Mucormycosis 

Mucormycosis refers to several different diseases caused by infection with fungi in the order of Mucorales. Rhizopus species are the most common causative organisms. In descending order, the other genera with mucormycosis-causing species include Mucor, Cunninghamella, Apophysomyces, Absidia, Saksenaea, Rhizomucor, and other species.^[1]

Most mucormycosis infections are life-threatening, and risk factors, such as diabetic ketoacidosis and neutropenia, are present in most cases. Severe infection of the facial sinuses, which may extend into the brain, is the most common presentation. Pulmonary, cutaneous, and gastrointestinal (GI) infections are also recognized.

Successful mucormycosis treatment requires correction of the underlying risk factor(s), antifungal therapy with amphotericin B, and aggressive surgery.

The following is a postmortem image of a patient who had diabetic ketoacidosis and left rhinocerebral mucormycosis.

See also Pediatric Mucormycosis and Rhinocerebral Mucormycosis.

Risk factors

Immunocompromising conditions are the main risk factor for mucormycosis. Patients with uncontrolled diabetes mellitus, especially with ketoacidosis, are at high risk. Patients with cancer—especially those who are neutropenic and receiving broad-spectrum antibiotics—as well as individuals receiving immunosuppressive agents—including oral or intravenous steroids and tumor necrosis factor (TNF)–alpha blockers—are at risk.

Extreme malnutrition is also linked to mucormycosis, especially the gastrointestinal (GI) form. Iron is a growth stimulant for Mucorales, and deferoxamine acts as a siderophore that delivers iron to the fungi. Deferoxamine therapy and all causes of iron overload are additional risk factors for mucormycosis. Trauma and the use of contaminated medical supplies over wounds are associated with cutaneous mucormycosis. In addition, patients with burns and those who use intravenous drugs are at a higher risk.

Some patients with mucormycosis have no identifiable risk factors.^[2]

Pathophysiology

Mucoraceae are ubiquitous fungi that are commonly found in soil and in decaying matter. Rhizopus can be found in moldy bread. Given the ubiquitous nature of these fungi, most humans are exposed to these organisms on a daily or weekly basis. Nonetheless, they rarely cause disease because of the low virulence of the organisms; instead, they mainly affect individuals with immunocompromising conditions. Immunocompromised hosts with poorly controlled diabetes mellitus (especially with ketoacidosis), who are receiving glucocorticosteroids, who have neutropenia in the setting of hematologic or solid malignancy, who have undergone transplantation, who have iron overload, and who have burns are at risk for disease.

The major route of infection is via inhalation of conidia; other routes include ingestion and traumatic inoculation (see the images below). Ingestion leads to GI disease and occurs primarily among malnourished patients, but it can also occur after ingesting nonnutritional substances (pica). Regarding cutaneous disease, nonsterile tape and contaminated wooden splints have caused wound infections. Such cases are associated with trauma, the presence of a preexisting wound, or both. Additionally, natural disasters (after hurricanes or tsunamis) may be associated with wound infections due to mucormycosis and should be considered in the setting of a necrotic-appearing wound or poor response to antibiotic treatment.^[3]

When spores are deposited in the nasal turbinates, rhinocerebral disease develops (see Rhinocerebral Mucormycosis); when spores are inhaled into the lungs, pulmonary disease develops; when ingested, GI disease ensues; and when the agents are introduced through abraded skin, cutaneous disease develops.

Mucoraceae are molds in the environment that become hyphal forms in tissues. Once the spores begin to grow, fungal hyphae invade blood vessels, producing tissue infarction, necrosis, and thrombosis. Neutrophils are the key host defense against these fungi; thus, individuals with neutropenia or neutrophil dysfunction (diabetes, steroid use) are at highest risk. Few cases of mucormycosis have been reported in patients with acquired immunodeficiency syndrome (AIDS), suggesting that the host defense against this infection is not primarily mediated by cellular immunity.

United States statistics

Rhinocerebral disease is the most common form in the United States, accounting for more than half of the cases. Other major syndromes include pulmonary, cutaneous, and disseminated diseases; rarer forms involve the GI tract and other organs. Most cases occur among severely immunocompromised persons. Mucormycosis has been reported in immunocompetent individuals, mostly after traumatic inoculation of fungal spores, but this is extremely rare.

Mucormycosis is extremely rare, and its incidence is difficult to calculate accurately. Further, since mucormycosis is not a reportable disease, the true incidence is unknown, but an estimated 500 cases occur in the United States annually.^[1]

A review of mucormycosis cases at one US cancer center found that 0.7% of patients had mucormycosis at autopsy and that 20 patients per 100,000 admissions had the disease.^[4] The 1-year cumulative incidence of mucormycosis has been estimated at approximately 4 cases per 1000 stem cell transplantations and 0.6 case per 1000 organ transplantations, accounting for 7% and 2% of all fungal infections in these populations, respectively.^[5]

The incidence of mucormycosis appears to be increasing secondary to rising numbers of immunocompromised persons. Further, there are increasing reports of breakthrough mucormycosis in the setting of antifungal prophylaxis or treatment that is effective against most fungi (eg, Aspergillus) but not mucormycosis.

International statistics

Mucormycosis was found in 1% of patients with acute leukemia in an Italian multicenter review.^[6]

A related disease, entomophthoramycosis, is rare in the United States but is most commonly found in Africa, Southeast Asia, Australia, and Central America. Entomophthoramycosis consists of 2 diseases: conidiobolomycosis (caused by Conidiobolus infection) and basidiobolomycosis (caused by Basidiobolus infection). Conidiobolomycosis presents as a painless, firm, subcutaneous mass that primarily involves the head and face, whereas basidiobolomycosis involves the trunk and/or extremities. In contrast with mucormycosis, entomophthoramycosis is associated with a lower mortality rate and usually affects immunocompetent hosts.

No racial or age factors that predispose people to mucormycosis exist, and a patient's sex is not likely to affect the occurrence of mucormycosis, because the underlying conditions are the major predisposing factors. Reviews of cases from single institutions show an equal sex distribution; however, a review of all published cases of pulmonary mucormycosis performed by Lee et al showed a male-to-female ratio of 3:1.^[7]

Rhinocerebral disease causes significant morbidity in patients who survive, because treatment usually requires extensive, and often disfiguring, facial surgery.

Surviving mucormycosis requires rapid diagnosis and aggressive coordinated medical and surgical therapy.

Mucormycosis carries a mortality rate of 50-85%. The mortality rate associated with rhinocerebral disease is 50-70%. Pulmonary and gastrointestinal (GI) diseases carry an even higher mortality rate, because these forms are typically diagnosed late in the disease course. Disseminated disease carries a mortality rate that approaches 100%. Cutaneous disease carries the lowest mortality rate (15%). The advent of novel antifungals, such as posaconazole, may offer improvement in these mortality rates; further studies are needed.