Time-course of sFlt-1 and VEGF-A release in neutropenic patients with sepsis and septic shock: a prospective study

Abstract

Background: Septic shock is the most feared complication of chemotherapy-induced febrile neutropenia. So far, there are no robust biomarkers that can stratify patients to the risk of sepsis complications. The VEGF-A axis is involved in the control of microvascular permeability and has been involved in the pathogenesis of conditions associated with endothelial barrier disruption such as sepsis. sFlt-1 is a soluble variant of the VEGF-A receptor VEGFR-1 that acts as a decoy receptor down-regulating the effects of VEGF-A. In animal models of sepsis, sFlt-1 was capable to block the barrier-breaking negative effects of VEGF-A and to significantly decrease mortality. In non-neutropenic patients, sFlt-1 has been shown to be a promising biomarker for sepsis severity.

Methods: We prospectively evaluated concentrations of sFlt-1 and VEGF-A at different time-points during febrile neutropenia, and evaluated the association of these levels with sepsis severity and septic shock development.

Results: Neutropenic patients that evolved with septic shock (n = 10) presented higher levels of sFlt-1 and VEGF-A measured 48 hours after fever onset than patients with non-complicated sepsis (n = 31) and levels of these biomarkers correlated with sepsis severity scores. Estimation of the diagnostic accuracy of sFlt-1 levels for the discrimination of patients that evolved to septic shock yielded promising results in our study population.

Discussion: Our data suggest that sFlt-1 and VEGF-A could be useful biomarkers for sepsis severity in patients with febrile neutropenia. In addition, the kinetics of sFlt-1 release in patients that evolve to septic shock suggest that the sFlt-1 could be a salvage compensatory mechanism in patients with septic shock, but that the magnitude of the sFlt-1 release observed in human sepsis is not sufficient to reproduce the beneficial anti-VEGF-A effects observed in animal models of sepsis.

Figure 1

Study flowchart.

Figure 2

Serum sFlt-1 and VEGF-A levels in FN. Serum sFlt-1 and VEGF-A levels in patients with FN. Box plots representing serial concentrations of sFlt-1 and VEGF-A in patients with FN with non-complicated sepsis (n = 31) or septic shock (n = 10) at fever onset and 48 hours thereafter. Mann-Whitney test.

Figure 3

sFlt-1 and VEGF-A levels in patients with FN. Combined analysis sFlt-1 and VEGF-A levels in patients with FN. Actual sFlt-1 and VEGF-A serum levels obtained at fever onset and after 48 hours are plotted simultaneously as well as median values for each marker at each time point (dotted lines). At fever onset, cases with non-complicated sepsis (empty circles) and septic shock (full circles) are spread evenly across the median values for both parameters (3a-b). After 48 hours, cases that evolved to septic shock seem to localize more frequently in the right upper quadrant (high VEGF-A and high sFlt-1) than cases with non-complicated sepsis, in which levels of both biomarkers change very little.