Survival of the Littlest: Navigating Sepsis Diagnosis beyond Inflammation in Preterm Neonates

Sepsis diagnosis in preterm neonates is challenging due
to symptom
overlap with non-infectious inflammatory conditions, and slow, unreliable
diagnostic practices. This case-control study aims to elucidate sepsis
pathophysiology, and identify metabolic biomarkers for timely, accurate
diagnosis, to prevent rapid health deterioration and unnecessary antibiotic
use. Liquid chromatography–mass spectrometry was performed
on 227 plasma samples, obtained from 94 preterm neonates, to measure
317 metabolites encompassing amines and signaling lipids. Linear mixed-effect
modeling, LASSO and logistic regression models were calculated to
assess metabolic alterations across control, systemic inflammation-no
sepsis (SINS), and sepsis groups. Stratification by sex and pathogen
type allowed identification of sex-specific responses and pathogen-driven
variations in sepsis. Key findings include (i) shared metabolic changes
in SINS and sepsis, (ii) progressive alterations from control to SINS
to sepsis, and (iii) sepsis-specific markers. Males exhibited a pro-inflammatory
phenotype while females showed an anti-inflammatory phenotype in response
to sepsis. Gram-positive and gram-negative bacterial sepsis revealed
distinct metabolic profiles. A diagnostic model comprising 5 metabolic
features and IL-6 distinguished SINS from sepsis at clinical suspicion
(AUC 0.79, sensitivity 0.85, specificity 0.82). These insights highlight
the potential of metabolomics to revolutionize neonatal sepsis management
with precision diagnostics and personalized treatment strategies.