# 113 - 220 Blastomycosis

### 220 Blastomycosis

profoundly hypoxemic and critically ill, many clinicians favor 
beginning therapy with an amphotericin B formulation combined 
with an oral triazole antifungal. The triazole antifungal therapy is 
continued alone once clinical improvement occurs and should be 
continued for 6 months to 1 year.
The nodules that may occur after primary pulmonary coccidi­
oidomycosis do not require treatment. As noted above, these nod­
ules are not easily distinguished from pulmonary malignancies by 
means of radiographic imaging. Close clinical follow-up and biopsy 
may be required to separate these two entities. Most pulmonary 
cavities do not require therapy. Antifungal treatment should be con­
sidered in patients with persistent cough, pleuritic chest pain, and 
hemoptysis. Occasionally, pulmonary coccidioidal cavities become 
secondarily infected (see above). This development is often mani­
fested by an air-fluid level within the cavity. Bacterial oral flora or 
Aspergillus species are commonly involved, and therapy directed 
at these organisms should be considered. Surgical removal of the 
cavity may be required in cases of persistent productive cough and 
hemoptysis or in those cases of a persistently growing cavity. In 
addition, cavities >4 cm in diameter are unlikely to resolve sponta­
neously, and surgical extirpation should be considered. Surgery is 
always required in cases of pyopneumothorax. For chronic pulmo­
nary coccidioidomycosis, prolonged antifungal therapy—lasting for 
at least 1 year—is usually required, with monitoring of symptoms, 
radiographic changes, sputum cultures, and serologic titers.
Most cases of disseminated coccidioidomycosis require pro­
longed antifungal therapy. The duration of treatment is based on 
clinical improvement in conjunction with a significant decline in 
serum CF antibody titer. Such therapy routinely is continued for at 
least several years. Relapse occurs in 15–30% of individuals once 
therapy is discontinued and it is important to continue to monitor 
such patients on a regular basis (e.g., every 3–4 months) after anti­
fungal therapy is discontinued.
Coccidioidal meningitis poses a special challenge. While most 
patients with this form of disease respond to treatment with oral tri­
azoles, 80% experience relapse when therapy is stopped. Therefore, 
lifelong therapy is recommended. In cases of triazole failure, intra­
thecal or intraventricular amphotericin B may be used. Installation 
requires considerable expertise and should be undertaken only by 
an experienced health care provider. Shunting of CSF in addition 
to appropriate antifungal therapy is required in cases of meningitis 
complicated by hydrocephalus. It is prudent to obtain expert con­
sultation in all cases of coccidioidal meningitis.
PREVENTION
There are no proven methods to reduce the risk of acquiring coccid­
ioidomycosis among residents of an endemic region, but avoidance 
of inhalation of uncultivated soil or dust is a reasonable measure. 
For individuals with suppressed cellular immunity, the risk of 
developing symptomatic coccidioidomycosis is greater than that in 
the general population. Among those about to undergo allogeneic 
solid-organ transplantation, antifungal therapy is appropriate prior 
to transplantation when there is evidence of active or recent coc­
cidioidomycosis. Several transplant centers in the endemic region 
provide universal antifungal prophylaxis for 6 months to 1 year 
after solid-organ and allogeneic stem cell transplantation, and 
lifelong universal prophylaxis has been advocated after lung trans­
plantation to prevent the development of coccidioidomycosis after 
transplantation.
Cases of donor-transmitted coccidioidomycosis have been 
reported. Donors who are living or have lived in a coccidioidal 
endemic region should be screened serologically for coccidioido­
mycosis before transplantation and organ donation deferred if there 
is evidence of active infection.
Data on the use of antifungal agents for prophylaxis in other 
situations are limited. The administration of prophylactic anti­
fungals is not recommended for HIV-1-infected persons who live 
in an endemic region. Most experts would administer a triazole 
antifungal to patients with a history of active coccidioidomycosis 

or a positive coccidioidal serology in whom therapy with tumor 
necrosis factor-α antagonists or other biological response modifiers 
is being considered.

There are recent efforts to develop a vaccine for coccidioido­
mycosis, and a live avirulent product has demonstrated promising 
results in a canine model. Future studies will determine if this is a 
viable strategy for preventing or ameliorating coccidioidal infection 
in humans.
■
■FURTHER READING
Galgiani JN et al: 2016 Infectious Diseases Society of America (IDSA) 
clinical practice guideline for the treatment of coccidioidomycosis. 
Clin Infect Dis 63:e112, 2016.
Gorris ME et al: Expansion of coccidioidomycosis endemic regions 
in the United States in response to climate change. Geohealth 3:308, 
2019.
Shubitz LF et al: Δcps1 vaccine protects dogs against experimentally 
induced coccidioidomycosis. Vaccine 39:6894, 2021.
Taylor JW, Barker BM: The endozoan, small-mammal reservoir 
hypothesis and the life cycle of Coccidioides species. Med Mycol 
57:S16, 2019.
Troung CN et al: Universal lifelong fungal prophylaxis and risk of 
coccidioidomycosis in lung transplant recipients living in an endemic 
area. Clin Infect Dis 74:1966, 2021.
CHAPTER 220
Gregory M. Gauthier, Bruce S. Klein

Blastomycosis
Blastomycosis
■
■DEFINITION
Blastomycosis is a pyogranulomatous disease that follows the inhalation 
of Blastomyces conidia or hyphal fragments. Typically, Blastomyces causes 
pulmonary infection; however, a subset of patients will have dissemi­
nated disease that involves organs such as the skin, bone, brain, or geni­
tourinary system. Blastomycosis is considered a primary fungal infection 
because it affects persons with either intact or impaired immune systems. 
A delay in diagnosis is common because blastomycosis mimics other 
diseases such as bacterial pneumonia, tuberculosis, and malignancy. 
Diagnosis involves culture- and nonculture-based tests. Amphotericin B 
formulations and triazoles are the drugs of choice for treatment.
■
■ETIOLOGY
Blastomyces is a species complex comprising B. dermatitidis, B. gil­
christii, B. helicus, B. percursus, B. emzantsi, B. silverae, and B. parvus. 
B. silverae and B. parvus are not known to commonly infect humans. 
Blastomyces species exhibit thermal dimorphism, which involves the 
ability to convert between hyphal and yeast morphologies in response 
to temperature. In the soil (22–25°C), Blastomyces grows as septate 
hyphae that produce infectious conidia. Among the Blastomyces spe­
cies, B. helicus is unique because its hyphae grow in a coiled pattern and 
it does not sporulate under in vitro growth conditions. In organs and 
tissues (37°C), Blastomyces grows as a pathogenic yeast (Fig. 220-1) 
that elicits pyogranulomatous inflammation. The yeast form of all Blas­
tomyces species grows as broad-based budding yeast cells, with subtle 
differences in size among the different species (4–29 μm).
■
■EPIDEMIOLOGY
Although the majority of Blastomyces infections occur in North America, 
blastomycosis is a systemic fungal infection of global importance, with 
infections also occurring in Africa and Asia. In the United States, the 
traditional geographic range for Blastomyces includes the Mississippi

FIGURE 220-1  Blastomyces yeast at 37°C, with broad-based budding between 
mother and daughter cells (arrow). Bar = 10 μm. (Gregory M. Gauthier, MD, MS.)
and Ohio River basins, the St. Lawrence River basin, states bordering 
the Great Lakes, and southeastern states. In Canada, the traditional 
geographic range includes the provinces of Saskatchewan, Manitoba, 
Ontario, and Quebec. In North America, B. dermatitidis is located 
throughout the traditional geographic range. B. gilchristii is geographi­
cally restricted to Minnesota, Wisconsin, Canada, and areas along the 
St. Lawrence River. B. dermatitidis and B. gilchristii are thought to 
have diverged 1.9 million years ago during the Pleistocene epoch, with 

B. gilchristii restricted to formerly glaciated areas. B. dermatitidis is found 
in glaciated and nonglaciated areas. In the environment, B. dermatitidis 
and B. gilchristii are not uniformly distributed; rather, they grow in eco­
logic niches often referred to as microfoci, which are characterized by 
acidic, sandy soils that are found near water and that contain decaying 
organic matter such as vegetation or wood. In upstate New York State, 
blastomycosis is an emerging pathogen in the Capitol District and upper 
Susquehanna River Subbasin with B. dermatitidis (88.4%) more com­
mon than B. gilchristii (11.6%). In Canada, blastomycosis is an emerging 
pathogen in the province of Saskatchewan. B. helicus infections have 
been reported in the western United States (California, Montana, Idaho, 
Colorado, Nebraska, Texas) and Canada (Saskatchewan, Alberta); their 
ecologic niche has yet to be defined. The geographic range and ecologic 
niche for B. parvus and B. silverae are unknown.
PART 5
Infectious Diseases
Outside of North America, blastomycosis has been reported in 
Africa (>100 cases), India (<10 cases), and Israel. On the basis of mor­
phologic analysis, nearly all clinical isolates of Blastomyces in Africa 
were originally thought to be B. dermatitidis. However, molecular 
phylogenetic analysis of human clinical isolates has demonstrated 
that multiple Blastomyces species exist in Africa, including B. derma­
titidis, B. gilchristii, B. percursus, and B. emzantsi. A combination of 
internal transcribed spacer (ITS) sequencing, multilocus sequence 
typing (MLST), and whole genome sequencing was used to identify a 
new species, B. emzantsi, and to differentiate B. percursus from other 
Blastomyces species. MLST has identified a B. dermatitidis isolate from 
Rwanda and B. gilchristii from Zimbabwe and South Africa. Analysis of 
20 isolates from South Africa collected over a 40-year period identified 
them as either B. emzantsi or B. percursus. The geographic distribu­
tion and ecologic niche of the four Blastomyces species in Africa are 
unknown. In India, there have been fewer than 10 autochthonous cases 
of blastomycosis, with the majority identified by morphologic analysis. 
One autochthonous case (caused by B. percursus) with molecular con­
firmation has been reported from Israel.
Epidemiologic information about blastomycosis derives primar­
ily from passive laboratory surveillance, retrospective studies, and 

outbreak investigations. The lack of sensitive skin testing and serologic 
testing, along with difficulty in isolating Blastomyces from the envi­
ronment by culture or molecular methods, has limited an in-depth 
epidemiologic understanding of blastomycosis. In North America, 
blastomycosis is reportable in five U.S. states (Minnesota, Wisconsin, 
Michigan, Arkansas, and Louisiana) and two Canadian provinces 
(Manitoba, Ontario). The annual incidence of blastomycosis in the tra­
ditional endemic area ranges from 0.11 to 2.17 cases/100,000 persons. 
In older persons (Medicare beneficiaries, 1999–2008), the nationwide 
annual incidence of blastomycosis was 0.7/100,000, with the highest 
rates in the midwestern and southern regions of the United States. 
Analysis of Healthcare Cost and Utilization Project (HCUP) data esti­
mated that 11,776 persons were hospitalized for blastomycosis in the 
United States from 2010 through 2020, with the majority of patients 
from midwestern (58.8%) and southern (31.4%) states. In certain 
places, such as Vilas County, Wisconsin, and Kenora, Ontario, blas­
tomycosis is hyperendemic, with annual incidence rates ranging from 
40 to 117 cases/100,000 persons. Incidence data likely underestimate 
the true burden of infection because they are limited to persons with 
clinically apparent infection. Patients with asymptomatic or subclinical 
infections are undercounted.
Most Blastomyces infections are sporadic and can occur in either 
rural or urban areas. There have been at least 20 outbreaks of blastomy­
cosis in the United States since the mid-1950s. Wisconsin, Minnesota, 
and North Carolina have had multiple outbreaks. The majority of 
outbreaks have been in rural areas, but several have occurred in urban 
settings. Activities associated with outbreaks include construction (of 
homes, cabins, factories, and roads), excavation of dirt, participation 
in water sports (canoeing, tubing on a river, and fishing), and exposure 
to a community compost pile or to beaver dams. Blastomyces infection 
is typically acquired from disturbed soil, which liberates infectious 
particles that are then inhaled into the lungs.
An investigation of a blastomycosis outbreak in Marathon County, 
Wisconsin (2009–2010), found that 45% of patients were of Hmong 
ethnicity. A retrospective study from the Marshfield Clinic in Wiscon­
sin (1999–2014) found that 14.4% of patients with blastomycosis were 
of Asian ethnicity—a figure higher than was anticipated given that 
<2.5% of the population within the catchment area is Asian, includ­
ing a large Hmong population. These findings suggest that persons of 
Hmong ethnicity have an increased risk of acquiring blastomycosis. A 
combination of whole genome sequencing and immunologic analyses 
indicated that polymorphisms in the interleukin 6 (IL-6) gene in the 
Hmong population result in decreased IL-6 production, which in turn 
impairs development of IL-17-producing CD4+ T lymphocytes. IL-17 
is a critical cytokine for recruitment and activation of innate immune 
cells such as neutrophils and macrophages active against Blastomy­
ces. Thus, alterations in IL-6 production may be responsible for the 
increased risk of blastomycosis in the Hmong population. Although 
data are limited, persons of Hmong ethnicity do not appear to be at 
increased risk for disseminated blastomycosis. Increased incidence 
rates of blastomycosis have also been reported in indigenous people of 
Canada and the United States. Compared with Caucasians, Asian and 
indigenous persons with blastomycosis tend to have fewer underlying 
medical conditions and to be younger.
■
■PATHOGENESIS
A defining feature of the Blastomyces species complex is the ability 
to respond to shifts in temperature by switching between hyphal and 
yeast forms. In the soil, Blastomyces grows as mold cells with hyphae 
that produce conidia. Hyphal growth promotes environmental sur­
vival, genetic diversity through mating, and production of infectious 
conidia that facilitate transmission of Blastomyces from the environ­
ment to mammals, including humans. At 37°C (the core temperature 
of mammals), Blastomyces hyphae and conidia convert into patho­
genic yeast that upregulate yeast phase–specific virulence factors and 
downregulate host immune defenses, thereby facilitating infection. 
Virulence traits that Blastomyces shares with Histoplasma, Coccidioides, 
Sporothrix, and Paracoccidioides are thermotolerance at 37°C, intracel­
lular survival, and capacity to cause infection in persons with either

healthy or impaired immune defenses. Although Emergomyces and 
Talaromyces marneffei (formerly Penicillium marneffei) exhibit thermal 
dimorphism, growth as yeast at 37°C, and intracellular survival, these 
dimorphic fungi tend to cause infection primarily in immunocompro­
mised persons.
The morphologic switch from hyphae to yeast at 37°C is driven 
chiefly by temperature and is coupled with the uptake of exogenous 
cysteine. Cysteine uptake is required to complete the transition to the 
yeast form because it helps restart mitochondrial respiration, which 
ceases during the morphologic switch. Over the past two decades, 
knowledge about the genetic mechanisms that promote the tempera­
ture-dependent transition between hyphae and yeast has substantially 
increased. The discovery of dimorphism-regulating kinase 1 (DRK1), 
which encodes a group III hybrid histidine kinase that is part of the 
high-osmolarity glycerol (HOG) signaling pathway, provided genetic 
proof that that the transition to yeast is essential for virulence of the 
thermally dimorphic fungi. Disruption of DRK1 by gene deletion or 
RNA interference resulted in Blastomyces cells that grew as hyphae at 
37°C instead of yeast. Although viable at 37°C, these cells had altered 
cell-wall composition, failed to upregulate the Blastomyces adhesin 1 
(BAD1, formerly WI-1) virulence factor, and were avirulent in a mouse 
model of lethal pulmonary infection. Subsequent studies of Histoplasma 
and Talaromyces demonstrated that the function of DRK1 is conserved 
with regard to thermal dimorphism and virulence.
The temperature-dependent transition in the other direction—from 
yeast to hyphae—is regulated in part by a GATA-transcription factor 
encoded by siderophore biosynthesis repressor in Blastomyces (SREB), 
which influences neutral lipid metabolism. In addition, sensing of chitin 
by NGT1 and NGT2 N-acetylglucosamine transporters accelerates the 
conversion to hyphae following a drop in temperature from 37°C to 
22°C. These two mechanisms are conserved in Histoplasma capsulatum.
As a primary fungal pathogen, Blastomyces is one of the few fungi 
that can infect immunocompetent persons. In its yeast form, Blastomy­
ces evades and modulates immune defenses. Following disruption of 
soil, conidia that are aerosolized and inhaled into the lungs are phago­
cytosed by pulmonary macrophages, in which a subset of the conidia 
germinate as yeast and replicate during the early phases of infection. 
Blastomyces is also capable of replicating outside of macrophages. Upon 
conversion to the yeast phase, an essential virulence factor encoded by 
BAD1 is upregulated. BAD1 encodes a multifunctional 120-KDa cellsurface protein that facilitates yeast adherence to lung epithelial cells via 
interaction with heparin sulfate, attachment to host immune cells by 
binding to CR3 and CD14 complement receptors, and downregulation 
of tumor necrosis factor alpha (TNF-α) in macrophages and neutro­
phils. In addition, the BAD1 protein impairs activation of CD4+ T lym­
phocytes, thereby decreasing the production of IL-17 and interferon 
gamma (IFN-γ). In vivo transcriptional profiling of B. dermatitidis 
yeast during pulmonary infection demonstrated that BAD1 is the most 
highly upregulated gene. Deletion of BAD1 renders B. dermatitidis 
avirulent in a murine model of pulmonary infection. Thus, BAD-1 
is essential for virulence in B. dermatitidis and likely in B. gilchristii 
as well. In contrast, BAD1 is absent from the sequenced genomes of 

B. helicus, B. parvus, B. silverae, B. percursus, and B. emzantsi.
Additional factors that contribute to the virulence of Blastomyces yeast 
include relative resistance to oxidative stress, upregulation of catalase 
and superoxide dismutase during infection, active uptake of zinc by a 
PRA1-encoded zincophore and transmembrane transporter (ZRT1), 
and cleavage of granulocyte-macrophage colony-stimulating factor by 
dipeptidyl peptidase IVA, which blocks activation of innate immune cells 
(macrophages, neutrophils) and their recruitment to the lung.
APPROACH TO THE PATIENT
Blastomycosis
On the basis of outbreak investigations, it is estimated that 50% 
of persons exposed to Blastomyces develop symptomatic infec­
tion after a 3-week to 3-month incubation period. The relatively 
long incubation period means that patients can be diagnosed with 

blastomycosis throughout the year. Blastomycosis has been referred 
to as the “the great pretender” because it can mimic infectious and 
noninfectious diseases. Blastomycotic pneumonia clinically and 
radiographically resembles community-acquired bacterial pneu­
monia, viral pneumonia, tuberculosis, and lung cancer. Patients 
often receive two or three courses of antibiotics before pulmonary 
blastomycosis is diagnosed. Without fungal stain and culture, cuta­
neous lesions can mimic skin cancer, sarcoidosis, and pyoderma 
gangrenosum. Rarely, blastomycosis can mimic laryngeal cancer. 
The most important aspect of the approach to a patient with a 
compatible illness is the consideration of Blastomyces as an etiologic 
agent in the differential diagnosis. This awareness facilitates early 
diagnosis and treatment, enhancing the potential for improved 
clinical outcomes. Clinical clues to blastomycosis, especially in 
persons who reside in or visit endemic regions, include pneumonia 
that does not improve with antibiotic treatment, pneumonia with 
extrapulmonary manifestations (e.g., skin lesions, osteomyelitis, 
central nervous system [CNS] involvement), and skin ulcers that 
do not respond to standard therapy. Blastomycosis should also be 
considered in persons from (or visited) an endemic area who have 
unexplained respiratory failure or acute respiratory distress syn­
drome (ARDS). In addition, a detailed exposure history can elevate 
blastomycosis in the differential diagnosis; approximately 50–60% 
of patients will have environmental risk factors for blastomycosis. 
This history should also include inquiries about a pet or family 
member with blastomycosis; these factors have been reported in 
7.7–10% and 4–9% of patients, respectively.
CHAPTER 220
■
■CLINICAL MANIFESTATIONS
Pulmonary Blastomycosis 
Pulmonary manifestations occur in 
69–93% of patients with symptomatic blastomycosis and are the most 
common clinical feature of infection. Signs and symptoms can include 
fever, chills, productive or nonproductive cough, shortness of breath, 
hemoptysis, malaise, and decreased appetite. Pulmonary blastomycosis 
also can manifest as asymptomatic infection, a brief influenza-like ill­
ness, acute pneumonia, chronic pneumonia, or ARDS. Radiographic 
findings in the lungs include lobar consolidation, a mass lesion, inter­
stitial infiltrates, nodule(s), a miliary pattern, cavitary disease, and dif­
fuse involvement of multiple lobes. Hilar adenopathy, pleural effusion, 
and empyema are uncommon. No distinctive features differentiate 
blastomycosis from other pulmonary diseases. Diabetes, receipt of a 
solid organ transplant, immunosuppression, and multilobar pneumo­
nia are risk factors for severe pulmonary blastomycosis. Approximately 
4–15% of patients with pulmonary blastomycosis develop ARDS, 
which is characterized by a fulminant course and high mortality rates 
ranging from 40 to 89% in most studies. The mortality rate in ARDS is 
increased when the diagnosis is delayed.
Blastomycosis
Disseminated Blastomycosis 
Disseminated blastomycosis occurs 
in 15–48% of patients and has the potential to involve nearly any organ 
in the body. The most common site of dissemination is the skin, in 
which the infection can manifest as papules, ulcers, verrucous lesions, 
or abscesses. The second most common site is bone, with consequent 
osteomyelitis characterized by bone pain, soft tissue swelling, soft tissue 
abscess, and sinus tract formation. Typically, a single bone is involved; 
however, multifocal osteomyelitis can occur. The most common sites for 
osteomyelitis include the spine, long bones, and ribs. Dissemination to 
the CNS (e.g., manifesting as meningitis, an abscess, or a mass lesion), 
the larynx, or the genitourinary system (e.g., to the prostate or epididy­
mis) occurs in fewer than 10%; the majority of the affected patients have 
concomitant involvement of other organs, such as the lung or the skin.
Factors that influence dissemination include the infecting Blasto­
myces species, the duration of pulmonary symptoms, and concomitant 
AIDS. Multiple studies from Wisconsin, a state in which B. derma­
titidis and B. gilchristii are endemic, have demonstrated that B. der­
matitidis is more likely to cause disseminated infection (31.4–47.8% 
of cases), whereas B. gilchristii tends to remain localized to the lung 
(90.7–92.2%). Surprisingly, immunosuppression has only a minimal

influence on dissemination, an observation suggesting that Blastomyces 
virulence factors have a greater impact than host immune defenses. The 
frequency of disseminated blastomycosis among solid organ transplant 
recipients, persons receiving cancer chemotherapy, and patients under­
going pharmacologic immunosuppression is similar to that among 
patients with intact immune systems. Although patients treated with 
TNF-α antagonists are considered at risk for blastomycosis, the clinical 
manifestations and frequency of disseminated disease are unknown in 
this group because of a paucity of published data. Persons with AIDS 
and CD4+ T lymphocyte counts of <100/μL are an exception: they are 
at increased risk for CNS dissemination. Blastomycosis in pregnancy 
is uncommon, is typically diagnosed in the second or third trimester 
(91%), and most frequently manifests as pneumonia (74%) or dis­
seminated infection (48%). Transmission to the neonate by either the 
transplacental route or aspiration of infected vaginal secretions is rare. 
Persons infected with B. helicus can have localized pulmonary infection 
or disseminated disease; they are typically immunosuppressed (e.g., as 
a result of solid organ transplantation, chemotherapy, HIV infection, 
or lupus) and have a high mortality rate (71.4% in seven patients). In 
contrast to B. dermatitidis and B. gilchristii, B. helicus commonly causes 
fungemia. Infections with B. percursus and B. emzantsi are often of long 
duration (persisting for 4 weeks to 5 years) and can involve the lungs or 
become disseminated (skin, bone, brain).

■
■DIAGNOSIS
Timely diagnosis of blastomycosis requires a high degree of clinical 
suspicion because its clinical and radiographic presentations mimic 
more common etiologies, such as community-acquired pneumonia, 
malignancy, and tuberculosis. Laboratory findings such as leukocy­
tosis, mild anemia, increased C-reactive protein level, and elevated 
erythrocyte sedimentation rate are nonspecific. Once suspected, the 
diagnosis of blastomycosis is straightforward and involves microscopic 
examination of stained specimens, fungal culture, and antigen testing. 
The poor sensitivity of complement fixation (9%) and immunodiffu­
sion (28%) renders serologic testing diagnostically dispensable. How­
ever, a recently developed serologic test designed to detect antibodies 
to BAD1 has a sensitivity of 87% and a specificity of 94–99%.
PART 5
Infectious Diseases
A presumptive diagnosis of blastomycosis can be made by staining 
of clinical specimens and looking for broad-based budding yeast with 
a doubly refractile cell wall. Along with the broad-based budding pat­
tern, yeast size (4–29 μm) allows Blastomyces to be distinguished from 
other fungi. An exception is B. helicus, which has the potential to be 
confused with Histoplasma because of its small-sized yeast. Respiratory 
tract specimens such as sputum, tracheal aspirate, and bronchoalveolar 
(BAL) fluid can be stained with calcofluor, 10% potassium hydroxide, 
or Papanicolaou stain. Purulent drainage can be stained in a similar 
manner. The sensitivity of staining of respiratory samples ranges from 
50 to 90%. Tissue samples for histopathology should be stained with 
Gomori methenamine silver or periodic acid–Schiff stain and assessed 
for pyogranulomatous inflammation and broad-based budding yeast. 
Traditional stains, such as Gram’s stain or hematoxylin and eosin, do 
not permit optimal visualization of Blastomyces yeast.
Growth of Blastomyces in cultures of respiratory tissue or body 
fluid samples provides a definitive diagnosis of blastomycosis but 
typically requires 5–28 days of incubation. Special media such as 
Sabouraud dextrose, potato dextrose, and brain–heart infusion are 
required because Blastomyces does not grow well on standard bacterio­
logic media. Most clinical microbiology laboratories incubate fungal 
cultures at 25–30°C, a temperature that results in hyphal growth of 
Blastomyces. Unfortunately, Blastomyces hyphae are not morphologi­
cally distinct enough to confirm diagnosis. Thus, fungal identification 
and diagnosis are commonly confirmed via chemiluminescent DNA 
probe or, less commonly, via conversion to yeast upon incubation at 
37°C. Diagnosis can also be confirmed by polymerase chain reaction. 
Neither the chemiluminescent DNA probe nor morphologic analysis of 
yeast by light microscopy differentiates among the different species of 
Blastomyces. Moreover, some species, such as B. emzantsi, are difficult 
to convert to yeast at 37°C. The species of Blastomyces is not typically 
determined in clinical labs because DNA sequencing is required.

An antigen test that detects a conserved galactomannan component 
in the Blastomyces cell wall has supplanted serologic testing. This test 
can be performed on urine, blood, BAL fluid, and cerebrospinal fluid. 
The sensitivity of the antigen test is 85–93% for urine and 57–82% for 
serum. Infection burden appears to influence test sensitivity, with a 
lower burden of infection resulting in reduced sensitivity. The antigen 
test can detect B. dermatitidis, B. gilchristii, and B. helicus; however, its 
utility for detection of other Blastomyces species is unknown. Crossreactions in the antigen test occur during infection with other dimor­
phic fungi, including H. capsulatum (96%), Paracoccidioides species 
(100%), and T. marneffei (70%). Among these, only H. capsulatum is 
found in the same endemic region as Blastomyces. Rare cross-reactions 
can occur with Aspergillus and Cryptococcus infections. Antigen levels 
in urine and blood decline with successful treatment, and their mea­
surement can be used to monitor the response to antifungal therapy.
TREATMENT
Blastomycosis
Guidelines for the treatment of blastomycosis have been published 
by the Infectious Diseases Society of America (2008), the American 
Thoracic Society (2011), the American Society of Transplanta­
tion (2019), and European Confederation of Medical Mycology 
(2021). Although there are isolated reports of self-limited pul­
monary blastomycosis, there are no criteria to determine which 
patients will experience a resolution of infection. Thus, treatment 
is recommended for all patients with blastomycosis in order to 
prevent progressive infection, respiratory failure, and disseminated 
disease. Antifungal selection is influenced by immune status, CNS 
involvement, pregnancy, medical comorbidities (e.g., congestive 
heart failure, prolonged QT interval), and drug–drug interactions. 
Antifungal drugs active against Blastomyces include amphotericin B 

(AmB) formulations and triazoles. The minimal amount of beta-
(1,3)-glucan in the Blastomyces yeast cell wall renders echinocan­
dins ineffective, and they should not be used to treat blastomycosis. 
Hematologic, hepatic, and renal function should be assessed prior 
to initiation of antifungal therapy, and possible drug–drug interac­
tions should be evaluated. In addition, patients should be educated 
about proper administration of triazole antifungals. For example, 
itraconazole capsules require an acidic gastric environment for 
optimal absorption and should be taken with food and an acidic 
beverage to improve bioavailability; they cannot be used by persons 
taking antacids, H2 antagonists, or proton pump inhibitors. In con­
trast, itraconazole solution can be given to patients receiving gastric 
acid–lowering therapies and should be taken without food.
Treatment for blastomycosis is summarized in Table 220-1. For 
immunocompetent patients with pulmonary or disseminated blasto­
mycosis of mild or moderate severity (e.g., treatable in the outpatient 
setting), itraconazole therapy for 6 months is recommended. For 
severe blastomycosis (e.g., that requiring hospitalization), induction 
therapy with lipid AmB for 7–14 days (or until clinical improve­
ment), followed by itraconazole treatment for 6–12 months, is 
recommended. Although not well studied, combination antifungal 
therapy with lipid AmB and itraconazole (or another azole) can be 
considered for patients with severe pulmonary blastomycosis. In 
patients with ARDS, prednisone can be considered; however, the 
benefits of steroids are unclear. Osteomyelitis due to blastomycosis 
requires at least 12 months of antifungal therapy, and some patients 
may require surgical debridement. For blastomycosis involving the 
CNS, lipid AmB is administered for 4–6 weeks and is followed by 
treatment with voriconazole, itraconazole, or fluconazole for at least 
12 months. Although fluconazole has excellent CNS penetration, its 
minimum inhibitory concentration (MIC) against B. dermatitidis 
and B. gilchristii is higher than that of either itraconazole or vori­
conazole. Emerging data suggest that isavuconazonium sulfate can 
be used for treatment of CNS blastomycosis.
Immunosuppressed patients should be treated with 7–14 days 
of lipid AmB followed by 12 months of itraconazole. For patients