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Summary: Background: Despite government efforts, tuberculosis (TB) remains a major public health threat in Brazil. In 2023, TB incidence was 39.8 cases per 100,000 population, far above the WHO’s target of 6.7 cases per 100,000. Using national-level datasets, we investigated and forecasted the potential impact of proposed public health interventions aimed at reducing TB incidence in Brazil. Methods: Monthly TB surveillance data (January 2018–December 2023) were collected from Brazilian national reporting systems: SINAN-TB (TB cases), SITE-TB (TB drug resistance), and IL-TB (preventive therapy). These data were used to create a multivariable Bayesian Structural Time-Series (BSTS) model, with 5000 Monte-Carlo simulations, which identified key predictors of TB incidence and forecasted these rates from 2024 to 2030 under various scenarios. Findings: Vulnerabilities including incarceration, TB-HIV coinfection and TB-diabetes mellitus, as well as coverages of directly observed therapy (DOT), contact investigation and preventive treatment (TPT) completion rates, were identified as key predictors of TB incidence. Under current trends, we forecasted TB incidence in Brazil to be 42.1 [34.1–49.8] per 100,000 person-years by 2030 (mean [95% prediction intervals]). A scenario considering decreases in TB cases among vulnerable populations resulted in an absolute reduction of −10.6 [−9.4 to −12.0] in projected TB incidence. Additional reductions were seen with increased coverage of DOT, TPT adherence, and contact investigation rates (−14.4 [−13 to −16.2]), and by combining these with efforts to reduce TB cases among vulnerable populations (−23.6 [−26.3 to −41.4]), potentially lowering incidence to 18.5 [7.8–28.4] per 100,000, though still above WHO targets. Interpretation: Our findings demonstrate that interventions focused on enhancing health policies focused on decreasing TB cases among vulnerable populations, such as individuals with TB-HIV coinfection, incarcerated populations, and those with TB-diabetes comorbidity, along with improvements in health management indicators such as DOT implementation, contact investigation coverage, and TPT completion rates, are effective in reducing TB incidence nationwide. Funding: Oswaldo Cruz Foundation.

Summary: Background: Since 2014, Brazil has gradually implemented the Xpert MTB/RIF (Xpert) test to enhance early tuberculosis (TB) and drug-resistant (DR-TB) detection and control, yet its nationwide impact remains underexplored. Our study conducts an intervention time-series analysis (ITSA) to evaluate how the Xpert's implementation has improved TB and DR-TB detection nationwide. Methods: 1,061,776 cases from Brazil's National TB Registry (2011–2022) were reviewed and ITSA (2011–2019) was used to gauge the impact of the Xpert's adoption on TB and DR-TB notification. Granger Causality and dynamic regression modelling determined if incorporating Xpert testing as an external regressor enhanced forecasting accuracy for Brazil's future TB trends. Findings: Xpert implementation resulted in a 9.7% increase in TB notification and substantial improvements in DR-TB (63.6%) and drug-susceptible TB (92.1%) detection compared to expected notifications if it had not been implemented. Xpert testing counts also presented a time-dependent relationship with DR-TB detection post-implementation, and improved predictions in forecasting models, which depicted a potential increase in TB and DR-TB detection in the next six years. Interpretation: This study underscores the critical role of Xpert's adoption in boosting TB and DR-TB detection in Brazil, reinforcing the case for its widespread use in disease control. Improvements in prediction accuracy resulting from integrating Xpert data are crucial for allocating resources and reducing the incidence of TB. By acknowledging Xpert's role in both disease control and improving predictions, we advocate for its expanded use and further research into advanced molecular diagnostics for effective TB and DR-TB control. Funding: FIOCRUZ.

Summary: Tuberculosis-diabetes mellitus (TB-DM) is linked to a distinct inflammatory profile, which can be assessed using multi-omics analyses. Here, a machine learning algorithm was applied to multi-platform data, including cytokines and gene expression in peripheral blood and eicosanoids in urine, in a Brazilian multi-center TB cohort. There were four clinical groups: TB-DM(n = 24), TB only(n = 28), DM(HbA1c ≥ 6.5%) only(n = 11), and a control group of close TB contacts who did not have TB or DM(n = 13). After cross-validation, baseline expression or abundance of MMP-28, LTE-4, 11-dTxB2, PGDM, FBXO6, SECTM1, and LINCO2009 differentiated the four patient groups. A distinct multi-omic-derived, dimensionally reduced, signature was associated with TB, regardless of glycemic status. SECTM1 and FBXO6 mRNA levels were positively correlated with sputum acid-fast bacilli grade in TB-DM. Values of the biomarkers decreased during the course of anti-TB therapy. Our study identified several markers associated with the pathophysiology of TB-DM that could be evaluated in future mechanistic investigations.

Introdução: A tuberculose (TB) permanece classificada entre as principais causas de morte no mundo devido a um único agente infeccioso. O diabetes mellitus (DM) pode afetar a ativação imune e tem sido associado a um risco aumentado de TB ativa e resultados desfavoráveis do tratamento da TB; podendo estar ligada a um perfil inflamatório distinto. Multi-ômica tem sido explorada para fornecer mais informações sobre as mudanças fisiológicas induzidas pela infecção por Mycobacterium tuberculosis. Neste estudo, um algoritmo de aprendizado de máquina foi aplicado a dados multiplataforma, incluindo citocinas e expressão gênica no sangue periférico e eicosanoides na urina, de um estudo de coorte multicêntrico brasileiro. Métodos: Trata-se de uma análise retrospectiva de um estudo observacional prospectivo com dados e espécimes coletados no âmbito do RePORT-Brasil, em Salvador, incluindo quatro grupos clínicos: TB-DM (n = 24), TB apenas (n = 28), apenas DM, definido como HbA1c HbA1c ≥ 6,5% (n = 11), e um grupo controle de contatos próximos de TB que não tinham TB ou DM (n = 13). Para realizar uma análise multiplataforma, usamos medidas transcriptômicas e de citocinas do sangue periférico e eicosanóides da urina. Para TB-DM, apenas TB e apenas DM, os dados foram avaliados no início do estudo e 2 e 6 meses após o início da terapia anti-TB (ATT). Um algoritmo de aprendizado de máquina foi aplicado aos dados multiplataforma. Resultados: Após validação cruzada, os marcadores Metaloproteinase de Matriz (MMP)-28, Leucotrieno E(LTE)-4, 11-dehidrotromboxano (dTx) B2, Metabólito D da Prostaglandida (PGDM), Proteína F-Box (FBXO)6, SECTM1 e LINCO2009 discriminaram os quatro grupos de pacientes. Nossos resultados revelaram um perfil multi-ômico distinto associado à TB, com maior expressão basal de LTE-4, 11dTxB2, PGDM, FBOX6, SECTM11 e LINCO2009 naqueles com TB, independentemente do estado glicêmico, quando comparados aos controles. Também avaliamos o impacto da terapia anti-tubercular na expressão/concentração desses marcadores. Além disso, os níveis de SECTM11 e FBOX6 mRNA foram positivamente correlacionados com o grau de bacilos álcool-ácido resistentes (BAAR) em TBDM. Conclusões: Os resultados apresentados em nosso estudo exploratório identificaram vários marcadores multi-ômicos associados à fisiopatologia da TB-DM que podem ser avaliados em futuras investigações mecanísticas.

Introdução: A tuberculose (TB) é uma das principais causas de morte no mundo, e o Diabetes Mellitus (DM) é uma das principais comorbidades associadas à doença. O DM afeta a resposta inflamatória crônica associada à TB, aumentando o risco de TB ativa e afetando a resposta ao tratamento. Aqui, avaliamos a dinâmica da expressão de RNA longo não codificante (lncRNA) e sua associação com TB e DM. Métodos: Dados de expressão gênica de TB, DM, TB/DM e controles saudáveis (HC) de 4 países foram obtidos. A expressão de RNAs não codificadores (ncRNA) foi recuperada e a análise de expressão diferencial foi realizada em dados brasileiros, comparando tanto TB quanto TB/DM com HC. Os ncRNAs (lncRNAs e miRNAs) expressos diferencialmente foram usados como entrada para um algoritmo de redução de dimensionalidade, para selecionar os ncRNAs mais informativos. A precisão dos lncRNA foi validada em amostras da Índia, Romênia e África do Sul. Para identificar as possíveis vias reguladas por esses lncRNAs, foi realizada uma análise de correlação entre os lncRNAs mais informativos e todos os genes. Os genes mais correlacionados foram usados na análise de enriquecimento. Resultados: Após redução da dimensão, identificamos 103 ncRNAs expressos diferencialmente na comparação TB e TB/DM. Destes, 5 lncRNAs: ADM-DT, LINC02009, LINC02471, SOX2-OT e GK-AS1. A análise de validação mostrou que os lncRNAs apresentaram acurácia moderada para classificar o DM de HC, com uma AUC de 0,652 (C.I. 0,44∼0,86). No entanto, eles tiveram precisão substancial ao discriminar TB de HC com AUC de 0,91 (C.I. 0,82∼0,99) e AUC de 0,98 (C.I. 0,95∼1,00) para TB/DM de HC. A análise de correlação para identificar os genes potencialmente associados identificou caminhos semelhantes no Brasil e na Índia para ambas as condições de TB e TB/DM. As vias identificadas estavam relacionadas à sinalização de interleucina e interferon, cascatas de receptores Toll-like, cascatas de receptores Toll-like, degranulação de neutrófilos e via de infecção. Conclusão: Apesar da escassez de informações sobre suas funções biológicas na literatura, os 5 lncRNAs mais informativos foram fortemente correlacionados com genes associados a vias relacionadas à regulação da resposta imune contra TB. Os genes fortemente correlacionados eram de vias relacionadas ao controle da TB, sugerindo papel importante dos lncRNA na regulação da resposta inflamatória na TB.

BackgroundOxidized lipid mediators such as eicosanoids play a central role in the inflammatory response associated with tuberculosis (TB) pathogenesis. Diabetes mellitus (DM) leads to marked changes in lipid mediators in persons with TB. However, the associations between diabetes-related changes in lipid mediators and clearance of M. tuberculosis (Mtb) among persons on anti-TB treatment (ATT) are unknown. Quantification of urinary eicosanoid metabolites can provide insights into the circulating lipid mediators involved in Mtb immune responses.MethodsWe conducted a multi-site prospective observational study among adults with drug-sensitive pulmonary TB and controls without active TB; both groups had sub-groups with or without dysglycemia at baseline. Participants were enrolled from RePORT-Brazil (Salvador site) and RePORT-South Africa (Durban site) and stratified according to TB status and baseline glycated hemoglobin levels: a) TB-dysglycemia (n=69); b) TB-normoglycemia (n=64); c) non-TB/dysglycemia (n=31); d) non-TB/non-dysglycemia (n=29). We evaluated the following urinary eicosanoid metabolites: 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (major urinary metabolite of prostaglandin E2, PGE-M), tetranor-PGE1 (metabolite of PGE2, TN-E), 9α-hydroxy-11,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (metabolite of PGD2, PGD-M), 11-dehydro-thromboxane B2 (11dTxB2), 2,3-dinor-6-keto-PGF1α (prostaglandin I metabolite, PGI-M), and leukotriene E4 (LTE4). Comparisons between the study groups were performed at three time points: before ATT and 2 and 6 months after initiating therapy.ResultsPGE-M and LTE4 values were consistently higher at all three time-points in the TB-dysglycemia group compared to the other groups (p

Background: A major goal of tuberculosis (TB) epidemiological studies is to obtain results that can be generalized to the larger population with TB. The ability to extrapolate findings on the determinants of TB treatment outcomes is also important. Methods: We compared baseline clinical and demographic characteristics and determinants of anti-TB treatment outcomes between persons enrolled in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort between June 2015 and June 2019, and the registry of TB cases reported to the Brazilian National TB Program (Information System for Notifiable Diseases [SINAN]) during the same time period. Multivariable regression models adjusted for the study site were performed using second-generation p-values, a novel statistical approach. Associations with unfavorable treatment outcomes were tested for both RePORT-Brazil and SINAN cohorts. Findings: A total of 1,060 culture-confirmed TB patients were enrolled in RePORT-Brazil and 455,873 TB cases were reported to SINAN. Second-generation p-value analyses revealed that the cohorts were strikingly similar with regard to sex, age, use of antiretroviral therapy and positive initial smear sputum microscopy. However, diabetes, HIV infection, and smoking were more frequently documented in RePORT-Brazil. Illicit drug use, the presence of diabetes, and history of prior TB were associated with unfavorable TB treatment outcomes; illicit drug use was associated with such outcomes in both cohorts. Conclusions: There were important similarities in demographic characteristics and determinants of clinical outcomes between the RePORT-Brazil cohort and the Brazilian National registry of TB cases.

Objective: Vaccination coverage is decreasing worldwide, favoring the potential reemergence of vaccine-preventable diseases. In this study, we performed a longitudinal characterization of vaccination coverage in Brazil and compared the profiles between the distinct regions in the country to test whether there has been a substantial change over the last 5 years. Methods: De-identified publicly available data were retrieved from the repository of the Brazilian Ministry of Health, comprising detailed information on vaccination coverage in all age groups between 1994 and 2019. The vaccination coverage for the whole country and for each Brazilian region, by year, was examined, and a time-series pattern analysis was performed. Results: A significant decrease in overall vaccination coverage across the country regions was observed between 2017 and 2019, especially in childhood immunization. A reduction in BCG, hepatitis B, influenza, and rotavirus vaccine coverage was observed. Conversely, vaccines against measles, mumps, rubella, varicella, and meningococcus showed an increase in coverage. Region-specific changes in vaccination patterns within the study period were observed. Conclusions: A substantial reduction in vaccination coverage was detected in Brazil, a country already highly susceptible to the emergence of epidemic infectious diseases. Continuing evaluation of the immunization program actions may help to improve vaccination coverage and prevent new epidemics.

There is currently no system to track the emergence of Zika virus (ZIKV) subtypes. We developed a surveillance system able to retrieve sequence submissions and further classify distinct ZIKV genotypes in the world. This approach was able to detect a new occurrence of ZIKV from an African lineage in Brazil in 2019.

Summary: Leishmania braziliensis infection frequently results in cutaneous leishmaniasis (CL). An increase in incidence of drug-resistant CL leading to treatment failure has been reported. Identification of reliable predictors of treatment outcomes is necessary to optimize patient care. Here, we performed a prospective case-control study in which plasma levels of cytokines and lipid mediators were assessed at different time points during antileishmanial therapy in patients with CL from Brazil. Multidimensional analyses were employed to describe a combination of biomarkers able to predict and characterize treatment failure. We found a biosignature influenced mainly by plasma levels of lipid mediators that accurately predicted treatment failure. Furthermore, transcriptomic analysis of a publicly available data set revealed that expression levels of genes related to lipid metabolism measured in skin lesions could distinguish treatment outcomes in CL. Thus, activation of pathways linked to lipid biosynthesis predicts treatment failure in CL. The biomarkers identified may be further explored as therapeutic targets.