Etiology

Zygomycosis refers to a group of opportunistic fungal infections caused by dimorphic fungi of the class Zygomycetes, which are primitive, fast-growing fungi that are largely saprophytic and ubiquitous. These organisms are found commonly in soil, in decaying plant and animal matter, and on moldy cheese, fruit, and bread.

This class is subdivided into 2 orders, Mucorales and Entomophthorales, each containing human pathogens. The term mucormycosis refers only to infections caused by Mucorales, which includes the genera Absidia, Apophysomyceae, Mucor, Rhizomucor, and Rhizopus and represents the more-common cause of zygomycosis in humans. Infections caused by organisms of the genera Cunninghamella, Saksenaea, and Cokeromyces are seen less often. Mucorales disease in humans is characterized by a rapidly evolving course, tissue necrosis, and blood vessel invasion in addition to subcutaneous infection. These infections are most acute and fulminant in debilitated patients. Genera of the order Entomophthorales causing infection in humans include Conidiobolus and Basidiobolus. These agents typically cause indolent sinus or subcutaneous infections in immunocompetent persons.

Epidemiology

Zygomycosis is primarily a disease of persons with underlying conditions that impair host immunity. Predisposing factors include diabetes, hematologic malignancies, persistent acidosis, corticosteroid or deferoxamine therapy, organ transplantation, prematurity, and, less commonly, AIDS. Fungi that are pathogenic in humans grow on almost any carbohydrate substrate and are able to grow at temperatures >37°C. Acidosis diminishes the phagocytic and chemotactic ability of neutrophils while increasing the availability of unbound iron. Deferoxamine-bound iron can also be used by the fungus to enhance its growth.

Pathogenesis

Macrophages and neutrophils are the main host defense against Zygomycetes and other filamentous fungi and provide almost complete immunity against Zygomycetes by phagocytosis and oxidative killing of spores, perhaps explaining the predilection for zygomycosis in patients with neutropenia or neutrophil dysfunction. The primary route of infection from Zygomycetes is inhalation of spores from the environment. In immunocompromised persons, if spores are not cleared by macrophages they germinate into hyphae, resulting in local invasion and tissue destruction. Cutaneous or percutaneous routes of infection can lead to cutaneous and subcutaneous zygomycosis. Ingestion of contaminated food or drinks has been linked to gastrointestinal disease.

Clinical Manifestations

There are no unique signs or symptoms of zygomycosis. It can occur as any of several clinical syndromes, including sinus/rhinocerebral, pulmonary, gastrointestinal, disseminated, or cutaneous or subcutaneous disease.

Sinus and rhinocerebral infection is the most common form of zygomycosis and occurs primarily in persons with diabetes mellitus or who are immunocompromised. Infection typically originates in the paranasal sinuses. Initial symptoms are consistent with sinusitis and include headache, retro-orbital pain, fever, and nasal discharge. Infection can evolve rapidly or be slowly progressive. Orbital involvement manifesting as periorbital edema, proptosis, ptosis, and ophthalmoplegia can occur early in the disease. The nasal discharge is often dark and bloody; examination of the nasal mucosa reveals black, necrotic areas. Extension beyond the nasal cavity into the mouth is common. Involved tissues become red, then violaceous, and then black as vessel thrombosis and tissue necrosis occur. Direct bony involvement is common as a result of contiguous pressure effects or because of direct invasion and infarction. Destructive paranasal sinusitis with intracranial extension can be demonstrated by CT or MRI. Cases complicated by cavernous sinus thrombosis and thrombosis of the internal carotid artery have been reported. Brain abscesses can occur in patients with rhinocerebral infection that extends directly from the nasal cavity and sinuses, usually to the frontal or frontotemporal lobes. In patients with disseminated disease, abscesses can involve the occipital lobe or brainstem.

Pulmonary zygomycosis infection usually occurs in severely neutropenic patients and is characterized by fever, tachypnea, and productive cough with pleuritic chest pain and hemoptysis. A wide range of pulmonary radiologic findings, including solitary pulmonary nodule, segmental or lobar consolidation, and cavitary and bronchopneumonic changes, are recognized.

Gastrointestinal zygomycosis is uncommon. It can occur as a complication of disseminated disease or as an isolated intestinal infection in diabetics, immunosuppressed or malnourished children, or preterm infants. Abdominal pain and distention with hematemesis, hematochezia, or melena can occur. Stomach or bowel wall perforation is not uncommon.

Disseminated zygomycosis is associated with a very high mortality rate, especially among immunocompromised persons. Pulmonary involvement is most common, but infection can originate from any of the primary sites of infection.

Cutaneous and soft tissue zygomycosis can complicate burns or surgical wounds. An outbreak occurred among preterm infants following the use of contaminated wooden tongue depressors to immobilize the extremities. Primary cutaneous disease may be invasive locally, progressing through all tissue layers, including muscle, fascia, and bone. Necrotizing fasciitis may occur. Infection manifests as an erythematous papule that ulcerates, leaving a black necrotic center. The skin lesions are painful, and affected patients may be febrile. Cutaneous lesions from hematogenous seeding tend to be nodular, with minimal destruction of the epidermis.

Diagnosis

The diagnosis relies on direct morphologic identification of mycotic elements and recovery of Zygomycetes in culture or by biopsy identification in specimens obtained at the site of presumed involvement. To identify the fungus from scrapings, sputum, and exudates under direct microscopy, the use of Calcofluor white or 10% potassium hydroxide and Parker ink is recommended. In lung and other tissue biopsy specimens, demonstration of fungal elements with fungal specific stains is recommended. Mucorales appear as broad (5-25 µm in diameter), infrequently septate, thin-walled hyphae, branching irregularly at right angles when stained with Gomori methenamine silver or hematoxylin and eosin. Secondary to their thin-walled structure and lack of regular septation, they often appear twisted, collapsed, or folded. Angiotrophism is a hallmark of zygomycosis. The fungi can be cultured on standard laboratory media from sputum, bronchoalveolar lavage fluid, skin lesions, or biopsy material. Mucorales are common culture contaminants. Serologic tests for detecting zygomycosis are not clinically useful. Real-time quantitative polymerase chain reaction assay targeting the 28S rRNA gene has been tested in a rabbit model of experimental pulmonary zygomycosis and shows great promise as a rapid, sensitive, and specific diagnostic test.

Treatment

All forms of the disease can be aggressive and difficult to treat, with high fatality rates. The optimal therapy for zygomycosis in children requires early diagnosis and prompt institution of medical therapy combined with extensive surgical debridement of all devitalized tissue. Correction of the underlying disease, if possible, is an essential component of management. Use of granulocyte colony stimulating factor or granulocyte-macrophage colony stimulating factor to reverse immunosuppression is recommended in conjunction with antifungal agents.

Amphotericin B deoxycholate (1-1.5 mg/kg/day to a total dose of 70 mg/kg or 3-4 g over several wk) or amphotericin B lipid complex (3-5 mg/kg/day) has been successful in treating infection. Anecdotal reports suggest that higher total doses of amphotericin B lipid complex (15-20 mg/kg/day) are associated with better outcomes in invasive infection. Pulmonary and cutaneous disease has been successfully treated with intermediate dosages of amphotericin B (30 mg/kg total dose).

Surveillance in the USA suggests an association between use of voriconazole prophylaxis and the emergence of zygomycosis in transplant patients, which might represent increased patient survival or selection of resistant organisms. Voriconazole is inactive against the Zygomycetes. Posaconazole appears to be active against most of the Zygomycetes both in vitro and in vivo and together with surgery has been associated with dramatic clinical responses and holds promise as a therapeutic agent for mucormycosis. Caspofungin has limited or no in vitro activity against Zygomycetes; however, when combined with amphotericin lipid complex, caspofungin has been found to be more active than lipid complex alone or caspofungin alone for the treatment of experimental zygomycosis in diabetic mice. Caspofungin has been shown to uncover β-glucan in the cell wall of Rhizopus, which results in an increase in neutrophil activity. Hyperbaric oxygen has been used anecdotally as an adjunctive therapy, and iron chelation with deferasirox has been tried as salvage therapy in refractory mucormycosis.