Fungal Infections in the Immunocompromised Host

For the most part, the Mucorales are considered to be opportunistic pathogens. They require a breakdown in the immune defenses, particularly disease processes that lead to neutropenia or neutrophil dysfunction. Although neutrophil dysfunction induced by ketoacidosis underlies the majority of cases of human zygomycosis, neutropenia induced by bone marrow suppression during chemotherapy or immunosuppression induced following transplantation is causing a growing proportion of cases. Specifically, the growing numbers of immunocompromised patients receiving organ transplants or cytotoxic therapies are changing the epidemiology of rhinocerebral mucormycosis (RCM). While diabetes mellitus accounts for 70% to 90% of RCM in earlier literature reviews, more recent studies have reported underlying diabetes in only 27% to 60% of patients with this disease (9). Currently, most patients with RCM have underlying hematologic disorders or are immunosuppressed recipients of organ transplants.

The mechanism responsible for increased susceptibility in various patient groups to mucormycosis is not clear. The reactive oxygen species generated by the phagocyte respiratory burst (including superoxide, hydrogen peroxide, and hypochlorous acid) have been demonstrated to be fungicidal against Rhizopus hyphae. The manner in which diabetes and steroid therapy interfere with the ability of the fungus to elicit these toxic phagocyte products is not known. Some researchers have postulated that once infection is established, neutrophils have a pivotal role in killing hyphae. This is presumed because hyphae are too large to be ingested, so the killing is an extracellular process. In the setting of DKA, each of four phases of neutrophil activation is impaired, essentially inducing functional neutropenia. Defensins, cationic proteins obtained from mammalian phagocytic cells, also have significant ability to kill Rhizopus oryzae spores and hyphae (7). The relative importance of oxidative and nonoxidative fungicidal mechanisms in the normal state and in situations of immunosuppression or diabetes remains a mystery.

At this time, it is still not possible to develop a unifying concept of the pathogenesis of mucormycosis. It is clear, however, that undefined defects of macrophages and neutrophils, present in diabetic and steroid-treated animals, are important in allowing the replication of the Mucorales. Moreover, immunologically healthy people can suppress the growth of the Mucorales and clear them from the lung with great efficiency. Finally, the relative paucity of cases of mucormycosis in patients with the acquired immunodeficiency syndrome (AIDS) attests to the importance of the neutrophil in inhibiting fungal spore development. However, cases of mucormycosis in AIDS patients do occur and may be secondary to quantitative and qualitative defects in neutrophils.

In the late 1980s, physicians began to notice the occurrence of a fulminant form of zygomycosis in patients on hemodialysis who were receiving deferoxamine/desferriox-amine for iron or aluminum overload (5). The more liberally the iron chelator was used, the more likely zygomycosis was to develop. A large body of evidence supports the theory that the Zygomycetes are able to utilize iron bound to iron chelators to enhance their growth, in which the drug acts as an iron siderophore to Mucorales species, even in the absence of iron overload. The presence of acidosis together with deferoxamine therapy may also be a fatal combination. By inhibiting the binding and sequestration of iron by transferrin, acidosis also serves to keep the concentrations of iron in the plasma high, allowing its use as a growth factor by the Zygomycetes. It has also been demonstrated that iron overload states, such as hemochromatosis, even in the absence of chelator usage, may pose a slightly increased risk for the development of zygomycosis in humans.

Most of the current understanding of the pathogenesis of mucormycosis is derived from the mouse and rabbit models of infection. In addition, Mucorales contains a ketone reductase system that lets it thrive in a glucose-rich, acidotic, and ketotic environment. Mucorales hyphae have a predilection for growth into arteries, lymphatics, and nerves. Vascular invasion of the hyphae produces a fibrin reaction and the development of Mucor thrombi, which occlude vessels, producing ischemia and infarction. This infarction produces the black, necrotic eschars in the nasal and oral cavities and on the face that are characteristic of mucormycosis. Vascular occlusion also produces an acidotic tissue that is ideal for fungal growth and is protected from intravenously administered antifungal agents.

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