Impaired Lymphocyte Responses in Pediatric Sepsis Vary by Pathogen Type

BackgroundSepsis is the leading cause of death in hospitalized children worldwide. Despite its hypothesized immune-mediated mechanism, targeted immunotherapy for sepsis is not available for clinical use. ObjectiveTo determine the association between cytometric, proteomic, bioenergetic, and metabolomic abnormalities and pathogen type in pediatric sepsis. MethodsSerial PBMC samples were obtained from 14 sepsis patients (34 samples) and 7 control patients for this pilot study. Flow cytometry was used to define immunophenotype, including T cell subset frequency and activation state, and assess intracellular cytokine production. Global immune dysfunction was assessed by TNF- production capacity and monocyte HLA-DR expression. Mitochondrial function was assessed by bulk respirometry. Metabolites were measured by liquid chromatography-mass spectrometry. Results were compared by timepoint and pathogen type. For detailed Methods, please see the Methods section in this articles Online Supplement. ResultsSepsis patients were older and had higher illness severity compared to controls; demographics were otherwise similar. Compared to controls, sepsis patients demonstrated global immune dysfunction, loss of peripheral of non-naive CD4+ T cells, and reduced PBMC mitochondrial function. Metabolomic findings in sepsis patients were most pronounced at sepsis onset and included elevated uridine and 2-dehydrogluconate and depleted citrulline. Loss of peripheral non-naive CD4+ T cells was associated with immune dysfunction and reduced cytokine production despite increased T cell activation. CD4+ T cell differentiation and corresponding pro- and anti-inflammatory cytokines varied by pathogen. ConclusionPediatric sepsis patients exhibit a complex, dynamic physiologic state characterized by immunometabolic dysregulation which varies by pathogen type. CLINICAL IMPLICATIONSComprehensive immune monitoring in critically-ill patients using small-volume samples yields novel insights into diverse T cell responses to pediatric sepsis, which may improve future personalized therapies for these high-risk patients.