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Background: Identifying patients at increased risk of loss to follow-up (LTFU) is key to developing strategies to optimize the clinical management of tuberculosis (TB). The use of national registry data in prediction models may be a useful tool to inform healthcare workers about risk of LTFU. Here we developed a score to predict the risk of LTFU during anti-TB treatment (ATT) in a nationwide cohort of cases using clinical data reported to the Brazilian Notifiable Disease Information System (SINAN). Methods: We performed a retrospective study of all TB cases reported to SINAN between 2015 and 2022; excluding children (< 18 years-old), vulnerable groups or drug-resistant TB. For the score, data before treatment initiation were used. We trained and internally validated three different prediction scoring systems, based on Logistic Regression, Random Forest, and Light Gradient Boosting. Before applying our models we splitted our data into training (~ 80% data) and test (~ 20%) sets, and then compared the model metrics using the test data set. Results: Of the 243,726 cases included, 41,373 experienced LTFU whereas 202,353 were successfully treated. The groups were different with regards to several clinical and sociodemographic characteristics. The directly observed treatment (DOT) was unbalanced between the groups with lower prevalence in those who were LTFU. Three models were developed to predict LTFU using 8 features (prior TB, drug use, age, sex, HIV infection and schooling level) with different score composition approaches. Those prediction scoring systems exhibited an area under the curve (AUC) ranging between 0.71 and 0.72. The Light Gradient Boosting technique resulted in the best prediction performance, weighting specificity and sensitivity. A user-friendly web calculator app was developed (https://tbprediction.herokuapp.com/) to facilitate implementation. Conclusions: Our nationwide risk score predicts the risk of LTFU during ATT in Brazilian adults prior to treatment commencement utilizing schooling level, sex, age, prior TB status, and substance use (drug, alcohol, and/or tobacco). This is a potential tool to assist in decision-making strategies to guide resource allocation, DOT indications, and improve TB treatment adherence. [ABSTRACT FROM AUTHOR]

Background Tuberculosis (TB) treatment–related adverse drug reactions (TB-ADRs) can negatively affect adherence and treatment success rates. Methods We developed prediction models for TB-ADRs, considering participants with drug-susceptible pulmonary TB who initiated standard TB therapy. TB-ADRs were determined by the physician attending the participant, assessing causality to TB drugs, the affected organ system, and grade. Potential baseline predictors of TB-ADR included concomitant medication (CM) use, human immunodeficiency virus (HIV) status, glycated hemoglobin (HbA1c), age, body mass index (BMI), sex, substance use, and TB drug metabolism variables (NAT2 acetylator profiles). The models were developed through bootstrapped backward selection. Cox regression was used to evaluate TB-ADR risk. Results There were 156 TB-ADRs among 102 of the 945 (11%) participants included. Most TB-ADRs were hepatic (n = 82 [53%]), of moderate severity (grade 2; n = 121 [78%]), and occurred in NAT2 slow acetylators (n = 62 [61%]). The main prediction model included CM use, HbA1c, alcohol use, HIV seropositivity, BMI, and age, with robust performance (c-statistic = 0.79 [95% confidence interval {CI},.74–.83) and fit (optimism-corrected slope and intercept of −0.09 and 0.94, respectively). An alternative model replacing BMI with NAT2 had similar performance. HIV seropositivity (hazard ratio [HR], 2.68 [95% CI, 1.75–4.09]) and CM use (HR, 5.26 [95% CI, 2.63–10.52]) increased TB-ADR risk. Conclusions The models, with clinical variables and with NAT2 , were highly predictive of TB-ADRs. [ABSTRACT FROM AUTHOR]

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]

Diabetes mellitus (DM) increases tuberculosis (TB) severity. We compared blood gene expression in adults with pulmonary TB, with or without diabetes mellitus (DM) from sites in Brazil and India. RNA sequencing (RNAseq) performed at baseline and during TB treatment. Publicly available baseline RNAseq data from South Africa and Romania reported by the TANDEM Consortium were also analyzed. Across the sites, differentially expressed genes varied for each condition (DM, TB, and TBDM) and no pattern classified any one group across all sites. A concise signature of TB disease was identified but this was expressed equally in TB and TBDM. Pathway enrichment analysis failed to distinguish TB from TBDM, although there was a trend for greater neutrophil and innate immune pathway activation in TBDM participants. Pathways associated with insulin resistance, metabolic dysfunction, diabetic complications, and chromosomal instability were positively correlated with glycohemoglobin. The immune response to pulmonary TB as reflected by whole blood gene expression is substantially similar with or without comorbid DM. Gene expression pathways associated with the microvascular and macrovascular complications of DM are upregulated during TB, supporting a syndemic interaction between these coprevalent diseases. [ABSTRACT FROM AUTHOR]

A new tuberculosis (TB) diagnostic cartridge assay, which detects a 3-gene TB signature in whole blood, was not diagnostic in women with maternal TB disease in India (area under the curve [AUC] = 0.72). In a cohort of pregnant women, we identified a novel gene set for TB diagnosis (AUC = 0.97) and one for TB progression (AUC = 0.96). [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]

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]

• Patients with tuberculosis (TB) are still unaware of their glycemic status. • Persistent dysglycemia is a common condition in patients with TB during anti-TB treatment. • PD is independently associated with unfavorable TB outcomes. • Control of PD must be ensured in the TB management. Dysglycemia (i.e., prediabetes or diabetes) in patients with tuberculosis (PWTB) is associated with increased odds of mortality and treatment failure. Whether such association holds true when dysglycemia is transient or persistent is unknown. In this study, we tested the association between persistent dysglycemia (PD) during anti-tuberculosis (TB) treatment and unfavorable treatment outcomes in PWTB from Lima, Peru. PWTB enrolled between February and November 2017 were followed for 24-months. Dysglycemia was measured through fasting glucose and HbA1c at baseline during the 2nd- and 6th-month of TB treatment. PD was defined as dysglycemia detected in 2 different visits. The association between PD and unfavorable TB treatment outcome was evaluated using logistic regression. Among 125 PWTB, PD prevalence was 29.6%. PD was associated with more lung lesion types, higher bacillary loads, low hemoglobin (Hb), and high body mass index (BMI). Unfavorable TB treatment outcome was associated with older age, higher BMI, more lung lesion types, and PD. After adjusting for age, Hb levels, smoking, and smear grade, PD was independently associated with unfavorable treatment outcomes (adjusted odds ratio (aOR): 6.1; 95% CI: 1.9–19.6). PD is significantly associated with higher odds of unfavorable TB treatment outcomes. Dysglycemia control during anti-TB treatment gives the opportunity to introduce appropriate interventions to TB management. [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]

Homeostatic perturbation caused by infection fosters two major defense strategies, resistance and tolerance, which promote the host's survival. Resistance relates to the ability of the host to restrict the pathogen load. Tolerance minimizes collateral tissue damage without directly affecting pathogen fitness. These concepts have been explored mechanistically in murine models of malaria but only superficially in human disease. Indeed, individuals infected with Plasmodium vivax may present with asymptomatic malaria, only mild symptoms, or be severely ill. We and others have reported a diverse repertoire of immunopathological events that potentially underly susceptibility to disease severity in vivax malaria. Nevertheless, the combined epidemiologic, clinical, parasitological, and immunologic features associated with defining the disease outcomes are still not fully understood. In the present study, we perform an extensive outlining of cytokines and inflammatory proteins in plasma samples from a cohort of individuals from the Brazilian Amazon infected with P. vivax and presenting with asymptomatic (n = 108) or symptomatic (n = 134) disease (106 with mild presentation and 28 with severe malaria), as well as from uninfected endemic controls (n = 128) to elucidate these gaps further. We employ highly multidimensional Systems Immunology analyses using the molecular degree of perturbation to reveal nuances of a unique profile of systemic inflammation and imbalanced immune activation directly linked to disease severity as well as with other clinical and epidemiologic characteristics. Additionally, our findings reveal that the main factor associated with severe cases of P. vivax infection was the number of symptoms, despite of a lower global inflammatory perturbation and parasitemia. In these participants, the number of symptoms directly correlated with perturbation of markers of inflammation and tissue damage. On the other hand, the main factor associated with non-severe infections was the parasitemia values, that correlated only with perturbation of inflammatory markers, such as IL-4 and IL-1β, with a relatively lower number of symptoms. These observations suggest that some persons present severe vivax regardless of pathogen burden and global inflammatory perturbation. Such patients are thus little tolerant to P. vivax infection and show higher susceptibility to disrupt homeostasis and consequently exhibit more clinical manifestations. Other persons are capable to tolerate higher parasitemia with lower inflammatory perturbation and fewer symptoms, developing non-severe malaria. The analytical approach presented here has capability to define in more details the determinants of disease tolerance in vivax malaria. Author summary: Plasmodium vivax infection can result in a broad spectrum of disease manifestations, ranging from asymptomatic malaria to severe life-threatening disease. Despite significant advances in the current understanding of the critical factors associated with the disease outcomes in vivax malaria, the immunopathological events responsible for the diversity of severe manifestations in the disease remain deeply unknown. Here, a large panel of cytokines/chemokines were assessed in plasma samples from a Brazilian cohort of P. vivax patients presenting with asymptomatic infection or symptomatic malaria at the time of diagnosis, as well as from uninfected endemic controls, to define the relationships between systemic inflammation, disease presentation, parasitemia, and epidemiologic characteristics. In-depth analyses using the molecular degree of perturbation were employed to reveal nuances of a unique profile of systemic inflammation and imbalanced immune activation directly linked to disease severity. Moreover, the discoveries diagrammed the occurrence of disease tolerance by narrowing down the interactions between the systemic degree of inflammatory perturbation and parasitemia values in vivax malaria patients. [ABSTRACT FROM AUTHOR]