Mucormycosis

Definition

Mucormycosis is the unifying term used to describe infections caused by fungi belonging to the order Mucorales. Mucorales typically cause aggressive, acute-onset, frequently fatal or disfiguring, angioinvasive infections, especially in immunosuppressed hosts.

Epidemiology

Mucorales fungi are distributed worldwide and found in decaying organic substrates. The true incidence of mucormycosis is not known and probably is underestimated because of difficulties in antemortem diagnosis. The most common microbiologically confirmed infecting species are Rhizopus (about 50% of cases); and Mucor (about 20% of cases), but other species include Cunninghamella bertholletiae , Apophysomyces elegans , Absidia , Saksenaea , and Rhizomucor pusillus . Apophysomyces is predominant in Asia, and Lichtheimia species predominate in Europe. The thermophilic Mucorales Saksenaea vasiformis elegans caused necrotizing soft tissue infections in victims of combat-related injuries in Afghanistan. Apophysomyces elegans were implicated in victims of the Joplin tornado in 2011, and a major mucormycosis outbreak in coronavirus disease 2019 (COVID-19) patients in India ^, was attributable to Apophysomyces and Rhizomucor species. Worldwide, COVID-19 infection has been associated with an increased incidence of mucormycosis, primarily but not exclusively in the nasopharynx, and typically appearing within 12 to 18 days after apparent recovery.

The classic risk factors for mucormycosis include hematologic malignancy, hematopoietic stem cell or solid organ transplantation, poorly controlled diabetes mellitus, chronic acidemia, prematurity, profound chronic debilitation, trauma, burns, and, very rarely, intravenous drug use. Nosocomial cutaneous infections related to contaminated materials or fomites can develop at sites of surgical wounds or intravenous catheter insertion. Breakthrough mucormycosis also is observed when patients with leukemia and recipients of hematopoietic stem cell transplants receive Aspergillus -active drugs without anti-Mucorales activity (e.g., voriconazole).

Pathobiology

Mucorales species are saprophytic, rapidly growing fungi. Angioinvasive growth that results in infarction and necrosis of surrounding tissue is the hallmark of mucormycosis. The major modes of transmission are inhalation, ingestion, and direct inoculation, with inhalation of spores from environmental sources being the most common. Cutaneous or percutaneous transmission with traumatic disruption of skin barriers is the most important mode of transmission in immunocompetent hosts. Gastrointestinal acquisition, although less common, has occurred in patients who repeatedly ingest spores in the setting of severe malnutrition; ingestion of non-nutritional substances (pica); and contaminated herbal, homeopathic, or medicinal products.

Host immunity in healthy hosts prevents germination of fungal spores unless the inoculum is heavy. To establish invasive infection, spores must overcome both innate and adaptive immune responses to germinate into hyphae. Defects in phagocytic activity (e.g., neutropenia) and functional defects (e.g., caused by glucocorticoids, hyperglycemia, and/or acidosis) allow unimpeded proliferation of fungi because of the absence of a coordinated, effective host response. Rhizopus interacts with glucose-regulated protein 78 (GRP78) on nasal epithelial cells via its spore coat protein CotH3 to invade and damage the nasal epithelial cells. Both GRP78 and CotH3 are upregulated in the acidemic hyperglycemic environment. Mucorales also produce a ricin-like toxin, called mucoricin, which can inhibit protein synthesis and increase its virulence. Mucormycosis is often disseminated in severely immunosuppressed patients, with high mortality rates.

Free iron is an essential component of the pathogenesis of mucormycosis, and patients with iron overload are predisposed to such infections, especially if they are being treated with deferoxamine to chelate iron. Rhizopus oryzae can utilize deferoxamine as a xenosiderophore to form a ferrioxamine complex and to obtain more iron for use.

Poorly controlled diabetes mellitus, which is a major predisposing factor, is reported in 36 to 88% of all cases of mucormycosis. In particular, diabetic patients with ketoacidosis are susceptible to mucormycosis. Normal human serum cannot support the growth of R. oryzae , whereas serum in diabetic patients can do so. Acidosis disrupts the normal inhibitory activity of serum by attenuating the ability of transferrin to bind iron from the fungus. In addition, quantitative and qualitative neutrophilic and phagocytic cell dysfunction in diabetic patients with ketoacidosis may play a role in the pathogenesis of mucormycosis.

Clinical Manifestations

The clinical presentation of mucormycosis depends on the host’s underlying immunologic status and medical condition. Patients often have indolent clinical presentations until extensive invasion or dissemination occurs.

Infectious syndromes associated with Mucorales are grouped based on clinical presentation into one of six categories: rhinocerebral (about 76% of cases); cutaneous (about 8.5% of cases); pulmonary (about 7.5% of cases); gastrointestinal; disseminated; and unusual presentations.

Rhino-orbital or rhinocerebral mucormycosis is the characteristic presentation in patients with diabetic ketoacidosis. Cutaneous mucormycosis is seen in both immunocompetent and immunocompromised hosts, typically following local trauma or burns that compromise skin integrity or after subcutaneous tissue injuries. Pulmonary mucormycosis is most common in neutropenic or corticosteroid-treated patients (e.g., hematopoietic stem cell and solid organ transplant recipients).