Primary cutaneous aspergillosis in six leukemic children

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Primary cutaneous aspergillosis in six leukemic children Marc E. Grossman, M.D., Ellen C. Fithian, M.D., Crystal Behrens, R.N., Janet Bissinger, R.N., Margaret Fracaro, R.N., and Harold C. Neu, M.D.

New York, NY We report a cluster of primary cutaneous aspergilloses in six children with hematologic malignancy. When first seen, they had hemorrhagic bullae caused by Aspergillusflavus (3), AspergiUusfim~igatus (2), and Aspergillus niger (1) at the sites of insertion of intravenous cannulas or where arm hoards had been taped to the extremities. Rapid diagnosis of cutaneous aspergillosis was made by direct examination of the blister roof with potassium hydroxide before it progressed to a necrotic ulcer. Intravenous amphotericin was instituted promptly in five of six patients, and none died of disseminated aspergillosis. Epidemiologic investigation tracked the source of Aspergillus to a storeroom with a false ceiling that had recently been repaired for a water leak. (J AM ACADDERMATOL12:313-318, 1985.)

Primary cutaneous aspergillosis has been reported in seven immunocompromised patients since 1970. t4 All had necrotic ulcers on the extremities due to Aspergillus flavus, usually at an intravenous site. All died within 9 months of the onset o f their infection, but in only four was death directly attributable to disseminated aspergillosis. We recently had six pediatric patients with leukemia who developed cutaneous A.wergillus infection. Our patients had hemorrhagic bullae due to A. flavus (3), AspergiUus fumigatus (2), and Aspergillus niger (1) at the sites of insertion of intravenous cannulas or where arm boards had been taped to the extremities. Rapid diagnosis was made by direct examination with potassium hyFrom the Departments of Dermatology and Medicine and Pharmacology, College of Physicians and Surgeons, Columbia University, and the Dermatology Consultation Service and the Division of Infectious Diseases and Epidemiology, Columbia-Presbyterian Medical Center. Accepted for publication Sept. 25, 1984. Reprint requests to: Dr. Marc E. Grossman, Department of Dermatology, Columbia-Presbyterian Medical Center, 630 West 168th St., V. C. 15, New York, NY 10032/212-694-4147.

droxide (KOH) of the blister roof before it progressed to a necrotic ulcer. Intravenous amphotericin was instituted promptly in five of the six patients, and none died of disseminated aspergillosis. CASE REPORTS

A summary of clinical features of patient presentation, treatment, and outcome is presented in Table I. DISCUSSION The six patients described were all children, 9 to 13 years of age, with newly diagnosed acute leukemia or acute leukemia in relapse. All had received induction chemotherapy within 2 to 3 weeks of the onset of their skin lesions and all were febrile and neutropenic (absolute neutrophil counts ranged from 0 to 60). Five of the six patients had just completed or were currently receiving broad-spectrum antibiotics at the time of Aspergillus infection. In all patients, cutaneous lesions developed at the sites of insertion of the intravenous eannulas or at points of contact where arm boards had been taped to the extremities. The 313

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Table I. Clinical data Skin lesions Case No. Age Sex Disease 1

5

F

Site

Morphology

Organism

AMML Right palm Hemorrhagic bulla A. niger Left palm

KOH of bullac ND

Treatment

iv ampho • wk

Purpuric pustules po rifampin • wk

A. fumigatus ( + )*

iv ampho • 1 day

2

4 F ALL

Right palm "Cellulitis" Right sole Purpuric nodules

3

7 F ALL

Left arm

Purpuric papule A. flavus with central vesicle expanded to hemorrhagic nodule with central eschar

ND

4

7 M ALL

Left palm

Purpuric papules A.flavus developed into hemorrhagic bullae

Roof(+) iv ampho

5

13 F ALL

6

9 M ALL

Left palm

Hemorrhagic bullae A. flavus

iv ampho • 3 days

• 7 days Topical anapho x 12 days Roof(+) iv and topical Fluid(+) ampho • 18 days

Right palm Hemorrhagic vesi- A. fumigatus Roof(+) Topical ampho cles/pustules Left arm Linear hemorrhagic A. fumigatus Fluid( + ) bullae, "contact dermatitis"

Outcome Complete healing of skin lesions (left palm 14 days, right palm 35 days); alive and well 19 mo later Death due to Pneumocystis pneumonia 14 days after skin lesions noted; autopsy Death (ALL resistant to chemotherapy) 19 days after skin lesions noted; no autopsy Complete healing of skin lesions by 1lth day Rx Complete healing of skin lesions by 18th day Rx 2 mo after skin lesions laparotomy for recurrent E. coli sepsis; spleen abscess cultured E. coli; A. fumigatus, liver; abscess KOH (+) but fungal culture overgrown by E. coli

ALL: Acute lymphocyticleukemia;AMML:acute myelomonocyticleukemia; ampho: amphotericin; iv: intravenous; KOH: microscopicexamination of potassiumhydroxidepreparation;ND: not done; po: per oral; Rx: therapy. *Hyphaedemonstratedafterovernightdigestionof skin biopsywith pepsin.

arm boards and tape had been in place from 4 to 14 days when the skin lesions were first observed. Lesions were either noted at the time the arm boards were removed, in which case they were

thought to represent an irritant dermatitis from the tape (Case 6), or were noted 1 to 2 days after removal of the intravenous lines. Nine separate cutaneous infections developed in six patients. Six

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lesions were located on the palm, two on the forearm, and one on the instep of the foot (Fig. 1). In several cases we were able to observe the natural progression of primary cutaneous aspergillosis. Lesions started as erythematous papules (Fig. 2) that progressed to hemorrhagic bullae (Figs. 3 and 4) and then ulcerated to form a purpuric plaque with a central necrotic eschar. The initial erythematous phase was often mistaken by housestaff for cellulitis or an irritant reaction to the arm boards or the tape (Fig. 5). The blistering phase of this infection is one that has not been reported previously. The importance of recognizing the hemorrhagic bullae is that a potassium hydroxide (KOH) examination of the blister roof can provide an immediate presumptive diagnosis. In three patients in whom this technic was employed, the KOH preparation was confirmed by finding broad septate hyphae in the hematoxylin and eosin preparation of the blister roof 48 hours later and by a positive fungal culture several days later. Therefore, although a hemorrhagic bulla on the extremity of an immunosuppressed, febrile, neutropenic patient is by no means diagnostic of aspergillosis, we feel that it should be suspected, particularly if the patient is receiving broad-spectrum antibiotics that would inhibit bacteria such as Pseudomonas aeruginosa, which can also produce bullae in these patients. The roof of the bullae should be examined with a KOH preparation and a fungal culture, in addition to a routine Gram's stain and bacteriologic culture. Diagnosis in the first three patients was made by histopathologic examination and culture of skin biopsy specimens obtained by d6bridement, excision, or punch biopsy. In these patients, septate, branching hyphae were seen in the dermis (Fig. 6). In one patient, they were noted within the lumen of a partially necrotic arteriole. Other findings were hemorrhage within the dermis and epidermal necrosis. A punch biopsy specimen from a foot lesion in Patient 2 demonstrated branching hyphae after overnight digestion of the tissue with pepsin (Fig. 7). The fourth patient had a biopsy specimen taken at the edge of a blister. The blister was not well delineated, and the level of separation could not be determined. However, septate hyphae were seen in both the epidermis and the dermis. A piece

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of the same biopsy specimen yielded a positive KOH preparation and culture for A. fumigatus. In the last two patients seen, the blister roof consisted of fragments of necrotic epidermis plus stratum comeum, while in the other specimen only stratum comeum was seen. Both specimens contained broad septate hyphae within the stratum corneum. The second specimen, however, required a periodic acid-Schiff (PAS) stain for visualization of the hyphae. KOH and culture of the same biopsy specimen were positive for AspergiUus. A. flavus was the causative organism in all previously reported cases of primary cutaneous aspergillosis in the immunocompromised host. In our series, three species of Aspergillus were involved. We present the first cases, in which A. fumigatus and A. niger were shown to cause a clinical picture identical to that seen with A. flavus. The clustering of five patients within the 7month period March 1980 through October 1980 led to an investigation for a source of Aspergillus organisms in Babies Hospital. This was undertaken by the hospital epidemiology team. Supplies used for intravenous therapy were stored in a room with a false ceiling that had recently been repaired for a water leak from the bathroom of the floor above. Cultures of materials in the storeroom and from the intravenous therapy cart resulted in isolation ofA. niger, A. flavus, and A. fumigatus from a variety of supplies, including adhesive tape, damaged ceiling tile from the storeroom, and arm board covers. The storeroom was closed, contents were discarded, and the area was cleaned. New supplies were placed in impermeable containers and new disposable arm boards were obtained. No new cutaneous cases occurred in the 3 years after these changes were made, although we continued to find Aspergillus infection in our transplant patients and in patients who had hematologic malignancy. It is interesting that none of the patients showed evidence of disseminated aspergillosis at the time skin lesions were noted. Chest radiographs were normal in four of the six patients and abnormal in two, but in one this was due to Pneumocystis carinii that was confirmed at autopsy examination. In the other patient a left lower lobe infiltrate and pleural effusion due to Escherichia coli resolved

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Fig. I. Purpuric nodules on the instep of the right foot of Patient 2 where an intravenons line had been removed 2 days earlier. Fig. 2. Purpuric papules and a bulla with a gray-black necrotic base on the left palm of Patient 4, Fig. 3. An erythematous plaque, 4 x 5 cm, with a 2 x 2-cm hemorrhagic bulla on the left palm of Patient 5.

with amikacin and moxalactam therapy. Fungal cultures o f blood and urine when obtained were negative for Aspergillus. All patients had negative serologic studies for Aspergillus, including the patient who had Aspergillus in his spleen at the site of the E. coli abscesses. Intravenous amphotericin therapy was recommended in all patients as soon as a positive KOH or culture of a skin lesion was obtained. In five of six patients, this resulted in institution of intravenous amphotericin within I to 12 days after the onset of infection. In patients treated promptly with amphotericin, none developed systemic aspergillosis. Unfortunately, two of the five patients died within 3 days of beginning amphotericin therapy and Patient 3, on whom postmortem exami-

nation was not done, succumbed to overwhelming leukemia resistant to chemotherapy. Patients 4 and 5 received 7- and 18-day courses of intravenous amphotericin and had complete healing of skin lesions within 1 to 3 weeks. These patients survived 11 and 15 months without futher evidence of cutaneous or disseminated aspergillosis. The fifth patient in the amphotericin-treated group (Patient 1) was alive and well at the time of writing (19 months after her cutaneous Aspergillus infection). She also had no spread or recurrence of infection. Patient 6 did not receive intravenous amphotericin against our advice--the hematology group felt that his leukemia was going into remission and that he would be able to combat the infection without amphotericin. Six weeks later

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Fig. 4. Hemorrhagic and necrotic vesiculopustules and bullae on the right palm of Patient 6. Fig. 5. A hemorrhagic bulla with linear vesicular borders on the forearm of Patient 6. The lesion was thought to be a contact irritant dermatitis until KOH preparation, biopsy, and culture demonstrated A. fumigatus. Fig. 6. There are numerous branching hyphae throughout the necrotic dermis of a skin biopsy specimen from Patient l. Fig. 7. Overnight digestion of a 4-ram punch biopsy specimen with pepsin and with Parker blue ink added demonstrated plump branching hyphae of Aspergillus. he underwent laparotomy to investigate filling defects found on the liver-spleen scan. Fungal cultures of a splenic abscess grew the same species of Aspergillus (A. fumigatus) that had been cultured from his skin. A KOH preparation of a liver abscess showed mycelia. Subsequently, he was treated with amphotericin and when he died 12

months later of Klebsiella pneumoniae sepsis resistant to antibiotics, no Aspergillus was present. Patient 1 received amphotericin in combination with rifampin, which showed much greater fungicidal activity against Aspergillus species than amphotericin alone in vitro? This combination is a potentially important consideration, as is gran-

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ulocyte transfusion in the therapy of neutropenic patients. Both treatments await in vivo confirmation of efficacy in clinical trials. CONCLUSION We saw six cases o f primary cutaneous aspergillosis in children with leukemia in relapse, following an environmental contamination. They were all neutropenic, had peripheral intravenous catheters, had received broad-spectrum antibiotics, and had prolonged hospitalization requiring intravenous therapy. Lesions typically occurred on the palm or the foot at the point of contact with tape or arm boards that secured intravenous infusion sets. Lesions began as erythematous papules or plaques and progressed through a hemorrhagic bullous stage to a purpuric ulcer with a central necrotic eshar. KOH mount of the blister roof demonstrated the presence of dimorphic hyphae that could be presumptively identified as Aspergillus. Skin biopsy specimens available at 24 to 48 hours and fungal cultures that often required 7 to 14 days confirmed the K O H findings. Skin biopsy specimens of ulcerated areas showed hyphae in the dermis, whereas biopsy specimens of blister roofs demonstrated characteristic hyphae in the stratum corneum. One biopsy specimen, taken from the margin of a blister, demonstrated hyphae both in the stratum corneum and the dermis. Although A. flavus was the most common species involved, A. fumigatus and A. niger were also identified. Prior to this report, no child had survived more than 3 months after the onset of cutaneous Aspergillus lesions, although Estes et aP reported a patient who was apparently cured of fungal disease but died abruptly 3 months later. In our own series no patient died of disseminated aspergillosis. Three patients who received intravenous amphotericin within 1 to 7 days of onset of skin lesions did not develop disseminated disease and survived 11 to 19 months after cutaneous infection. One of them was still alive at the time of writing. We believe that early diagnosis by KOH preparation of a blister roof and prompt institution of intravenous amphotericin are mandatory in this disease of previously universal mortality. Clusters of nosocomial Aspergillus infections

in immunocompromised patients during hospital consta'uction or renovation 6,7 have been reported in the medical literature. Outbreaks of aspergillosis in susceptible populations warrant careful environmental investigation. Hospital epidemiologists should be notified of hospital construction or repair so that preventive measures can be instituted, s In areas used by immunosuppressed patients, cultures of dust above ceiling tiles should be obtained before false ceilings are disturbed. If Aspergillus is detected, several measures are advised: (1) immunosuppressed patients should be relocated to unaffected hospital areas before work is started; (2) impermeable barriers should be erected so that spores from work areas will not enter ventilation systems or be carried to other hospital areas; (3) work areas should be cleaned thoroughly before the return of patients. A multidisciplinary approach, involving maintenance, engineering, and housekeeping personnel as well as doctors and nurses, is needed to make these preventive measures effective. A b o v e all, it is necessary to think of Aspergillus since it is easy to attribute cutaneous lesions in the neutropenic individual to bacteria or to the basic disease when only cultures are performed and KOH preparations are not done.

REFERENCES

1. Young RC, Bennet JE, Boge] CL, et al: Aspergillosis. Medicine 49:147-173, 1970: 2. Prystowsky SD, VogelsteinB, Ettingcr DS, et al: Invasive aspergillosis. N Engl J Med 295:655-658, 1976. 3. Carlile RJ, Millet RE, Cho CT, et al: Primary cutaneous aspergillosis in a leukemic child. Arch Dermatol 114:7880, 1978. 4. Estes SA, Hendricks AA, Merz WG, Prystowsky SD: Primary cutaneous aspergillosis. J AM ACADDERMATOL 3:397-400, 1980. 5. Hughes CE, Harris C, Moody JA, et al: In vitro activities of amphotericin B in combination with four antifungal agents and rifampin against Aspergillus sp. Antimicrob Agents Chemother 25:560-562, 1984. 6. Mahoney DH, Steuber CP, StarIing KA, et al: An outbreak of aspergillosis in children with acute leukern[a. J Pediatr 95:70-72, 1970. 7. Sarubbi FA, Kopf HB, Wilson MB, et al: Increased recovery of Aspergillusfiavus from specimens during hospital construction. Am Rev Respir Dis 125:33-38, 1982. 8. Arnow PM, Andersen RL, Mairows PO, et al: Pulmonary aspergillosis during hospital renovation. Am Rev Respir Dis 118:49-53, 1978.