Enhancing Angiogenesis in Invasive Aspergillosis: A Novel Therapeutic Approach

Invasive aspergillosis is one of the most devastating opportunistic infections in immunocompromised hosts, such as those with hematologic malignancies and those undergoing hematologic cell transplantation (HCT). Despite the recent availability of potent antifungal agents, mortality rates remain unacceptably high for invasive aspergillosis in these 2 patient groups, at 42% and 58%–72%, respectively [1–3]. One of the reasons for this lack of improvement in outcomes with current therapeutic regimens may lie in the pathogenesis of invasive aspergillosis. The major risk factors for invasive aspergillosis are neutropenia (ie, chemotherapy-induced neutropenia in patients with hematologic malignancies and HCT recipients in the early, preengraftment phase) and corticosteroid treatment (ie, for graft-versus-host disease during the postengraftment phase of HCT). The immunosuppression induced by these agents and the resulting pathogenesis of invasive aspergillosis may differ between these 2 immunosuppressive states. Aspergillus conidia are inhaled through the sinopulmonary tract and land in the pulmonary alveoli. In the immunocompetent host, the first lines of defense are the alveolar macrophage and the neutrophil. If the patient is immunosuppressed, either with cytotoxic agents (inducing neutropenia) or corticosteroids (impairing macrophage function), conidia survive and go on to germinate into hyphae. These hyphae then proceed to invade the alveolar endothelial cells and extend into the pulmonary arterioles, the final act of angioinvasion. Penetration of endothelial cells results in endothelial cell damage, proinflammatory cytokine release, activation of the coagulation cascade, and intravascular coagulation [4]. These events, in turn, lead to tissue hypoperfusion and tissue necrosis. Intravascular coagulation, tissue hypoperfusion, and necrosis lead to an ideal state for the survival and progression of Aspergillus hyphae, a sequestered infection in a privileged site without access to fungicidal macrophages or neutrophils or antifungal agents. There are differences, however, between the responses in neutropenic and corticosteroid-treated hosts. While the pulmonary lesions in neutropenic patients consist predominantly of angioinvasion and intravascular hemorrhage, the lesions in corticosteroid-treated patients consist mainly of neutrophilic and monocytic infiltrates and inflammatory necrosis [5]. Thus, although the result, tissue necrosis, is the same in both types of immunosuppression, the mechanisms, coagulative vs inflammatory necrosis, differ. Angiogenesis, the formation of new blood vessels from existing blood vessels, is a physiologic response to tissue inflammation and ischemia [6]. Thus, it is not surprising that Aspergillus infection induces angiogenesis. It was demonstrated that Aspergillus fumigatus hyphae stimulate the production of the proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 8 (IL-8) by endothelial cells [7] and that these are potent inducers of proangiogenic signaling pathways involving vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) [8]. A. fumigatus, however, produces many metabolites, including fumagillin and gliotoxin, that demonstrate antiangiogenic activity [9–12]. Thus, to determine the balance between proangiogenic and antiangiogenic factors in invasive aspergillosis, Ben-Ami et al [13] studied angiogenesis in a neutropenic model of cutaneous invasive aspergillosis. They noted that angiogenesis was suppressed by Aspergillus-infected mice, when compared to uninfected mice. The antiangiogenic effect was completely abolished Received and accepted 10 December 2012; electronically published 9 January 2013. Correspondence: James I. Ito, MD, Division of Infectious Diseases, City of Hope Comprehensive Cancer Center, 1500 E Duarte Rd, Duarte, CA 91010 ( jito@coh.org). The Journal of Infectious Diseases 2013;207:1031–3 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/infdis/jis944