Multicohort assessment of plasma metabolic signatures of tuberculosis disease in children: a retrospective cross-sectional study

Microbiological tests for tuberculosis (TB) disease in children have suboptimal accuracy and respiratory samples are often challenging to obtain. Using liquid chromatography/mass spectrometry, we performed plasma 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. All children underwent a standard clinical evaluation and were followed up after 3 months. Children were classified as Confirmed (n = 104), Unconfirmed (n = 108), or Unlikely TB (n = 226) as per NIH consensus definitions. Controlling for age and study site, we found creatine, alanine, retinol, citrulline, fumarate, and tryptophan to be significantly decreased in children with Confirmed TB disease versus those with Unlikely TB, while cortisol, nicotinamide, and butyrylcarnitine were increased (FDR-corrected p-value < 0.2). Using logistic regression, we found this nine-metabolite signature had an area under the receiver operator characteristic curve (AUC) of 0.72 (95% CI (0.67 - 0.82) in the test set of participants with Confirmed and Unlikely TB and an AUC of 0.49 (95% CI 0.42 - 0.55) in the Unconfirmed TB group. These results show a nine-metabolite plasma signature has moderate accuracy for identification of Confirmed TB disease in children.