Black molds are ubiquitous, darkly pigmented (dematiaceous) fungi. They have been increasingly reported in solid-organ transplant recipients (1). They have usually been treated with a combination of surgical resection and antifungal agents. We present three cases from our unit with a brief review of the literature.
A 65-year-old male farmer with end-stage renal failure secondary to immunoglobulin A nephropathy underwent a cadaveric renal transplant at the end of the year 2000. This was complicated in the first month posttransplantation by acute rejection (grade IA, Banff 97), which was treated with pulse intravenous methylprednisolone and antithymocyte gamma globulin. He was subsequently maintained with tacrolimus and mycophenolate mofetil immunosuppression. His operation was complicated by wound breakdown, and he developed transplant-related diabetes mellitus.
Three months posttransplantation, the patient noticed dark, fungating, and ulcerating lesions on both legs. The lesions first appeared as small tender lumps under the skin that gradually enlarged during the ensuing 4 months (Fig. 1). At presentation, the lesions were up to 2 cm in diameter and were surrounded by cellulitis.
Histopathologic examination of these lesions revealed filamentous fungal hyphae and a dense granulomatous reaction. Alternaria alternatum was isolated from tissue biopsies. Terbinafine hydrochloride was given in a dose of 200 mg daily for 30 days with no clinical response. Itraconazole suspension (200 mg twice/day) produced a prompt clinical response and was continued for 6 months. The tacrolimus dose required reduction during itraconazole therapy.
Complete resolution of these lesions occurred in 6 months without surgical resection.
A 45-year-old man with end-stage renal disease secondary to interstitial nephritis underwent a cadaveric renal transplant. Transplant-related diabetes mellitus, urinary tract obstruction, and cytomegalovirus infection complicated the postoperative period. His maintenance immunosuppression consisted of cyclosporine and mycophenolate mofetil.
He noticed a painful lump on the medial aspect of his left foot 5 days posttransplantation. He did not report this until 2 months later when it had reached 1.5 cm in diameter. Aspiration of this lesion revealed abundant fungal hyphae, which were unable to be identified further. He underwent wide excision followed by skin grafting. Histopathologic examination revealed abundant fungal hyphae in the midst of a vigorous granulomatous reaction (Fig. 2).
He was treated with liposomal amphotericin B for 1 week after this surgery, but he developed recurrent lesions on the anterior margin of the skin graft 3 months later. On this occasion, Phialophora richardsiae was isolated from tissue samples. He underwent repeat debridement and was treated with liposomal amphotericin B for 2 weeks followed by itraconazole (200 mg twice/day) for 6 weeks. He made a good recovery, and at follow-up 12 months after completing treatment there has been no recurrence of his lesions.
A 54-year-old woman with polycystic kidney disease underwent a living-related renal transplant in early 2001. This was complicated on day 7 by vascular rejection (grade IIA, Banff 97), which was treated with OKT-3. She was subsequently treated with FK506 and mycophenolate mofetil. She developed transplant-related diabetes mellitus. Eight months posttransplantation, she noticed two lesions on her leg that were dark, tender, and 0.5 cm in diameter. She was given itraconazole suspension orally (200 mg twice/day). Excision biopsy revealed black fungal hyphae, which were later identified as Alternaria alternatum. At follow-up 20 months after completing treatment, she continues to be free of any recurrence.
To our knowledge, the first of these cases is the first report of complete resolution of subcutaneous black fungal lesions in a transplant recipient without the need for surgical excision. All three patients received a renal allograft, received steroids and mycophenolate mofetil, and developed transplant-related diabetes mellitus. It should be noted that two of the patients experienced episodes of significant rejection early in the posttransplant period and had enhanced immunosuppression with antilymphocyte antibodies, which clearly increased their risk of opportunistic infections. There was no clear history of trauma or occupational exposure in any of the three cases; however, it should be noted that the first patient was a farmer.
The dematiaceous, or pigmented (black), fungi may cause invasive disease (phaeohyphomycosis), superficial subcutaneous infection with nodules or verrucous masses (chondroblastomycosis), or tumorous growth of the skin with draining sinuses (mycetoma). Although chromoblastomycosis and mycetoma are most commonly seen in tropical and subtropical regions, phaeohyphomycosis seems to have a worldwide distribution (2). The dematiaceous fungi are commonly found in soil and decomposing plant material (3). Melanin, present in their cell walls, is thought to offer protection from environmental stress and to make the organism more resistant to the host’s phagocytic mechanisms. Close to 100 species from at least 60 genera have been identified. The most common species causing human disease are Alternaria sp, Bipolaris sp, Cladophialophora sp, Curvularia sp, and Phialophora sp (4). Infections with these organisms increasingly have been reported in solid-organ transplant recipients (5).Corticosteroid therapy may offer an additional risk (6), and underlying diabetes mellitus may also play a role (7).
Infection may follow inhalation or traumatic implantation of the fungus. The limbs are the most common sites of subcutaneous infection, with the formation of slowly enlarging firm, sometimes tender nodules that can form cystic abscesses (3). Dermatologic differential diagnosis of these lesions includes neoplastic conditions such as Kaposi’s sarcoma, and the lesions can also be confused with the initial lesions of chromoblastomycosis, sporotrichosis, blastomycosis, coccidioidomycosis, and paracoccidioidomycosis, as well as with cutaneous leishmaniasis (3). Inhalation is presumed to be the cause of paranasal sinus infections, which may cause slowly progressive destructive lesions with cerebral invasion (7). Computed tomography scanning is important for the diagnosis and determination of the extent of disease (1). Despite cerebral “invasion,” it is unusual to recover fungal elements from cerebrospinal fluid examination. Other less common sites of infection include endocarditis of artificial valves, continuous ambulatory peritoneal dialysis peritonitis, osteomyelitis, and septic arthritis (1).
Diagnosis of phaeohyphomycosis rests on the demonstration of pigmented septate mycelia with occasional branching surrounded by a granulomatous tissue reaction. Confirmation of dematiaceous mold by a melanin-specific stain such as Masson-Fontana stain is recommended. Isolation of the organism may require prolonged culture (1–3 weeks) on Sabouraud dextrose agar (3). Identification of the organism may be enhanced by close liaison with the microbiology laboratory to ensure that biopsy specimens are processed using appropriate stains and culture methods. In vitro susceptibility testing is useful.
Surgical resection and antifungal therapy with itraconazole for 2 to 3 months has been effective in most patients without disseminated disease (8). In contrast, disseminated phaeohyphomycosis, which most commonly occurs in immunocompromised patients, has an overall mortality of 79% despite treatment with amphotericin B and surgical resection when possible (2). Liposomal amphotericin B is the preferred option to reduce the risk of nephrotoxicity. Consideration should be given to the reduction of immunosuppression in disseminated cases (5) (Table 1). To our knowledge, our first case is the first reported transplant recipient in whom cure of phaeohyphomycosis was achieved with medical treatment alone. The optimum treatment for phaeohyphomycosis is not clear. Many isolates are resistant to amphotericin B. Itraconazole, given in doses of 100 to 600 mg per day for several months, has been used successfully in patients whose disease failed to respond to amphotericin B (9). New antifungal agents such as voriconazole, terbinafine, and caspofungin given alone or in combination may improve the prognosis of these infections in the future (2,10).
It should be noted that caspofungin does not seem to be as active in vitro as the azole compounds, and its role in the treatment of these infections is unclear at the present time (11).
Suspicious skin lesions developing in transplant recipients should be treated aggressively. Surgical debridement with subsequent histologic examination and appropriate cultures should be pursued. In selected patients, cure can be achieved with medical treatment alone.
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