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Gorgas Case 2018-07

Epidemiology: Born and still resides in Pucallpa, in the Amazonian jungle. Rice and corn farmer; also carries and sells wood. Contact with chickens, cows, dogs, and cats. Walks by rivers, and is often bare footed.  No known TB contact.

Physical Examination on Admission: BP: 120/80 mmHg. HR: 74 bpm. RR: 18 rpm. Afebrile. Sat: 98 % (FiO2: 0.21). Skin: Diffuse and extensive lesions of the left lower limb, with multiple erythematous nodules and slightly elevated plaques. The lesions are markedly hyperkeratotic, dry looking, verrucous with central atrophic scarring, some of them present black dots (upper panel) and no suppuration (Image A). There is no lymphedema, sinus tracts, synovitis, joint effusions or restricted range of motion of joints. No lesions were found elsewhere. Rest of the physical exam is unremarkable including the neurologic examination.

Discussion: Chromoblastomycosis was confirmed through the detection of pathognomonic muriform cells with a potassium hydroxide (KOH) preparation (Image C) of the superficial skin scrapings which had intentionally focused on the areas with black dots as this may increase the likelihood of detecting fungal elements (See video). Muriform cells are double-walled yellow-brown structures with a diameter of 4 to 10 microns that resemble copper pennies. Thick and dark hyphae are sometimes identified (Image D). Fungal culture in Sabouroud´s Agar, grew a dematiaceous black fungus (Image E) compatible with Fonsecae pedrosoi by recognition of the conidiophore micromorphology. Confirmation of the pathogen by PCR is pending.

Chromoblastomycosis is considered the second most common soil transmitted or inoculation mycoses in the world after Sporotrichosis [Lancet Infect Dis 2017;17:e367] and it is clinically restricted to sub-cutaneous tissues. The disease occurs mostly among farmers through skin inoculation after trauma.

Chromoblastomycosis occurs worldwide, including in the USA, but 70% of cases are estimated to occur in the moist tropics. Most cases in Latin America are from the humid Amazon of Brazil, from Mexico and from Costa Rica, but cases are reported from Colombia, Ecuador, Venezuela, Argentina, the Dominican Republic and Cuba. Many cases are reported from Madagascar and South Africa. Up to 90% of cases occur in males likely due to occupational factors. Incidence rates in Madagascar have been estimated in 1 per 6800 inhabitants.

Subcutaneous mycoses are a heterogeneous group of diseases and organisms that share the characteristic that they develop at the site of skin penetrating trauma. Etiologic agents of subcutaneous mycoses are divided into several clinical groups:

1. The eumycetomas typically cause locally invasive purulent and destructive disease that will eventually destroy underlying soft tissue and bone while sparing nerve and vasculature. Sinus tracts with granule production is common. Madura foot and related lesions are caused by Madurella mycetomatis(by far the most common cause of Madura foot in Peru; produces dark granules), Exophiala sp. and Pyrenochaeta sp., as well as Fusarium and Acremonium(produce pale granules).
2. Phaeohyphomycosis is caused by dematiaceous (pigmented) fungi but is not limited to skin or subcutaneous tissue and is associated with a wide range of inflammatory responses mainly in the sinuses, lungs, and brain. Disseminated disease beyond skin is usually in compromised hosts. Most frequent causes are Exophialajeanselmei, Wangiella dermatitidis, and Bipolarisspecies. Hyphae are typically seen histologically.
3. Chromoblastomycosis is characterized by papular lesions with chronic onset that progress (often over many years) to nodules or plaques, most often with a hyperkeratotic verrucous surface. Sclerotic bodies or also known as muriform cells are typically seen histologically, and invasion or spread beyond the local subcutaneous tissue does not occur. The most common etiologic agents are Fonsecaea pedrosoi (moist environments) and Cladophialophora carrionii (drier environments), with Phialophora verrucosa, and Rhinocladiella aquaspersa being less common. Clinical forms of the disease may be associated with cytokine response with tumor necrosis factor and interleukin 10 being reported in severe cases [Clin Microbiol Rev 2017;30:233].

The differential diagnosis of a life-long subcutaneous indolent infection like this includes: sporotrichosis [Gorgas Case 2008-01], eumycetoma [Gorgas Case 2002-04] (no drainage with grains were reported in this case), actinomycetoma [Gorgas Case 2001-09], lobomycosis (lacaziosis) [Gorgas Case 2005-03], subcutaneous zygomycosis, subcutaneous phaeohyphomycosis, botryomycosis [Gorgas Case 2003-04], leishmaniasis [Gorgas Case 2004-01], nocardiosis [Gorgas Case 2011-01], and tuberculosis verrucosa cutis. Squamous cell carcinoma and leprosy are less likely.

Treatment of chromoblastomycosis is often difficult and is based on case reports and case series; there are no controlled trials [Lancet Infect Dis 2017;17:e367]. Surgical excision of early lesions is recommended. Treatment choices include itraconazole alone or in combination with terbinafine (expensive and not typically available in the tropics). With very chronic infection like this, itraconazole may induce significant fibrosis that impairs functionality of the extremity. Duration of treatment is no less than 1 year starting at 200mg tid for 3 days, then 200mg bid. Measurement of serum drug levels is recommended to improve outcomes. Response is observed after 3-4 months of therapy; sustained response is not always observed due to its fungistatic nature.

Of the newer azoles, voriconazole has potent in vitro activity against Cladophialophora carrionii, F. pedrosoi, and P. verrucosa; posaconazole is approved in Europe for refractory chromoblastomycosis; and caspofungin has potent in vitro activity against F. pedrosoi [Med Mycol. 2011 Apr;49(3):225-36].

Our patient was started on itraconazole but presented marked oral intolerance with severe nausea and vomiting and was switched to terbinafine 500 mg per day. After two weeks of treatment, he mentioned some flattening of old lesions. The planned duration of treatment in this patient is no less than 1 year.