Blastomycosis, also known as Gilchrist's disease, is a fungal infection, typically of the lungs, which can spread to brain, stomach, intestine and skin, where it appears as crusting purplish warty plaques with a roundish bumpy edge and central depression. Around half of the people with the disease have symptoms, which can include fever, cough, night sweats, muscle pains, weight loss, chest pain, and fatigue. Symptoms usually develop between three weeks and three months after breathing in the spores. In 25% to 40% of cases, the infection also spreads to other parts of the body, such as the skin, bones, or central nervous system. Although blastomycosis is especially dangerous for those with weak immune systems, most people diagnosed with blastomycosis have healthy immune systems.
Blastomyces dermatitidis is found in the soil and decaying organic matter like wood or leaves. Outdoor activities like hunting or camping in wooded areas increase the risk of developing blastomycosis. There is no vaccine, but the risk of the disease can be reduced by not disturbing the soil. Treatment is typically with an azole drug such as itraconazole for mild or moderate disease. In severe cases, patients are treated with amphotericin B before azole treatment. In either event, the azole treatment lasts for 6–12 months. Overall, 4–6% of people who develop blastomycosis die; however, if the central nervous system is involved, this rises to 18%. People with AIDS or on medications that suppress the immune system have the highest risk of death at 25–40%.
Blastomycosis is endemic to the eastern United States and Canada, especially the Ohio and Mississippi River valleys, the Great Lakes, and the St. Lawrence River valley. In these areas, there are about 1 to 2 cases per 100,000 per year. Less frequently, blastomycosis also occurs in Africa, the Middle East, India, and western North America. Blastomycosis also affects a broad range of non-human mammals, and dogs in particular are an order of magnitude more likely to contract the disease than humans. The ecological niche of Blastomyces in the wild is poorly understood, and it is unknown if there are any significant host animals.
Blastomycosis has existed for millions of years but was first described by Thomas Caspar Gilchrist in 1894. Because of this, it is sometimes called "Gilchrist's disease".
Signs and symptoms
The symptoms of blastomycosis cover a wide range, overlapping with more common conditions; for this reason, blastomycosis has often been called "the great pretender". Many cases are asymptomatic or subclinical. Lung symptoms are common because the lungs are infected in 79% of blastomycosis cases. However, in 25–40% of cases, the disease also disseminates to other organs, including the skin.
The extent and severity of symptoms depend in part on a person's immune status; less than 50% of healthy people with blastomycosis have symptoms, while immunocompromised patients are especially likely to have the disease spread beyond the lungs to other organs like the skin and bones.
Blastomycosis manifests as a primary lung infection in about 79% of cases. The onset is relatively slow, and symptoms are suggestive of bacterial pneumonia, often leading to initial treatment with antibacterials. Because the symptoms are variable and nonspecific, blastomycosis is often not even considered in differential diagnosis until antibacterial treatment has failed, unless there are known risk factors or skin lesions. The disease may be misdiagnosed as a carcinoma, leading in some cases to surgical removal of the affected tissue. Upper lung lobes are involved somewhat more frequently than lower lobes. If untreated, many cases progress over months to years to become disseminated blastomycosis.
Blastomycosis in the lungs may present a variety of symptoms, or no symptoms at all. If symptoms are present they may range from mild pneumonia resembling a pneumococcal infection to acute respiratory distress syndrome (ARDS). Common symptoms include fever, chills, headache, coughing, difficulty breathing, chest pain, and malaise. Without treatment, cases may progress to chronic pneumonia or ARDS.
ARDS is an uncommon but dangerous manifestation of blastomycosis. It was seen in 9 of 72 blastomycosis cases studied in northeast Tennessee. Such cases may follow massive exposure, such as during brush clearing operations. In the Tennessee study, the fatality rate was 89% in the ARDS cases, but only 10% in the non-ARDS cases.
In disseminated blastomycosis, the large Blastomyces yeast cells translocate from the lungs and are trapped in capillary beds elsewhere in the body, where they cause lesions. The skin is the most common organ affected, being the site of lesions in approximately 60% of cases. The signature image of blastomycosis in textbooks is the indolent, verrucous or ulcerated dermal lesion seen in disseminated disease. Osteomyelitis is also common (12–60% of cases). Other recurring sites of dissemination are the genitourinary tract (kidney, prostate, epididymis; collectively ca. 25% of cases) and the brain (3–10% of cases). Among immunocompromised individuals, 40% have CNS involvement presenting as brain abscess, epidural abscess or meningitis.
Blastomycosis in non-lung organs, such as the skin, may present a very wide range of symptoms, including the following: skin lesions, which may be verrucous (wart-like) or ulcerated with small pustules at the margins. bone or joint pain due to bone lytic lesions. pain when urinating due to prostatitis. hoarseness due to laryngeal involvement. headache, confusion or other neurological symptoms caused by central nervous system involvement.
Cause
Blastomycosis is caused by dimorphic fungi in the genus Blastomyces, in the phylum Ascomycota and family Ajellomycetaceae. In eastern North America, the most common cause of blastomycosis is Blastomyces dermatitidis, but Blastomyces gilchristii has been associated with some outbreaks. In western North America, many cases of blastomycosis are caused by Blastomyces helicus, which most commonly attacks immunodeficient people and domestic animals. The species Blastomyces percursus causes many cases of blastomycosis in Africa and the Middle East. In Africa, blastomycosis may also be caused by Blastomyces emzantsi, which is often associated with infections outside the lungs.
In endemic areas, Blastomyces dermatitidis lives in soil and rotten wood near lakes and rivers. Although it has never been directly observed growing in nature, it is thought to grow there as a cottony white mold, similar to the growth seen in artificial culture at 25 °C. The moist, acidic soil in the surrounding woodland harbors the fungus.
Pathogenesis
Inhaled conidia of Blastomyces are phagocytosed by neutrophils and macrophages in alveoli. Some of these escape phagocytosis and transform into the yeast phase rapidly. Having thick walls, these are resistant to phagocytosis. Once they have transitioned to the yeast phase, the Blastomyces cells express the protein BAD-1, which helps the yeast cells attach to host cells, and also impairs the activation of immune cells while inhibiting the release of tumor necrosis factor. In lung tissue, the cells multiply and may also disseminate through blood and lymphatics to other organs, including the skin, bone, genitourinary tract, and brain. The incubation period for pulmonary blastomycosis is 3 to 15 weeks, although 30–50% of infections are asymptomatic.
Diagnosis Because the symptoms of blastomycosis resemble those of many other conditions, including tuberculosis and lung cancer, diagnosis is often delayed. In 40% of cases, the diagnosis takes more than a month. A rapid diagnosis can, however, be made based on microscopic examination of sputum samples or samples obtained from a tissue biopsy or bronchoalveolar lavage.
Once suspected, the diagnosis of blastomycosis can usually be confirmed by demonstration of the characteristic broad-based budding organisms in sputum or tissues by KOH prep, cytology, or histology. Tissue biopsy of the skin or other organs may be required to diagnose extra-pulmonary disease. Blastomycosis is histologically associated with granulomatous nodules.
Commercially available urine antigen testing appears to be quite sensitive in suggesting the diagnosis in cases where the organism is not readily detected. However, commercial antigen tests have a high degree of cross-reactivity with other endemic fungal conditions such as histoplasmosis, and thus cannot distinguish blastomycosis from other similar conditions. This cross-reactivity is caused by these related fungal organisms using similar galactomannans in the cell wall.
While a culture of the Blastomyces organism remains the definitive diagnostic standard, its slow-growing nature can lead to a delay of up to four weeks. In addition, sometimes blood and sputum cultures may not detect blastomycosis. Cultures of the cerebrospinal fluid also have poor sensitivity compared to histopathological examination of the affected tissue.
Treatment
Under Infectious Disease Society of America guidelines, severe cases of blastomycosis and cases with central nervous system (CNS) involvement are treated initially with amphotericin B, followed by a lengthy course of an azole drug such as itraconazole. In most cases the amphotericin treatment lasts for 1–2 weeks, but in cases of CNS involvement it may last for up to 6 weeks. Cases that do not require amphotericin B treatment are treated with a lengthy course of an azole drug.
Among azole drugs, itraconazole is generally the treatment of choice. Voriconazole is often recommended for CNS blastomycosis cases due to its ability to pass the blood–brain barrier. Other azole drugs that may be used include fluconazole. Ketoconazole was the azole drug first used for blastomycosis treatment, but has been largely replaced by itraconazole because ketoconazole is less effective and less tolerated by patients. The azole treatment generally lasts for a minimum of six months. Cure rates from itraconazole treatment are nearly 95%. Relapse is rare but does occur even after a full course of treatment.
Prognosis
Published estimates of the case fatality rate for blastomycosis have varied from 4% to 78%. A 2020 meta-analysis of published studies found an overall mortality rate of 6.6%. This rose to 37% for immunocompromised patients and 75% for patients with ARDS. A 2021 analysis of 20 years of disease surveillance data from the five US states where blastomycosis is reportable found an overall mortality rate of 8% and a hospitalization rate of 57%. These numbers may be affected by the under-reporting of mild cases.
Epidemiology
Incidence in most endemic areas is about 0.5 per 100,000 population, with occasional local areas attaining as high as 12 per 100,000. Most Canadian data fit this picture. In Ontario, Canada, considering both endemic and non-endemic areas, the overall incidence is around 0.3 cases per 100,000; northern Ontario, mostly endemic, has 2.44 per 100,000. Manitoba is calculated at 0.62 cases per 100,000. Remarkably higher incidence was shown for the Kenora, Ontario region: 117 per 100,000 overall, with Aboriginal reserve communities experiencing 404.9 per 100,000. In the United States, the incidence of blastomycosis is similarly high in hyperendemic areas. For example, the city of Eagle River, Vilas County, Wisconsin, has an incidence rate of 101.3 per 100,000; the county as a whole has been shown in two successive studies to have an incidence of about 40 cases per 100,000. An incidence of 277 per 100,000 was roughly calculated based on 9 cases seen in a Wisconsin aboriginal reservation during a time in which extensive excavation was done for new housing construction. The new case rates are greater in northern states such as Wisconsin, where from 1986 to 1995 there were 1.4 cases per 100,000 people.