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Background It is unknown whether dysglycemia is associated with Mycobacterium tuberculosis transmission. Methods We assessed epidemiological and clinical characteristics of patients with culture-confirmed pulmonary tuberculosis and their close contacts, enrolled in a multicenter prospective cohort in Brazil. Contacts were investigated at baseline and 6 months after enrollment. QuantiFERON positivity at baseline and conversion (from negative to positive at month 6) were compared between subgroups of contacts according to glycemic status of persons with tuberculosis (PWTB) as diabetes mellitus (DM) or prediabetes. Multivariable mixed-effects logistic regression models were performed to test independent associations with baseline QuantiFERON positive and QuantiFERON conversion. Results There were 592 PWTB (153 DM, 141 prediabetes, 211 normoglycemic) and 1784 contacts, of whom 658 were QuantiFERON-positive at baseline and 106 converters. Multivariable analyses demonstrated that tuberculosis-prediabetes cases, acid-fast bacilli-positive, pulmonary cavities, and living with someone who smoked were independently associated with QuantiFERON positive in contacts at baseline. DM, persistent cough, acid-fast bacilli-positive, and pulmonary cavities in tuberculosis source cases were associated with QuantiFERON conversion. Conclusions Contacts of persons with pulmonary tuberculosis and dysglycemia were at increased risk of being QuantiFERON positive at baseline or month 6. Increased focus on such close contacts could improve tuberculosis control.

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.

Background: The present study evaluated factors associated with losses in the latent tuberculosis infection (LTBI) cascade of care in contacts of tuberculosis (TB) patients, in a referral center from a highly endemic region in Brazil. Methods: Contacts of 1672 TB patients were retrospectively studied between 2009 and 2014. Data on TB screening by clinical investigation, radiographic examination and tuberculin skin test (TST) were extracted from medical records. Losses in the cascade of care and TB incidence within 2-year follow-up were calculated. Results: From a total of 1180 TB contacts initially identified, only 495 were examined (58% loss), and 20 were diagnosed with active TB at this stage. Furthermore, 435 persons returned for TST result interpretation and 351 (∼81%) were TST positive. Among those with positive TST, 249 (73%) were treated with isoniazid for 6 months whereas 51 abandoned therapy early. Three individuals who did not receive LTBI treatment, one with incomplete treatment and another who completed treatment developed active TB. A logistic regression analysis revealed that increases in age were associated with losses in the LTBI cascade independent of other clinical and epidemiological characteristics. Conclusions: Major losses occur at initial stages and older patients are at higher risk of not completing the LTBI cascade of care. Keywords: Tuberculosis, Latent TB infection, LTBI cascade, Treatment for latent TB

The interferon gamma release assay (IGRA) has emerged as a useful tool for identifying latent tuberculosis infection (LTBI). This assay can be performed through testing platforms such as the QuantiFERON-TB Gold Plus (QFT-Plus) assay. This in vitro test has been incorporated into several guidelines worldwide and has recently been considered by the World Health Organization (WHO) for the diagnosis of LTBI. The possibility of systematically implementing IGRAs such as the QFT-Plus assay in centers that perform LTBI screening has been accelerated by the decreased availability of the tuberculin skin test (TST) in several countries. Nevertheless, the process to implement IGRA testing in routine clinical care has many gaps. The study utilized the expertise acquired by the laboratory teams of the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil consortium during study protocol implementation of LTBI screening of tuberculosis (TB) close contacts. RePORT-Brazil includes clinical research sites from Brazilian cities and is the largest multicenter cohort of TB close contacts in the country to date. Operational and logistical challenges faced during IGRA implementation in all study laboratories are described, as well as the solutions that were developed and led to the successful establishment of IGRA testing in RePORT-Brazil. The descriptions of the problems identified and resolved in this study can assist laboratories implementing IGRAs, in addition to manufacturers of IGRAs providing effective technical support. This will facilitate the implementation of IGRA testing in countries with large TB burdens, such as Brazil. IMPORTANCE The IGRA has emerged as a useful tool for identifying persons with LTBI. Although the implementation of IGRAs is of utmost importance, to our knowledge there is scarce information on the identification of logistical and technical challenges for systematic screening for LTBI on a large scale. Thus, the descriptions of the problems identified and resolved in this study can assist laboratories implementing IGRAs, in addition to manufacturers of IGRAs providing effective technical support. This will facilitate the implementation of IGRA testing in countries with large TB burdens, such as Brazil.

BackgroundThere are scarce data on the prevalence and disease presentation of HIV in patients with tuberculosis (TB) and dysglycemia (diabetes [DM] and prediabetes [PDM]), especially in TB-endemic countries.MethodsWe assessed the baseline epidemiological and clinical characteristics of patients with culture-confirmed pulmonary TB, enrolled in a multicenter prospective cohort in Brazil (RePORT-Brazil) during 2015-2019. Dysglycemia was defined by elevated glycated hemoglobin and stratified as PDM or DM. Additionally, we used data from TB cases obtained through the Brazilian National Notifiable Diseases Information System (SINAN), during 2015-2019. In SINAN, diagnosis of diabetes was based on self-report. Logistic regression models were performed to test independent associations between HIV, dysglycemia status, and other baseline characteristics in both cohorts.ResultsIn the RePORT-Brazil cohort, the prevalence of DM and of PDM was 23.7% and 37.8%, respectively. Furthermore, the prevalence of HIV was 21.4% in the group of persons with TB-dysglycemia and 20.5% in that of patients with TBDM. In the SINAN cohort, the prevalence of DM was 9.2%, and among the TBDM group the prevalence of HIV was 4.1%. Logistic regressions demonstrated that aging was independently associated with PDM or DM in both the RePORT-Brazil and SINAN cohorts. In RePORT-Brazil, illicit drug use was associated with PDM, whereas a higher body mass index (BMI) was associated with DM occurrence. Of note, HIV was not associated with an increased risk of PDM or DM in patients with pulmonary TB in both cohorts. Moreover, in both cohorts, the TBDM-HIV group presented with a lower proportion of positive sputum smear and a higher frequency of tobacco and alcohol users.ConclusionThere is a high prevalence of dysglycemia in patients with pulmonary TB in Brazil, regardless of the HIV status. This reinforces the idea that DM should be systematically screened in persons with TB. Presence of HIV does not substantially impact clinical presentation in persons with TBDM, although it is associated with more frequent use of recreational drugs and smear negative sputum samples during TB screening.

Background It is unclear whether diabetes or prediabetes affects unfavorable treatment outcomes and death in people with tuberculosis (PWTB). Methods Culture-confirmed, drug-susceptible PWTB, enrolled in the Regional Prospective Observational Research in Tuberculosis (RePORT)–Brazil cohort between 2015 and 2019 (N = 643) were stratified based on glycemic status according to baseline glycated hemoglobin. Unfavorable tuberculosis (TB) outcome was defined as treatment failure or modification, recurrence, or death; favorable outcome was cure or treatment completion. We corroborated the findings using data from PWTB reported to the Brazilian National System of Diseases Notification (SINAN) during 2015–2019 (N = 20 989). Logistic regression models evaluated associations between glycemic status and outcomes. Results In both cohorts, in univariate analysis, unfavorable outcomes were more frequently associated with smoking, illicit drug use, and human immunodeficiency virus infection. Diabetes, but not prediabetes, was associated with unfavorable outcomes in the RePORT-Brazil (adjusted relative risk [aRR], 2.45; P < .001) and SINAN (aRR, 1.76; P < .001) cohorts. Furthermore, diabetes was associated with high risk of death (during TB treatment) in both RePORT-Brazil (aRR, 2.16; P = .040) and SINAN (aRR, 1.93; P = .001). Conclusions Diabetes was associated with an increased risk of unfavorable outcomes and mortality in Brazilian PWTB. Interventions to improve TB treatment outcomes in persons with diabetes are needed.

IntroductionFactors associated with losses in the latent tuberculosis infection (LTBI) cascade of care in contacts of patients with tuberculosis (TB) were investigated in a multicentre prospective cohort from highly endemic regions in Brazil.MethodsClose contacts of 1187 patients with culture-confirmed pulmonary TB were prospectively studied between 2015 and 2019, with follow-up of 6–24 months. Data on TB screening by clinical investigation, radiographic examination and interferon-gamma release assay (IGRA) were collected. Multivariable regressions were used to identify determinants of losses in the LTBI cascade.ResultsAmong 4145 TB contacts initially identified, 1901 were examined (54% loss). Among those examined, 933 were people living with HIV, ≤5 years old and/or had positive IGRA results, and therefore had a recommendation to start TB preventive treatment (TPT). Of those, 454 (23%) initiated treatment, and 247 (54% of those initiating; 26% of those in whom treatment was recommended) completed TPT. Multivariable regression analysis revealed that living with HIV, illiteracy and black/pardo (brown) race were independently associated with losses in the cascade.ConclusionThere were losses at all LTBI cascade stages, but particularly at the initial screening and examination steps. Close contacts of low socioeconomic status and living with HIV were at heightened risk of not completing the LTBI cascade of care in Brazil.

BackgroundInterferon-gamma release assay (IGRA) has emerged as a useful tool in identifying latent tuberculosis infection (LTBI). This assay can be performed through testing platforms, such as QuantiFERON-TB Gold Plus (QFT®-Plus). This in vitro test has been incorporated by several guidelines worldwide and has recently been considered for the diagnosis of LTBI by the World Health Organization (WHO). The possibility of systematically implementing IGRAs such as QFT®-Plus in centers that perform LTBI screening has been accelerated by the decreased availability of tuberculin skin testing (TST) in several countries. Nevertheless, the process to implement IGRA testing in routine clinical care has many gaps.MethodsThe study utilized the expertise acquired by the laboratory teams of the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil consortium during study protocol implementation of LTBI screening of TB close contacts.ResultsRePORT-Brazil includes clinical research sites from Brazilian cities and is the largest multicenter cohort of TB close contacts to date in the country. Operational and logistical challenges faced during IGRA implementation in all four study laboratories are described, as well as the solutions that were developed and led to the successful establishment of IGRA testing in RePORT-Brazil.ConclusionsThe problems identified and resolved in this study can assist laboratories implementing IGRAs, in addition to manufacturers of IGRAs providing effective technical support. This will facilitate the implementation of IGRA testing in countries with a high TB burden, such as Brazil.ImportanceThe interferon-gamma release assay (IGRA) has emerged as a useful tool in identifying persons with latent tuberculosis infection (LTBI). Although the implementation of IGRAs is of utmost importance, to our knowledge, there is scarce information on identification of logistical and technical challenges of systematic screening of for LTBI on a large scale. Thus, the problems identified and resolved in this study can assist laboratories implementing IGRAs, in addition to manufacturers of IGRAs providing effective technical support. This will facilitate the implementation of IGRA testing in countries with a high TB burden, such as Brazil.

Background: To evaluate the accuracy of distinct diabetes mellitus (DM) screening methods in persons with active Tuberculosis PWTB.Methods: Levels of fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) at the time of tuberculosis diagnosis at the study clinics were assessed from two distinct retrospective cohorts of PWTB from Brazil (n=116) and Peru (n=136) to evaluate accuracy for detecting pre-DM and DM cases. Additionally, we investigated the association of clinical and sociodemographic factors with tuberculosis and pre-DM or DM in each country.Results: When comparing PWTB from Brazil and Peru, Peruvian individuals presented higher FPG levels at baseline (median [IQR] 91 [81–106 vs 95 [88.4–102.1]]; p=0.02), while those from Brazil had significant higher levels of HbA1c (median [IQR] 6.3 [5.7-7.15] vs 5.1 [4.9-5.4]; pConclusion: Our findings indicate that there are significant differences in the total accuracy of the glycemic screening methods evaluated between PWTB from two highly endemic countries from South America, highlighting the need to revisit the diagnostic criteria of DM/PDM in individuals with tuberculosis.

To evaluate the accuracy of distinct diabetes mellitus (DM) screening methods in persons with active Tuberculosis PWTB.Levels of fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) at the time of tuberculosis diagnosis at the study clinics were assessed from two distinct retrospective cohorts of PWTB from Brazil (n=116) and Peru (n=136) to evaluate accuracy for detecting pre-DM and DM cases. Additionally, we investigated the association of clinical and sociodemographic factors with tuberculosis and pre-DM or DM in each country.When comparing PWTB from Brazil and Peru, Peruvian individuals presented higher FPG levels at baseline (median [IQR] 91 [81–106 vs 95 [88.4–102.1]]; p=0.02), while those from Brazil had significant higher levels of HbA1c (median [IQR] 6.3 [5.7-7.15] vs 5.1 [4.9-5.4]; p

BackgroundIt is unclear whether diabetes or prediabetes drives adverse treatment outcomes and death in people with tuberculosis (PWTB).MethodsCulture-confirmed PWTB, enrolled in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort between 2015 and 2019 (n=756) were stratified based on glycemic status by baseline glycated hemoglobin levels. Unfavorable TB outcome was defined as treatment failure or modification, recurrence or death, whereas favorable outcome was cure or treatment completion. We validated the findings using data from PWTB reported to the Brazilian National System of Diseases Notification (SINAN) during 2015-2019 (n=20,989). Stepwise binary multivariable regression analysis models evaluated associations between glycemic status and unfavorable outcomes.ResultsIn both cohorts, in univariate analysis, unfavorable outcomes were more frequently associated with drug resistance and HIV infection. Diabetes was associated with unfavorable outcomes in the RePORT (aOR: 2.85, p=0.001) and in SINAN (aOR: 1.56, p=0.040) cohorts. Furthermore, diabetes was associated with higher risk of death in both, RePORT-Brazil (aOR:3.23, p=0.006) and in the SINAN (aOR:2.75, p= 0.047) cohorts.ConclusionDiabetes was associated with an increased risk of unfavorable outcomes and mortality in Brazilian PWTB. Interventions to improve tuberculosis treatment outcomes in persons with diabetes are needed.40-word summary of the article’s main pointIn a multicenter prospective cohort study from Brazil, diabetes was associated with an increased risk of unfavorable treatment outcomes, including mortality, in pulmonary tuberculosis patients. These observations were validated in the Brazilian National Disease Notification System during the same period.

BackgroundFactors associated with losses in the latent tuberculosis infection (LTBI) cascade of care in contacts of tuberculosis (TB) patients were investigated in a multicenter prospective cohort from highly endemic regions in Brazil.MethodsClose contacts of 1,187 culture-confirmed pulmonary TB patients were prospectively studied between 2015 and 2019, with follow-up between 6 and 24 months. Data on TB screening by clinical investigation, radiographic examination and interferon-gamma release assay (IGRA) were collected. Stepwise multivariable models were used to identify determinants of losses in the LTBI cascade.ResultsAmong 4,145 TB contacts initially identified, 1,901 were examined (54% loss). Within those individuals, 933 were people living with HIV, ≤5 years-old and/or had positive IGRA results, therefore having recommendation to start TB preventive treatment (TPT). Of those, 454 (23%) initiated treatment, and 247 (6% of all TB contacts) completed TPT. Multivariable regression analysis revealed that living with HIV, illiteracy, and black/pardo (brown) race were independently associated with losses in cascade.ConclusionThere were losses at all LTBI cascade stages, but particularly at the initial screening and examination steps. Close contacts who are socially vulnerable and living with HIV were at heightened risk of not completing the LTBI cascade of care in Brazil.40-word summary of the article’s main pointWe investigated factors associated with losses in the latent tuberculosis infection cascade of care in a large cohort of contacts in Brazil. Social vulnerability and HIV infection were the most relevant determinants of losses in the LTBI cascade of care.

Background: Approximately 1·4 million people die annually worldwide from tuberculosis. Large epidemiologic studies can identify determinants of unfavorable clinical outcomes according to age, which can guide implementation of public health policies and clinical management to improve outcomes. Methods: We obtained data from the national tuberculosis case registry: cases reported to the Brazilian National Program (SINAN) between 2010-2019. Clinical and epidemiologic variables were compared between age groups (child

Background: A major goal of tuberculosis (TB) epidemiologic studies is to obtain results that can be generalized to the larger population with TB. The ability to extrapolate findings on 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 into 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 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: 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, 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. Interpretations: 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. Funding Statement: Fundacao Jose Silveira and Ministerio da Saude, Brazil and the National Institutes of Allergy and Infectious Diseases. Declaration of Interests: All authors: none reported. Ethics Approval Statement: All clinical investigations were conducted according to the principles of the Declaration of Helsinki. The RePORT-Brazil protocol, informed consent, and study documents were approved by the institutional review boards at each study site and at Vanderbilt University Medical Center. Participation in RePORT Brazil was voluntary, and written informed consent was obtained from all such participants. For the data extracted from SINAN, the anonymity of study subjects was preserved, and all data were de-identified.

Diabetes mellitus (DM) increases risk for pulmonary tuberculosis (TB) and adverse treatment outcomes. Systemic hyper-inflammation is characteristic in people with TB and concurrent DM (TBDM) at baseline, but the impact of TB treatment on this pattern has not been determined. We measured 17 plasma cytokines and growth factors in longitudinal cohorts of Indian and Brazilian pulmonary TB patients with or without DM. Principal component analysis revealed virtually complete separation of TBDM from TB individuals in both cohorts at baseline, with hyper-inflammation in TBDM that continued through treatment completion at six months. By one year after treatment completion, there was substantial convergence of mediator levels between groups within the India cohort. Non-resolving systemic inflammation in TBDM comorbidity could reflect delayed lesion sterilization or non-resolving sterile inflammation. Either mechanism portends unfavorable long-term outcomes including risk for recurrent TB and for damaging immune pathology., eLife digest Tuberculosis is the leading cause of death from infection worldwide. The bacteria that causes tuberculosis infect one in every four people on the planet, though most never develop the disease. People with diabetes are more likely to develop tuberculosis and they develop more severe symptoms, which may contribute to further spread of the disease. As diabetes rates are growing worldwide, particularly in countries with a high burden of tuberculosis, it is becoming to increasingly important to understand how these two conditions interact. People with diabetes often have more severe inflammation at the time they are diagnosed with tuberculosis than tuberculosis patients without diabetes. Inflammation can cause permanent lung damage in patients with tuberculosis, which can have serious consequences. Learning more about how treatment for tuberculosis affects inflammation in people with diabetes could help improve the outcomes for these patients. Now, Kumar, Fukutani et al. show that people with diabetes experience higher levels of inflammation than patients without diabetes throughout the course of treatment for tuberculosis. The analysis compared 17 markers of inflammation in tuberculosis patients with and without diabetes at diagnosis, and at two time periods during the 6-month course of treatment. Kumar, Fukutani et al. also looked at two separate groups of patients, one from India and one from Brazil. Inflammation was measured in the patients in India one year after the completion of treatment. One-year after treatment for tuberculosis in India, inflammation levels were the same in patients with and without diabetes. Persistently higher levels of inflammation likely explain why patients with diabetes experience more severe symptoms and suggests they may have more permanent lung damage after tuberculosis. Scientists are currently developing new treatments that can be used with antibiotics to more quickly cure tuberculosis and protect the lungs by reducing inflammation. Patients with diabetes and tuberculosis may benefit from these new treatments or from existing drugs like metformin or statins that may reduce inflammation.

In trials evaluating the immune responses to Bacille of Calmette-Guérin (BCG), the genetic background and the nutritional status are host-related factors that could affect the heterogeneity in these parameters. The IFNG+874 A/T (rs 62559044) polymorphism has been reported to influence the IFN-γ production by BCG-vaccinated individuals challenged in vitro with mycobacterial antigens. The body mass index (BMI) is a proxy for the nutritional status and has been associated both with the susceptibility to tuberculosis and with the IFN-γ response. We show that although the IFNG+874 A/T polymorphism was not associated with the heterogeneity of IFN-γ production in a randomized controlled trial that evaluated long-term immune responses to BCG revaccination previously conducted in Salvador, Bahia, Brazil, the effect of this polymorphism on the observed increase in IFN-γ production among revaccinated subjects was adjusted in individuals with a low BMI.