Abstract
Disseminated aspergillosis is responsible for a high mortality rate, despite the use of antifungal drugs. Adjuvant therapies are urgently needed to improve the outcome. The aim of this study was to demonstrate that the cytoprotective effect of erythropoietin (EPO) combined with amphotericin B can reduce the mortality rate in a murine model of disseminated aspergillosis. After infection with Aspergillus fumigatus, neutropenic mice were randomized to receive vehicle or 7.5 mg/kg liposomal amphotericin B (LAmB) or 7.5 mg/kg LAmB combined with 1000 IU/kg EPO (16 mice per group). Aspergillus galactomannan and organ cultures were performed to evaluate fungal burden at day 5. Cumulative long-term survival was analyzed at day 12 post-infection according to the Kaplan–Meier method. At day 5, fungal burden was similar between non-treated and treated groups. At day 12, mortality rates were 75, 62.5, and 31% in control group, LAmB group, and EPO/LAmB group, respectively. We observed a significant decrease in mortality using EPO/LAmB combination compared to control group (p < 0.01). LAmB single treatment did not improve the survival rate compared to control group (p = 0.155). Our results provide the first evidence that EPO improved the outcome of mice presenting with disseminated aspergillosis when combined with amphotericin B.
Highlights
Aspergillus fumigatus is a ubiquitous and opportunistic fungi, responsible for disseminated infections in immunocompromised patients including hematopoietic stem cell transplant, solid organ transplant recipients, and patients receiving immunosuppressive drugs [1]
A. fumigatus growing in the respiratory tract is responsible for epithelial and endothelial cells injuries, disruption of the blood vessels integrity leading to hemorrhages and fungemia [6, 7]
In order to document our hypothesis, we set up a murine model of disseminated aspergillosis and we studied the effect on the mortality rate of a combination of EPO high doses associated to amphotericin B
Summary
Aspergillus fumigatus is a ubiquitous and opportunistic fungi, responsible for disseminated infections in immunocompromised patients including hematopoietic stem cell transplant, solid organ transplant recipients, and patients receiving immunosuppressive drugs [1]. Invasive aspergillosis (IA) is the second most frequent invasive fungal infection in neutropenic patients [2] leading to a high mortality rate, despite the use of last generation antifungals [3]. While new antifungals have been developed and widely used to treat this disease, there is evidence that the outcome is highly associated with the time of treatment induction. We wondered whether the concept of cell protective therapy in combination with antifungals may help to improve the outcome of disseminated aspergillosis for high-risk patients at an early stage of this disease. In order to document our hypothesis, we set up a murine model of disseminated aspergillosis and we studied the effect on the mortality rate of a combination of EPO high doses associated to amphotericin B
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