A six molecule nenonatal serum metabolite biosignature has high neonatal sepsis predictability and resolves upon treatment completion

Abstract

ABSTRACTBackgroundSepsis, a life-threatening disorder with multi-organ dysfunction, is a leading cause of neonatal mortality. Current microbiology-based sepsis diagnosis is time-consuming, and identification of deregulated host serum metabolite signatures might be useful to develop early screening tools and host-directed therapeutics.MethodsIn this multi-institutional study, 500 neonates (41.2% female) were classified to culture-positive (CP) or negative sepsis (CN) cases and controls (no sepsis: NS, healthy control: HC) based on their microbial culture and mass spectrometry test results. The neonates were randomly grouped into two discovery sets (I:n=71; II:n=269), a validation set (n=60), and a longitudinally followed-up population (n=100). Serum samples of these neonates were processed and profiled using gas chromatography coupled to either quadrupole or time-of-flight mass spectrometry (GC-MS/-TOF-MS). Deregulated (log2case/control ≥±0.58, p<0.05) serum metabolites in sepsis cases were identified from the discovery sets and their predictive accuracy in the validation set was calculated using area under the receiving operator characteristic curve (AUC of ROC). The abundance of these deregulated metabolites was monitored in the longitudinally followed-up neonates (CP:n=29, CN:n=35, and NS:n=36) completing therapeutic intervention.ResultsMost of the CP cases wereKlebsiella pneumoniae(28.6%) orAcinetobacter baumannii(20.6%) positive. Gestational age (CP: 30.9±1.9 weeks, CN: 30.9±1.8 weeks, HC: 32.3±1.3 weeks, NS: 31.6±1.5 weeks) and birthweight (CP: 1.4±0.3 kg, CN: 1.4±0.4 kg, HC: 1.7±0.3 kg, NS: 1.6±0.3 kg) were lower in sepsis neonates compared to controls. Out of 57 identified serum metabolites, a set of six (1,5-Anhydro-D-sorbitol-Lactic-acid-Malic-acid-Myo-inositol-Phenylalanine-Lysine) were identified as sepsis biosignature. The AUC of ROC of the biosignature to predict CP or CN from HC was 0.97 and from NS was 0.84 and 0.64, respectively. Myo-inositol, malic acid, and 1,5-anhydro-D-sorbitol revert to the HC levels in neonates completing therapeutic intervention.ConclusionsA serum metabolite signature showed a >97% predictive accuracy for sepsis and could be further explored for its diagnostic and host-directed therapeutic potential.