Blastomycosis

Published on 18/03/2015 by admin

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Blastomycosis

Wanda Sonia Robles and Mahreen Ameen

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

(From Lebwohl, M.G., 2003. The Skin and Systemic Disease: A Color Atlas, second ed. Churchill Livingstone, with permission from Elsevier.)

Blastomycosis is a systemic, suppurative granulomatous infection caused by the thermally dimorphic fungus Blastomyces dermatitidis. It is acquired by inhalation of the conidia which are transformed into the yeast form in the lungs. It is an endemic mycosis that is most prevalent in the North American continent, particularly in the states that border Mississippi and Ohio rivers, and the Great Lakes region. Cases have also been reported in Latin America, Africa, the Middle East and India. Consequently, the term ‘North American blastomycosis’ is now obsolete. Point source epidemics have been reported in endemic regions relating to recreational activities in wooded areas along waterways.

Blastomycosis is associated with a spectrum of disease ranging from subclinical infection to an acute or chronic pneumonia. Most cases are restricted to the respiratory system, and many are asymptomatic. Extrapulmonary infection occurs in 25–40% of cases, and most commonly affects the skin. Cutaneous manifestations range from papules to verrucous and ulcerative lesions. The bones, genitourinary system and central nervous system (CNS) may also be involved. Dissemination occurs more frequently in the immunocompromised, such as organ transplant recipients and those with HIV infection. The immunocompromised are at high risk of CNS involvement and adult respiratory distress syndrome. Their prognosis is poor and therefore they require aggressive management. There are also rare reports of primary cutaneous blastomycosis acquired after accidental inoculation, and in some cases infection has been self-limiting.

Management strategy

In the immunocompetent individual, acute pulmonary blastomycosis may be mild and self-limiting. However, all diagnosed cases are treated in order to prevent extrapulmonary dissemination. Itraconazole is the drug of choice for the treatment of non-CNS infection that is not life-threatening. A loading dose of 200 mg three times daily for 3 days followed by 200 mg once or twice daily for 6 to 12 months is recommended. Serum itraconazole levels should be measured 2 weeks after commencement of treatment. Ketoconazole (400–800 mg daily) and fluconazole (400–800 mg daily) are second line agents as they have lower efficacy against blastomyces. In addition, long-term treatment with ketoconazole is associated with adverse effects. The new generation azoles, voriconazole and posaconazole, have demonstrated activity against B. dermatitidis in in vitro and animal studies. There have been reports of the successful use of voriconazole in the treatment of CNS blastomycosis. Amphotericin B is the treatment of choice for those who fail on treatment with azoles, severe infection, the immunosuppressed, in pregnancy, and with CNS involvement. The experience to date has been largely with the use of amphotericin B deoxycholate. Liposomal amphotericin B is recommended for CNS infection as it achieves higher CNS penetration and is better tolerated with prolonged therapy. After an initial response with amphotericin B, step-down therapy to an azole is common practice.

Specific investigations

Definitive diagnosis of blastomycosis is based on the identification of characteristic thick-walled, broad-based budding yeasts by direct examination of tissue or the isolation of Blastomyces in culture. Specimens for direct microscopy in 10% KOH can be skin scrapings, pus from skin lesions, sputum, and biopsy tissue from any lesion suspicious of infection. Successful culture of sputum, tissue biopsy specimens, cerebrospinal fluid or urine produces a white mould at 25°C on Sabouraud’s agar, and a brown wrinkled colony at 37°C on blood agar. Histopathology of infected tissues reveals a pyogranulomatous response without caseation, and pseudoepitheliomatous hyperplasia. A Blastomyces antigen assay is available to test urine, blood and other fluids, but it is not always specific. Antibody assays are non-specific and insensitive.

First-line therapies

image Itraconazole B
image Amphotericin B C

Second-line therapies

image Ketoconazole B
image Fluconazole B
image Voriconazole D
image Caspofungin E

Treatment of blastomycosis and histoplasmosis with ketoconazole. Results of a prospective randomized clinical trial.

National Institute of Allergy and Infectious Diseases Mycoses Study Group. Dismukes WE, Cloud G, Bowles C. Ann Intern Med 1985; 103: 861–72.

This was a multicenter, prospective, randomized trial. Of 65 patients with blastomycosis treated for 6 months or more, high-dose ketoconazole (800 mg daily) was significantly more effective than low-dose ketoconazole (400 mg daily) (100% vs 79% cure rate, p = 0.001). Adverse effects occurred in 60% of patients, and were more common in those treated at higher doses. Therefore the study group recommended that treatment should commence at the lower dose.

Despite its efficacy, ketoconazole is now rarely used because of its associated adverse effects as well as the availability of better tolerated azoles.

Treatment of blastomycosis with fluconazole: a pilot study.

The National Institute of Allergy and Infectious Disease Mycoses Study Group. Pappas PG, Bradsher RW, Chapman SW, Kauffman CA, Dine A, Cloud GA, Dismukes WE. Clin Infect Dis 1995; 20: 267–71.

A multicenter, randomized open-label pilot study compared two doses of fluconazole (200 and 400 mg daily) for the treatment of non-life-threatening blastomycosis. The analysis data included 23 patients who were treated for a minimum 6-month period. There was a successful outcome in 65% of patients (15/23) with no relapse at follow-up at 7 months. Of those who responded, 62% (8/15) had received 200 mg daily and 70% (7/10) received 400 mg daily.

The results of this study were disappointing. However, fluconazole has excellent CNS penetration and may therefore have a better role in the treatment of CNS infection, although there are no studies to support this.

Guidelines

Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America.

Chapman SW, Dismukes WE, Proia LA, Bradsher RW, Pappas PG, Threlkeld MG, Kauffman CA, Infectious Diseases Society of America. Clin Infect Dis 2008; 46: 1801–12.

This updated evidence-based guideline replaces the previous guidelines published in 2000. Treatment is guided by the extent of infection, CNS involvement, and the immune state of the host. Previously, mild cases of pulmonary blastomycosis were managed conservatively as they are sometimes self-limiting. However, with the advent and high efficacy of oral azoles, primarily itraconazole, most cases are now actively treated in order to prevent extrapulmonary spread and any risk of future reactivation.

image Itraconazole is the drug of choice for the treatment of mild to moderate pulmonary or disseminated infection. The recommended dose is an initial loading dose of 200 mg three times daily for 3 days, followed by 200 mg once or twice daily for 6 to 12 months. Serum levels should be measured after 2 weeks to ensure adequate drug exposure.

image Amphotericin B is the treatment of choice for those with severe pulmonary or disseminated infection, and in the immunocompromised. Either the lipid formulation (3–5 mg/kg/day) or amphotericin deoxycholate (0.7–1 mg/kg/day) is given for 1 to 2 weeks or until improvement is noted. Itraconazole is then recommended as step-down therapy (loading dose and then 200 mg twice daily for 6 to 12 months except in the immunocompromised who require at least 12 months of treatment or until immunosuppression has been reversed).

image Liposomal amphotericin B at a dose of 5 mg/kg/day is the recommended treatment for CNS infection. Treatment should be given for 4 to 6 weeks followed by an oral azole (fluconazole 800 mg daily/itraconazole 200 mg two to three times daily/voriconazole 200–400 mg twice daily), which should be given for at least 12 months and until there is resolution of CSF abnormalities.

image Amphotericin B is the drug of choice for patients who have failed to respond to azole treatment.

image Amphotericin B is the only drug approved for the treatment of blastomycosis in pregnant women.

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