A High Angiopoietin-2/Angiopoietin-1 Ratio Independently Predicts Septic Shock Development in Patients with Chemotherapy-Associated Febrile Neutropenia and Hematological Malignancies.

Febrile neutropenia (FN) patients with hematologic malignancies present a high risk of septic shock. Clinical scores such as MASCC can identify low-risk patients with FN, mainly in the outpatient setting, but are not very informative for high-risk patients (MASCC<21), which is the category that most patients with hematologic malignancies fit in. Endothelial barrier breakdown is a key element in septic shock, so that proteins involved in this process are currently considered among the most promising biomarkers and therapeutic targets in sepsis. Notably, angiopoietins (Ang) 1 and 2 are key elements of embryonic vascular development, with vessel-stabilizing and -destabilizing properties respectively. In an exploratory study, we previously demonstrated that levels of these proteins are increased in neutropenic patients with septic shock. Materials and Methods: here we prospectively evaluated the significance of VEGF-A, sFlt-1, Ang-1 and Ang-2 levels as biomarkers of septic shock progression in an independent population of patients with chemotherapy-associated FN and hematological malignancies. The study was deliberately designed to mimic real-life conditions in which a sepsis biomarker would be ordered. All patients admitted to the Hematology or BMT wards of our Institution for the treatment of FN between April 2011 and March 2012 were invited to participate. Blood samples were collected in the morning after enrollment, along with the routine blood work-up, by non-study staff. Biomarker levels were obtained by commercially-available ELISA. Primary clinical endpoints were septic shock development or mortality from infection, in 30 days from fever onset. Results: Of the 99 patients that fulfilled the inclusion criteria, 20 (19.8%) developed septic shock and 17 (16.8%) died from infection. Of these, 78 (78.8%) were classified as high-risk according to the MASCC score, a distribution characteristic of hematological malignancies. There were no significant clinical and demographic differences between patients with non-complicated FN and septic shock. No significant difference could be detected in VEGF-A or sFlt-1 levels between outcome groups either. In contrast, Ang-2 concentrations were increased in patients with septic shock (6,494 pg/ml, range 1,730–49,611 pg/ml) compared to non-complicated FN (4,467 pg/ml, range 1,289–37,318 pg/ml; P=0.02), whereas an inverse finding was observed for Ang-1 concentrations, which were lower in patients that developed septic shock (898.8 pg/ml, range 77.87–5,420 pg/ml) than in patients with non-complicated FN (1,220 pg/ml, range 32.55–47,924 pg/ml; P=0.07). Because imbalances between Ang-1 and Ang-2 could be more informative than each isolated biomarker, we calculated the Ang-2/Ang-1 ratio, which was much higher in patients with septic shock (5.29, range 0.58–57.14) than in non-complicated FN (1.99, range 0.06–64.62; P = 0.01). When analyzed as a continuous variable, the Ang-2/Ang-1 ratio proved to be an independent factor for shock septic development. The presence of a threshold level of Ang-2/Ang-1 ratio for an increase in the risk of shock septic could be demonstrated by dichotomizing the ratio by the median and by the optimal cut-off value identified using a ROC procedure (Ang-2/Ang-1=5.0). After adjustment for confounding factors, the multivariate risk for septic shock development was RR=5.47 (CI95% 1.93–15.53) for values above 5.0 and RR=2.99 (CI95%1.02–8.42) for values above the median. Similar results were obtained for 30-day mortality from infection. Conclusion: the prognostic impact of a high Ang-2/Ang-1 ratio as a biomarker for septic shock development was demonstrated in an independent and representative population of high-risk FN patients. The persistence of statistical significance of this association in a much less controlled context than in exploratory studies of biomarker research highlights the strength of the association between this important modulator of endothelial barrier integrity and progression to septic shock. This information has important implications for the clinical management of patients with FN and hematological malignancies, for whom no validated sepsis biomarkers are used in clinical practice, as well as for the development of new therapeutic strategies for the treatment of septic shock.

No relevant conflicts of interest to declare.