Basidiobolomycosis

Basidiobolomycosis is a chronic infection caused by Basidiobolus ranarum, a fungus of the order Entomophthorales (subphylum Entomophthoromycotina). It occurs in two main forms: a subcutaneous infection of the trunk and limbs, and a gastrointestinal infection that mimics inflammatory bowel disease or neoplasm. Both usually affect people with no recognised immunodeficiency.

Basidiobolus differs from the Mucorales in host, tempo and tissue reaction. Mucorales cause acute, angioinvasive, necrotising disease in people with diabetic ketoacidosis, neutropenia or iron overload. Basidiobolus causes indolent, granulomatous, eosinophil rich disease in healthy hosts, with little vessel invasion and little necrosis.

Epidemiology:

• Tropical and subtropical regions: West, Central and East Africa (Nigeria, Uganda, Kenya, Tanzania, Cameroon, Ivory Coast), India, Southeast Asia, and Brazil.
• Subcutaneous disease is commonest in children and young adults, with a male predominance of about 3 to 1.
• Gastrointestinal disease clusters in the Arabian peninsula, the southwestern United States (Arizona) and Brazil, and affects children and adults.
• Rainy season and rural exposure raise incidence.

The cell wall is chitin and chitosan rich, with little beta glucan. Echinocandins are inactive, and the beta D glucan assay is usually negative.

• Basidiobolus lives in soil, decaying vegetation and leaf litter, and in the gut of amphibians (frogs, toads), reptiles (lizards), bats and insects, whose faeces contaminate the environment.
• Subcutaneous disease follows minor trauma: insect bites, thorn pricks, abrasions, intramuscular injections, or contact with contaminated soil and vegetation.
• Gastrointestinal disease is believed to follow ingestion of contaminated soil, food or water. Reduced gastric acidity (proton pump inhibitors, H2 receptor antagonists, peptic ulcer disease) has been proposed as a risk factor.
• Person to person transmission does not occur.

Inoculated spores germinate in the subcutis and grow slowly through fat and connective tissue along fascial planes, with little spread to bone. The host response is a chronic granulomatous reaction with abundant eosinophils, driven by a Th2 pattern. Splendore Hoeppli material forms from antigen antibody complexes and eosinophil products deposited around the hyphae. It is a marker of the reaction and is not specific for the organism, because it also surrounds Conidiobolus, Sporothrix, mycetoma grains and some bacteria and parasites.

Eosinophilia, raised ESR and raised IgE are common. Angioinvasion is uncommon, and vascular involvement is mostly reported in the gastrointestinal form. Immunodeficiency is not required, but rare invasive and disseminated cases occur in immunocompromised hosts.

• Firm, painless, woody swelling of the trunk, buttocks, thighs, shoulders or proximal limbs, that enlarges slowly over weeks to months into a large, well circumscribed, disc shaped mass.
• Edges are sharply defined, and the mass moves freely over deeper tissue (the "slipping" mass).
• The overlying skin is intact, tense and shiny, sometimes erythematous or hyperpigmented, and may become ulcerated late in the course. Sinuses and grain discharge, which distinguish mycetoma, are absent.
• Symptoms are few: a sense of weight, mild pain, or no discomfort. Fever and systemic upset are unusual.
• Regional lymphadenopathy is occasional, and bone involvement is rare.
• Lymphoedema and limb deformity develop in long standing disease.

• Abdominal pain, fever, weight loss, a palpable mass, constipation, rectal bleeding, vomiting or diarrhoea, evolving over weeks to months.
• The colon is most often affected, followed by the liver, stomach, small bowel and spleen. Disease is often transmural, with a thick walled, mass like segment.
• Blood eosinophilia is frequent and may be marked, with anaemia, raised CRP and raised ESR.
• Complications: obstruction, perforation, abscess, fistula, hepatic mass, vascular invasion and dissemination.
• The presentation is commonly mistaken for Crohn disease, colonic carcinoma, lymphoma, tuberculosis or amoebic liver abscess, and corticosteroids given for presumed inflammatory bowel disease worsen the outcome.
• Mortality is substantial in reported series, and is highest with late diagnosis and disseminated disease.

Rare presentations include pulmonary disease, nasal and sinus disease, orbital disease, osteoarticular infection, and disseminated infection in immunocompromised patients.

• Deep tissue biopsy is the specimen of choice. A superficial swab is inadequate. For gastrointestinal disease, endoscopic or surgical biopsy is taken, and fine needle aspiration of a mass can supply material.
• Histopathology: granulomatous inflammation with eosinophils, giant cells and fibrosis, and broad, sparsely septate hyphae with an eosinophilic sleeve on haematoxylin and eosin. Because Grocott methenamine silver and periodic acid Schiff may stain poorly, a negative special stain does not exclude the diagnosis.
• Culture: tissue is minced and plated on Sabouraud dextrose agar without cycloheximide at 30 degrees Celsius and 37 degrees Celsius, held for 4 weeks. Growth is rapid, with flat, waxy colonies, forcibly discharged conidia on the lid, and zygospores with a beak like projection on microscopy.
• Molecular identification: sequencing of the internal transcribed spacer region from culture or tissue identifies the species and separates Basidiobolus from Conidiobolus.
• Serology: immunodiffusion for Basidiobolus antibodies is available in reference laboratories, with limited standardisation.
• Blood tests: eosinophil count, ESR, CRP and total IgE.
• Imaging: ultrasonography shows a hypoechoic soft tissue mass. MRI and CT show a mass in the subcutis and muscle with limited bone involvement. In the gastrointestinal form, CT shows segmental bowel wall thickening or a mass, with enlarged lymph nodes and sometimes hepatic lesions.

Evidence comes from case series and reports. Itraconazole is the most widely used agent, and treatment is prolonged.

Surgery:

• Subcutaneous disease usually needs no surgery. Debulking of a very large mass may be combined with drug therapy.
• Gastrointestinal disease needs surgical resection of the affected bowel segment and drainage of abscesses, combined with antifungal therapy for at least 6 to 12 months.
• Response is judged by regression of the mass, normalisation of eosinophilia and inflammatory markers, and imaging resolution. Relapse follows early cessation.
• Corticosteroids are avoided unless a separate indication exists.

Itraconazole is hepatotoxic, negatively inotropic and a strong CYP3A4 inhibitor, and is avoided in heart failure and pregnancy. Liver tests are checked at baseline, 2 to 4 weeks, and every 1 to 3 months. Voriconazole and posaconazole need level monitoring and interaction review. Liposomal amphotericin B needs monitoring of creatinine, potassium and magnesium.

Footwear and protective clothing in rural work, early cleaning of wounds and insect bite sites, and early presentation of any painless, enlarging subcutaneous swelling. There is no known measure to eliminate the environmental reservoir.