Mycobacterium tuberculosis transmission among child and adolescent contacts of people with pulmonary tuberculosis in Brazil: a multi-center prospective cohort study

BackgroundNon-sputum biomarkers to monitor tuberculosis (TB) treatment and predict poor outcomes are lacking. We evaluated host-blood transcriptomic signatures for treatment monitoring and prognosis (death, treatment failure, recurrence) in adults with pulmonary TB.MethodsAdults with culture-confirmed, drug-susceptible pulmonary TB were enrolled at five Brazilian sites. Whole-blood PAXgene samples were collected at baseline, month 2 (M2), and end of treatment (EoT). Treatment failure was defined as sputum culture positivity at month 5 or later. Participants were followed for 24 months from treatment initiation for clinical or microbiological TB recurrence. Unfavourable outcomes were matched ~1:3 to recurrence-free cure. Twenty-two published blood transcriptomic signatures were measured by microfluidic RT-qPCR and benchmarked against the WHO Target Product Profile (TPP) criteria.ResultsWe matched 263 participants with recurrence-free cure to 33 with treatment failure, 24 who died (TB/unknown cause), and 9 with recurrence. Signature scores generally declined from baseline to EoT. Multiple signatures predicted recurrence at baseline and M2 (AUC range 0.71–0.91), with waning performance at EoT (AUC range 0.42–0.89). Against the WHO TPP, 2/22 signatures met minimum criteria at baseline, 13/22 at M2, and none at EoT. Prediction of treatment failure was poor across timepoints (AUC <0.70). In contrast, Thompson5 and others at baseline predicted death during treatment or follow-up (AUC ≥0.80).ConclusionBlood transcriptomic signatures tracked treatment response and predicted recurrence and death, meeting WHO TPP benchmarks at baseline and M2. These findings support prospective, biomarker-guided trials to individualise TB therapy—shortening regimens for early responders and intensifying care for high-risk patients.FundingThis work was supported by the U.S. National Institutes of Health, CRDF Global, and Departamento de Ciência e Tecnologia (DECIT) - Secretaria de Ciência e Tecnologia (SCTIE), Ministério da Saúde (MS), Brazil.

Social inequalities play a crucial role in the incidence of TB, making it plausible that they act as effect modifiers on the impact of active case-finding (ACF) strategies in the detection of the disease. We estimated the association between ACF strategies and TB detection rates and evaluated their effect modification due to social inequalities in Brazilian municipalities. We included 5033 municipalities that reported at least one new TB case. We defined the TB detection rate as the outcome variable. Our exposure variables were the proportion of primary care team (PCT) reporting community-based ACF for TB and household contact investigation (HCI) of new TB cases. We also assessed the Municipal Human Development Index (MHDI) and the Social Vulnerability Index (SVI) as potential effect modifier variables. The TB detection rate was positively associated with both the proportion of PCTs conducting community-based ACF and the proportion conducting HCI. These associations weakened as MHDI increased (interaction incident rate ratio [IRR] 0.95, 95% CI 0.90 to 0.98 for ACF; IRR 0.93, 95% CI 0.89 to 0.96 for HCI) and strengthened with higher SVI values (IRR 1.11, 95% CI 1.02 to 1.22 and IRR 1.17, 95% CI 1.08 to 1.27, respectively). Social inequalities in Brazilian municipalities modify the effect of ACF strategies on TB detection rates.

The COVID-19 pandemic disrupted tuberculosis (TB) control, increasing mortality and potentially worsening disparities. This study aimed to analyze the temporal trends of TB mortality in Brazil and to trace the COVID-19 pandemic's effect using a Bayesian approach, focusing on nationwide data. An ecological study of TB deaths recorded in the Mortality Information System (SIM) from 2012 to 2022 was conducted. Trends and percentage changes in the mortality were estimated. A Bayesian Structural Time Series model combined with an Autoregressive Integrated Moving Average model was used to assess the pandemic's effect on TB. A total of 51,809 TB deaths were identified, with a mortality rate of 2.27 per 100,000. Higher rates were found among the elderly (6.86), indigenous populations (5.58), and black individuals (4.21). The Bayesian model estimated a 9.9% (CI 8.8-11%) increase in TB mortality due to COVID-19. The Midwest region showed the highest increase (30%, 25-35%). Females experienced a greater post-pandemic monthly increase (2.80%) in mortality than males (0.72%). The Bayesian analysis revealed a significant rise in TB mortality during the COVID-19 pandemic, with notable disparities affecting females, the elderly, the indigenous, and the black populations. These findings highlight the pandemic's long-term impact on TB and stress the need for equity-focused, data-driven public health responses in Brazil.

Even after successful treatment, individuals surviving tuberculosis (TB) disease experience elevated mortality rates. However, there is limited evidence on how these risks vary over time and by individual characteristics. We conducted a retrospective cohort study of individuals diagnosed with TB in Brazil, using national TB notifications and linked mortality records for 2007-2016. We estimated mortality rate ratios (MRRs) and cumulative mortality by year since TB diagnosis, compared to general population mortality matched on age, sex, year, and state. We identified clinical and sociodemographic factors associated with elevated post-TB mortality, and compared the distribution of causes of death to the general population. The study sample included 834,594 individuals, with 4.1 million person-years of follow-up (average: 4.9 years). The TB cohort had elevated mortality compared to the general population, particularly in the first year post-diagnosis (MRR 11.28, 95%CI: 11.18-11.37). Post-TB MRRs declined from 3.59 (3.53-3.64) in year 2 to 1.46 (1.34-1.59) in year 10. Cumulative excess mortality was 6.12% (6.07-6.17) after 1 year and 9.90% (9.58-10.24) after 10 years. MRRs were highest for individuals 30-44 years-old at diagnosis. Relapse, loss to follow-up, and co-prevalent conditions like HIV and alcohol use disorder were strongly associated with higher MRRs. Over time, major causes of death in the TB cohort shifted from TB and HIV to cardiovascular disease, cancer, and non-TB respiratory diseases. Individuals developing TB disease face elevated mortality up to 10 years after diagnosis. These excess risks vary across demographic and clinical characteristics.

Incidence and mortality by pulmonary tuberculosis in Brazil: Trends and projections, 2002-2034.

Introduction: Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis, with a high morbidity and mortality rate in Brazil, reflecting a serious public health problem, in view of this, the World Health Organization recommends the organization and performance of services in the health promotion of the population, thus, Primary Health Care (PHC), being the gateway to the SUS, it is essential in epidemiological surveillance, early detection, and adherence to TB treatment. Objective: to study the profile of TB consultations in PHC Health in Brazil from 2015 to 2024. Results: TB consultations in PHC totaled n=68964 consultations, with a mean=6896.40 (±11132.6) and Coefficient of Variation (CV)=161.43%; Consultations with the identification of new cases resulted in n=45159 consultations, and n=23805 consultations were carried out with patients cured of tuberculosis under supervised treatment. As for gender, males predominate, representing 60% of the sample, and the age group from 30 to 34 with n=4783 had more consultations, followed by the age group from 20 to 24 with n=4740 consultations. Final Considerations: In view of this, it was observed that Brazil has high rates of tuberculosis and the number of consultations in primary care, especially of new cases, but also of cured cases, leads us to the need for actions to prevent the disease, as well as the need to strengthen PHC in Brazil to the point of meeting the spontaneous demand that shows a growing trend of need for consultations of new cases and treated cases, but above all, in the fulfillment of one of its purposes that is still being exercised in an immature way, which is health promotion, aiming at the prevention of tuberculosis cases, given the importance of PHC in the control of epidemics, outbreaks and endemics, with emphasis on the control of infectious-contagious diseases in order to prevent the spread of diseases such as TB.

Tuberculosis (TB) is the most common comorbidity in people living with HIV/AIDS (PLWH), including those under antiretroviral treatment. PLWH are 28 times more likely to develop TB in Brazil, the leading cause of HIV-related deaths globally, with approximately 161,000 reported deaths worldwide in 2023. Early diagnosis of latent tuberculosis infection (LTBI) and prophylactic therapy can reduce TB cases, prevent disease progression, and decrease transmission in high-risk populations. This study assessed the prevalence of LTBI in PLWH using the interferon-gamma release assay (IGRA) and the impact of the 3HP regimen (isoniazid [INH]/rifapentine [RPT]) as prophylactic treatment. Blood samples from 335 PLWH (78% of the 427 in the cohort) were tested for IGRA; 50 PLWH (15%) tested positive and were treated with 3HP. Treatment included 900 mg of INH and 900 mg of RPT in 12 weekly doses according to the Brazilian health guidelines. No specific risk factors, including nadir CD4+T count, age, gender, or antiretroviral therapy (ART), were more frequently observed in the PLWH with LTBI compared to the PLWH without LTBI. All PLWH with LTBI received treatment and no cases of active TB were observed. Our findings highlight the need for wider LTBI screening and treatment among PLWH in the latent phase, emphasizing more stringent approaches for implementing 3HP prophylaxis.

Tuberculosis is a globally distributed infectious disease of great importance to public health due to its zoonotic nature. In addition to its major impact on public health, bovine tuberculosis causes major economic losses due to reduced herd productivity and carcass losses in slaughterhouses. Given the critical importance of the disease, it is of utmost importance to enhance the accuracy of diagnostic methods in programs aimed at controlling and eradicating bovine tuberculosis in Brazil. The objective of this research project is to diagnose bovine tuberculosis in dairy herds that previously tested negative in the intradermal tuberculin test using commercial ELISA (enzyme-linked immunosorbent assay). Samples from 17,917 cattle from dairy herds distributed across five farms in the Campos Gerais region of the state of Paraná were analyzed. For serological diagnosis, the commercial ELISA/IDEXX® kit was used to detect anti-Mycobacterium bovis antibodies in cattle herds. Of the 17,917 animals tested, the ELISA Mycobacterium bovis Antibody Test (IDEXX®) identified 399 (2.3%) reactive animals and 17,518 (97.7%) non-reactive animals. The highest number of positive animals in the ELISA was observed on farm B, with 375 (2.5%) reactive animals. Given the challenges faced in Brazil regarding the diagnostic confirmation of tuberculosis and the absence of validated reagents and methods, the importance of implementing new validated diagnostic methods is evident. The use of ELIST could serve as a complementary alternative to the official intradermal tuberculin test, potentially detecting false-negative animals and aiding in the control of the disease.

Social and health factors associated with unfavourable treatment outcomes in children and adolescents with drug-sensitive tuberculosis in Brazil: a national retrospective cohort study

Bovine tuberculosis is one of the primary infectious diseases affecting cattle. Although several countries have managed to eradicate this zoonosis it remains endemic and uncontrolled across many countries in Africa, Asia, Latin America, and the Middle East. Brazil launched its national control and eradication program in 2001, and since then, epidemiological studies have been carried out to define optimal control strategies and to enable the management of the process in each region. This study covered the state of Pará, which was divided into three regions, in each of which a pre-established number of properties were randomly selected, and within each property, a minimum number of animals were drawn to be tested by the tuberculin test to classify the farm as infected or free of the disease. A questionnaire was administered to the selected properties to identify the risk factors for the disease. A total of 976 properties comprising 17,151 animals were tested. The prevalence of infected properties in the regions ranged from 3.1% [1.3; 4.9] to 18.6% [14.3; 22.9], while tuberculin-positive animals ranged from 0.24% [0.09; 0.40] to 4.8% [2.4; 7.3]. The introduction of cattle untested for bTB and the renting of pastures have been identified as risk factors for the disease in this state. Pará has one of the highest prevalences of bovine tuberculosis in Brazil, and the implications of these results for public health were discussed. We therefore proposed that the state's Official Veterinary Service, together with the private dairy and meat sectors, pursue the objective of controlling or eradicating the disease, along with mechanisms to verify its effectiveness. The differences between the two objectives were discussed, but in both cases, an education program is necessary to inform cattle and buffalo breeders that they need to test animals for tuberculosis before introducing them to their farms, and also to avoid renting pastures for cattle to graze and rest while moving on foot, as these practices have contributed the most to the spread of bTB in the state.

Tuberculosis (TB) and depression are highly comorbid and linked to higher rates of death and disability. Several evidence-based treatments for depression have been successfully implemented in low- and middle-income countries, but more knowledge is needed on how to bring these innovations to scale within complex 'real world' public health systems. To explore whether the principles of social network analysis could be used to enhance receptivity to integrating depression treatment into primary care for individuals with and without TB in Brazil. We used existing scales to identify settings and providers with high receptivity and connectivity within the primary care network. We trained and supervised existing staff in three primary care sites to deliver a brief evidence-based intervention over one year, coupled with active dissemination activities. Afterwards, we reassessed receptivity among individuals involved, and not involved, in the pilot. Highly significant changes were observed in mental health literacy, attitudes towards evidence-based practices, work self-efficacy, and implementation leadership supporting our hypothesis. Limited social connections between primary care clinics precluded the examination of the hypothesis that targeting settings with high connectivity could capitalize on the information flow between and transcend the decentralized structure of the network, but leveraging the centralized nature of the TB program to integrate mental health services emerged as a promising alternative. The findings of this study strongly suggest that social networks may be leveraged to change individual providers' attitudes, thereby contributing to the enhanced dissemination of evidence-based interventions.

We conducted a matched retrospective cohort study comparing mortality among individuals receiving a false-positive tuberculosis (TB) diagnosis (n = 3701) to individuals correctly diagnosed with TB (n = 8595) in Brazil from 2007 to 2016. Over an average 5.4-year follow-up period, we estimated a mortality rate ratio of 1.95 (95% confidence interval, 1.80-2.11) for individuals incorrectly diagnosed with TB compared to controls. The leading causes of death among the misdiagnosed were malignant neoplasms (40.9%) and respiratory system disorders (15.9%), conditions with symptoms similar to TB. Our findings highlight the need for improved follow-up care after identification of false-positive cases to increase survival for this high-risk population.

Genetic polymorphisms have been associated with risk of antituberculosis treatment toxicity. We characterized associations with adverse events and treatment failure/recurrence among adults treated for tuberculosis in Brazil. Participants were followed in Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil. We included persons with culture-confirmed drug-susceptible pulmonary tuberculosis who started treatment between 2015 and 2019, and who were eligible for pharmacogenetics. Treatment included 2 months of isoniazid, rifampin or rifabutin, pyrazinamide, and ethambutol, then 4 months of isoniazid and rifampin or rifabutin, with 24-month follow-up. Analyses included 43 polymorphisms in 20 genes related to antituberculosis drug hepatotoxicity or pharmacokinetics. Whole exome sequencing was done in a case-control toxicity subset. Among 903 participants in multivariable genetic association analyses, NAT2 slow acetylator status was associated with increased risk of treatment-related grade 2 or greater adverse events, including hepatotoxicity. Treatment failure/recurrence was more likely among NAT2 rapid acetylators, but not statistically significant at the 5% level. A GSTM1 polymorphism (rs412543) was associated with increased risk of treatment-related adverse events, including hepatotoxicity. SLCO1B1 polymorphisms were associated with increased risk of treatment-related hepatoxicity and treatment failure/recurrence. Polymorphisms in NR1/2 were associated with decreased risk of adverse events and increased risk of failure/recurrence. In whole exome sequencing, hepatotoxicity was associated with a polymorphism in VTI1A , and the genes METTL17 and PRSS57 , but none achieved genome-wide significance. In a clinical cohort representing three regions of Brazil, NAT2 acetylator status was associated with risk for treatment-related adverse events. Additional significant polymorphisms merit investigation in larger study populations, particularly regarding risk of treatment failure/recurrence.

Nationwide economic analysis of pulmonary tuberculosis in the Brazilian healthcare system over seven years (2015–2022): a population-based study

Abstract Background In 2022, tuberculosis caused 11,200 deaths in Brazil and 1,300,000 globally. With 87,344 new cases, it remains a leading infectious cause of death, second only to COVID-19. Prompt detection is critical, particularly with the growing resistance to rifampicin and isoniazid, highlighting the need for molecular testing. External Quality Assessment Programs (EQAP) are essential to ensure the accuracy, reliability, and harmonization of laboratory results amid the complexities of M. tuberculosis infection. Here, we evaluate the overall performance of participating laboratories (labs) in three EQAP related to tuberculosis: M. tuberculosis molecular detection (MTB), Rifampicin resistance detection (RIF), and Isoniazid resistance detection (INH). All are organized by a Brazilian provider accredited according to the ABNT NBR ISO/IEC 17043:2011 standard. Methods The EQAP samples were suspensions containing human cells, with or without the addition of cultured, inactivated, and lyophilized M. tuberculosis. Labs received two samples quarterly for testing accuracy, sensitivity, and specificity. We computed these metrics along with participant and round numbers. The Mann-Kendall test assessed accuracy trends over time. Furthermore, kit type accuracies for in-vitro diagnostic (IVD) vs. laboratory-developed tests (LDT), World Health Organization recommended (WHO-recommended) vs. other kits (non-WHO), and methods (qPCR vs. PCR) were compared using chi-square tests and odds-ratio calculations. Results In the MTB EQAP (2018-2022), 63 labs participated over 20 rounds, with 22 (range: 6-48) labs per round on median, achieving 96.6% accuracy (853/883), 97.5% sensitivity (556/570), and 94.9% specificity (297/313). The Mann-Kendall test found no significant accuracy trends over time (τ = -0.91, p = 0.36). IVDs outperformed LDTs with 97.8% (751/768) vs. 87.9% (102/116) accuracy (OR=6.0, 95%CI 3.42-20.9, p&amp;lt;0.0001). WHO-recommended kits were more accurate than non-WHO kits, 98.2% (674/686) vs. 90.4% (179/198) (OR=5.96, 95%CI 1.05-12.7, p&amp;lt;0.0001). qPCR exceeded the accuracy of PCR, 97.2% (833/857) versus 74% (20/27) (OR=12.1, 95%CI 4.8-32.9, p&amp;lt;0.0001). For RIF EQAP (2020-2022), 49 laboratories in 9 rounds, with 25 (range: 18-42) laboratories per round on median, showed 97.4% accuracy (297/305), 97.2% sensitivity (176/181), and 97.6% specificity (121/124). In the INH EQAP (2021-2022), 7 laboratories over 7 rounds, with 4 (range: 2-5) laboratories per round on median, reached 95.2% accuracy (20/21), 100% sensitivity (4/4), and 94.1% specificity (16/17). Differences between types of kits and methods for RIF and INH, as well as trends over time, were not significant or could not be calculated due to the limited number of samples. Conclusions The MTB EQAP underscored the high participation and suitability of labs, along with excellent diagnostic performance; IVD kits were 6 times more likely to yield adequate results than LDTs. WHO-recommended kits were 5.9 times more likely to produce adequate results than non-WHO kits. qPCR was 12.6 times more likely to achieve adequate results than PCR. Despite fewer participants in RIF and INH, their performance rates were high; more data are needed for conclusive results on kit and method types. This study affirms the quality of molecular diagnostics for tuberculosis in Brazil, informs on kit and method selection, and underscores the critical role of EQAPs in combating a significant global health issue.

RESUMEN Estúdio transversal caracterizando epidemiológica y sociodemográficamente la morbilidad por Tuberculosis Extrapulmonar (TBEP) en Brasil de 2010 a 2021. Se evaluaron los porcentajes de TBEP en los espacios: pleural, ganglios periféricos, genitourinario, óseo, ocular, miliar, meningoencefálico, cutáneo, laríngeo y otros. La estadística descriptiva resumió las características socioepidemiológicas por regiones. Se utilizó el modelo de regresión joinpoint para analizar y representar gráficamente la tendencia. Para estimar la relación y efecto de las variables sobre los casos se utilizó la correlación bivariada de Pearson y el modelo de regresión de Poisson. La pleura fue el ámbito más afectado, así como la región sudeste. Predominaron los hombres, negros, el grupo etario de 15 a 59 años y el VIH/SIDA como enfermedad más asociada a la TBEP. Las tasas de incidencia mostraron caída entre 2019 y 2021 en las regiones Norte, Centro-Oeste y Sur. En el país predominó el descenso de la tendencia, excepto en niños de 0 a 14 años, con aumento significativo del sexo femenino a partir de 2019. Este estudio proporcionó informaciones socioepidemiológicas sobre el acaecimiento de TBEP, destacando la importancia de verificar la cobertura y la calidad de la atención por parte de los equipos de salud de la familia.

Introduction: tuberculosis (TB) is a public health problem. Brazil is among the group of 22 countries responsible for 90% of the world’s TB cases. High proportions of abandonment of treatment may contribute to this epidemiological scenario that is difficult to control. Objective: to analyze the factors associated with abandonment of tuberculosis treatment (ATT). Methods: this is a cross-sectional study of individuals diagnosed with tuberculosis in Brazil between 2014 and 2019 whose cases had been reported to the Notifiable Diseases Information System. Poisson regression of robust variance was used according to hierarchical levels. Results: a total of 508,787 cases were reported, and 59,871 patients (16.4%) abandoned treatment. The prevalence of abandonment was higher in homeless individuals (PR 2.75; 95%CI 2.10-3.61), black race/skin color (PR 1.79; 95%CI 1.46-2.20), HIV/AIDS (PR 1.59; 95%CI 1.30-1.93), alcoholics (PR 1.38; 95%CI 1.14-1.68), illicit drug use (PR 1.85; 95%CI 1.49-2.28), and in individuals who resumed treatment after abandonment (PR 1.91; 95%CI 1.54-2.37). Conclusion: social vulnerability is associated with the abandonment of tuberculosis treatment.

Tuberculosis (TB) causes over 1million deaths annually. Providing effective treatment is a key strategy for reducing TB deaths. In this study, we identified factors associated with unsuccessful treatment outcomes among individuals treated for TB in Brazil. We obtained data on individuals treated for TB between 2015 and 2018 from Brazil's National Disease Notification System (SINAN). We excluded patients with a history of prior TB disease or with diagnosed TB drug resistance. We extracted information on patient-level factors potentially associated with unsuccessful treatment, including demographic and social factors, comorbid health conditions, health-related behaviors, health system level at which care was provided, use of directly observed therapy (DOT), and clinical examination results. We categorized treatment outcomes as successful (cure, completed) or unsuccessful (death, regimen failure, loss to follow-up). We fit multivariate logistic regression models to identify factors associated with unsuccessful treatment. Among 259,484 individuals treated for drug susceptible TB, 19.7% experienced an unsuccessful treatment outcome (death during treatment 7.8%, regimen failure 0.1%, loss to follow-up 11.9%). The odds of unsuccessful treatment were higher with older age (adjusted odds ratio (aOR) 2.90 [95% confidence interval: 2.62-3.21] for 85-100-year-olds vs. 25-34-year-olds), male sex (aOR 1.28 [1.25-1.32], vs. female sex), Black race (aOR 1.23 [1.19-1.28], vs. White race), no education (aOR 2.03 [1.91-2.17], vs. complete high school education), HIV infection (aOR 2.72 [2.63-2.81], vs. no HIV infection), illicit drug use (aOR 1.95 [1.88-2.01], vs. no illicit drug use), alcohol consumption (aOR 1.46 [1.41-1.50], vs. no alcohol consumption), smoking (aOR 1.20 [1.16-1.23], vs. non-smoking), homelessness (aOR 3.12 [2.95-3.31], vs. no homelessness), and immigrant status (aOR 1.27 [1.11-1.45], vs. non-immigrants). Treatment was more likely to be unsuccessful for individuals treated in tertiary care (aOR 2.20 [2.14-2.27], vs. primary care), and for patients not receiving DOT (aOR 2.35 [2.29-2.41], vs. receiving DOT). The risk of unsuccessful TB treatment varied systematically according to individual and service-related factors. Concentrating clinical attention on individuals with a high risk of poor treatment outcomes could improve the overall effectiveness of TB treatment in Brazil.

To describe the sociodemographic and clinical-epidemiological profile of homeless people affected by tuberculosis in Brazil, from 2015 to 2021. This is a descriptive, population-based epidemiological study, carried out from the tuberculosis notification records in the Brazilian homeless people, available in the Notifiable Diseases Information System. There was a predominance of male people, of mixed race/color, aged between 30 and 49 years, with (in) complete elementary education and who did not receive social benefits. Regarding the clinical-epidemiological aspects, the type of entry as a new case predominated, with the pulmonary form of the disease, directly observed treatment not performed, with loss of follow-up. The prevalence of alcohol and illicit drug use stands out, in addition to the large number of people who used tobacco. This scenario represents a great challenge, since the presence of tuberculosis prevails in this population, especially as a result of numerous risk factors and situations of vulnerability arising from being homeless. Thus, it is necessary to plan and improve actions that consider the specificities of the group, through inter- and intra-sectoral strategies, focusing on the articulation between public health services and social assistance.