title: Pathophysiology of Pediatric Multiple Organ Dysfunction Syndrome.
abstract: OBJECTIVE
  To describe the pathophysiology associated with multiple organ dysfunction syndrome in children.
  
  
  METHODS
  Literature review, research data, and expert opinion.
  
  
  METHODS
  Not applicable.
  
  
  METHODS
  Moderated by an experienced expert from the field, pathophysiologic processes associated with multiple organ dysfunction syndrome in children were described, discussed, and debated with a focus on identifying knowledge gaps and research priorities.
  
  
  RESULTS
  Summary of presentations and discussion supported and supplemented by relevant literature.
  
  
  CONCLUSIONS
  Experiment modeling suggests that persistent macrophage activation may be a pathophysiologic basis for multiple organ dysfunction syndrome. Children with multiple organ dysfunction syndrome have 1) reduced cytochrome P450 metabolism inversely proportional to inflammation; 2) increased circulating damage-associated molecular pattern molecules from injured tissues; 3) increased circulating pathogen-associated molecular pattern molecules from infection or endogenous microbiome; and 4) cytokine-driven epithelial, endothelial, mitochondrial, and immune cell dysfunction. Cytochrome P450s metabolize endogenous compounds and xenobiotics, many of which ameliorate inflammation, whereas damage-associated molecular pattern molecules and pathogen-associated molecular pattern molecules alone and together amplify the cytokine production leading to the inflammatory multiple organ dysfunction syndrome response. Genetic and environmental factors can impede inflammation resolution in children with a spectrum of multiple organ dysfunction syndrome pathobiology phenotypes. Thrombocytopenia-associated multiple organ dysfunction syndrome patients have extensive endothelial activation and thrombotic microangiopathy with associated oligogenic deficiencies in inhibitory complement and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13. Sequential multiple organ dysfunction syndrome patients have soluble Fas ligand-Fas-mediated hepatic failure with associated oligogenic deficiencies in perforin and granzyme signaling. Immunoparalysis-associated multiple organ dysfunction syndrome patients have impaired ability to resolve infection and have associated environmental causes of lymphocyte apoptosis. These inflammation phenotypes can lead to macrophage activation syndrome. Resolution of multiple organ dysfunction syndrome requires elimination of the source of inflammation. Full recovery of organ functions is noted 6-18 weeks later when epithelial, endothelial, mitochondrial, and immune cell regeneration and reprogramming is completed.
authors.affiliation: 1Department of Critical Care Medicine and Pediatrics, University of Pittsburgh, Pittsburgh, PA. 2Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA. 3Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH. 4Department of Pediatrics, University of Michigan, Ann Arbor, MI. 5Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, OH. 6Department of Pediatrics, Texas Children's Hospital, Houston, TX.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Carcillo
authors.forename: Bradley
authors.initials: B
authors.lastname: Podd
authors.forename: Rajesh
authors.initials: R
authors.lastname: Aneja
authors.forename: Scott L
authors.initials: SL
authors.lastname: Weiss
authors.forename: Mark W
authors.initials: MW
authors.lastname: Hall
authors.forename: Timothy T
authors.initials: TT
authors.lastname: Cornell
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Shanley
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Doughty
authors.forename: Trung C
authors.initials: TC
authors.lastname: Nguyen
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002648:Child; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D055501:Macrophage Activation Syndrome / Q000503:physiopathology; D008928:Mitochondria / Q000378:metabolism; D009102:Multiple Organ Failure / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D010372:Pediatrics; D013921:Thrombocytopenia / Q000503:physiopathology
chemical_list: D015415:Biomarkers; D003577:Cytochrome P-450 Enzyme System