Blastomyces Species (Blastomycosis)

Microbiology

Over the past decade there has been extensive revision of Blastomyces taxonomy. Currently, there are 7 Blastomyces species: B. dermatitidis, B. gilchristii, B. helicus, B. percursus, B. silverae, B. parvus, and B. emzantsi . Five are known to infect humans, including B. dermatitidis, B. gilchristii, B. helicus, B. percursus , and B. emzantsi . The defining biologic feature of Blastomyces spp. is the ability to undergo a temperature-dependent conversion between two distinct morphologic forms, mycelia and yeast. In the soil (22°C–25°C), Blastomyces cells grow as septated mycelia (1–2 μm in diameter) that produce infectious conidia (4–5 μm in diameter). ^, B. dermatitidis hyphae produce one conida per conidiophore, whereas B. percursus , B. parvus , B. silverae , and B. ezmzantsi can produce clusters of conidia on a single conidiophore. ^, B. helicus is characterized by coiled hyphae that does not sporulate under in vitro growth conditions. ^, Soil disruption by human activities (e.g., construction) aerosolizes mycelial fragments and conidia, which convert to yeast when inhaled into the lungs of a human host (37°C). B. dermatitidis and B. gilchristii yeast are 8–15 μm in size and have a distinct morphologic appearance characterized by a broad-based bud and a refractile (i.e., double-contoured) cell wall ( Fig. 252.1 ). ^, B. helicus yeast are slightly smaller in size (4–9 μm), variably-shaped, and can grow as short or branched chains with broad-based budding. ^, The yeast cells of B. percursus (7.2–24.0 μm), B. parvus (4.7–15.7 μm), B. silverae (9.2–28.7 μm), and B. ezmzantsi also exhibit broad-based budding. ^,

In addition to growing as mycelia or yeast, Blastomyces organisms exist in an asexual (imperfect, anamorphic) state or a sexual (perfect, teleomorphic) state. Sexual reproduction occurs in the mycelial phase when hyphae with different mating-type loci (e.g., MAT1-1 and MAT1-2) fuse and form specialized reproduction structures. Although mating contributes to genetic diversity, its impact on virulence is unknown. ^,

Pathogenesis And Immunity

The reversible switch between mycelial and yeast morphologies is critical to the biology and life cycle of Blastomyces and those of other thermally dimorphic fungi. Growth as mycelia (22°C–25°C) promotes environmental survival and transmission to new hosts by infectious spores, in addition to genetic diversity through sexual reproduction. Growth in the yeast phase (37°C) facilitates evasion of hosts’ immune defenses. Inhaled spores are phagocytosed by pulmonary macrophages and converted to yeast organisms, which survive and replicate within macrophages during the early stages of Blastomyces infection. Extrapulmonary dissemination occurs by lymphohematogenous spread, and in children this most commonly affects the skin and bones.

Genetic regulation of the morphologic switch between mycelial and yeast forms has been the focus of intense research, given the importance of this event on pathogenesis. The discovery of dimorphism-regulating kinase-1 (DRK1), which encodes a histidine kinase, provided the first genetic proof (by deletion experiments in the mouse model) that the conversion from mycelia (or spores) to yeast was essential for virulence. The function of DRK1 also is conserved in other dimorphic fungi, such as Histoplasma capsulatum and Talaromyces marneffei (formerly Penicillium marneffei ). ^, The reverse morphologic switch, from yeast to mycelia, is regulated by a transcription factor encoded by SREB (siderophore biosynthesis repressor in Blastomyces ) and is influenced by N-acetylglucosamine transporters NGT1 and NGT2 . ^,

In the yeast phase, an immunogenic protein encoded by Blastomyces adhesin-1 ( BAD1, formerly WI-1 ) is upregulated and is essential for virulence in the mouse model for B. dermatitidis and B. gilchristii . Interestingly, BAD1 is not present in the genomes of either B. percurus and B. emzantsi . BAD1 functions as an adhesin that binds yeast cells to host tissue and acts as an immune evasin to downregulate host immune defenses. The core tandem repeats bind heparin sulfate in host tissues to promote adherence of yeast. Soluble and cell wall–bound BAD1 bind CR3 and CD14 receptors, impairing production of tumor necrosis factor (TNF) by macrophages and neutrophils. BAD1 also inhibits activation of CD4 ⁺ T lymphocytes, reducing production of interferon γ (INFγ) and interleukin-17 (IL-17). The ability of BAD1 to induce a humoral immune response is being used to develop a new sensitive and specific serologic test for diagnosis of blastomycosis.

The cells of the innate and adaptive immune system are critical for host defense against B. dermatitidis infection, whereas humoral immunity is dispensible. Lung epithelial cells also contribute to host defense by activating natural Th17 T lymphocytes, which produce IL-17 and granulocytes-macrophage colony stimulating factor (GM-CSF) to promote fungicidal activity of alveolar macrophages, dendritic cells, and neutrophils. Spores that survive the initial host response germinate as yeast cells, which are relatively resistant to reactive oxygen species, scavenge zinc, suppress nitric oxide production, inhibit cytokine production, block immune cell recruitment to the lung by inactivating GM-CSF, and impede CD4 ⁺ T-lymphocyte activation. ^{, , ,} Despite the ability of B. dermatitidis to modulate host immune responses, Th1 and Th17 T lymphocytes can activate macrophage fungicidal activity to successfully combat infection in some patients. ^, Approximately 50% of those infected with B. dermatitidis develop asymptomatic or subclinical infections. After recovery from blastomycosis, children and adults develop T-lymphocyte–mediated immunity against B. dermatitidis that can last for at least 2 years.

Epidemiology and Acquisition

The lack of reliable skin and serologic tests, difficulty in isolating the fungus from the environment, and reliance on passive surveillance and retrospective studies have hampered the development of in-depth epidemiologic knowledge about Blastomyces species. Currently blastomycosis is reportable in 5 US states (MN, WI, MI, AR, LA) and in 2 Canadian provinces (Manitoba, Ontario). Although underestimated, the incidence of blastomycosis ranges from 0.2–2.17 cases per 100,000 population annually. ^{, ,} In Wisconsin, persons of Asian ethnicity, particularly those of Hmong ethnicity, are at increased risk for blastomycosis. In a retrospective study at the Marshfield Clinic, 14.4% of pediatric patients with blastomycosis were Asian, which was higher than expected (<2.5% of the population in the Marshfield Clinic catchment area is Asian). In a large blastomycosis outbreak in Marathon County (2009–2010), 45% of patients were of Hmong ethnicity. Whole genome sequencing and immunologic analyses pointed to polymorphisms at the interleukin-6 ( IL6 ) locus in the Hmong population that result in impaired production of IL-6 and development of memory CD4 ⁺ T helper-17 cells. Although persons of Hmong ethnicity are at increased risk for acquiring blastomycosis, limited data suggests they are not at increased risk for disseminated infection. ^, Increased incidence of blastomycosis has also been reported in indigenous peoples of Canada and Native Americans in the US. ^, Several studies have demonstrated that Asian and Native American persons with blastomycosis tend to be younger in age with fewer underlying medical conditions compared with Caucasian patients. ^{, ,}

The traditional geographic range of Blastomyces in North America includes the Mississippi River and Ohio River basins, areas along the St. Lawrence River, the southeastern US, and 4 Canadian provinces ( Fig. 252.2 ). B. dermatitidis is found throughout the traditional geographic range. In contrast, B. gilchristii is geographically restricted to Canada, Minnesota, Wisconsin, and areas along the St. Lawrence River drainage basin. In the endemic region, Blastomyces grows in an ecologic niche near freshwater sources (rivers, streams, lakes) that have sandy soils with an acidic pH and decaying vegetation or rotting wood. ^{, ,} In addition to B. dermatitidis and B. gilchristii , B. helicus causes infection in humans and animals in North America, primarily in the western US and western Canada. B. parvus and B. silverae have also been identified in North America, but their geographic range has yet to be defined. ^, The ecologic niche inhabited by B. helicus , B. parvus , and B. silverae is unknown.

Although uncommon, autochthonous cases of human blastomycosis have been reported from Africa (>100 cases), India (fewer than 10 cases), and Israel (1 case). ^{, ,} Until recently, nearly all clinical isolates of Blastomyces from Africa were thought to be B. dermatitidis , which was based primarily on morphologic analysis. Molecular phylogenetic analysis of a limited number of Blastomyces isolates from sub-Saharan Africa (Rwanda, South Africa, Zimbabwe) via multi-locus sequence typing (MLST) identified B. dermatitidis and B. gilchristii . A larger analysis of 20 isolates from human specimens from South Africa determined that they were B. percursus or B. emzantsi ; none were B. dermatitidis . Collectively, these data suggest a diversity of Blastomyces species in Africa; however, the distribution and ecologic niche of B. dermatitidis , B. gilchristii , B. percursus , and B. emzantsi in sub-Saharan and northern African countries remains unknown.

Most patients with blastomycosis acquire the infection by inhaling spores and mycelial fragments after disruption of the soil. Activities associated with acquisition in sporadic or outbreak settings include home remodeling, road construction, hunting, clearing brush and cutting trees, using a community compost pile, exploration of underground forts and beaver dams, and canoeing or fishing in endemic regions. ^{, ,} In rare cases, B. dermatitidis infection can result from cutaneous trauma. Blastomycosis during pregnancy has the potential to result in perinatal transmission through aspiration of infected secretions during birth or transplacentally.

Clinical Manifestations

The incubation period for blastomycosis ranges from 3 weeks to 3.5 months. ^{, ,} The average age of pediatric patients with blastomycosis is 9–12 years (range, 18 days to 18 years). ^{, ,} Blastomycosis is rare in neonates and infants. ^, In most studies the gender distribution is skewed toward males. ^{, , , , ,} The majority of children with blastomycosis are previously healthy and not immunosuppressed. ^, Similar to adults, children with blastomycosis may require admission to the hospital. ^,

Clinical manifestations of pulmonary infection are variable and include nonspecific symptoms, such as headache, cough, chest pain, weight loss, fever, abdominal pain, and night sweats ( Table 252.1 ). ^{, ,} Disseminated blastomycosis occurs in 21%–53% of patients. ^{, ,} The skin and bone are the most common sites of extrapulmonary infection ( Table 252.1 ). In contrast, disseminated disease in children infected in an outbreak setting is rare ( Table 252.1 ). ^, Pulmonary blastomycosis can be complicated by respiratory failure, ARDS, and death. The full clinical spectrum of blastomycosis is summarized in Fig. 252.3 .

Along with differences in geography, emerging evidence suggests that clinical presentation is influenced by the infecting Blastomyces species. Within the traditional endemic region, localized pulmonary blastomycosis is more common with B. gilchristii (90.7%–92.2%), whereas disseminated disease occurs most commonly with B. dermatitidis (31.4%–47.8%). ^{, ,} To date, only 1 study has focused on pediatric patients regarding differences between B. dermatitidis and B. gilchristii . Similar findings have been demonstrated among pediatric patients with 87.5% (42 of 48) of patients with B. gilchristii having localized pulmonary disease and 75% (3 of 4) with B. dermatitidis having disseminated infection.

To date, B. helicus has only been acquired in western North America with the majority of patients having underlying immunocompromising conditions (e.g., HIV, chemotherapy, solid-organ transplant, lupus) and half exhibiting fungemia. Not surprisingly, B. helicus had a high mortality rate (71.4%, 5 of 7 patients) in whom clinical outcomes were known. Of the 10 reported cases, clinical manifestations of B. helicus ranged from localized pulmonary infection to disseminated disease involving the brain. Information about B. percursus and B. emzantsi primarily comes from South Africa. Extrapulmonary disease involving the skin (ulcer, verrucous lesions, subcutaneous abscess) or bone (clavicle, ribs, fibula, spine) of long-standing duration (4 weeks to 5 years) is common for patients infected with B. percursus and B. emzantsi . A subset of patients have concomitant pulmonary disease.

Acute and Chronic Pulmonary Infection

Acute pulmonary infection is the most common manifestation of blastomycosis in children. ^{, , , ,} The spectrum of severity ranges from mild or no illness ( Fig. 252.4 ) to respiratory failure, including ARDS. ^{, ,} Symptoms often mimic community-acquired pneumonia and include fever, chills, a productive cough with or without hemoptysis, shortness of breath, chest pain, and malaise. ^{, , , ,} Cutaneous findings (e.g., plaques, nodules, or ulcers) in a patient with pneumonia are highly suggestive of fungal pneumonia, including blastomycosis. Immune-mediated cutaneous findings (e.g., erythema nodosum or erythema multiforme), which can be observed in patients with histoplasmosis or coccidioidomycosis, are rare with blastomycosis. ^, Unrecognized or untreated acute pulmonary blastomycosis can lead to chronic pneumonia, characterized by fever, night sweats, weight loss, cough, and chest pain. Chronic pulmonary blastomycosis mimics tuberculosis, other mycoses, and neoplasms.

Radiographic manifestations of pulmonary blastomycosis are heterogeneous and nonspecific. The most frequent radiographic pattern is consolidation, which is indistinguishable from that seen in community-acquired pneumonia. ^{, ,} Consolidation is typically unilateral (62.5%–76.5%), frequently associated air bronchograms (76.5%), and can involve upper, middle, or lower lung lobes. ^, Nodular and interstitial infiltrates also are common and can be present in conjunction with consolidation. Masses and cavities, which mimic malignancy and tuberculosis, can occur in children. ^, A subset of patients with cavitary disease will have a bubbly pattern, which is multiple small cavities distributed along the bronchial tree. Hilar lymphadenopathy and pleural effusion on chest x-ray are uncommon, occurring in <27% of patients; however, with CT imaging, up to 50% of patients can have mediastinal lymphadenopathy. ^, Lymph node calcification is rare in blastomycosis. Pleural effusion is uncommon. In patients with severe disease, radiographic findings can be slow to resolve. Approximately 70% of patients will have residual scarring; however, most patients recover without long-term loss of pulmonary function.

Extrapulmonary Manifestations

Extrapulmonary blastomycosis occurs in 21%–53% of pediatric patients and can involve any organ. ^{, ,} The duration of infection (i.e., time from symptom onset to diagnosis), rather than age, is thought to influence the rate of dissemination. ^{, , ,} Most patients with disseminated disease have concurrent pulmonary symptoms or chest radiographic abnormalities; however, pulmonary disease can resolve before disseminated blastomycosis is diagnosed. ^,

Cutaneous Manifestations

Skin lesions are common in disseminated infections, observed most often in sporadic cases and infrequently in outbreak settings. ^{, ,} Cutaneous disease often begins as minimally tender papules that evolve into verrucous or ulcerative lesions; both types can be present simultaneously. Verrucous lesions have raised irregular borders, crusting, and purulent drainage ( Fig. 252.5A ). In ulcerative forms, borders are sharp and heaped up, and granulation tissue and exudate are seen centrally ( Fig. 252.5B ). Chronic disseminated cutaneous blastomycosis has been reported rarely. Histopathologic findings characteristic of blastomycosis include pseudoepitheliomatous hyperplasia with neutrophilic and granulomatous inflammation (i.e., pyogranulomatous inflammation).

Osseous Manifestations

Acute or subacute suppurative osteomyelitis can occur in 21%–50% of children with sporadic blastomycosis. ^{, ,} The most commonly affected bones are the long bones (e.g., tibia, femur), vertebral bodies, ribs, and skull ( Fig. 252.6 ). ^{, , ,} Blastomycotic osteomyelitis is characterized by lytic bone destruction with associated bone pain. Complications include pathologic fracture; vertebral body collapse; soft tissue abscess with or without sinus tract formation; and extension into the joint space, causing septic arthritis. ^,

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