Novel perspectives on mucormycosis: pathophysiology, presentation, and management

Abstract

Mucormycosis is a life-threatening fungal infection that occurs in immunocompromised patients. These infections are becoming increasingly common, yet survival remains very poor. A greater understanding of the pathogenesis of the disease may lead to future therapies. For example, it is now clear that iron metabolism plays a central role in regulating mucormycosis infections and that deferoxamine predisposes patients to mucormycosis by inappropriately supplying the fungus with iron. These findings raise the possibility that iron chelator therapy may be useful to treat the infection as long as the chelator does not inappropriately supply the fungus with iron. Recent data support the concept that high-dose liposomal amphotericin is the preferred monotherapy for mucormycosis. However, several novel therapeutic strategies are available. These options include combination therapy using lipid-based amphotericin with an echinocandin or with an azole (largely itraconazole or posaconazole) or with all three. The underlying principles of therapy for this disease remain rapid diagnosis, reversal of underlying predisposition, and urgent surgical debridement.

Figures

FIG. 1.

Pathogenetic mechanisms of and host defense mechanisms against mucormycosis. To cause disease, the agents of mucormycosis must scavenge from the host sufficient iron for growth, must evade host phagocytic defense mechanisms, and must access vasculature to disseminate. A) In a normal host, primary defense mechanisms against mucormycosis include sequestration of iron in serum by specialized iron-binding proteins (1), phagocytes including circulating neutrophils (2a) and tissue macrophages (2b), and endothelial cells (3), which regulate vascular tone and permeability. Acting in concert, these mechanisms prevent establishment of infection in tissue and subsequent endovascular invasion. B) In susceptible hosts, normal defense mechanisms break down. For example, in diabetic ketoacidosis (DKA), the acidic pH of the serum causes dissociation of free iron from sequestering proteins (1). This release of free iron allows rapid fungal growth. Defects in phagocytic defense mechanisms (2), for example, deficiency in cell number (neutropenia) or functional defects caused by corticosteroids or the hyperglycemia and acidosis of diabetic ketoacidosis, allow proliferation of the fungus. Finally, adherence to and damage of endothelial cells by the fungus (3) allows fungal angioinvasion and vessel thrombosis and subsequent tissue necrosis and dissemination of the fungal infection.