BackgroundFebrile 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.MethodsWe 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.ResultsPatients 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.ConclusionsOur 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.

BackgroundSeptic 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.MethodsWe 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.ResultsNeutropenic 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.DiscussionOur 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.

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Background The novel coronavirus disease‐2019 (COVID‐19) caused a sudden and unexpected increase in the number of hospital admissions and deaths worldwide. The impact of social distancing on blood stocks was significant. Data on the use of blood products by patients with COVID‐19 are scarce. Material and methods A retrospective observational study was conducted by analysing the medical records of 3014 hospitalized COVID‐19 patients in 16 Brazilian hospitals. Individual data related to clinical, laboratory and transfusion characteristics and outcomes of these patients were collected. Patients characteristics association with mortality and transfusion need were tested independently by logistic regression models. Results Patients mean age was 57·6 years. In 2298 (76·2%) patients, there was an underlying clinical comorbidity. A total of 1657 (55%) patients required admission to intensive care unit (ICU), and 943 (31%) patients required ventilatory support and orotracheal intubation (OTI). There was a total of 471 (15·6%) deaths among all patients. 325 patients (10·7%) required blood transfusion; 3187 blood products were transfused: 1364 red blood cells in 303 patients, 1092 platelet units in 78 patients, 303 fresh frozen plasma in 49 patients and 423 cryoprecipitates in 21 patients. The mortality among patients who received transfusion was substantially higher than that among the total study population. Conclusion Need for transfusion was low in COVID‐19 patients, but significantly higher in patients admitted to ICU and in those who needed OTI. Knowledge of the transfusion profile of these patients allows better strategies for maintaining the blood stocks of hospitals during the pandemic.

Introduction: Sepsis in febrile neutropenia (FN) is a life threatening condition, and a health problem of increasing proportions. Although multiple organ dysfunction syndrome (MODS) frequently precedes death in patients with sepsis, the ultimate mechanisms responsible for organ dysfunction and tissue damage in sepsis are yet to be determined. Currently, tissue damage is attributed to an exacerbated response of the immune and hemostatic systems, mediated by endothelial cells, platelets and neutrophils. Of note, recent evidence demonstrated that neutrophils, platelets and fibrin participate in this response by mediating neutrophil extracellular traps (NET) formation, and promoting the hemostatic containment of infectious foci. In animal models, down-regulation of NET formation, coagulation and platelet activation are usually associated with deficiencies in pathogen clearance. Unfortunately, activation of hemostasis and NET formation could potentially contribute to tissue damage by a process called "immunethrombosis". Although the increase of sepsis severity in patients with severe neutropenia is well described, the mechanisms of sepsis-associated tissue damage in the context of severe neutropenia/thrombocytopenia are yet to be determined. Methods: In order to investigate the mechanisms of tissue damage in the context of severe neutropenia/thrombocytopenia, we compiled clinical data from two different prospective sepsis cohorts (A, neutropenic; n=129; and B, non-neutropenic; n=30) followed at our Institution. In addition, we reviewed histopathological data from 16 autopsies of individuals with hematological malignancies and septic shock from our institution (cohort C; n=16). H&E-stained slides from liver, kidneys and lungs were systematically analyzed by one investigator, and reviewed by 2 experienced pathologists, all of them blind to the presence or absence of neutropenia and thrombocytopenia. In each organ, we characterized (as present or absent) three main organic lesions: thrombi in microvessels, microorganism colonies, and inflammatory infiltrate (mononuclear and polymorphonuclear). Inflammation was graded as weak or intense, and only considered when there was no neoplastic infiltration. Results: Median ages of patients from cohorts A and B were respectively 46.0 years (13-78), and 59.4 years (22-85); P<0.0001. In cohort A, neutrophil counts were < 100/mcl in 55.8% of patients and between 100-500/mcl in 42.6%. Platelet counts were also lower in cohort A (30,126 vs 213,933/mcl; P<0.0001). Median SOFA scores (at admission) were 4 (0-15) and 5 (0-17); P=0.3 in neutropenic and non-neutropenic patients respectively, and sepsis-related mortality was 22.5% and 10.3% in the same groups (P=0.19). Among patients with a higher SOFA score, mortality was higher in neutropenic patients (100% vs 33.3%; p=0.04). The frequencies of clinically-evident infection foci were 60% in cohort A and 100% in cohort B (P=0.0001). In contrast, positive blood cultures were present in 38% of neutropenic, but in only 3.3% of non-neutropenic patients (P<0.0001). The autopsy-based study included 10 patients with lymphoma and 6 with acute leukemia. The cause of death was septic shock in all of them, and three patients presented severe neutropenia (<500/mcl). The main histological findings are shown in table 1. The only neutropenic patient with microthrombi presented AML-M3 and leukostasis. Using H&E staining, no bacterial colonies were found in any slide. Conclusions: as expected, septic patients with severe neutropenia presented a worse outcome compared to non-neutropenic patients in our cohort. In addition, the lower frequency of clinically-defined infectious foci, coupled with a strikingly higher frequency of positive blood cultures, suggest that severe neutropenia and thrombocytopenia could impair pathogen containment and clearance. Severe neutropenia/thrombocytopenia was compatible with inflammatory infiltrates and microvascular thrombosis in lungs, although the latter was only observed in a patient with leukostasis and promyelocityc acute leukemia. Table 1. Histological findings in autopsies of neutropenic and non-neutropenic patients Microthrombi Inflammation (weak/intense) Lungs Kidney Liver Lungs Kidney Liver Neutropenic 33% 33% 0% 50%/50% 0%/0% 0%/0% Non-neutropenic 56.25% 25% 6.25% 70%/20% 34%/9% 67%/0% Disclosures No relevant conflicts of interest to declare.