A Systemic Inflammation Mortality Risk Assessment Contingency Table for Severe Sepsis

Abstract

Objectives: We tested the hypothesis that a C-reactive protein and ferritin-based systemic inflammation contingency table can track mortality risk in pediatric severe sepsis.

Design: Prospective cohort study.

Setting: Tertiary PICU.

Patients: Children with 100 separate admission episodes of severe sepsis were enrolled.

Interventions: Blood samples were attained on day 2 of sepsis and bi-weekly for biomarker batch analysis. A 2 × 2 contingency table using C-reactive protein and ferritin thresholds was developed.

Measurements and main results: A C-reactive protein 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" C-reactive protein greater than or equal to 4.08 mg/dL and ferritin greater than or equal to 1,980 ng/mL category (6/13 [46.15%]) compared with the "intermediate-risk" C-reactive protein greater than or equal to 4.08 mg/dL and ferritin less than 1,980 ng/mL or C-reactive protein less than 4.08 mg/dL and ferritin greater than or equal to 1,980 ng/mL categories (2/43 [4.65%]), and the "low-risk" C-reactive protein less than 4.08 mg/dL and ferritin less than 1,980 ng/mL category (0/44 [0%]) (odds ratio, 36.43 [95% CI, 6.16-215.21]). The high-risk category was also associated with the development of immunoparalysis (odds ratio, 4.47 [95% CI, 1.34-14.96]) and macrophage activation syndrome (odds ratio, 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 (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 C-reactive protein- and ferritin-based contingency table effectively assessed mortality risk. Reduction in systemic inflammation below a combined threshold C-reactive protein of 4.08 mg/dL and ferritin of 1,980 ng/mL appeared to be a desired response in children with severe sepsis.

Figure 1

Receiver Operator Characteristics Curves for the continuous variables PRISM (AUC 0.669, 95% confidence interval 0.394 – 0.945), CRP at initial sampling (AUC 0.770, 95% confidence interval 0.607–0.934) and Ferritin at initial sampling (AUC 0.878, 95% confidence interval 0.751–1.000).

Figure 2

Subsequent mortality in children according to initial C-reactive protein and ferritin risk categories. Subsequent mortality in the ‘At Risk’ categories, combined “High Risk” and “Intermediate Risk” boxes, was greater than in the “Low Risk” category (8/56 (14.29%) vs 0/44 (0%), p < 0.05).

Figure 3

Subsequent mortality among the patients who were in the PICU long enough for serial blood sampling who were in the ‘At Risk’ categories at first sampling (n = 39). The desired response, migration to the “Low Risk” box, was associated with reduced mortality (p < 0.05).

Figure 4

This patient migrated from the ‘Intermediate Risk’ Box D (Ferritin < 1,980 ng/ mL and CRP ≥ 4.08 mg/dL) to the ‘Low Risk’ Box C and survived. The child never developed immunoparalysis or macrophage activation syndrome as inflammation resolved with appropriate antibiotics for bacterial pneumonia and septic shock.

Figure 5

This patient migrated from the ‘High Risk’ category Box B ( Ferritin ≥ 1,980 ng/mL and a CRP ≥ 4.08 mg/dL) to the ‘Low Risk’ Box C and survived. The child developed immunoparalysis (ex vivo TNFα response < 200 pg/mL) which resolved over time with immune suppressant tapering and appropriate antibiotic therapies. There was a secondary infection at day 23 which resolved with new antibiotics.