Entomophthoromycosis

Etiology

Entomophthoromycosis is caused by fungi belonging to the order Entomopthorales. The Zygomycota phylum included orders Mucorales and Entomopthorales, among others. Mucorales included genera such as Rhizopus and Mucor. Entomophthorales comprised of Basidiobolus and Conidiobolus genera. Zygomycota was found to be polyphyletic and has since been eliminated as a phylum. Zygomycosis and mucormycosis were terms at times used interchangeably, leading to confusion. Entomophthoramycotina is a new subphylum created to include Basidiobolomycetes (includes Basidiobolus spp.), Neozygitomycetes, and Entomophthoramycetes (includes Conidiobolus spp.). With the changes in the order Entophthorales, revision of classification with broad consensus is needed for wide clinical use.[1][2]

Entomophthoromycosis has two clinically distinct forms:

1. Basidiobolus spp causes basidiobolomycosis (subcutaneous zygomycosis).
2. Bonidiobolus spp causes conidiobolomycosis (rhinofacial zygomycosis).

Human pathogenic isolates for Basidiobolus are Basidiobolus ranarum, and for Conidiobolus, are Conidiobolus coronatus and Conidiobolus incongruus.[4][5]

Epidemiology

Entomophthoromycosis have a high prevalence in tropical and subtropical regions. Basidiobolus ssp. are endemic in India, Pakistan, Uganda, Kenya, Ivory Coast, Myanmar, Ghana, and South America.[6] There have been cases identified in the southeastern United States, especially in Arizona.[7] Basidiobolus is a filamentous fungus isolated from amphibians, reptiles, horses, dogs, and bats, along with woodlice, plant debris, and soil. This form is predominant in children (80% below the age of 20 years) with a male to female ratio of 3 to 1.[2]

Conidiobolus spp. have been found in soil and decaying plant material, mainly in high humidity areas, such as beaches of the United Kingdom, the eastern coast of the United States, India, and the western region of Africa. Most cases of Conidiobolomycosis have been reported in the African continent, mainly Nigeria. Conidiobolus exists parasitically in insects, sheep, and horses. The male-to-female ratio is 10:1, and disease is predominantly seen in young adults.[1][2]

Pathophysiology

Entomopthorales thrive in fatty substances. Therefore, there is a predilection of the organism for areas with adipose tissue. Virulence factors for these organisms include lipases and proteases such as elastase, esterase, collagenase, and many other enzymes that help penetrate and invade human tissues. Basidiobolomycosis is believed to spread by traumatic implantation of the fungus into the thigh, buttock, or trunk subcutaneous tissues.

Conidiobolomycosis is transmitted by inhalation of fungal spores, which involve the nasal tissue, paranasal sinuses, facial soft tissues. Host defense includes macrophages with epithelioid and multinucleate giant cell formations, eosinophils, lymphocytes, and plasma cells, resulting in a chronic granulomatous reaction.[1][3]

Histopathology

Entomophthoramycotina is differentiated from other fungi by their characteristic hyphal morphology. Hyphae are broad, thin-walled, ribbon-like, and mostly aseptate with right or wide-angle branching. The inflammatory reaction seen has a predominance of lymphocytes, plasma cells, epithelioid cells, multinucleate giant cells, and histiocytes. The Splendore-Hoeppli phenomenon can be a histological finding seen in entomophthoromycosis, eosinophilic hyaline material around hyphae in hematoxylin eosin-stained sections. This finding is not pathognomic of entomophthoromycosis as this can also be seen in other infections such as sporotrichosis, blastomycosis, and schistosomiasis. Histologically there is no evidence of angioinvasion, necrosis, or tissue infarction.[2][3]

History and Physical

Basidiobolomycosis presents as a disc-shaped, rubbery, mobile mass that may be large, and these lesions are usually located in the thorax, back, or thighs. Lesions are painless and firm, but the inflammation results in skin erythema and warmth. These patients might present with significant nonpitting edema of the area involved, skin ulceration, and lymph node enlargement. It is a slowly progressive disease and is rarely life-threatening.

Uncommon presentations include extracutaneous involvement, primarily gastrointestinal and systemic dissemination. Gastrointestinal basidiobolomycosis (GIB) can present with abdominal pain, mass, fever, nausea, vomiting, diarrhea, constipation, bloody mucus discharge, and weight loss. The symptoms can mimic that of colon cancer and inflammatory bowel disease. We need to consider GIB as a differential in tropical and subtropical regions for patients presenting with any gastrointestinal mass with subacute onset of abdominal pain, weight loss, and fever with labs showing eosinophilia.[8][7][9][10]

Conidiobolomycosis usually presents with nasal drainage and obstruction along with paranasal sinus pain. This condition is often confined to the rhinofacial area, and medical care is not sought until there is substantial swelling of the upper lip or face. Swelling is usually firm and painless. It may slowly extend into the nasal bridge and upper and lower face, including orbit. There is no angioinvasion, and intracranial extension is uncommon. There are case reports of invasive forms of the disease in the immunocompromised host where the organism act as an opportunistic pathogen. Endocarditis and fatal dissemination have also been seen.[2][11][12]

Evaluation

The clinician and histopathologist need a high index of suspicion for diagnosis. A thorough examination helps with localizing the extent of the lesion. In some cases, the clinical picture might be obvious, but definitive diagnosis relies on demonstrating fungal elements and diagnostic culture findings. Leukocytosis with eosinophilia can be present.[13] The gold standard approach is histological examinations and mycological cultures. Specimen preferred is a biopsy to collect a tissue specimen and not pus as this has a better chance of showing fungal element on potassium hydroxide preparation and culture. Fluorescent dye wet mount preparation under fluorescent microscopy increases the sensitivity of diagnosis.

Inoculation of culture specimen should be done soon after specimen collection as organisms do not survive at 4 degrees Celsius.[14] Culture media used include sabouraud dextrose agar, potato dextrose agar, or cornmeal agar. Colonies are characteristic of dense, radially furrowed, and waxy with rapid growth at 37 degrees Celsius. Propulsion of conidia can be observed because conidia stick to the petri dish lid clouding the view. Culture also helps in determining the susceptibility of antifungal agents. Cultures can be negative on many occasions as hyphae in specimens may be damaged during tissue processing. In culture-negative cases, molecular identification can be considered to confirm the diagnosis using freshly frozen or paraffin-embedded tissue. Different molecular methods with DNA probes, fungal primers, and PCR can be used. Serologic tests are not often used but are available.[2]

Imaging with computed tomography or magnetic resonance imaging should be performed for further evaluation to assess the extent of infection, track therapeutic response, and also helps surgeons plan invasive procedures. If the gastrointestinal disease is suspected, colonoscopy should be considered which would allow for visualization of the lesions and obtain biopsies.[1]

Treatment / Management

Treatment consists of medical management with prolonged antifungal therapy and consideration of surgery. Potassium iodide, cotrimoxazole, amphotericin B, imidazoles, and hyperbaric oxygen have been used with varying success. Standard treatment is with potassium iodide and triazoles (particularly itraconazole). Due to relative resistance to antifungals, prolonged daily therapy for months is recommended.[15](B3)

Surgery alone has a limited role as there is a risk of recurrence; therefore needs to be used in conjunction with antifungal therapy. Surgery in nasofacial conidiobolomycosis in the early stages can limit severe cosmetic damage. Still, in advanced stages, facial reconstructive surgery may be necessary as extensive fibrosis persists even after eradicating the fungus. Nasal symptoms and central facial swelling improve with antifungal treatment and surgical excision. Cryotherapy has been tried with limited success. In cases of gastrointestinal basidiobolomycosis, resection of the affected bowel followed by prolonged antifungals is very important.[16]

Hyperbaric oxygen leads to free radicals, increases the fungicidal activity of neutrophils, and causes vasodilation increasing perfusion to affected tissues. Hyperbaric oxygen can theoretically help with the healing process, but further studies are needed.[17][2](B2)

Differential Diagnosis

Differentials for Basidiobolomycosis[2]

• Tuberculosis
• Localized elephantiasis
• Onchocerciasis
• Scleroderma
• Burkitt lymphoma
• Granulomatosis with polyangiitis

Differentials for Gastrointestinal Basidiobolomycosis[2]

• Gastrointestinal tumors/ colon cancer
• Chronic granulomatous diseases like Crohn disease, tuberculosis, schistosomiasis, 
• Lymphoma
• Rhabdomyosarcoma

Differentials for Conidiobolomycosis[2]

• Mucormycosis
• Cellulitis
• Rhinoscleroma
• Lymphoma
• Sarcoma

Prognosis

Entomophthoromycosis is a slowly progressive disease and is rarely life-threatening. Basidiobolomycosis and conidiobolomycosis cause more of a cosmetic issue which leads to patients seeking medical care. Conidiobolus infection in immunocompromised hosts can lead to profoundly invasive and atypical infection (for example, periorbital disease). There are reported cases of fatal cardiopulmonary, disseminated, endocardial, and pulmonary-mediastinal infections. Atypical and disseminated infection, absence of Splendore-Hoeppli phenomenon (reflecting impaired immune response), and elephantiasis were related to worse outcomes and mortality.[18][1]

Complications

Cosmetic injury is a common complication of Basidiobolomycosis and Conidiobolomycosis, which occurs due to progressive disfigurement from intractable fibrosis and scarring. Fibrosis and scarring can cause lymphatic obstruction and lymphedema, leading to further disfigurement with loss of function of the infected area. Conidiobolomycosis can be complicated with facial elephantiasis, i.e., enlargement and hardening of tissue due to edema, hypertrophy, and fibrosis of the subcutaneous and skin tissue due to obstruction of lymphatic vessels. Facial elephantiasis is associated with persistent or progressive rhinofacial conidiobolomycosis.[1] Gastrointestinal basidiobolomycosis may lead to inflammatory obstruction. Misdiagnosis may lead to a delay in proper treatment, causing an increase in morbidity and mortality.[8][2]