Biomarkers of endothelial dysfunction predict sepsis mortality in young infants: a matched case-control study

Abstract

BackgroundReducing death due to neonatal sepsis is a global health priority, however there are limited tools to facilitate early recognition and treatment. We hypothesized that measuring circulating biomarkers of endothelial function and integrity (i.e. Angiopoietin-Tie2 axis) would identify young infants with sepsis and predict their clinical outcome.MethodsWe conducted a matched case-control (1:3) study of 98 young infants aged 0–59 days of life presenting to a referral hospital in Bangladesh with suspected sepsis. Plasma levels of Ang-1, Ang-2, sICAM-1, and sVCAM-1 concentrations were measured at admission. The primary outcome was mortality (n = 18); the secondary outcome was bacteremia (n = 10).ResultsAng-2 concentrations at presentation were higher among infants who subsequently died of sepsis compared to survivors (aOR 2.50, p = 0.024). Compared to surviving control infants, the Ang-2:Ang-1 ratio was higher among infants who died (aOR 2.29, p = 0.016) and in infants with bacteremia (aOR 5.72, p = 0.041), and there was an increased odds of death across Ang-2:Ang-1 ratio tertiles (aOR 4.82, p = 0.013).ConclusionsThis study provides new evidence linking the Angiopoietin-Tie2 pathway with mortality and bacteremia in young infants with suspected sepsis. If validated in additional studies, markers of the angiopoietin-Tie2 axis may have clinical utility in risk stratification of infants with suspected sepsis.Electronic supplementary materialThe online version of this article (10.1186/s12887-018-1087-x) contains supplementary material, which is available to authorized users.

Host-Based Prognostic Biomarkers to Improve Risk Stratification and Outcome of Febrile Children in Low- and Middle-Income Countries

“…Levels of Ang-1, Ang-2, and sTie-2 have also been examined in other causes of sepsis. Results are mostly comparable to the malaria studies, as elevated Ang-2 and reduced Ang-1 levels have been associated with disease severity, intensive care unit (ICU) admission, shock, organ dysfunction, and death ( 54 , 61 , 79 , 96 – 99 ).…”

“…Molecules indicative of endothelial activation and dysfunction include mediators of endothelial cell function, components of the coagulation pathway, soluble cell surface adhesion molecules, and regulators of vascular tone and permeability (25). Among them, a growing body of evidence demonstrates that elevated levels of soluble intercellular adhesion molecule-1 (sICAM-1) are associated with disease severity and prognosis in malaria, dengue, and other causes of sepsis (72)(73)(74)(78)(79)(80). Soluble Fmslike tyrosine kinase 1 (sFlt-1) is another interesting marker of endothelial activation, which binds to vascular endothelial growth factor (VEGF).…”

Clinical trials to assess adjuvant therapeutics for severe malaria

“…In contrast to lactate, the Ang/Tie2 axis has been shown to have a causal relationship to severity and death for malaria [32] and Ang-2 concentrations are associated with multi-organ dysfunction leading to death, including acute kidney injury and coma [26,41]. High Ang-2 concentrations have been linked to multi-organ dysfunction and mortality for multiple causes of sepsis, including malaria [27,[42][43][44][45]. Specifically, Ang-2 has been demonstrated to be elevated in patients with SM and to be an independent and quantitative predictor of mortality [27,33].…”

Vascular Endothelium in Neonatal Sepsis: Basic Mechanisms and Translational Opportunities

“…Furthermore, the correlation between plasma levels of Ang-1, Ang-2, sICAM-1, and sVCAM-1 and the occurrence of death or bacteremia in term infants admitted for suspected sepsis has been investigated. Ang-2 was shown to be higher at admission in non-survivors, as well as Ang-2: Ang-1 ratio that also correlated with bacteremia (146). Similar results were obtained by other investigators (147).…”