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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]

Background Despite widespread availability of curative therapy, tuberculosis (TB) treatment outcomes remain suboptimal. Clinical prediction models can inform treatment strategies to improve outcomes. Using baseline clinical data, we developed a prediction model for unsuccessful TB treatment outcome and evaluated the incremental value of human immunodeficiency virus (HIV)–related severity and isoniazid acetylator status. Methods Data originated from the Regional Prospective Observational Research for Tuberculosis Brazil cohort, which enrolled newly diagnosed TB patients in Brazil from 2015 through 2019. This analysis included participants with culture-confirmed, drug-susceptible pulmonary TB who started first-line anti-TB therapy and had ≥12 months of follow-up. The end point was unsuccessful TB treatment: composite of death, treatment failure, regimen switch, incomplete treatment, or not evaluated. Missing predictors were imputed. Predictors were chosen via bootstrapped backward selection. Discrimination and calibration were evaluated with c-statistics and calibration plots, respectively. Bootstrap internal validation estimated overfitting, and a shrinkage factor was applied to improve out-of-sample prediction. Incremental value was evaluated with likelihood ratio–based measures. Results Of 944 participants, 191 (20%) had unsuccessful treatment outcomes. The final model included 7 baseline predictors: hemoglobin, HIV infection, drug use, diabetes, age, education, and tobacco use. The model demonstrated good discrimination (c-statistic = 0.77; 95% confidence interval,.73–.80) and was well calibrated (optimism-corrected intercept and slope, –0.12 and 0.89, respectively). HIV-related factors and isoniazid acetylation status did not improve prediction of the final model. Conclusions Using information readily available at treatment initiation, the prediction model performed well in this population. The findings may guide future work to allocate resources or inform targeted interventions for high-risk patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Severity stratification scores developed in intensive care units (ICUs) are used in interventional studies to identify the most critically ill. Studies that evaluate accuracy of these scores in ICU patients admitted with pneumonia are lacking. This study aims to determine performance of severity scores as predictors of mortality in critically ill patients admitted with pneumonia. Methods Prospective cohort study in a general ICU in Brazil. ICU severity scores (Simplified Acute Physiology Score 3 [SAPS 3] and Sepsis-Related Organ Failure Assessment [qSOFA]), prognostic scores of pneumonia (CURB-65 [confusion, urea, respiratory rate, blood pressure, age] and CRB-65 [confusion, respiratory rate, blood pressure, age]), and clinical and epidemiological variables in the first 6 hours of hospitalization were analyzed. Results Two hundred patients were included between 2015 and 2018, with a median age of 81 years (interquartile range, 67–90 years) and female predominance (52%), primarily admitted from the emergency department (65%) with community-acquired pneumonia (CAP, 80.5%). SAPS 3, CURB-65, CRB-65,and qSOFA all exhibited poor performance in predicting mortality. Multivariate regression identified variables independently associated with mortality that were used to develop a novel pneumonia-specific ICU severity score (Pneumonia Shock score) that outperformed SAPS 3, CURB-65, and CRB-65. The Shock score was validated in an external multicenter cohort of critically ill patients admitted with CAP. Conclusions We created a parsimonious score that accurately identifies patients with pneumonia at highest risk of ICU death. These findings are critical to accurately stratify patients with severe pneumonia in therapeutic trials that aim to reduce mortality. [ABSTRACT FROM AUTHOR]

Background Diagnosis of active tuberculosis (ATB) currently relies on detection of Mycobacterium tuberculosis (Mtb). Identifying patients with extrapulmonary TB (EPTB) remains challenging because microbiological confirmation is often not possible. Highly accurate blood-based tests could improve diagnosis of both EPTB and pulmonary TB (PTB) and timely initiation of anti-TB therapy. Methods A case-control study was performed using discriminant analyses to validate an approach using Mtb-specific CD4+T-cell activation markers in blood to discriminate PTB and EPTB from latent TB infection (LTBI) as well as EPTB from PTB in 270 Brazilian individuals. We further tested the effect of human immunodeficiency virus (HIV) coinfection on diagnostic performance. Frequencies of interferon-γ +CD4+T cells expressing CD38, HLADR, and/or Ki67 were assessed by flow cytometry. Results EPTB and PTB were associated with higher frequencies of CD4+T cells expressing CD38, HLADR, or Ki67 compared with LTBI (all P values <.001). Moreover, frequencies of HLADR+ (P =.03) or Ki67+ (P <.001) cells accurately distinguished EPTB from PTB. HIV infection did not affect the capacity of these markers to distinguish ATB from LTBI or EPTB from PTB. Conclusions Cell activation markers in Mtb-specific CD4+T cells distinguished ATB from LTBI and EPTB from PTB, regardless of HIV infection status. These parameters provide an attractive approach for developing blood-based diagnostic tests for both active and latent TB. [ABSTRACT FROM AUTHOR]

Background: Zika virus (ZIKV) is an emergent flavivirus initially considered a benign and self-limited exanthematic illness. In 2015, a new epidemic emerged in northeastern of Brazil with increased incidence of a previously rare clinical outcome, microcephaly, in newborns from mothers who were infected during pregnancy. Little is known about the immunopathogenesis of ZIKV-associated microcephaly. Understanding the inflammatory profile and degree of inflammation of persons affected with such condition is an important step towards development of innovative therapeutic strategies.Methods: A case-control study compared plasma levels of several inflammatory biomarkers from newborns with ZIKV microcephaly, asymptomatic ZKV infection, or uninfected controls. Plasma biomarkers were assessed using Luminex. A series of multidimensional analysis was performed to characterize the systemic immune activation profile of the clinical groups.Results: We identified an inflammatory signature associated with ZIKV microcephaly that suggested an increased inflammation. Network analysis suggested that ZIKV microcephaly is associated with imbalanced immune activation and inflammation. The cephalic perimeter was inversely proportional with the degree of inflammatory perturbation. Furthermore, a combination of plasma inflammatory biomarkers could discriminate ZIKV with microcephaly from those with ZIKV without microcephaly or uninfected neonates.Conclusions: An intense inflammatory imbalance that is proportional to the disease severity hallmarks ZIKV microcephaly. [ABSTRACT FROM AUTHOR]

Background: Weight change may inform tuberculosis treatment response, but its predictive power may be confounded by human immunodeficiency virus (HIV).Methods: We prospectively followed up adults with culture-confirmed, drug-susceptible, pulmonary tuberculosis receiving standard 4-drug therapy (isoniazid, rifampin, pyrazinamide, and ethambutol) in Brazil. We examined median weight change 2 months after treatment initiation by HIV status, using quantile regression, and unsuccessful tuberculosis treatment outcome (treatment failure, tuberculosis recurrence, or death) by HIV and weight change status, using Cox regression.Results: Among 547 participants, 102 (19%) were HIV positive, and 35 (6%) had an unsuccessful outcome. After adjustment for confounders, persons living with HIV (PLWH) gained a median of 1.3 kg (95% confidence interval [CI], -2.8 to .1) less than HIV-negative individuals during the first 2 months of tuberculosis treatment. PLWH were at increased risk of an unsuccessful outcome (adjusted hazard ratio, 4.8; 95% CI, 2.1-10.9). Weight change was independently associated with outcome, with risk of unsuccessful outcome decreasing by 12% (95% CI, .81%-.95%) per 1-kg increase.Conclusions: PLWH gained less weight during the first 2 months of tuberculosis treatment, and lack of weight gain and HIV independently predicted unsuccessful tuberculosis treatment outcomes. Weight, an easily collected biomarker, may identify patients who would benefit from alternative treatment strategies. [ABSTRACT FROM AUTHOR]

Background The role of genetic polymorphisms in latent tuberculosis (TB) infection and progression to active TB is not fully understood. Methods We tested the single-nucleotide polymorphisms (SNPs) rs5743708 (TLR2), rs4986791 (TLR4), rs361525 (TNFA), rs2430561 (IFNG) rs1143627 (IL1B) as risk factors for tuberculin skin test (TST) conversion or development of active TB in contacts of active TB cases. Contacts of microbiologically confirmed pulmonary TB cases were initially screened for longitudinal evaluation up to 24 months, with clinical examination and serial TST, between 1998 and 2004 at a referral center in Brazil. Data and biospecimens were collected from 526 individuals who were contacts of 177 active TB index cases. TST conversion was defined as induration ≥5 mm after a negative TST result (0 mm) at baseline or month 4 visit. Independent associations were tested using logistic regression models. Results Among the 526 contacts, 60 had TST conversion and 44 developed active TB during follow-up. Multivariable regression analysis demonstrated that male sex (odds ratio [OR]: 2.3, 95% confidence interval [CI]: 1.1–4.6), as well as SNPs in TLR4 genes (OR: 62.8, 95% CI: 7.5–525.3) and TNFA (OR: 4.2, 95% CI: 1.9–9.5) were independently associated with TST conversion. Moreover, a positive TST at baseline (OR: 4.7, 95% CI: 2.3–9.7) and SNPs in TLR4 (OR: 6.5, 95% CI: 1.1–36.7) and TNFA (OR: 12.4, 95% CI:5.1–30.1) were independently associated with incident TB. Conclusions SNPs in TLR4 and TNFA predicted both TST conversion and active TB among contacts of TB cases in Brazil. [ABSTRACT FROM AUTHOR]