Clinical manifestations and diagnosis of blastomycosis

INTRODUCTION — Blastomycosis is a systemic pyogranulomatous infection that arises after inhalation of the conidia of the thermally dimorphic fungus Blastomyces dermatitidis or Blastomyces gilchristii. Most cases of blastomycosis have been reported in North America.

Blastomyces is a member of the family Ajellomycetaceae and order Onygenales. Fungal nomenclature has been changing based on multilocus phylogenetic analyses and sequencing, and Blastomyces helicus, Blastomyces parvus, Blastomyces silverae, and Blastomyces percursus have been placed in the genus Blastomyces rather than the genus Emmonsia [1,2]. B. helicus has been associated with disease in a small number of immunocompromised humans and domestic animals [3].

The clinical manifestations and diagnosis of blastomycosis will be reviewed here. The mycology, pathogenesis, epidemiology, and treatment of blastomycosis are discussed separately. (See "Mycology, pathogenesis, and epidemiology of blastomycosis" and "Treatment of blastomycosis".)

CLINICAL MANIFESTATIONS

Spectrum of disease — The clinical manifestations of blastomycosis are varied and include asymptomatic infection, acute or chronic pneumonia, and extrapulmonary disease [4]. Up to 50 percent of blastomycosis infections are asymptomatic [5-9]. The incubation period from exposure until the onset of pulmonary symptoms is approximately three to six weeks [6]. The incubation period from exposure to the onset of extrapulmonary symptoms is highly variable. Reactivation (both with pulmonary and extrapulmonary symptoms) can occur in immunocompromised patients (eg, individuals taking tumor necrosis factor (TNF)-alpha inhibitors or corticosteroids).

Although blastomycosis has been reported to involve almost every organ, the lungs are the most common site of infection, followed by the skin, bones, and genitourinary system [10,11]. As an example, in a study of 326 patients with blastomycosis, the following distribution of organ involvement was observed [10]:

●Pulmonary – 91 percent

●Skin – 18 percent

●Bone – 4 percent

●Genitourinary – 2 percent

●Central nervous system (CNS) – 1 percent

●Other (laryngeal involvement, soft tissue, lymphatic, esophageal, joint, and tracheal involvement) – 3 percent

In this study, 56 patients (17 percent) had multiorgan involvement, primarily involving either the lungs (95 percent) and/or the skin (77 percent).

Extrapulmonary disease results from hematogenous spread from a primary pulmonary infection. Studies performed prior to the availability of effective therapy indicated that approximately two-thirds of patients with blastomycosis had multiorgan involvement [12,13] and that the disease was progressive with reported mortality rates of up to 90 percent [14]. However, most of these earlier studies were autopsy based; thus, multiorgan disease was probably overrepresented. Later reports in Arkansas [15], Wisconsin [16], Mississippi [10], and Manitoba, Canada [17] described a lower frequency of extrapulmonary disease.

Pulmonary involvement — The lungs are the usual portal of entry for blastomycosis. Patients may present with either acute or chronic pneumonia, although chronic pneumonia is more common. Acute respiratory distress syndrome (ARDS) associated with blastomycosis has also been reported [11,18].

In a study that included 326 patients with blastomycosis, the following presenting symptoms were observed [10]:

●Cough – 73 percent

●Fever – 54 percent

●Sputum production – 50 percent

●Chest pain – 41 percent

●Shortness of breath – 38 percent

●Weight loss of at least 5 percent – 37 percent

●Night sweats – 31 percent

●Chills – 28 percent

●Hemoptysis – 23 percent

Other symptoms may include arthralgias, myalgias, and pleuritic chest pain.

Acute pneumonia — Acute infection is frequently unrecognized unless related to an epidemiologic cluster of cases. The signs and symptoms of acute pulmonary blastomycosis usually begin abruptly three to six weeks after infection and are often indistinguishable from viral or bacterial pneumonia [4]. Occasionally, pneumonia may occur months to years after leaving the area of exposure [19].

Patients with blastomycosis often have a history of pet dogs that are ill with pneumonia or have died from blastomycosis, suggesting that both humans and their pets have become infected by aerosol inhalation from the environment. Obtaining this history can be a valuable clue to the diagnosis of possible blastomycosis in a patient presenting with community-acquired pneumonia [20].

Cough is initially nonproductive but often becomes productive of purulent sputum as the disease progresses. Patients may also experience fever, shortness of breath, weight loss, night sweats, and/or other pulmonary or constitutional signs and symptoms. (See 'Pulmonary involvement' above.)

Laboratory findings are similar to those found in other forms of community-acquired pneumonia, such as leukocytosis and elevated inflammatory markers.

Chest radiography most commonly reveals alveolar infiltrates or a mass lesion, although miliary or reticulonodular patterns can also occur [21,22]. Chest computed tomography (CT) scanning may show nodules, consolidation with or without cavitation, and/or tree-in-bud opacities (image 1 and picture 1) [23]. Small pleural effusions are frequent. The lack of significant hilar adenopathy may be helpful in distinguishing blastomycosis from histoplasmosis, in which adenopathy is common. (See "Pathogenesis and clinical features of pulmonary histoplasmosis".)

Spontaneous resolution of acute pulmonary blastomycosis has been reported, but its frequency is unknown; patients with extrapulmonary manifestation often describe prior lung infection [9,24].

Acute respiratory distress syndrome (ARDS) — Rarely, patients may present with diffuse pneumonitis associated with ARDS [4,25-27]. In a series of 114 patients with blastomycosis from Indiana, ARDS was found in 17 percent [11]. In a retrospective cohort study of 1848 patients hospitalized with blastomycosis, patients requiring mechanical ventilation (12 percent) had higher mortality compared with patients who did not require mechanical ventilation (40 versus 2.5 percent) [28]. Mortality rates in mechanically ventilated patients were similar to mortality rates seen in patients with moderate to severe ARDS from all causes. In another small case series, the mortality rate associated with ARDS due to blastomycosis was over 50 percent [25,26], and most deaths occurred during the first few days of treatment [26].

Chronic pneumonia — Patients diagnosed with blastomycosis may have a chronic pneumonia that is clinically similar to tuberculosis, other fungal infections (eg, histoplasmosis), or bronchogenic carcinoma [4]. Diagnosis is often delayed for more than one month, even when patients seek medical attention within seven days of onset of illness, allowing patients to transition from acute to chronic pneumonia [10]. Many of these patients receive multiple rounds of antibiotics before the diagnosis is established. Additionally, some patients are initially asymptomatic but progress over time into the chronic form of blastomycosis. Symptoms include low-grade fever, productive cough, hemoptysis, chest pain, and/or weight loss.

Laboratory findings are nonspecific and may include leukocytosis, thrombocytosis, and elevated inflammatory markers (eg, erythrocyte sedimentation rate, C-reactive protein). However, many infected individuals may not have any laboratory abnormalities.

The radiographic findings are varied. Alveolar infiltrates with or without cavitation, mass lesions, and fibronodular infiltrates are most common [4,10]. Infiltrates are more frequently reported in the upper lobes. Small pleural effusions and pleural thickening have been reported, but large pleural effusions are uncommon. Significant pleural involvement was associated with a poor outcome in one series [29].

Extrapulmonary blastomycosis — Although extrapulmonary disease has been reported in over 50 percent of patients with chronic blastomycosis, most of these studies were autopsy based or were published prior to the availability of effective therapy [12,13,30-34]. In contrast, more recent studies have documented multiorgan disease in approximately 20 percent of patients [10,15-17]. Extrapulmonary disease can be seen with or without active pulmonary infection (usually chronic pneumonia) and in the absence of systemic symptoms (see 'Spectrum of disease' above). Many forms of extrapulmonary blastomycosis (bone, prostate, breast, thyroid) occur after the pulmonary infection has resolved and in the absence of systemic symptoms.

Skin — Skin disease is the second most common manifestation of blastomycosis after pneumonia. The majority of cutaneous lesions are from hematogenous spread, and very few are from direct inoculation. Almost all purported inoculation infections are likely due to silent pulmonary infection followed by hematogenous spread [4,35]. The mold form of B. dermatitidis that exists in the environment causes infection via inhalation with subsequent transformation of the organism in the respiratory tract to the yeast form, which is responsible for clinical disease. Trauma to the skin is known to precede discovery of bacterial [36] or fungal [37] infection that has spread hematogenously to the site of trauma, giving rise to the supposition that the organisms were directly inoculated.

The characteristic cutaneous finding is a verrucous lesion, with irregular borders (picture 2 and picture 3 and picture 4). The color may range from gray to violet. This lesion may mimic squamous cell carcinoma. Microabscesses form at the periphery of verrucous lesions, and biopsies taken from the margins usually reveal broad-based budding organisms on microscopy. Ulcerative lesions that bleed easily and have well-demarcated, heaped-up borders may also occur (picture 5 and picture 6) [4].

Subcutaneous nodules are cold abscesses that can be seen in patients with disseminated disease (picture 7). Microscopic examination from these lesions reveals broad-based budding yeasts typical of Blastomyces (picture 8 and picture 9).

Bone and joint — Osteomyelitis is the next most common extrapulmonary manifestation of blastomycosis after cutaneous involvement, occurring in up to one-quarter of cases of patients with multiorgan disease [38]. A retrospective study of 45 patients hospitalized with blastomycosis of the bones or joints revealed that cutaneous disease was present in 33 (73 percent) and pulmonary disease in 29 (64 percent) [39]. This study is consistent with results from the University of Mississippi Medical Center, in which patients with isolated skin disease were at risk for infection in other nonpulmonary sites [10]. Any bone may be involved, although the most common are the vertebrae, pelvis, and sacrum [4].

Patients often present with soft tissue swelling or a chronic draining sinus tract adjacent to the focus of osteomyelitis [4]. There is usually little or no bone pain associated with osteomyelitis due to blastomycosis.

A well-circumscribed, osteolytic lesion is the most common radiographic finding. Vertebral disease can be radiographically similar to tuberculosis, with anterior involvement of the vertebral body and destruction of the disc interspace [40]. Paravertebral abscesses are also commonly associated with vertebral blastomycosis [41]. Biopsy of bone lesions caused by Blastomyces dermatitidis may reveal granuloma formation, suppuration, and/or necrosis [4].

Arthritis due to blastomycosis usually results from direct extension from osteomyelitis and may be acute or chronic in its presentation.

Genitourinary system — Extrapulmonary blastomycosis occurs more commonly in men; genitourinary system involvement presents as prostatitis and epididymoorchitis [42,43]. Some patients have asymptomatic pyuria. Urine cultures are more likely to be positive if specimens are obtained after prostatic massage and the sediment is cultured after centrifugation.

Rare cases of tuboovarian abscess or endometritis have been reported in women [44]. In one case report, a woman acquired blastomycosis by sexual transmission from a man who had disseminated disease [4].

Central nervous system (CNS) — Blastomycosis of the CNS is uncommon in immunocompetent hosts and has been reported in fewer than 5 percent of cases. CNS involvement may occur in immunocompromised patients, especially those with acquired immunodeficiency syndrome (AIDS) [45]. In a retrospective study of patients with human immunodeficiency virus (HIV) and blastomycosis, 6 of 15 had CNS involvement, usually manifested as single or multiple brain abscesses [45]. However, in another review, 10 of 22 patients with CNS blastomycosis were not considered to be immunosuppressed [46]. Of note, 17 of the 22 patients had evidence of blastomycosis in other organs as well.

CNS infection may present as meningitis, epidural abscess, or intracranial abscesses, particularly in the cerebellum [46]. If meningitis is present, cerebrospinal fluid (CSF) analysis typically shows lymphocytic pleocytosis with elevated protein and low glucose.

Other sites — B. dermatitidis has been reported to involve almost every organ, including lymph nodes, liver, spleen, breast, adrenal gland, thyroid, and eye [4]. Blastomycosis has also been reported in the mucosa of the nose, mouth, and larynx.

Special populations

Children — An estimated 10 percent of patients reported with blastomycosis are children [5,17,47]. The clinical spectrum in pediatric disease is similar to that in adults.

Pregnancy and perinatal transmission — Blastomycosis has been reported, albeit infrequently, during pregnancy. Pregnant women are more likely to have disseminated disease than nonpregnant individuals; this may be related to the depressed cellular immunity associated with pregnancy [48].

Perinatal transmission has been documented. Infection may result from aspiration of infected vaginal secretions during childbirth [49], an ascending vaginal infection associated with premature rupture of the membranes, or transplacental infection.

Immunocompromised hosts — Blastomyces can behave as an opportunistic pathogen, especially in patients with AIDS, transplant recipients, those who are taking certain immunocompromising agents (eg, glucocorticoids, TNF-alpha inhibitors), and other immunocompromised patients [4,50-52]. Pulmonary disease tends to be more severe in immunocompromised hosts, including higher mortality rates and findings of diffuse pulmonary infiltrates, large pleural effusions, and/or respiratory failure. As an example, in a retrospective review of 106 patients, those who were immunocompromised had more severe infections, higher rates of respiratory failure, and higher mortality rates compared with immunocompetent patients [53]. In contrast to other endemic mycoses (eg, histoplasmosis, coccidioidomycosis), immunosuppression has not been associated with increased risk of dissemination in blastomycosis. These findings suggest that pathogen-related factors may play a larger role in risk of dissemination than the immune status of the host [53].

Frequent relapses have been reported in patients with AIDS and in patients who remain on immunosuppressive therapy. This is discussed in detail separately. (See "Treatment of blastomycosis", section on 'Immunocompromised patients'.)

Infection with B. helicus has been described in a small number of humans in western Canada and western United States [3]. In this report, six of the seven patients with available clinical data had immunocompromising conditions, including HIV/AIDS, liver transplantation, lupus erythematosus, chronic leukemia with use of corticosteroids, and diabetes mellitus with concurrent alcoholism [3]. The organism was isolated in cultures of blood, CSF, and/or bronchoalveolar fluid, and only two of the seven patients survived.

DIAGNOSIS

When to suspect blastomycosis — Timely diagnosis of blastomycosis warrants a high index of clinical suspicion, since the infection is uncommon and not easily diagnosed with routine culture methods. Blastomycosis should be suspected in a patient who resides in or has recently traveled (within the last 2 to 3 years) to a Blastomyces-endemic area and has at least one of the following features [54]:

●Community-acquired pneumonia of unknown etiology that has not responded to a course of empiric antibiotics

●Community-acquired pneumonia with associated skin lesions

●Characteristic skin lesions (picture 2 and picture 3 and picture 4 and picture 5 and picture 6)

●Clinical manifestations consistent with extrapulmonary blastomycosis (eg, osteomyelitis, epididymitis, prostatitis, brain abscess) with negative bacterial cultures and no response to initial treatment

●Radiographic pulmonary and/or bone findings concerning for malignancy, mycobacterial infections (including tuberculosis), or other endemic infections (eg, histoplasmosis, coccidioidomycosis)

●Presence of granulomas with neutrophilic predominance on histopathology

Presence of additional risk factors, such as engaging in outdoor activities (eg, fishing, hunting, canoeing, rafting, composting), exposure to home remodeling or construction sites, or cutting and stacking wood, should increase the index of clinical suspicion for blastomycosis.

Diagnosis of blastomycosis is often delayed. In one survey, infectious diseases physicians reported more than a one-month delay in diagnosis in 40 percent of endemic mycosis cases; the delay in diagnosis had a moderate or major impact on clinical care in 66 percent of cases [55].

Approach to diagnosis

Initial testing — When blastomycosis is suspected, we send urine antigen as well as any available respiratory specimens (eg, sputum, bronchoalveolar lavage [BAL] fluid) and/or other aspirated material or tissue collected from biopsy for direct microscopy, fungal culture, and histopathology [54]. We ask the microbiology laboratory to incubate the culture for six weeks to allow for fungal growth and alert them to our suspicion for blastomycosis so laboratory staff can take appropriate precautions when handling the specimens. Some contributors also send a serum antigen at the same time as the urine antigen to increase the sensitivity of the tests, especially in patients who are critically ill.

In patients who are not producing sputum or in whom lung imaging indicates the possibility of malignancy, bronchoscopy is particularly useful [56]. Bronchial washings, BAL fluid, and postbronchoscopy sputum samples should be sent for cytology and fungal staining and culture; the organism is often visualized on Papanicolaou preparations [57]. When available, samples can also be sent for polymerase chain reaction (PCR) and antigen testing.

For patients suspected of having central nervous system (CNS) blastomycosis, we perform a lumbar puncture and send cerebrospinal fluid (CSF) for fungal culture/staining as well as antigen testing. Although the sensitivity of antigen testing in the CSF is low, a positive result is helpful in supporting the diagnosis of CNS blastomycosis.

Serology assays have low sensitivity and specificity and are not recommended for diagnostic purposes.

Establishing a diagnosis — Definitive diagnosis requires growth or visualization of the organism from a clinical specimen [4]. Unlike Candida and Aspergillus spp, colonization or contamination with Blastomyces does not occur, which means that visualizing the organism or obtaining a positive culture confirms the diagnosis of blastomycosis. Visualization of broad-based budding yeasts on direct microscopy is the most rapid way to make a presumptive diagnosis of blastomycosis, as growth on culture often takes up to four weeks.

In the appropriate clinical situation (eg, acute respiratory distress syndrome [ARDS] or rapid clinical worsening in a patient), a positive urine antigen test may justify beginning empirical antifungal therapy. Although urine antigens have a high sensitivity (80-95 percent), they are sent out to other laboratories, prolonging the turn-around time for results, and have a lower specificity due to cross-reactivity with other endemic mycoses, especially histoplasmosis. For patients in whom histoplasmosis is also on the differential, identification of Blastomyces spp by histology or culture is necessary to make the correct diagnosis. Since the initial treatment for histoplasmosis and blastomycosis is similar, treatment that is initiated while awaiting confirmatory results will treat both infections. (See "Treatment of blastomycosis".)

Diagnostic tests — Diagnostic tests for blastomycosis include fungal culture, visualization of Blastomyces spp on direct microscopy or histopathology, antigen testing, molecular methods, and serology. Details of each testing modality is discussed below.

●Culture – Identification of Blastomyces spp by culture depends upon growth of the organism in the mycelial phase at room temperature and then sending the isolate to a reference laboratory for definitive identification [58]. The mold form of the organism is not difficult to culture from most clinical specimens using fungal media (Sabouraud dextrose agar and potato dextrose agar) at 25 to 30°C; it typically grows within one to four weeks [4]. Confirmation of the identity of Blastomyces is now done with mass spectrometry (MALDI-TOF). The mycelial phase produces spherical, oval, or pyriform conidia from aerial hyphae. At 37°C, B. dermatitidis colonies are wrinkled, pasty, and moist. The yeast cell, whether in vitro or in tissue, is thick walled and spherical, producing single buds with a broad base of attachment between the bud and parent cell (picture 9 and picture 8).

In adult patients with pulmonary blastomycosis, sputum culture has a high yield (75 percent per single sample, 86 percent per patient) [56]. Specimens obtained for culture by bronchoscopy yield a positive diagnosis in 92 percent of patients.

CSF culture has a lower yield of around 45 percent [46].

●Direct microscopy – Although wet preparations have a relatively low diagnostic yield (36 percent for a single specimen and 46 percent for multiple specimens) [56], the simplicity and low cost of the procedure, as well as its potential for rapid presumptive diagnosis, justify a wet preparation on all clinical specimens.

Fresh wet preparations of sputum, pleural fluid, BAL fluid, CSF, urine, purulent material, skin scrapings, or tissue impression smears may be examined directly with calcofluor white, 10 percent potassium hydroxide (KOH), or both. KOH has been recommended to lyse mammalian cells, which aids in finding yeast and fungal elements, but most laboratories have supplanted this with calcofluor white, which causes the yeast cell wall to fluoresce. Calcofluor white staining requires use of a fluorescence microscope but is easy, rapid, and particularly useful when organisms are sparse.

It is useful to concentrate clinical specimens, such as sputum, urine, pleural fluid, and CSF by centrifugation. It is also helpful to digest sputum samples with trypsin and smear the centrifuged sediment.

When visualized, the yeast cells are easily differentiated from others on the basis of their size (8 to 15 microns in diameter), refractile cell wall, and single, broad-based buds (picture 9 and picture 8 and picture 10). Occasionally, the endospores of Coccidioides species may resemble single yeast cells, but the presence of broad-based budding yeasts can be used to distinguish Blastomyces. Paracoccidioides brasiliensis, rarely seen in the United States, is distinguished from Blastomyces by the presence of multiple, narrow-based buds arranged around the periphery of the mother cell. Blastomyces may sometimes be as small as Cryptococcus neoformans, although the capsule and narrow-based bud of the latter aid in differentiation. (See "Coccidioidomycosis: Laboratory diagnosis and screening" and "Clinical manifestations and diagnosis of chronic paracoccidioidomycosis" and "Microbiology and epidemiology of Cryptococcus neoformans infection".)

●Histopathology – A pyogranulomatous tissue response is frequently seen in blastomycosis and should signal the possibility of this fungus. Yeast forms may be difficult to visualize with routine hematoxylin and eosin stains and are much better visualized on special stains, such as the methenamine silver stain or the periodic acid-Schiff stain (picture 1).

●Antigen testing – An antigen detection assay for blastomycosis is currently available for clinical use [59,60]. The sensitivity of this assay is 89 percent in disseminated blastomycosis and 93 percent overall. Sensitivity is higher in urine than in serum. However, specificity is around 79 percent due to cross-reactivity with antigens present in histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, and talaromycosis [61]. Cross-reactivity was less than 5 percent for patients with aspergillosis or cryptococcosis and less than 2 percent in healthy adults [59].

Antigen detection in the CSF can also be used to diagnose CNS blastomycosis, although interpretation is difficult as test characteristics have not been fully elucidated for these specimens [46,62]. Antigen detection can be used on BAL fluid, but sensitivity and specificity have not been defined.

Antigen levels appear to decline with successful treatment and increase with recurrence of illness [63,64]. In one review, 23 of 27 patients (85 percent) with recently diagnosed blastomycosis had antigenuria detected, while none of 50 control subjects had B. dermatitidis antigenuria [65].

●Molecular testing – Molecular testing (eg, PCR) exists and is increasingly being used for the diagnosis of severe pulmonary blastomycosis. Molecular testing is becoming more available but has not been evaluated for diagnostic purposes in large studies [66,67].

Molecular identification of B. dermatitidis has been accomplished by a variety of techniques, including PCR assays for ribosomal genes [68,69], the ITS-region [68], repetitive sequences [69], and species- or genus-specific genes [70,71]. In addition, real-time PCR assays that can identify B. dermatitidis in culture specimens, in various clinical specimens (eg, bronchial washings, bronchoalveolar fluid, pleural fluid, sputum, blood), and in paraffin-embedded tissue have been developed [66,72]. A number of case reports have used detection of B. dermatitidis deoxyribonucleic acid (DNA) in histology tissue blocks to confirm the diagnosis of blastomycosis as this technique has become increasingly available [73,74]. However, PCR techniques are labor intensive, and although promising, the sensitivity and specificity of these tests on various specimens have not been defined, and their utility has not been confirmed in large prospective studies.

●Serology – Serologic testing is not useful for the diagnosis of blastomycosis [59], owing to the high degree of cross-reactivity shared by the endemic mycoses, most notably Histoplasma capsulatum. Immunodiffusion assays that measure antibody to Blastomyces dermatitidis A antigen are relatively specific, but sensitivity is only 28 to 64 percent [75,76]. Complement fixation tests perform even less well, with sensitivities of 9 to 43 percent and poor specificity [75,76]. Enzyme immunoassays employing A antigen are the least reliable, with greater sensitivity but lower specificity compared with other methods [75-78]. Serologic studies using yeast phase lysates from multiple sources of B. dermatitidis have been explored for immunoglobin (Ig) M and IgG antibody detection in an effort to improve immunodiagnostic testing for blastomycosis [79,80]. This test is available only from the reference laboratory (MiraVista, Indianapolis, IN) that developed the assay. Although these tests are promising, they have not been validated using human specimens. A study of patients with blastomycosis reported 88 percent sensitivity of an enzyme immunoassay employing the BAD1 surface protein of B. dermatitidis [81].

Postdiagnostic evaluation — We obtain a chest radiograph in all patients diagnosed with blastomycosis, even if no evidence of lung involvement is present [82]. We also obtain a urine antigen level if one has not yet been obtained, as it sometimes can help in assessing treatment response. Additionally, in patients presenting with neurological signs or symptoms (eg, headache, paresthesias), we obtain magnetic resonance imaging (MRI) of the brain with contrast and a lumbar puncture to evaluate for CNS involvement.

DIFFERENTIAL DIAGNOSIS — Both acute and chronic blastomycosis may mimic other diseases [50,83]. This is due to the variability of the presentation of blastomycosis and its relative rarity. Epidemiologic clues in the patient's history may help in differentiating blastomycosis from the other conditions, but culture and histopathology evaluation are necessary for diagnosis.

The differential diagnosis depends on the patient's geographic location and travel history, the clinical presentation, and which organ systems are involved:

●Acute pulmonary blastomycosis is often initially misdiagnosed as community-acquired bacterial or viral pneumonia. Nonresolving pneumonia that does not respond to a course of empiric antibiotics should prompt suspicion for endemic mycoses, such as blastomycosis, in patients who reside in or have traveled to an endemic area.

●Chronic pulmonary blastomycosis is often initially thought to be malignancy or tuberculosis. It can also present similarly to chronic noninfectious pneumonias (eg, cryptogenic organizing pneumonia), other nontuberculous mycobacterial pulmonary infections, or other endemic fungal infections (eg, histoplasmosis, coccidioidomycosis). Blastomycosis is more likely to have skin involvement compared with other similar infections or noninfectious causes. Unlike histoplasmosis, blastomycosis rarely presents with hilar adenopathy.

●Skin lesions caused by blastomycosis are frequently misdiagnosed as keratoacanthoma, pyoderma gangrenosum, or squamous cell carcinoma.

●Osseous blastomycosis is often initially thought to be tuberculosis or malignancy.

●Involvement of other areas of the body (eg, larynx, brain, lymph nodes) may be misdiagnosed initially as malignancy.

SUMMARY

●Spectrum of disease – The clinical manifestations of blastomycosis are varied and include asymptomatic infection, acute or chronic pneumonia, and extrapulmonary disease. Although blastomycosis has been reported to involve almost every organ, the lungs are the most common site. (See 'Spectrum of disease' above.)

●Clinical presentation – Most patients present with chronic pneumonia. Skin disease is the second most common manifestation and is characterized by verrucous lesions (picture 2 and picture 3 and picture 4), ulcerative lesions (picture 5 and picture 6), or subcutaneous nodules (picture 7). Osteomyelitis is the next most common extrapulmonary manifestation. (See 'Chronic pneumonia' above and 'Skin' above and 'Bone and joint' above.)

●When to suspect blastomycosis – Blastomycosis should be suspected in a patient who resides in or has recently traveled (within the last 2 to 3 years) to a Blastomyces-endemic area and has at least one of the following features [54]:

•Community-acquired pneumonia of unknown etiology that has not responded to a course of empiric antibiotics

•Community-acquired pneumonia with associated skin lesions

•Characteristic skin lesions (picture 2 and picture 3 and picture 4 and picture 5 and picture 6)

•Clinical manifestations consistent with extrapulmonary blastomycosis (eg, osteomyelitis, epididymitis, prostatitis, brain abscess) with negative bacterial cultures and no response to initial treatment

•Radiographic pulmonary and/or bone findings concerning for malignancy, mycobacterial infections (including tuberculosis), or other endemic infections (eg, histoplasmosis, coccidioidomycosis)

•Presence of granulomas with neutrophilic predominance on histopathology (see 'When to suspect blastomycosis' above)

●Initial testing – When blastomycosis is suspected, we send urine antigen as well as any available respiratory specimens (eg, sputum, bronchoalveolar lavage [BAL] fluid) and/or other aspirated material or tissue collected from biopsy for direct microscopy, fungal culture, and histopathology. (See 'Initial testing' above.)

●Establishing the diagnosis – Definitive diagnosis requires growth or visualization of the organism from a clinical specimen. If the patient is critically ill and the clinical picture is consistent with blastomycosis, a positive urine antigen test may justify beginning empirical antifungal therapy. (See 'Establishing a diagnosis' above.)

●Postdiagnostic evaluation – We obtain a chest radiograph and a baseline urine antigen level in all patients diagnosed with blastomycosis. In patients presenting with neurological signs or symptoms (eg, headache, paresthesias), we obtain an MRI of the brain with contrast and a lumbar puncture to evaluate for central nervous system (CNS) involvement. (See 'Postdiagnostic evaluation' above.)

●Differential diagnosis – Both acute and chronic blastomycosis often mimic other diseases. Acute pulmonary blastomycosis may be initially diagnosed as community-acquired bacterial or viral pneumonia, whereas chronic pulmonary blastomycosis is most often thought to be malignancy or tuberculosis. Acute infection is frequently unrecognized unless related to a cluster of cases. (See 'Differential diagnosis' above.)