Three Hypothetical Inflammation Pathobiology Phenotypes and Pediatric Sepsis-Induced Multiple Organ Failure Outcome

Abstract

Objectives: We hypothesize that three inflammation pathobiology phenotypes are associated with increased inflammation, proclivity to develop features of macrophage activation syndrome, and multiple organ failure-related death in pediatric severe sepsis.

Design: Prospective cohort study comparing children with severe sepsis and any of three phenotypes: 1) immunoparalysis-associated multiple organ failure (whole blood ex vivo tumor necrosis factor response to endotoxin < 200 pg/mL), 2) thrombocytopenia-associated multiple organ failure (new onset thrombocytopenia with acute kidney injury and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 activity < 57%), and/or 3) sequential multiple organ failure with hepatobiliary dysfunction (respiratory distress followed by liver dysfunction with soluble Fas ligand > 200 pg/mL), to those without any of these phenotypes.

Setting: Tertiary children's hospital PICU.

Patients: One hundred consecutive severe sepsis admissions.

Interventions: Clinical data were recorded daily, and blood was collected twice weekly.

Measurements and main results: Multiple organ failure developed in 75 cases and eight died. Multiple organ failure cases with any of the three inflammation phenotypes (n = 37) had higher inflammation (C-reactive protein, p = 0.009 and ferritin, p < 0.001) than multiple organ failure cases without any of these phenotypes (n = 38) or cases with only single organ failure (n = 25). Development of features of macrophage activation syndrome and death were more common among multiple organ failure cases with any of the phenotypes (macrophage activation syndrome: 10/37, 27%; death: 8/37, 22%) compared to multiple organ failure cases without any phenotype (macrophage activation syndrome: 1/38, 3%; p = 0.003 and death: 0/38, 0%; p = 0.002).

Conclusions: Our approach to phenotype categorization remains hypothetical, and the phenotypes identified need to be confirmed in multicenter studies of pediatric multiple organ dysfunction syndrome.

Figure 1. Distribution of single organ failure, multiple organ failure with and without inflammation phenotypes, and macrophage activation syndrome in the severe sepsis population

Nearly one half of MOF patients had one or more of the three inflammation phenotypes (Top panel). Macrophage Activation Syndrome (MAS) was more commonly found in MOF patients with the inflammation phenotypes (10/37) than MOF patients without any of the inflammation phenotypes (1/38); Fisher’s exact test p = 0.003 (Bottom Panel). Single organ failure (SOF); Multiple organ failure (MOF); Immune paralysis Associated MOF (IP MOF); Thrombocytopenia Associated MOF (TAMOF); Sequential MOF (SMOF); Macrophage Activation Syndrome (MAS)

Figure 2. Mortality distribution in the severe sepsis population

All mortality occurred among MOF cases with one or more of the inflammation phenotypes (Fisher’s exact test - MOF with phenotypes 8/37, 28% vs MOF without phenotypes 0/38, 0%; p = 0.002) and was highest among those who developed MAS (Fisher’s exact test - MOF with inflammation phenotypes and MAS 7/10, 70% vs MOF with inflammation phenotypes without MAS 1/27, 4%; p < 0.001). SOF= Single Organ Failure; MOF = Multiple Organ Failure TAMOF = Thrombocytopenia Associated MOF; SMOF = Sequential MOF; IP MOF = Immune paralysis Associated MOF; MAS = Macrophage Activation Syndrome

Figure 3. First four time point (Days 2 through 12) confirmatory biomarker levels for survivors with each inflammation pathobiology phenotype (ex vivo TNF response pg/mL, ADAMTS13 activity % of control, and sFASL pg/mL median with 5^th and 95^th percentile)

GM-CSF administration and withdrawal of immune suppressants occurred in 8 of 19 Immune Paralysis survivors. Plasma exchange was given to 6 of 9 TAMOF survivors. No patients received Anakinra, Eculizumab, Rituximab, or Etoposide.

Figure 4. First four time point (Days 2 through 12) confirmatory biomarker levels for non-survivors with the inflammation pathobiology phenotypes (ex vivo TNF response pg/mL, ADAMTS13 activity % of control, and sFASL pg/mL median with 5^th and 95^th percentile)

GM-CSF administration and withdrawal of immune suppressants occurred in 0 of 5 Immune Paralysis non-survivors. Plasma exchange was given to 4 of 6 TAMOF non-survivors. No patients received Anakinra, Eculizumab, Rituximab, or Etoposide.