Clinical evaluation of modulators of endothelial permeability as biomarkers for risk stratification in sepsis patients with hematological malignancies and febrile neutropenia

Author(s)

Maiara Marx Luz Fiusa

• Document type: Master's Dissertation
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2013-03-14

Examining board members

Erich Vinicius De Paula; Reinaldo Salomão; Rodrigo Nogueira Angerami

• Advisor: Erich Vinicius De Paula

Abstract

Febrile neutropenia (FN) in patients with hematologic malignancies is characterized by a high risk of sepsis complications and septic shock. Although the use of clinical scores such as the MASCC allows the identification of low-risk patients, this score is much less informative in high-risk patients, a category in which most patients with hematologic malignancies, and those undergoing intensive chemotherapy regimens, fit in. At the same time, the use of classical biomarkers such as procalcitonin in non-neutropenic patients is controversial in patients with FN. Endothelial barrier breakdown is a key element in septic shock, so that proteins involved in this process are attractive candidates as biomarkers of sepsis severity. In this study, we prospectively evaluated the value of VEGF-A, sFlt-1, Ang-1 and Ang-2 serum levels as biomarkers of progression to septic shock in 120 patients with FN. Patients hospitalized in the Hematology and Bone Marrow Transplantation in-patient units of a university hospital (HC-UNICAMP) for the treatment of FN between March 2011 and March 2012 were invited to participate. Samples were collected in the following morning after study entry, along with the collection of routine labs. The study was designed to mimic the conditions of blood sample collection and processing that would be encountered in "real-world" clinical practice. Clinical outcomes were (1) progression to septic shock and (2) death within 28 days from fever onset. Results were compared with classical prognostic markers such as C-reactive protein, and MASCC and SOFA scores. In total, 99 patients met the inclusion criteria, of which 19.8% progressed to septic shock. No differences clinical and demographic differences were observed between patients with uncomplicated-FN or septic shock, except for a higher SOFA scores in the latter group. Levels of VEGF-A and sFlt-1 were similar between the two groups. In contrast, serum levels of Ang-2 were increased in patients with septic shock, whereas serum levels of Ang-1 were decreased in these patients. Considering the antagonistic role of angiopoietins 1 and 2 in regulating endothelial permeability, the Ang-2/Ang-1 ratio was calculated as an indicator of imbalances in the concentration of these modulators. In fact, a high Ang-2/Ang-1 ratio was found in patients with septic shock (5.29 - range 0.58 to 57.14) compared to patients with uncomplicated FN (1.99 - range 0.06 to 64.62, P = 0.01). In univariate and multivariate analysis, the Ang-2/Ang-1 ratio proved to be an independent risk factor for the development of septic shock and for 28-day sepsis-related mortality. Thus, we concluded that a high Ang-2/Ang-1 ratio is associated with increased risk of septic shock and mortality in patients with FN, even when collected under conditions close to those encountered in real-world clinical practice (AU)

• FAPESP's process: 11/03078-5 - Clinical and functional evaluation of new biomarkers for risk stratification in patients with sepsis in hematological malignancies and febrile neutropenia
• Grantee: MAIARA MARX LUZ FIUSA
• Support Opportunities: Scholarships in Brazil - Master