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School of Molecular & Biomedical Science
The University of Adelaide
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Zygomycosis

Description:

The term zygomycosis describes in the broadest sense any infection due to a member of the Zygomycetes. These are primitive, fast growing, terrestrial, largely saprophytic fungi with a cosmopolitan distribution. To date, some 665 species have been described although infections in humans and animals are generally rare. Medically important orders and genera include:

1. Mucorales, causing subcutaneous and systemic zygomycosis (Mucormycosis) - Rhizopus, Mycocladus (Absidia), Rhizomucor, Mucor, Cunninghamella, Saksenaea, Apophysomyces, Cokeromyces and Mortierella.

2. Entomophthorales, causing subcutaneous zygomycosis (Entomophthoromycosis) - Conidiobolus and Basidiobolus.

Clinical manifestations:

Zygomycosis in the debilitated patient is the most acute and fulminate fungal infection known. The disease typically involves the rhino-facial-cranial area, lungs, gastrointestinal tract, skin, or less commonly other organ systems. It is often associated with acidotic diabetes, starvation, severe burns, intravenous drug abuse, and other diseases such as leukemia and lymphoma, immunosuppressive therapy, or the use of cytotoxins and corticosteroids, therapy with desferrioxamine (an iron chelating agent for the treatment of iron overload) and other major trauma. The infecting fungi have a predilection for invading vessels of the arterial system, causing embolization and subsequent necrosis of surrounding tissue. A rapid diagnosis is extremely important if management and therapy are to be successful.

1. Rhinocerebral zygomycosis:

Predisposing factors include uncontrolled diabetes mellitus or acidosis, steroid induced hyperglycemia, especially in patients with leukemia and lymphoma, renal transplant and concomitant treatment with corticosteroids and azathioprine. Infections usually begin in the paranasal sinuses following the inhalation of sporangiospores and may involve the orbit, palate, face, nose or brain.

Rhinocerebral zygomycosis

Rhinocerebral zygomycosis showing involvement of the palate.

2. Pulmonary zygomycosis:

Predisposing conditions include haematological malignancies, lymphoma and leukemia, or severe neutropenia, treatment with cytotoxins and corticosteroids, desferrioxamine therapy; diabetes and organ transplantation. Infections result by inhalation of sporangiospores into the bronchioles and alveoli, leading to pulmonary infraction and necrosis with cavitation.

3. Gastrointestinal zygomycosis:

A rare entity, usually associated with severe malnutrition, particularly in children, and gastrointestinal diseases which disrupt the integrity of the mucosa. Primary infections probable result following the ingestion of fungal elements and usually present as necrotic ulcers.

4. Cutaneous zygomycosis:

Local traumatic implantation of fungal elements through the skin, especially in patients with extensive burns, diabetes or steroid induced hyperglycemia and trauma. Lesions vary considerably in morphology but include plaques, pustules, ulcerations, deep abscesses and ragged necrotic patches.

Ulcerated cutaneous zygomycosis on forearm
Ulcerated cutaneous zygomycosis.

Debridement of subcutaneous zygomycosis
Debridement of subcutaneous zygomycosis.

5. Disseminated zygomycosis:

May originate from any of the above, especially in severely debilitated patients with haematological malignancies, burns, diabetes or uraemia.

6. Central Nervous System alone:

Intravenous drug abuse. Traumatic implantation leading to brain abscess.

7. Infections caused by entomophthoraceous fungi:

Zygomycosis due to entomophthoraceous fungi is caused by species of two genera, Basidiobolus and Conidiobolus. Infections are chronic, slowly progressive and generally restricted to the subcutaneous tissue in otherwise healthy individuals. Other characteristics that separate these infections from those caused by mucoraceous fungi are a lack of vascular invasion or infarction and the production of a prolific chronic inflammatory response, often with eosinophils and Splendore-Hoeppli phenomena around the hyphae.

Zygomycosis caused by B. ranarum is a chronic inflammatory or granulomatous disease generally restricted to the subcutaneous tissue of the limbs, chest, back or buttocks, primarily occurring in children and with a predominance in males. Initially, lesions appear as subcutaneous nodules which develop into massive, firm, indurated, painless swellings which are freely movable over the underlying muscle, but are attached to the skin which may become hyperpigmented but not ulcerated.

Zygomycosis caused by B. ranarum
Zygomycosis caused by B. ranarum.

Zygomycosis caused by Conidiobolus sp. is a chronic inflammatory or granulomatous disease that is typically restricted to the nasal submucosa and characterised by polyps or palpable restricted subcutaneous masses. Clinical variants, including pulmonary and systemic infections have also been described. Human infections occur mainly in adults with a predominance in males (80% of cases). Most cases have been reported from the tropical rain forest areas of central and west and south and central America. Infections usually begin with unilateral involvement of the nasal mucosa. Symptoms include nasal obstruction, drainage and sinus pain. Subcutaneous nodules develop in the nasal and perinasal regions and progressive generalised facial swelling may occur. Infections also occur in horses usually producing extensive nasal polyps and other animals. Conidiobolus coronatus is also a recognised pathogen of termites, other insects and spiders.

Zygomycosis caused by Conidiobolus
Zygomycosis caused by Conidiobolus.

Laboratory diagnosis:

1. Clinical Material: Skin scrapings from cutaneous lesions; sputum and needle biopsies from pulmonary lesions; nasal discharges, scrapings and aspirates from sinuses in patients with rhinocerebral lesions; and biopsy tissue from patients with gastrointestinal and/or disseminated disease.

Warning: zygomycetous fungi have primitive coenocytic hyphae that will often be damaged and become non-viable during the biopsy procedure (especially scrapings and aspirates), or by the chopping up or tissue grinding process in the laboratory. This is why zygomycetous fungi that are clearly visible in direct microscopic or histopathological mounts are often difficult to grow in culture from clinical specimens. If on clinical and/or radiological evidence zygomycosis is suspected then try to avoid excessive tissue damage when collecting the specimen and in the laboratory gently tease the tissue apart and inoculate it directly onto the isolation media. If you are not sure hold the specimen in saline or BHI broth until the results of the direct microscopy or frozen histology sections are known. If zygomycetous hyphae are present proceed as above, otherwise homogenised the specimen and plate out.

2. Direct Microscopy: (a) Scrapings, sputum and exudates should be examined using 10% KOH & Parker ink or Calcofluor mounts; and (b) Tissue sections should be stained with H&E and GMS. Examine specimens for broad, infrequently septate, thin-walled hyphae, which often show focal bulbous dilations and irregular branching.

Interpretation: As a rule, a positive direct microscopy, especially from a sterile site, should be considered significant, even if the laboratory is unable to culture the fungus.

Tissue morphologyzygomycosis
Tissue morphology in zygomycosis showing distinctive infrequently septate thin walled hyphae with focal bulbous dilations and irregular branching, typical for those species belonging to the Mucorales.

GMS stained tissue from a lung
GMS stained tissue section from a lung showing typical zygomycete hyphae and by chance a sporangium of Mycocladus (Absidia) corymbifera.

H&E stained section of tissue
H&E stained section of infected tissue showing broad, infrequently septate, hyphae surrounded by an eosinophilic sheath [Splendore-Hoeppli phenomena], typical of zygomycosis caused by Basidiobolus ranarum.

3. Culture: Inoculate specimens onto primary isolation media, like Sabouraud's dextrose agar. Most zygomycetes are sensitive to cycloheximide (actidione) and this agent should not be used in culture media. Look for fast growing, white to grey or brownish, downy colonies.

Interpretation: Despite being recognised as common laboratory contaminants, zygomycetes are infrequently isolated in the clinical laboratory. Therefore, in patients with any of the above predisposing conditions, especially diabetes or immunosuppression and/or clinical symptoms, the isolation of any zygomycete fungus should be regarded as potentially significant. Obviously, in patients without predisposing conditions, the isolation of a zygomycete from a non-sterile site, such as skin or sputum, must be interpreted with caution, especially in the absence of direct microscopy.

4. Serology: There are currently no commercially available serological procedures for the diagnosis of zygomycosis. Although some laboratories have developed ELISA tests for the detection of antibodies to Zygomycetes.

5. Identification: Zygomycetes are usually fast growing fungi characterised by primitive coenocytic (mostly aseptate) hyphae. Asexual spores include chlamydoconidia, conidia and sporangiospores contained in sporangia borne on simple or branched sporangiophores. Sexual reproduction is isogamous producing a thick-walled sexual resting spore called a zygospore.

Most isolates are heterothallic i.e. zygospores are absent, therefore identification is based primarily on sporangial morphology. This includes the arrangement and number of sporangiospores, shape, colour, presence or absence of columellae and apophyses, as well as the arrangement of the sporangiophores and the presence or absence of rhizoids. Growth temperature studies (25,37,45C) can also be helpful. Tease mounts are best, use a drop of 95% alcohol as a wetting agent to reduce air bubbles. Laboratory identification of some zygomycetous fungi, especially Apophysomyces elegans and Saksenaea vasiformis may be difficult or delayed because of the mould's failure to sporulate on the primary isolation media or on subsequent subculture onto potato dextrose agar. Sporulation may be stimulated by the use of nutrient deficient media, like cornmeal-glucose-sucrose-yeast extract agar, Czapek Dox agar, or by using the agar block method on water agar.

Causative agents:

Mycocladus (Absidia0 corymbifera, Apophysomyces elegans, Basidiobolus ranarum, Conidiobolus coronatus, Cunninghamella bertholletiae, Mortierella wolfii, Mucor sp., Rhizomucor pusillus, Rhizopus oryzae, Rhizopus sp., Saksenaea vasiformis, Syncephalestrum sp.

Treatment Guidelines

 

Further reading:

Ellis, D.H. 1997. Zygomycetes. Chapter 16 In Topley and Wilson's Microbiology and Microbial Infections. 9th edition Edward Arnold London pp247-277.

Kwon-Chung KJ and JE Bennett 1992. Medical Mycology Lea & Febiger.

Richardson MD and DW Warnock. 1993. Fungal Infection: Diagnosis and Management. Blackwell Scientific Publications, London.

Rippon JW. 1988. Medical Mycology WB Saunders Co.

Warnock DW and MD Richardson. 1991. Fungal infection in the compromised patient. 2nd edition. John Wiley & Sons.