Blastomycosis

1. 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.

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 cases and may present
with:
 Cutaneous lesions – Usually either verrucous or ulcerative and may be
asymptomatic
 Osteoarticular lesions – Cause bone or joint pain; soft-tissue swelling possible;
possible involvement of any bone may be involved, but the vertebrae and pelvis are
common sites
 Genitourinary manifestations including prostatitis and epididymitis – May be
asymptomatic or may cause pain on urinating
 Other sites – Blastomycosis dermatitidis has been reported to involve almost all
organs including the eye, liver, sleep, breast, thyroid, and adrenal gland.
 Central nervous system involvement – Intracranial or epidural abscesses and
meningitis
See Clinical Presentation for more detail.
Diagnosis
Diagnostic studies include the following:
 Sputum specimens processed with 10% potassium hydroxide, cytology smears, or a
fungal stain
 Culture of sputum or tissue specimens
 Enzyme immunoassay (EIA) techniques on sputum, tissue, or bronchoscopic
specimens
 Imaging studies (eg, chest radiography, CT, MRI)
See Workup for more detail.
Management
Antifungal treatment is as follows:
 Patients with mild to moderate pulmonary disease - Oral azole such as itraconazole
 Patients with moderate-to-severe disseminated disease or immune compromise -
Initial amphotericin B with step-down to an oral azole after clinical improvement
 CNS disease should always be treated with amphotericin B initially

Background
Blastomycosis is a fungal infection caused by inhalation of aerosolized
conidia (spores) of Blastomyces dermatitidis. Clinical presentations occur
across a wide spectrum, ranging from an asymptomatic, self-limited
pulmonary infection to widely disseminated life-threatening disease.
Blastomycosis is endemic to the United States and Canada and most
cases are clustered around the Mississippi and Ohio River Valley states
and Canadian provinces around the Great Lakes. Within the United
States, the most commonly affected states are Arkansas, Illinois,
Kentucky, Louisiana, Mississippi, North Carolina, Tennessee, and
Wisconsin. Prior epidemiologic studies reported a higher incidence of
infection in men; however, some of these studies were from Veterans
Administration medical centers, which provided a male bias to the data.
More recent series have shown no predilection for any sex, age, race, or
occupation or any seasonal variation. Rather, exposure to soil is the
common factor associated with contracting this disease. Blastomycosis is
rare in children and is recognized increasingly in immunocompromised
hosts, particularly in patients with acquired immune deficiency syndrome
(AIDS). [1] (See Epidemiology.)
The diagnosis of blastomycosis is readily obtained by microscopic
identification of the fungus in the affected body fluid or tissue specimens
followed by confirmatory culture. Culture is usually positive within 2-4
weeks. In one 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. [2] (See Workup.)
Chest imaging findings are nonspecific and may range from scattered
centrilobular nodules to areas of dense consolidation on high resolution
computed tomography (CT). (see Workup.)
Oral azoles, usually itraconazole or amphotericin B are the first line
treatment for blastomycosis depending on the severity of disease, clinical
form, and immune status of the host. In general, mild-to-moderate
disease is typically treated with oral itraconazole except in pregnant
women and those with CNS disease who should always receive
amphotericin B. Moderately severe to severe disseminated disease
should receive amphotericin B followed by a long-term oral azole when
they clinically improve. [3]
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.
Patients with severe disease occasionally require even longer treatment.

Pathophysiology
Blastomycosis is a systemic pyogranulomatous infection caused by the
inhalation of conidia (spores) of Blastomyces dermatitidis, the asexual
(imperfect) form of Ajellomyces dermatitidis, dimorphic fungus. The
mycelial form grows as a fluffy white mold at 25°C and a brown folded
yeast at 37°C. The conidia are round, ranging from 2-10 μm in diameter.
Conidia 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, B dermatitidis convert
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.
Another virulence factor is the expression of BAD-1, an immune-
modulating glycoprotein that is expressed on the cell surface and
released into the extracellular matrix. [4] 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. [4]
Blastomycosis may be asymptomatic in nearly 50% of infected person. In
the remainder, the median incubation period from inhalation of the fungus
to manifestations of symptoms is 45 days (range 21-106 d). 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 and in one study, pulmonary
involvement was present 91% of all cases. [5] Pulmonary symptoms range
from acute and chronic pneumonias to 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: [5]
  Bone - 5%
 Prostate and other genitourinary organs - 2%
 Meninges and brain - 1%
 Other (lymph nodes, adrenal, eye, liver, sleep, 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 only rarely a site of reactivation.
As dogs are infected in a similar way and often in the same place as
humans, an early clue to a 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. [6] Blastomycosis has also been
reported in other animals, including the horse, cow, cat, bat, and lion.

Etiology
Blastomyces 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 and a brown folded yeast at 37°C,
body temperature. The fungus is usually isolated in the soil in its mycelial
form wet earth that has been enriched with animal droppings, rotting
wood, and other decaying vegetable matter.
The conidia are round, ranging from 2-10 μm in diameter. Conidia
become aerosolized when the fungus in the mycelia phase is disturbed.
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.

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. [7] The disease is endemic in the central and
southeastern parts of the country, near the Mississippi River, Ohio River,
and Great Lakes. The states commonly affected are Arkansas, Kentucky,
Mississippi, North Carolina, Tennessee, Louisiana, Illinois, and
Wisconsin. [8]
The true incidence and prevalence are unknown, because there are no
reliable antigen markers for skin testing. Based on confirmed cases, the
annual incidence is less than 1 case per 100,000 people in Mississippi,
Kentucky, Arkansas, and Wisconsin. Within the endemic areas (eg, Vilas
County, Wisconsin), infection in hyperendemic foci is reported at an
annual incidence rate of 40 per 100,000. [9] and 3-6 cases per million
persons require hospitalization annually. [10]
National data are limited, but analysis of the 2002 Nationwide Inpatient
Sample (NIS), a national database of hospital inpatient stays, revealed
703 adults and children with blastomycosis were hospitalized in US
hospitals. [11]
Significant construction, such as interstate road expansion, can
release Blastomyces spores from the soil. [12] One such urban outbreak
was the identification of 34 confirmed cases of blastomycosis in
Indianapolis from 2005-2008, which coincided with a period of major
highway construction in the same area. [12] Residence near rivers and
waterways is also associated with an increased risk of blastomycosis. In
Vilas County, north-central Wisconsin, 73 patients with laboratory-
confirmed blastomycosis were identified over an 11-year period, and 82%
of these patients lived or had visited within 500 m of rivers or associated
waterways. [13]
Canine blastomycosis can be an early warning sign for concomitant
blastomycosis in humans. One case series of 5 households in which 6
patients were diagnosed with blastomycosis, one or more pet dogs were
diagnosed with blastomycosis on average 6 months before the patients
became symptomatic.[6]
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 [14] and
Zimbabwe, [15] although cases have been seen in Nigeria [16] and
Tunisia. [17, 18] Often the disease is mistaken for pulmonary tuberculosis or
malignancy, and only after lack of response to standard treatment is the
diagnosis made. [16, 15, 19] Cases have also been reported from disparate
regions, including Mexico, South America, the Middle East, and India.
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, [20] and an analysis of Missouri cases in which 57% of those
affected were black although blacks account for only 13% of the
population. [21] 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 because of greater occupational and recreational exposure. Men
were more likely to participate in activities associated with B
dermatitidis, such as fishing, hunting, and camping. In Wisconsin from
1986-1995, 60% of cases were in males. [22] However, analysis of
outbreak cases from a common source and recent reports do not indicate
a significant sex difference. [23] Additionally, historically, epidemiological
reports were skewed due to the collection of data from Veterans
Administration (VA) hospitals nationwide, which serve predominantly
male patients. [24]
The mean age at diagnosis is approximately 45 years. Most patients are
30-69 years of age; however, persons of any age can acquire the
disease. Blastomycosis also occurs in infants and in very elderly
persons. [25]
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 from 1983-1995. [26] 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 generally do not experience complications
and can expect a full recovery. In contrast, prognosis is poor for
immunocompromised patients with blastomycosis. Cellular immunity is
the fundamental host defense against B dermatitidis. The loss or
compromise in T-lymphocyte function, for example in HIV/AIDs or
immune suppression after solid organ transplant, can predispose to
severe disseminated disease, cavitary lung disease, and often involves
the CNS. [27, 28, 29]
Mortality rates of 30-40% have been reported in patients with AIDS who
develop blastomycosis. Pulmonary disease complicated by respiratory
failure and acute respiratory distress syndrome (ARDS) has a high
mortality rate with only 3 out of 10 surviving to long-term follow up in one
small case series. [30] In another series, 8% of patients with pulmonary
blastomycosis had ARDS, 78% of whom died of respiratory
failure. [28] Most deaths tend to occur within the first few weeks of therapy.
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 ARDS occurs in approximately 20% of
compromised hosts.[30] CNS disease appears to be 3-5 times more
common in immunocompromised patients than in normal hosts.
Meningitis or mass lesions 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, nodules, an
extensive cutaneous lesions may undergo central healing with scarring
and contracture.
Osteomyelitis occurs in approximately 25% of extrapulmonary
cases, [8] 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 abscess.
Mortality/morbidity
Retrospective reports in the 1960s indicated a mortality rate of 42% in
untreated blastomycosis and 5% in treated cases. Reports in the 1990s
indicated a mortality rate of 0-2% in treated cases among
immunocompetent patients. In contrast, the mortality rate is 29% in
immunocompromised patients (eg, transplant recipients, patients
receiving immunosuppressive or cytotoxic therapy [27] ) and 40% in the
subgroup of patients with AIDS. [1] The reported mortality rate of patients
presenting with ARDS is 68%. [30] Most deaths occur within the first few
weeks of therapy.
 2. PRESENTATION

History
Patients with blastomycosis may present with any of several patterns of
illness and 30-50% of persons infected may remain asymptomatic. A
flulike illness with fever, chills, myalgia, headache, chest pain, and a
nonproductive cough may occur, 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; 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. Sputum is mucopurulent or purulent, and
hemoptysis may be present. Often these patients receive multiple
courses of antibiotics before the diagnosis is made.
Other patients, often older patients or those with immune compromise,
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.
Extrapulmonary features may include the following:
 Skin lesions – The skin is the second-most common site of spread
after the lungs. The commonly seen skin manifestations are a
purplish-gray verrucous lesions with heaped borders or friable
lesions that ulcerate. Micro-abscesses and subcutaneous nodules
can also be seen.
 Bone lytic lesions – Seen in 25% of cases with extrapulmonary
manifestations, [8] this 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, [6]and rare cases of endometritis and tubo-ovarian abscess
have been reported in women.
  Central nervous system 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, findings may be present
that are 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. Early
in the disease course, the lesions are sharply demarcated papules or
pustules, or 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.
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 atrophic scar studded with
telangiectasia.
Although the vast majority of patients with cutaneous blastomycosis acquire it by
dissemination from a pulmonary focus, 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.
Bone involvement rarely leads to a draining abscess. The involved joint may be
tender and swollen.

3. 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. Other pulmonary disorders
to consider in the differential diagnosis are sarcoidosis, tuberculosis, and other
endemic mycoses.
Blastomycosis has a propensity to mimic carcinoma. Pulmonary blastomycosis
may resemble lung cancer, and blastomycosis osteomyelitis may resemble bony
metastasis. The typical verrucous or ulcerative cutaneous lesions of blastomycosis
may mimic skin cancers, such as basal cell carcinoma and squamous cell
carcinoma. Central nervous system blastomycosis may resemble brain neoplasm.
Skin disorders to consider include the following:
 Squamous Cell Carcinoma
 Pyoderma Gangrenosum
 Keratoacanthoma
 Halogenoderma
 Chromoblastomycosis
 Atypical mycobacterial infection
 Tuberculosis verrucosa cutis
 Lupus vulgaris
 Blastomycosislike pyoderma
Differential Diagnoses
 Actinomycosis
 Aspergillosis
 Bacterial Pneumonia
 Cryptococcosis
 Histoplasmosis
 Influenza
 Metastatic Cancer With Unknown Primary Site
 Sarcoidosis
 Sporotrichosis
 Tuberculosis
 Viral Pneumonia

4. WORKUP

Approach Considerations
There are no clinical presentations or imaging abnormalities that provide
a definitive diagnosis of blastomycosis. Direct visualization of B
dermatitidis is essential in order to provide a definitive diagnosis. For
most specimens, direct visualization should precede culture to confirm the
diagnosis. Sputum specimens processed with 10% potassium hydroxide
or a 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.
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 the commercially available chemiluminescent DNA
probe (AccuProbe; GenProbe Inc., San Diego, CA). Although it produces
a positive result with all Paracoccidioides brasiliensis species, 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. Newer tests that use more specific cell
wall antigens, radioimmunoassays (RIAs), and Western blot techniques
have improved sensitivity and specificity but are not yet available for
widespread clinical use. [2, 31]
Skin testing is not reliable for diagnosis and is not commercially available.
Antigen detection in serum and urine lacks specificity.
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 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 organ (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. [32]
Diagnosis of central nervous system blastomycosis is difficult. Lumbar
puncture and cerebrospinal fluid 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 out of 22
patients with confirmed blastomycosis meningitis.
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, and although the
overall sensitivity of this test is modest (less than 40%), the potential for
rapid identification of the pathogen makes it a reasonable initial
option. [2] 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 micrometers in size, with single,
broad-based buds, double refractile walls, and multiple nuclei, are
extremely characteristic of Blastomyces dermatitidis.
Microscopic examination of a potassium hydroxide wet mount can also be
performed on aspirated pus, fistulae, or subcutaneous abscesses. These
will reveal characteristic broad-based budding yeast. Identification of B
dermatitidis by calcofluor 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 UV light
from a fluorescent microscope.

Culture
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. 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.
Because primary cutaneous blastomycosis has been reported by
accidental autoinoculation, clinical laboratory personnel and pathologists
should be notified about the possibility of blastomycosis in the differential
diagnosis 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, and cross-reactivity with other fungi. A recently developed
enzyme immunoassay with the A-antigen of B dermatitidis has been
shown to be more sensitive than CF and ID tests; 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 small case series of four patients with
Blastomycosis, β-d-glucan was detected in only one patient with
disseminated disease.

Chest Radiography
Chest radiograph findings 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 vary but, in
many cases, demonstrates lobar or segmental airspace opacities. A focal
mass is common with well-defined margins and can range from 5-10 cm
in size. These masses may be mistaken for neoplasm. Cavitary lesions
are uncommon in immunocompetent patients.
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 an example of chest radiography findings in the image below.
Lateral chest radiograph reveals the ill-defined lingular opacity and an absence of
pleural effusions.

Computed Tomography
Chest computed tomography (CT) is not always necessary, but can
provide better definition of the character and distribution of abnormalities
observed on a chest radiograph and 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. Magnetic resonance imaging is
more sensitive for this purpose, however, and a radionuclide bone scan is
also an alternative.

Bronchoscopy
Bronchoscopy has a higher sensitivity than sputum examination and
yields a positive diagnosis in 92% of patients with pulmonary
blastomycosis. 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

In recent years, serious infection with blastomycosis has been recognized
increasingly in immunocompromised hosts, especially patients with 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 Blastomyces 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. On the other hand, the
hyperplastic epidermis lacks the cytological 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;
organisms are best visualized with the diastase-digested periodic acid-
Schiff staining procedure or with the methenamine silver stain. 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
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 8-15 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.

5. 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.
Therapeutic approaches have evolved in recent years with the advent of
oral azoles, primarily itraconazole, which has replaced amphotericin B for
mild-to-moderate pulmonary blastomycosis in adult patients, and is used
for completion of therapy after initial amphotericin treatment in more
severe cases. [3, 33, 34, 35]Voriconazole may have a role in the treatment of
CNS blastomycosis. [36, 37]
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 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).

Antifungal Treatment
Amphotericin B and itraconazole continue to be the main drugs used in
blastomycosis. Clinical data on using newer drugs (ie, posaconazole,
caspofungin, micafungin) for the treatment of blastomycosis are
insufficient.
Itraconazole is the drug of choice in mild-to-moderate pulmonary
blastomycosis. It offers the 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. [3] However, it
has a worse safety profile than itraconazole and higher relapse rates.
Patients with mild-to-moderate disseminated blastomycosis without 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. [30] A high incidence of
serious adverse effects has been reported with ketoconazole, along with
relapse rates of 10-14%. [3] 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. [3]
If 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, ARDS) or
extrapulmonary, should be treated with amphotericin B at a high dose of
0.7-1 mg/kg/d 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
dosage recommended is the same as in life-threatening
disease. [3] Liposomal amphotericin B can also be used for severe disease
at a dose of 3-5 mg/kg per 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. [3]

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. [37] Current 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 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 per day for 4-6 weeks followed by an oral azole for at least one year.
Voriconazole, a newer antifungal agent, has good cerebrospinal fluid
penetration. [38, 39]
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 AIDS with 30 mg/kg of
amphotericin B over 4-6 weeks, followed by itraconazole for at least 6 months in
those who have responded to a primary course of amphotericin B.
Blastomycosis should be treated in pregnant women. Liposomal amphotericin B, 3-
5 mg/kg per day, is recommended. Azoles are contraindicated because of possible
teratogenicity embryotoxicity.

Consultations
Since 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
specialist (pulmonologist or infectious disease specialist) for diagnosis
and treatment recommendations. Consult a pulmonologist or an
intensivist for patients who present with or develop 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). Alert the microbiologist to the possibility of
blastomycosis before sending any specimen to the laboratory, 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, Mississippi, and Wisconsin,
blastomycosis is a reportable disease, and the treating physician needs to
contact the state department of health.

Deterrence/Prevention
Ongoing studies of cell wall properties of Blastomyces dermatitidis are
promising for the development of a preventive vaccine. Such a vaccine
could be targeted to patients at high risk of exposure and
immunocompromised patients.[40]
Although immunocompromised patients (including those with 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).
No specific data are available regarding blastomycosis in children with
HIV. Nevertheless, administering lifelong suppressive therapy with
itraconazole after an acute episode of the disease is reasonable.

6. MEDICATION

Medication Summary
Medication for the treatment of blastomycosis should be selected on the
basis of the type, extent, and severity of 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 antifungals 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
 View full drug information
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)
 View full drug information
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)
 View full drug information
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.
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
 View full drug information
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)
 View full drug information
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)
 View full drug information
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.