Blastomycosis 

Updated: Jan 09, 2019
Author: Chidinma Chima-Melton, MD; Chief Editor: Zab Mosenifar, MD, FACP, FCCP 

Overview

Practice Essentials

Blastomycosis is a systemic pyogranulomatous infection usually caused by the inhalation of (spores) conidia of Blastomyces dermatitidis. Clinical presentations vary widely, ranging from an asymptomatic, self-limited pulmonary infection to acute respiratory distress syndrome (ARDS), a life-threatening disease.[1]

Composite photomicrograph of a tissue specimen fro 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.

Signs and symptoms

Blastomycosis is usually localized to the lungs and may present with:

  • A self-limited flulike illness with fever, chills, myalgia, headache, and a nonproductive cough

  • An acute illness resembling bacterial pneumonia, with high fever, chills, a productive cough, and pleuritic chest pain; mucopurulent or purulent sputum

  • Chronic illness, with low-grade fever, a productive cough, fatigue, night sweats, and weight loss

  • Rapidly progressive, and severe disease (eg, multilobar pneumonia or ARDS), with fever, shortness of breath, tachypnea, hypoxemia and, finally, hemodynamic collapse

Extrapulmonary manifestations are present in 25-40% of patients, who may present with:

  • Cutaneous lesions - Usually either verrucous or ulcerative and may be asymptomatic

  • Osteoarticular lesions - Cause bone or joint pain; possible soft-tissue swelling; possible involvement of any bone, but the vertebrae and pelvis are common sites

  • Genitourinary manifestations including prostatitis and epididymitis - May be asymptomatic or may cause pain on urination

  • Other sites - B dermatitidis has been reported to involve almost all organs, including the eye, liver, spleen, breast, thyroid, and adrenal gland.

  • Central nervous system involvement - Intracranial or epidural abscesses and meningitis

See Presentation for more detail.

Diagnosis

Culture and cytopathology are the gold standard for the diagnosis of blastomycosis. The fastest way to diagnose blastomycosis is direct identification of the broad based budding yeast forms under microscopy. Identification from culture may not be evident for 2 to 4 weeks, and it often requires invasive procedures such as bronchoscopy or tissue biopsy to obtain specimens.[1]  

More recently, molecular DNA probes have been developed to facilitate the rapid identification of B dermatitidis from clinical specimens. A commercially available chemiluminescent DNA probe assay (AccuProbe) is commonly used and produces results from culture within hours once there is adequate growth.[2]

In addition, tests targeting virulence factors BAD1 and DRK1 through real-time polymerase chain reaction (RT-PCR) and serologic antibody-based assays have been developed but are as yet not commercially available.[3, 4, 5]

Chest imaging findings are nonspecific and may range from scattered centrilobular nodules to areas of dense consolidation. Computed tomography (CT) scanning is not always necessary, but it can provide better definition of the character and distribution of abnormalities observed on a chest radiograph.

See Workup for more detail.

Management

Antifungal treatment is as follows:

  • Patients with mild to moderate pulmonary disease - Oral azole (eg, itraconazole)

  • Patients with moderate-to-severe disseminated disease or immune compromise: Initially, amphotericin B with step-down to an oral azole after clinical improvement

  • Patients with central nervous system (CNS) disease as well as pregnant women: Always be treat initially with amphotericin B 

See Treatment and Medication for more detail.

Background

Oral azoles, usually itraconazole or amphotericin B, are first-line treatment for blastomycosis depending on the severity of the disease, its clinical form, and the host's immune status. In general, mild to moderate disease is typically treated with oral itraconazole—except in pregnant women and those with CNS disease, all of whom should always receive amphotericin B. Patients with moderately severe to severe disseminated disease should receive amphotericin B followed by a long-term oral azole when they clinically improve.[6]

Blastomycosis requires prolonged treatment. Patients with mild to moderate disseminated blastomycosis without central nervous system involvement should be treated for 6 months. In patients with bone involvement, the treatment period should be extended to 12 months. Individuals with severe disease occasionally require even longer treatment. See Treatment and Medication.

Pathophysiology

Blastomycosis is a systemic pyogranulomatous infection caused by the inhalation of conidia (spores) of B dermatitidis, the asexual (imperfect) form of Ajellomyces dermatitidis, a dimorphic fungus. The mycelial form grows as a fluffy white mold at 25°C (77°F) and a brown folded yeast at 37°C (98.6°F). The conidia are round, ranging from 2 to 10 μm in diameter, and become aerosolized when the fungus in the mycelia phase in the soil is disturbed. These can be inhaled, passing into the lower respiratory tract and resulting in pulmonary infection.

The inhaled conidia are phagocytized by bronchopulmonary mononuclear cells. The organism’s susceptibility to phagocytosis and killing by neutrophils, monocytes, and alveolar macrophages explain why some individuals remain asymptomatic despite exposure to environments that would cause clinical infection in others. At 37°C (98.6°F), B dermatitidis converts from the mycelial form to the yeast form.

This transformation provides a survival advantage to the infecting fungus, as the yeast form is larger, at 8-10 μm in diameter, and possesses a thick cell wall that provides greater resistance to phagocytosis and killing. The histidine kinase DRK1 regulates dimorphism from mold to yeast and virulence gene expression in B dermatitidis. DRK1 knockout strain grown at 37°C (98.6°F) is locked in the mold morphology.[7]  Another virulence factor is BAD-1, an immune-modulating glycoprotein that is expressed on the cell surface and released into the extracellular matrix.[8] BAD-1 facilitates the binding of B dermatitidis to macrophages. The yeast forms multiply and may disseminate through the blood and lymphatics to other organs. The evoked pyogranulomatous inflammatory response is a distinctive feature of blastomycosis characterized by an initial influx of neutrophils, followed by macrophage and granuloma formation. 

Blastomycosis may be asymptomatic in nearly 50% of infected persons. In the remainder, the median incubation period from inhalation of the fungus to manifestations of symptoms is 45 days (range: 21-106 days). Symptoms of blastomycosis are similar to influenza, with most patients presenting with cough, fever, sputum production, chest pain, and dyspnea. Cellular immunity is a major protective factor in preventing progressive disease secondary to B dermatitidis.

The lungs are the usual point of entry. In one study, pulmonary involvement was present in 91% of all cases.[9] Pulmonary symptoms range from acute and chronic pneumonias to acute respiratory distress syndrome (ARDS). Evidence of dissemination to other organs may be present.

Rarely, an extrapulmonary site (eg, skin, bone) may be the only presenting clinical manifestation.

In earlier reported case series, extrapulmonary involvement was noted in 50% of chronic blastomycosis cases. However, in present times, with earlier recognition and effective treatment, the extrapulmonary manifestations are seen in only about 20% of cases. Extrapulmonary dissemination occurs more commonly in patients with chronic pulmonary illness or immunocompromise.

Skin is the most common site of extrapulmonary blastomycosis and is involved in about 20% of cases. Other areas affected, and the approximate frequency of such involvement, are as follows[9] :

  • Bone - 5%

  • Prostate and other genitourinary organs - 2%

  • Meninges and brain - 1%

  • Other (lymph nodes, adrenal, eye, liver, spleen, trachea, breast, and thyroid) - 3%

Reactivation of blastomycosis may occur after a pulmonary infection that resolved, with or without treatment. An extrapulmonary site (eg, skin, bone, brain) is rarely a site of reactivation.

Etiology

Relatively recent advances in genotyping of Blastomyces by microsatellite typing and ITS2 sequencing have demonstrated that there are two unique clades, or species, of Blastomyces: B dermatitidis infection is more prevalent in patients with comorbidities and more likely to cause disseminated infection, and B gilchristii is more likely to cause isolated pulmonary disease. In a retropective review of children with blastomycosis confirmed by culture or cytopathology, the majority of the children had isolated pulmonary disease with systemic findings.[10] Those with extrapulmonary disease were less likely to have systemic symptoms or additional laboratory evidence of infection, which made delays in diagnosis more common. More than 90% of the pediatric cases were caused by B gilchristii.[11]

B dermatitidis is the asexual (imperfect) form of Ajellomyces dermatitidis, which is a thermal dimorphic fungus. The mycelial form grows as a fluffy white mold at 25°C (77°F) and a brown folded yeast at 37°C (98.6°F) body temperature. The fungus is usually isolated in the soil in its mycelial form  in wet earth that has been enriched with animal droppings, rotting wood, and other decaying vegetable matter.

The conidia are round, ranging from 2 to 10 μm in diameter, and become aerosolized when the fungus in the mycelia phase is disturbed. The conidia are inhaled, passing into the lower respiratory tract and resulting in pulmonary infection. In infected tissue specimens, B dermatitidis appears as a characteristic thick-walled yeast, 8-10 μm in diameter, which provides greater resistance to phagocytosis and killing.

As dogs are infected with blastomycosis in a similar way and often in the same place as humans, an early clue to the diagnosis in humans is a history of a fungal infection in a pet dog. Blastomycosis is not transferred from animals to humans other than from bite wounds.[12]  This condition has also been reported in other animals, including horses, cows, cats, bats, foxes, and lions. 

Epidemiology

United States statistics

Blastomycosis can be endemic or sporadic. Most cases of blastomycosis occur in the United States and Canada, although occasional cases have been reported in Central and South America, Africa, the United Kingdom, India, and the Middle East.[13] The disease is endemic in the central and southeastern parts of the United States, near the Mississippi River, Ohio River, and Great Lakes. Thus, Arkansas, Kentucky, Mississippi, North Carolina, Tennessee, Louisiana, Illinois, and Wisconsin are commonly affected.[14]  However, blastomycosis is reportable only in five states: Arkansas, Louisiana, Michigan, Minnesota, and Wisconsin.[15]

The true incidence and prevalence of blastomycosis are unknown, because there are no reliable antigen markers for skin testing. Its incidence in Northern Ontario has been reported as 117.2 cases per 100,000 population, the highest incidence in North America.[16]  Based on confirmed cases, the annual US incidence is 1-2 cases per 100,000 people in Arkansas, Louisiana, Michigan, Minnesota, and Wisconsin.[6]  Wisconsin may have the highest incidence of blastomycosis of any state, with yearly rates ranging from 10 to 40 cases per 100,000 persons in some northern counties,[17]  and 2.9 hospitalizations per 100,000 person-years.[18]  2012 data from Illinois and Wisconsin found an annual incidence of 0.4-2.6 cases per 100,000 population; in contrast, 2007-2017 data from New York revealed an average annual incidence of 0.1-0.2 cases per 100,000.[15]

There were 1,216 blastomycosis-related deaths in the United States during 1990–2010.[19] Among those 1,216 deaths, blastomycosis was reported as the underlying cause of death for 741 (60.9%) and as a contributing cause of death for 475 (39.1%). The overall age-adjusted mortality rate for the period was 0.21 per 1 million person-years.[19]  

Significant construction, such as interstate road expansion, can release Blastomyces spores from the soil.[20] One such urban outbreak comprised 34 confirmed cases of blastomycosis in Indianapolis from 2005 to 2008, which coincided with a period of major highway construction in the same area.[20] Residence near rivers and waterways is also associated with an increased risk of blastomycosis, particularly major freshwater drainage basins such as those of the Nelson River, St Lawrence River and northeast Atlantic Ocean Seaboard, Mississippi River System, and Gulf of Mexico Seaboard and southeast Atlantic Ocean Seaboard.[21] In Vilas County, north-central Wisconsin, 73 patients with laboratory-confirmed blastomycosis were identified over an 11-year period, in which 82% of these patients lived or had visited within 500 m of rivers or associated waterways.[22]

As noted under Etiology, canine blastomycosis can be an early warning sign for concomitant blastomycosis in humans. One case series of five households in which six patients were diagnosed with blastomycosis, one or more pet dogs were diagnosed with blastomycosis an average of 6 months before the patients themselves became symptomatic.[12]

International statistics

Blastomycosis can be seen outside of the United States. Internationally, most reported cases stem from Canada (Ontario, Manitoba) and Africa. Most African cases originate from South Africa[23] and Zimbabwe,[24] although cases have also been seen in Nigeria[25] and Tunisia.[26, 27]  The disease is often mistaken for pulmonary tuberculosis or malignancy, and only after lack of response to standard treatment is the diagnosis made.[24, 25, 28] Cases have also been reported from disparate regions, including China,[16]  Mexico, South America, the Middle East, and India.[13]

Because of the erroneous belief that the disease is limited to the United States, blastomycosis is often referred to as North American blastomycosis, which is an obsolete term. The term European blastomycosis is a confusing synonym of cryptococcosis, a systemic infection caused by the yeastlike fungus Cryptococcus neoformans. Likewise, South American blastomycosis (ie, Brazilian blastomycosis) is an older name for paracoccidioidomycosis, a chronic, often fatal, mycosis caused by a large dimorphic fungus, Paracoccidioides brasiliensis.

Racial, sexual, and age-related differences in incidence

Most studies of blastomycosis have shown no racial disparity in susceptibility. Rather, the distribution tends to mirror the ethnic and racial makeup of the area affected. However, in a few case series, certain races show a higher incidence of the disease. Some examples include an outbreak in Wisconsin, where 20 of the 55 patients affected were Hmong,[29] and an analysis of Missouri cases in which 57% of those affected were black although black individuals account for only 13% of the population.[30] One possible explanation for these findings is that these groups have greater exposure to environments containing wet soil or organic matter where B dermatitidis thrives.

Blastomycosis has been reported to occur more frequently in males, possibly due to greater occupational and recreational exposure. Men are more likely to participate in activities associated with B dermatitidis, such as fishing, hunting, and camping. In Wisconsin from 1986 to 1995, 60% of cases were in males.[31] However, analysis of outbreak cases from a common source and more recent reports do not indicate a significant sex difference.[32]  Moreoever, historically, epidemiologic reports were skewed due to the collection of data from Veterans Administration (VA) hospitals nationwide, which predominantly serve male patients.[33]

The mean age at diagnosis is approximately 45 years, with most patients aged 30-69 years. However, persons of any age can acquire the disease, including infants and very elderly persons.[34]

The disease is rare in children and adolescents. A retrospective study at a children's hospital in Arkansas identified only 10 patients diagnosed with the disease between 1983 and 1995.[35] In past reviews, however, about 2-10% of patients reported were younger than 15 years. In children, both sexes are equally susceptible.

Prognosis

Immunocompetent patients with blastomycosis generally do not experience complications and can expect a full recovery. Relapse or recurrence of blastomycosis is rare, and it varies by the therapeutic agent, treatment length, and patient's immune capacity. Successful blastomycosis treatment is achieved in 80-95% of cases.[10] In contrast, immunocompromised patients with blastomycosis have a poor prognosis.

Cellular immunity is the fundamental host defense against B dermatitidis. Loss or compromise in T-lymphocyte function—for example, in human immunodeficiency virus infection / acquired immunodeficiency syndrome (HIV/AIDs) or with immune suppression after solid organ transplant, can predispose to severe disseminated disease or cavitary lung disease, and it often involves the central nervous system (CNS).[36, 37, 38]

Complications

Potential complications include progressive pulmonary disease and extrapulmonary dissemination. Risk of dissemination is increased in immunocompromised individuals. Severe pulmonary disease complicated by cavitary lesions and acute respiratory distress syndrome (ARDS) occurs in approximately 20% of compromised hosts.[39]  CNS disease appears to be 3-5 times more common in immunocompromised patients than in immunocompetent hosts. Meningitis or mass lesions has/have been reported to occur in approximately 40% of adult patients with AIDS.

Extrapulmonary disease, frequently to the skin, bones, genitourinary system, and CNS, can occur in 25-40% of patients with blastomycosis. The skin is the second-most common site of involvement after the lungs, and cutaneous findings range from the characteristic verrucous lesions to friable ulcerative lesions. Complications include abscesses and nodules, and extensive cutaneous lesions may undergo central healing with scarring and contracture.

Osteomyelitis occurs in approximately 25% of extrapulmonary cases,[14]  usually concomitantly with pulmonary blastomycosis. The infection can spread into nearby joints, leading to septic arthritis, or contiguous spread from the vertebral bodies can cause psoas abscesses.

Patient Education

Although immunocompromised patients (including those with human immunodeficiency virus infection / acquired immunodeficiency syndrome [HIV/AIDS]) living in or visiting blastomycosis-endemic areas cannot completely avoid exposure to B dermatitidis, they should be counseled about reducing the risk of acquiring blastomycosis by avoidance of occupational and recreational activities known to be associated with increased risk (eg, wooded areas along waterways).

 

Presentation

History

Patients with blastomycosis may present with any of several patterns of illness, but 30-50% of persons infected may remain asymptomatic. Indeed due to this variability in its clinical presentation, blastomycosis has been dubbed "the great pretender" and a high index of suspicion is required to make an accurate diagnosis.[37]

The initial presentation may be a nonspecific flulike illness with fever, chills, myalgia, headache, chest pain, and a nonproductive cough, which resolves within days. Because of the brief and self-limited nature of these symptoms, blastomycosis may go undiagnosed except in the setting of a known outbreak. Alternatively, patients may present with an acute illness resembling bacterial pneumonia, with high fever, chills, a productive cough, and pleuritic chest pain; the sputum is mucopurulent or purulent.

A chronic pneumonia may occur and simulate tuberculosis or lung cancer, with low-grade fever, a productive cough, night sweats, chest pain, and weight loss. The sputum is mucopurulent or purulent, and hemoptysis may be present. Often, these patients receive multiple courses of antibiotics before the diagnosis of blastomycosis is made. Chronic blastomycosis pneumonia is progressive without antifungal therapy.

Other patients, often older persons or those with immune compromise states (such as patients with human immunodeficiency virus infection / acquired immunodeficiency syndrome [HIV/AIDS] or solid organ transplant recipients) may present with an acute, rapidly progressive, severe disease. These cases manifest as acute respiratory distress syndrome (ARDS), with fever, shortness of breath, tachypnea, hypoxemia, and diffuse pulmonary infiltrates. The mortality rate for ARDS-associated blastomycosis is high, ranging from 33% to 67%.[40, 41]

Extrapulmonary features may include the following:

  • Skin lesions - The skin is the second-most common site of spread after the lungs. Commonly seen skin manifestations are purplish-gray verrucous lesions with heaped borders or friable lesions that ulcerate. Microabscesses and subcutaneous nodules can also be seen.

  • Bone lytic lesions - Seen in 25% of cases with extrapulmonary manifestations,[14] these lesions may present with bone or joint pain, and soft-tissue swelling may be present. Osteomyelitis can involve any bone, although the lower spine and pelvis are most commonly affected. Contiguous spread of bone disease can result in deep abscesses or arthritis.

  • Genitourinary - Prostatitis, orchitis, or epididymitis can be seen in men,[12] and rare cases of endometritis and tubo-ovarian abscess have been reported in women.

  • Central nervous system (CNS) involvement - In 5-10% of cases, meningitis and intracranial or epidural abscesses may be seen. Cases of central diabetes insipidus have been reported from CNS blastomycosis.

Unusual sites of disseminated infection include the larynx (manifesting as hoarseness), uterus, reticuloendothelial system (liver, spleen, lymph nodes, bone marrow), oropharynx, nose, and thyroid.

Physical Examination

The physical examination in patients with blastomycosis may not reveal any abnormal findings. In the pneumonic form, there may be findings associated with pneumonic consolidation (eg, dullness on percussion, bronchial breath sounds, egophony, rales). Decreased or absent breath sounds suggest pleural effusion.

Skin lesions are more common on the face, neck, and extremities, and they often represent the strongest indication of the diagnosis of blastomycosis. Early in the disease course, the lesions are sharply demarcated papules or pustules, or they present as subcutaneous nodules. Multiple lesions may appear simultaneously or in sequence.

Within a few weeks to months, the primary lesions evolve into ulcers, with indurated dusky or violaceous granulomatous or verrucous borders, or into vegetating plaques (see the image below). Typically, the border is arciform or serpiginous, contains numerous tiny pustules or microabscesses covered with crust, and rises abruptly from the normal surrounding skin.

Cutaneous blastomycosis. Cutaneous blastomycosis.

Over a period of months to years, the lesions enlarge, eventually involving a substantial portion of the face, for example, and produce severe disfigurement. As the lesions enlarge, they heal centrally, with an atrophic scar studded with telangiectasia.

Although the vast majority of patients with cutaneous blastomycosis acquire it by dissemination from a pulmonary focus,[42] a few well-documented cases of primary cutaneous (inoculation) blastomycosis have been described in laboratory workers. The skin lesions are described as "chancriform" and are accompanied by nodular lymphangitis.

Rarely, bone involvement leads to a draining abscess. The affected joint may be tender and swollen.

 

DDx

Diagnostic Considerations

Blastomycosis should be considered in the differential diagnosis of an atypical pulmonary infection in regions where it is endemic, even in urban areas.

Blastomycosis may present as a community-acquired pneumonia; in addition, it should be considered in any patient with pneumonia that is not resolving, or one who presents with acute respiratory distress syndrome (ARDS). Establishing blastomycosis as the cause of pneumonia is often difficult, and most patients received multiple antibiotic courses before being diagnosed. Delays in diagnosis of pulmonary blastomycosis can be reduced if a higher clinical suspicion exists and there is earlier use of sputum potassium hydroxide (KOH) fungal smear, especially after a course of antibiotics has failed to result in clinical improvement.[43]

Other pulmonary disorders to consider in the differential diagnosis are sarcoidosis, tuberculosis, and other endemic mycoses such as histoplasmosis and coccidioidomycosis.

Blastomycosis has a tendency to mimic carcinoma. Pulmonary blastomycosis may resemble lung cancer, and blastomycosis osteomyelitis may resemble bony metastasis. Central nervous system blastomycosis may resemble brain neoplasm. The typical verrucous or ulcerative cutaneous lesions of blastomycosis may mimic skin cancers, such as basal cell carcinoma and squamous cell carcinoma. Other skin disorders to consider include the following:

  • Pyoderma gangrenosum

  • Keratoacanthoma

  • Halogenoderma

  • Chromoblastomycosis

  • Atypical mycobacterial infection

  • Tuberculosis verrucosa cutis

  • Lupus vulgaris

  • Blastomycosis-like pyoderma

Differential Diagnoses

 

Workup

Approach Considerations

No clinical presentations or imaging abnormalities exist that provide a definitive diagnosis of blastomycosis. Culture and cytopathology, with direct visualization of B dermatitidis, is the gold standard to provide a definitive diagnosis. In a study of patients with pulmonary involvement, sputum culture was positive for the organism in 86% of cases and 100% of bronchial washings in patients with confirmed pulmonary disease.[44]

The fastest way to diagnose blastomycosis is direct identification of the broad-based budding yeast forms under microscopy. For most specimens, direct visualization should precede culture to confirm the diagnosis. Sputum specimens processed with 10% potassium hydroxide or calcofluor white fungal stain are examined first in adolescent and adult patients, because these specimens have a high overall yield (approximately 80%). Isolation and identification of the organism on sputum culture provides absolute confirmation of the diagnosis. Identification from culture may not be evident for 2 to 4 weeks, and it often requires invasive procedures such as bronchoscopy or tissue biopsy to obtain specimens.[1]

With regard to serologic tests, complement fixation and immunodiffusion tests lack sensitivity and cannot be used to exclude the diagnosis. A commonly used test is a commercially available chemiluminescent DNA probe (AccuProbe), which produces results from culture within hours once there is adequate growth. However, this test also produces a positive result with all Paracoccidioides brasiliensis species, a dimorphic fungus endemic to Central and South America. Nonetheless, P brasiliensis is very rare in the United States, so this probe remains useful. P brasiliensis can be differentiated from B dermatitidis by the appearance of the yeast phase.[2]  

In addition, tests have been developed that target Blastomyces virulence factors BAD1 and DRK1 through real-time polymerase chain reaction (RT-PCR) and serologic antibody-based assays, and they have high sensitivity and specificity. The antibodies can be detected in 87.8% of the patients with blastomycosis by the enzyme immunoassay compared to 15.0% by immunodiffusion.[3, 4, 5]

Immunodiffusion and complement fixation of the antigen in serum and urine lacks specificity, and the combination of urine and serum testing does not improve sensitivity significantly. Negative findings should be confirmed with culture and cytology. However, results from one study found serial urine antigen concentrations to be useful in monitoring treatment and relapse from infection.[1]

Skin testing is not reliable for the diagnosis of blastomycosis and is not commercially available.

The diagnosis of blastomycosis is more difficult in children. Children with pulmonary disease who are unable to produce sputum may require invasive procedures, such as bronchoscopy with bronchoalveolar lavage, percutaneous needle biopsy of the lung, and open lung biopsy, for diagnostic confirmation.

A leukocyte and differential count may show leukocytosis with a left shift, particularly in cases with a pneumonic presentation; however, the test has low sensitivity and specificity. Pulse oximetry is appropriate in detecting hypoxemia in cases that present as pneumonia. Arterial blood gases are indicated in patients with tachypnea, pulmonary infiltrates, and hypoxemia by pulse oximetry.

Chest radiography findings vary and lack diagnostic specificity. Other imaging studies or bronchoscopy may be indicated in select situations.

In patients with extrapulmonary disease, percutaneous needle or surgical biopsy of the affected area (eg, skin, subcutaneous nodule, bone) may be helpful. Histology and culture of biopsy specimens may reveal the organism. DNA probe may be useful in identifying B dermatitidis in formaldehyde-fixed tissue samples.[45]

Diagnosis of central nervous system blastomycosis is difficult. Lumbar puncture and cerebrospinal fluid (CSF) analysis may demonstrate a neutrophil predominance, but this is rarely definitive. Ventricular fluid specimens have provided slightly higher rates of culture positivity but are still not sensitive. In one case series, CSF culture identified only 2 of 22 patients with confirmed blastomycosis meningitis.[46]

Prostatic massage may be necessary to facilitate diagnosis in men with blastomycosis of the genitourinary tract. The urine collected after a prostatic massage is likely to have a higher diagnostic yield.

Sputum Examination

Sputum microscopy is a simple and inexpensive test to identify Blastomyces, and although the overall sensitivity of this test is modest (< 40%), the potential for rapid identification of the pathogen makes it a reasonable initial option.[44] In patients with pneumonia or acute respiratory distress syndrome, the sensitivity is much higher (approximately 75%).

Sputum microscopy is performed by placing a small sample of freshly expectorated sputum on a slide digested with 10% potassium hydroxide. Under the microscope, yeasts 8-20 μm in size, with single, broad-based buds, double refractile walls, and multiple nuclei, are extremely characteristic of B dermatitidis.

Microscopic examination of a potassium hydroxide wet mount can also be performed on aspirated pus, fistulae, or subcutaneous abscesses. These will reveal the characteristic broad-based budding yeast. Identification of B dermatitidis by calcofluor white staining under a fluorescent microscope is an easy and rapid method of diagnosis. Calcofluor white is a fluorochrome compound that binds to chitin present in the cell walls of B dermatitidis and fluoresces when exposed to short-wavelength ultraviolet light from a fluorescent microscope.

Culture

Culture and cytopathology are the gold standard for the diagnosis of blastomycosis. Isolation and identification of the organism in an appropriate laboratory culture medium provides absolute confirmation of the diagnosis. The organism can be cultured on brain-heart infusion, potato dextrose agar, potato flake agar, and Sabouraud dextrose agar at room temperature. Cultures may become positive in as few as 5 days or many as 30 days when incubated at 25°-30°C (77°-86°F). B dermatitidis colonies are creamy white and transform to a brown-gray color as hyphae grow.

B dermatitidis mold has a distinctive “lollipop” appearance with oval conidia, 2-4 μm in diameter at the tips of thin conidiophores. They also have thin septate hyphae, 1-2 μm in diameter.

Specimens for culture may consist of sputum, tracheal aspirates, bronchoalveolar lavage fluid, tissue biopsy samples, cerebrospinal fluid, or urine. Because colonization with B dermatitidis does not occur, detection of the fungus from any sterile site is diagnostic.

Primary cutaneous blastomycosis has been reported by accidental autoinoculation, therefore, clinical laboratory personnel and pathologists should be notified about the possibility of blastomycosis in the differential diagnosis if they fall ill when handling potential infected tissue or body fluid specimens.

Skin Tests and Serodiagnosis

Skin testing and serodiagnosis of blastomycosis using complement fixation (CF) antibodies and immunodiffusion (ID) precipitin bands currently have very limited roles in diagnosis because of poor sensitivity and specificity, as well as cross-reactivity with other fungi. An enzyme immunoassay with the A antigen of B dermatitidis has been shown to be more sensitive than CF and ID tests[47, 48, 49, 50] ; however, this test is not available in most commercial laboratories.

Detection of (1→3)-β-d-glucan in serum specimens is of limited benefit in patients with blastomycosis. In one case series of four patients with blastomycosis, β-d-glucan was detected in only one patient with disseminated disease.[51]

Chest Radiography

Chest radiograph findings in patients with blastomycosis vary depending on the immune status of the host but, in general, are abnormal in two thirds of cases. In the immunocompetent patient, chest radiography findings can be variable but, in many cases, demonstrate lobar or segmental airspace opacities. A focal mass is common with well-defined margins and can range from 5 to 10 cm in size. These masses may be mistaken for neoplasms. Cavitary lesions are uncommon in immunocompetent patients.

In a single-institution retrospective study (2005-2016) of 36 pediatric patients (age 0-18 years) with pulmonary blastomycosis who underwent chest imaging, the most common pattern of lung involvement was a combination of consolidations (94.4%) with bilateral lung nodules (50%) and reticulonodular opacification (41.2%).[52] The upper (70.6%) and middle (47.1%) lobes were most often affected.

However, in the immunocompromised host, cavitary lesions are more common, and disseminated disease can lead to diffuse interstitial infiltrates on the chest radiograph. Pleural effusion is uncommon, but pleural thickening adjacent to an infiltrate may be observed. Hilar or mediastinal lymph node enlargement rarely occurs.

See the image below.

Lateral chest radiograph reveals the ill-defined l Lateral chest radiograph reveals the ill-defined lingular opacity and an absence of pleural effusions.

 

Computed Tomography Scanning

Chest computed tomography (CT) scanning is not always necessary in the evaluation of patients with suspected blastomycosis, but this imaging modality can provide better definition of the character and distribution of abnormalities observed on a chest radiograph, and it is helpful in identifying mediastinal abnormalities and loculated pleural effusions. A head CT scan is useful in the detection of brain abscesses.

CT scanning can also be used to detect skeletal involvement in some cases of extrapulmonary blastomycosis. However, magnetic resonance imaging (MRI) is more sensitive for this purpose; radionuclide bone scanning is also an alternative imaging option.

Bronchoscopy

Flexible bronchoscopy has a higher sensitivity than sputum examination for the diagnosis of blastomycosis. One study demonstrated a positive diagnosis in 92% of patients with pulmonary blastomycosis; cultures of bronchial secretions and bronchoalveolar lavage fluid were positive in 100% and 67% of patients, respectively.[44]  Bronchoscopy (with washings, brushings, and a biopsy) is indicated in the following situations:

  • Absence of sputum

  • Nondiagnostic sputum microscopic examination

  • Undiagnosed pulmonary mass density, atelectasis, or consolidation

  • Hemoptysis

Immune Deficiency Workup

Serious infection with blastomycosis has been increasingly recognized in immunocompromised hosts, especially patients with acquired immunodeficiency syndrome (AIDS). However, other fungal infections, such as progressive disseminated histoplasmosis or cryptococcal meningitis, are more likely to be opportunistic. Blastomycosis is not an AIDS-defining illness and no official recommendations regarding screening for human immunodeficiency virus (HIV) infection in patients diagnosed with blastomycosis are recognized.

Histologic Findings

The yeast forms of B dermatitidis are best visualized with a periodic acid-Schiff (PAS) stain. Methenamine silver and Papanicolaou stains are also reliable.

Demonstration of the yeasts is particularly important in blastomycosis that involves sites with squamous epithelium (eg, skin, larynx, trachea). In these tissues, the fungal infection may provoke a hyperplastic response that simulates squamous cell carcinoma. However, the hyperplastic epidermis lacks the cytologic atypia of squamous cell carcinoma.

Skin lesions of disseminated blastomycosis are characterized by the following histologic features:

  • Pseudoepitheliomatous hyperplasia of the epidermis

  • Intraepidermal microabscesses

  • A suppurating granulomatous reaction in the dermis

Intraepidermal abscesses contain abundant neutrophils and organisms; the organisms are best visualized with the diastase-digested PAS staining procedure or with the methenamine silver stain. The yeasts are present extracellularly in the dermis or intracellularly in multinucleated giant cells. Intracellular yeasts are easily identified on routine hematoxylin and eosin (H&E)–stained sections of skin as punched-out "holes" in the cytoplasm of the giant cells. The inflammatory infiltrate is polymorphous, containing lymphocytes, histiocytes, and neutrophils.

On cytologic examination of specimens such as sputum or tissue aspirates, B dermatitidis typically appears as a round, multinucleate yeast ranging from 8 to 15 μm in diameter, with a broad-based bud.

Granuloma formation is unusual. If it does occur, it generally does not demonstrate caseation or calcification, as is typical of tuberculosis.

 

Treatment

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]

 

 

Medication

Medication Summary

Medication for the treatment of blastomycosis should be selected on the basis of the type, extent, and severity of the disease; the immune status of the patient; and the toxicity of the drug.

Amphotericin B and itraconazole continue to be the main drugs of choice.

Alternative antifungal agents include ketoconazole, fluconazole, and voriconazole. Fluconazole and voriconazole have good cerebrospinal fluid penetration. Voriconazole has been successfully used in immunocompromised patients and in those with central nervous system (CNS) infection.

Antifungals, Systemic

Class Summary

The mechanism of action of antifungal agents may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.

Amphotericin B deoxycholate

Amphotericin B deoxycholate

Amphotericin B is the initial drug of choice for blastomycosis in patients with severe illness (eg, rapidly progressive infections, CNS disease), immunocompromised hosts, and special circumstances (eg, pregnant women, children). This agent alters fungal cell membrane permeability by binding with ergosterol, resulting in cell component leakage and death.

Amphotericin B is administered intravenously and must be mixed with dextrose in water. Infusion of saline before, during, and after amphotericin reduces renal toxicity.

Amphotericin B liposomal (AmBisome)

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 and pregnant women.

Itraconazole (Sporanox, Onmel, Tolsura)

Itraconazole is a synthetic thiazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450-dependent synthesis of ergosterol, a vital component of fungal cell membranes. Compared with other oral azoles, itraconazole is better absorbed and has enhanced antimycotic activity with fewer adverse effects. A new formulation of itraconazole is now available that utilizes SUBA (SUper-BioAvailable) technology to improve the bioavailability of poorly soluble drugs.

Oral itraconazole (at a dosage of 200-400 mg/d) is the azole of choice in adult patients with indolent nonmeningeal blastomycosis of mild-to-moderate severity. It may be given as primary therapy to stable patients or as step-down therapy following a course of amphotericin B.

Ketoconazole

Ketoconazole is an effective alternative agent in the treatment of immunocompetent patients with mild-to-moderate blastomycosis. High rates of serious adverse effects and of relapse limit its usefulness.

Fluconazole (Diflucan)

Fluconazole is a highly selective inhibitor of the fungal cytochrome P-450–dependent enzyme lanosterol 14-alpha-demethylase. Subsequent loss of normal sterols correlates with accumulation of 14 alpha-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole. It has a limited role in the treatment of blastomycosis; however, it can be used as step-down therapy in CNS blastomycosis due to its excellent nervous system penetration.

Voriconazole (Vfend)

A triazole antifungal agent, voriconazole acts by inhibition of fungal cytochrome P-450 and sterol C-14 alpha-demethylation. Voriconazole has good cerebrospinal fluid penetration and has been recommended for step-down therapy from amphotericin B in patients with CNS blastomycosis.