Group-based multi-trajectory analysis of c-reactive protein and ferritin levels in pediatric sepsis

ABSTRACT

INTRODUCTION: Interest in using bedside C-reactive protein and ferritin levels to identify patients with hyperinflammatory sepsis who might benefit from anti-inflammatory therapies piqued with the COVID-19 pandemic experience. These widely available low-cost biomarkers might be similarly useful for assessing inflammatory profiles of all critically ill children with sepsis and septic shock and eventually guiding the use of precision anti-inflammatory therapies. We hypothesized groupbased trajectories of CRP and ferritin among critically ill children with sepsis would be associated with mortality and distinct inflammatory cytokine profiles. METHODS: Children with sepsis and organ failure from 9 pediatric intensive care units were enrolled in a prospective, observational cohort. Plasma CRP (mg/dL), ferritin (ng/mL), and 29 cytokine levels were measured at two samplings during sepsis (median Day 2 and Day 5). Group-based multi-trajectory models (GBMTM) identified groups of children with distinct patterns of CRP and ferritin. RESULTS: Two hundred and fifty-five children had at least 2 CRP and ferritin measurements. Five distinct clinical multitrajectory groups were identified with significantly different median maximum organ failures (MOF) and mortality. Group 1 had normal CRP and ferritin levels (n = 8;median MOF 2.0 [interquartile range 1.0, 2.0] and 0 % mortality);Group 2 had high CRP levels that became normal, with normal ferritin levels throughout (n = 80;median MOF 2.0 [1.0, 2.0] and 5% mortality);Group 3 had high ferritin levels alone (n=16;median MOF 2.5 [2.0, 3.0] and 6.3% mortality);Group 4 had very high CRP levels, and increased ferritin levels (n = 121;median MOF 2.0 [2.0, 4.0] and 10.7% mortality);and, Group 5 had very high CRP and very high ferritin levels (n = 30;median MOF 3.0 [2.0, 4.0] and 40% mortality). Cytokine responses differed across the 5 groups, with ferritin levels associated with macrophage inflammatory protein 1 a, and CRP levels reflective of many cytokines. CONCLUSIONS: Bedside CRP and ferritin levels can be used together to compute distinct groups of children with sepsis who have different systemic inflammation cytokine responses and mortality risks potentially targetable in clinical trials evaluating specific anti-inflammatory therapies.