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. The clinical manifestations of blastomycosis are varied and include asymptomatic infection, acute or chronic pneumonia, and extrapulmonary disease [1]. 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. Extrapulmonary disease results from hematogenous spread from a primary pulmonary infection.
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 [2,3]. B. helicus has been associated with disease in a small number of immunocompromised humans and domestic animals [4].
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".)
SITES OF INVOLVEMENT — The lungs are the most common site of infection, followed by the skin, bones, and genitourinary tract [5,6]. As an example, in a study of 326 patients with blastomycosis, the following distribution of organ involvement was observed [5]:
●Pulmonary – 91 percent
●Skin – 18 percent
●Bone – 4 percent
●Genitourinary – 2 percent
●Central nervous system – 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). Acute respiratory distress syndrome (ARDS) associated with blastomycosis has also been reported [6,7]. In a series of 114 patients with blastomycosis from Indiana, ARDS was found in 17 percent [6].
Studies performed prior to the availability of effective therapy indicated that approximately two-thirds of patients with blastomycosis had multiorgan involvement [8,9] and that the disease was progressive with reported mortality rates of up to 90 percent [10]. However, most of these earlier studies were autopsy-based; thus, multiorgan disease was probably overrepresented. Later reports in Arkansas [11], Wisconsin [12], Mississippi [5], and Manitoba, Canada [13] described a lower frequency of extrapulmonary disease.
Both acute and chronic blastomycosis may mimic other diseases [14]. This is due to the variability of the presentation of blastomycosis and its relative rarity. As an example, acute pulmonary blastomycosis may be initially diagnosed as community-acquired bacterial or viral pneumonia, whereas chronic pulmonary blastomycosis is often initially thought to be malignancy or tuberculosis. Skin lesions are frequently misdiagnosed as pyoderma gangrenosum or keratoacanthoma. Involvement of the larynx, brain, lymph nodes, skin, or other organs may be thought to be carcinoma.
Thus, a high index of suspicion and aggressive collection of samples for microbiology and histologic evaluation should be performed when the diagnosis is uncertain and patients live in or have traveled to areas endemic for blastomycosis. (See 'Diagnosis' below.)
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. As defined in point source outbreaks, up to 50 percent of blastomycosis infections are asymptomatic [15-19]. The incubation period from exposure until the onset of pulmonary symptoms is approximately three to six weeks [16]. The incubation period from exposure to the onset of extrapulmonary symptoms is highly variable.
In a study that included 326 patients with blastomycosis, the following presenting symptoms were observed [5]:
●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 a cluster of cases. The signs and symptoms of acute pulmonary blastomycosis usually begin abruptly and may be indistinguishable from viral or bacterial pneumonia [1].
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.)
Chest radiography most commonly reveals alveolar infiltrates or a mass lesion, although miliary or reticulonodular patterns can also occur [20,21]. Chest computed tomography (CT) scanning may show nodules, consolidation with or without cavitation, and/or tree-in-bud opacities (image 1 and picture 1) [22]. 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 [19,23].
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 [1]. 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 [5]. Many of these patients received multiple rounds of antibiotics before the diagnosis was established. Additionally, some patients are initially asymptomatic but progress over time into the chronic form of blastomycosis. Symptoms may include low-grade fever, productive cough, hemoptysis, chest pain, and/or weight loss.
The radiographic findings are varied. Alveolar infiltrates with or without cavitation, mass lesions, and fibronodular infiltrates are most common [1,5]. 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 [24].
Acute respiratory distress syndrome — Rarely, patients may present with diffuse pneumonitis associated with acute respiratory distress syndrome (ARDS) [1,25-27]. In a retrospective cohort study of 1848 patients hospitalized with blastomycosis, patients requiring mechanical ventilation (12 percent of the cohort) 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].
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 [8,9,29-33]. In contrast, more recent studies have documented multiorgan disease in approximately 20 percent of patients [5,11-13]. Extrapulmonary disease is usually seen in conjunction with active pulmonary infection. (See 'Sites of involvement' above.)
Skin — Skin disease is the second most common manifestation of blastomycosis after pneumonia. 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) [1].
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).
Patients with cutaneous disease resulting from dissemination of lung disease have little or no regional lymphadenopathy. In contrast, lymphadenitis is a prominent finding in patients with inoculation blastomycosis due to a dog bite or inoculation of pathology staff by autopsy accident [34-36]. There is a report of transmission of blastomycosis after a bite wound from a kinkajou, an exotic pet [37]. However, the vast majority of cutaneous lesions are from hematogenous spread and not from direct inoculation. Patients with blastomycosis often have a history of pet dogs that died from blastomycosis. This suggests that both humans and their pets have become infected by aerosol inhalation from the environment.
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 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 [5]. Any bone may be involved, although the most common are the vertebrae, pelvis, and sacrum [1].
Patients often present with soft tissue swelling or a chronic draining sinus tract adjacent to the focus of osteomyelitis [1]. 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 [1].
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 most 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 [1].
Central nervous system — Blastomycosis of the central nervous system (CNS) is uncommon in immunocompetent hosts, and has been reported in fewer than 5 percent of cases. CNS infection may present as meningitis, epidural abscess, or intracranial abscesses, particularly in the cerebellum [45]. CNS involvement may occur in immunocompromised patients, especially those with acquired immunodeficiency syndrome (AIDS) [46]. In a retrospective study of human immunodeficiency virus (HIV)-infected patients with blastomycosis, 6 of 15 had CNS involvement, usually manifested as single or multiple brain abscesses [46]. In one review, 10 of 22 patients with CNS blastomycosis were not considered to be immunosuppressed [45]. Of note, 17 of the 22 patients had evidence of blastomycosis in other organs as well.
Other sites — B. dermatitidis has been reported to involve almost every organ, including lymph nodes, liver, spleen, breast, adrenal gland, thyroid, and eye [1]. 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 [13,15,47]. 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, 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 advanced AIDS, transplant recipients, those who are prescribed TNF-alpha inhibitors, and other immunocompromised patients [1,14,49,50]. Pulmonary disease tends to be more severe in immunocompromised hosts, including findings of diffuse pulmonary infiltrates, large pleural effusions, and/or respiratory failure, and higher mortality rates. 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 [51]. 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.
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".)
Infection with B. helicus has been described in a small number of humans in western Canada and western United States [4]. 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 [4]. The organism was isolated in cultures of blood, cerebrospinal fluid, and/or bronchoalveolar fluid, and only two of the seven patients survived.
DIAGNOSIS — Definitive diagnosis requires growth of the organism from a clinical specimen [1]. Unlike Candida and Aspergillus spp, colonization or contamination with Blastomyces does not occur, which means that visualizing the organism on histology or obtaining a positive culture confirms the diagnosis of blastomycosis. Presumptive diagnosis of blastomycosis may be made by visualization of the characteristic yeast form in clinical specimens, such as sputum, tissue, or purulent material. In the appropriate clinical situation, visualization may justify beginning empirical antifungal therapy. Serology is not useful for the diagnosis of blastomycosis.
Culture — Identification of Blastomyces by culture depends upon growth of the organism in the mycelial phase and conversion of the mycelial phase to the yeast phase, or use of a commercially available deoxyribonucleic acid (DNA) probe that allows the rapid identification of a mold that has grown in culture as being B. dermatitidis [52]. The mold form of the organism is not difficult to culture from most clinical specimens using Sabouraud dextrose agar without cycloheximide at 25 to 30ºC; it typically grows within one to four weeks [1]. The mycelial phase produces spherical, oval, or pyriform conidia from aerial hyphae. At 37ºC, 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) [53]. Specimens obtained for culture by bronchoscopy yield a positive diagnosis in 92 percent of patients. Specimens are frequently contaminated with bacteria that inhibit fungal growth and should thus also be cultured on medium containing chloramphenicol.
Direct examination of clinical specimens — Although wet preparations have a relatively low diagnostic yield (36 percent for a single specimen and 46 percent for multiple specimens) [53], the simplicity and low cost of the procedure, as well as its potential for rapid diagnosis, justify a wet preparation on all clinical specimens.
Fresh wet preparations of sputum, pleural fluid, bronchoalveolar lavage fluid, cerebrospinal fluid, 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 aid 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 cerebrospinal fluid 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".)
In patients who are not producing sputum or in whom lung imaging indicates the possibility of malignancy, bronchoscopy is particularly useful [53]. In addition to fungal staining and culture, bronchial washings, bronchoalveolar lavage fluid, and post-bronchoscopy sputum samples should be evaluated using cytology because the organism is often visualized on Papanicolaou preparations [54].
Histopathology — A pyogranulomatous tissue response is frequently seen in blastomycosis and should signal the possibility of this fungus. Yeast forms can be difficult to visualize with routine hematoxylin and eosin stains, and special stains, such as the methenamine silver stain or the periodic acid-Schiff (PAS) stain, are particularly useful for examining tissue for the presence of fungal elements (picture 1).
Serologic testing — Serologic testing is not useful for the diagnosis of blastomycosis [55], 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 [56,57]. Complement fixation tests perform even less well, with sensitivities of 9 to 43 percent and poor specificity [56,57]. Enzyme immunoassays employing A antigen are the least reliable, with greater sensitivity but lower specificity compared with other methods [56-59]. Serologic studies using yeast phase lysates from multiple sources of B. dermatitidis have been explored for IgM and IgG antibody detection in an effort to improve immunodiagnostic testing for blastomycosis [60,61]. 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 [62], but the test is not yet commercially available.
Nucleic acid detection — Molecular identification of B. dermatitidis has been accomplished by a variety of techniques, including polymerase chain reaction (PCR) assays for ribosomal genes [63,64], the ITS-region [63], repetitive sequences [64], and species- or genus-specific genes [65,66]. 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 [67,68]. A number of case reports have used detection of B. dermatitidis DNA in histology tissue blocks to confirm the diagnosis of blastomycosis as this technique has become increasingly available [69,70]. However, PCR techniques are labor intensive, and although promising, their utility has not been confirmed in large prospective studies.
Antigen detection — The detection of fungal antigens in serum and urine has proven useful in the diagnosis and treatment of patients with certain invasive mycoses, such as histoplasmosis [55]. An antigen detection assay for blastomycosis is currently available for clinical use [71]. 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 modest, 79 percent overall, and due to cross-reactive antigens present in specimens obtained from patients with histoplasmosis, paracoccidioidomycosis, and penicilliosis [72]. Cross-reactivity was less than 5 percent for patients with aspergillosis or cryptococcosis and less than 2 percent in healthy adults [55].
Antigen levels appear to decline with successful treatment and increase with recurrence of illness [73,74]. In a more recent review, 23 of 27 patients (85 percent) with recently diagnosed blastomycosis had antigenuria detected while none of 50 control subjects had B. dermatitidis antigenuria [75]. Despite the benefits of antigen detection, its utility is limited given the ease of diagnosis by conventional methods and the modest specificity provided by these assays.
SUMMARY
●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 'Introduction' above.)
●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 'Sites of involvement' above and 'Acute pneumonia' above.)
●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.)
●In immunocompromised hosts, pulmonary disease tends to be more severe, and there is a higher mortality rate (up to 40 percent) compared with immunocompetent patients. . In contrast to other endemic mycoses (eg, histoplasmosis, coccidioidomycosis), immunosuppression has not been associated with increased risk of dissemination in blastomycosis. However, infection with Blastomyces helicus, an organism that is distinct from Blastomyces dermatitidis and Blastomyces gilchristi, has been seen primarily in patients with immunocompromising conditions. (See 'Immunocompromised hosts' above.)
●Definitive diagnosis requires culturing the organism from clinical specimens, but a presumptive diagnosis of blastomycosis may be made by visualization of the characteristic yeast form in clinical specimens such as sputum, tissue, or purulent material. (See 'Diagnosis' above.)
