Approach Considerations
Patients with a subclinical disease (presence of serologic or other markers without symptoms) can be observed and do not require antifungal treatment. Mild to moderate disease should be treated in all patients. All immunocompromised patients and patients with progressive pulmonary disease or extrapulmonary disease require treatment.
Based on the 2008 clinical practice guidelines from the Infectious Diseases Society of America (IDSA), itraconazole has replaced amphotericin B for mild-to-moderate pulmonary blastomycosis in adult patients, and it is used for completion of therapy after initial amphotericin B treatment in more severe cases. [6, 53, 54, 55] Pregnant women should receive the lipid formulation of amphotericin B; azoles should be avoided because of possible teratogenicity. Voriconazole may have a role in the treatment of central nervous system (CNS) blastomycosis, but the lipid formulation of amphotericin B remains first line. [56, 57]
The need for inpatient and intensive care unit (ICU) care is based on the acuity and pace of the disease progression as well as the immune status of the patient. Admit severely and progressively ill patients to the ICU, including those with acute respiratory distress syndrome (ARDS).
Inpatient care often is needed for the workup and treatment of blastomycosis presenting as an undiagnosed pneumonia, for pleural effusion, and for extrapulmonary manifestations such as meningitis. In addition, initiation of amphotericin B treatment is preferably performed in an inpatient setting (ie, with infusion through an indwelling central venous line in an observation room with a trained staff). Prior to the initiation of amphotericin B or azole therapy, baseline renal and hepatic function tests should be obtained.
Antifungal Treatment
Amphotericin B and itraconazole continue to be the main drugs used in the treatment of blastomycosis. Clinical data are insufficient on using newer drugs (ie, posaconazole, caspofungin, micafungin) for treating affected patients.
Itraconazole is the drug of choice in mild-to-moderate pulmonary blastomycosis. It offers ease of oral administration, low toxicity, and high efficacy. The appropriate dose is 600 mg per day for 3 days, then 200-400 mg per day for 6-12 months. Gastric acidity is required for absorption of itraconazole. Ketoconazole is an effective alternative to itraconazole in mild to moderate disease in open-label trials. [6] However, it has a worse safety profile than itraconazole as well as higher relapse rates.
Patients with mild-to-moderate disseminated blastomycosis without central nervous system (CNS) involvement should be treated with itraconazole 200-400 mg per day for 6-12 months. The treatment period should be 12 months in patients with osteoarticular disease.
Other azoles (eg, ketoconazole, fluconazole) are less desirable alternatives. Itraconazole is absorbed better, has less toxicity, and has a stronger antifungal effect than ketoconazole. [39] A high incidence of serious adverse effects has been reported with ketoconazole, along with relapse rates of 10-14%. [6] If ketoconazole is used, close follow-up monitoring for 1-2 years is warranted.
Fluconazole has only a limited role in therapy for blastomycosis. Although this agent demonstrates excellent CNS penetration, only anecdotal evidence supports its use in the treatment of blastomycotic meningitis and cerebral abscesses. [6]
If the disease progresses while the patient is on any azole, therapy should be changed to amphotericin B. Azoles are contraindicated in pregnancy.
Patients with life-threatening disease, pulmonary (eg, acute respiratory distress syndrome [ARDS]) or extrapulmonary, should be treated with amphotericin B at a high dose of 0.7-1 mg/kg/day to a total dose of 1.5-2 g. Amphotericin B is also the recommended drug for patients with moderately severe to severe pulmonary disease or disseminated disease and, in most cases, the recommended dosage is the same as in life-threatening disease. [6] Liposomal amphotericin B can also be used for severe disease at a dose of 3-5 mg/kg/day.
Cure without relapse has been reported in 77-91% of patients who receive total amphotericin doses of greater than 1 g. Cure rates of 97% have been reported with total doses greater than 2 g. [6]
Amphotericin is associated with several toxic effects, most notably renal impairment. Other effects include thrombophlebitis at the injection site, chills, fever, nausea, hypokalemia, and anemia. Toxicity often necessitates interruption of therapy. The lipid formulation of amphotericin (daily intravenous at 3-5 mg) is less likely to cause renal impairment and may be a better alternative in patients with CNS infection.
Once patients receiving amphotericin demonstrate clinical improvement, switching to an oral azole is the standard of care. [57] Expert opinion is to treat with itraconazole 200 mg 3 times daily for 3 days, then twice daily for 6 months. It is recommended to check the serum itraconazole level 2 weeks into the treatment to ensure the level is appropriate.
Patients with CNS blastomycosis should be treated with amphotericin B, using the same dose schedule as in life-threatening disease. However, liposomal amphotericin B is preferred because of its better CNS penetration at a dose of 5 mg/kg/day for 4-6 weeks followed by an oral azole for at least 1 year. Voriconazole, a newer antifungal agent, has good cerebrospinal fluid penetration. [56, 58, 59]
Immunocompromised patients should be treated early and aggressively with amphotericin B as in life-threatening disease. After the amphotericin B course, chronic suppressive therapy with itraconazole may be needed in most cases. Most experts recommend treating blastomycosis in children with acquired immunodeficiency syndrome (AIDS) with 30 mg/kg of amphotericin B over 4-6 weeks, followed by itraconazole for at least 6 months in those with a clinical response to a primary course of amphotericin B.
Blastomycosis should be treated in pregnant women. Liposomal amphotericin B, 3-5 mg/kg/day, is recommended. Azoles are contraindicated because of possible teratogenicity and embryotoxicity.
Consultations
As blastomycosis is rarely encountered, it is advisable for primary care physicians to seek consultation with a physician more experienced with this disease. In cases with extrapulmonary involvement, consult a pulmonologist or infectious disease specialist for diagnosis and treatment recommendations. Consult a pulmonologist or an intensivist for patients who present with or develop acute respiratory distress syndrome (ARDS).
Surgical consultation may be needed for a tissue biopsy, but only rarely for adjunctive surgical treatment (eg, evacuation of a joint abscess, pleural empyema). Before sending any specimen to the laboratory, alert the microbiologist to the possibility of blastomycosis because of the risk of cutaneous infection from accidental autoinoculation. Consultation with a dermatologist may facilitate making the diagnosis by recognition of typical skin lesions, aspiration, or expression of microbiologically diagnostic pus, or skin biopsy.
In Arkansas, Louisiana, Michigan, Minnesota, and Wisconsin, blastomycosis is a reportable disease. Treating physicians need to contact the state department of health. [15]
Deterrence/Prevention
Ongoing studies of cell wall properties of B dermatitidis are promising for the development of a preventive vaccine. The use of BAD-1-deficient B dermatitidis has been investigated as a vaccine against multiple endemic mycosis in North America (Coccidioides posadasii, Histoplasma capsulatum, and B dermatitidis). [60] This vaccine was sufficient to protect against all the tested fungi in mice. The protection was mediated by T-helper 17 (Th17) cells, which recruited and activated neutrophils and macrophages to the alveolar space. [60] Such a vaccine could be targeted to patients at high risk of exposure and to immunocompromised patients. [61]
Canadian researchers have proposed using a targeting surveillance system to document the prevalence, distribution, seasonality, and disease manifestations of blastomycosis in red foxes as a sentinel for an increased risk of human blastomycosis in endemic areas. [62]
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Cutaneous blastomycosis.
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Lateral chest radiograph reveals the ill-defined lingular opacity and an absence of pleural effusions.
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Composite photomicrograph of a tissue specimen from a patient with blastomycosis infection shows an abundance of large budding cells that had been configured in chains. Courtesy of CDC/Dr. Lucille K. George.
