Multicohort assessment of plasma metabolic signatures of tuberculosis disease in children.

Current microbiological tests for tuberculosis (TB) disease in children have suboptimal accuracy and rely on respiratory samples which may be challenging to obtain. We sought to use high-resolution metabolomics (HRM) to identify blood-based biomarkers associated with TB disease in children. We analyzed plasma samples from 438 children 0-14 years being evaluated for TB disease in India, Peru, Uganda, The Gambia, and South Africa.

Population pharmacokinetics and dosing of dispersible moxifloxacin formulation in children with rifampicin-resistant tuberculosis.

Aims: Moxifloxacin is a priority drug for treating rifampicin-resistant tuberculosis (RR-TB). We assessed the pharmacokinetics of a child-friendly, dispersible 100 mg tablet moxifloxacin formulation (dispersed in water) compared to the standard 400 mg non-dispersible formulation (crushed and suspended in water) in children and evaluated current dosing recommendations.

Methods: The CATALYST trial investigated the pharmacokinetics of moxifloxacin in children with RR-TB.

Tuberculosis disease among people with HIV: therapeutic advances.

Over the past 80 years, tuberculosis treatment has evolved with the development of all-oral treatments, which are now given for 4-6 months for drug-sensitive tuberculosis and 6-9 months for drug-resistant tuberculosis. Treatment success is often reduced among people with HIV due to an interplay of factors, including immune dysregulation, lower drug concentrations, complexities of cotreatment (eg, high pill burden and overlapping toxicities), and social factors. Recent clinical trials have shown that among adults and adolescents, treatment duration can be decreased to 4 months with repurposed therapeutics for drug-sensitive tuberculosis, and a four-drug regimen of isoniazid, rifapentine, moxifloxacin, and pyrazinamide has become part of WHO recommendations.

Population pharmacokinetics and dosing of dispersible moxifloxacin formulation in children with rifampicin-resistant tuberculosis.

Aims: Moxifloxacin is a priority drug for treating rifampicin-resistant tuberculosis (RR-TB). We assessed the pharmacokinetics of a child-friendly, dispersible 100 mg tablet moxifloxacin formulation (dispersed in water) compared to the standard 400 mg non-dispersible formulation (crushed and suspended in water) in children and evaluated current dosing recommendations.

Methods: The CATALYST trial investigated the pharmacokinetics of moxifloxacin in children with RR-TB.

Treatment outcomes among children and adolescents with extensively drug-resistant (XDR) and pre-XDR tuberculosis: Systematic review and meta-analysis.

Extensively drug-resistant (XDR) and pre-XDR- tuberculosis (TB) account for approximately a third of pediatric MDR-TB cases globally. Clinical management is challenging; recommendations are based on limited evidence. We assessed the clinical outcomes for children and adolescents treated for XDR-and pre-XDR-TB.

Predictive metabolite signatures for risk of progression to active TB from QuantiFERON supernatants of household contacts of TB patients.

The identification of individuals with the greatest risk of progression to active tuberculosis (TB) disease from the huge reservoir of () infected individuals continues to remain an arduous ascent in the global effort to control TB. In a two-year prospective study, we analysed metabolic profiles in the unstimulated and TB antigen stimulated QuantiFERON supernatants of 14 healthy household contacts (HHCs) who progressed to TB disease (Progressors) and 14 HHCs who remained healthy (Non-Progressors). We identified 21 significantly dysregulated metabolites in the TB antigen-stimulated QuantiFERON supernatants of Progressors, of which the combination of Malic acid and N-Arachidonoylglycine had maximum AUC of 0.

Pharmaceutical cost dynamics for the treatment of rifampicin-resistant tuberculosis in children and adolescents in South Africa, India, and the Philippines.

Rifampicin-resistant (RR) tuberculosis (TB) in children is a major global health concern but is often neglected in economics research. Accurate cost estimations across the spectrum of paediatric RR-TB treatment regimens are critical inputs for prioritisation and budgeting decisions, and an existing knowledge gap at local and international levels. This normative cost analysis was nested in a Phase I/II pharmacokinetics, safety, tolerability, and acceptability trial of TB medications in children in South Africa, the Philippines and India.

Factors Associated With Unfavorable Treatment Outcomes Among Persons With Pulmonary Tuberculosis: A Multicentric Prospective Cohort Study From India.

In this prospective cohort of 2006 individuals with drug-susceptible tuberculosis in India, 18% had unfavorable treatment outcomes (4.7% treatment failure, 2.5% recurrent infection, 4.

Drug Resistance and Epidemiological Success of Modern Mycobacterium tuberculosis Lineages in Western India.

Background: Drivers of tuberculosis (TB) transmission in India, the country estimated to carry a quarter of the world's burden, are not well studied. We conducted a genomic epidemiology study to compare epidemiological success, host factors, and drug resistance among the 4 major Mycobacterium tuberculosis (Mtb) lineages (L1-L4) circulating in Pune, India.

Methods: We performed whole-genome sequencing (WGS) of Mtb sputum culture-positive isolates from participants in two prospective cohort studies and predicted genotypic susceptibility using a validated random forest model.

The sound of silent RNA in tuberculosis and the lncRNA role on infection.

Tuberculosis (TB) is one of the leading causes of death worldwide, and Diabetes Mellitus is one of the major comorbidities (TB/DM) associated with the disease. A total of 103 differentially expressed ncRNAs have been identified in the TB and TB/DM comparisons. A machine learning algorithm was employed to identify the most informative lncRNAs: ADM-DT, LINC02009, LINC02471, SOX2-OT, and GK-AS1.

Clinical and laboratory risk factors for pulmonary tuberculosis recurrence in three pooled Indian cohorts.

Some individuals with drug-susceptible pulmonary tuberculosis (PTB) experience tuberculosis recurrence. To evaluate the incidence of and risk factors for recurrence following completion of antituberculosis therapy, we pooled data from three prospective observational Indian PTB cohorts with 1164 individuals ≥14 years old included in our analysis. Ninety-five (8%) experienced recurrence with an 8.

Early Microbiologic Markers of Pulmonary Tuberculosis Treatment Outcomes.

Earlier biomarkers of pulmonary tuberculosis (PTB) treatment outcomes are critical to monitor shortened anti-TB treatment (ATT). To identify early microbiologic markers of unfavorable TB treatment outcomes. We performed a subanalysis of 2 prospective TB cohort studies conducted from 2013 to 2019 in India.

Comparative immune responses to in people with latent infection or sterilizing protection.

There is great need for vaccines against tuberculosis (TB) more efficacious than the licensed BCG. Our goal was to identify new vaccine benchmarks by identifying immune responses that distinguish individuals able to eradicate the infection (TB-resisters) from individuals with latent infection (LTBI-participants). TB-resisters had higher frequencies of circulating CD8 glucose monomycolate (GMM)+ Granzyme-B+ T cells than LTBI-participants and higher proportions of polyfunctional conventional and nonconventional T cells expressing Granzyme-B and/or PD-1 after stimulation of blood mononuclear cells.

QuantiFERON Supernatant-Based Host Biomarkers Predicting Progression to Active Tuberculosis Disease Among Household Contacts of Tuberculosis Patients.

Background: The positive predictive value of tuberculin skin test and current generation interferon gamma release assays are very low leading to high numbers needed to treat. Therefore, it is critical to identify new biomarkers with high predictive accuracy to identify individuals bearing high risk of progression to active tuberculosis (TB).

Methods: We used stored QuantiFERON supernatants from 14 household contacts of index TB patients who developed incident active TB during a 2-year follow-up and 20 age and sex-matched non-progressors.

Impact of Undernutrition on Tuberculosis Treatment Outcomes in India: A Multicenter, Prospective, Cohort Analysis.

Background: Undernutrition is the leading risk factor for tuberculosis (TB) globally. Its impact on treatment outcomes is poorly defined.

Methods: We conducted a prospective cohort analysis of adults with drug-sensitive pulmonary TB at 5 sites from 2015-2019.

Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial.

Background: Pediatric tuberculous meningitis (TBM) commonly causes death or disability. In adults, high-dose rifampicin may reduce mortality. The role of fluoroquinolones remains unclear.

The Kynurenine/Tryptophan Ratio Is a Sensitive Biomarker for the Diagnosis of Pediatric Tuberculosis Among Indian Children.

Objectives: Pediatric tuberculosis (TB) remains difficult to diagnose. The plasma kynurenine to tryptophan ratio (K/T ratio) is a potential biomarker for TB diagnosis and treatment response but has not been assessed in children.

Methods: We performed a targeted diagnostic accuracy analysis of four biomarkers: kynurenine abundance, tryptophan abundance, the K/T ratio, and IDO-1 gene expression.

Baseline IL-6 is a biomarker for unfavourable tuberculosis treatment outcomes: a multisite discovery and validation study.

Background: Biomarkers of unfavourable tuberculosis (TB) treatment outcomes are needed to accelerate new drug and regimen development. Whether plasma cytokine levels can predict unfavourable TB treatment outcomes is unclear.

Methods: We identified and internally validated the association between 20 selected plasma inflammatory markers and unfavourable treatment outcomes of failure, recurrence and all-cause mortality among adults with drug-sensitive pulmonary TB in India.

Host lipidome and tuberculosis treatment failure.

Introduction: Host lipids play important roles in tuberculosis (TB) pathogenesis. Whether host lipids at TB treatment initiation (baseline) affect subsequent treatment outcomes has not been well characterised. We used unbiased lipidomics to study the prospective association of host lipids with TB treatment failure.

Integration of metabolomics and transcriptomics reveals novel biomarkers in the blood for tuberculosis diagnosis in children.

Pediatric tuberculosis (TB) remains a major global health problem. Improved pediatric diagnostics using readily available biosources are urgently needed. We used liquid chromatography-mass spectrometry to analyze plasma metabolite profiles of Indian children with active TB (n = 16) and age- and sex-matched, Mycobacterium tuberculosis-exposed but uninfected household contacts (n = 32).

Tuberculosis preventive treatment should be considered for all household contacts of pulmonary tuberculosis patients in India.

The World Health Organization (WHO) recently changed its guidance for tuberculosis (TB) preventive treatment (TPT) recommending TPT for all pulmonary TB (PTB) exposed household contacts (HHC) to prevent incident TB disease (iTBD), regardless of TB infection (TBI) status. However, this recommendation was conditional as the strength of evidence was not strong. We assessed risk factors for iTBD in recently-exposed adult and pediatric Indian HHC, to determine which HHC subgroups might benefit most from TPT.