A high angiopoietin-2/angiopoietin-1 ratio is associated with a high risk of septic shock in patients with febrile neutropenia

Abstract

Introduction: Endothelial barrier breakdown is a hallmark of septic shock, and proteins that physiologically regulate endothelial barrier integrity are emerging as promising biomarkers of septic shock development. Patients with cancer and febrile neutropenia (FN) present a higher risk of sepsis complications, such as septic shock. Nonetheless, these patients are normally excluded or under-represented in sepsis biomarker studies. The aim of our study was to validate the measurement of a panel of microvascular permeability modulators as biomarkers of septic shock development in cancer patients with chemotherapy-associated FN.

Methods: This was a prospective study of diagnostic accuracy, performed in two distinct in-patient units of a university hospital. Levels of vascular endothelial growth factor A (VEGF-A), soluble fms-like tyrosine kinase-1 (sFlt-1) and angiopoietin (Ang) 1 and 2 were measured after the onset of neutropenic fever, in conditions designed to mimic the real-world use of a sepsis biomarker, based on our local practice. Patients were categorized based on the development of septic shock by 28 days as an outcome.

Results: A total of 99 consecutive patients were evaluated in the study, of which 20 developed septic shock and 79 were classified as non-complicated FN. VEGF-A and sFlt-1 levels were similar between both outcome groups. In contrast, Ang-2 concentrations were increased in patients with septic shock, whereas an inverse finding was observed for Ang-1, resulting in a higher Ang-2/Ang-1 ratio in patients with septic shock (5.29, range 0.58 to 57.14) compared to non-complicated FN (1.99, range 0.06 to 64.62; P = 0.01). After multivariate analysis, the Ang-2/Ang-1 ratio remained an independent factor for septic shock development and 28-day mortality.

Conclusions: A high Ang-2/Ang-1 ratio can predict the development of septic shock in cancer patients with febrile neutropenia.

Figure 1

Study flowchart.

Figure 2

Vascular permeability-related biomarkers in FN patients. Serum concentrations of soluble fms-like tyrosine kinase-1 (sFlt-1), vascular endothelial growth factor-A (VEGF-A) and angiopoietin (Ang) -1 and Ang-2 in patients with non-complicated febrile neutropenia (FN) (n = 79) or septic shock (n = 20). Horizontal bars represent median values; Mann-Whitney test.

Figure 3

Ang-2/Ang-1 ratio in FN patients. Angiopoietin- (Ang)-2/Ang-1 ratio in patients with non-complicated febrile neutropenia (FN) (n = 79) or septic shock (n = 20). Horizontal bars represent median values; Mann-Whitney test.

Figure 4

Twenty-eight-day survival and septic shock development in high-risk FN patients. Kaplan-Meier estimates of 28-day (a) survival and (b) septic shock development of patients with febrile neutropenia (FN) according to angiopoietin (Ang)-2/Ang-1 ratio. The ratio was dichotomized by the median Ang-2/Ang-1 ratio (2.2) in all patients (right) or by an optimal cut-off level of 5.0 (left), defined by a receiver operator characteristic (ROC) analysis.