Primary cutaneous aspergillosis

Primary cutaneous aspergillosis Stephen A. Estes, M.D.,* Andrew A. Hendricks, M.D., William G. Merz, Ph.D., and Stephen D. Prystowsky, M.D.

Baltimore, MD. and San Francisco. CA A 6-year-old boy with acute monocytic leukemia and therapy-induced leukopenia developed multiple necrotizing skin lesions where an intravenous administration unit had been secured to his arm and hand. Biopsy and cultures demonstrated Aspergillus jim-us as the etiologic agent without evidence of systemic dissemination. Resolution of the infection occurred following systemic amphotericin B therapy and a granulocyte transfusion. (J A\I ACAD DER.'IATOL 3:397-400, 1980.)

Primary cutaneous aspergillosis in an immunocompromised patient is a serious, life-threatening disease. Of the six cases reported to date, all died within 9 months of the onset of their infection (Table I). In four of these patients, death was attributable directly to disseminated aspergillosis.t- 3 In this report, we describe a patient with primary cutaneous aspergillosis who was successfully treated with a granulocyte transfusion and amphotericin B. CASE REPORT A 6~-year-old boy developed acute monocytic leukemia in November, 1976. He was hospitalized several times during the next 2 months and given several chemotherapeutic regimens without inducing a remission of his leukemia. Beginning on Jan. 18, 1977, he received a 3-day course of doxorubicin, 30 mg/m 2 /day, with some improvement in his leukemia as evidenced by a subsequent bone marrow aspirate. A second course of doxorubicin was started on Feb. 15, 1977. The patient was hospitalized on March 7, 1977, for evaluation of a fever of unknown origin associated with neutropenia. The admission physical examination was From !he Depariment of Dermatology and !he Department of Laboratory Medicine. Johns Hopkins Medical Institutions, Baltimore, and the Department of Dermatology, University of California. San Francisco. Reprint requests to: Dr. Stephen A. Estes, 234 Goodman Ave., Pavilion A. Room 315. Cincinnati, OH 45267/513-872-4310. 'Currently in the Department of Dermatology, University of Cincinnati College of Medicine.

0190-9622/80/100397 +04S00.40/0 © 1980 Am Acad Dermatol

remarkable for a rectal temperature of 38.40 C, pallor, diffuse scalp alopecia, periorbital edema, and slight hepatomegaly. His white blood count was 1,600/mm 3 , with many atypical cells. A bone marrow aspirate showed 18% blast cells. Bacterial and fungal cultures of his blood, urine, throat, stool, and cerebrospinal fluid were negative. Methicillin, ampicillin, and gentamicin were started; he was afebrile in 2 days. On March 11, 1977, he was given methotrexate, 500 mg/m 2 intravenously and 12 mg/m 2 intrathecally, followed by leucovorin rescue. He became febrile with negative cultures. Ampicillin was discontinued and carbenicillin was added with defervescence of his fever. He received cyclophosphamide, cystosine arabinoside, and vincristine on March 20, 1977. He spiked a fever but cultures were negative. The white blood count fell to 22/mm 3 on AprilS, 1977. Over the next 2 days, an enlarging, 2 em, tender, erythematous nodule with central necrosis was noted on the extensor aspect of the left forearm. His left palm and third, fourth, and fifth fingers were tender, slightly swollen, and had a mottled purple coloration. Crusted areas were noted in the interdigital spaces between the third, fourth, and fifth fingers. His left hand and arm had been taped to an IV board for several days prior to the onset of the skin eruption. Skin specimens were obtained on April 8 and 9, 1977, from the left forearm and left hand. Tissue touch preparations were negative. Frozen sections and routine histopathology showed septate, pseudodichotomously branching hyphae (Fig. 1). Lesion scrapings and skin biopsies were positive on potassium hydroxide (KOH) preparations, and A. jiavlIs grew from both. Blood

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Esles el a/

Table I. Primary cutaneous aspergillosis in immunocompromised patients Reference

Disease

History of trauma at site

Organism

15 mo

M

Aplastic anemia

Irritation from paper-covered board for IV administration

A. jla\'//s

25 mo

F

Leukemia, type not stated

Paper-covered board for I V administration at site of both lesions

A. jlm·lIs

40 yr

M

None

A. jI{/\,//s

5 yr

M

Myelogenous leukemia Aplastic anemia

Under tape at IV administration site

A. jI{/\,//s

Young et al 2

5 yr

M

Acute Iymphocytic leukemia

Site of IV needle

A. jlm·lIs

Carlile et aP

5 yr

M

Acute Iymphocytic leukemia

Paper-covered board for IV administration

A. jI{/\,//s

Present case

6 yr

M

Acute monocytic leukemia

Taped to paper-covered board for IV administration

A. jlal'lls

Prystowsky et all

*Ampholericin B.

Fig. 1. Septate, pseudodichotomously branching hyphae coursing throughout the dermis. (Hematoxylin-eosin stain; x250.)

Volume 3 Number 4 October. 1980

Treatment

Primm)' cutaneous aspergillosis

Outcome

Studies

Amph B*

Death 3 mo after lesion noted

Amph B

Death 3 week after lesion noted

Amph B; 5-fluorocytosine

Death 9 mo after lesion noted Death 44 days after skin lesions noted Death 9 days after lesion noted

Amph B, systemic and topical; 5-fluorocytosine Not stated Topical nystatin

Death 15 days after lesion noted

Amph B; WBC transfusion

Apparently cured but died 3 mo later after intracerebral bleed

cultures for fungi and bacteria were negative. Two serum immunodiffusion tests for anti-Aspergillus antibodies were negative. X-ray examination of the chest and left arm revealed no abnormalities. The patient received a test dose of amphotericin B, 0.1 mg/kg intravenously, on April 11, 1977, and subsequently 0.75 mg/kg daily. The patient's fever resolved during the next 48 hours. On April 13, 1977, the patient received a granulocyte transfusion consisting of 6x 10 10 white blood cells from a donor with chronic myelocytic leukemia. The donor's cells were irradiated with 1,500 rads prior to transfusion. The patient's white blood count increased to 1,463/mm3 , with 52% neutrophils. His amphotericin B dose was advanced to 1.0 mg/kg every day or every other day. Repeat skin scrapings for KOH examination and cultures were negative for fungus. The skin lesions healed during the next 2 weeks. He was discharged from the hospital on April 30, 1977, after having received 297 mg of amphotericin B. Cancer chemotherapy was resumed on an outpatient basis, but the patient died suddenly on July 17, 1977. An autopsy was not performed, but death was thought to be due to intracerebral bleeding.

DISCUSSION Infection is a major cause of morbidity and mortality in patients with leukemia and other neoplastic diseases. The incidence of invasive aspergillosis is seven times greater in patients with leu-

399

Autopsy-grew A. jim'us and A. jUllligatus from left knee fluid; Aspergillus seen in lung; Candida sp. from liver, spleen, humerus Autopsy-disseminated Aspergillus in liver, spleen, heart, lungs, kidneys; A. jial'lls grown from urine and skin No autopsy No autopsy, disseminated aspergillosis suspected Autopsy-Aspergillus disseminated in lungs, liver, kidney, heart; A. jiavus grown from lung Autopsy-Aspergillus-like organism still in dermis without evidence of dissemination; Phycomycetes found in lung No autopsy

kemia than in those with lymphoma ..f This may be related to the disease process or its therapy. Recently, Rippon and Anderson 5 demonstrated that cyclophosphamide and prednisone, in doses equivalent to human therapeutic doses for the treatment of leukemia, remarkably lowered the resistance of rabbits to aspergillus challenges. Primary cutaneous aspergillosis should be considered in the differential diagnosis of necrotizing skin lesions in the immunocompromised patient, especially with a history of trauma to the area. Since 1970, seven cases of primary cutaneous aspergillosis have been reported in immunocompromised patients (Table I). A. jiavlls was the causative species in every case. Trauma related to intravenous administration sites was a predisposing factor in six of seven cases. The skin manifestation of primary cutaneous aspergillosis is an erythematous to violaceous, edematous, indurated plaque that rapidly progresses to a necrotic ulcer with a central black eschar. One or more lesions may appear, and the clinical features are not specific. Similar lesions are noted with other opportunistic fungi and some bacterial infections. 1.6. i The appearance of such lesions in an immunocompromised patient requires a careful diag-

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nostic and therapeutic approach. Recent reports have emphasized the importance of this for the successful treatment of disseminated aspergillosis. 8 •9 Skin specimens should be cultured and sent for routine histopathology. Touch preparations and frozen sections may enable a rapid diagnosis, thereby avoiding delay in therapy. Fungal cultures of the overlying bandages, tape, or intravenous administration materials may be helpful. Recent outbreaks of Rhizoplls species infections were traced to contaminated elastic bandages. *.10.11 Blood cultures and serologic tests ~re usually negative in systemic aspergillosis. :t,12.13 Systemic amphotericin B therapy is the treatment of choice for disseminated aspergillosis. 8 It is also the preferred treatment for primary cutaneous aspergillosis in the immunocompromised host due to the high incidence of secondary invasion in these patients. Granulocyte transfusions, though controversial, may be useful in the neutropenic patient. 8.14 Topical antifungal therapy may also be indicated but should not delay therapy for an undei-Iying systemic fungal infection. 3 • 15 *Keys TF, Haldorson AM, Rhodes KH, et al: Nosocomial outbreak of Rlzizopus infections associated with elastoplast wound dressings-Minnesota. Mortality Morbidity Weekly Rep 27:3334, 1978.

REFERENCES I. Prystowsky SD, Vogelstein B, Ettinger DS, et al: Invasive aspergillosis. N Engl J Med 295:655-658, 1976. 2. Young RC, Bennett JE, Bogel CL, et al: Aspergillosis. Medicine (Baltimore) 49:147-173, 1970.

Journal of the American Academy of Dermatology 3. Carlile JR, Millet RE, Cho CT, et al: Primary cutaneous aspergillosis in a leukemic child. Arch Dermatol 114: 78-80, 1978. 4. Meyer RD, Young LS, Armstrong D, et al: Aspergillosis complicating neoplastic disease. Am J Med 54:6-15, 1973. 5. Rippon JW, Anderson DN: Experimental mycosis in immunosuppressed rabbits: Acute and chronic aspergillosis. Mycopathologia 64:97-100, 1977. 6. Estes SA, Merz WG, Maxwell LG: Primary cutaneous phaeohyphomycosis caused by Drechsclera spicifera. Arch Dermatol 113:813-815, 1977. 7. Perry HO, Winkelmann RK: Bullous pyoderma gangrenosum and leukemia. Arch Dermatol 106:901-905, 1972. 8. Aisner J, Schimpff SC, Wiernik PH: Treatment of invasive aspergillosis: Relation of early diagnosis and treatment to response. Ann Intern Med 86:539-543, 1977. 9. Gercovich FG, Richman SP, Rodriguez V, et al: Successful control of systemic Aspergillus niger infections in two patients with acute leukemia. Cancer 36:22712276, 1975. 10. Hammond DE, Winkelmann RK: Cutaneous phycomycosis: Report of three cases with identification of Rhizopus. Arch DermatoI115:990-992, 1979. 11. Bottone EJ, et al: Rhizopus rhizopodiforlllis: Emerging etiological agent of mucormycosis. J Clin Microbiol 9:530-537, 1979. 12. Kammer RB, Utz JP: Aspergillus species endocarditis: The new face of a not so rare disease. Am J Med 56:506-521, 1974. 13. Young RC, Bennett JE: Invasive aspergillosis: Absence of detectable antibody response. Am Rev Respir Dis 104:710-716, 1971. 14. Strauss RG: Therapeutic neutrophil transfusions: Are controlled studies no longer appropriate? Am J Med 65:1001-1006,1978. 15. Cahill KM, EI Mofty AM, Kawaguchi TP: Primary cutaneous aspergillosis. Arch Dermatol 96:545-547, 1967.