IIllI
Primary cutaneous mucormycosis in a healthy young girl Report of a case caused by Mucor hiemalis Wehmer R u u d L. M. A. Prevoo, MD, Theo M. Starink, MD, and Peter de Haan, PhD A m s t e r d a m , The Netherlands We report an unusual case of primary cutaneous mucormycosis caused by Mucor hiemalis Wehmer that occurred in a healthy young girl after an insect bite. The patient had a slowly extending, indurated, erythematous, and sealing eruption on the right cheek. Histologic examination revealed granulomatous dermatitis and characteristic broad, nonseptate, palestaining hyphae. This is the first report of an infection in a human being caused by Mucor hiemalis Wehmer. The infection was cured with intravenous amphotericin B. (J AM ACAI~ DERMATOI. 1991 ;24:882-5.)
Mucormycosis is caused by saprophytic fungi of the order Mucorales (class Zygomycetes). Primary cutaneous mucormycosis is uncommon and may be fatal if adequate treatment is delayed. I-3 This form occurs most often in patients with diabetes who have superficial ulcers, or in immunocompromised patients.2, 4-9 W e report a case of primary cutaneous mucormycosis caused by Mucor hiemalis Wehmer in an otherwise healthy young girl--a type of occurrence, that to our knowledge, has not been reported before.
CASE REPORT Our patient was a 10-year-old white girl. Ten months before her visit to our clinic, she had noticed an insect bite on the lateral right eyebrow that had gradually extended. Skin biopsy specimens revealed mucormycosis. Both topical antimycotic treatment and oral treatment with griseofulvin and ketoconazole were unsuccessful. Physical examination showed an erythematous, scaly, infiltrated, sharply demarcated plaque on the right cheek that extended to the right ear and the right temporal region (Fig. 1). Microscopic examination of K O H prepa-
From the Department of Der,natology, Academic l-lospital Free University. Reprint requests: Theo M. Starlnk, MD, Dep~mment of Derlnatology, Academic I lospital Free University, De Boelelaan 1117, NL-1081 HV Amsterdam, The Netherlands. 16/4/22894
882
Fig. 1. Asymmetric, sharply demarcated, erythematous, scaly, and infiltrated area on the right cheek. rations of skin scrapings showed no hyphae. General examination revealed no abnormalities. A biopsy specimen revealed mild epidermal spongiosis and a superficial and deep nodular granuZomatous dermatitis (Fig, 2). The granulomas consisted of lymphocytes and histioeytes with a number of foreign-body giant cells and few plasma cells. In addition, several broad, right angle-branching, nonscptate, pale-staining hyphae were seen (Fig. 3). Cultures &skin scrapings and a biopsy specimen gave the results shown in Fig. 4 after only 2 days. Further study
Volume 24 Number 5, Part 2 May 1991
Primary cutaneous mucormycosis in a healthy young girl
883
Fig. 2. Superficial and deep nodular granulomatous dermatitis with foreign-body giant cells. (Hematoxylin-eosin stain; x50.)
Fig. 3. Highermagnificationofgiantcellwithcrosssectionsofcoarsepale-staininghyphae (Hematoxylin-eosin stain; X 1000.) in the Centraal Bureau voor Schimmelcultures (CBS, Netherlands National Fungus Laboratory, Baarn) identiffed this fungus as M. hiemalis Wehmer. Routine laboratory tests revealed no evidence of diabetes mellitus or any other abnormality. The ratio of T/ B lymphocytes, the ratio of CD4/CD8 T lymphocytes, IgA, IgM, and IgG levels and complement were all normal. Lymphocytes from the patient and from three healthy donors were used to perform transformation tests with isolated antigens l~ from cultures of M. hiemalis Wehmer and Trichophyton rubrum (concentration 5
/~g/ml). Pokeweed mitogen was used as a control. 11 The results revealed transformation of lyrnphoeytes from the patient and the donors with pokeweed mitogen. Transformation with T. rubrum antigen (stimulation index >2) was seen in two of three healthy donors, whereas the patient's lymphoeytes showed no transformation. With Mucor antigen, stimulation tests were negative for lyrnphocytes from the patient and from all three healthy donors. However, the stimulation indexes of the healthy donors were higher than those of the patient. Initially, the patient's parents refused to allow intrave-
884
Journal of the American Academy of Dermatology
R u u d et al.
cosis is the least common form, accounting for less than 10% of reported cases. The diagnosis can be made on the basis of histologic examination or by culture. The hyphae of these fungi are characteristically nonseptate and are much broader than those of other fungi with a filamentous tissue form. The hyphae have nonparallel sides and show nondichotomous branching. Most cases of primary cutaneous mucormycosis reported thus far are first seen as gangrenous cellulitis and occur in patients with carcinomas, leukemia, multiple myeloma, chronic kidney failure, second- or third-degree burns, severe diabetic acidosis, and general immunosuppression; the disease also occurs in patients whose surgical wounds have been dressed with contaminated elasticized tape.2, 4-9
Fig. 4. Culture plate after 48 hours' incubation at 25 ~ C shows very rapid growth of M. hiemalis Wehmer. nous treatment with amphotericin B. Therefore treatment with potassium iodide (saturated solution 15 ml daily) was started. This treatment resulted in moderate improvement in 7 months, after which the patient returned to our clinic and again cultures of skin scrapings grew M. hiernalis Wehmer. In vitro, growth inhibition tests showed sensitivity only to amphotericin B. Intravenous treatment with amphotericin B (1 mg/kg body weight per day) for 4 weeks resulted in a cure. Six months later there was no recurrence of the disease. DISCUSSION The agents of mucormycosis are classified in the order of Mucora|es (class Zygomycetes). The three most common pathogenic genera in the family Mucoraceae are Rhizopus, Absidia, and Mucor. t-3 These fungi are common in soil and have been found in decomposing plant and animal matter. Large numbers of small sporangiospores are released into the air. Inhalation of these airborne spores is the usual mode of infection in human beings. Less commonly, infection m a y occur after ingestion or direct inoculation through the skin. Because the spores are ubiquitous, the likelihood of infection depends primarily on the host's resistance. 2 M u c o r species known to be pathogenic in humans and animals are M. circinelloides, M. ramosissimus, M. amphibiorum, M. indicus, and 34. racemosus, l The five major forms of mucormycosis include rhinocerebral, pulmonary, gastrointestinal, and disseminated infection. Primary cutaneous mucormy-
In our patient, the clinical, histologic, mycologic, and immunologic findings were unusual. Clinically, the lesions were superficial and resembled tinea faciei; vascular involvement was notably absent. We assume that this was because the optimal growth temperature for M. hiemalis Wehmer is approximately 25~ unlike the more commonly seen pathogenic species of these fungi, it does not grow at temperatures above 32 ~ C. 12 M. hiemalis was described in 1907 by Wehmer] 2 and, to our knowledge, no reports about its pathogenicity in humans or higher vertebrates have appeared. Apparently sporangiospores were inoculated into the skin of our patient by an insect bite. Although no general immunologic defect or underlying disease could be found, her stimulation index in transformation tests with Mucor antigen was low compared with that of healthy donors. Moreover, she had no lymphocyte transformation to 7". rubrum antigen (a recall antigen). REFERENCES 1. Scholer H J, M/.iller E, Schipper MAA. Mucorales. In: Howard DH, ed. Fungi pathogenic for humans and animals. New York: Marcel Dekker, 1983:9-59. 2. Wong B, Armstrong D. Clinical manifestations and management of mucormycosis in the compromised patient. In: Warnock DW, Richardson MD, eds. Fungal infections in the compromised patient. Chichester, England: John Wiley & Sons, 1982:156-81. 3. Baker RD. The epidemiology of mucormycosis. In: Youscf AD, ed. The epidemiology of human mycotic disease. Springfield, Ill. Charles C Thomas, 1975:197-204. 4. Roberts HJ. Cutaneous mucormycosis. Arch Intern Med 1962;t 10:108-16. 5, Gartenberg G, Bottone E J, Keusch GT, et al. Hospital acquired mucormycosis of skin and subcutaneous tissue, N Engl J Med 1978;299:1115-7.
Volume 24 Number 5, Part 2 May 1991
Primary cutaneous mucormycosis in a healthy y o u n g girl
6. Bateman CPL, Umland ET, Beckel LE. Cutaneous zygomycosis in a patient with lymphoma. J AM ACADDERMATOL 1983;8:890-4. 7. Feuilhade M, Revuz J, Touraine R. Mucormycose cutanb.e primitive chez un transplant6 r6nal. Ann Dermatol Venereol 1982;109:765-6. 8. Bruck HM, Nash G, Foley FD, Pruitt BA. Opportunistic fungal infection of the burn wound with Phycomycetesand Aspergillus. Arch Surg 1971;102:476-82. 9. Umbert IJ, Su WPD. Cutaneous mucormycosis. J AM ACAD DERMATOL1989;21:1232-4.
885
10. Haan P de, Raaij van der-Helmer EMH, Boorsma DM. Diversity of antigenic extracts from the dermatophyte Trichophyton rubrum. Mykosen 1987;30:427-33. 1I. Pehamberger H. In-vitro methods for studying lymphocyte functions. In: Skerrow D, Skerrow C J, eds. Methods of'skin research. Chichester, England: John Wiley & Sons, 1985: 143-73. 12. Schipper MAA. A study on variability in Mucor hiemalis and related species. Mycology 1973;65:1-40.
Primary cutaneous mucormycosis in a healthy young girl Report of a case caused by Mucor hiemalis Wehmer R u u d L. M. A. Prevoo, MD, Theo M. Starink, MD, and Peter de Haan, PhD A m s t e r d a m , The Netherlands We report an unusual case of primary cutaneous mucormycosis caused by Mucor hiemalis Wehmer that occurred in a healthy young girl after an insect bite. The patient had a slowly extending, indurated, erythematous, and sealing eruption on the right cheek. Histologic examination revealed granulomatous dermatitis and characteristic broad, nonseptate, palestaining hyphae. This is the first report of an infection in a human being caused by Mucor hiemalis Wehmer. The infection was cured with intravenous amphotericin B. (J AM ACAI~ DERMATOI. 1991 ;24:882-5.)
Mucormycosis is caused by saprophytic fungi of the order Mucorales (class Zygomycetes). Primary cutaneous mucormycosis is uncommon and may be fatal if adequate treatment is delayed. I-3 This form occurs most often in patients with diabetes who have superficial ulcers, or in immunocompromised patients.2, 4-9 W e report a case of primary cutaneous mucormycosis caused by Mucor hiemalis Wehmer in an otherwise healthy young girl--a type of occurrence, that to our knowledge, has not been reported before.
CASE REPORT Our patient was a 10-year-old white girl. Ten months before her visit to our clinic, she had noticed an insect bite on the lateral right eyebrow that had gradually extended. Skin biopsy specimens revealed mucormycosis. Both topical antimycotic treatment and oral treatment with griseofulvin and ketoconazole were unsuccessful. Physical examination showed an erythematous, scaly, infiltrated, sharply demarcated plaque on the right cheek that extended to the right ear and the right temporal region (Fig. 1). Microscopic examination of K O H prepa-
From the Department of Der,natology, Academic l-lospital Free University. Reprint requests: Theo M. Starlnk, MD, Dep~mment of Derlnatology, Academic I lospital Free University, De Boelelaan 1117, NL-1081 HV Amsterdam, The Netherlands. 16/4/22894
882
Fig. 1. Asymmetric, sharply demarcated, erythematous, scaly, and infiltrated area on the right cheek. rations of skin scrapings showed no hyphae. General examination revealed no abnormalities. A biopsy specimen revealed mild epidermal spongiosis and a superficial and deep nodular granuZomatous dermatitis (Fig, 2). The granulomas consisted of lymphocytes and histioeytes with a number of foreign-body giant cells and few plasma cells. In addition, several broad, right angle-branching, nonscptate, pale-staining hyphae were seen (Fig. 3). Cultures &skin scrapings and a biopsy specimen gave the results shown in Fig. 4 after only 2 days. Further study
Volume 24 Number 5, Part 2 May 1991
Primary cutaneous mucormycosis in a healthy young girl
883
Fig. 2. Superficial and deep nodular granulomatous dermatitis with foreign-body giant cells. (Hematoxylin-eosin stain; x50.)
Fig. 3. Highermagnificationofgiantcellwithcrosssectionsofcoarsepale-staininghyphae (Hematoxylin-eosin stain; X 1000.) in the Centraal Bureau voor Schimmelcultures (CBS, Netherlands National Fungus Laboratory, Baarn) identiffed this fungus as M. hiemalis Wehmer. Routine laboratory tests revealed no evidence of diabetes mellitus or any other abnormality. The ratio of T/ B lymphocytes, the ratio of CD4/CD8 T lymphocytes, IgA, IgM, and IgG levels and complement were all normal. Lymphocytes from the patient and from three healthy donors were used to perform transformation tests with isolated antigens l~ from cultures of M. hiemalis Wehmer and Trichophyton rubrum (concentration 5
/~g/ml). Pokeweed mitogen was used as a control. 11 The results revealed transformation of lyrnphoeytes from the patient and the donors with pokeweed mitogen. Transformation with T. rubrum antigen (stimulation index >2) was seen in two of three healthy donors, whereas the patient's lymphoeytes showed no transformation. With Mucor antigen, stimulation tests were negative for lyrnphocytes from the patient and from all three healthy donors. However, the stimulation indexes of the healthy donors were higher than those of the patient. Initially, the patient's parents refused to allow intrave-
884
Journal of the American Academy of Dermatology
R u u d et al.
cosis is the least common form, accounting for less than 10% of reported cases. The diagnosis can be made on the basis of histologic examination or by culture. The hyphae of these fungi are characteristically nonseptate and are much broader than those of other fungi with a filamentous tissue form. The hyphae have nonparallel sides and show nondichotomous branching. Most cases of primary cutaneous mucormycosis reported thus far are first seen as gangrenous cellulitis and occur in patients with carcinomas, leukemia, multiple myeloma, chronic kidney failure, second- or third-degree burns, severe diabetic acidosis, and general immunosuppression; the disease also occurs in patients whose surgical wounds have been dressed with contaminated elasticized tape.2, 4-9
Fig. 4. Culture plate after 48 hours' incubation at 25 ~ C shows very rapid growth of M. hiemalis Wehmer. nous treatment with amphotericin B. Therefore treatment with potassium iodide (saturated solution 15 ml daily) was started. This treatment resulted in moderate improvement in 7 months, after which the patient returned to our clinic and again cultures of skin scrapings grew M. hiernalis Wehmer. In vitro, growth inhibition tests showed sensitivity only to amphotericin B. Intravenous treatment with amphotericin B (1 mg/kg body weight per day) for 4 weeks resulted in a cure. Six months later there was no recurrence of the disease. DISCUSSION The agents of mucormycosis are classified in the order of Mucora|es (class Zygomycetes). The three most common pathogenic genera in the family Mucoraceae are Rhizopus, Absidia, and Mucor. t-3 These fungi are common in soil and have been found in decomposing plant and animal matter. Large numbers of small sporangiospores are released into the air. Inhalation of these airborne spores is the usual mode of infection in human beings. Less commonly, infection m a y occur after ingestion or direct inoculation through the skin. Because the spores are ubiquitous, the likelihood of infection depends primarily on the host's resistance. 2 M u c o r species known to be pathogenic in humans and animals are M. circinelloides, M. ramosissimus, M. amphibiorum, M. indicus, and 34. racemosus, l The five major forms of mucormycosis include rhinocerebral, pulmonary, gastrointestinal, and disseminated infection. Primary cutaneous mucormy-
In our patient, the clinical, histologic, mycologic, and immunologic findings were unusual. Clinically, the lesions were superficial and resembled tinea faciei; vascular involvement was notably absent. We assume that this was because the optimal growth temperature for M. hiemalis Wehmer is approximately 25~ unlike the more commonly seen pathogenic species of these fungi, it does not grow at temperatures above 32 ~ C. 12 M. hiemalis was described in 1907 by Wehmer] 2 and, to our knowledge, no reports about its pathogenicity in humans or higher vertebrates have appeared. Apparently sporangiospores were inoculated into the skin of our patient by an insect bite. Although no general immunologic defect or underlying disease could be found, her stimulation index in transformation tests with Mucor antigen was low compared with that of healthy donors. Moreover, she had no lymphocyte transformation to 7". rubrum antigen (a recall antigen). REFERENCES 1. Scholer H J, M/.iller E, Schipper MAA. Mucorales. In: Howard DH, ed. Fungi pathogenic for humans and animals. New York: Marcel Dekker, 1983:9-59. 2. Wong B, Armstrong D. Clinical manifestations and management of mucormycosis in the compromised patient. In: Warnock DW, Richardson MD, eds. Fungal infections in the compromised patient. Chichester, England: John Wiley & Sons, 1982:156-81. 3. Baker RD. The epidemiology of mucormycosis. In: Youscf AD, ed. The epidemiology of human mycotic disease. Springfield, Ill. Charles C Thomas, 1975:197-204. 4. Roberts HJ. Cutaneous mucormycosis. Arch Intern Med 1962;t 10:108-16. 5, Gartenberg G, Bottone E J, Keusch GT, et al. Hospital acquired mucormycosis of skin and subcutaneous tissue, N Engl J Med 1978;299:1115-7.
Volume 24 Number 5, Part 2 May 1991
Primary cutaneous mucormycosis in a healthy y o u n g girl
6. Bateman CPL, Umland ET, Beckel LE. Cutaneous zygomycosis in a patient with lymphoma. J AM ACADDERMATOL 1983;8:890-4. 7. Feuilhade M, Revuz J, Touraine R. Mucormycose cutanb.e primitive chez un transplant6 r6nal. Ann Dermatol Venereol 1982;109:765-6. 8. Bruck HM, Nash G, Foley FD, Pruitt BA. Opportunistic fungal infection of the burn wound with Phycomycetesand Aspergillus. Arch Surg 1971;102:476-82. 9. Umbert IJ, Su WPD. Cutaneous mucormycosis. J AM ACAD DERMATOL1989;21:1232-4.
885
10. Haan P de, Raaij van der-Helmer EMH, Boorsma DM. Diversity of antigenic extracts from the dermatophyte Trichophyton rubrum. Mykosen 1987;30:427-33. 1I. Pehamberger H. In-vitro methods for studying lymphocyte functions. In: Skerrow D, Skerrow C J, eds. Methods of'skin research. Chichester, England: John Wiley & Sons, 1985: 143-73. 12. Schipper MAA. A study on variability in Mucor hiemalis and related species. Mycology 1973;65:1-40.
