SUMMARY SETTING India accounts for the largest burden of tuberculosis (TB) worldwide, with 26% of the world’s cases. OBJECTIVE To assess the association between novel modifiable risk factors and TB in Indian children. DESIGN Cases were children aged ≤5 years with confirmed/probable TB based on World Health Organization definitions (definition 1). Controls were healthy children aged ≤5 years. Logistic regression was performed to estimate the adjusted odds ratio (aOR) of being a TB case given exposure, including indoor air pollution (IAP; exposure to tobacco smoke and/or biomass fuels) and vitamin D deficiency. Cases were re-analyzed according to a new consensus research definition of pediatric TB (definition 2). RESULTS Sixty cases and 118 controls were enrolled. Both groups had high levels of vitamin D deficiency (55% vs. 50%, P = 0.53). In multivariable analysis, TB was associated with household TB exposure (aOR 25.41, 95%CI 7.03–91.81), household food insecurity (aOR 11.55, 95%CI 3.33–40.15) and IAP exposure (aOR 2.67, 95%CI 1.02–6.97), but not vitamin D deficiency (aOR 1.00, 95%CI 0.38–2.66). Use of definition 2 reduced the number of cases to 25. In multivariate analysis, TB exposure, household food insecurity and IAP remained associated with TB. CONCLUSIONS Household TB exposure, exposure to IAP and household food insecurity were independently associated with pediatric TB.

Background Pediatric tuberculous meningitis (TBM) commonly causes death or disability. . In adults, high-dose rifampicin may reduce mortality. Fluoroquinolones’ role remains unclear. There have been no antimicrobial treatment trials for pediatric TBM. Methods TBM-KIDS (NCT02958709) was a Phase II open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (a) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, Arm 1); (b) high-dose rifampicin and levofloxacin (R30HZL, Arm 2); or (c) standard-dose rifampicin and ethambutol (R15HZE, Arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL). Results Of 2487 children pre-screened, 79 were screened, and 37 enrolled. Median age was 72 months. 49%, 43%, and 8% had Stage I, II, and III disease. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in Arms 1, 2, and 3, with one death (Arm 1) and six early treatment discontinuations (4 in Arm 1, 1 each in Arms 2 and 3). By Week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in Arm 1 than Arm 3 in fine motor, receptive language, and expressive language domains (p<0.01). Conclusions In a pediatric TBM trial, functional outcomes were excellent overall. The trend towards higher frequency of adverse events but better neurocognitive outcomes in children receiving high-dose rifampicin requires confirmation in a larger trial.

Abstract Introduction Tuberculous meningitis (TBM) results in significant morbidity and mortality among children worldwide. Associated neurocognitive complications are common but not well characterized. The Mullen Scales of Early Learning (MSEL), a well-established measure for assessment of neurodevelopment, has not yet been adapted for use in India. This study’s goal was to adapt the MSEL for local language and culture to assess neurocognition among children in India, and apply the adapted measure for assessment of children with TBM. Methods Administration of MSEL domains was culturally adapted. Robust translation procedures for instructions took place for three local languages: Marathi, Hindi and Tamil. Multilingual staff compared instructions against the original version for accuracy. The MSEL stimuli and instructions were reviewed by psychologists and pediatricians in India to identify items concerning for cultural bias. Results MSEL stimuli unfamiliar to children in this setting were identified and modified within Visual Reception, Fine-Motor, Receptive Language and Expressive Language Scales. Item category was maintained for adaptations of items visually or linguistically different from those observed in daily life. Adjusted items were administered to six typically developing children to determine modification utility. Two children diagnosed with confirmed TBM (ages 11 and 29 months) were evaluated with the adapted MSEL before receiving study medications. Skills were below age-expectation across visual reception, fine motor and expressive language domains. Conclusions This is the first study to assess children with TBM using the MSEL adapted for use in India. Future studies in larger groups of Indian children are warranted to validate the adapted measure.

OBJECTIVE: To assess Xpert® MTB/RIF (Xpert) and Xpert® MTB/RIF Ultra (Ultra) performance in diagnosing pediatric tuberculous meningitis (TBM).METHODS: We conducted a study among children with suspected meningoencephalitis in Pune, India. Clinical, radiological, laboratory, and treatment data were analyzed to classify disease as definite, probable, possible or no TBM, using microbiologic or composite reference standards. We tested cerebrospinal fluid (CSF) either using Xpert or Ultra and estimated test performance characteristics.RESULTS: Of 341 participants, 149 (43.7%) were tested using Ultra and 192 (56.3%) with Xpert. Ultra had higher sensitivity (50% vs. 18%), lower specificity (91% vs. 99%), poor positive predictive value (PPV) (13% vs. 75%), and higher negative predictive value (NPV) (99% vs. 93%) than Xpert using the composite reference standard, with similar results by the microbiologic reference standard. Of 10 participants with trace positivity on Ultra, none met clinical TBM definitions.CONCLUSION: This is the first study to report on diagnostic performance of Ultra in pediatric TBM, which showed higher sensitivity and NPV than Xpert. For children presenting with nonspecific clinical features, Ultra is a promising diagnostic test. Further studies are required to define its optimal clinical use, including interpretation of trace positive results.