A Systemic Inflammation Mortality Risk Assessment Contingency Table for Severe Sepsis*

Abstract

Objective We tested the hypothesis that a c-reactive protein (CRP) and ferritin based systemic inflammation contingency table can track mortality risk in pediatric severe sepsis. Design Prospective cohort study Setting Tertiary Pediatric Intensive Care Unit Patients Children with 100 separate admission episodes of severe sepsis were enrolled. Interventions Blood samples were attained on day two of sepsis and bi-weekly for biomarker batch analysis. A 2 × 2 contingency table using CRP and ferritin thresholds was developed. Measurements and Main Results A CRP of 4.08 mg/dL and a ferritin of 1,980 ng/mL were found to be optimal cutoffs for outcome prediction at first sampling (n = 100) using the Youden Index. PICU mortality was increased in the ‘High risk’ CRP ≥ 4.08 mg/dL and Ferritin ≥ 1,980 ng/mL category (6/13, 46.15%) compared to the ‘Intermediate risk’ CRP ≥ 4.08 mg/dL and Ferritin < 1,980 ng/mL or CRP < 4.08 mg/dL and Ferritin ≥ 1,980 ng/mL categories (2/43, 4.65%), and the ‘Low risk’ CRP < 4.08 mg/dL and Ferritin < 1,980 ng/mL category (0/44, 0%) (OR 36.43 [95% CI: 6.16–215.21]). The ‘High risk’ category was also associated with the development of Immunoparalysis (OR 4.47 [95% CI 1.34–14.96]) and Macrophage Activation Syndrome (OR 24.20 [95% CI 5.50–106.54]). Sixty three children underwent sequential blood sampling; those who were initially in the ‘Low risk’ category (n = 24) and those who subsequently migrated to (n =19) to the ‘Low risk’ category all survived, whereas those who remained in the ‘At risk’ categories had increased mortality (7/20 = 35%; p < 0.05). Conclusions A CRP and ferritin based contingency table effectively assessed mortality risk. Reduction in systemic inflammation below a combined threshold CRP of 4.08 mg/dL and ferritin of 1,980 ng / mL appeared to be a desired response in children with severe sepsis.

Hyperferritinemia and inflammation

“…In the setting of ongoing infection, CpG DNA from viral or bacterial pathogens triggers TLR9-mediated signaling. This TLR9 stimulation has been shown to activate inflammasome activity, leading to IL-1β and IL-18 production (71,74). IL-1β activation can then in turn increase the translation of FTH mRNA through direct interaction with the 5′ UTR (36).…”

“…Hyperferritinemia, regardless of the underlying pathology, is associated with high mortality (74)(75)(76). As a marker of significant macrophage activation, individuals manifesting a hyperferritinemic phenotype show a typical pattern of reticuloendothelial system activation and multiple organ dysfunction (74)(75)(76)(77)(78)(79)(80). This phenotype is classically described in primary or familial hemophagocytic lymphohistiocytosis (FHLH), a recessive genetic disorder of excessive macrophage activation driven by IFN-γ that results from an inability to clear pathogen subsequent to inherited defects of CTL and NK cell-mediated cytolytic killing.…”

Cytokine Release Syndrome in COVID-19 Patients, A New Scenario for an Old Concern: The Fragile Balance between Infections and Autoimmunity

“…In particular, it has been hypothesized that during an ongoing infection, the signaling mediated by bacterial/viral CpG DNA and TLR9 could activate the inflammasome, leading to IL-1 and IL-18 production [18][19][20]. Through DAMP signaling, infection could also increase the production of hemoglobin [21] and activate macrophages, which are prominent producers of ferritin [22,23], amplifying the inflammatory loop [23].…”

Ferritin in the coronavirus disease 2019 (COVID‐19): A systematic review and meta‐analysis

“…Hyperferritinemia caused by the excessive inflammation due to the infection is associated with the admission to the intensive care unit and high mortality, and represents an indication to recognize high‐risk patients to guide the therapeutic intervention to control inflammation 7‐9 . Serum ferritin, a feature of hemophagocytic lymphohistiocytosis, which is a known complication of viral infection, is closely related to poor recovery of COVID‐19 patients, and those with impaired lung lesion are more likely to have increased ferritin levels 6,10,11 .…”