An integrative multi-omics approach to characterize interactions between tuberculosis and diabetes mellitus.

Tuberculosis-diabetes mellitus (TB-DM) is linked to a distinct inflammatory profile, which can be assessed using multi-omics analyses. Here, a machine learning algorithm was applied to multi-platform data, including cytokines and gene expression in peripheral blood and eicosanoids in urine, in a Brazilian multi-center TB cohort. There were four clinical groups: TB-DM(n = 24), TB only(n = 28), DM(HbA1c ≥ 6.5%) only(n = 11), and a control group of close TB contacts who did not have TB or DM(n = 13). After cross-validation, baseline expression or abundance of MMP-28, LTE-4, 11-dTxB2, PGDM, FBXO6, SECTM1, and LINCO2009 differentiated the four patient groups. A distinct multi-omic-derived, dimensionally reduced, signature was associated with TB, regardless of glycemic status. SECTM1 and FBXO6 mRNA levels were positively correlated with sputum acid-fast bacilli grade in TB-DM. Values of the biomarkers decreased during the course of anti-TB therapy. Our study identified several markers associated with the pathophysiology of TB-DM that could be evaluated in future mechanistic investigations.

BACH1 promotes tissue necrosis and Mycobacterium tuberculosis susceptibility.

Oxidative stress triggers ferroptosis, a form of cellular necrosis characterized by iron-dependent lipid peroxidation, and has been implicated in Mycobacterium tuberculosis (Mtb) pathogenesis. We investigated whether Bach1, a transcription factor that represses multiple antioxidant genes, regulates host resistance to Mtb. We found that BACH1 expression is associated clinically with active pulmonary tuberculosis. Bach1 deletion in Mtb-infected mice increased glutathione levels and Gpx4 expression that inhibit lipid peroxidation. Bach1-/- macrophages exhibited increased resistance to Mtb-induced cell death, while Mtb-infected Bach1-deficient mice displayed reduced bacterial loads, pulmonary necrosis and lipid peroxidation concurrent with increased survival. Single-cell RNA-seq analysis of lungs from Mtb-infected Bach1-/- mice revealed an enrichment of genes associated with ferroptosis suppression. Bach1 depletion in Mtb-infected B6.Sst1S mice that display human-like necrotic lung pathology also markedly reduced necrosis and increased host resistance. These findings identify Bach1 as a key regulator of cellular and tissue necrosis and host resistance in Mtb infection.

Interplay between systemic inflammation, anemia, and mycobacterial dissemination and its impact on mortality in TB-associated HIV: a prospective cohort study.

Introduction: Anemia frequently affects people living with HIV (PLHIV). Nevertheless, the impact of anemia on treatment outcomes of patients with HIV-associated tuberculosis (TB) and the underlying molecular profiles are not fully characterized. The aim of this study was to investigate the interplay between anemia, the systemic inflammatory profile, dissemination of TB and death in HIV-TB patients in an ad hoc analysis of results from a prospective cohort study. Methods: 496 hospitalized PLHIV ≥18 years old, with CD4 count <350 cells/µL and high clinical suspicion of new TB infection were enrolled in Cape Town between 2014-2016. Patients were classified according to anemia severity in non-anemic, mild, moderate, or severe anemia. Clinical, microbiologic, and immunologic data were collected at baseline. Hierarchical cluster analysis, degree of inflammatory perturbation, survival curves and C-statistics analyses were performed. Results: Through the analysis of several clinical and laboratory parameters, we observed that those with severe anemia exhibited greater systemic inflammation, characterized by high concentrations of IL-8, IL-1RA and IL-6. Furthermore, severe anemia was associated with a higher Mtb dissemination score and a higher risk of death, particularly within 7 days of admission. Most of the patients who died had severe anemia and had a more pronounced systemic inflammatory profile. Discussion: Therefore, the results presented here reveal that severe anemia is associated with greater TB dissemination and increased risk of death in PLHIV. Early identification of such patients through measurement of Hb levels may drive closer monitoring to reduce mortality. Future investigations are warranted to test whether early interventions impact survival of this vulnerable population.

Machine learning algorithms using national registry data to predict loss to follow- up during tuberculosis treatment.

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 2015-2022; 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 split our data into train (~80% data) and test (~20%), and then we compare model metrics using a test data set. Results: Of the 243,726 cases included, 41,373 experienced LTFU whereas 202,353 were successfully treated and cured. 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 system 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 sensibility. A user-friendly web calculator app was created (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. This is a potential tool to assist in decision-making strategies to guide resource allocation, DOT indications, and improve TB treatment adherence.

Determinants of losses in the tuberculosis infection cascade of care among children and adolescent contacts of pulmonary tuberculosis cases: A Brazilian multi-centre longitudinal study.

Background: Approximately 10% of the global tuberculosis (TB) burden is in children. Identification, diagnosis, and early treatment of Mycobacterium tuberculosis infection (TBI) is critical to prevent progression to TB in children. The risk of TB, including severe disease, is highest in children <5 years old. We evaluated the cascade of TBI care among child and adolescent TB contacts to identify factors associated with losses in the cascade. Methods: Close contacts ≤ 18 years old of pulmonary TB patients enrolled between 2015 and 2019 in a multi-centre Brazilian cohort were followed for up to 24 months and classified according to age groups: <5 years, 5-9 years, 10-14 years and 15-18 years. Data on clinical investigation, radiographic examination, IGRA testing at baseline and 6 months, initiation and completion of TB preventive treatment (TPT) were collected. Multivariable regression analyses identified factors associated with TBI and losses in the cascade of care in children and adolescents. Findings: Among 1795 TB contacts initially identified, 530 (29·5%) were ≤18 years old. Losses for all steps in the cascade were especially high in children <5 years old (88%) because at this age all contacts are recommended to initiate TPT. As a proportion of all children, completion of TPT was low (between 10% and 13%) in all age-groups. Furthermore, multivariable regression revealed that younger age of contacts and TB index cases who were female, had pulmonary cavities, and persistent cough were independently associated with losses in the cascade of care among persons ≤18 years old. Interpretation: Losses in the TBI cascade were the highest among children <5 years, which was the group at highest risk for TB among the four age groups. The findings highlight the need to improve screening, initiation, and completion of TPT of young children who are close contacts of people with TB in Brazil. Funding: National Institutes of Allergy and Infectious Diseases.

Host-directed therapies in pulmonary tuberculosis: Updates on anti-inflammatory drugs.

Tuberculosis (TB) is a lethal disease and remains one of the top ten causes of mortality by an infectious disease worldwide. It can also result in significant morbidity related to persistent inflammation and tissue damage. Pulmonary TB treatment depends on the prolonged use of multiple drugs ranging from 6 months for drug-susceptible TB to 6-20 months in cases of multi-drug resistant disease, with limited patient tolerance resulting from side effects. Treatment success rates remain low and thus represent a barrier to TB control. Adjunct host-directed therapy (HDT) is an emerging strategy in TB treatment that aims to target the host immune response to Mycobacterium tuberculosis in addition to antimycobacterial drugs. Combined multi-drug treatment with HDT could potentially result in more effective therapies by shortening treatment duration, improving cure success rates and reducing residual tissue damage. This review explores the rationale and challenges to the development and implementation of HDTs through a succinct report of the medications that have completed or are currently being evaluated in ongoing clinical trials.

Association between severe anaemia and inflammation, risk of IRIS and death in persons with HIV: A multinational cohort study.

BACKGROUND: After initiating antiretroviral therapy (ART), approximately 25% of people with HIV (PWH) may develop Immune Reconstitution Inflammatory Syndrome (IRIS), which is associated with increased morbidity and mortality. Several reports have demonstrated that low haemoglobin (Hb) levels are a risk factor for IRIS. To what extent the severity of anaemia contributes to the risk of IRIS and/or death is still insufficiently explored. METHODS: We investigated both the presence and severity of anaemia in PWH in a multinational cohort of ART-na..ve patients. A large panel of plasma biomarkers was measured pre-ART and patients were followed up for 6 months. IRIS or deaths during this period were considered as outcomes. We performed multidimensional analyses, logistic regression, and survival curves to delineate associations. FINDINGS: Patients with severe anaemia (SA) presented a distinct systemic inflammatory profile, characterized by higher TNF, IL-6, and IL-27 levels. SA was independently associated with IRIS, with a higher risk of both early IRIS onset and death. Among IRIS patients, those with SA had a higher risk of mycobacterial IRIS. INTERPRETATION: PWH with SA display a more pronounced inflammatory profile, with an elevated risk of developing IRIS earlier and a statistically significant higher risk of death. FUNDING: Intramural Research Program of National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH). Coordena...·o de Aperfei..oamento de Pessoal de N.ível Superior (Finance code: 001) and the Conselho Nacional de Desenvolvimento Cient.ífico e Tecnol..gico (CNPq), Brazil.

Diagnostic biomarkers for active tuberculosis: progress and challenges.

Tuberculosis (TB) is a leading cause of morbidity and mortality from a single infectious agent, despite being preventable and curable. Early and accurate diagnosis of active TB is critical to both enhance patient care, improve patient outcomes, and break Mycobacterium tuberculosis (Mtb) transmission cycles. In 2020 an estimated 9.9 million people fell ill from Mtb, but only a little over half (5.8 million) received an active TB diagnosis and treatment. The World Health Organization has proposed target product profiles for biomarker- or biosignature-based diagnostics using point-of-care tests from easily accessible specimens such as urine or blood. Here we review and summarize progress made in the development of pathogen- and host-based biomarkers for active TB diagnosis. We describe several unique patient populations that have posed challenges to development of a universal diagnostic TB biomarker, such as people living with HIV, extrapulmonary TB, and children. We also review additional limitations to widespread validation and utilization of published biomarkers. We conclude with proposed solutions to enhance TB diagnostic biomarker validation and uptake.

Tuberculosis treatment outcomes of diabetic and non-diabetic TB/HIV co-infected patients: A nationwide observational study in Brazil.

Background: Tuberculosis (TB) is a worldwide public health problem, especially in countries that also report high numbers of people living with HIV (PLWH) and/or diabetes mellitus (DM). However, the unique features of persons with TB-HIV-DM are incompletely understood. This study compared anti-TB treatment (ATT) outcomes of diabetic and non-diabetic TB/HIV co-infected patients. Methods: A nationwide retrospective observational investigation was performed with data from the Brazilian Tuberculosis Database System among patients reported to have TB-HIV co-infection between 2014 and 2019. This database includes all reported TB cases in Brazil. Exploratory and association analyses compared TB treatment outcomes in DM and non-DM patients. Unfavorable outcomes were defined as death, treatment failure, loss to follow-up or recurrence. Multivariable stepwise logistic regressions were used to identify the variables associated with unfavorable ATT outcomes in the TB-HIV population. Results: Of the 31,070 TB-HIV patients analyzed, 999 (3.2%) reported having DM. However, in these TB-HIV patients, DM was not associated with any unfavorable treatment outcome [adjusted Odds Ratio (aOR): 0.97, 95% CI: 0.83-1.12, p = 0.781]. Furthermore, DM was also not associated with any specific type of unfavorable outcome in this study. In both the TB-HIV group and the TB-HIV-DM subpopulation, use of alcohol, illicit drugs and tobacco, as well as non-white ethnicity and prior TB were all characteristics more frequently observed in persons who experienced an unfavorable ATT outcome. Conclusion: DM is not associated with unfavorable TB treatment outcomes in persons with TB-HIV, including death, treatment failure, recurrence and loss to follow up. However, consumption habits, non-white ethnicity and prior TB are all more frequently detected in those with unfavorable outcomes in both TB-HIV and TB-HIV-DM patients.

GPX4 regulates cellular necrosis and host resistance in Mycobacterium tuberculosis infection.

Cellular necrosis during Mycobacterium tuberculosis (Mtb) infection promotes both immunopathology and bacterial dissemination. Glutathione peroxidase-4 (Gpx4) is an enzyme that plays a critical role in preventing iron-dependent lipid peroxidation-mediated cell death (ferroptosis), a process previously implicated in the necrotic pathology seen in Mtb-infected mice. Here, we document altered GPX4 expression, glutathione levels, and lipid peroxidation in patients with active tuberculosis and assess the role of this pathway in mice genetically deficient in or overexpressing Gpx4. We found that Gpx4-deficient mice infected with Mtb display substantially increased lung necrosis and bacterial burdens, while transgenic mice overexpressing the enzyme show decreased bacterial loads and necrosis. Moreover, Gpx4-deficient macrophages exhibited enhanced necrosis upon Mtb infection in vitro, an outcome suppressed by the lipid peroxidation inhibitor, ferrostatin-1. These findings provide support for the role of ferroptosis in Mtb-induced necrosis and implicate the Gpx4/GSH axis as a target for host-directed therapy of tuberculosis.

Effect of Dysglycemia on Urinary Lipid Mediator Profiles in Persons With Pulmonary Tuberculosis.

Background: Oxidized lipid mediators such as eicosanoids play a central role in the inflammatory response associated with tuberculosis (TB) pathogenesis. Diabetes mellitus (DM) leads to marked changes in lipid mediators in persons with TB. However, the associations between diabetes-related changes in lipid mediators and clearance of M. tuberculosis (Mtb) among persons on anti-TB treatment (ATT) are unknown. Quantification of urinary eicosanoid metabolites can provide insights into the circulating lipid mediators involved in Mtb immune responses. Methods: We conducted a multi-site prospective observational study among adults with drug-sensitive pulmonary TB and controls without active TB; both groups had sub-groups with or without dysglycemia at baseline. Participants were enrolled from RePORT-Brazil (Salvador site) and RePORT-South Africa (Durban site) and stratified according to TB status and baseline glycated hemoglobin levels: a) TB-dysglycemia (n=69); b) TB-normoglycemia (n=64); c) non-TB/dysglycemia (n=31); d) non-TB/non-dysglycemia (n=29). We evaluated the following urinary eicosanoid metabolites: 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (major urinary metabolite of prostaglandin E2, PGE-M), tetranor-PGE1 (metabolite of PGE2, TN-E), 9α-hydroxy-11,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (metabolite of PGD2, PGD-M), 11-dehydro-thromboxane B2 (11dTxB2), 2,3-dinor-6-keto-PGF1α (prostaglandin I metabolite, PGI-M), and leukotriene E4 (LTE4). Comparisons between the study groups were performed at three time points: before ATT and 2 and 6 months after initiating therapy. Results: PGE-M and LTE4 values were consistently higher at all three time-points in the TB-dysglycemia group compared to the other groups (p<0.001). In addition, there was a significant decrease in PGI-M and LTE4 levels from baseline to month 6 in the TB-dysglycemia and TB-normoglycemia groups. Finally, TB-dysglycemia was independently associated with increased concentrations of PGD-M, PGI-M, and LTE4 at baseline in a multivariable model adjusting for age, sex, BMI, and study site. These associations were not affected by HIV status. Conclusion: The urinary eicosanoid metabolite profile was associated with TB-dysglycemia before and during ATT. These observations can help identify the mechanisms involved in the pathogenesis of TB-dysglycemia, and potential biomarkers of TB treatment outcomes, including among persons with dysglycemia.

Relationship Between Anemia and Systemic Inflammation in People Living With HIV and Tuberculosis: A Sub-Analysis of the CADIRIS Clinical Trial.

People with HIV (PWH) are at increased risk of developing active tuberculosis (TB), and anemia is a common complication in both conditions. Anemia in TB patients has been linked to immune activation, levels of inflammatory biomarkers in blood, and risk for HIV disease progression and death. In this study we show that anemia was associated with a more pronounced inflammatory profile in HIV-TB coinfected persons in a cohort of 159 individuals with advanced HIV disease (CD4 count < 100 cells/µL) recruited as part of a randomized clinical trial (NCT00988780). A panel of plasma biomarkers was assessed on plasma obtained prior to combination antiretroviral therapy (cART) initiation. We performed a series of multidimensional analyses including clinical variables and concentrations of inflammatory biomarkers to profile systemic inflammation of PWH with and without anemia. We observed that TB participants presented with moderately lower levels of hemoglobin than non-TB participants. These participants also presented a higher Degree of Inflammatory Perturbation (DIP) score, related to increased levels of IFN-γ and TNF. The DIP was associated with TB coinfection and anemia before cART initiation. Future mechanistic studies are warranted to assess the determinants of such associations and the implications on treatment outcomes.

Possible sex difference in latent tuberculosis infection risk among close tuberculosis contacts.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Immunologic Biomarkers in Peripheral Blood of Persons With Tuberculosis and Advanced HIV.

Introduction: Tuberculosis (TB) is a common opportunistic infection among people living with HIV. Diagnostic tests such as culture, Xpert-MTB-RIF, and ULTRA have low sensitivity in paucibacillary TB disease; a blood biomarker could improve TB diagnostic capabilities. We assessed soluble factors to identify biomarkers associated with TB among persons with advanced HIV. Methods: A case-control (1:1) study was conducted, with participants from Rio de Janeiro and Manaus, Brazil. People living with HIV presenting with CD4 count ≤100 cells/mm3 were eligible to participate. Cases had culture-confirmed TB (N=15) (positive for Mycobacterium tuberculosis [Mtb]); controls had HIV-infection only (N=15). Study visits included baseline, month 2 and end of TB therapy, during which samples of peripheral blood were obtained. A panel containing 29 biomarkers including cytokines, chemokines and growth factors was utilized to assess candidate biomarkers using Luminex technology in cryopreserved EDTA plasma samples. We used neural network analysis, based on machine learning, to identify biomarkers (single or in combination) that best distinguished cases from controls. Additional multi-dimensional analyses provided detailed profiling of the systemic inflammatory environment in cases and controls. Results: Median CD4 count and HIV-1 RNA load values were similar between groups at all timepoints. Persons with TB had lower body mass index (BMI) (median=19.6, Interquartile Range [IQR]=18.6-22.3) than controls (23.7; IQR: 21.8 = 25.5, p=0.004). TB coinfection was also associated with increased frequency of other comorbidities. The overall profile of plasma cytokines, chemokines and growth factors were distinct between the study groups at all timepoints. Plasma concentrations of IL-15 and IL-10 were on average lower in TB cases than in controls. When used in combination, such markers were able to discriminate between TB cases and controls with the highest degree of accuracy at each study timepoint. Conclusion: Among persons with advanced HIV, plasma concentrations of IL-15 and IL-10 can be used in combination to identify TB disease regardless of time on anti-TB treatment.

Frequency of CXCR3+ CD8+ T-Lymphocyte Subsets in Peripheral Blood Is Associated With the Risk of Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome Development in Advanced HIV Disease.

Background: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a clinical aggravation of TB symptoms observed among a fraction of HIV coinfected patients shortly after the start of antiretroviral therapy (ART). Of note, TB-IRIS is characterized by exacerbated inflammation and tissue damage that occurs in response to the elevated production of CD4+ T cell-derived IFN-γ. Nevertheless, the possible participation of CD8+ T cells in TB-IRIS development remains unclear. Methods: We performed a comprehensive assessment of the composition of CD8+ T cell memory subsets and their association with circulating inflammation-related molecules in TB-HIV coinfected patients initiating ART. Results: We found that TB-IRIS individuals display higher frequencies of Antigen-experienced CD8+ T cells during the onset of IRIS and that the levels of these cells positively correlate with baseline mycobacterial smear grade. TB-IRIS individuals exhibited higher frequencies of effector memory and lower percentages of naïve CD8+ T cells than their Non-IRIS counterparts. In both TB-IRIS and Non-IRIS patients, ART commencement was associated with fewer significant correlations among memory CD8+ T cells and cells from other immune compartments. Networks analysis revealed distinct patterns of correlation between each memory subset with inflammatory cytokines suggesting different dynamics of CD8+ T cell memory subsets reconstitution. TB-IRIS patients displayed lower levels of memory cells positive for CXCR3 (a chemokine receptor that plays a role in trafficking activated CD8+ T cells to the tissues) than Non-IRIS individuals before and after ART. Furthermore, we found that CXCR3+ naïve CD8+ T cells were inversely associated with the risk of TB-IRIS development. On the other hand, we noticed that the frequencies of CXCR3+ effector CD8+ T cells were positively associated with the probability of TB-IRIS development. Conclusion: Our data suggest that TB-IRIS individuals display a distinct profile of memory CD8+ T cell subsets reconstitution after ART initiation. Moreover, our data point to a differential association between the frequencies of CXCR3+ CD8+ T cells and the risk of TB-IRIS development. Collectively, our findings lend insights into the potential role of memory CD8+ T cells in TB-IRIS pathophysiology.

Persistent dysglycemia is associated with unfavorable treatment outcomes in patients with pulmonary tuberculosis from Peru.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

The Effect of Diabetes and Prediabetes on Antituberculosis Treatment Outcomes: A Multicenter Prospective Cohort Study.

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.

Immunomodulatory and Anti-fibrotic Effects Following the Infusion of Umbilical Cord Mesenchymal Stromal Cells in a Critically Ill Patient With COVID-19 Presenting Lung Fibrosis: A Case Report.

Background: The patients with coronavirus disease 2019 (COVID-19) associated with severe acute respiratory distress syndrome (ARDS) may require prolonged mechanical ventilation which often results in lung fibrosis, thus worsening the prognosis and increasing fatality rates. A mesenchymal stromal cell (MSC) therapy may decrease lung inflammation and accelerate recovery in COVID-19. In this context, some studies have reported the effects of MSC therapy for patients not requiring invasive ventilation or during the first hours of tracheal intubation. However, this is the first case report presenting the reduction of not only lung inflammation but also lung fibrosis in a critically ill long-term mechanically ventilated patient with COVID-19. Case Presentation: This is a case report of a 30-year-old male patient with COVID-19 under invasive mechanical ventilation for 14 days in the intensive care unit (ICU), who presented progressive clinical deterioration associated with lung fibrosis. The symptoms onset was 35 days before MSC therapy. The patient was treated with allogenic human umbilical-cord derived MSCs [5 × 107 (2 doses 2 days interval)]. No serious adverse events were observed during and after MSC administration. After MSC therapy, PaO2/FiO2 ratio increased, the need for vasoactive drugs reduced, chest CT scan imaging, which initially showed signs of bilateral and peripheral ground-glass, as well as consolidation and fibrosis, improved, and the systemic mediators associated with inflammation decreased. Modulation of the different cell populations in peripheral blood was also observed, such as a reduction in inflammatory monocytes and an increase in the frequency of patrolling monocytes, CD4+ lymphocytes, and type 2 classical dendritic cells (cDC2). The patient was discharged 13 days after the cell therapy. Conclusions: Mesenchymal stromal cell therapy may be a promising option in critically ill patients with COVID-19 presenting both severe lung inflammation and fibrosis. Further clinical trials could better assess the efficacy of MSC therapy in critically ill patients with COVID-19 with lung fibrosis associated with long-term mechanical ventilation.

Dynamics of T-Lymphocyte Activation Related to Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome in Persons With Advanced HIV.

Most persons living with HIV (PLWH) experience a significant restoration of their immunity associated with successful inhibition of viral replication after antiretroviral therapy (ART) initiation. Nevertheless, with the robust quantitative and qualitative restoration of CD4+ T-lymphocytes, a fraction of patients co-infected with tuberculosis develop immune reconstitution inflammatory syndrome (TB-IRIS), a dysregulated inflammatory response that can be associated with significant tissue damage. Several studies underscored the role of adaptive immune cells in IRIS pathogenesis, but to what degree T lymphocyte activation contributes to TB-IRIS development remains largely elusive. Here, we sought to dissect the phenotypic landscape of T lymphocyte activation in PLWH coinfected with TB inititating ART, focusing on characterization of the profiles linked to development of TB-IRIS. We confirmed previous observations demonstrating that TB-IRIS individuals display pronounced CD4+ lymphopenia prior to ART initiation. Additionally, we found an ART-induced increase in T lymphocyte activation, proliferation and cytotoxicity among TB-IRIS patients. Importantly, we demonstrate that TB-IRIS subjects display higher frequencies of cytotoxic CD8+ T lymphocytes which is not affected by ART. Moreover, These patients exhibit higher levels of activated (HLA-DR+) and profilerative (Ki-67+) CD4+ T cells after ART commencenment than their Non-IRIS counterparts. Our network analysis reveal significant negative correlations between Total CD4+ T cells counts and the frequencies of Cytotoxic CD8+ T cells in our study population which could suggest the existance of compensatory mechanisms for Mtb-infected cells elimination in the face of severe CD4+ T cell lymphopenia. We also investigated the correlation between T lymphocyte activation profiles and the abundance of several inflammatory molecules in plasma. We applied unsupervised machine learning techniques to predict and diagnose TB-IRIS before and during ART. Our analyses suggest that CD4+ T cell activation markers are good TB-IRIS predictors, whereas the combination of CD4+ and CD8+ T cells markers are better at diagnosing TB-IRIS patients during IRIS events Overall, our findings contribute to a more refined understanding of immunological mechanisms in TB-IRIS pathogenesis that may assist in new diagnostic tools and more targeted patient management.

Lower Levels of Vitamin D Are Associated with an Increase in Insulin Resistance in Obese Brazilian Women.

Adult women are more likely to be obese than men. Moreover, there is evidence that obesity is a risk factor for increased insulin resistance (IR) and hypovitaminosis D (VITD), conditions related to metabolic and endocrinologic disturbance. We performed a cross-sectional study with 103 women diagnosed with obesity, recruited between 2009 and 2013, in an obesity referral outpatient clinic in Bahia, Brazil. Laboratory and clinical characteristics were compared between the groups according to the degree of obesity (I, II and III), and levels of 25-hydroxyvitamin D [25(OH)D] were used to define the VITD status (insufficiency and no insufficiency). We calculated the homeostatic model assessment-IR (HOMA-IR) index to assess insulin resistance in the groups. Our analyses revealed that HOMA-IR values and VITD levels were inversely correlated. Furthermore, we observed a distinct expression profile of values of laboratory markers according to 25(OH)D levels. Negative correlations were found between HOMA-IR and body mass index (BMI) in VITD insufficient participants but not in those with the sufficiency. Furthermore, multivariate regression demonstrated independent associations between lower levels of 25(OH)D and increased values of HOMA-IR. These findings suggests that lower levels of VITD are strongly associated with the increased IR in obese women.