Abstract
IntroductionPulmonary tuberculosis (TB) is a major worldwide health problem that lacks robust blood-based biomarkers for detection of active disease. High-resolution metabolomics (HRM) is an innovative method to discover low-abundance metabolites as putative blood biomarkers to detect TB disease, including those known to be produced by the causative organism, Mycobacterium tuberculosis (Mtb).MethodsWe used HRM profiling to measure the plasma metabolome for 17 adults with active pulmonary TB disease and 16 of their household contacts without active TB. We used a suspect screening approach to identify metabolites previously described in cell culture studies of Mtb based on retention time and accurate mass matches.ResultsThe association of relative metabolite abundance in active TB disease subjects compared to their household contacts predicted three Mtb-associated metabolites that were significantly increased in the active TB patients based on accurate mass matches: phosphatidylglycerol (PG) (16:0_18:1), lysophosphatidylinositol (Lyso-PI) (18:0) and acylphosphatidylinositol mannoside (Ac1PIM1) (56:1) (p<0.001 for all). These three metabolites provided excellent classification accuracy for active TB disease (AUC = 0.97). Ion dissociation spectra (tandem MS/MS) supported the identification of PG (16:0_18:1) and Lyso-PI (18:0) in the plasma of patients with active TB disease, though the identity of Ac1PIM1 could not be definitively confirmed.ConclusionsPresence of the Mtb-associated lipid metabolites PG (16:0_18:1) and Lyso-PI (18:0) in plasma accurately identified patients with active TB disease. Consistency of in vitro and in vivo data suggests suitability for exploring these in future studies for possible development as TB disease biomarkers.
Highlights
Rapid and accurate detection of active TB disease remains a major challenge in global control efforts, with less than two thirds of estimated TB cases diagnosed in 2016 [1]
The poor performance characteristics of available diagnostic tests for pulmonary TB, especially smear microscopy, which is frequently used in low- and middle-income countries, is a major contributor to suboptimal case detection and diagnostic delays [2]
Acid-fast bacilli (AFB) culture is the gold standard for diagnosis, but can take 2–6 weeks for definitive results and the infrastructure required for culture is often unavailable in resource-limited settings [3]
Summary
We used HRM profiling to measure the plasma metabolome for 17 adults with active pulmonary TB disease and 16 of their household contacts without active TB. We performed a cross-sectional analysis of plasma HRM profiles for 17 patients with active TB disease selected from a randomized, controlled trial of high-dose cholecalciferol treatment of patients with pulmonary TB conducted in the country of Georgia (clinicaltrials.gov identifier NCT00918086) [18]. Inclusion criteria for patients included age 18 years, newly diagnosed, symptomatic active TB disease, suggested by a positive AFB sputum smear and confirmed by semi-quantitative sputum culture for Mtb (performed at the Georgian National TB Reference Laboratory (NRL) [18]. Patients infected with Mtb isolates resistant to isoniazid and rifampin were considered to have multidrug resistant (MDR)-TB
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