Imbalances in serum angiopoietin concentrations are early predictors of septic shock development in patients with post chemotherapy febrile neutropenia

Abstract

Background: Febrile neutropenia carries a high risk of sepsis complications, and the identification of biomarkers capable to identify high risk patients is a great challenge. Angiopoietins (Ang -) are cytokines involved in the control microvascular permeability. It is accepted that Ang-1 expression maintains endothelial barrier integrity, and that Ang-2 acts as an antagonizing cytokine with barrier-disrupting functions in inflammatory situations. Ang-2 levels have been recently correlated with sepsis mortality in intensive care units.

Methods: We prospectively evaluated concentrations of Ang-1 and Ang-2 at different time-points during febrile neutropenia, and explored the diagnostic accuracy of these mediators as potential predictors of poor outcome in this clinical setting before the development of sepsis complications.

Results: Patients that evolved with septic shock (n = 10) presented higher levels of Ang-2 measured 48 hours after fever onset, and of the Ang-2/Ang-1 ratio at the time of fever onset compared to patients with non-complicated sepsis (n = 31). These levels correlated with sepsis severity scores.

Conclusions: Our data suggest that imbalances in the concentrations of Ang-1 and Ang-2 are independent and early markers of the risk of developing septic shock and of sepsis mortality in febrile neutropenia, and larger studies are warranted to validate their clinical usefulness. Therapeutic strategies that manipulate this Ang-2/Ang-1 imbalance can potentially offer new and promising treatments for sepsis in febrile neutropenia.

Figure 1

Flowchart of the study.

Figure 2

Serum angiopoietin levels in patients with febrile neutropenia stratified by outcome group. Box plots representing serial concentrations of angiopoietins in patients with febrile neutropenia that presented non-complicated sepsis (n = 31) or septic shock (n = 10). Ang-1 at the time of fever onset (a) and after 48 hours (b). Ang-2 at the time of fever onset (c) and after 48 hours (d). Ang-2/Ang-1 ratio at the time of fever onset (e) and after 48 hours (f). Horizontal bars indicate median values. Mann-Whitney test.

Figure 3

Correlation of angiopoietin levels with the SOFA sepsis severity score. Scatter plots showing linear regression analysis between Sequential Organ Failure Assessment (SOFA) scores and (a) Ang-2 concentrations measured 48 h after fever onset, (b) Ang-2/Ang-1 ratio measured at fever onset (b) and 48 hours thereafter (c).

Figure 4

Survival of patients with febrile neutropenia according to Ang-2/Ang-1 ratio at the time of fever onset. Kaplan-Meier curve (less versus greater than median; * Logrank test.