Treating Rare Fungal Infections: Cutaneous Blastomycosis

Blastomycosis is a rare fungal infection first identified by Thomas Casper Gilchrist in 1894 that commonly involves the lungs and skin.1 Primary infection of the lungs occurs after inhalation of Blastomyces dermatitidis (B. dermatitidis) spores. Pulmonary blastomycosis can disseminate to involve the skin and other sites, including bone, genitourinary tract and the central nervous system.2 Cutaneous blastomycosis presents with verrucous plaques, ulcers or pustules. Rarely, an isolated cutaneous infection can occur from direct innoculation. Diagnosis relies on histopathologic identification of B. dermatitidis yeast forms and fungal culture confirmation. Blastomycosis can be self-limiting in immunocompetent patients but is commonly treated with antifungal therapy.1

Epidemiology and Pathogenesis

Blastomycosis traditionally occurs in the Ohio and Mississippi River valleys, northern Midwestern states and the Great Lakes region.3 Cases of blastomycosis were also reported in Indianapolis between 2005 and 2008.4 Endemic infections typically occur in middle-aged individuals who participate in outdoor activities, often in proximity to freshwater.5 This infection is rare in children and adolescents, but the Children’s Hospital of Wisconsin identified pediatric cases with cutaneous involvement between 1999 and 2009.6

Blastomycosis is predominantly a pulmonary infection that can disseminate to involve the skin. B. dermatitidis is a thermally dimorphic fungus with a mycelial form at 30° C and a yeast form at 37° C.7 Primary pulmonary infection occurs via inhalation of B. dermatitidis conidia released from mycelia after the disruption of wet, contaminated soil.5 Alveolar macrophages inhibit the transformation of conidia to yeast form, thus impeding formation of its thick capsule.5 When pulmonary defenses fail, lymphohematogenous dissemination triggers a suppurative response followed by non-caseating granuloma formation.5,6 Cases of primary cutaneous blastomycosis are rare and occur after direct innoculation from an outdoor injury or an animal bite in endemic areas.5

Clinical Presentation

Blastomycosis can present as a pulmonary infection, disseminated infection or primary cutaneous infection.7 Pulmonary blastomycosis is the most common manifestation and can range from mild flu-like symptoms to fulminant pneumonia and acute respiratory distress syndrome.3 Pulmonary infection may disseminate to involve the skin and other sites including bone, genitourinary tract and the central nervous system.2

More than half (60%) of patients with blastomycosis have cutaneous involvement, the majority of which results from dissemination.3 Lesions are painless and occur on the head and neck, extremities and occasionally on the back and buttocks.1,3 Disseminated cutaneous blastomycosis typically presents with ulcers or verrucous plaques, though it can present as a purely pustular form.7 Disseminated disease most commonly manifests as either pustules that progress to ulcers with raised borders (Figure 1) or as verrucous plaques with a cribriform center and peripheral pustules (Figure 2).3,7 Subcutaneous nodules may occur, which spontaneously drain and form chronic, sometimes non-healing ulcerations.3,8 Isolated pustular blastomycosis involving the face, abdomen and trunk is noted in both immunocompromised and healthy individuals.7 Primary cutaneous blastomycosis from direct inoculation results in chancre formation with associated lymphangitis and lymphadenitis (Figure 3).1,8-9 The variable cutaneous presentations of blastomycosis provide for a broad differential diagnosis. See Table 1.

FIGURES 1-3 and TABLE 1

Editor's Note: Please click on the image to see the full-size version.

Figure 1 Figure 1 (left): Blastomycosis ulceration.Figure 2

 Figure 2 (right): Blastomycosis verrucous plaques

 

 

Figure 3

Table 1Figure 3 (left): Primary cutaneous blastomycosis.

Table 1 (right): Cutaneous blastomycosis differential diagnosis.

 

 

Histopathology

Figure 4Figure 5B. dermatitidis remains primarily in yeast form when inside the human host. Histopathological findings from cutaneous drainage, lesion biopsy or bronchial washings treated with potassium hydroxide (KOH) show 8-15 μm diameter multinucleate yeast forms with broad-based bud attachment (4-5 μm) and thick cell walls.1,5,10 Biopsies stained with hematoxylin and eosin demonstrate yeast forms, associated granulomas and surrounding inflammatory response (Figure 4, left).10 Early infection demonstrates polymorphonuclear leukocyte predominance with copious visible yeast forms (Figure 5, right); later, as granulomas form, B. dermatitidis organisms are not as prominent in biopsy specimens.5 Cutaneous scrapings and biopsies are characterized by pseudoepitheliomatous hyperplasia and micro abscesses resembling squamous cell carcinoma.5

Diagnostic Tests

The most efficient way to detect B. dermatitidis is with a KOH prep of lesion drainage, deep tissue biopsy or scrapings showing broad-based bud attachment bases.1,11 Addition of calcofluor white to the KOH prep causes the fungal chitin to fluoresce under shortwave ultraviolet light.5 Visualization of the yeast with KOH should be followed by culture, which remains the gold standard in diagnosis of B. dermatitidis.11 Culture confirms B. dermatitidis in KOH preps with atypical histologic findings such as filamentous yeast forms or small yeast cells (2-4 μm in diameter). Such anomalous findings are easily misperceived as Histoplasma capsulatum, which has an epidemiologic territory overlapping that of B. dermatitidis.5 Histologic diagnosis correlates with blood cultures, which grow on Sabouraud’s agar or potato agar within 2 to 4 weeks.1,5,10 Urinary antigen identification has 93% sensitivity and 79% specificity in pulmonary and extrapulmonary blastomycosis.12 Antigen tests often cross-react with H. capsulatum,5 and thus culture is the only definitive diagnostic tool to confirm blastomycosis infection.

Treatment

Table 2Acute blastomycosis can resolve spontaneously without treatment; however, antifungal treatment can hasten recovery. The treatment of choice for cutaneous blastomycosis is itraconazole, although other azoles can be used as well (Table 2). Itraconazole 200 mg orally once or twice daily is effective treatment in immunocompetent patients, as is fluconazole.5 Adverse effects of azoles warrant monitoring throughout the course of treatment. Aminotransferase levels should be monitored for liver toxicity and patients should be screened for dysfunctional steroidogenesis if ketoconazole is used.5 Symptoms of adrenal insufficiency, menstrual abnormalities and impotence suggest ketoconazole interference with steroidogenesis; in contrast, fluconazole and itraconazole have little effect on steroidogenesis. Itraconazole, though the drug of choice for non-severe blastomycosis infection, may cause hypertension, edema and hypokalemia and is contraindicated in patients with congestive heart failure.5 Amphotericin B is the preferred drug for severe cases of pulmonary blastomycosis and for cases with central nervous system involvement.5,11 Treatment with IV amphotericin B for 1 to 2 weeks is followed by 6 to 12 months of oral azole therapy.5 The therapeutic agent should be chosen based on clinical presentation and extent of organ system involvement.

Key Points

• Blastomycosis is predominantly a pulmonary infection that can disseminate to involve the skin. Rarely, primary cutaneous blastomycosis occurs after direct inoculation.

• The geographic distribution of blastomycosis includes the Mississippi and Ohio River valleys and the Great Lakes region.

• Clinical presentation of disseminated cutaneous blastomycosis can manifest as verrucous plaques, ulcers with raised borders or pustules.

• Primary cutaneous blastomycosis from direct innoculation manifests as a chancre with associated lymphangitis and lymphadenitis.

• B. dermatitidis is detected with a KOH prep of lesion drainage, deep tissue biopsy or scrapings.

• Histopathological findings show 8-15 μm diameter, multi-nucleate yeast forms with broad-based bud attachment (4-5 μm) and thick cell walls.

• Treatment of choice is itraconazole 200-400 mg daily for 6-12 months, and severe pulmonary or disseminated blastomycosis is treated with IV amphotericin B followed by an oral azole.

Mrs. Barnes is with the Center for Dermatology Research and the department of dermatology at Wake Forest University School of Medicine in Winston-Salem, NC.

Mr. Al-Dabagh is with the Center for Dermatology Research and the department of dermatology at Wake Forest University School of Medicine in Winston-Salem, NC. He is also a 4th year medical student at Case Western Reserve University School of Medicine in Cleveland, OH.

Dr. Feldman is with the Center for Dermatology Research and the Departments of Dermatology, Pathology and Public Health Sciences at Wake Forest University School of Medicine.

Disclosures: The Center for Dermatology Research is supported by an unrestricted educational grant from Galderma Laboratories, L.P.

Dr. Feldman is a consultant and speaker for Galderma, Stiefel/GlaxoSmithKline, Abbott Labs, Warner Chilcott, Janssen, Amgen, Photomedex, Genentech, BiogenIdec, and Bristol Myers Squibb. Dr. Feldman has received grants from Galderma, Astellas, Abbott Labs, Warner Chilcott, Janssen, Amgen, Photomedex, Genentech, BiogenIdec, Coria/Valeant, Pharmaderm, Ortho Pharmaceuticals, Aventis Pharmaceuticals, Roche Dermatology, 3M, Bristol Myers Squibb, Stiefel/GlaxoSmithKline, Novartis, Medicis, Leo, HanAll Pharmaceuticals, Celgene, Basilea, and Anacor and has received stock options from Photomedex. He is owner of www.DrScore.com and a founder of Causa Research.

Mrs. Barnes and Mr. Al-Dabagh have no conflicts to disclose.

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