Blastomycosis

Etiology

Blastomyces is a member of the family Ajellomycetaceae and order Onygenales. B dermatitidis and B gilchristii are the most common causative agents of blastomycosis. Blastomyces helicus (formerly Emmonsia helica) is morphologically distinct from B dermatitidis and B gilchristii and can cause infection in both humans and animals. Blastomyces helicus typically affects immunocompromised individuals, producing severe, frequently fatal systemic infection.[4] 

B dermatitidis and B gilchristii are thermally dimorphic fungi and are genetically distinct but morphologically indistinguishable. At 25 °C, the mycelial form grows as a fluffy white mold (see Image. Blastomycosis Culture), whereas at 37 °C, the organism grows as a brown, folded yeast. The fungus can be isolated in the soil, where it forms a mycelium that penetrates the substratum on which it grows.

The fungus reproduces asexually by producing small conidia, 2 to 10 µm in diameter. In infected cells, Blastomyces organisms appear as relatively large, multinucleated, budding yeast cells, measuring 8 to 15 µm in diameter, with thick, refractile cell walls. Reproduction occurs through a single broad-based bud (see Image. Blastomycosis dermatitidis in Lung Tissue).[5]

Epidemiology

Blastomycosis is endemic in the Ohio and Mississippi River valleys in the US, near the Great Lakes, and in the southeastern United States. Both B dermatitidis and B gilchristii are endemic in the midwestern United States and parts of Canada, including Ontario, Quebec, and Manitoba. B dermatitidis is more widespread in North America, whereas B gilchristii is restricted to certain areas in northwestern Ontario, Minnesota, and northern Wisconsin.[6][7] The geographic distribution of Blastomyces species has expanded beyond these traditional regions, in part due to climate change. Cases of blastomycosis have been found in the following: New York,[8] Vermont,[9] Ontario,[10] and Colorado.[11] 

Blastomyces species are widely endemic throughout Africa, the Middle East, and India. Results from 1 study identified cases of blastomycosis among individuals in 25 African countries and 5 Middle Eastern countries. Blastomyces percursus is widely endemic in this region, with Blastomyces emzantsi found in South Africa, B dermatitidis in the Democratic Republic of the Congo, and B gilchristii in South Africa and Zimbabwe.[12] B dermatitidis is also endemic in India.[13][14] B helicus, by comparison, has been more commonly isolated in the western United States, including Nebraska, Texas, Colorado, Idaho, Montana, Utah, and California, as well as in Alberta and Saskatchewan in western Canada, although the precise geographic distribution remains unknown.[4] 

The annual incidence of blastomycosis is approximately 2 cases per 100,000 population, with rates varying substantially between and within states in the United States. Wisconsin reports the highest incidence of blastomycosis in the United States; however, only 8 states report cases (Arkansas, Colorado, Connecticut, Louisiana, Michigan, Minnesota, Vermont, and Wisconsin).[CDC. Reportable Fungal Diseases by State] Thus, the true incidence of blastomycosis is unknown because cases are frequently underdiagnosed and underreported. 

Blastomycosis primarily affects middle-aged adults, with roughly 70% of cases occurring in men. Although cases most commonly occur in White individuals, higher rates have been observed in American Indian or Alaska Native and Asian populations.[15] Risk is highest in the Midwest and Southern United States, and parts of Canada. Occupational and recreational exposure to Blastomyces species appears to be a risk factor for infection, with a high incidence of blastomycosis among individuals who visit rivers and waterways.[16] In 2022 to 2023, a large outbreak of blastomycosis associated with a paper mill in Michigan, United States, resulted in 131 diagnosed cases.[17]

Pathophysiology

Blastomyces species are thermally dimorphic fungi that exist as a mold (mycelium) in the environment and a budding yeast in the host. Blastomycosis occurs following the inhalation of Blastomyces conidia from disturbed soil. After conidia are inhaled, they pass into the lower respiratory tract and are converted from the mycelial form into budding yeast. The conidia can be phagocytosed by bronchopulmonary mononuclear cells and killed by neutrophils and macrophages, resulting in asymptomatic infection.

When Blastomyces converts to the yeast form, the thick cell wall confers resistance to phagocytosis and killing, leading to symptomatic pulmonary infection. In addition, the immunomodulatory glycoprotein Blastomyces adhesin-1 (BAD-1) facilitates binding to macrophages, allowing dissemination through the blood and lymphatics to other areas of the body. The pyogranulomatous inflammatory response is a unique feature of blastomycosis and is characterized by an influx of neutrophils and macrophages, followed by granuloma formation.[18]

Histopathology

Histopathologic changes are characterized by a mixed suppurative and granulomatous tissue response, often featuring prominent pseudoepitheliomatous hyperplasia (see Image. Blastomyces dermatitidis of Skin). Thick-walled yeast with characteristic single, broad-based budding is seen (see Image. Blastomyces dermatitidis). Pyogranulomatous inflammation and microabscesses with neutrophils are commonly seen, particularly in cutaneous and lung tissue. 

History and Physical

Because pulmonary involvement is the most common manifestation of blastomycosis, presenting symptoms frequently include pulmonary and systemic infectious symptoms. Results from 1 study of 326 cases of blastomycosis showed that the most common presenting symptom was cough, occurring in 73% of individuals. Other common symptoms included fever (54%) and sputum production (50%). Approximately 40% of individuals experienced chest pain, shortness of breath, and weight loss, and approximately 30% experienced night sweats and chills.[3] An estimated 50% of individuals have minimal to no symptoms.[2]

The incubation period for pulmonary blastomycosis ranges from approximately 3 weeks to 3 months following exposure. In individuals with acute pneumonia, the incubation period typically ranges from 4 to 6 weeks.[19] Differentiating the symptoms of pulmonary blastomycosis from those of viral and bacterial pneumonia can be challenging.

With acute blastomycosis, chest radiography most commonly reveals airspace consolidation, often in the upper lobes and involving more than 1 lobe.[20] Individuals with chronic pulmonary blastomycosis often present with cough, chest pain, and systemic infectious symptoms, including fever, night sweats, and weight loss. Symptoms can be indistinguishable from tuberculosis and other fungal etiologies. On chest radiography, individuals with chronic blastomycosis can have airspace consolidation, similar to acute pulmonary blastomycosis, but more commonly present with mass lesions and cavitation.[19] 

Acute respiratory distress syndrome is a rare presentation of pulmonary blastomycosis, occurring in up to 10% of cases. Acute respiratory distress syndrome is associated with a mortality rate of 50% to 90%.[21] In contrast, extrapulmonary infection typically results from hematogenous spread. Cutaneous blastomycosis is the second most common manifestation of blastomycosis, typically presenting as papules that progress to crusted, vegetative plaques, often with central clearing or ulceration. Lymphangitis and lymphadenopathy may also be present.

Osteomyelitis is the second most common extrapulmonary manifestation of blastomycosis, occurring in 25% of extrapulmonary cases.[5] Although osteomyelitis can involve any bone or joint, the lower spine and pelvis are most commonly affected. Individuals often present with soft tissue swelling or a chronically draining sinus. Other findings of extrapulmonary infection can include prostatitis, orchitis, or epididymitis. The central nervous system is involved in 5% to 10% of extrapulmonary cases, including cases of meningitis and intracranial or epidural abscesses.[22]

Evaluation

As with other dimorphic fungi (eg, Coccidioides and Histoplasma), clinicians need a high index of suspicion to diagnose blastomycosis because infection is uncommon compared with many other causes of community-acquired pneumonia (eg, bacteria and viruses), and Blastomyces grows slowly on culture. Although culture is highly specific (approximately 100%), sensitivity is much lower, ranging from 66% to 86%.[23] Blastomycosis should be suspected in individuals with community-acquired pneumonia who live in or have traveled to a Blastomyces-endemic area within the prior 3 years and have:

• Pulmonary symptoms that did not improve with empiric antibiotics
• Skin lesions characteristic of cutaneous blastomycosis
• Clinical findings of extrapulmonary blastomycosis with negative bacterial cultures
• Findings on radiography that are suspicious for malignant neoplasm, mycobacterial infections, or fungal infection
• Granulomas with neutrophilic predominance on histopathology [24]

Additionally, engaging in frequent outdoor recreational activities (eg, fishing, canoeing, or rafting) in areas endemic for Blastomyces or working in occupations that may increase the risk of exposure to Blastomyces (eg, construction work, working in a paper mill, or logging) should also increase the suspicion for blastomycosis in the right clinical setting. Clinicians should send a Blastomyces urine antigen test in addition to specimens for culture (or tissue for histopathology and culture, if applicable), if blastomycosis is suspected. Biopsy and histopathological examination of skin lesions reveal pseudoepitheliomatous hyperplasia with neutrophilic abscesses.

Organisms can be difficult to identify and are often found within histiocytes or abscesses in the dermis. The yeast cells are 8 to 15 µm in diameter, have thick, double-contoured walls, and display broad-based budding. Culture has variable sensitivity, and growth typically takes 2 to 4 weeks, although growth can take up to 6 weeks in some cases.

Clinicians should alert laboratory staff when blastomycosis is suspected so they can take appropriate precautions to protect themselves from exposure and incubate cultures for 6 weeks, which is longer than many laboratories typically incubate fungal cultures. Molecular testing (eg, polymerase chain reaction) is increasingly used to diagnose blastomycosis, although, as with polymerase chain reaction testing for other pathogens, it is expensive, has variable sensitivity and specificity, and lacks standardization. Serology has low sensitivity for Blastomyces and a high degree of cross-reactivity with other dimorphic fungi (eg, Coccidioides and Histoplasma), so it is not a preferred modality for the diagnosis of blastomycosis.

Treatment / Management

Although mild pulmonary blastomycosis may be self-limiting in immunocompetent individuals,[25] antifungal therapy is recommended for all infected individuals to prevent extrapulmonary dissemination. All individuals with moderate to severe pneumonia, disseminated blastomycosis, and individuals who are immunocompromised should be treated with antifungals.(B3)

Pulmonary Blastomycosis

First-line treatment of mild to moderate pulmonary blastomycosis is oral itraconazole 200 mg 3 times daily for 3 days, followed by 200 mg twice daily for 6 to 12 months. For moderately severe or severe disease, initial treatment with liposomal amphotericin B is recommended, at 3 to 5 mg/kg intravenously daily. If a lipid formulation of amphotericin B is unavailable, amphotericin B deoxycholate 0.7 to 1.0 mg/kg intravenously daily should be used.

Once clinical improvement is noted, individuals can be transitioned to oral itraconazole and should be treated for 6 to 12 months. Therapeutic drug monitoring is recommended after at least 2 weeks of antifungal treatment.[26] Other azoles, such as posaconazole, isavuconazole, voriconazole, and fluconazole, can be used in place of itraconazole, although they are less well-studied for the treatment of blastomycosis.(A1)

Disseminated Extrapulmonary Blastomycosis

For mild to moderate disease, oral itraconazole 200 mg 3 times daily for 3 days, followed by 200 mg twice daily for 6 to 12 months, is recommended. Individuals with osteoarticular blastomycosis should receive at least 12 months of antifungal treatment. For moderately severe and severe disease, initial treatment with liposomal amphotericin B is recommended: 3 to 5 mg/kg intravenously daily for 1 to 2 weeks or until improvement is noted, followed by oral itraconazole 200 mg 3 times daily for 3 days, then 200 mg twice daily for 12 months. If a lipid formulation of amphotericin B is unavailable, amphotericin B deoxycholate 0.7 to 1.0 mg/kg intravenously daily should be used. Therapeutic drug monitoring is recommended after at least 2 weeks of antifungal treatment.[26](A1)

Central Nervous System Blastomycosis

Liposomal amphotericin B at 5 mg/kg intravenously daily for 4 to 6 weeks is recommended, followed by an oral azole. If a lipid formulation of amphotericin B is unavailable, amphotericin B deoxycholate 1.0 mg/kg intravenously daily should be used. Fluconazole 800 mg daily, itraconazole 200 mg 2 or 3 times daily, or voriconazole 200 to 400 mg twice daily for at least 12 months and until resolution of cerebrospinal fluid abnormalities is recommended.[26](A1)

Immunosuppressed Individuals with Blastomycosis 

Liposomal amphotericin B at 3 to 5 mg/kg intravenously daily for 1 to 2 weeks or until clinical improvement is recommended, followed by oral itraconazole 200 mg 3 times daily for 3 days, followed by 200 mg twice daily for 12 months. If a lipid formulation of amphotericin B is unavailable, amphotericin B deoxycholate 0.7 to 1.0 mg/kg intravenously daily should be used. Therapeutic drug monitoring is recommended after at least 2 weeks of antifungal treatment. Lifelong suppressive therapy with oral itraconazole 200 mg daily may be required in cases where immunosuppression cannot be reversed.[26](A1)

Blastomycosis in Pregnant Women and Children

During pregnancy, liposomal amphotericin B at 3 to 5 mg/kg intravenously daily is recommended as azoles are contraindicated due to concerns about teratogenicity. If the newborn shows evidence of infection, amphotericin B deoxycholate 1.0 mg/kg intravenously daily is recommended. For children with mild to moderate blastomycosis, oral itraconazole 10 mg/kg daily (maximum dose 400 mg) for 6 to 12 months is recommended. For severe blastomycosis, amphotericin B deoxycholate at 0.7 to 1.0 mg/kg intravenously daily, or liposomal amphotericin B at 3 to 5 mg/kg intravenously daily, is recommended, followed by oral itraconazole at 10 mg/kg daily (maximum dose, 400 mg) for a total of 12 months. Therapeutic drug monitoring is recommended after at least 2 weeks of antifungal treatment.[26](A1)

Differential Diagnosis

The differential diagnosis of blastomycosis includes the following:

Pulmonary

• Bacterial pneumonia
• Other fungal infections (eg, histoplasmosis or coccidioidomycosis)
• Pulmonary tuberculosis
• Lung cancer
• Sarcoidosis

Cutaneous

• Squamous cell carcinoma
• Pyoderma gangrenosum
• Keratoacanthoma
• Other deep fungal infections (eg, sporotrichosis)
• Tuberculosis verrucosa cutis

Extrapulmonary

• Lymphoma
• Bone tumors
• Tuberculous osteomyelitis 

Prognosis

Individuals who are immunocompetent generally have a good prognosis, with successful treatment occurring in approximately 80% to 95% of cases.[3][27] Results from 1 large study spanning 20 years (1990–2010) showed that risk factors for poor prognosis included increased age, male sex, individuals living in the South and Midwest United States, American Indian ethnicity, and Black race.[28] Individuals who are immunocompromised have a notably poorer prognosis, with mortality rates of approximately 30%.[29] If acute respiratory distress syndrome occurs, the mortality rate can be much higher, often greater than 50%.[18]

Complications

Complications of blastomycosis include relapse and severe, life-threatening conditions such as acute respiratory distress syndrome. If dissemination occurs, cutaneous lesions, osteomyelitis, prostatitis, and meningitis can occur. Disseminated blastomycosis is associated with longer treatment duration and increased morbidity and mortality.