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Background The high burden of drug-resistant tuberculosis (TB) is a problem to achieve the goals of the End TB Strategy by 2035. Whether isoniazid monoresistance (Hr) affects anti-TB treatment (ATT) outcomes remains unknown in high-burden countries. Methods We evaluated determinants of ATT outcome among pulmonary TB cases reported to the National Notifiable Disease Information System (SINAN) between June 2015 and June 2019, according to drug sensitivity testing (DST) results. Binomial logistic regression models were employed to evaluate whether Hr was associated with an unfavorable ATT outcome: death or failure, compared to cure or treatment completion. Results Among 60 804 TB cases reported in SINAN, 21 197 (34.9%) were included in the study. In this database, the frequency of unfavorable outcomes was significantly higher in those with Hr in contrast to isoniazid-sensitive persons with pulmonary TB (9.1% vs 3.05%; P <.001). Using a binomial logistic regression model, Hr was independently associated with unfavorable outcomes (odds ratio, 3.34 [95% confidence interval, 2.06–5.40]; P <.001). Conclusions Hr detected prior to ATT was predictive of unfavorable outcomes at the national level in Brazil. Our data reinforce the need for high-TB-burden countries to prioritize DST to detect Hr. Effective treatment regimens for Hr-TB are needed to improve outcomes. [ABSTRACT FROM AUTHOR]

• Overall, 6% more female close contacts developed latent tuberculosis infection than men. • Modeling resulted in limited attenuation of observed sex-specific effect sizes. • Subtle differences in quantitative assay measurements may reveal a biological basis. • Findings should be confirmed in other study populations to increase precision. • Yet, this provides some evidence for an unconfounded sex difference. More men than women develop and die of tuberculosis (TB). Fewer data exist on sex differences in latent TB infection (LTBI). We assessed for potential sex differences in LTBI acquisition among close TB contacts. Regional Prospective Observational Research for TB-Brazil is an observational multi-center cohort of individuals with culture-confirmed pulmonary TB and their close contacts. Participants were enrolled from five sites in Brazil from June 2015 - June 2019. Close contacts were followed for 24 months after enrollment, with LTBI defined as a positive interferon-γ release assay (IGRA; QuantiFERON 3rd or 4th generation) at baseline or 6 months. We performed univariate, bivariate, and multivariable logistic regression and propensity-score weighted models to assess odds ratios (OR) and 95% confidence intervals (CI) for LTBI acquisition by birth sex among close contacts. Of 1093, 504 (46%) female close contacts were IGRA positive compared to 295 of 745 (40%) men. The unadjusted OR for IGRA positivity among women vs men was 1.31 (95% CI: 1.08-1.58). Bivariate adjustments yielded ORs in women vs men ranging from 1.19 to 1.33 (P -value range: <0.01-0.07). Multivariable regression and weighted models yielded similar ORs in women vs men, of 1.14 (95% CI: 0.92-1.41) and 1.15 (95% CI: 0.94-1.40), respectively. The point estimate for LTBI among close TB contacts in Brazil was higher in women, though less pronounced in multivariable models. If the sex difference in LTBI is confirmed in additional settings, studies of possible underlying differences in socio-behavioral factors or TB pathogenesis are warranted. [ABSTRACT FROM AUTHOR]

• Laboratory results from 178 887 Brazilian COVID-19 patients and controls were evaluated. • Distinct disease profiles influenced by age and sex were detected. • Such profiles may underly the occurrence of severe disease. The progression and severity of COVID-19 vary significantly in the population. While the hallmarks of SARS-CoV-2 and severe COVID-19 within routine laboratory parameters are emerging, the impact of sex and age on these profiles is still unknown. A multidimensional analysis was performed involving millions of records of laboratory parameters and diagnostic tests for 178 887 individuals from Brazil, of whom 33 266 tested positive for SARS-CoV-2. Analyzed data included those relating to complete blood cell count, electrolytes, metabolites, arterial blood gases, enzymes, hormones, cancer biomarkers, and others. COVID-19 induced similar alterations in laboratory parameters in males and females. CRP and ferritin were increased, especially in older men with COVID-19, whereas abnormal liver function tests were common across several age groups, except for young women. Low peripheral blood basophils and eosinophils were more common in the elderly with COVID-19. Both male and female COVID-19 patients admitted to intensive care units displayed alterations in the coagulation system, and higher values for neutrophils, CRP, and lactate dehydrogenase. Our study uncovered the laboratory profiles of a large cohort of COVID-19 patients, which formed the basis of discrepancies influenced by aging and biological sex. These profiles directly linked COVID-19 disease presentation to an intricate interplay between sex, age, and immune activation. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to assess the performance of a commonly used ICU severity score (SAPS3) and determine whether an alternative scoring system may be more accurate across all age strata. Methods: Retrospective cohort study in a general ICU in Brazil. A secondary analysis was performed with clinical and epidemiological data, present in the first 24 hours of unit admission. Then, a binary logistic regression, followed by cross-validation, was made to develop a novel prognostic tool. ICU mortality was the primary outcome evaluated. Results: A total of 3042 patients were included over the study period between August 2015 and July 2018 with a median age of 67 ± 18.4 years. SAPS3 performed fairly in prediction of ICU mortality, particularly in the 80 years or older subset. Multivariable regression identified variables independently associated with mortality that were used to develop the Age Calibrated ICU Score (ACIS) tool that performed similarly to SAPS3 across age categories, being slightly superior in the very elderly population (AUC 0.80 vs 0.72). Conclusions: The ACIS offers a robust and simple tool to predict ICU mortality, particularly in an increasingly elderly critical care population. [ABSTRACT FROM AUTHOR]

• There has been a recent reduction in vaccination coverage across the Brazilian regions. • The most relevant reduction in vaccination coverage has occurred in childhood immunization. • Increased web searches for anti-vaccine material has been associated with the reduction in immunization coverage. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

• Cascade of LTBI care was evaluated in 1264 potential contacts of TB patients. • Major losses occur at initial stages of the LTBI cascade of care. • Older patients are at higher risk of not completing the LTBI cascade of care. • All TB contacts who developed active TB were ≤14years-old. 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. 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. 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. Major losses occur at initial stages and older patients are at higher risk of not completing the LTBI cascade of care. [ABSTRACT FROM AUTHOR]

• High frequency of TST positivity in TB contacts from Brazil was observed. • SNPs in type-I IFN pathway, DNA and RNA sensing genes were screened in TB contacts. • SNPs in PYHIN1-IFI16-AIM2 and in IRF7 were linked to altered susceptibility to TB. Host genetic polymorphisms may be important in determining susceptibility to Mycobacterium tuberculosis (Mtb) infection, but their role is not fully understood. Detection of microbial DNA and activation of type I interferon (IFN) pathways regulate macrophage responses to Mtb infection. We examined whether seven candidate gene SNPs were associated with tuberculin skin test (TST) positivity in close contacts of microbiologically confirmed pulmonary TB patients in Brazil. Independent associations with TST positivity were tested using multivariable logistic regression (using genotypes and clinical variables) and genetic models. Among 482 contacts of 145 TB index cases, 296 contacts were TST positive. Multivariable regression analysis adjusted for population admixture, age, family relatedness, sex and clinical variables related to increased TB risk demonstrated that SNPs in PYHIN1-IFI16-AIM2 rs1101998 (adjusted OR [aOR]: 3.72; 95%CI = 1.15–12.0; p = 0.028) and in PYHIN1-IFI16-AIM2 rs1633256 (aOR = 24.84; 95%CI = 2.26–272.95; p = 0.009) were associated with TST positivity in a recessive model. Furthermore, an IRF7 polymorphism (rs11246213) was associated with reduced odds of TST positivity in a dominant model (aOR: 0.50, 95%CI: 0.26-0.93; p = 0.029). Polymorphisms in PYHIN1- IFI16 -AIM2 rs1633256, rs1101998 and in IRF7 rs11246213 were associated with altered susceptibility to Mtb infection in this Brazilian cohort. [ABSTRACT FROM AUTHOR]

Objective: ICU severity scores such as the Sequential Organ Failure Assessment (SOFA) determine neurologic dysfunction based on the Glasgow Coma Scale, a tool that may be limited in a critically ill population. It remains unknown whether alternative methods to assess for neurologic dysfunction, such as FOUR and RASS, are superior. This study aimed to determine the predictive performance of a modified SOFA tool in a large Brazilian ICU cohort. Design: Prospective cohort single center study. Setting: Mixed surgical and medical ICU in Salvador, Bahia, Brazil between August 2015 and December 2018. Patients: All acutely ill ICU admissions, other than postoperative patients or those with insufficient data, were eligible for study inclusion. Measurements and main results: 2147 patients were admitted to the ICU, of which 999 meeting inclusion criteria were included in the final analysis with a median age of 72 years (IQR 58–83) and a female predominance 545 (54%). The SOFA score using GCS, RASS and FOUR for the neurologic component performed marginally in the ability to predict general ICU mortality (SOFAGCS AUC 0.74 vs SOFARASS AUC 0.71 and SOFAFOUR AUC 0.67), with SOFAFOUR performing significantly lower compared to either SOFARASS and SOFAGCS (p<0.04, p<0.004 respectively). All three scores demonstrated decreased discriminate function in the mechanically ventilated population (SOFAGCS AUC 0.70 vs SOFARASS AUC 0.70 and SOFAFOUR AUC 0.55), though SOFAFOUR remained significantly worse when compared to SOFAGCS or SOFARASS (p = 0.034, p = 0.014, respectively).. Furthermore, performance was poor in a subset of patients with sepsis (n = 145) at time of admission (SOFAGCS AUC 0.66 vs SOFARASS AUC 0.55 and SOFAFOUR AUC 0.56). Conclusion: Modification of the neurologic component in the SOFA score does not appear to improve mortality prediction in the ICU. [ABSTRACT FROM AUTHOR]

Background: The implementation of antiretroviral (ARV) therapy caused a significant decrease in HIV-associated mortality worldwide. Nevertheless, mortality is still high among people living with HIV/AIDS and tuberculosis (TB). ARV-naïve HIV patients coinfected with tuberculosis (TB) have more options to treat both diseases concomitantly. Nevertheless, some TB-HIV patients undertaking ARVs (ARV-experienced) are already failing the first line efavirenz-based regimen and seem to display different response to second line ARV therapy and exhibit other predictors of mortality. Methods: We performed a retrospective cohort study including 273 patients diagnosed with TB-HIV and treated at a referral center in Rio de Janeiro, Brazil, between 2008 and 2016. Multivariate analysis and Cox regression models were used to evaluate the effectiveness of ARV therapy regimens (viral load [VL] <80 copies from the 4th to 10th months after TB therapy introduction) and to identify predictors of early mortality (100 days after TB therapy initiation) considering ARV-naïve and ARV-experienced patients adjusting for sociodemographic, clinical and therapeutic covariates. Findings: Survival analysis included 273 patients, out of whom 154 (56.4%) were ARV-naïve and 119 (43.6%) were ARV-experienced. Seven deaths occurred within 6 months of anti-TB treatment, 4 in ARV-naïve and 3 in ARV-experienced patients. Multivariate analysis revealed that in ARV-naïve patients, the chance of death was substantially higher in patients who developed immune reconstitution inflammatory syndrome during the study follow up (HR = 40.6, p<0.01). For ARV-experienced patients, similar analyses failed to identify factors significantly associated with mortality. Variables independently associated with treatment failure for the ARV-naïve group were previous TB (adjusted OR [aOR] = 6.1 p = 0.03) and alcohol abuse (aOR = 3.7 p = 0.01). For ARV-experienced patients, a ritonavir boosted. Protease Inhibitor-based regimen resulted in a 2.6 times higher risk of treatment failure compared to the use of efavirenz based ARV regimens (p = 0.03) and High baseline HIV VL (p = 0.03) were predictors of treatment failure. Conclusions: Risk factors for mortality and ARV failure were different for ARV-naïve and ARV-experienced patients. The latter patient group should be targeted for trials with less toxic and rifampicin-compatible drugs to improve TB-HIV treatment outcomes and prevent death. [ABSTRACT FROM AUTHOR]

• The Brazilian sequence ZIKV lineage proportion changed across five years. • The automated surveillance system helps identify ZIKV molecular epidemiology. • A new lineage emerged in Brazil and could be a potential risk of a new epidemic. 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. [ABSTRACT FROM AUTHOR]

Background: Mycobacterium tuberculosis infection is known to cause inflammation and lung tissue damage in high-risk populations. Nevertheless, direct associations between mycobacterial loads, systemic inflammation and pulmonary lesions upon treatment initiation have not been fully characterized. In the present exploratory study, we prospectively depict the immune profile, microbial clearance and evolution of radiographic lesions in a pulmonary tuberculosis (PTB) patient cohort before and 60 days after anti-tuberculous treatment (ATT) initiation.Methods: Circulating levels of cytokines (IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α) and C-reactive protein (CRP), as well as values of erythrocyte sedimentation rate (ESR) were measured in cryopreserved serum samples obtained from 73 PTB patients at pre-ATT and day 60 of treatment. Changes of the immune profile over time were compared with mycobacterial loads in sputum and culture conversion at day 60 of ATT. Additional analyses tested associations between improvement of chest radiographic lesions at day 60 and pre-treatment status of inflammation and mycobacterial loads.Results: Within the inflammatory parameters evaluated, values of CRP, IL-2, IL-4, TNF-α and ESR significantly decreased upon treatment initiation. On the converse, IL-10 levels substantially increased at day 60 of ATT, whereas concentrations of IL-6 and IFN-γ remained unchanged. Multidimensional analyses revealed that ESR, IL-2, IL-4 and CRP were the parameters with the highest power to discriminate individuals before and after treatment initiation. We further demonstrated that higher bacterial loads in sputum at pre-ATT were associated with increased systemic inflammation and higher risk for positive M. tuberculosis sputum cultures at day 60 of treatment. Furthermore, we found that pre-ATT mycobacterial loads in sputum and systemic inflammation synergistically associated with the status of radiographic lesions during treatment (Relative risk for chest X-ray improvement: 10.0, 95 % confidence interval: 2.4-40.0, P = 0.002).Conclusions: M. tuberculosis loads in sputum are directly associated to the status of systemic inflammation and potentially impact the immune profile, culture conversion and evolution of lung lesions upon ATT initiation. [ABSTRACT FROM AUTHOR]

Background: The rising prevalence of diabetes mellitus (DM) worldwide, especially in developing countries, and the persistence of tuberculosis (TB) as a major public health issue in these same regions, emphasize the importance of investigating this association. Here, we compared the clinical profile and disease outcomes of TB patients with or without coincident DM in a TB reference center in Brazil. Methods: We performed a retrospective analysis of a TB patient cohort (treatment naïve) of 408 individuals recruited at a TB primary care center in Brazil between 2004 and 2010. Data on diagnosis of TB and DM were used to define the groups. The study groups were compared with regard to TB disease presentation at diagnosis as well as to clinical outcomes such as cure and mortality rates upon anti-tuberculosis therapy (ATT) initiation. A composite score utilizing clinical, radiological and microbiological parameters was used to compare TB severity between the groups. Results: DM patients were older than non-diabetic TB patients. In addition, diabetic individuals more frequently presented with cough, night sweats, hemoptysis and malaise than those without DM. The overall pattern of lung lesions assessed by chest radiographic examination was similar between the groups. Compared to non-diabetic patients, those with TB-diabetes exhibited positive acid-fast bacilli in sputum samples more frequently at diagnosis and at 30 days after ATT initiation. Notably, higher values of the TB severity score were significantly associated with TB-diabetes comorbidity after adjustment for confounding factors. Moreover, during ATT, diabetic patients required more frequent transfers to TB reference hospitals for complex clinical management. Nevertheless, overall mortality and cure rates were indistinguishable between the study groups. Conclusions: These findings reinforce the idea that diabetes negatively impacts pulmonary TB severity. Our study argues for the systematic screening for DM in TB reference centers in endemic areas. [ABSTRACT FROM AUTHOR]

Background: The Ministry of Health in Brazil included ethambutol in the intensive phase of sensible tuberculosis (TB) treatment in March 2010, due to the increasing drug resistance, and implemented the fixed dose combination in the TB treatment guidelines. Methods: A retrospective cohort study was performed to determine the impact of change from three to four drugs schemes on the TB cure and frequency of adverse drug reactions (ADRs) in TB patients. To answer this question, we used data from 730 randomly selected patients who received anti-TB treatment between January 2007 and December 2014 in a reference center from Salvador, Brazil. Findings: TB patients who received the RHEZ regimen (n = 365) developed ADRs more frequently than those treated with the RHZ (n = 365) (86 [23.6%] vs. 55 [15.1%]; p = 0.01). This difference in ADR incidence was even higher in patients above 30 years-old (64 [74.4%] vs. 36 [65.5%]; p = 0.01). The overall number of ADR episodes was greater in patients from the RHEZ group than in the group that received RHZ (170 [61.4%] vs. 107 [38.6%]; p = 0.03). Multivariable logistic regression analysis adjusted for age, alcohol use and diabetes demonstrated that patients receiving the RHEZ regimen had increased odds of developing ADRs than those undertaking the RHZ scheme (odds ratio [OR]: 1.61, 95% confidence interval [CI]: 1.10–2.35; p = 0.015). The overall cure rate was similar between the distinct treatment groups. Conclusion: The patients treated with the four-drug regimen exhibited increased risk of ADRs compared to those who received the three-drug regimen, and especially in patients older than 30 years of age. [ABSTRACT FROM AUTHOR]