THE YALE JOURNAL OF BIOLOGY AND MEDICINE 63 (1990), 9-13

Fatal Subcutaneous Aspergillosis Following Necrotizing Fasciitis: A Case Report ANN R. FALSEY, M.D.,a R. DAVID GOLDSTICKER, M.D.,b AND MARY JEAN AHERN, M.D.C

aFellow, Infectious Diseases, Yale University School of Medicine, New Haven, Connecticut; bResident, Pathology, Hospital of St. Raphael, New Haven, Connecticut; cAssociate Director, Infectious Diseases, Hospital of St. Raphael, and Associate Clinical Professor, Yale University School of Medicine, New Haven, Connecticut Received July 14, 1989 Skin or subcutaneous infection with aspergillus is uncommon. It has been described in disseminated aspergillosis, as localized infection in the immunocompromised host and as a complication of trauma and burns. Described in this paper is a diabetic patient who developed a fatal Aspergillus infection following debridement of a necrotizing fasciitis. "Fruiting bodies," rarely found in vivo, were seen on pathologic examination of subcutaneous tissue. Her course was similar to that of burn patients with invasive fungal disease, where mortality is high and radical debridement is the only chance for cure.

Aspergillus is a ubiquitous, saprophytic mold which grows well in soil and on organic debris [1]. Aspergillosis is a significant cause of morbidity and mortality in patients with altered host defenses. Patients with hematologic malignancies and neutropenia are the most commonly affected, but Aspergillus infection has also been described in patients with collagen vascular disease, sarcoid, and organ transplants as well [1]. Invasive or disseminated aspergillosis is rare in the normal host [2,3]. Although Aspergillus may invade almost any tissue, the lung, gastrointestinal tract, and the central nervous system are the most frequent sites of infection [1,4]. Cutaneous Aspergillus infection is uncommon. A recent review of aspergillosis from the National Cancer Institute noted that only two out of 98 patients had skin involvement [2]. In this report we describe a diabetic patient who developed a rapidly progressive, fatal Aspergillus fumigatus infection of a wound following debridement for necrotizing fasciitis. Fungal infections of wounds have been reported in trauma [5] and burn victims [21-23], but to our knowledge aspergillosis has not been previously described following a surgical debridement procedure. CASE REPORT A 60-year-old, insulin-dependent diabetic white female was admitted to the Hospital of St. Raphael with severe necrotizing fasciitis. Her past medical history was notable for penicillin allergy and chronic renal failure, requiring hemodialysis. She had not been previously maintained on peritoneal dialysis.

9 Address reprint requests to: Ann R. Falsey, M.D., Division of Infectious Diseases, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642 Copyright © 1990 by The Yale Journal of Biology and Medicine, Inc. All rights of reproduction in any form reserved.

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FIG. 1. Anterior abdominal wall debridement site. Necrotic areas showing extensive mycelial growth are visible on the surface of the subcutaneous tissue.

One week prior to admission, the patient developed a labial abscess and low-grade fever. The abscess progressed rapidly to a necrotizing fasciitis, involving the anterior abdominal wall, thigh, and perineum. On the day of admission she was febrile with a toxic appearance. She was taken to the operating room for extensive debridement and begun on vancomycin, gentamicin, and metronidazole. Cultures of debrided tissue grew E. coli, S. faecalis, and microaerophilic streptococcus. Her post-operative course was complicated by hypotension, adult respiratory distress syndrome, and disseminated intravascular coagulation. Despite her initial difficult course, the patient stabilized, fever and leukocytosis gradually resolved, and antibiotics were discontinued after 12 days. She was treated with intensive local care and whirlpool therapy. The wound was packed with sterile gauze. No elastic wraps or bandages were used. Despite this regimen, one week later she again became hypotensive and febrile, and the wound appeared purulent. Cultures grew Pseudomonas maltophilia, Klebsiella pneumoniae, and E. coli. Ceftazidime, gentamicin, and metronidazole were begun with a good clinical response. On the tenth day of her second course of antibiotics, dry, black areas of necrosis appeared on the wound surface. Within 24 hours, a blue green mold was observed to be growing in areas of necrosis (see Fig. 1). The patient was taken for her third debridement. Operating room specimens showed fungal invasion of the subcutaneous tissue and muscle (Figs. 2, 3). The cultures grew Aspergillus fumigatus. She was begun on amphotericin B at a dose of 1.0 milligrams per kilogram per day following debridement. Antibacterial agents were discontinued. Within 72 hours of surgery, grossly obvious fungal growth recurred. Topical amphotericin B was added to systemic treatment. A fourth debridement was attempted. Deep tissue necrosis was found, with involvement of the small bowel. Pathology of the small bowel was not obtained. The fungal infection was felt to be so extensive that resection was not possible. Comfort measures were instituted, and dialysis and amphotericin were stopped. She had received approximately 500 milligrams of intravenous amphotericin B. She died on the forty-first hospital day. Permission for autopsy was not granted.

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FIG. 2. Periodic Acidxmg.;

~~~~~~~Schiff stain of subcutaneous tissue biopsy. Dichotomously branched, septate hyphae, characteristic of Aspergillus, can be seen invading deep into tissue section (original magnification, 100 x)

DISCUSSION Cutaneous aspergillosis can be divided into three main categories: (1) skin lesions associated with disseminated disease, (2) primary cutaneous aspergillosis, and (3) aspergillus infection complicating burn wounds. Fungal infection associated with burn wounds is most analogous to the patient in this case report. Invasion of the dermis in disseminated aspergillosis is uncommon, occurring in less than 5 percent of cases [6]. Lesions are multiple, suggesting embolic, hematogenous spread, usually from a primary lung source [ 1,6]. The typical rash begins as erythematous pustules which ulcerate and become necrotic. Aspergillusfumigatus has been the most common isolate [1,6,7]. Primary cutaneous lesions may occur in normal hosts or in immunocompromised patients. In normal hosts, infection typically follows minor trauma and follows an indolent course, requiring only local therapy [8-12]. Elasticized bandages have been associated with outbreaks of fungal infections such as Mucor in surgical patients. The bandages themselves have been found to be the source of fungal contamination [13]. Our patient was never exposed to tape, elastic bandages, or wraps. Her wound was dressed with individually sterilized, pre-packaged gauze, which was widely used throughout the hospital. While the gauze was not cultured, there were no other cases of Aspergillus wound infections reported in the hospital during this period to suggest this possibility as a source of contamination. The surfaces of the whirlpool tank were cultured for fungal colonization and were found to be free of Aspergillus. Localized primary Aspergillus infection in the immunocompromised host usually occurs in clusters and has been related to trauma from intravenous catheters, armboards, or tape. Aspergillus flavus is the most common isolate [7,14-18]. When outbreaks of cutaneous aspergillosis occur, wound dressings and tape should be cultured. Successful treatment requires the resolution of neutropenia, systemic amphotericin B therapy, catheter removal, and local wound care [ 17]. Fungal infection of traumatic wounds and burns has been described in the surgical literature. While Candida frequently colonizes burns, true fungal invasion is most commonly attributed to various species of Zygomycetes and Aspergillus [19-21].

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FIG. 3. Grocott's methenamine silver stain of biopsy taken from tissue surface. Note the numerous conidiophores (original magnificaa

tion,400x).

Isolation of Aspergillus from a burn wound or devitalized tissue is rarely colonization and often carries a grave prognosis [20]. In a study of 30 burn patients, indications of fungal infection were: superficial necrosis, violaceous discoloration, or "black spots." As with our patient, the surface appearance did not convey the extent or depth of tissue necrosis [22]. Biopsy frequently shows invasion of hyphae into deep tissue and thrombosis of blood vessels with ischemia and gangrene. Extensive spread beneath intact skin may be found [21]. "Fruiting bodies" or conidiophores of Aspergillus are seen almost exclusively in culture media, and the presence of fruiting bodies in vivo is exceedingly rare. There has been only one prior case report of "fruiting bodies" isolated from a patient, an individual with extensive burn wounds [23]. Hyphae invasion is typically seen in tissues rather than conidiophores, which were seen in this patient. The primary mode of therapy is wide surgical excision or amputation [18-22,24]. Topical or systemic antifungals were never individually successful in controlling the infection. Recurrence after debridement was very common, occurring in 33-83 percent of cases [22]. Stone et al. suggested that systemic amphotericin B and topical antifungals were beneficial in adjunctive roles in preventing recurrent disease following debridement. Even with optimal therapy, mortality is high, estimated to be between 30-78 percent [21,22,24]. Our patient is analogous to the burn patient with large areas of devitalized, exposed tissue. She was also immunocompromised by virtue of her diabetes and chronic renal failure. In this population, cutaneous aspergillus carries a grave prognosis. Unlike other forms of cutaneous aspergillosis, systemic amphotericin is only adjunctive therapy. The primary mode of treatment is debridement. In this type of patient, Aspergillus isolated from the surface of the wound should not be considered a contaminant or superficial colonization. Prompt evaluation of the depth of fungal penetration and appropriate surgical intervention is imperative. ACKNOWLEDGEMENTS We wish to thank David N. Korones for his help in preparation and Frank J. Bia for reviewing this manuscript.

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REFERENCES 1. Young RC, Bennett JE, Vogel CL, et al: Aspergillosis-the spectrum of disease in 98 patients. Medicine 49:147-173, 1970 2. Karam GH, Griffin EM: Invasive pulmonary aspergillosis in non-immunocompromised, nonneutropenic hosts. Rev Infect Dis 8:357-363, 1986 3. D'Silva H, Burke JF, Cho SY: Disseminated aspergillosis in a presumably immunocompetent host. JAMA 248:1495-1497, 1982 4. Fisher BD, Armstrong D, Yu B, Gold JW: Invasive aspergillosis-progress in early diagnosis and treatment. Am J Med 71:571-577, 1981 5. Vainrob B, Macareno A, Mandel S, Musher DM: Wound zygomycosis (mucormycosis) in otherwise healthy adults. Am J Med 84:546-548, 1988 6. Findlay GH, Roux HF, Simson IW: Skin manifestations in disseminated aspergillosis. Br J Derm 85:94-97, 1971 7. Prystowsky SD, Vogelstein B, Ettinger DS, et al: Invasive aspergillosis. N Engl J Med 295:655-658, 1976 8. Myers JT, Dunn AD: Aspergillus infection of the hand. JAMA 95:794-796,1930 9. Frank L, Alton OM: Aspergillosis: A case of post-operative skin infection. JAMA 100:2007-2008, 1933 10. Cheetham HD: Subcutaneous infection due to Aspergillus terreus. J Clin Path 17:251-253, 1964 11. Suseelan AV, Gugnani HC, Ojukwu JO: Primary cutaneous aspergillosis due to Aspergillus terreus. Arch Dermatol 112:1468-1469, 1976 12. Cahill KM, ElMofty AM, Kawaguchi P: Primary cutaneous aspergillosis. Arch Dermatol 96:545-547, 1967 13. Patterson JE, Barden GE, Bia FJ: Hospital-acquired gangrenous mucormycosis. Yale J Biol Med

59:453-459,1986 14. Carilile JR, Millet RE, Cho CT, et al: Primary cutaneous aspergillosis in a leukemic child. Arch Dermatol 114:78-80,1978 15. Langlois RP, Flegel KM, Meakins JL, et al: Cutaneous aspergillus with fatal dissemination in a renal transplant recipient. Can Med Assoc J 120:673-676, 1980 16. Estes SA, Hendricks AA, Merz WG, et al: Primary cutaneous aspergillosis. Am Acad Dermatol 3:397-400,1980 17. Allo MD, Miller J, Townsend T, et al: Primary cutaneous aspergillosis associated with Hickman intravenous catheters. N Engl J Med 317:1105-1108, 1987 18. Grossman ME, Fithian EC, Behrens C, et al: Primary cutaneous aspergillosis in six leukemic children. J Am Acad Dermatol 12:313-318, 1985 19. Nash G, Foley FD, Goodwin MN, et al: Fungal burn wound infection. JAMA 215:1664-1666,1971 20. Brock HM, Nash G, Stein JM, et al: Studies on the occurrence and significance of yeasts and fungi in the burn wound. Ann Surg 176:108-110,1971 21. Salisbury RE, Silverstein P, Goodwin MN: Upper extremity fungal invasions secondary to large burns. Plastics Reconst Surg 54:654-659, 1974 22. Bruck HM, Nash G, Foley D, et al: Opportunistic fungal infection of the burn wound with Phycomycetes and aspergillus. Arch Surg 102:476-482, 1971 23. Panke TW, McManos AT, McLeod CG: "Fruiting bodies" of aspergillus on the skin of a burned patient. Am J Clin Pathol 69:188-189, 1978 24. Stone H, Cuzzell JZ, Kolb LD, et al: Aspergillus infection of the burn wound. J Trauma 19:765-767, 1979