ANSWER TO THE PHOTO QUIZ

Philip A. Mackowiak, Section Editor

Verrucous Lesions and Ectropion in an Immunocompetent Individual

(See pages 13901 for the Photo Quiz.)

Diagnosis: Disseminated Cutaneous Blastomycosis The diagnosis of blastomycosis was established by analysis of purulent exudate and deep shave biopsy of the buttock lesion (Figures 1A and 1B, and 2A). Numerous, broad-based, budding yeast were observed following staining of the exudate with 10% KOH and staining of the tissue with periodic acid-Schiff (Figure 2B and 2C). The progression of his infection, degree of facial destruction, and ill-dened central nervous system symptoms prompted evaluation for additional sites of dissemination. Chest roetenography (posteroanterior and lateral) demonstrated a calcied nodule in the right lung but no evidence of active pneumonia. Maxillofacial computed tomography with intravenous contrast did not demonstrate involvement of the bone, extension to postseptal tissues, or invasion of the eye globe. Ophthalmologic examination did not reveal intraocular disease such as chorioretinitis, uveitis, or iritis. Lumbar puncture showed a normal cell count (<1 nucleated cell), protein (40 mg/ dL), and glucose (61 mg/dL). Cerebrospinal uid (CSF) culture and CSF Blastomyces antigen were negative. Urine Blastomyces antigen was positive at 2.87. Human immunodeciency virus serology was negative and the CD4+ cell count was normal (995 cells/L; 49%). Blastomyces dermatitidis, the etiologic agent of blastomycosis, belongs to a group of thermally dimorphic ascomycete fungi that also include Histoplasma capsulatum, Coccidioides

Figure 1. Purulent and hemorrhagic plaques and verrucous lesions involving the face (A) and left buttock (B ).

immitis and C. posadasii, Paracoccidioides brasiliensis, Sporothrix schenckii, and Penicillium marneffei [1]. Within North America, B. dermatitidis is geographically restricted to the midwest, south-central, and southeastern regions of the United States, and several Canadian provinces. Several areas are hyperendemic for blastomycosis including Washington Parish, LA (6.8 annual incidence/100 000 population), Eagle River, WI (101.3/100 000), and the Kenora Catchment area (117.2/100 000) [24]. In nature, B. dermatitidis thrives in forested, sandy soils of acidic pH that are near water and contain decaying organic matter [5]. Blastomycosis is almost exclusively acquired from the environment, and infection is associated with activities that disturb the soil such as construction or recreational activities along waterways. Following the disruption of soil when the temperature is 2225C, infectious conidia (asexual spores) and mycelial fragments that are aerosolized can be inhaled into the warm lungs of a human host at 37C and can convert to pathogenic yeast that cause pneumonia [1]. Symptomatic infection is estimated to develop in approximately 50% of persons exposed to B. dermatitidis, and 25%40% of those infected develop disseminated disease [6]. Unlike most human pathogenic fungi, B. dermatitidis infects persons with intact as well as impaired cell-mediated immune defenses. Populations at risk for more severe disease include patients who have undergone solid organ transplantation or have received TNF-alpha inhibitors [7, 8]. The most common site of extrapulmonary dissemination is the skin (40%80%) [6]. Cutaneous blastomycosis classically presents as verrucous lesions, purulent plaques, or subcutaneous nodules, and if left untreated, these will expand radially in an asymmetric fashion with subsequent ulceration and necrosis. Less commonly, blastomycosis can manifest as a draining sinus tract or ulcer from underlying osteomyelitis or soft tissue abscess. Ophthalmic dissemination is rare, and only a few cases of blastomycosis-induced ectropion have been described [9]. Histologically, cutaneous blastomycosis is characterized by pseudoepitheliomatous hyperplasia or extreme epidermal overgrowth that is accompanied by extensive purulent and granulomatous inammation (Figure 2A and 2B). Entities that

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Figure 2. A, Hematoxylin and eosin staining of a skin biopsy specimen demonstrating pseudoepitheliomatous hyperplasia (arrowhead), intraepithelial microabscess (arrow), and suppurative and granulomatous inammation; the scale bar is 50 m. B, A periodic acid-Schiff stain revealing an intraepithelial microabscess that contains yeast (arrow); the scale bar is 10 m. C, A periodic acid-Schiff stain showing B. dermatitidis yeast with broad-based budding and doubly refractile cell walls; the scale bar is 5 m.

histologically mimic blastomycosis with pseudoepitheliomatous hyperplasia include chromoblastomycosis, paracoccidioidomycosis, coccidioidomycosis, sporotrichosis, tuberculosis verrucosa cutis, atypical mycobacteria infections, halogenoderma, pyoderma gangrenosum, pemphigus vegetans, sarcoidosis, and squamous cell carcinoma [10]. The presence of broadbased budding yeast with a doubly refractile cell wall is strongly suggestive for B. dermatitidis and are most commonly found in areas of high neutrophil density (Figure 2B). Yeast are often present in the purulent exudates of cutaneous lesions, which can facilitate rapid diagnosis. Non-culture methods, such as serum or urine Blastomyces antigen (sensitivity 89.3%, specicity 79.3%), can aid in the diagnosis of

blastomycosis; however, there is cross-reactivity with other fungi, particularly H. capsulatum [11]. Once the diagnosis of blastomycosis is established, therapeutic options are limited to polyene (amphotericin B deoxycholate and liposomal formulations) and azole (itraconazole, voriconazole, posaconazole) antifungals [6]. Echinocandins have poor activity against B. dermatitidis yeast, which have low amounts of -(1,3)-glucan in the cell wall [1, 6]. Because of the severity of infection, the case patient underwent induction therapy with liposomal amphotericin B for 9 days, which was followed by itraconazole for a total of 9 months. Within days of starting antifungal therapy, the cutaneous lesions underwent necrotic evolution, which was followed by scarring (Figure 3). His

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Figure 3. Response of cutaneous blastomycosis to antifungal therapy. The lesions healed in a centrifugal pattern leaving atrophic scars. The ectropion did not improve with antifungal therapy and required reconstructive surgery.

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treatment course was complicated by a morbilliform rash from liposomal amphotericin B and 2 episodes of facial cellulitis that required oral antibiotics. Ten months after completing therapy, there has been no evidence of relapse, and the ectropion was corrected by reconstructive surgery.
Note
Potential conicts of interest. All authors: No reported conicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conicts of Interest. Conicts that the editors consider relevant to the content of the manuscript have been disclosed.

5.

6.

7. 8.

9. Jessica Saucier
1,2

and Gregory Gauthier

1,2

Departments of 1Medicine, and 2Dermatology, University of Wisconsin School of Medicine and Public Health, Madison

10. 11.

References
1. Gauthier GM, Klein BS. Insights into fungal morphogenesis and immune evasion. Microbe 2008; 3:41623. 2. Lowry PW, Kelso KY, McFarland LM. Blastomycosis in Washington Parish, Louisiana, 19761985. Am J Epidemiol 1989; 130:1519. 3. Baumgardner DJ, Buggy BP, Mattson BJ, Burdick JS, Ludwig D. Epidemiology of blastomycosis in a region of high endemicity in north central Wisconsin. Clin Infect Dis 1992; 15:62935. 4. Dwight PJ, Naus M, Sarseld P, Limerick B. An outbreak of human blastomycosis: the epidemiology of blastomycosis in the Kenora

catchment region of Ontario, Canada. Can Commun Dis Rep 2000; 26:8291. Klein BS, Vergeront JM, Weeks RJ, et al. Isolation of Blastomyces dermatitidis in soil associated with a large outbreak of blastomycosis in Wisconsin. N Engl J Med 1986; 314:52934. Chapman SW, Dismukes WE, Proia LA, et al. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis 2008; 46:180112. Gauthier GM, Safdar N, Klein BS, Andes DR. Blastomycosis in solid organ transplant recipients. Transpl Infect Dis 2007; 9:3107. Smith JA, Kauffman CA. Endemic fungal infections in patients receiving tumour necrosis factor-alpha inhibitor therapy. Drugs 2009; 69: 140315. Pariseau B, Lucarelli MJ, Appen RE. A concise history of ophthalmic blastomycosis. Ophthalmology 2007; 114:e2732. Zayour M, Lazova R. Pseudoepitheliomatous hyperplasia: a review. Am J Dermatopathol 2001; 33:11222. Durkin M, Lemonte A, Wheat B, et al. Antigen assay with the potential to aid in the diagnosis of blastomycosis. J Clin Microbiol 2004; 42:48735.

Correspondence: Gregory Gauthier, MD, MS, Assistant Professor (CHS), Dept of Medicine, Section of Infectious Diseases, University of Wisconsin School of Medicine and Public Health, University of WisconsinMadison, Microbial Sciences Building, 1550 Linden Dr, Rm 4301, Madison, WI 53706 (gmg@medicine.wisc.edu). Clinical Infectious Diseases 2012;55(10):14268 The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@ oup.com. DOI: 10.1093/cid/cis666

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