OVERVIEW: What every clinician needs to know

Pathogen name and classification

Blastomyces dermatitidis, a thermally dimorphic fungus, causes blastomycosis. This fungus exists as a mold at room temperature in the laboratory and in the environment; it is a yeast at 37°C in the laboratory and in human tissues.

What is the best treatment?

  • Patients who have severe pulmonary or disseminated infection with B. dermatitidis should be treated initially with an amphotericin B (AmB) formulation. This includes patients who have central nervous system (CNS) disease and those who are immunosuppressed.

    A lipid formulation of AmB, either liposomal amphotericin B or amphotericin B lipid complex, is preferred because of reduced toxicity. The dosage is 3-5mg/kg daily IV.

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    After a clinical response is seen, which is usually several weeks, therapy can be stepped down to oral itraconazole, 200mg tid for 3 days, then 200mg twice daily to finish a total of 12 months of therapy.

    For CNS blastomycosis, the dosage of lipid formulation AmB should be 5mg/kg daily IV and should be given for 4-6 weeks before changing to an oral azole agent. Options for oral azole therapy include voriconazole 200-400mg bid, itraconazole 200mg bid or tid, or fluconazole 800mg once daily. Treatment should continue for at least 12 months and until all cerebrospinal fluid (CSF) abnormalities have resolved.

  • Patients who have mild to moderate pulmonary or disseminated infection without CNS involvement should be treated with itraconazole.

    A loading dose of 200mg tid for 3 days is given followed by 200mg once or twice daily for 6-12 months, depending on the extent of infection.

    If osteoarticular disease is present, therapy should be continued for 12 months

  • Comments about azole therapy of blastomycosis

    Itraconazole capsules must be taken with food, and gastric acidity is important for absorption. Thus, patients should not be taking concomitant proton pump inhibitors, H2-blockers, or antacids when the capsule formulation is used.

    In contrast, itraconazole solution is taken on an empty stomach and absorption is not heavily dependent on gastric acidity. This formulation is preferred because it gives higher serum concentrations, but many people cannot tolerate the gastrointestinal side effects that commonly occur.

    All patients who are treated with itraconazole should have serum levels measured when steady state is reached, which is usually about 2 weeks after therapy is started. Serum concentrations >1ug/mL are recommended.

    Fluconazole is not as active as itraconazole against B. dermatitidis, and is a second-line agent for those patients unable to take itraconazole.

    Voriconazole is increasingly used to treat blastomycosis, including CNS infection, and appears to be effective. However, no clinical trials have been performed to assess the efficacy of voriconazole for blastomycosis.

    Posaconazole has been used in very few patients with blastomycosis, and its efficacy is not known.

    The appropriate azole to use for CNS blastomycosis is a difficult therapeutic decision. Fluconazole achieves the highest levels in CSF, but is less active than itraconazole, which does not achieve measurable CSF levels. However, there are case reports showing success with either agent. Voriconazole is increasingly reported as efficacious for CNS blastomycosis; it achieves CSF levels that are approximately 50% of serum levels and has good in vitro activity against the organism. The decision which agent to use will depend partly on the tolerability of the agent. There are no data to suggest that one agent is superior.

  • Resistance to antifungal agents has not been described with B. dermatitidis.

How do patients contract this infection, and how do I prevent spread to other patients?

  • Epidemiology:

    Blastomycosis is acquired by inhalation of the conidia of the mold phase of B. dermatitidis from the environment. The organism is found in soil and rotting wood and vegetation, especially in those areas near to waterways. Exposure can be through activities of daily living in persons who live in areas highly endemic for B. dermatitidis. In other instances, infection has occurred secondary to activities, such as cleaning an old cabin, tearing apart an abandoned beaver dam, cleaning brush from the land. Hunters and their dogs are both at risk of acquiring infection when they are hunting in the woods. Although most cases are sporadic, outbreaks have been described, usually related to communal activities that involve moving soil or clearing brush.

    Blastomycosis is geographically restricted (Figure 1). The endemic areas are the Mississippi and Ohio River basins, including the north central United States around the Great Lakes and extending into the Canadian Provinces of Manitoba and Ontario and the St. Lawrence Seaway. Sporadic cases have been reported from Colorado, Hawaii, South America, and Africa, presumably related to microfoci in which the organism exists. Certain areas in the upper midwest, around the Great Lakes have been identified as being highly endemic for blastomycosis; in these areas, both dogs and humans have high attack rates.

  • There are no Infection control issues as this disease is not spread from person to person.

  • There is no vaccine available

  • There is no prophylaxis recommended

Figure 1.

Distribution of the endemic mycoses in the United States.

What host factors protect against this infection?

  • Immunity to B. dermatitidis is comprised of both non-specific innate responses and specific cell-mediated immunity. After inhalation of the conidia of the mold form of the organism from the environment, neutrophils and alveolar macrophages phagocytize and kill the conidia. Organisms that have not been killed undergo a change to the yeast phase in the lungs. Spread occurs hematogenously to distant organs, especially the skin, osteoarticular structures, and genitourinary tract. Most healthy persons are able to restrict the growth of the yeast phase organisms to the lung. However, even healthy hosts not infrequently develop skin lesions that are established by hematogenous spread. immunosuppressed individuals are more likely to have widespread dissemination to many organs. Persons at greatest risk include those who have deficient cell-mediated immunity, including those who have HIV infection with low CD4 counts and transplant recipients. Less commonly, persons receiving tumor necrosis factor (TNF) inhibitors can develop disseminated blastomycosis.

  • B. dermatitidis infects healthy individuals who are exposed to the aerosolized conidia. It is not more likely to infect immunosuppressed hosts. However, the disease manifestations in those who are immunosuppressed are much more likely to be severe, and the mortality rate is higher.

  • The tissue response to B. dermatitidis is a mixture of pyogenic and granulomatous inflammation. Skin lesions typically show pseudoepitheliomatous hyperplasia and a dermal infiltrate comprised of both neutrophils and macrophages that form granulomas. The organisms can be found inside the granulomas or lying free. In immunosuppressed patients, the tissue response is not as vigorous and many broad-based budding yeasts can be seen with few inflammatory cells.

What are the clinical manifestations of infection with this organism?

  • Pulmonary blastomycosis

    Pulmonary infection is the most common manifestation of infection with B. dermatitidis, but in most persons, infection is asymptomatic. Of the patients who are symptomatic, blastomycosis is most often manifested as a mild self-limited pulmonary infection. Symptoms are fever, night sweats, cough, fatigue, and anorexia. Most patients are thought to have an atypical bacterial pneumonia and treated with antibiotics, which, of course, have no benefit. Only then does the subject of a fungal pneumonia arise, and the diagnosis of blastomycosis is pursued.

    Acute respiratory distress syndrome (ARDS) occurs in a small proportion of patients who have pulmonary blastomycosis. Severe pulmonary involvement can be seen in patients with defective cell-mediated immunity, such as patients with AIDS. However, just as frequently, the patient who develops this severe form of blastomycosis is a previously healthy person. The presumption is that perhaps they inhaled a large inoculum of Blastomyces condidia, which overwhelmed the host immune response.

    Chronic pulmonary blastomycosis resembles tuberculosis. Symptoms include cough, purulent sputum, hemoptysis, fever, malaise, and weight loss. Chest radiographs can show mass-like lesions, upper lobe cavitary infiltrates, or scattered nodules.

  • Disseminated blastomycosis

    The skin, osteoarticular structures, and the genitourinary system (in men) are the most frequently involved sites of dissemination. In some patients, the pneumonia has resolved before the skin lesions or other manifestations of dissemination appear. In others, dissemination occurs promptly and the patient has both pulmonary involvement and skin lesions or other organ involvement.

    Skin lesions classically are multiple, verrucous, crusting, and have central punctate draining microabscesses; other patients have nodules, ulcers, or pustules (Figure 2, Figure 3). It is important to remember that skin lesions do not occur from direct inoculation, but are related to hematogenous spread from the primary focus in the lung.

    Osteoarticular infection is less common than cutaneous lesions. In some patients, bony lesions underlie cutaneous lesions, but in others, osteoarticular involvement is not related to the cutaneous lesions.

    Genitourinary tract involvement occurs mostly in men, and the prostate is involved most often. Symptoms include dysuria, perineal discomfort, frequency, and urgency.

    CNS infection is rare. Meningitis, brain abscesses, and cord lesions can occur. CNS involvement is often one manifestation of disseminated infection in immunosuppressed patients, but in those who are immunocompetent, isolated chronic lymphocytic meningitis is more common. Mortality remains high for CNS blastomycosis.

Figure 2.

Verrucous lesion on the leg of an elderly man who had disseminated blastomycosis.

Figure 3.

Skin lesions of blastomycosis in a dark-skinned man.

What common complications are associated with infection with this pathogen?

  • Acute respiratory distress syndrome (ARDS), which carries a high mortality rate (>50%), can occur with pulmonary blastomycosis

  • Dissemination to the CNS is a severe complication as treatment is prolonged and difficult.

How should I identify the organism?

  • What tissue samples will provide the highest diagnostic yield?

    Lung biopsy and skin biopsy are most often helpful in diagnosing blastomycosis, but any organ that is involved can be sampled and sent for histopathological examination.

    Sputum and bronchoalveolar lavage (BAL) samples can reveal the organism when pneumonia is present.

  • A presumptive diagnosis of blastomycosis, while awaiting growth of the organism in culture, can be made from examination of tissue or body fluid samples because the organism is so distinctive.

    B. dermatitidis is a large (8-15um), thick-walled yeast that has a single broad-based bud attaching the daughter cell that is often almost as large as the parent cell.

    The most appropriate stains for fungus identification in tissues are the periodic Schiff (PAS) stain and the methenamine silver stain (Figure 4).

    In cytology preparations, the Papanicolau stain is very useful in showing the large, thick walled broad-based budding yeast (
    Figure 5)

    Sputum and BAL samples can be stained with calcofluor white which highlights the cell wall of many fungi

  • How should you culture the organism?

    B. dermatitidis grows in several weeks as a white mold at room temperature on Sabouraud’s dextrose agar

    The conidia are not distinctive and further testing is necessary for identification

    The simplest and fastest test to confirm the mold as B. dermatitidis is the Blastomyces DNA probe, which is very specific and can be performed as soon as growth of mold is detected on the agar plate

    The standard test, which is rarely used today except in reference laboratories, is to convert the mold phase to the yeast phase on blood agar at 37°C. This may take weeks and is not easily performed.

  • Antibody assays for B. dermatitidis have been studied for decades, but none have proved clinically useful because of low sensitivity and specificity

  • There is a commercially available antigen assay to aid in the diagnosis of blastomycosis. It is an enzyme immunoassay (EIA) that is performed on urine and serum and is very similar to the more widely used assay for histoplasmosis. In fact, there is almost 100% cross-reactivity between the assays for histoplasmosis and blastomycosis because they share cell wall polysaccharide structures. The antigen assay is most helpful for cases with disseminated infection and severe pulmonary infection with a large burden of B. dermatitidis. It is unlikely to be positive in cases with a few skin lesions or a localized pulmonary infiltrate.

  • PCR tests have been reported to be helpful when performed on tissue samples, but none of these are commercially available

Figure 4.

Lung biopsy stained with PAS stain showing thick-walled, broad-based budding yeast typical of B. dermatitidis.

Figure 5.

Papanicoulau stain showing B. dermatitidis in bronchoalveolar lavage fluid.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Saccente, M, Woods, GL. “Clinical and laboratory update on blastomycosis”. Clin Microbiol Rev. vol. 23. 2010. pp. 367-381. (Nice overview of the microbiology and epidemiology aspects of B. dermatitidis.)

Martynowicz, MA, Prakash, UB. “Pulmonary blastomycosis: an appraisal of diagnostic techniques”. Chest. vol. 121. 2002. pp. 768-773. (Although slightly dated because of increasing use of the relatively new antigen test for blastomycosis, this is nonetheless, an excellent comparison of the various diagnostic modalities available for blastomycosis.)

Durkin, M, Witt, J, LeMonte, A, Wheat, B, Connolly, P. “Antigen assay with the potential to aid in diagnosis of blastomycosis”. J Clin Microbiol. vol. 42. 2004. pp. 4873-4875. (First paper that shows results with the Blastomyces antigen assay.)

Gauthier, GM, Safdar, N, Klein, BS, Andes, DR. “Blastomycosis in solid organ transplant recipients”. Transpl Infect Dis. vol. 9. 2007. pp. 310-317. (Presents cases from the author's experience at a large transplant center in the endemic area.)

Kauffman, CA, Bowden, RA, Ljungman, P, Snydman, DR. “Endemic mycoses after hematopoietic stem cell or solid organ transplantation”. Transplant Infections. 2010. pp. 607-16. (Overview of blastomycosis and other endemic mycoses in transplant recipients).

Bariola, JR, Perry, P, Pappas, PG. “Blastomycosis of the central nervous system: a multicenter review of diagnosis and treatment in the modern era”. Clin Infect Dis. vol. 50. 2010. pp. 797-804. (Very nice review of recent cases of CNS blastomycosis, emphasizing clinical findings and treatment aspects, including the use of voriconazole for this complication of blastomycosis.)

Chapman, SW, Dismukes, WE, Proia, LA. “Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America”. Clin Infect Dis. vol. 46. 2008. pp. 1801-1812. (This is the latest edition of the IDSA guidelines for treatment of all forms of blastomycosis.)

Freifeld, A, Proia, LA, Andes, D. “Voriconazole use for endemic fungal infections”. Antimicrob Agrents Chemother.. vol. 53. 2009. pp. 1648-1651. (Early experience using voriconazole for endemic mycoses. This agent does not have approval for these infections but appears to be increasingly used and is effective.)