Chromoblastomycosis

Chromoblastomycosis (chromomycosis) is a chronic, slowly progressive, granulomatous fungal infection of the skin and subcutaneous tissue caused by several species of dematiaceous (melanised) fungi. It follows traumatic inoculation, usually of the lower limb, and produces verrucous, nodular or plaque lesions that enlarge over years. It is distinguished from phaeohyphomycosis by the tissue form of the organism, the muriform (sclerotic) cell, and from eumycetoma by the absence of grains and sinus tracts.

The disease is endemic in tropical and subtropical rural regions: Madagascar, Brazil, Costa Rica, the Dominican Republic, Venezuela, Mexico, Cuba, South Africa, Japan, Australia and parts of China and India. Cases occur in Kenya and elsewhere in sub-Saharan Africa. Most patients are male agricultural workers aged 30 to 60 who walk barefoot or with poor protection.

It is a neglected tropical disease. Presentation is usually late, with extensive lesions, which makes treatment difficult.

All are dematiaceous Ascomycota of the order Chaetothyriales, apart from a few rare causes.

The fungi live in soil, rotting wood, decaying vegetation and plant debris, and have also been isolated from wood splinters and thorns.

The organisms enter by thorn or splinter trauma, often to the foot or lower leg. Infection is established by implantation of conidia or hyphal fragments into the dermis and subcutis.

Key features:

• Melanin: the dark pigment in the cell wall protects against phagocytic killing and oxidative damage and gives the lesions and the cells their colour.
• Muriform cells: the tissue form is a thick walled, rounded, brown sclerotic cell. It divides by internal septation (not budding), and a cell divides into several daughter cells by cross walls in one or two planes. These cells resist phagocytosis, and persist in tissue for years.
• Host response: a mixed suppurative and granulomatous reaction. Strong Th1 responses with interferon gamma are associated with milder, localised, verrucous disease, and weak or Th2 skewed responses with severe, extensive disease and abundant muriform cells. Antibody responses are present, and they do not control the infection. CARD9 deficiency is a recognised cause of unusually severe, extensive or disseminated chromoblastomycosis and phaeohyphomycosis.
• Epidermal reaction: pseudoepitheliomatous hyperplasia and transepidermal elimination of muriform cells. The cells are shed to the surface through the epidermis and appear as black dots on the surface of lesions, which gives the characteristic dermoscopic finding.
• Spread: autoinoculation by scratching, lymphatic spread, and, rarely, haematogenous dissemination to brain, lung and bone. Contiguous infection through scratching creates satellite lesions.

The incubation period is months. The lesion begins as a small, pink, scaly papule at the site of injury, which enlarges slowly over months to years. Pain is minor, and itch is common. The lower limbs are most often involved, and the upper limbs, trunk and face less so. Secondary bacterial infection produces pain, ulceration and odour.

Multiple forms often coexist in one patient.

Severity grading guides treatment:

Complications:

• Secondary bacterial infection (Staphylococcus aureus, streptococci, gram negative bacteria), with ulceration, cellulitis and lymphoedema.
• Lymphatic obstruction, lymphoedema and elephantiasis after chronic infection and scarring.
• Squamous cell carcinoma (Marjolin ulcer) in long standing lesions; any ulcer or change in a chronic lesion needs biopsy.
• Ankylosis and functional loss, and occasionally bone destruction.
• Dissemination to brain and viscera is rare and associated with immunodeficiency and with Fonsecaea monophora.
• Psychosocial effects: stigma, disability and loss of livelihood.

• Direct microscopy: crusts, scale and pus from black dots, placed in 10 to 20 percent potassium hydroxide, show brown, round, thick walled muriform cells (sclerotic or Medlar bodies, copper pennies) of 5 to 12 micrometres, singly or in clusters, with internal septa. They are visible without staining. Demonstration of muriform cells is diagnostic of chromoblastomycosis and is considered pathognomonic.
• Histopathology: pseudoepitheliomatous hyperplasia, a mixed neutrophilic and granulomatous infiltrate with microabscesses and giant cells, and brown muriform cells in giant cells, abscesses and the superficial dermis on haematoxylin and eosin, with no need for special stains. Fontana Masson shows melanin, and periodic acid Schiff and Grocott methenamine silver show the cell wall.
• Culture: Sabouraud dextrose agar with chloramphenicol, with and without cycloheximide, at 25 to 30 degrees Celsius. Colonies are slow growing (2 to 4 weeks), dark olive to black, velvety, with a black reverse. Cultures are held for 4 weeks. Culture identifies the species. Microscopic morphology differs: Fonsecaea forms conidia on short chains in rhinocladiella, cladosporium and phialophora patterns; Cladophialophora carrionii forms long, branched chains of oval conidia (cladosporium type); Phialophora verrucosa forms flask shaped phialides with a distinct collarette.
• Molecular identification: sequencing of the internal transcribed spacer region is required for accurate species identification, because morphology is unreliable.
• Dermoscopy: black dots, and red dots and globules, with a yellow background.
• Imaging and bacterial cultures: radiography for bone involvement and ultrasonography or MRI for deep extension, and bacterial culture for secondary infection.
• Serology is research only.

Chromoblastomycosis is difficult to cure, and relapse is frequent. Choice of therapy depends on lesion size and severity. Success is judged by clinical resolution, negative direct microscopy, negative culture and absence of muriform cells in histology. Treatment is prolonged, lasting months to years.

Mild disease

• Surgical excision with a wide margin, with or without antifungal cover for 2 to 3 months, when the lesion is small and anatomically suitable. Excision of larger lesions is avoided because it risks spread and poor healing.
• Cryotherapy with liquid nitrogen, with repeated freeze thaw cycles every 3 to 4 weeks, with or without oral therapy.
• Oral itraconazole 200 to 400 mg once daily or terbinafine 250 to 500 mg once daily when surgery is not feasible.

Moderate and severe disease

Adjunctive and physical measures:

• Local heat therapy: the organisms are sensitive to heat, and applying heat to the lesion has been used, with limited evidence.
• Cryotherapy combined with oral drug therapy in verrucous lesions.
• Photodynamic therapy and topical imiquimod: used in resistant lesions in small studies.
• Surgical debulking of large verrucous masses, with antifungal cover.
• Treatment of bacterial superinfection, compression and limb care for lymphoedema.
• Biopsy of any ulcerated or changing lesion to exclude squamous cell carcinoma.
• Immunomodulation with interferon gamma has been used in refractory cases, with limited evidence.

Drug safety and interactions

Itraconazole is a strong CYP3A4 inhibitor, is negatively inotropic, and is hepatotoxic. Liver tests are checked at baseline, at 2 to 4 weeks, and every 1 to 3 months. It is avoided in heart failure and in pregnancy.

Terbinafine is avoided in chronic or active liver disease and when creatinine clearance is below 50 mL per minute.

Flucytosine causes dose related bone marrow suppression and hepatotoxicity, and needs blood count monitoring, and it is avoided with renal failure unless adjusted. Posaconazole and voriconazole interact with many drugs and need level monitoring.

Follow up and prevention

Review every 1 to 3 months during therapy, with photographs and measurements. After clinical cure, follow up continues for at least 1 to 2 years, because relapse is common. Prevention depends on protective footwear, long trousers and gloves for agricultural work, and prompt treatment of puncture injuries. Early diagnosis is the main determinant of outcome.