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Background: The incidence, manifestations, outcome and clinical predictors of paradoxical TB-IRIS in patients with HIV and culture confirmed pulmonary tuberculosis (PTB) in India have not been studied prospectively. Methods: HIV+ patients with culture confirmed PTB started on anti-tuberculosis therapy (ATT) were followed prospectively after anti-retroviral therapy (ART) initiation. Established criteria for IRIS diagnosis were used including decline in plasma HIV RNA at IRIS event. Pre-ART plasma levels of interleukin (IL)-6 and C-reactive protein (CRP) were measured. Univariate and multivariate logistic regression models were used to evaluate associations between baseline variables and IRIS. Results: Of 57 patients enrolled, 48 had complete follow up data. Median ATT-ART interval was 28 days (interquartile range, IQR 14–47). IRIS events occurred in 26 patients (54.2%) at a median of 11 days (IQR: 7–16) after ART initiation. Corticosteroids were required for treatment of most IRIS events that resolved within a median of 13 days (IQR: 9–23). Two patients died due to CNS TB-IRIS. Lower CD4+ T-cell counts, higher plasma HIV RNA levels, lower CD4/CD8 ratio, lower hemoglobin, shorter ATT to ART interval, extra-pulmonary or miliary TB and higher plasma IL-6 and CRP levels at baseline were associated with paradoxical TB-IRIS in the univariate analysis. Shorter ATT to ART interval, lower hemoglobin and higher IL-6 and CRP levels remained significant in the multivariate analysis. Conclusion: Paradoxical TB–IRIS frequently complicates HIV-TB therapy in India. IL-6 and CRP may assist in predicting IRIS events and serve as potential targets for immune interventions. [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]

Background: Gene expression profiling is emerging as a tool for tuberculosis diagnosis and treatment response monitoring, but limited data specific to Indian children and incident tuberculosis infection (TBI) exist.Methods: Sixteen pediatric Indian tuberculosis cases were age- and sex-matched to 32 tuberculosis-exposed controls (13 developed incident TBI without subsequent active tuberculosis). Longitudinal samples were collected for ribonucleic acid sequencing. Differential expression analysis generated gene lists that identify tuberculosis diagnosis and tuberculosis treatment response. Data were compared with published gene lists. Population-specific risk score thresholds were calculated.Results: Seventy-one genes identified tuberculosis diagnosis and 25 treatment response. Within-group expression was partially explained by age, sex, and incident TBI. Transient changes in gene expression were identified after both infection and treatment. Application of 27 published gene lists to our data found variable performance for tuberculosis diagnosis (sensitivity 0.38-1.00, specificity 0.48-0.93) and treatment response (sensitivity 0.70-0.80, specificity 0.40-0.80). Our gene lists found similarly variable performance when applied to published datasets for diagnosis (sensitivity 0.56-0.85, specificity 0.50-0.85) and treatment response (sensitivity 0.49- 0.86, specificity 0.50-0.84).Conclusions: Gene expression profiles among Indian children with confirmed tuberculosis were distinct from adult-derived gene lists, highlighting the importance of including distinct populations in differential gene expression models. [ABSTRACT FROM AUTHOR]

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). Metabolomic data were integrated with whole blood transcriptomic data for each participant at diagnosis and throughout treatment for drug-susceptible TB. A decision tree algorithm identified 3 metabolites that correctly identified TB status at distinct times during treatment. N-acetylneuraminate achieved an area under the receiver operating characteristic curve (AUC) of 0.66 at diagnosis. Quinolinate achieved an AUC of 0.77 after 1 month of treatment, and pyridoxate achieved an AUC of 0.87 after successful treatment completion. A set of 4 metabolites (gamma-glutamylalanine, gamma-glutamylglycine, glutamine, and pyridoxate) identified treatment response with an AUC of 0.86. Pathway enrichment analyses of these metabolites and corresponding transcriptional data correlated N-acetylneuraminate with immunoregulatory interactions between lymphoid and non-lymphoid cells, and correlated pyridoxate with p53-regulated metabolic genes and mitochondrial translation. Our findings shed new light on metabolic dysregulation in children with TB and pave the way for new diagnostic and treatment response markers in pediatric TB. [ABSTRACT FROM AUTHOR]

• There is a distinct systemic inflammatory profile in pediatric TB. • Plasma levels of MMP-7, LBP and CRP distinguish pulmonary from extrapulmonary TB. • Biological sex influences the inflammatory profile of pediatric TB. The immune profile associated with distinct clinical forms of tuberculosis (TB) has been extensively described for adult populations. Nevertheless, studies describing immune determinants of pulmonary or extrapulmonary TB (PTB or EPTB, respectively) in children are scarce. Here, we retrospectively assessed plasma levels of several mediators of inflammation in age and sex-matched children from South India presenting with PTB (n = 14) or EPTB (n = 22) as well as uninfected healthy controls (n = 19) to identify biomarkers that could accurately distinguish different TB clinical forms. Furthermore, we performed exploratory analyses testing the influence of sex on the systemic inflammatory profile. The analyses identified a biosignature of 10 biomarkers capable of distinguishing the three clinical groups simultaneously. Machine-learning decision trees indicated that C-reactive protein (CRP), matrix metalloproteinase (MMP)-7 and lipopolysaccharide-binding protein (LBP) were the markers that, when combined, displayed the highest accuracy in identifying the clinical groups. Additional exploratory analyses suggested that the disease signatures were highly influenced by sex. Therefore, sex differentially impacted status of systemic inflammation, immune activation and tissue remodeling in children with distinct clinical forms of TB. Regardless of such nuances related to biological sex, MMP-7, CRP and LBP were strong discriminators of active TB and thus could be considered as biomarkers useful in discrimination different TB clinical forms. These observations have implications on our understanding of the immunopathology of both clinical forms of TB in pediatric patients. If validated by other studies in the future, the combination of identified biomarkers may help development of point-of-care diagnostic or prognostic tools. [ABSTRACT FROM AUTHOR]