Metabolomic and single-cell sequencing analyses reveal the complexity of sepsis in burn patients

Author(s):
Carly Knuth; Sarah Rehou; Dalia Barayan; Diana Tedesco; Punit Bhattachan; Marc Jeschke

Background:

Sepsis is the leading cause of mortality in burn patients. Despite its well-delineated clinical significance, the underlying pathophysiology is poorly understood. This prospective trial aims to enhance our understanding of molecular and metabolic aspects in septic burn patients and identify potential therapeutic avenues.

Hypothesis:

Sepsis increases energy demands and fatty acid metabolism, triggering metabolic shifts that exacerbate organ dysfunction, complications, and mortality post-burn.

Methods:

Over 15 years, 3,152 burn patients were assessed; 1,748 were excluded based on age (<18 y), etiology, total body surface area (TBSA; <5%), and survival (<3 d post-injury). The analysis included 1,404 patients: 299 septic and 1,105 non-septic controls. Sepsis was identified using Sepsis-3 criteria and burn staff diagnosis. Clinical outcomes, biomarkers, and metabolic profiling were analyzed, including proteomics, metabolomics, and single-nuclei RNA sequencing.

Results:

Septic patients showed increased complications, including pneumonia, infection, and graft loss. Cardiac, renal, and hepatic responses were altered immediately post-admission. Mortality significantly rose in septic patients (18% vs. 4% in controls), with an equivalent TBSA burn injury. Metabolically, septic patients exhibited early signs of hyperglycemia, hyperlactemia, and acidosis. Altered anti- and pro-inflammatory mediators were observed, including increases in FLT-3L, IFN-γ, IL-1α, IL-1β, IL-4 IL-6, IL-7, IL-15, and TNF-α, and a decrease in EGF. Serum amyloid A was significantly elevated in septic patients. Single-nuclei RNA profiling indicated changes in cell populations before sepsis onset. Lipidomic analyses revealed significant alterations, with upregulation of 134 lipid species and downregulation of 86, particularly triglycerides. Metabolomic analyses identified increased phenylalanine, tyrosine, and beta-alanine metabolism, indicating heightened adrenergic stimulation and upregulated glucose metabolism.

Conclusions:

Sepsis post-burn injury induces profound metabolic derangements, altering inflammatory profiles and triggering a metabolic shift toward glucose and lipid release, resulting in severe organ dysfunction, damage, and increased mortality in septic burn patients.