Linking Acute Pediatric Sepsis to Chronic Autoimmune Risks

Introduction: Sepsis represents an acute challenge in pediatrics while also reflecting potential for underexplored chronic outcomes. The PHENOtyping sepsis-induced Multiple organ failure Study (PHENOMS), using 24-hour-based unsupervised clustering of clinical and laboratory data, has identified four subgroups of pediatric sepsis. It is unknown how these subgroups are associated with chronic transitions, including autoimmunity.


Methods: We applied blood metabolomics to a subset of PHENOMS samples representing all four subgroups (n=27 per group), followed by subgroup-specific metabolite analysis. These were linked to a separate cohort of pediatric multiple organ dysfunction syndrome (MODS) patients (n=27) assessed over nine days with blood metabolomics and transcriptomics to impute subgroup dynamics into transcriptomics. Finally, we built an acute-to-chronic pediatric sepsis simulated storytelling model from the lens of patients, caregivers, and clinicians using AI-assisted capture of real community-level insights.


Results: Metabolomics revealed Group D patients, those with the highest mortality rate (34%) and most organs in failure, were enriched for 157 metabolites across pathways, including Aminosugar Metabolism, Lactoyl Amino Acid, Modified Peptides, Purine Metabolism, and TCA Cycle. Among these, (S)-α-amino-ω-caprolactam (p-value 2E-13), creatinine (p-value 1E-12), and 5-methylthioribose (p-value 2E-12) were most significant. Antibodies against Epstein-Barr Virus (EBV) clustered significantly with bilirubin (p-value 1E-5). The MODS cohort revealed shared metabolites to Group D patients, while transcriptomics showed a role of neutrophil extracellular traps (NETosis) with early autoantibody clonal expansion linked to chronic states involving double-stranded DNA, particularly in EBV-positive individuals. The simulated narratives highlighted prolonged functional, cognitive, and emotional sequelae matching acute-to-chronic sepsis with autoimmunity dynamics.


Conclusions: This work lays a foundation for insights into the linkage of acute sepsis dynamics to chronic autoimmune states, particularly for MODS pediatric sepsis patients. There is a need for innovative interventions and follow-up protocols to mitigate long-term autoimmunity risks in children with sepsis.