Scott L Weiss1,2,3, Donglan Zhang3, Jenny Bush1, Kathryn Graham1, Jonathan Starr1,3, Jennifer Murray4, Florin Tuluc4, Sarah Henrickson5,6, Clifford S Deutschman7, Lance Becker8, Francis X McGowan1,3, Douglas C Wallace3. 1. Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. 2. Pediatric Sepsis Program at the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 3. Center for Mitochondrial and Epigenomic Medicine at the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 4. Flow Cytometry Research Core, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 5. Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. 6. Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. 7. Feinstein Institute for Medical Research at Hofstra-Northwell School of Medicine, New York. 8. Department of Emergency Medicine at Hofstra-Northwell School of Medicine, New York.
Abstract
OBJECTIVE: Immune dysregulation is a defining feature of sepsis, but the role for mitochondria in the development of immunoparalysis in pediatric sepsis is not known. We sought to determine if mitochondrial dysfunction measured in peripheral blood mononuclear cells (PBMCs) is associated with immunoparalysis and systemic inflammation in children with sepsis. DESIGN: Prospective observational study. SETTING: Single-academic pediatric intensive care unit (PICU). PATIENTS: One hundred sixty-one children with sepsis/septic shock and 18 noninfected PICU controls. MEASUREMENTS AND MAIN RESULTS: Mitochondrial respiration in PBMCs, markers of immune function, and plasma cytokines were measured on days 1 to 2 (T1), 3 to 5 (T2), and 8 to 14 (T3) after sepsis recognition, and once for controls. Immunoparalysis was defined as whole-blood ex vivo lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-α) ≤200 pg/mL or monocyte human leukocyte antigen-DR ≤30%. Mitochondrial respiration was lower in children with versus without immunoparalysis measured at the same timepoint. Mitochondrial respiration measured early (at T1 and T2) was also lower in those with immunoparalysis at T2 and T3, respectively. Although most patients with immunoparalysis exhibited low mitochondrial respiration, this metabolic finding was not specific to the immunoparalysis phenotype. Plasma cytokines, including IL-8, IL-10, TNF-α, and MCP-1, were highest in the subset of sepsis patients with immune paralysis or low mitochondrial respiration at T1. CONCLUSIONS: Children with sepsis had lower PBMC mitochondrial respiration when immunoparalysis was present compared with those without immunoparalysis. The subsets with immune paralysis and low mitochondrial respiration exhibited the highest levels of systemic inflammation.
OBJECTIVE: Immune dysregulation is a defining feature of sepsis, but the role for mitochondria in the development of immunoparalysis in pediatric sepsis is not known. We sought to determine if mitochondrial dysfunction measured in peripheral blood mononuclear cells (PBMCs) is associated with immunoparalysis and systemic inflammation in children with sepsis. DESIGN: Prospective observational study. SETTING: Single-academic pediatric intensive care unit (PICU). PATIENTS: One hundred sixty-one children with sepsis/septic shock and 18 noninfected PICU controls. MEASUREMENTS AND MAIN RESULTS:Mitochondrial respiration in PBMCs, markers of immune function, and plasma cytokines were measured on days 1 to 2 (T1), 3 to 5 (T2), and 8 to 14 (T3) after sepsis recognition, and once for controls. Immunoparalysis was defined as whole-blood ex vivo lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-α) ≤200 pg/mL or monocyte human leukocyte antigen-DR ≤30%. Mitochondrial respiration was lower in children with versus without immunoparalysis measured at the same timepoint. Mitochondrial respiration measured early (at T1 and T2) was also lower in those with immunoparalysis at T2 and T3, respectively. Although most patients with immunoparalysis exhibited low mitochondrial respiration, this metabolic finding was not specific to the immunoparalysis phenotype. Plasma cytokines, including IL-8, IL-10, TNF-α, and MCP-1, were highest in the subset of sepsispatients with immune paralysis or low mitochondrial respiration at T1. CONCLUSIONS:Children with sepsis had lower PBMC mitochondrial respiration when immunoparalysis was present compared with those without immunoparalysis. The subsets with immune paralysis and low mitochondrial respiration exhibited the highest levels of systemic inflammation.
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