Pathophysiology of Pediatric Multiple Organ Dysfunction Syndrome

Abstract

Objective: To describe the pathophysiology associated with multiple organ dysfunction syndrome in children.

Data sources: Literature review, research data, and expert opinion.

Study selection: Not applicable.

Data extraction: 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.

Data synthesis: 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.

Figure 1

Four conditions are observed in pediatric MODS; 1) reduced cytochrome P450 activity, 2) increased circulating Damage Associated Molecular Pattern molecules (DAMPS), 3) increased circulating Pathogen Associated Molecular Pattern molecules (PAMPS), and 4) macrophage activation driven cytokine release associated with epithelial, endothelial, mitochondrial, and immune cell dysfunction and apoptosis.

Figure 2

Environmental and genetic factors can impair the ability of the child with MODS to resolve inflammation: 1) Immunoparalysis is a condition in which antigen presenting cells are unable to present and remove microbes and dead tissue, 2) Thrombocytopenia associated multiple organ failure (TAMOF) is a condition in which complement activation is unopposed by inhibitory complement and von Willebrand factor (vWF) microvascular thrombosis is unopposed by ADAMTS13 (vWF cleaving protease), and 3) Sequential MODS is a condition in which CTL and NK cells cannot induce virus, cancer, or activated immune cell death and sFasL-Fas interactions cause liver failure. The common end pathway of uncontrolled inflammation is macrophage activation syndrome which can be associated with one or more of these phenotypes, or an inability to remove the source of inflammation for other reasons, or the presence of other pediatric hyper-inflammatory syndromes including the CAPS (Cryopyrin Associated Autoinflammatory Periodic Syndromes) spectrum. HLA - Human leukocyte antigen; TNF – Tumor necrosis factor; LPS – Lipopolysaccharide; TAMOF - Thrombocytopenia associated multiple organ failure; Plt Ct – Platelet count; AKI – Acute kidney injury; DIC – Disseminated intravascular coagulation; SMOF – Sequential multiple organ failure; EBV - Epstein Barr Virus; sFASL - Soluble Fas ligand; IL – Interleukin

Figure 3

Phenotype specific therapies reported as effective in resolving inflammation and facilitating MODS recovery. HLA - Human leukocyte antigen; TNF – Tumor necrosis factor; LPS – Lipopolysaccharide; TAMOF - Thrombocytopenia associated multiple organ failure; Plt Ct – Platelet count; AKI – Acute kidney injury; DIC – Disseminated intravascular coagulation; SMOF – Sequential multiple organ failure; IVIG- Intravenous immunoglobulin; PTLD - Post-transplant lymphoproliferative disorder; HLH - Hemophagocytic lymphohistiocytosis; sFASL - Soluble Fas ligand; IRAP - Interleukin-1 (IL-1) receptor antagonist protein

Figure 4

The dynamic immune response in MODS. Children who experience an uncomplicated recovery (black bars) frequently demonstrate prompt resolution of systemic inflammation with mild and transient reduction in immune function. Children with complicated courses (gray bars) often have persistently high levels of systemic inflammation concomitant with markedly reduced immune function. *Elevations in levels of suppressor cells have been demonstrated in critically ill adults, but have not yet been found in children. HLA - Human leukocyte antigen; IL – Interleukin; LPS – Lipopolysaccharide; T_reg - Regulatory T cell; MDSC - Myeloid-derived suppressor cell, TNF - Tumor necrosis factor