The Serum Proteomic Signatures Associated With Organ Dysfunction Based on Phoenix Criteria in Pediatric Sepsis: A Pilot Study

OBJECTIVES: To investigate the serum proteomic characteristics linked to sepsis-induced organ dysfunction, as defined by the Phoenix Pediatric Sepsis (PPS) criteria. DESIGN AND SETTING: We conducted a serum proteomic study using data-independent acquisition mass spectrometry in pediatric patients with sepsis, admitted to the PICU at a tertiary, university-affiliated children's hospital in China. PATIENTS: Thirty-eight patients with sepsis and 19 healthy controls were included from November 2020 to June 2022. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 403 differentially expressed proteins (DEPs) were identified in the serum of pediatric sepsis patients compared with healthy controls. Gene Set Enrichment Analysis revealed that DEPs across the four PPS-defined organ dysfunction were enriched in the antimicrobial humoral response, negative regulation of inflammation, plasminogen activation, and cytokine-mediated signaling pathways. Weighted Gene Co-Expression Network Analysis (WGCNA) showed that the MEgreen module was highly associated with the PPS score and was enriched in neutrophils. Further analysis identified seven hub proteins (tissue inhibitor of metalloproteinase-1 [TIMP1], cathepsin L peptidase 1, β-1,4-galactosyltransferase 1, carbonic anhydrase 3, interleukin 1 receptor like 1, olfactomedin 4, and cathepsin G [CATG]) as candidate serum proteomic markers of organ dysfunction risk. We used the expression of these seven hub proteins in a least absolute shrinkage and selection operator regression model to predict organ system dysfunction. It achieved an area under the curve of 0.857 for the coagulation system and 0.769 for the cardiovascular system. All seven hub proteins were significantly correlated with lactic acid and the international normalized ratio (all p < 0.05); CATG was positively correlated with mean arterial pressure (p = 0.005), TIMP1 displayed a positive correlation with d-dimer (p = 0.021) and a negative correlation with platelet (p = 0.005). CONCLUSIONS: We identified seven hub proteins that constitute a novel proteomic signature for predicting sepsis-associated organ dysfunction based on the Phoenix criteria. It is particularly relevant to the coagulation and cardiovascular systems.