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Blastomycosis and HIV
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Introduction
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Clinical Presentations
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transparent imageSubclinical or Asymptomatic Blastomycosis
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transparent imageAcute Blastomycosis
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transparent imageExtrapulmonary Blastomycosis
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transparent imageDisseminated Blastomycosis
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Diagnosis
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Treatment
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Summary
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References
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Related Resources
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Introduction
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Blastomycosis is a systemic fungal infection endemic in the south central, southeastern, and Midwestern United States, and the Canadian provinces bordering the Great Lakes.(1,2,3) In 1998, two cases of occupationally acquired blastomycosis occurred in Boulder, Colorado, suggesting that Blastomyces dermatitidis may be present elsewhere in the United States in low density.(4) Blastomyces infection has also been described in Africa.(5,6) Blastomycosis should be included in the differential diagnosis of acute pneumonia occurring in the setting of prolonged exposure of soil containing high nitrogen and organic content. After inhalation of the spores, which are taken up by bronchopulmonary macrophages, there is an approximate 30- to 45-day incubation period. In the Boulder outbreak, however, the incubation period was much shorter (between 13 and 18 days), suggesting that this may be related to the inoculum size.(4) The initial response in the infected site is suppurative and progresses to granuloma formation (also referred to as a pyogranulomatous response). B dermatitidis most commonly infects the lungs, followed by skin, bone, prostate, and the central nervous system (CNS).

Unlike many of the other systemic dimorphic mycoses, blastomycosis usually occurs in healthy hosts and is frequently associated with point-source exposure.(1,2) It occurs more commonly in men than women, which may reflect a larger number of male occupational exposures. However, in more recent reports, occupational exposure accounts for a smaller proportion of cases, presumably as recreational exposures increase. Immunosuppressed patients typically develop infection following exposure to the organism, but reactivation may also occur. Blastomycosis is uncommon among people infected with HIV and is not recognized as an AIDS-defining illness. In the setting of AIDS or other marked immune suppression, the disease is usually more severe with multiple-system involvement, including the CNS, and progresses rapidly to a fatal course.

In a review of 133 Canadian patients with blastomycosis, nearly half had underlying medical conditions, but not those typically associated with marked immunosuppression.(3) Of the 67 patients with an underlying medical condition, 10% had diabetes, 9% had hypertension, 8% had asthma, and 7% had heart disease. Only 2 of the 133 patients had HIV infection. One pregnant woman with blastomycosis did transmit the disease vertically to her fetus. The overall mortality was 6.3%, and mean duration of symptoms before diagnosis was significantly shorter (25.8 ± 10.5 days) among those who died compared with survivors (70.0 ± 83.2 days).

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Clinical Presentations
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(Also refer to references 1,2,3)

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Subclinical or Asymptomatic Blastomycosis
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Approximately 60% of people living in an endemic area with occupational exposure have laboratory evidence of antibodies to Blastomyces but no clinical disease.

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Acute Blastomycosis
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Blastomycosis typically presents as a flulike illness characterized by fever, malaise, fatigue, weight loss, and pulmonary involvement. It occurs most commonly in men 25-50 years of age with occupational or environmental exposure. Children rarely are infected except in epidemics. Patients may develop acute pneumonia indistinguishable from other more commonly seen bacterial pneumonias, characterized by fever, chills, purulent sputum, and sometimes hemoptysis. Patients may have skin manifestations including erythema nodosum. The chest radiograph most commonly reveals alveolar or masslike infiltrates. In the vast majority of cases, the pneumonia is self-limited to 1-2 weeks with complete resolution of symptoms and does not require therapy. Some individuals, including those with underlying lung disease, may go on to develop a chronic pneumonia with symptoms lasting 2-6 months. Patients typically present with weight loss, night sweats, fever, chest pain, and productive cough mimicking tuberculosis. An infrequent complication is adult respiratory distress syndrome. All immunocompromised patients and anyone with progressive pulmonary disease must be treated.

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Extrapulmonary Blastomycosis
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Cutaneous forms of blastomycosis are very common. They vary from nodules to verrucous lesions and may become ulcerative. They may mimic squamous cell cancer and keratoacanthoma. Like Cryptococcus neoformans, B dermatitidis has been isolated in the urine after prostatic massage and may cause prostatitis and epididymo-orchitis. Female genital tract infections have been reported secondary to transmission by male sexual partners with cutaneous forms of the disease. Osteomyelitis is diagnosed in up to 25% of extrapulmonary blastomycosis with the vertebrae, skull, ribs, and long bones being most commonly affected.(7) Noncaseating granulomas, suppuration, or necrosis in the bone may occur and may require surgical debridement in addition to antifungal treatment. Bone disease is more difficult to treat and has a higher relapse rate than other extra-pulmonary forms of blastomycosis. Diagnosis of extrapulmonary blastomycosis should always prompt chest radiography, as simultaneous pulmonary infection is almost always present.

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Disseminated Blastomycosis
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As with all the systemic mycoses, B dermatitidis may invade multiple body systems. Dissemination occurs in approximately one in three cases of symptomatic blastomycosis. On autopsy, B dermatitidis has been found in the brain, skeletal system, prostate, myocardium, pericardium, sinuses, pituitary, and adrenal glands. It may also invade the reticuloendothelial system. Epidural or cranial abscesses, as well as meningitis occur in 5-10% of individuals with disseminated blastomycosis and in up to 40% of patients with AIDS and chronic blastomycosis.(8) Recurrent CNS blastomycosis is rare.(9)

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Diagnosis
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Skin tests and serologic markers are useful epidemiologic tools but are of inadequate sensitivity and specificity to be diagnostic. Diagnosis depends on direct examination of tissue or the isolation of Blastomyces in culture. In the mold form, B dermatitidis has round to pyriform 4- to 5-µm conidia attached directly to the hyphae or on short stalks. Initially the colony appears yeastlike at room temperature and then develops hyphal projections eventually becoming a fluffy white mold. The spores are difficult to isolate from the soil or bird droppings but have been recovered from wet soil. The yeast form grows as a brown, wrinkled, folded colony at 37°C. Microscopically, the yeasts appear as round, budding, thick-walled cells with a daughter cell forming a single bud that has a broad base 5-15 µm in diameter and that may be found extracellularly or within in macrophages.

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Treatment
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Therapy for blastomycosis is determined by the severity of the clinical presentation and consideration of the toxicities of the antifungal agent. There are no randomized, blinded trials comparing antifungal agents, and there are limited data available on the treatment of blastomycosis in patients infected with HIV.

Typically pneumonia is self-limited to 1-2 weeks and does not require therapy. If the pneumonia persists or the patient develops respiratory insufficiency or pleural disease, treatment with itraconazole 200-400 mg/day orally is recommended.(2) Amphotericin B, up to 2.5 g, is recommended in life-threatening systemic disease, CNS disease, and in patients with immune suppression, including AIDS. Ketoconazole or fluconazole 400-800 mg/day for at least 6 months is effective alternative therapy for non-life-threatening disease in immunocompetent individuals with blastomycosis.(2)

In a retrospective study of 326 patients with blastomycosis, those receiving amphotericin B had a cure rate of 86.5% with a relapse rate of 3.9%, and those receiving ketoconazole had a cure rate of 81.7% with a relapse rate of 14%.(10) A prospective, open-label, randomized trial of 65 patients reported a cure rate of 100% among patients receiving ketoconazole 800 mg daily for 6 months or more compared with 79% among those receiving 400 mg daily for more than 6 months.(11) Relapse rates are in the order of 10-14% in patients taking ketoconazole.(10,11) In a multicenter, nonrandomized, open-label trial of 48 patients with blastomycosis receiving itraconazole 200-400 mg daily, the overall cure rate for patients treated for more than 2 months was 95%.(12) Itraconazole, 200-400 mg/day orally is better absorbed, has enhanced antimycotic activity, and is better tolerated than ketoconazole; hence, itraconazole is the recommended first-line azole in non-life-threatening, non-CNS disease in non-immunocompromised patients.(2,12).

Fluconazole has excellent CNS penetration and may be considered as an alternative to amphotericin B for the treatment of CNS blastomycosis.(2) In a multicenter, randomized, open-label trial of 2 doses of fluconazole among 39 evaluable subjects, the success rates were 89% for the 400-mg dose and 85% for the 800-mg dose; however, subjects with CNS disease were excluded.(13) Therefore, the efficacy of fluconazole use in patients with life-threatening or CNS disease is unknown. Because neither ketoconazole nor itraconazole penetrates the blood-brain barrier, these drugs are not recommended for CNS involvement.

Although data is limited, chronic suppressive therapy is generally recommended in patients with HIV who have been treated for blastomycosis. Fluconazole, itraconazole, and ketoconazole are all used as chronic suppressive therapy; however, given the higher relapse rate observed with ketoconazole, itraconazole is preferred. Patients with CNS disease or intolerance to itraconazole should be treated with fluconazole for chronic suppression.

Although animal data suggests that voriconazole may have activity against blastomycosis, there are no human clinical studies demonstrating efficacy.(14) In addition, data on the use of liposomal amphotericin B for blastomycosis are limited to case reports, and its use should be based upon clinical judgment and expertise.

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Summary
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In summary, blastomycosis is a relatively uncommon fungal infection among individuals infected with HIV and is not considered an AIDS-defining illness. There are limited data on the occurrence of blastomycosis in this population, and the optimal treatment is unknown. The Infectious Disease Society of America (IDSA) guidelines recommend that all patients with HIV and blastomycosis be treated with 1.5-2.5 g of amphotericin B, with consideration of switching to itraconazole after 1 g of amphotericin B in those individuals without CNS involvement.(2) Despite treatment with amphotericin B, mortality remains high (30-40%) during the first few weeks, and relapse is more common than in the HIV-uninfected population. It is recommended that patients with HIV remain on chronic suppressive therapy with itraconazole or, in patients intolerant of itraconazole or with CNS involvement, possibly fluconazole. Unlike histoplasmosis or cryptococcosis, there are no data on the discontinuation of chronic suppressive therapy following improved immunologic responses on antiretroviral therapy; therefore, the decision to discontinue therapy should be made on an individual basis and only with expert guidance.

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References

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1.   Bradsher RW. Histoplasmosis and blastomycosis. Clin Infect Dis. 1996 May;22 Suppl 2:S102-11.
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2.   Chapman SW, Bradsher RW Jr, Campbell GD Jr, Pappas PG, Kauffman CA. Practice guidelines for the management of patients with blastomycosis. Infectious Diseases Society of America. Clin Infect Dis. 2000 Apr;30(4):679-83.
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3.   Crampton TL, Light RB, Berg GM, Meyers MP, Schroeder GC, Hershfield ES, Embil JM. Epidemiology and clinical spectrum of blastomycosis diagnosed at Manitoba hospitals. Clin Infect Dis. 2002 May 15;34(10):1310-6.
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4.   Hannah EL, Bailey AM, Hajjeh R, Gershman K, Lindsley M, Hoffman RE. Public health response to 2 clinical cases of blastomycosis in colorado residents. Clin Infect Dis. 2001 Jun 1;32(11):E151-3.
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5.   Baily GG, Robertson VJ, Neill P, Garrido P, Levy LF. Blastomycosis in Africa: clinical features, diagnosis, and treatment. Rev Infect Dis. 1991 Sep-Oct;13(5):1005-8.
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6.   Carman WF, Frean JA, Crewe-Brown HH, Culligan GA, Young CN. Blastomycosis in Africa. A review of known cases diagnosed between 1951 and 1987. Mycopathologia. 1989 Jul;107(1):25-32.
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7.   Saccente M, Abernathy RS, Pappas PG, Shah HR, Bradsher RW. Vertebral blastomycosis with paravertebral abscess: report of eight cases and review of the literature. Clin Infect Dis. 1998 Feb;26(2):413-8.
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8.   Pappas PG, Pottage JC, Powderly WG, Fraser VJ, Stratton CW, McKenzie S, Tapper ML, Chmel H, Bonebrake FC, Blum R, et al. Blastomycosis in patients with the acquired immunodeficiency syndrome. Ann Intern Med. 1992 May 15;116(10):847-53.
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9.   Chowfin A, Tight R, Mitchell S. Recurrent blastomycosis of the central nervous system: case report and review. Clin Infect Dis. 2000 Jun;30(6):969-71.
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10.   Chapman SW, Lin AC, Hendricks KA, Nolan RL, Currier MM, Morris KR, Turner HR. Endemic blastomycosis in Mississippi: epidemiological and clinical studies. Semin Respir Infect. 1997 Sep;12(3):219-28.
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11.   Treatment of blastomycosis and histoplasmosis with ketoconazole. Results of a prospective randomized clinical trial. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Ann Intern Med. 1985 Dec;103(6 ( Pt 1)):861-72.
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12.   Dismukes WE, Bradsher RW Jr, Cloud GC, Kauffman CA, Chapman SW, George RB, Stevens DA, Girard WM, Saag MS, Bowles-Patton C. Itraconazole therapy for blastomycosis and histoplasmosis. NIAID Mycoses Study Group. Am J Med. 1992 Nov;93(5):489-97.
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13.   Pappas PG, Bradsher RW, Kauffman CA, Cloud GA, Thomas CJ, Campbell GD Jr, Chapman SW, Newman C, Dismukes WE. Treatment of blastomycosis with higher doses of fluconazole. The National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis. 1997 Aug;25(2):200-5.
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14.   Sugar AM, Liu XP. Efficacy of voriconazole in treatment of murine pulmonary blastomycosis. Antimicrob Agents Chemother. 2001 Feb;45(2):601-4.
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