Blastomycosis

Template:Hatnote Template:Infobox medical condition (new) 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.<ref name=John2017>Template:Cite book</ref><ref name=CDC>Template:Cite web</ref> 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.<ref name="Symptoms">Template:Cite web</ref> Symptoms usually develop between three weeks and three months after breathing in the spores.<ref name="Symptoms"/> 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.<ref name="mcbride2017">Template:Cite journal</ref> Although blastomycosis is especially dangerous for those with weak immune systems, most people diagnosed with blastomycosis have healthy immune systems.<ref name="mcbride2017"/>

Blastomyces dermatitidis is found in the soil and decaying organic matter like wood or leaves.<ref name="CDC HP">Template:Cite web</ref> Outdoor activities like hunting or camping in wooded areas increase the risk of developing blastomycosis.<ref name=Prevention>Template:Cite web</ref> There is no vaccine, but the risk of the disease can be reduced by not disturbing the soil.<ref name=Prevention/> Treatment is typically with an azole drug such as itraconazole for mild or moderate disease.<ref name="idsa2008"/> In severe cases, patients are treated with amphotericin B before azole treatment.<ref name="idsa2008"/> In either event, the azole treatment lasts for 6–12 months.<ref>Template:Cite web</ref> 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%.<ref>Template:Cite journal</ref>

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.<ref name="CDC HP"/> In these areas, there are about 1 to 2 cases per 100,000 per year.<ref>Template:Cite web</ref> Less frequently, blastomycosis also occurs in Africa, the Middle East, India, and western North America.<ref name="mcbride2017"/><ref name="schwartz2021"/> 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.<ref name="schwartz2018"/> The ecological niche of Blastomyces in the wild is poorly understood, and it is unknown if there are any significant host animals.<ref name="baumgardner2016">Template:Cite journal</ref>

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".<ref name=Gilchrist>Template:Cite book</ref>

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".<ref name="mcbride2017"/> Many cases are asymptomatic or subclinical. Lung symptoms are common because the lungs are infected in 79% of blastomycosis cases.<ref name="mcbride2017"/> However, in 25–40% of cases, the disease also disseminates to other organs, including the skin.<ref name="mcbride2017"/>

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.<ref name="Murray 2015">Template:Cite book</ref>

Blastomycosis manifests as a primary lung infection in about 79% of cases.<ref name="mcbride2017"/> 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.<ref name="mcbride2017"/> The disease may be misdiagnosed as a carcinoma, leading in some cases to surgical removal of the affected tissue.<ref>Template:Cite journal</ref> Upper lung lobes are involved somewhat more frequently than lower lobes.<ref name=kwonchung1992/> 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.<ref name="mcbride2017"/> If symptoms are present they may range from mild pneumonia resembling a pneumococcal infection to acute respiratory distress syndrome (ARDS).<ref name="mcbride2017"/> Common symptoms include fever, chills, headache, coughing, difficulty breathing, chest pain, and malaise.<ref name="mcbride2017"/> Without treatment, cases may progress to chronic pneumonia or ARDS.<ref name="mcbride2017"/>

ARDS is an uncommon but dangerous manifestation of blastomycosis. It was seen in 9 of 72 blastomycosis cases studied in northeast Tennessee.<ref name="vasquez1998"/> 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.<ref name="vasquez1998"/>

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.<ref name=kwonchung1992/> 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).<ref name=kwonchung1992/> Among immunocompromised individuals, 40% have CNS involvement presenting as brain abscess, epidural abscess or meningitis.Template:Citation needed

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.<ref name="schwartz2021">Template:Cite journal</ref> In Africa, blastomycosis may also be caused by Blastomyces emzantsi, which is often associated with infections outside the lungs.<ref>Template:Cite journal</ref>

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. <ref>Template:Cite journal</ref> 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.<ref name="khuu-2014">Template:Cite journal</ref>

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.<ref name="mazi2021">Template:Cite journal</ref> A rapid diagnosis can, however, be made based on microscopic examination of sputum samples or samples obtained from a tissue biopsy or bronchoalveolar lavage.<ref name="nel2018">Template:Cite journal</ref>

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.<ref name="veligandla2002"/> 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.<ref name="nel2018"/> 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.<ref name="nel2018"/><ref name="linder2021">Template:Cite journal</ref> This cross-reactivity is caused by these related fungal organisms using similar galactomannans in the cell wall.<ref name="linder2021"/>

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.<ref name="mazi2021"/> In addition, sometimes blood and sputum cultures may not detect blastomycosis.<ref>Template:Cite journal</ref> Cultures of the cerebrospinal fluid also have poor sensitivity compared to histopathological examination of the affected tissue.<ref>Template:Cite journal</ref>

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.<ref name="idsa2008">Template:Cite journal</ref> 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.<ref name="idsa2008"/> Cases that do not require amphotericin B treatment are treated with a lengthy course of an azole drug.<ref name="idsa2008"/>

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.<ref name="idsa2008"/> 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.<ref name="idsa2008"/> The azole treatment generally lasts for a minimum of six months. Cure rates from itraconazole treatment are nearly 95%.<ref name="idsa2008"/> Relapse is rare but does occur even after a full course of treatment.<ref name="idsa2008"/>

Prognosis

Published estimates of the case fatality rate for blastomycosis have varied from 4% to 78%.<ref name="carignan-2020">Template:Cite journal</ref> A 2020 meta-analysis of published studies found an overall mortality rate of 6.6%.<ref name="carignan-2020"/> This rose to 37% for immunocompromised patients and 75% for patients with ARDS.<ref name="carignan-2020"/> 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%.<ref name="benedict-2021">Template:Cite journal</ref> These numbers may be affected by the under-reporting of mild cases.<ref name="benedict-2021"/>

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.<ref name=kwonchung1992/><ref name=rippon1988/><ref name=manetti1991/><ref name=cano2003/> 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.<ref name=morris2006/> Manitoba is calculated at 0.62 cases per 100,000.<ref name=crampton2002/> 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.<ref name=dwight2000/> 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.<ref name=baumgardner1998/> 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.<ref name=baumgardner2002/> 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.<ref name=mmwr1996/>

The study of outbreaks as well as trends in individual cases of blastomycosis has clarified several important matters. Some of these relate to the ongoing effort to understand the source of the infectious inoculum of this species, while others relate to which groups of people are especially likely to become infected. Human blastomycosis is primarily associated with forested areas and open watersheds;<ref name=kwonchung1992/><ref name=disalvo1992/><ref name=baumgardner2005a/><ref name=baumgardner2006/> It primarily affects otherwise healthy, vigorous people, mostly middle-aged,<ref name=klein1987/> who acquire the disease while working or undertaking recreational activities in sites conventionally considered clean, healthy and in many cases beautiful.<ref name=kwonchung1992/><ref name=rippon1988/> Repeatedly associated activities include hunting, especially raccoon hunting,<ref name=armstrong1987/> where accompanying dogs also tend to be affected, as well as working with wood or plant material in forested or riparian areas,<ref name=kwonchung1992/><ref name=kesselman2005/> involvement in forestry in highly endemic areas,<ref name=vaaler1990/> excavation,<ref name=baumgardner1998/> fishing<ref name=klein1987/><ref name=baumgardner1992/> and possibly gardening and trapping.<ref name=dwight2000/><ref name=baumgardner1998/>

Urban infections

There is also a developing profile of urban and other domestic blastomycosis cases, beginning with an outbreak tentatively attributed to construction dust in Westmont, Illinois.<ref name=kitchen1977/> The city of Rockford, Illinois, was also documented as a hyperendemic area based on incidence rates as high as 6.67 per 100,000 population for some areas of the city. Though proximity to open watersheds was linked to incidence in some areas,<ref name=baumgardner2006/> suggesting that outdoor activity within the city may be connected to many cases, there is also an increasing body of evidence that even the interiors of buildings may be at-risk areas. An early case concerned a prisoner who was confined to prison during the whole of his likely blastomycotic incubation period.<ref name=renston1992/> An epidemiological survey found that although many patients who contracted blastomycosis had engaged in fishing, hunting, gardening, outdoor work, and excavation, the most strongly linked association in patients was living or visiting near waterways.<ref name=baumgardner1992/> Based on a similar finding in a Louisiana study, it has been suggested that place of residence might be the most important single factor in blastomycosis epidemiology in north central Wisconsin.<ref name=lowry1989/> Follow-up epidemiological and case studies indicated that clusters of cases were often associated with particular domiciles, often spread out over years and that there were uncommon but regularly occurring cases in which pets kept mostly or entirely indoors, in particular cats, contracted blastomycosis.<ref name=blondin2007/><ref name=baumgardner2001/> The occurrence of blastomycosis, then, is an issue strongly linked to housing and domestic circumstances.

Seasonal trends

Seasonality and weather also appear to be linked to the contraction of blastomycosis. Many studies have suggested an association between blastomycosis contraction and cool to moderately warm, moist periods of the spring and autumn<ref name=kwonchung1992/><ref name=dwight2000/><ref name=rudmann1992/> or, in relatively warm winter areas.<ref name=arceneaux1998/> However, the entire summer or a known summer exposure date is included in the association in some studies.<ref name=klein1987/><ref name=archer1987/> Occasional studies fail to detect a seasonal link.<ref name=chapman1997/> In terms of weather, both unusually dry weather<ref name=proctor2002/> and unusually moist weather<ref name=degroote2000/> have been cited. The seemingly contradictory data can most likely be reconciled by proposing that B. dermatitidis prospers in its natural habitats in times of moisture and moderate warmth, but that inoculum formed during these periods remains alive for some time and can be released into the air by subsequent dust formation under dry conditions. Indeed, dust per se or construction potentially linked to dust has been associated with several outbreaks<ref name=vasquez1998/><ref name=kitchen1977/><ref name=baumgardner1991/> The data, then, tend to link blastomycosis to all weather, climate, and atmospheric conditions except freezing weather, periods of snow cover, and extended periods of hot, dry summer weather in which soil is not agitated.

Gender bias

Sex is another factor inconstantly linked to the contraction of blastomycosis: though many studies show more men than women affected,<ref name=kwonchung1992/><ref name=morris2006/> some show no sex-related bias.<ref name=dwight2000/><ref name=baumgardner1992/> As mentioned above, most cases are in middle-aged adults, but all age groups are affected, and cases in children are not uncommon.<ref name=kwonchung1992/><ref name=dwight2000/><ref name=morris2006/>

Ethnic populations

Ethnic group or race is frequently investigated in epidemiological studies of blastomycosis, but is potentially confounded by differences in residence, quality, and accessibility of medical care, factors that have not been stringently controlled to date. In the United States, some studies show a disproportionately high incidence and/or mortality rate for blastomycosis among Black people.<ref name=manetti1991/><ref name=cano2003/><ref name=dworkin2005/><ref name=lemos2000/>

In Canada, some studies, but not others,<ref name=crampton2002/> indicate that First Nations people have a disproportionately high incidence of blastomycosis.<ref name=dwight2000/><ref name=kepron1972/> Incidence in First Nations children may be unusually high.<ref name=dwight2000/> The Canadian data in some areas may be confounded or explained by the tendency to establish indigenous communities in wooded, riparian, northern areas corresponding to the core habitat of B. dermatitidis, often with known B. dermatitidis habitats such as woodpiles and beaver constructions in the near vicinity.

Communicability

Blastomycosis is not considered contagious, either among humans or between animals and humans.<ref name="Prevention"/> However, there are a very small number of cases of human-to-human transmission of B. dermatitidis related to dermal contact<ref name=bachir2006/> or sexual transmission of disseminated blastomycosis of the genital tract among spouses.<ref name=kwonchung1992/>

History

The organisms causing blastomycosis have existed for millions of years. The pathogenic group of onygenalean fungi that give rise to conditions including blastomycosis and histoplasmosis emerged approximately 150 million years ago.<ref name="caballerovandyke-2019">Template:Cite journal</ref> The most closely related blastomycosis-causing fungi, Blastomyces dermatitidis and Blastomyces gilchristii, diverged during the Pleistocene, approximately 1.9 million years ago.<ref name="klein2021">Template:Cite book</ref>

At the Koster Site in Illinois, evidence pointing to possible blastomycosis infections among Late Woodland Native Americans has been identified. At that site, Dr. Jane Buikstra found evidence for what may have been an epidemic of a serious spinal disease in adolescents and young adults. Several of the skeletons showed lesions in the spinal vertebrae in the lower back. Two modern diseases produce lesions in the bone similar to the ones Dr. Buikstra found in these prehistoric specimens: spinal tuberculosis and blastomycosis. The bony lesions in these two diseases are practically identical. Blastomycosis seems more probable as these young people in Late Woodland and Mississippian times may have been affected because they were spending more time cultivating plants than their Middle Woodland predecessors had done. If true, it would be another severe penalty Late Woodland people had to pay as they shifted to agriculture as a way of life, and it would be a contributing factor to shortening their lifespans compared to those of the Middle Woodland people.<ref>Struever, Stuart and Felicia Antonelli Holton (1979). Koster: Americans in Search of Their Prehistoric Past. New York: Anchor Press / Doubleday. Template:ISBN.</ref>

Blastomycosis was first described by Thomas Caspar Gilchrist in 1894, as a skin disease. Because of this, blastomycosis is sometimes called "Gilchrist's disease".<ref name=Gilchrist/> Gilchrist initially identified the cause of the disease as a protozoan, but later correctly identified it as a fungus.<ref name="espinelingroff1996">Template:Cite book</ref> In 1898, he and William Royal Stokes published the first description of Blastomyces dermatitidis.<ref name="espinelingroff1996"/> Gilchrist referred to the disease as "blastomycetic dermatitis".

The systemic spread of blastomycosis was first described in 1902, in a case that had been misdiagnosed as a combination of tuberculosis and a blastomycosis skin infection. In 1907, the dimorphic nature of the Blastomyces fungus was first identified.<ref name="espinelingroff1996"/> In 1912, the first case of canine blastomycosis was reported.<ref name="schwartz2018"/>

Prior to the 1930s, blastomycosis was not clearly distinguished from similar fungal conditions.<ref name="espinelingroff1996"/> A paper by Rhoda Williams Benham in 1934 distinguished the causative agent of blastomycosis from cryptococcosis and coccidioidomycosis.<ref name="espinelingroff1996"/>

In the early 1950s, blastomycosis was first determined to be a primarily respiratory disease, with most skin lesions caused by systemic spread from an initial lung infection.<ref>Template:Cite book</ref> In 1952, the first documented case outside North or Central America, in Tunisia, was reported.<ref>Template:Cite book</ref> The 1950s also saw the first introduction of antifungal drugs including amphotericin B.<ref name="espinelingroff1996"/> Before 1950, the fatality rate for disseminated blastomycosis was 92%, and treatment options were limited to iodide compounds, radiation therapy, and surgery.<ref name="espinelingroff1996"/> The first azole antifungal drug, ketoconazole, was developed in the 1970s and approved in the United States in 1981.<ref name="espinelingroff1996"/>

Before 2013, the only species known to cause blastomycosis was B. dermatitidis. Since that time, genomic analysis has identified multiple other Blastomyces species causing blastomycosis, including B. gilchristii (2013), B. helicus (reassigned from the genus Emmonsia in 2017), B. percursus (2017), and B. emzantsi (2020).<ref name="klein2021"/>

The largest-ever blastomycosis outbreak in United States history occurred at an Escanaba, Michigan, paper mill in 2023. Template:As of, one person had died and almost a hundred more had fallen ill.<ref>Template:Cite news</ref><ref>Template:Cite news</ref>

Other animals

Blastomycosis affects a broad range of mammals. As with humans, most animals that become infected were formerly healthy and immunocompetent.<ref name="schwartz2018">Template:Cite book</ref> Dogs are frequently affected; blastomycosis is eight to ten times more common in dogs than in humans.<ref name="schwartz2018"/> Sporting and hound breeds are at the greatest risk.<ref name="rudmann1992"/> Cats and horses can also be infected. Cats with feline immunodeficiency virus are particularly at risk. However, the overall risk of blastomycosis in cats is 28 to 100 times lower than in dogs.<ref name="schwartz2018"/> Cases of blastomycosis have also been reported in captive lions and tigers, in a wild North American black bear, and in marine mammals such as the Atlantic bottlenose dolphin.<ref name="schwartz2018"/>

The nonspecific symptoms that make blastomycosis difficult to diagnose in humans also complicate veterinary diagnosis. Cats, in particular, are often only diagnosed after death.<ref name="schwartz2018"/>

Dogs and humans frequently acquire blastomycosis from the same exposure event.<ref name="schwartz2018"/> In most such cases, the infection in the dog becomes apparent before the human infection.<ref name="schwartz2018"/> This may be due to a shortened incubation period, caused by the dog inhaling larger quantities of Blastomyces spores than the human.<ref name="schwartz2018"/>

In veterinary care, blastomycosis is typically treated with itraconazole.<ref name="merck">Template:Cite web</ref> 70% of treated dogs respond to medication and recover.<ref name="merck"/> In dogs as in humans, the prognosis for blastomycosis depends on the severity of the symptoms.<ref name="merck"/>

Additional images

Granuloma with early suppuration. The fungal organisms are difficult to recognize at this low magnification.
Large yeast-like fungi seen within giant cells at arrows.
Large yeast-like fungi seen within giant cells at arrows. Budding yeasts in the cytoplasm of giant cells at the arrows. Broad-based budding and double-contoured cell walls are seen in the giant cell in the center are characteristic of Blastomyces dermatitidis.
Nodular skin lesions of blastomycosis, one of which is a bullous lesion on top of a nodule.