Persistent subcutaneous Scedosporium apiospermum infection

ARTICLE

Auteur(s) : Patrizia POSTERARO¹, Camille FRANCES⁴, Biagio DIDONA², Richard DORENT⁵, Brunella POSTERARO³, Giovanni FADDA³

¹ Department of Clinical and Molecular Pathology Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Via dei Monti di Creta, 104, 00167 Rome, Italy
² Department of Dermatology, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Via dei Monti di Creta, 104, 00167 Rome, Italy
³ Institute of Microbiology, Università Cattolica del Sacro Cuore, L.go Francesco Vito, 1, 00168 Rome, Italy
⁴ Department of Medicine Surgery, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
⁵ Department of Cardiac Surgery, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

Article accepted on 25/09/2003

Opportunistic fungal infections due to Aspergillus, Scedosporium, Fusarium and other monialiaceous fungi are increasing in debilitated individuals (AIDS and neoplasma patients, organ transplantation and prosthetic device implantation recipients) as a result of prolonged chemotherapeutic and immunosuppressive regimens. In some instances, these infections are invasive and life threatening [1-2].
With regards to Scedosporium, two well known species, S. apiospermum and S. prolificans, can infect several body sites by penetrating accidentally in the host. When the host defenses are lowered, these fungi cause diseases ranging from localized to disseminated forms, involving virtually any organ [3-6]. An early diagnosis and a promptly established treatment should be the key to a successful outcome.
Recently, several cases of skin infections caused by S. apiospermum, the anamorphic state of Pseudoallescheria boydii, the main causative agent of mycetoma, have been described, although these infections remain uncommon [7-14]. We describe the case of a heart transplant recipient who developed a localized subcutaneous infection due to S. apiospermum, that differed from the more common manifestations of scedosporiosis, such as granuloma and mycetoma, by the histopathological features and absence of granules. Despite surgical and medical treatment which was promptly initiated, the patient presented recurrent lesions for a prolonged period.

Case report

S.D., a 52-year-old Italian man had undergone heart transplantation in the Department of Cardiovascular Surgery of Groupe Hospitalier Pitié-Salpétrière in Paris, France, as a consequence of a dilatative cardiomyopathy, in January 1994. Since then, he had taken oral cyclosporin (275 mg/day) and prednisolone (8 mg/day) as an immunosuppressive regimen. Five years after transplantation, the patient had developed multiple subcutaneous nodules on the dorsum of his right hand. In January 2000, he was referred to the Department of Dermatology of the Groupe Hospitalier Pitié-Salpétrière in Paris, where a diagnosis of subcutaneous infection due to Scedosporium sp. was made, based on microbiological tests. The patient decided to return in Italy, and was then referred to the Istituto Dermopatico dell'Immacolata in Rome in March 2000. The patient reported a history of frequent hand escoriations by picking mushrooms, and probably he had inoculated himself with the fungus during this activity. On physical examination, a dozen of non-inflammatory, painless, and tender upon pressure nodules of 1-3 cm, localized on the right hand, were present (Fig. 1). Surprisingly, when two nodules were excised for routine laboratory investigation, they showed a cystic aspect with a thin membrane and a purulent content. One of the excised nodules was divided in two parts that were subjected to histological and microbiologic examination, respectively. Findings from the histopathologic evaluation revealed a cystic structure containing an infiltrate of inflammatory cells, mainly neutrophils, and numerous periodic acid-Schiff (PAS) positive granular and filamentous fungal elements (Fig. 2). Smears prepared from the skin biopsy specimen and stained with white calcofluor showed septate hyphal elements. No granules, the hallmark of mycetoma, were observed in the purulent fluid. The culture of the same material performed on Sabouraud dextrose agar (SDA) yielded a very rapidly growing fungus, that appeared cottony and white at first, becoming smoky gray as conidia were produced. Microscopic examination of the mould showed solitary ovoid conidia arising from short hyalin conidiophores (Fig. 3). A second conidial state was observed, named Graphium, in which conidiogenous cells were borne on erect synnemata, and the conidia appeared cylindric and longer than the ovoid conidia formed on the solitary annellides. This fungus was identified as S. apiospermum and differentiated from the S. profilicans on the basis of its resistance to cycloheximide and poor growth at 45 °C. When antifungal drug susceptibility testing was performed, the isolate was found to be resistant to amphotericin B, flucytosine, and fluconazole, but susceptible to itraconazole and ketoconazole. The patient's health was good; he was afebrile and did not present respiratory symptoms, osteoalgia or arthralgia. Palpation of the liver and spleen revealed them to be of normal size. No lymphadenopathy signs were present. Laboratory tests, including neutrophil count, resulted in a normal range. Total body computed tomography did not reveal abnormal findings. Due to the above mentioned drug susceptibility testing results of the Scedosporium isolate, we decided to treat the patient with oral itraconazole (100 mg twice a day) and to excise all nodules. The cyclosporin therapy dose was then reduced from 275 to 225 mg daily, because the drug serum level was found over the normal range. The patient returned three months later presenting new lesions that were surgically removed. Although itraconazole treatment was continued, three further relapses of the infection occurred during the next two years, making necessary other surgical interventions. At the time of writing, complete remission has been achieved with a disease free follow-up of 15 months.

Discussion

Scedosporium sp. is soil-, sewage- and water- inhabiting. Two species, S. apiospermum, and S. prolificans are known to cause deep human infections. Since 1948, when the mould was recognized as a human pathogen and causative agent of meningitis [15], an increasing number of cases of pneumonitis, osteomyelitis, arthritis, endophtalmitis, brain ascess, endocarditis, sinusitis have been reported, whereas cutaneous and subcutaneous infections are rare, apart from mycetoma [13-14, 16-20]. In most cases, the fungus is introduced into humans by inhalation or accidentally via thorns or splinters. Rarely, introduction of the fungus into body occurs by means of contaminated surgical instruments and prosthetic devices. Generally, Scedosporium infections remain localized; however, dissemination may occur in immunocompromised patients, leukemic patients or transplant recipients [14, 21-24]. Skin scedosporiosis occurs as a result of colonization and/or invasion of the cutaneous and subcutaneous tissue by the microorganism, depending on the local and general immunologic and physiologic state of the host.
To assess the fungal etiology of cutaneous infection, repeated isolation of the same fungal species from multiple consecutive specimens and demonstration of the isolate capability to grow at or near body temperature are required. In our case, the role of S. apiospermum in determining disease was ascertained by isolating the microorganism from two biopsy specimens, in France and then in our laboratory. Histopathological examination of sections from the excised nodules showed a cystic structure containing an inflammatory infiltrate, with absence of granulomatous giant cells. At microscopic examination, no granules typical of mycetoma could be found in the purulent content of the nodules. In the absence of any detectable systemic symptom and sign of infection, we concluded that our case was a rare form of localized skin infection, as already described by Kim et al. [12]. Probably, this condition was related to the immunosuppressive status of the patient induced by the long-term therapy with cyclosporin and corticosteroids post-heart transplantion.
As recently reviewed by Miyamoto et al. [9], the outcome of S. apiospermum skin infections ranges from a complete healing of lesions to a rarely encountered persistence, as in our case where the infection recurred, despite prompt and prolonged itraconazole treatment. The therapeutic decision was based on the susceptibility testing results of our isolate, that was found to be resistant to several antifungal agents with the exception of itraconazole and ketoconazole.
Although azole antifungal agents, especially itraconazole, have been proven to be effective in vitro and have been successfully employed in the treatment of scedosporiosis [7, 14, 25], therapeutic failures of these drugs have been reported, demonstrating that the in vitro susceptibility to antifungal agents does not always correlate with the in vivo outcome, and making necessary the development of new pharmacological approaches [8, 26]. Recently, four novel triazoles (posoconazole, ravucanozole, voriconazole and UR-9825) were tested in vitro and showed activity against the two species of Scedosporium [27-28].
In our case, the cystic nature of the lesions may have in part hampered the penetration of itraconazole and its inhibitory effect against the fungus, also making necessary repeated surgical interventions to eradicate the infection. n

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