Altered Cholesterol Homeostasis Within Neonatal Sepsis

Background: Sepsis remains a leading cause of mortality in the neonatal period. Hypocholesterolemia has been recognized as an excellent early prognosticator of mortality risk in critically ill patients. Statin therapy has also been demonstrated to improve survival in adult sepsis epidemiological studies. Nevertheless, the underlying pathophysiologic mechanisms as well as clinical implications of lipids within sepsis remain poorly understood.

Objectives: We hypothesize that hypocholesterolemia induced by inflammatory states may be an immunologic set-point to limit pathogen spread with detrimental hemodynamic consequences. Here, we aim to investigate the role of cholesterol homeostasis within the context of neonatal sepsis.

Design/Methods: A retrospective longitudinal cohort analysis was performed of preterm infants with and without development of culture positive, late-onset neonatal sepsis at a priori timepoints of sex, birthweight, and gestational age-matched neonates. Furthermore, a B6 murine model of neonatal sepsis utilizing a neonatal-specific pathogen E. coli K1 was utilized to assess the effect of statin treatment on neonate pup mortality. Mouse pups were injected with Simvastatin 40 mg/kg or buffered saline 14 and 2 hours prior to sepsis initiation. Sepsis was induced via IP injection of 2.3x103 CFU E. coli K1 on P5. Pup survival was followed for 100 hours after injection and morbidity was determined by clinical scoring for 100 hours post infection. Differences between groups were evaluated with a log-rank test.

Results: Total cholesterol, LDL-c, and HDL-c were found to nadir on D0-D3 from day of sepsis evaluation with preterm infants compared to gestational age, sex, and birthweight match preterm infants. While less sensitive as a biomarker for distinguishing culture positive and culture-negative sepsis, total cholesterol levels correlate with clinical NSOFA scores and need for vasopressor support during sepsis progression. A murine model of neonatal sepsis utilizing a neonatal-specific pathogen E. coli K1 demonstrates that pre-infection statin therapy exhibited an overall survival benefit.

Conclusions: Systematic reviews link derangements in cholesterol metabolism with critical illness. Here, we demonstrate that circulating total cholesterol levels decrease during neonatal LOS, extending these findings within the preterm population & further supporting a mechanistic role for altered sterol metabolism within infection and immunity.