radiographic lesions (p=0.003), and diabetes (p=0.035). There were 25 LD, 40% had positive QFT. Positive QFT was associated with a positive TST (p=0.002). Positive QFT results increased INH referral in 80%. Post-transplant TB incidence was 2.6% in a median follow-up of 2 (1-33) months. No variables were associated with post-transplant TB. TB patients had inferior, although non-significant, 5-year graft survival (66.7% vs. 76.5%) (p = 0.402). Conclusion: In the present study, the association of QFT to our routine LTBI screening incremented INH treatment referral, but there was still a high incidence of post-transplant TB, possibly related to other forms of infection, such as new exposure and donor transmission.

Resumo Histórico: Tuberculose (TB) é uma infecção relativamente comum pós-transplante renal (TR) em países com alta prevalência da doença. O rastreamento de infecção latente por tuberculose (ILTB) inclui histórico prévio de TB, achados de radiografia do tórax, resultados do teste tuberculínico (TT) e/ou de ensaio de liberação de interferon-gama (IGRAs). Nosso objetivo foi comparar nossa avaliação de rotina de candidatos ao TR e doadores vivos (DV) com seus resultados de IGRA, avaliando se aumentaria o encaminhamento para tratamento com isoniazida (INH). Métodos: Avaliamos candidatos adultos ao TR e DV com rastreamento para ILTB de rotina completo e coleta de testes QuantiFERON-TB® Gold In-Tube (QFT). Coletamos amostras sanguíneas de 4 de Abril, 2014 - 31 de Outubro, 2018, com acompanhamento até 31 de Outubro, 2019. Resultados: Avaliamos 116 receptores de TR, 30% sendo QFT-positivo. QFT positivo foi associado ao histórico prévio de TB (p=0,007), TT positivo (p<0,0001), lesões radiográficas residuais (p=0,003), diabetes (p=0,035). Avaliamos 25 DV, 40% apresentaram QFT positivo. QFT positivo foi associado a TT positivo (p=0,002). Resultados positivos do QFT aumentaram o encaminhamento para INH em 80%. A incidência de TB pós-transplante foi 2,6% em uma mediana de acompanhamento de 2 (1-33) meses. Nenhuma variável foi associada à TB pós-transplante. Pacientes com TB tiveram sobrevida do enxerto em 5 anos inferior, embora não-significativa (66,7% vs. 76,5%) (p = 0,402). Conclusão: Neste estudo, a associação do QFT à nossa avaliação de ILTB de rotina aumentou o encaminhamento para tratamento com INH, mas ainda houve alta incidência de TB pós-transplante, possivelmente relacionada a outras formas de infecção, como nova exposição e transmissão pelos doadores.

Prevalencia de tuberculosis latente determinada mediante la prueba de derivado proteico purificado (PPD) en una población de pacientes adultos con artritis reumatoide llevados a terapia biotecnológica / Prevalence of latent tuberculosis determined using the Purified Protein Derivative (PPD) test in adult patients with rheumatoid arthritis receiving biotechnological therapy

RESUMEN Introducción: Colombia es un país endémico para tuberculosis (TB), con una prevalencia de 26 casos por millón. Sin embargo, no se cuenta con datos recientes y claros respecto a la prevalencia de tuberculosis latente (TBL) en la población con artritis reumatoide (AR) candidata a terapia biotecnológica. Metodología: Estudio de corte transversal con componente analítico para determinar la pre-valencia de TBL en pacientes con AR candidatos a terapia biotecnológica. Resultados: La prevalencia de TBL en pacientes con AR candidatos a terapia biotecnológica es alta, del 18,3% (IC 95% 14,7-21,9), y en los cruces exploratorios se encontró una relación entre TBL y la variable género masculino (p ≤ 0,001), hallazgos anormales en la radiografía de tórax (p = 0,039) y el tabaquismo (p = 0,028). Conclusión: La prevalencia de TBL en pacientes con AR candidatos a terapia biotecnológica es alta. Se requieren estudios prospectivos para evaluar la incidencia de TB en este grupo de pacientes y así corroborar su asociación.

ABSTRACT Introduction: Although tuberculosis (TB) is endemic in Columbia, with a prevalence of 26 cases per million, there are no recent and clear data regarding the prevalence of latent tuberculosis (LBT) in the population with rheumatoid arthritis (RA), candidates for biotechnological therapy. Methodology: A cross-sectional study with an analytical component to determine the prevalence of LBT in patients with RA who are candidates for biotechnological therapy. Results: The prevalence of LTB in RA patients who are candidates for biotechnological therapy is high, 18.3% (95% CI: 14.7-21.9). In the exploratory analysis, a relationship between LBT and male gender was found (P ≤ .001), as well as abnormal findings on chest radiography (P = .039), and smoking (P = .028). Conclusion: The prevalence of LTB in patients with RA who are candidates for biotechnological therapy is high. Prospective studies are needed to evaluate the incidence of TB in this group of patients and corroborate this association.