Biomarkers estimating baseline mortality risk for neonatal sepsis: nPERSEVERE: neonate-specific sepsis biomarker risk model

Abstract

Background: Prognostic biomarker research neonatal sepsis is lacking. We assessed the utility of a validated pediatric prognostic tool called PERSEVERE II that uses decision tree methodology to predict mortality at discharge in neonates who experienced sepsis.

Methods: Prospective study in a dual-center cohort of neonates with sepsis admitted between June 2020 and December 2021. Biomarker analysis was done on serum samples obtained at the time of evaluation for the event.

Results: In a cohort of 59 neonates with a mortality rate of 15.3%, PERSEVERE II was 67% sensitive and 59% specific for mortality, p 0.27. Amongst PERSEVERE II biomarkers, IL-8 showed good prognostic performance for mortality prediction with a cutoff of 300 pg/mL (sensitivity 100%, specificity 65%, negative predictive value 100%, AUC 0.87, p 0.0003). We derived a new decision tree that is neonate specific (nPERSEVERE) with improved performance compared to IL-8 (sensitivity 100%, specificity 86%, negative predictive value 100%, AUC 0.95, p < 0.0001).

Conclusions: IL-8 and nPERSEVERE demonstrated good prognostic performance in a small cohort of neonates with sepsis. Moving toward precision medicine in sepsis, our study proposes an important tool for clinical trial prognostic enrichment that needs to be validated in larger studies.

Impact: Prognostic and predictive biomarker research is lacking in the newborn intensive care unit. Biomarkers can be used at the time of evaluation for neonatal sepsis (blood culture acquisition) to identify neonates with high baseline mortality risk. Stratification is an important step toward precision medicine in neonatal sepsis.

Figure 1.. Study Flow Chart.

71 events were evaluated, after exclusions, 58 neonates were included in the analysis.

Figure 2.. IL-8 Is a Candidate Biomarker for Mortality Prediction.

a. The median and the minimum to maximum range of IL-8 levels in non-survivors (red) vs. survivors (green), 10,114 pg/mL vs. 207 pg/mL respectively, p 0.0001 using the Mann-Whitney U test. b. Receiving-operator curve for IL-8, area under the curve 0.87 (95% CI 0.77 to 0.98).

Figure 3.. The Pruned Final Version of nPERSEVERE.

After pruning, we decided on this tree to test in the cohort. The Terminal node that are labeled with a green tag are low-risk (predicted survivors) while the ones labeled with red tags are high-risk (predicted non-survivors). The survival rate of those classified in the green nodes is 100% compared to 44% of those classified in red nodes.

Figure 4.. Survival Trends of Neonates According to nPERSEVERE Classification.

a. Neonates classified as high-risk (nHR red square) had a survival rate of 44% compared to 100% survival for neonates classified as low-risk (nLR green square), p <0.0001. The entire cohort’s (EC black square) survival curve is depicted for comparison. b. Distribution of mortality timing shows that most deaths occur within the first month of the sepsis event (67%) with the majority occurring in the first two weeks.