Lobomycosis

Lobomycosis (Jorge Lobo disease, keloidal blastomycosis) is a chronic granulomatous fungal infection of the skin and subcutaneous tissue caused by Paracoccidioides loboi, formerly Lacazia loboi. It produces slowly growing, firm, keloid like nodules and plaques. The organism has never been cultured, so the diagnosis rests on direct microscopy and histopathology.

It is a rare disease. Most human cases occur in the Amazon basin and adjacent tropical forest regions of Brazil, Colombia, Venezuela, Suriname, French Guiana, Peru, Bolivia, Ecuador, Panama and Costa Rica, and affect rural residents, forest workers and indigenous communities. Isolated cases outside South America are reported in travellers and in dolphin handlers.

The same organism infects dolphins (bottlenose dolphins and Guiana dolphins) in the Atlantic coast of Florida and of Brazil, and in the Gulf of Mexico. A case of probable zoonotic transmission from a dolphin to a handler has been described.

Paracoccidioides loboi belongs to the Onygenales, within the family Ajellomycetaceae, and is closely related to Paracoccidioides brasiliensis, which was shown by sequencing.

Key features:

• Uncultivable: it does not grow on artificial media in the laboratory at any temperature, and it has not been convincingly propagated in cell cultures. It has been transferred to the footpad of the armadillo and the mouse in experiments, producing infection.
• Tissue form: round to lemon shaped, thick walled, double contoured yeast cells of 6 to 12 micrometres (some larger), arranged in chains of 2 to 20 or more cells, connected by narrow tubular bridges. Single cells and budding forms are also present. The chain is characteristic, and no other fungus produces this pattern.
• Staining: the cells stain with Grocott methenamine silver and periodic acid Schiff. They are visible in potassium hydroxide mounts and on haematoxylin and eosin, with a pale refractile wall.
• Dimorphism: unknown, because the mould phase has not been grown.
• Environmental reservoir: unknown, and probably soil, vegetation or water of the humid tropics. The ecology in dolphins points to an aquatic niche.

The infection follows traumatic implantation of the organism into the skin, with minor trauma (insect bites, thorn injury, injury from snakes or stingrays, and contact with aquatic animals) as precipitating events. Incubation is long, from 1 to 2 years, and often longer. Adult men aged 20 to 40 working in forests and rivers are the main group affected. Person to person transmission is not established, although a few cases reportedly occurred by direct inoculation from an infected patient.

Pathogenic features:

• Yeasts persist in the dermis and spread by contiguity, lymphatics and autoinoculation. Haematogenous spread is rare.
• The host response is a chronic granulomatous reaction, with macrophages, giant cells and abundant organisms, and a fibroblastic reaction that causes keloidal scarring. Lymphocytic response is weak, with impaired cellular immunity to the organism.
• The melanin like and glucan rich cell wall resists host killing.
• Host genetic and immune susceptibility is suspected, and no specific immunodeficiency has been defined.
• Visceral involvement and systemic spread have not been confirmed, apart from regional lymph nodes in some patients.

• Slowly progressive, firm, shiny, smooth, painless nodules, plaques and papules with a keloid like surface, which may be skin coloured, pink, red, brown, or hyperpigmented, sometimes verrucous or ulcerated.
• Lesions are mostly localised, and may be single or multiple, with satellite lesions and confluent plaques.
• Sites: the external ear (pinna), lower limbs, upper limbs and face, which are exposed body parts. The trunk is less often affected.
• The skin is itchy or asymptomatic, and sometimes numb or mildly tender.
• Morphological variants are keloidal, gummatous, ulcerated, infiltrative, verrucous and plaque like.
• Regional lymph node involvement occurs in a minority.
• Chronic disease lasts decades. The course is slow, with no tendency to resolve.
• Complications: secondary bacterial infection, ulceration, disfigurement, contractures, lymphatic obstruction, and, rarely, squamous cell carcinoma in long standing lesions, which needs biopsy for any change in a chronic lesion.
• Systemic symptoms are absent. The disease does not typically affect the lungs or other organs.

• Direct microscopy: scrapings, crusts or biopsy imprints in 10 to 20 percent potassium hydroxide show chains of round to lemon shaped, thick walled yeast cells linked by tubular connections. This finding is diagnostic.
• Histopathology: a dense granulomatous infiltrate of macrophages, multinucleate giant cells and fibrosis, with abundant organisms within giant cells and macrophages, often with an overlying atrophic epidermis, a Grenz zone, and sometimes epidermal hyperplasia. Grocott methenamine silver and periodic acid Schiff give the clearest view of the chains. Asteroid bodies are rare.
• Culture: negative, and cultures grow only contaminants or other organisms. A negative culture does not exclude the diagnosis.
• Molecular testing: polymerase chain reaction and sequencing on tissue (gp43 and ITS targets) are used in reference laboratories to confirm the species and to separate it from Paracoccidioides brasiliensis.
• Serology: antibodies to Paracoccidioides brasiliensis gp43 cross react in some patients, with limited reliability.
• Staging: physical examination for lymph nodes, imaging in suspected deep extension, and biopsy of any ulcerated or changing lesion to exclude squamous cell carcinoma.

No effective drug regimen has been established, because the organism cannot be cultured and there are no susceptibility data or controlled trials. Evidence comes from case reports and small series.

Surgery

Wide surgical excision, including a margin of normal skin, is the treatment of choice for localised, small lesions. Recurrence is frequent after incomplete excision. Large or multiple lesions are harder to manage, and reconstruction is needed. Cryotherapy with liquid nitrogen, and electrosurgery, are alternatives for small lesions.

Medical therapy

Combined surgery and medical therapy is used when lesions are extensive. Improvement is assessed by reduction of lesion size, flattening, and clearance of organisms on repeat microscopy. Follow up is long term, because recurrence occurs years after apparent cure.

Drug safety and monitoring

Itraconazole is hepatotoxic, negatively inotropic, and a strong CYP3A4 inhibitor, with liver tests checked at baseline and during treatment. Clofazimine accumulates in tissue and discolours the skin and body fluids, and causes gastrointestinal symptoms with rare serious abdominal complications at long exposure, and QT prolongation.

Prognosis and follow up

The disease is chronic, disfiguring and non fatal in most. Regular review every 3 to 6 months identifies recurrence and malignant change. Psychosocial support and rehabilitation are part of care.

Prevention rests on protective clothing and footwear in forest and river work, and wound care. Handlers of dolphins and other marine mammals use gloves and hygiene. Infected animals are a reservoir of organisms, and veterinary surveillance in marine mammal populations is used. Early recognition and treatment lower the burden of disability.