Primary Cutaneous Cryptococcosis due to Cryptococcus neoformans in an Immunocompetent Host Treated with Itraconazole and Drainage: Case Report and Review of the Literature

Cryptococcus neoformans is an opportunistic germ, usually causing infections in immunocompromised patients. The main sources of infection with C. neoformans are excrements from birds, decomposing wood, fruit, and vegetables. Primary cutaneous cryptococcosis (PCC) is a clinical entity, differing from secondary cutaneous cryptococcosis and systemic infection [1-4].

We present the case of an immunocompetent woman with PCC due to C. neoformans in her right thumb, together with a review of the current literature.

A 60-year-old woman presented to our department with a 4-day-old swelling and erythema around the right thumb, having already been treated with cefuroxime for 3 days by her general practitioner without any improvement. She reported an accidental injury 5 days previously caused by a rose thorn while she was gardening. The patient was in good health and had not taken any immunosuppressives or other drugs. There was no history of any contact with avian excretions, pigeons, or other animals, and she denied recent travelling.

On dermatological examination, we found an erythematous ulcerated nodule with elevated borders, suppuration, and central necrosis (Fig. 1a). There was no regional lymphadenopathy and no other skin involvement. Routine blood examination, a total lymphocyte count, and blood immunoglobulins were normal. The C-reactive protein level was 55 mg/L, while the erythrocyte sedimentation rate was 77 mm/h. HIV and hepatitis B and C serology results were negative. X-rays of the chest and the right thumb were also normal. At first, we suspected a bacterial or herpetic infection, but the lesion swab cultures for bacteria and the PCR examination for Mycobacterium as well as herpes simplex virus were also negative. We performed a biopsy for histological examination from skin lesion fragments after surgical debridement, removing necrotic tissue from the right thumb (Fig. 1b). The histology picture showed cutaneous and subcutaneous fibrinoid necrosis with bleeding, an abscess forming, neutrophil-rich cellular infiltration, and the presence of multiple PAS-, colloid iron- and mucin-positive spores (Fig. 2).

A swab sample from the lesion was inoculated on tubes with slide Sabouraud chloramphenicol and BBL^TM Mycosel^TM agar and incubated at 30 and 35°C. On day 3, milky and creamy colonies of C. neoformans started to grow on the Mycosel agar at 30°C. Then, colonies were transferred to an agar plate (Sabouraud chloramphenicol agar and ChromID Candida; bioMérieux) and incubated at the same temperatures. Microscopical examination showed globose-to-ovoid, budding, yeast-like cells. Identification of C. neoformans was possible with matrix-assisted laser desorption ionization-time of flight mass spectrometry [5]. We diagnosed PPC in an immunocompetent patient.

For antifungal susceptibility assessment, we used the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines [6]. The antifungals tested were amphotericin (0.5 mg/L), ketoconazole (0.64 mg/L), itraconazole (0.121 mg/L), 5-fluorocytosine (1 mg/L), voriconazole (0.064 mg/L), and fluconazole (4 mg/L).

In addition to the debridement, we performed two lateral incisions in a sterile area next to the medial and lateral perionychium to drain collections. The necrotic epidermis of the fingertip was completely detached in its superficial layer. After the surgical debridement, the patient needed periodic dressing. Complementary to surgical therapy, we started treatment with itraconazole 100 mg/12 h for 6 months, with rapid clinical improvement and without relapse to infection during the 6-month follow-up after the systemic antifungal therapy (Fig. 3).

The genus Cryptococcus comprises the two clinically relevant species C. neoformans and C. gattii among few other species. Whilst C. neoformans is mainly observed in patients with immunodeficiency and rarely in immunocompetent patients, C. gattii is found in immunocompetent patients in endemic areas [4, 5]. The main sources of infection with C. neoformans are excrements from pigeons or other birds, as well as decomposing wood, fruit, and vegetables [3]. C. gattii is not present in birds’ feces, but it inhabits a variety of arboreal species, including several types of eucalyptus tree [1].

PCC is a separate clinical entity distinct from secondary cutaneous cryptococcosis, the latter of which mainly occurs in patients with lung cryptococcosis and systemic infection. Generally, secondary cutaneous cryptococcosis infection occurs in immunocompromised hosts and rarely in immunocompetent hosts [7, 8]. PCC is a rare infection that can present with quite unspecific clinical pictures, including acneiform lesions, purpura, vesicles, nodules, abscesses, ulcers, granulomas, pustules, draining sinuses, and cellulitis [9, 10].

For a long time, the existence of PCC as a clinical entity had been in doubt. In the year 1972, Noble and Fajardo [10] proposed three diagnostic criteria for PCC (Table 1). We recorded the features of both our case and the 21 additional cases of PCC in immunocompetent patients due to C. neoformans in the last 20 years [11-27]. We excluded cases of PCC due to C. gattii, which is well known to be a cause of infection of immunocompetent patients in endemic areas [1]. Our case and the other cases reviewed fulfill all diagnostic criteria by Noble and Fajardo (Table 1).

Parameters such as year of diagnosis, age, gender, predisposing factors, clinical manifestation(s), treatment prescribed, and outcome are reported separately (Table 2). The male sex was more affected (17/22 cases). The patients’ ages ranged from 10 to 81 years (mean 60.13). The most frequent site of infection was the forearm (9/22), followed by the hand and fingers (6/22). Clinical manifestations consisted of nodules, sometimes ulcerated (9/22), infiltrative lesions (4/22), plaques (3/22), papules (1/22), cellulitis (2/22), granulomata (1/22), erythema with edema (1/22), and lipoma-like swelling (1/22) (Table 2). Only in 10 of the 22 patients was there a history of trauma prior to infection. Nine of the 22 cases reported contact with avian excreta. In 8 of the 22 cases, the source of infection was totally unknown.

Concerning the kind of inflammation, it should be kept in mind that the different well-known patterns or stages of cutaneous cryptococcosis (suppurative, gelatinous, and granulomatous) are reflecting the dynamic process and ability of the hosts’ immune system to get rid of the infectious agents, which usually takes a few years. As PCC is a rare event in immunocompetent patients, unlike in systemic disease, treatment in this setting is not well defined.

Nonetheless, itraconazole was effective in curing the lesions in 10/22 cases; 8 of these cases were treated with itraconazole only, whereas in 1 case itraconazole was the final treatment after switching from fluconazole (case 3) and in 1 case itraconazole was the final treatment after previous treatment with fluconazole and amphotericin (case 5).

Fluconazole alone was administered in 11/22 cases, but healing could only be achieved in 9 of these cases; in the remaining 2 cases (cases 3 and 5), it was necessary to switch to itraconazole and in 1 case healing was achieved after combined treatment with fluconazole and amphotericin (case 15). The range of itraconazole dosage was 100–400 mg/day for a duration of 3–6 months. The range of fluconazole dosage was 200–800 mg/day for a duration of 2 weeks to 1 year.

Two of the 22 cases reviewed, including ours, had also undergone surgical debridement before being given itraconazole. One patient (case 18) healed without treatment, and in 1 case the treatment is unknown (case 2).

Despite the limited number of cases, itraconazole seems to be the most effective treatment. Fluconazole showed high efficacy as well; however, in 2 cases, treatment had to be switched to itraconazole as the final treatment. In our patient, surgical debridement in combination with a prolonged therapy with itraconazole was very effective in clearing the lesions within 6 months (Fig. 3).

PCC is a rare primary infection limited to the skin which can heal without further systemic dissemination in individuals with a competent immune system. Based on our experience and the reviewed cases, itraconazole seems to be the most effective treatment.

The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The patient has given written informed consent for the publication of this case report (including images).

The authors have no conflicts of interest to declare.

This case report did not receive funding from third parties.

All authors have made substantial contributions to all of the following: (1) the conception and design of the review and the analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content; and (3) final approval of the version to be submitted.