CONTENTS

• Basics
• Epidemiology
• Clinical manifestations
  • Acute pulmonary blastomycosis
    • Radiology
  • Chronic pulmonary blastomycosis
    • Radiology
  • Disseminated blastomycosis
• Laboratory evaluation
• Treatment
• Podcast
• Questions & discussion
• Pitfalls

abbreviations used in the pulmonary section: 2

• ABPA: Allergic bronchopulmonary aspergillosis 📖
• AE-ILD: Acute exacerbation of ILD 📖
• AEP: Acute eosinophilic pneumonia 📖
• AFB: Acid Fast Bacilli
• AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
• ANA: Antinuclear antibody 📖
• ANCA: Antineutrophil cytoplasmic antibodies 📖
• ARDS: Acute respiratory distress syndrome 📖
• ASS: Antisynthetase Syndrome 📖
• BAL: Bronchoalveolar lavage 📖
• BiPAP: Bilevel positive airway pressure 📖
• CEP: Chronic eosinophilic pneumonia 📖
• COP: Cryptogenic organizing pneumonia 📖
• CPAP: Continuous positive airway pressure 📖
• CPFE: Combined pulmonary fibrosis and emphysema 📖
• CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
• CTEPH: Chronic thromboembolic pulmonary hypertension 📖
• DAD: Diffuse alveolar damage 📖
• DAH: Diffuse alveolar hemorrhage 📖
• DIP: Desquamative interstitial pneumonia 📖
• DLCO: Diffusing capacity for carbon monoxide 📖
• DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
• EGPA: Eosinophilic granulomatosis with polyangiitis 📖
• FEV1: Forced expiratory volume in 1 second 📖
• FVC: Forced vital capacity 📖
• GGO: Ground glass opacity 📖
• GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
• HFNC: High flow nasal cannula 📖
• HP: Hypersensitivity pneumonitis 📖
• IPAF: Interstitial pneumonia with autoimmune features 📖
• IPF: Idiopathic pulmonary fibrosis 📖
• IVIG: Intravenous immunoglobulin 📖
• LAM: Lymphangioleiomyomatosis 📖
• LIP: Lymphocytic interstitial pneumonia 📖
• MAC: Mycobacterium Avium complex 📖
• MCTD: Mixed connective tissue disease 📖
• NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
• NSIP: Nonspecific interstitial pneumonia 📖
• NTM: Non-tuberculous mycobacteria 📖
• OP: Organizing pneumonia 📖
• PAP: Pulmonary alveolar proteinosis 📖
• PE: Pulmonary embolism 📖
• PFT: Pulmonary function test 📖
• PLCH: Pulmonary Langerhans Cell Histiocytosis 📖
• PPFE: Pleuroparenchymal fibroelastosis 📖
• PPF: Progressive pulmonary fibrosis 📖
• PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
• RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
• RP-ILD: Rapidly progressive interstitial lung disease 📖
• TNF: tumor necrosis factor
• UIP: Usual Interstitial Pneumonia 📖

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basics

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• Blastomycosis is an endemic mycosis that is distributed primarily within the Eastern United States.
• Blastomycosis is somewhat unusual among fungal infections for the following reasons:
  • (1) It often affects people with minimal or no immunosuppression.
  • (2) It can progress relatively rapidly. For example, pulmonary blastomycosis may resemble a typical bacterial pneumonia (and is often misdiagnosed as such).

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epidemiology

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blastomycosis is contracted from the environment

• Blastomycosis is acquired by inhaling fungus from soil or rotting vegetation, often after disruption of soil.
• Common risk factors for acquisition:
  • Camping, hunting, hiking.
  • Logging, construction, forestry. Rarely, construction or excavation may lead to outbreaks. (34016289)
• 🐶 Dogs may also contract blastomycosis. A sick pet dog may be a clue regarding the diagnosis.
• The incubation period is usually ~1-2 months (but may range from 21-106 days). (Fishman 2023)
• Latent disease may become reactivated (e.g., in the context of immunosuppression), but this is felt to be uncommon. (36675937)

most patients are immunocompetent

• Blastomycosis usually affects immunocompetent people (unlike histoplasmosis and coccidioidomycosis). (34016289)
• However, immunocompromised patients often fare worse. Risk factors for more severe disease include:
  • • Transplantation.
    • HIV with CD4 count below ~200/uL. (Murray 2022)
    • Immunosuppression (especially chronic steroid use, TNF inhibitors).
    • Malignancy.
    • Diabetes.

geographic distribution may be growing

• The geographic incidence of blastomycosis seems to be expanding. For example, cases have been reported in people living in states not thought to harbor Blastomyces (e.g., Colorado, Oregon, Nebraska, and Florida). (Fishman 2023)

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acute pulmonary blastomycosis

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acute pulmonary blastomycosis often mimics bacterial pneumonia

• Abrupt onset of respiratory symptoms:
  • Cough (dry or productive).
  • Dyspnea.
  • Pleuritic chest pain.
• Constitutional symptoms (fevers, chills, night sweats, weight loss, malaise).
• Patients will often be treated for bacterial pneumonia. Thus, blastomycosis may be suspected only when considering the causes of nonresolving pneumonia. Often, patients will receive multiple courses of antibiotics prior to correct diagnosis.

blastomycosis causing ARDS 

• Rapid progression to ARDS may occur in ~10-15% of patients.
• Radiographically, this may correlate with multifocal airspace disease or miliary patterns.
• About half of patients with ARDS are immunosuppressed. (Murray 2022)
• Among patients who progress to ARDS, mortality is high (perhaps ~50%). (Fishman 2023)

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radiology of acute blastomycosis

Three predominant abnormalities may be typically seen: 

#1/3) consolidation

• Airspace consolidation is the most common radiologic finding in blastomycosis, which is unfortunate because this will usually be mistaken for a bacterial pneumonia.
• Consolidation may be multifocal and/or patchy, sometimes appearing mass-like. Areas of confluence can become large, but lobar consolidation is considered uncommon. (17495283)
• Cavitation may occur.

#2/3) miliary disease

• This involves bilateral diffuse nodules <3 mm.
• Clinically this is usually associated with acute, severe disease, and dissemination. (26965979) 
• Epidemiologically, miliary disease is more likely to occur among patients with immunocompromise. (17495283)

#3/3) intermediate-sized nodules

• Multiple 0.5 – 3 cm nodules may occasionally occur.
• These may be seen in combination with consolidation, which may help suggest the diagnosis of fungal pneumonia. (17495283)

additional findings

• The following features tend to occur alongside other abnormalities:
• Tree-in-bud pattern: This is usually bilateral and diffuse. It often occurs along with a consolidation, mass, or cavity.
• Pleural effusion usually occurs, with cytology occasionally showing Blastomyces. (31266012)
• Hilar lymphadenopathy can occur, albeit much less frequently (10%) than with histoplasmosis (>60%) or coccidioidomycosis (40%). (Fishman 2023)

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chronic pulmonary blastomycosis

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clinical presentation

• Chronic pneumonia is the most common clinical presentation.
• Patients often present after 3-6 months of insidious illness.
• Symptoms may include:
  • Chronic cough, hemoptysis.
  • Constitutional symptoms (low-grade fever, night sweats, weight loss).
• Chronic pulmonary blastomycosis may often be confused with malignancy or tuberculosis.

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radiology of chronic blastomycosis

There is some overlap between the radiology of acute blastomycosis and the radiology of chronic blastomycosis. For example, intermediate size nodules or cavitation can occur in acute or chronic blastomycosis. However, the following radiologic features are more consistent with chronicity: 

consolidation

• Consolidation may be seen in either acute or chronic blastomycosis.
• In chronic disease, there is a greater tendency to undergo cavitation.

masses

• Well-defined masses may occur, usually between 3-10 cm large. (17495283)
• These may mimic lung cancer.
• Smaller satellite nodules may sometimes be seen, surrounding a large mass.
• Cavitation and lymphadenopathy can occur, but not usually.

cavitation, fibronodular opacities

• Cavitation and/or fibronodular opacities may occur, reflecting disease resolution or chronicity. However, this is less common than in histoplasmosis or coccidioidomycosis (occurring in <10% of cases). (Fishman 2023)
• Cavities are usually located in the upper lobes, mimicking other granulomatous diseases. (17495283)

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disseminated blastomycosis

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The primary site of inoculation is almost always the lungs (or much less often the skin). Only ~25% of infections will disseminate beyond the lungs. Almost every organ can be involved, but the most common sites of involvement are as follows: 

skin is the most common extrapulmonary site

• Skin manifestations are seen in 70% of patients with disseminated disease (~20% of all patients with blastomycosis). (25846538)
• Two forms may occur:
  • (1) Painless vegetating plaques with hyperkeratotic or verrucous borders.
  • (2) Subcutaneous abscesses. These may drain spontaneously, producing chronic ulcerations with sharp, heaped-up borders.
• Purulent drainage or tissue biopsy may be used to yield the diagnosis.

bone and joint infection

• Blastomycosis may involve nearly any bone, but there is a proclivity for involving the vertebrae.
• Overlying skin and subcutaneous tissue can become involved due to abscess extension or fistulization. (32000282)
• Lytic or sclerotic bone lesions may mimic metastatic disease. (36675937)

genitalia

• Males: Prostatitis or epididymitis occur in ~25% of patients with systemic infection.
• Females: Tubo-ovarian abscesses, endometritis, or salpingitis may rarely occur.

central nervous system

• Involved in ~10% of patients with disseminated disease. (31378870)
• Discussed further in the next section:

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CNS blastomycosis

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clinical features

• Pneumonia is generally the primary manifestation, with CNS manifestations being relatively uncommon.
• Potential manifestations of CNS blastomycosis include:
  • Intracranial and/or epidural abscess.
  • Meningitis (acute or chronic).
• Symptoms may include: (31378870)
  • Headache (~75%).
  • Focal neurologic deficits (~60%).
  • Altered mental status, seizures, nausea/vomiting.
• ~80% of patients with CNS blastomycosis have involvement of other non-pulmonary organs. (30921084)
  • Skin manifestations are common (including subcutaneous nodules, ulcers, and painless vegetating plaques).
  • The genitourinary tract and skeleton may also be involved (e.g., causing purulent vertebral osteomyelitis). (26633781)

CSF studies

• Pleocytosis is common (with neutrophilic predominance initially and a subsequent transition to lymphocytic predominance).
• Protein is elevated.
• Glucose is reduced.
• CSF cultures are often negative, or extremely sluggish to return (requiring up to a month to grow). (31378870)
• CSF Blastomyces antigen levels may be helpful in patients with meningitis. (32629490)

other investigations

• Blastomyces serum and urine antigen have a sensitivity of ~80%. This isn't entirely specific (since it cross-reacts with other endemic fungi such as Histoplasma), but it may be extremely useful to direct the evaluation towards an endemic fungus. (31378870)
• Skin lesions may be biopsied.
• Brain abscess may require aspiration to yield a diagnosis.

imaging

• (1) Meningitis may cause leptomeningeal enhancement on MRI.
• (2) Brain abscess(es) may occur in ~60% of patients with CNS involvement:
  • Lesions may be solitary or multiple.
  • Tendency to involve the cerebellum, midbrain, basal ganglia, and pituitary stalk.
  • MRI may show restricted diffusion in a heterogeneous, peripheral ring, or in a central pattern. (31378870) 

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laboratory evaluation

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staining & culture of respiratory specimens

• Sputum or bronchoalveolar lavage may be utilized.
• Fungal stains may reveal large, broad-based budding yeast. Sensitivity may be ~50-90%. (Fishman 2023) 
• Culture takes up to five weeks to grow. (36894264) Yield is limited (even with bronchoscopy, sensitivity is <70%). (Murray 2022)
• Blastomycosis never causes colonization, so if isolated, this represents an invasive infection.

antigen assay

• Urine Blastomyces antigen assay has ~90% sensitivity in disseminated or pulmonary blastomycosis. (32629490)
  • False-positive antigen assay may occur in patients with histoplasmosis, paracoccidioidomycosis, or talarmycosis (previously known as penicilliosis). There is up to 90% cross-reactivity between histoplasmosis and blastomycosis urine antigens (but this isn't highly problematic since the initial treatment of both disorders is similar). (34016289)
• Serum Blastomyces antigen is less sensitive (~70%). (36675937)
• Beta-D-glucan 📖 is negative in blastomycosis.

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treatment

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All patients should generally be treated (unlike histoplasmosis and coccidioidomycosis), due to a risk of dissemination or progression to chronic infection. (Fishman 2023)

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[#1] induction therapy with amphotericin

indications for induction therapy include:

• (1) Severe pneumonia.
• (2) CNS involvement.
• (3) Should be considered for patients with substantial immunocompromise (e.g., organ-transplant recipients). (36675937)
• (4) Pregnancy (azoles cannot be used during pregnancy).

severe pneumonia

• Amphotericin
  • The initial treatment is liposomal amphotericin 5 mg/kg IV q24 hours 💉. (34364529)
  • Duration of amphotericin?
    • Amphotericin should be continued until there are signs of clinical improvement.
    • Typically, this involves ~1-2 weeks of treatment (a lack of improvement after two weeks raises concern for treatment failure).
    • Increasing the duration of amphotericin therapy increases the likelihood of nephrotoxicity. Worsening kidney function may prompt consideration of either transitioning to azole therapy or dose-reduction to 3 mg/kg IV amphotericin daily.
• Steroid: The use of adjunctive steroids may be beneficial for patients with ARDS, but this is supported by only case-series level evidence. (26020566)

CNS involvement

• The initial treatment is liposomal amphotericin dosed at 5 mg/kg q24 hours 💉.
• The duration of induction therapy is longer than for pneumonia (e.g., ~4-6 weeks).

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[#2] maintenance therapy with an azole (usually itraconazole)

itraconazole 💉

• Itraconazole is generally utilized as front-line therapy for mild-moderate pneumonia (including chronic pneumonia) or step-down therapy for severe pneumonia (following amphotericin induction).
• Variable bioavailability may limit the use of itraconazole, especially among intubated patients receiving continuous enteral nutrition. Additionally, the half-life is ~36 hours, so it takes days for itraconazole to reach steady-state concentrations.

voriconazole 💉

• Voriconazole generally has good in vitro activity against Blastomyces.
• The primary advantage of voriconazole over itraconazole is improved bioavailability (with an intravenous formulation available for critically ill patients).
• Voriconazole has traditionally been considered a second-line azole for managing blastomycosis. However, voriconazole is preferred among patients with CNS involvement (due to high activity and good CNS penetration). Retrospective studies support voriconazole in CNS blastomycosis. (20166817)

isavuconazole 💉

• Isavuconazole has excellent in vitro activity against blastomyces and has been utilized. Clinical data is limited but accumulating (a recent case series describes 14 patients with an 80% cure rate). (35821730) The measured MIC appears tiny (<0.015 ug/mL), which would predict excellent target attainment. (35821730)

posaconazole 💉

• Posaconazole is expected to be active against Blastomycosis based on low MIC values.
• Clinical experience is limited. One report describes a successful response to posaconazole in two patients unable to tolerate itraconazole. (22564845) One abstract from the Medical College of Wisconsin describes favorable results among nine patients. (Baca A et al. 2021)
• One advantage of posaconazole may be good tolerability.

fluconazole 💉

• Given fluconazole's excellent CNS penetration, it may be considered for patients with CNS blastomycosis in whom voriconazole cannot be used. Unfortunately, fluconazole is relatively ineffective against blastomycosis, so fluconazole may not actually have a substantial advantage over itraconazole (itraconazole has lower CNS penetration but superior activity against blastomycosis).
• If fluconazole is used for mild disease, success rates may be higher at relatively high doses (400-800 mg/day). (36675937, 34364529)

duration of azole therapy

• Treatment duration ranges from 6 months (for mild disease) to >1 year (for CNS blastomycosis).
• Chronically immunosuppressed patients may require chronic suppressive therapy. (36894264)

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questions & discussion

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