Impaired Lymphocyte Responses in Pediatric Sepsis Vary by Pathogen Type
Background: Sepsis 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. Objective: To determine the association between cytometric, proteomic, bioenergetic, and metabolomic abnormalities and pathogen type in pediatric sepsis. Methods: Serial 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-α 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 article's Online Repository at www.jacionline.org. Results: Sepsis 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. Conclusion: Pediatric sepsis patients exhibit a complex, dynamic physiologic state characterized by immunometabolic dysregulation which varies by pathogen type.