Introduction

Coccidioidomycosis is a systemic disease caused by the dimorphic fungus Coccidioides, endemic in parts of the Southwestern USA and Central and South America [1].

In 2002, on the basis of genomic analysis, the genus Coccidioides was differentiated into two species: Coccidioides immitis including isolates from California and Coccidioides posadasii including isolates from outside of California [2, 3].

Inhalation of arthroconidia is the common route of infection and can result in a pulmonary infection, often self-limited. Dissemination occurs in approximately 1 % of infections [1]. Primary cutaneous coccidioidomycosis (PCC) has been reported rarely.

We report an unusual case of PCC diagnosed in Italy.

Case Report

A 56-year-old immunocompetent Italian nun living in Argentina has been suffering from a 4-year-persistent erythematous papular plaque on the right cheek. The lesion appeared in September 2000 as brown, lenticular, itching macula, progressively thickened and evolved into a papule (December 2000). The lesion progressively increased in size but ceased to itch. From 2002 to 2005, several histological examinations were performed in different American countries with diverse diagnoses: sarcoidosis resulting in a 6-month steroid therapy with deterioration of the lesion, lupus vulgaris, leishmaniosis, squamous carcinoma and cutaneous coccidioidomycosis, resulting in a one-year therapy with itraconazole (100 mg/die) without improvement.

In January 2005, while she was in Italy, the patient was admitted to the Dermatology Department of IRCCS Ospedale Maggiore Policlinico. At the time of admission, the lesion appeared as an erythematous papular plaque 3 × 1.5 cm in size, irregular and oval with a central scar due to previous biopsies (Fig. 1). No other symptoms were present. Lymph nodes were not detectable. The patient was otherwise in good health. She did not remember any previous skin trauma, respiratory symptoms, headache or fever. A punch biopsy was performed.

Fig. 1
figure 1

Erythematous papular plaque 3 × 1.5 cm in size, irregular and oval with a central scar due to previous biopsies

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Histopathology revealed a diffuse inflammatory infiltrate in the dermis and two small granulomas. A characteristic spherule of 30 µm in diameter, containing eosinophilic endospores (2 µm) within a multinucleated giant cell, and fragments of fungal walls within a granuloma were observed (Fig. 2).

Fig. 2
figure 2

Histopathology of the punch biopsy: hematoxylin–eosin (HE) and periodic acid–Schiff (PAS). Diffuse inflammatory infiltrate in the dermis (lymphocytes and monocytes) and two small granulomas. A characteristic spherule of 30 µm in diameter containing eosinophilic endospores (2 µm) within a multinucleated giant cell and fragments of fungal walls within a granuloma

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White, cottony colonies grew in culture after one week at 30 °C. Microscopically, hyaline, septate hyphae and abundant barrel-shaped arthroconidia were observed, highly suspicious of Coccidioides. The isolate was identified as C. posadasii (100 %) by a broad-range PCR assay for amplification of the internal transcribed spacer (ITS) regions of rDNA and by sequence analysis within the internal GenBank of reference strains [3]. The sequence was deposited in NCBI GenBank (http://www.ncbi.nlm.nih.gov/genbank/) with the accession number KR109218. Antibody screening (complement fixation test, immunodiffusion test and IgM/IgG western blot) was negative.

Unfortunately, the patient was lost to follow-up.

Discussion

Coccidioidomycosis is a disease with a broad spectrum of clinical manifestations that can affect both immunocompetent and immunocompromised individuals. It is caused by a fungus distributed in the arid regions of the Southwestern USA, Mexico and Central and South America. Our otherwise healthy patient from Italy had lived in Argentina, known for endemic zones of C. posadasii. Only two cases of pulmonary coccidioidomycosis have been reported in Italians so far, who acquired their infection after a stay in Arizona/California and in Venezuela, respectively [4, 5].

Cutaneous manifestations of coccidioidomycosis most commonly occur due to dissemination. PCC does occur, but it is rare. In 1953, Wilson et al. [6] formulated criteria for documentation of PCC, namely no history of pulmonary disease immediately preceding the appearance of the cutaneous lesion, a history suggestive of traumatic inoculation, a relatively painless, indurate nodule or plaque with central ulceration and local lymphadenitis/lymphangitis.

Serology may be useful in differentiating PCC from disseminated disease. PCC may be associated with the presence of IgM coccidioidal antibodies early in the course of the disease, while IgG antibodies can rarely be detected or not at all. In contrast, the disseminated disease in immunocompetent patients is associated with high levels of specific IgG antibodies [7, 8].

To our knowledge, only 39 human cases of PCC, including the present one, have been described (Table 1). Most cases occurred as a consequence of traumatic percutaneous implantation in a natural setting in endemic areas, but several cases are secondary to accidental inoculation in laboratory workers [6].

Table 1 Characteristics of cases of primary cutaneous coccidioidomycosis reported in the literature
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Despite the usefulness of Wilson’s criteria in defining PCC cases, some findings are not always documentable, as patients, like in our case, often come to observation several months after the lesion developed, do not remember a trauma or do not display regional lymphadenitis.

The most common lesions of PCC were verrucous plaques or granulomatous nodules; lesions resembling acne papules, rosacea, warts or skin cancer have also been described. Diagnosis was done by histological examination of tissue biopsy in all cases, and Coccidioides was frequently cultured.

In general, the prognosis of PCC is excellent, although diagnosis and treatment can take years, like in our case. Resolution has been reported in almost every case: by spontaneous healing or after surgical excision followed or not by antifungal treatment. Nevertheless, regardless of the relatively low dosage of itraconazole which our patient had already received for one year, a serum level of itraconazole during systemic treatment is recommended, which was not documented in our patient. So it remains open whether the dosage had been inadequate or the serum level did not reach a promising therapeutic level.

Physicians, including dermatologists, should consider coccidioidomycosis in patients returning from travels in or emigrating from endemic areas. In addition, they have to alert the laboratory workers about the clinical suspicion so that appropriate precautions are taken, such as handling specimens and cultures with extreme care only in biosafety cabinets, sealing plates accurately and not setting up slide cultures.