Blastomyces dermatitidis

Background

Microbiology

• Broad-based dimorphic budding yeast
• Mold at 25-28ºC and yeast at 37ºC
• Branching hyphae 2-3 µm in diameter and right-angle conidiophores resembling lollipops
  • Conidia become airborne when disturbed

Epidemiology

Distribution of blastomycosis

• Present in the Mississippi, Ohio, and St. Lawrence River Valleys, the Great Lakes regions, and western Ontario
• May also be endemic to Africa and India, though it's unclear whether these are true cases or late reactivation
• Hosts include humans, dogs, cats, horses, brown bears, and exotic pets like the kinkajou and red ruffed lemur
• There have been point-source outbreaks associated with occupational and recreational activities, usually along streams or rivers enriched with decaying vegetation
• Possibly has cold-weather seasonality

Pathophysiology

• Inhalation of conidia into the lungs
• Macophages can phagocytize and kill the conidia, and can also slow conversion into yeast form
  • A thick cell wall helps to prevent phagocytosis
• Some conidia successfully convert to the pathogenic yeast form
• Major antigens include BAD1 on the cell wall surface and binds CR3 (CD11b/CD18) and CD14
• Humoral immunity has little effect; rather, immune response relies on cell-mediated immunity

Clinical Manifestations

• Can be acute pneumonia (followed by either recovery or chronic infection), or asymptomatic (followed by recovery or chronic infection)
  • About 50% overall resolve without treatment
  • About half of symptomatic patients have isolated lung involvement and half are disseminated
• When symptomatic, may have non-specific and constitutional symptoms
• Can be primary or reactivation
• Incubation period 3 weeks to 3 months

Respiratory Blastomycosis

• Respiratory symptoms are the most common focus
• Can mimic community-acquired pneumonia or tuberculosis, and may have hemoptysis
  • Less likely cavitary, but possible
• Can be acute or chronic presentation, or asymptomatic
  • Chronic typically lasts 2 to 6 months, with constitutional symptoms
• Even if there is non-pulmonary infection, there are often findings on chest x-ray
• Can also cause ARDS in about 10% of cases, which distinguishes it from histoplasmosis

Extra-Pulmonary Blastomycosis

• Next most common feature is dissemination to skin
  • Lesions usually either verrucous or ulcerative
  • May be misdiagnosed as pyoderma gangrenosum, keratoacanthoma, BCC, squamous cell carcinoma, or mycosis fungoides
  • Differential also contains NTM, other fungal infections, lupus
• Osteomyelitis, with or without evidence of lung involvement, is the third most common form
  • There are no specific clinical or radiographical features of blastomycosis
• Genitourinary involvement, especially prostatitis and epididymo-orchitis, are next most common
  • May be cultured in urine collected after prostate massage
• Meningitis and cerebritis/abscess are possible
  • Consider screening for it in immunocompromised people
  • Cerebellum more common
  • CSF culture is insenitive, though PCR is better
  • Found in 5-10% of cases of disseminated blasto, but associated with high mortality
  • Can have ocular involvement, as well
  • Differential would involve bacterial and fungal meningitis/abscess (including cryptococcosis), and Nocardia
• Can also affect larynx, lymphatics or lymph nodes, spleen, and any other organ, though fungemia is rarely found
• Infection can cause endocrinologic abnormalities including adrenal insufficiency, thyroid infection, hypercalcemia (granulomatous)
  • There are case reports of diabetes insipidus, and hyperprolactinemia
• Because it can occur in any organ, there are also case reports of breast lesions, tubo-ovarian abscess, otitis media, branchial cleft cyst infection

Pregnancy

• May be higher risk group, and can transmit it to the newborn

Immunocompromised Patients

• Not as commonly described as an opportunistic infection as the other endemic fungi
• Few cases with advanced HIV, but possible
• Sarcoidosis, transplantation, and steroid use are all risk factors
• Infliximab and etanercept are higher risk

Diagnosis

• Requires a microbiologic diagnosis

Microscopy

• Can be directly visualized on exudate, sputum, tissue, or really any sample
• Fairly easy to see with KOH or calcofluor, showing thick-walled, multinucleated, broad-based budding yeast
• Can be seen on histology of skin lesion biopsy with Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) stains

Culture

• Grows as mycelial (mold) form at 25-30ºC, usually after 1 to 3 weeks, starting as a white mold that slowly turns light brown
  • Grows 5-10 days before they develop conidia, so relatively low risk of infection early on
• Usually needs a DNA probe to confirm the species
• Biosafety level 3 pathogen, so needs to be sent to Public Health

Serology

• Antibody
  • Complement fixation is insensitive (Sn 9 to 43%); EIA is more sensitive but less specific
  • Immunodiffusion is likely better, though sensitivity still rather poor (Sn 28 to 64%, Sp 100%)
    • Immunodiffusion for A band is what is done in Ontario
  • BAD1 antigen antibodies is 85% sensitive but not yet used
• Urinary antigen has 93% sens and 80% spec
  • It cross-reacts with other dimorphic fungi, especially histoplasmosis
  • Can be trended to monitor response during therapy
• Can check 1,3-β-d-glucan, but not specific or particularly sensitive

Molecular Methods

• Not yet well-developed, but theoretically possible to do PCR

Management

• Chronic blastomycosis doesn't resolve without treatment, and mortality is as high as 60%
• Although many cases of acute pulmonary blastomycosis self-resolve, it is still recommended to treat, since triazoles are well-tolerated
• Severity is based on clinical judgement, as there are no validated criteria

Pulmonary Blastomycosis

• Mild-to-moderate: itraconazole 200 mg po tid for 3 days followed by bid for 6-12 months
• Moderate severe-to-severe: liposomal amphotericin B 3-5 mg/kg per day for 1-2 weeks or until improvement, followed by itraconazole 200 mg po tid for 3 days, followed by itraconazole 200 mg po bid, for a total of 6 to 12 months
  • May need up 6 to 8 weeks of induction with liposomal amphotericin B
• Monitor serum itraconazole after 2 weeks, targeting 1 to 10 μg/mL

Disseminated Extrapulmonary Blastomycosis

• Same as for pulmonary blastomycosis, but treated for at least 12 months if bone involvement

CNS Blastomycosis

• Amphotericin B 5 mg/kg per day for 4-6 weeks followed by an azole for at least 12 months and until resolution of CSF abnormalities
• Azoles include fluconazole 800 mg daily, itraconazole 200 mg bid or tid, or voriconazole 200-300 mg bid
  • Voriconazole may be better for CNS disease (better CNS penetration than itraconazole, and very good in vitro activity)

Immunocompromised Patients

• Same as for severe pulmonary blastomycosis, but duration is at least 12 months
• May be followed by lifelong suppressive itraconazole 200 mg po daily if immunosuppression cannot be decreased and they have relapsed despite appropriate therapy

Pregnant women

• Use liposomal amphotericin B 3-5 mg/kg per day
• Avoid azoles for risk of teratogenicity

Children

• Blastomycosis in newborns: amphotericin B deoxycholate 1 mg/kg per day
• Blastomycosis in children
  • Mild-to-moderate: itraconazole 10 mg/kg po per day (up to 400 mg) for 6 to 12 months
  • Severe blastomycosis: amphotericin B deoxycholate 0.7-1 mg/kg per day or liposomal amphotericin B at 3-5 mg/kg per day, followed by itraconazole 10 mg/kg po per day (up to 400 mg), for a total of 12 months
  • Monitor serum levels after 2 weeks

Itraconazole

• Tablet formulation has poorer oral bioavailability than liquid formulation
• Need to avoid PPIs and H2 blockers, as it needs an acidic stomach environment to get absorbed, especially for tablet formulation
• Not as good CNS penetration as other triazoles
• Needs therapeutic drug monitoring after 2 weeks with goal of maintaining serum levels between 1.0 and 10.0 μg/ml

Other Azoles

• Voriconazole is the second-line azole that is most frequently recommended
  • However, relatively high risk of liver toxicity
• If there are contraindications to voriconazole, then consider
  • Posaconazole, which is recommended by some experts1 based on some case reports23, though liver toxicity is likely around the same as voriconazole4, and itraconazole and fluconazole5
  • Isavuconazole, which has clinical data that include both case reports and a case series67, and far fewer hepatobiliary adverse events than voriconazole8

Further Reading

• Chapman SW et al. Clinical Practice Guidelines for the Management of Blastomycosis: 2008 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2008 46(12):1801-1812.