Subcutaneous phaeohyphomycosis and nocardiosis in a kidney transplant patient Heather F. McCown, and Eleanor E. Sahn, MD Charleston, South Carolina Phaeohyphomycosis and nocardiosis are uncommon infections that are more frequently reported in immunocompromised patients. To our lmowledge, this is the first report of subcutaneous phaeohyphomycosis caused by Exophialajeanselmei in association with systemic infection with Nocardia asteroides. The patient's phaeohyphomycosis responded to surgical excision and multi-drug therapy, and the patient underwent prolonged therapy with trimethoprim/sulfamethoxazole for treatment of the nocardiosis. (J Am Acad Dermatol 1997;36:863-6.)
~Ilae dematiacious fungi are responsible for a specmma of diseases including mycetomas, phaeohyphomycosis, and chromoblastomycosis. The term phaeohyphomycosis was coined by Ajello in an attempt to correct the confusion and misuse associated with the term chromoblastomycosis.1 Phaeohyphomycosis can cause a wide variety of infections that are characterized by the presence of hyphae, pseudohyphae, yeast-like cells, or a combination of these forms in tissue. Chromoblastomycosis differs by the presence of characteristic sclerotic bodies, also known as muriform cells, Medlar bodies, or copper pennies. The sclerotic bodies are not yeast forms, but are created by the formation of cross walls within the mature cell.2 Exophialajeanselmei, a common cause of phaeohyphomycosis, is an opportunistic pathogen that affects humans and animals.2, 3 The species is ubiquitous in nature and is generally saprophytic. Typically, it causes infections in the extremities where it gains access via traumatic implantation. Nocardia species are ubiquitous, aerobic saprophytes that are present in soil and organic matter. They are tree bacteria that form delicate, branching, gram-positive filaments and can cause either cutaneous or systemic disease. From 80% to 90% of systemic nocardiosis is caused by infection with ORTHO
This article is made possible through an educational grant from the Dermatological Division, Ortho Pharmaceutical Corporation.
From the Departments of Dermatology and Pediatrics, Medical University of South Carolina, Charleston. Reprint requests: Eleanor E. Sahn, MD, 171 Ashley Ave. Charleston, SC 29425-2215. Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97/$5.00 + 0 16/4/78247
Nocardia asteroides. Typically, N. asteroides is acquired by inhalation and is disseminated hematogenously.4, 5 Dissemination can produce cerebral metastasis, which occurs in 27% of primary pulmonary infections and carries a mortality rate of more than 80% .6 The advent of the newer immunosuppressive drugs has revolutionized organ transplantation, while increasing the morbidity and mortality from opportunistic microorganisms. The presence of two separate organisms in the same patient can produce a diagnostic and therapeutic dilemma. We describe a renal transplant recipient with concurrent subcutaneous phaeohyphomycosis and disseminated nocardiosis. CASE REPORT
A 59-year-old man had a nodule on his right third finger 8 months ago. He first noticed the lesion in December 1994 after he had gotten a splinter while hammering. In April 1995, several other nodules developed on his right forearm. The lesions were not painful and he denied fever, chills, or weight loss. The patient had received a cadaveric kidney transplant in May 1994. He had experienced two episodes of rejection, and his medications included FK-506, azathioprine, prednisone, diltiazem, atenolol, and sodium bicarbonate. Examination in August 1995 revealed a 1.7 x 1.5 cm verrucous crusted nodule with surrounding hyperpigmentation on his right third finger (Fig. 1). There were multiple, small, mobile, subcutaneous nodules on the dorsum of the right forearm (Fig. 2). A larger, 1 cm, mobile nodule surrounded by a hypopigmented patch was found in the antecubital fossa. There was no axillary lymphadenopathy or hepatosplenomegaly. A biopsy specimen from the right foreama revealed a 863
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Fig. ,'-1. Verrucous crusted nodule on right third digit. Fig. 3. Pigmented hyphae within dermal granuloma in forearm nodule seen in Fig. 2. Cktlmre revealed Exophiala jeanselmei. (Hematgxylin-eosin; original magnification x400.)
Fig. 2. Subcutaneous nodule on right forearm.
granuloma in the reticular dermis that showed some palisading. Within the granuloma were small microabscesses adjacent to pigmented fungal hyphae (Fig. 3). Dense fibrosis and a mixed inflammatory inftltrate surrounded the granuloma. A biopsy specimen from the right third finger revealed irregular epidermal hyperplasia overlying dermal suppurative granulomas. Giant cells containing numerous pigmented hyphae were seen. A diagnosis of subcutaneous phaeohyphomycosis was made. Culture of the right forearm and the right third finger yielded E. jeanselmei. There was no growth of bacteria from either site. In September 1995, the patient presented with swelling and pain in his left arm, axilla, and subscapular region. There was no history of trauma to these areas. On admission he was afebrile, with an edematous and erythematous left elbow. There was point tenderness in the left axilla and left subscapular region. The patient denied pulmonary symptoms. The lesions on his right finget and forearm remained unchanged from the previous examination. Laboratory values included the following: leukocyte count, 17.4 x 103/ram 3, hemoglobin, 10.7 gm/ dl; hematocrit, 30.8%; blood urea nitrogen, 37 mg/dl; and creafinine, 2.4 mg/dl. The patient tested negative for HIV. A chest x-ray examination revealed a new left apical density suggestive of a mycotic or other infection. Blood cultures were obtained and the patient was treated empirically with amphotericin B, flucytosine, and itraconazole
for a possible disseminated phaeohyphomycotic infection, as well as with ciprofloxacin for a possible urinary tract infection. All immunosuppressive agents were stopped except for prednisone 10 mg/day. Blood cultures were negative for both bacteria and yeast. Magnetic resonance imaging of the left upper extremity revealed edema or inflammation within the deep muscle compartments of the distal left humerus, as well as a 7 x 4 cm soft tissue abscess laterally. An area of edema or inflammation was also found between the left scapular tip and the chest wall. The patient subsequently underwent incision and drainage of the left elbow abscess, excision of the nodules on his right third finger and forearm, and bronchoalveolar lavage with transbronchial biopsy of his left upper lobe. Cultures obtained from the abscess and from the bronchoalveolar lavage revealed N. asteroides: Amphotericin B, flucytosine, and ciprofloxacin were discontinued and tfimethoprim/sulfamethoxazole (TMP/SMX) and imipenem were begun for the treatment of disseminated nocardiosis. A computed tomography scan showed no cerebral abscesses. After 11 days, the patient's condition had improved, and he was discharged from the hospital. DISCUSSION This immunocomprornised patient had a subcutaneous infection with E. jeanselmei and pulmonary disease with secondary cutaneous involvement from N. asteroides. Immunosuppression was probably the main cause of his susceptibility. Phaeohyphomycosis can be difficult to diagnose clinically because o f its m a n y clinical presentations. The disease has been classified into four types by Fader and McGinnis. 7 Superficial phaeohyphomycosis, like tinea nigra and black piedra, is the first
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type and is limited to nonviable epithelium with little or no tissue response. The next category includes cutaneous and corneal phaeohyphomycosis. This infection involves keratinized tissues, and there is often extensive tissue damage. The third category is subcutaneous phaeophyphomycosis, and it usually results from traumatic implantation of the fungus with localized abscess formation. The final category consists of the rare systemic phaeohyphomycosis that disseminates from the lungs] ~lqe most common cause of subcutaneous phaeohyphomycosis is E. jeanselmei. 3 The lesion typically presents as a single, encapsulated, asymptomatic nodule, usually of an extremity. The infection tends to be chronic because of the slow growth of the organism. The lesion begins as a solid, tuberculoid granuloma. In time, the center undergoes focal necrosis with the formation of small stellate abscesses. Eventually these microabscesses coalesce into a unilocular flucmant abscess in the dermis and subcutaneous tissue. 8 Usually the epidermis is spared. Phaeohyphomycosis characteristically does not cause lymphadenopathy.9 Although the fungus is usually seen on a potassinm hydroxide preparation, diagnosis can be difficult because of its slow growth in culture. Furthermore, even if fungi are seen in tissue, cultures may yield no growth. 1° Several techniques can be used to help identify the fungus. A potassium hydroxide preparation of E. jeans'elmei will reveal brown, septate, branched or unbranched hyphae.ll The hyphae are typically 2 to 6 gm in diameter and can vary in length up to 25 pm, or even 75 bun.12 The yeast cells are thick-walled, and buds and chains are common. At intervals along the hyphae, elongated conidiophores are present. The conidiophores are characteristically tapered at the tilts where elliptical conidia canbe found. 9, 13The fungi are usually visible on routine hematoxyiin and eosin or periodic acid-Schiff stains, but melanin stains, Gomori methanamine-silver nitrate, or Fontana-Masson stains can be used for more definitive identification.V, 14 The fungus can be cultured on potato dextrose agar or Sabouraud glucose agar. It grow.,; best at 25 ° to 30°C and is usually visible by 1 to 2 weeks, but can take up to 4 weeks to grow. The colonies are typically olive-brown to black with a velvety appearance.9 The typical histopathologic feature of a subcutaneous cyst consists of dense fibrous tissue encapsulating the abscess. However, there have been reports
McCown and Sahn 865 in which file abscess was not encapsulated. 8' 9 The inner edge of the capsule consists of macrophages, multinucleated giant cells, polymorphonuculear lymphocytes, and an occasional eosinophil or lymphocyte. The center of the abscess is often necrotic and filled with neutrophils. Sometimes vegetable matter can be found in the abscess. Fungi are usually identified both in the walls and in the center of the abscess. 2 Treatment involves surgical removal of the phaeohyphomycotic cyst. Medical therapy has also been used with varying success. Amphotericin B, 5-flucytosine, and ketoconazole have been used, but the organisms have variable susceptibility to these drags. 9 Itraconazole, which is fungistatic and inhibits ergosterol synthesis, appears to be the most effective agent, especially against Exophiala species. ~2 The diagnosis of nocardiosis in our patient was complicated by the existing diagnosis of phaeohyphomycosis. Although it is unusual for E. jeanselmei to cause disseminated disease, in an immunosuppressed patient dissemination must be considered. However, our patient had several risk factors that predisposed him to nocardiosis. Renal transplant recipients account for 2% to 13% of all cases of nocardiosis. The infection also predominates in males, with a male to female ratio of 2-3:1. Another risk factor was the two episodes of rejection that required intensive drug-induced immunosuppression. Intense immunosuppression, combined with uremia from a poorly functioning donor kidney, increases the risk of infection from suppression of cellular immune function. 5 The diagnosis of nocardiosis is further complicated by the lack of specific clinical manifestations of pulmonary nocardiosis. Our patient presented with subcutaneous abscesses as his chief complaint. Typically, patients present with fever, anorexia, weight loss, cough, dyspnea, and pleuritic chest pain. Radiologic findings are also nonspecific and range from interstitial or nodular infiltrates to mass lesions and effusions. 5 Pulmonary nocardiosis can mimic tuberculosis, malignancy, or invasive fungal infection. TMP/SMX has been the mainstay of treatment of nocardiosis.15 Other antimicrobial agents that have good activity in combination with TMP/SMX include imipenem, amikacin, cycloserine, and ampicillin. 5 Most authors recommend prolonged therapy ranging from 2 to 3 months up to 1 year after remission of the disease. To avoid relapse, in certain cases,
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lifetime maintenance therapy with TMP/SMX has been recommended. 15 REFERENCES 1. Noel SB, Greer DL, Abadie SM, et al. Primary cutaneous phaeohyphomycosis. J Am Acad Dermato11988;18:102330. 2. McGinnis MR. Chromoblastomycosis and phaeohyphomycosis: new concepts, diagnosis, and mycology. J Am Acad Dermatol 1983;8:1-16. 3. Mirza SH, Hannan A, Ahmad A, et al. Subcutaneous phaeohyphomycosis. J Infect 1993;27:75-8. 4. Vogel PS, Helmet WL, Sau P, et al. Primary cutaneous Nocardia infection due to Nocardia asteroides. Int J Dermatol 1993;32:811-2. 5. Wilson JP, Turner HR, Kirchner KA, et al. Nocardial infections in renal transplant recipients.Medicine 1989 ;68:3857. 6. Gutierrez H, Salgado O, Garcia R, et al. Nocardiosis in renal transplant patients. Transplant Proc 1994;26:341-2. 7. Fader RC, McGinnis MR. Infections caused by dematiaceous fungi: chromoblastomycosis and phaeohyphomycosis. Infect Dis North Am 1988;2:925-38.
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8. Ronan SG, Uzoaru I, Nadimpalli V, et al. Primary cutaneous phaeohyphomycosis: report of seven cases. J Cutan Pathol 1993;20:223-8. 9. Sudduth EJ, Cmmbley AJ, Farrar WE. Phaeohyphomycosis due to Exophiala species: clinical specmam Of disease in humans. Clin Infect Dis 1992;15:639-44. 10. Zackheim HS, Halde C, Goodman RS, et al. Phaeohyphomycotic cyst of the skin caused by Exophialajeanselmei. J Am Acad Dermatol 1985;12:207-12. 11. Hachisuka H, Matsumoto T, Kusuhara M, et al. Cutaneous phaeohyphomycosis caused by ExophialajeanseImei after renal transplantation, hat J Dermatol 1990;29:198200. 12. Gold WL, Vellend H, Salit IE, et al. Successful treamaent of systemic and local infections due to ExophiaIa species. Clin Infect Dis 1994;19:339-41. 13. Crissey JT, Lang H, Parish LC. Diseases caused by dematiaceous fungi. In: Manual of medical mycology. Massachusetts: Blackwell Sciences, 1995:161-75. 14. Sharkey PK, et al. Itraconazole treamaent of phaeohyphomycosis. J Am Acad Dermatol 1990;23:577-86. 15. King CT, Chapman SW, Butkus DE. Recurrent nocardiosis in a renal transplant recipient. South Med J 1993; 86:225-7.