Tuberculosis (TB) still causes significant morbidity and mortality worldwide, especially in persons living with human immunodeficiency virus (HIV). This disease is hallmarked by persistent oxidative stress and systemic inflammation. N-acetylcysteine (NAC), a glutathione (GSH) precursor, has been shown in experimental models to limit Mycobacterium tuberculosis infection and disease both by suppression of the host oxidative response and through direct antimicrobial activity. In a recent phase II randomized clinical trial (RIPENACTB study), use of NAC as adjunct therapy during the first two months of anti-TB treatment was safe. Whether adjunct NAC therapy of patients with TB-HIV coinfection in the context of anti-TB treatment could directly affect pro-oxidation and systemic inflammation has not been yet formally demonstrated. To test this hypothesis, we leveraged existing data and biospecimens from the RIPENACTB trial to measure a number of surrogate markers of oxidative stress and of immune activation in peripheral blood of the participants at pre-treatment and at the day 60 of anti-TB treatment. Upon initiation of therapy, we found that the group of patients undertaking NAC exhibited significant increase in GSH levels and in total antioxidant status while displaying substantial reduction in lipid peroxidation compared to the control group. Only small changes in plasma concentrations of cytokines were noted. Pharmacological improvement of the host antioxidant status appears to be a reasonable strategy to reduce TB-associated immunopathology.

Background It is unclear whether diabetes or prediabetes affect unfavorable treatment outcomes and death in people with tuberculosis (PWTB). Methods Culture-confirmed drug-susceptible PWTB, enrolled in Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil between 2015-2019 (n=643) were stratified based on glycemic status according to baseline glycated hemoglobin. Unfavorable 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 HIV infection. Diabetes, but not prediabetes, was associated with unfavorable outcomes in the RePORT-Brazil (adjusted Relative Risk [aRR]: 2.45, p<0.001) and SINAN (aRR: 1.76, p<0.001) cohorts. Furthermore, diabetes was associated with high risk of death (during TB treatment) in both RePORT-Brazil (aRR:2.16, p=0.040) and SINAN (aRR:1.93, p= 0.001). Conclusion Diabetes 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.

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Bacteriological confirmation of extrapulmonary tuberculosis (EPTB) is challenging for several reasons: the paucibacillary nature of the sample; scarce resources, mainly in middle and low-income countries; the need for hospitalization; and unfavorable outcomes. We evaluated the diagnostic role of respiratory specimen examination prospectively in a cohort of patients with presumptive EPTB. Methods: From July 2018 to January 2019, in a tuberculosis (TB)/HIV reference hospital, a cohort of 157 patients with presumed EPTB was evaluated. Xpert 1 MTB/RIF Ultra or a culture-positive result was considered for bacteriologically confirmed TB. Results: Out of 157 patients with presumptive EPTB, 97 (62%) provided extrapulmonary and respiratory specimens and 60 (38%) extrapulmonary specimens only. Of the 60 patients with extrapulmonary samples, 5 (8%) were positive. Of those with respiratory and extrapulmonary samples, 27 (28%) were positive: 10 in both the respiratory and extrapulmonary samples, 6 in the extrapulmonary sample only, and 11 in the respiratory sample only. A respiratory specimen examination increased by 6-fold the chance of bacteriological confirmation of TB (odds ratio = 5.97 [1.11-47.17]). Conclusion:We conclude that respiratory samples should be examined in patients with presumptive EPTB.

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.

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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.

Background: It is unclear whether diabetes or prediabetes drives adverse treatment outcomes and death in people with tuberculosis (PWTB). Methods: Culture-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. Results: In 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. Conclusion: Diabetes 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.